Compositions, devices, and kits for selective internal radiation therapy for hepatocellular carcinoma

Abstract

This invention relates to a dose regimen of radionuclides for use in the treatment of gastrointestinal cancers such as hepatocellular carcinoma (HCC) via brachytherapy, characterized by a two-component surgical sealant and / or adhesive such as tissue glue and a microsphere loaded with a radioisotope. The radioactive dose to be administered is in the range of 0.4 to 220 MBq, based on the size of the target tumor.

Description

[Technical Field]

[0001] The present invention relates to a radionuclide dose regimen for use in the treatment of gastrointestinal cancers such as hepatocellular carcinoma (HCC), pancreatic lesions, and metastatic lesions (mCRCs) of primary colon cancer, and is characterized by a transdermal two-component surgical sealant and / or adhesive and a microsphere carrying a radioisotope. The radioactive dose to be administered is in the range of 0.4 to 220 ± 30% MBq, based on the size of the target tumor. [Background technology]

[0002] This technology and method relates to radiotherapy in general, and more specifically to compositions, devices, and methods comprising carrier matrices and radiotherapeutic particles for the treatment of various neoplastic and proliferative diseases, including but not limited to breast cancer and liver cancer.

[0003] Intraductal carcinoma (DCIS), or stage 0 breast cancer, is a biologically and clinically heterogeneous disease, with its natural course influenced by both tumor and host factors. Consequently, the treatment of DCIS after breast-conserving surgery (BCS) is controversial. While it is estimated that treating nine patients is necessary to prevent one local recurrence, some studies have shown that intraoperative radiotherapy (IORT) can lead to acceptable outcomes and may be a viable alternative to conventional whole-breast irradiation in certain selected groups of low-risk early-stage breast cancer patients.

[0004] External beam radiation therapy to the breast after bone-chain sclerosing (BCS) reduces the 10-year recurrence rate of breast tumors from 25-30% to less than 10%. However, finding the optimal treatment modality remains a challenge for the remaining 10% of breast cancer patients whose tumors recur several years after BCS and external beam radiation therapy (EBRT). Normal tissue tolerance does not allow for a second full-dose radiation therapy to the entire breast after a second BCS, even after several years have passed. In particular, for patients with small, localized recurrences where local excision is technically possible, mastectomy is generally preferred over BCS due to concerns about poor prognosis due to the omission of radiation therapy. Until the 1980s, mastectomy was the standard treatment for DCIS patients, with a local control rate of approximately 98%. Considering not only the extent and / or multicentricity of the lesion but also patient preference, mastectomy continues to be performed in at least one-third of DCIS cases since 2000. Recent data from the United States regarding early-stage breast cancer (stages I and II) indicate that, due to insufficient access to radiation therapy and low patient compliance, up to 60% of patients may not receive radiation therapy, and therefore mastectomy remains the preferred treatment.

[0005] However, with advances in diagnostic modalities and increased regular follow-up visits, recurrent breast tumors are often diagnosed at a very small tumor size. Furthermore, the most common and prognostic limiting problem for these patients is usually not a localized situation within the breast, but an increased risk of developing distant metastases. After all, more than 90% of all ipsilateral breast tumor recurrences occur near the primary lesion. A new option is to treat these patients with partial breast irradiation after re-excision of the recurrent tumor. This approach is based on the hypothesis that re-irradiation to a limited volume is effective and results in side effects with an acceptable incidence. IORT is one option for delivering high doses to a limited-risk area, namely the tissue adjacent to the tumor cavity after tumor resection. IORT can be delivered by a dedicated linear accelerator in the operating room or by novel mobile devices using electrons or low-energy X-rays.

[0006] IORT allows for same-day treatment completion by replacing postoperative whole breast irradiation with a single dose of radiotherapy at an equivalent dose during surgery. Recent trials, such as the ELIOT trial comparing intraoperative electron beam radiotherapy with external beam radiotherapy for early-stage breast cancer, and the TARGIT-A trial comparing targeted intraoperative radiotherapy with whole breast radiotherapy for breast cancer, have demonstrated that IORT can lead to acceptable outcomes and thus be a viable alternative to conventional whole-breast radiotherapy in specific selected groups of low-risk early-stage breast cancer patients.

[0007] In the ELIOT trial, 1,305 patients were randomly assigned (654 to external beam radiotherapy and 651 to intraoperative radiotherapy) with a follow-up period of 5–8 years. The results of this trial showed that local recurrence in the intraoperative radiotherapy group was lower than that achieved after mastectomy in a previous study (Milan I trial). The TARGIT-A trial was a randomized non-inferiority trial comparing risk-adaptive radiotherapy with single-dose targeted intraoperative radiotherapy (TARGIT) and fractionated EBRT in breast cancer patients. The 5-year results in 3,451 patients (1,721 randomly assigned to TARGIT and 1,730 to EBRT) demonstrated that the combination of mastectomy and TARGIT in a risk-adaptive approach should be considered as an option for eligible breast cancer patients. This study demonstrated that 20 Gy of intraoperative radiotherapy (IORT), with whole breast irradiation (WBRT) added only to patients with risk factors, was non-inferior in terms of local control compared to standard WBRT (50-56 Gy) after breast-conserving surgery in selected patients. A meta-analysis by Vaidya et al. showed that in women with breast cancer, partial breast irradiation (PBI) instead of whole breast irradiation (WBI) resulted in a small but definite reduction in mortality. Based on the two statistical models used by Vaidya et al., the absolute difference in non-breast cancer mortality was between 1.1% and 1.3%, and was statistically significant (P=.023 or P=.011). The absolute difference in overall mortality was between 1.0% and 1.3%. Low P values ​​of P=0.15 or P=0.05 indicate that the probability of observing this difference is low if there is no true difference between PBI and WBI. Even from a relative standpoint, considering the total mortality rate was only 4.9% (207 out of 4231 people), this means that PBI reduced mortality by 25%. Therefore, this is clinically significant.

[0008] Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and the leading cause of death in people with cirrhosis. It occurs in the context of chronic hepatitis and is most closely associated with chronic viral hepatitis infection (hepatitis B or C) or exposure to toxins such as alcohol and aflatoxins. Certain conditions, such as hemochromatosis and alpha-1 antitrypsin deficiency, significantly increase the risk of developing HCC, while metabolic syndrome and non-alcoholic steatohepatitis are also increasingly recognized as risk factors for HCC. As with all cancers, the treatment and prognosis of HCC vary depending on the histology, size, local / distal metastasis, and details of the patient's overall condition. Outcomes are significantly improved if treatment is initiated early in the disease process. For subjects with early-stage HCC, three types of treatment are usually proposed: (1) orthotopic liver transplantation in selected cases; (2) surgical resection of the affected liver segment; and (3) localized therapies, including percutaneous or catheter-based treatments. Most percutaneous ablations currently performed have been shown to be as effective as surgical excision. They are also less invasive and less burdensome for patients and medical facilities. However, due to many reasons, including the size of the lesion and its anatomical location, achieving "surgical" negative margins is often difficult. This means that the surrounding areas of the neoplastic lesion with satellite micrometastases may be missed and not necrotize. This, in turn, creates a clear possibility of tumor recurrence. The overall success rates currently reported are actually 70-80% for thermal ablation (e.g., radiofrequency, laser, microwave), 70-80% for cryoablation, and 60-80% for ethanol injection (Mayo Clinic 2017 data). Therefore, at least 20% of neoplastic lesions are accompanied by local recurrence.

[0009] Percutaneous local ablation (PLA) techniques are currently considered the best treatment option for patients with early-stage hemoglobin cancer (HCC) who are not candidates for surgical resection. They are safe, minimally invasive, effective, and cost-effective. While radiofrequency ablation is considered a first-line treatment in some institutions, most guidelines recommend radiofrequency ablation for small HCC that cannot be surgically resected. PLA is a relatively simple and minimally invasive procedure that selectively targets the tumor and an additional 0.5–1.0 cm of intentionally created margins of healthy tissue. These additional margins contribute to achieving complete ablation (A0), similar to postoperative R0 resection. Furthermore, hepatectomy is not an ideal treatment for very small HCC cases due to the potential loss of liver function and the high risk of complications. In this regard, an international panel of ablation experts recently published a position paper on PLA for hepatic metastases of colon cancer. A strong level of consensus was reached for the treatment of nodules up to 5 cm in size when they are in a good location (easily accessible). Similarly, a strong level of consensus was reached regarding combination strategies with systemic therapy alone. The panel also agreed that PLA, when used as a first-line treatment for resectable patients, can be curative. Selective internal radiotherapy (SIRT, also known as transarterial radioembolization (TARE)), 131 The clinical efficacy of radiolabeled Lipiodol with 1I was first demonstrated in 1994 based on a randomized study of patients with portal vein thrombosis. In particular, one retrospective study showed that glass microspheres achieved a significantly improved rate of downstaging and significantly fewer side effects compared to chemoembolization in patients with stage T3 HCC, while another study showed a significantly improved progression-free survival in HCC patients treated with local therapies such as chemoembolization or radioembolization. 90Y-resin microspheres (SIR-SPHERES®-Sirtex Medical) are CE-marked brachytherapy devices and are recommended for selected patients with chemotherapy-resistant colon cancer liver metastases, either in the liver alone or with the liver as the primary lesion, through the guidelines of the National Comprehensive Cancer Network and the European Society for Medical Oncology. [Overview of the project]

[0010] 90 Based on 15 years of clinical experience in treatment involving transarterial injection of Y-coated microspheres, appropriate activity is achieved. 90 Administering Y should reduce the likelihood of local recurrence, which occurs in the majority of cases at the resection site. As disclosed herein, for example, embedded in surgical sealants and / or adhesives such as tissue glue materials. 90 Specific radioactive doses of Y-coated microspheres are considered effective in treating hepatocellular carcinoma (HCC) and have a better safety / tolerability profile compared to transarterial radioembolization. These radioactive doses may range from 0.4 to 220 MBq, such as a dose selected from the group consisting of 0.48 MBq, 2.4 MBq, 7 MBq, 17 MBq, 28 MBq, 30 MBq, 48 MBq, 75 MBq, 114 MBq, 160 MBq, and 219 MBq, where tumor size may vary from 5 mm to 50 mm, and the dose may be adjusted according to tumor size. In some variant forms, the radioactive dose may vary within a range of ±30%, such as ±5, 10, 15, 20, or ±25%, preferably ±20%. This treatment may also be suitable for other types of gastrointestinal cancers, such as HCC or metastatic liver lesions (mCRCs) originating from primary colon cancer. In certain variant forms, gastrointestinal cancer is hepatocellular carcinoma (HCC) and / or metastatic lesions (mCRC) originating from primary colorectal cancer. Furthermore, in some variant forms, this treatment may also be appropriate for other types of lesions, such as liver lesions, e.g., primary / secondary liver lesions, pancreatic lesions, or metastatic lesions.

[0011] In some variations, a mammalian, e.g., human patient, can be treated with a localized carrier agent, including but not limited to, a biogel or hydrogel, and 90 Y microspheres. This combination therapy can be directly injected into a tumor, a postoperative tumor site, or a biopsy site. In some further variations, this combination therapy can be provided without a pretreatment imaging examination (e.g., a technetium-99 scan) to evaluate shunts to other non-target sites such as the liver, lung, or aneurysms or arteriovenous malformations (AVMs). This is because the shunting effect of the localized carrier is reduced, minimized, or eliminated. As a result, since a pretreatment imaging examination to evaluate the shunt is not required, a pretreatment procedure to treat a potential shunt is also not required. This can shorten the period until treatment initiation by 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days or more. Because the treatment is not delayed by a pretreatment shunt imaging examination, a pretreatment shunt reduction procedure, and a pretreatment rescan to evaluate the effectiveness of the shunt reduction procedure. Shunt procedures that may no longer be required or performed may include arterial embolization, hepatic vein balloon occlusion, and aneurysm and AVM occlusion. Since dose adjustment to account for the shunt is no longer required, dose calculation can also be simplified, for example, adjustments based on the shunt rate and / or the lung dose limit are not required. Patients with a large proportion of liver, lung, or hepatopulmonary shunts also no longer need to be excluded from treatment. One or more of these features in a tumor treatment protocol can be included in the various treatments described herein.

[0012] In one embodiment, a method of treating a human patient is provided, the method comprising determining a therapeutically effective 90 dose of Y for a tumor site using a localized carrier and 90 performing a dose calculation of Y, and delivering the dose of Y to the tumor site using the localized carrier, where the treatment is without the localized carrier 90 Y dose of 90Compared to delivering a dose of Y, progression-free survival is extended. In some further embodiments, pretreatment imaging to assess the shunt is not required. By not performing pretreatment imaging, treatment time may be reduced by at least one day. Pretreatment imaging scans may not be required or may be performed as technetium-99m scans. The shunt may be a hepatopulmonary shunt. The localization carrier may be a combination of glutaraldehyde and bovine serum albumin. The tumor site is an unresectable tumor or a post-resectable tumor bed. In some embodiments, pre-procedure calculation of shunt rate estimates and / or post-procedure in vivo distribution imaging are not performed. Pre-procedures involving arterial embolization, hepatic vein balloon occlusion, and / or varicose vein or arteriovenous malformation occlusion are not required. In some embodiments, 90 The Y dose calculation does not include adjustments based on estimated shunt rates and / or lung dose limits. Lung dose limits may be 30 Gy or less for a single treatment procedure and 50 Gy or less for multiple procedures. This method may not exclude patients with shunt rate limits, e.g., those with a hepatopulmonary shunt rate exceeding 20%.

[0013] In another embodiment, without performing a pretreatment technetium-99m scan, 90 A method for treating a patient at Y is provided, and in another embodiment, without determining the shunt rate 90 A method for treating patients with Y is provided. In yet another embodiment, without excluding patients whose hepatopulmonary shunt rate exceeds a threshold, 90 A method for treating patients is provided in Y.

[0014] To treat patients with DCIS or other forms of early-stage breast cancer, and to evaluate the efficacy and safety of radioactivity-based ablation of surgical margins after DCIS resection, 90 Exemplary devices, kits, and methods combining a Y-matrix and a delivery system are disclosed. These exemplary devices, kits, and methods are used to treat hepatocellular carcinoma, including, but not limited to, injection or administration into or to a treatment site after resection of the lesion. The delivery kit is:90 It features a coaxial dual-lumen catheter used to provide direct, image-guided intratumor injection of a Y microsphere-matrix combination.

[0015] In some variants, patients selected for treatment may include those with stage 0 breast cancer (e.g., DCIS) treated with intratumoral injection or tumor bed injection. In other variants, patients may have stage I or II breast cancer treated with intratumoral injection or treatment of the tumor bed after tumor resection. This variant may also include patients with stage IIA and / or IIB, and may involve intratumoral injection into one or more axillary lymph nodes.

[0016] 90 The Y-matrix and delivery system are thought to enable effective and safe radioablation of surgical margins after DCIS resection, thereby 90 Compared to Y microsphere therapy alone, this offers a novel technique for localized treatment of early-stage breast cancer.

[0017] In other variants, patients selected for treatment may include patients with hepatocellular carcinoma, and patients with metastatic liver tumors, whether resectable or not. HCC patients may include patients with primary tumors of T1, T1a, T1b, T2, T3, or T4, as well as patients with regional lymph node metastases, those without, or those whose status is unknown, and patients with distant metastases (including HCC patients of stages IA, IB, II, IIIA, IIIB, IVA, and IVB). Treatment may include intratumoral administration or administration to the tumor bed after resection in the liver, lymph nodes, or distant metastatic sites.

[0018] In one embodiment, 90 The Y-matrix system consists of BIOGLUE® (CryoLife; Kennesaw, GA), which is a mixture of bovine serum albumin and glutaraldehyde in a 4:1 ratio, and a pure beta-emitting isotope. 90This is a combination of SIR-SPHERES® microspheres (Sirtex Medical; North Sydney, AU) coated with Y. This mixture is delivered using a dual-chamber syringe. 90 Microspheres pre-loaded with Y are then mixed with a glue component and used to perform radioablation of the surgical margins at the treatment site.

[0019] In various embodiments, systems, kits, and methods for preparing an infusion system using selective internal radiation therapy and / or treating a target lesion are provided, comprising a double-barrel syringe filled with a two-component surgical sealant and / or adhesive such as tissue glue and a radioisotope-laden microsphere. The microsphere is filled into the syringe based on the size of the target site and injected using a needle or a dual-lumen catheter. Dose regimens are provided for treating breast cancer lesions up to 130 mm in diameter and hepatocellular carcinoma lesions up to 50 mm in diameter.

[0020] In one embodiment, a method is provided for preparing an implantable radiotherapeutic agent, the method comprising: mixing radioactive isotope microspheres with a suspension medium, wherein the microspheres are located in the suspension medium contained in a first container; determining the transfer volume of the mixed microspheres based on the target size; and filling the injection system with the transfer volume, wherein the injection system comprises a first compartment having a first cross-sectional area and a second compartment having a second cross-sectional area, wherein the first and second cross-sectional areas have an X:Y ratio; and transferring a first ratio of the transfer volume to the first compartment and a second ratio of the transfer volume to the second compartment, wherein the first and second ratios have an X:Y ratio. The radioactive microspheres may be provided settled in a container within a predetermined volume of the suspension medium. The method may further include removing a removal volume of suspension medium from a predetermined volume of the suspension medium before mixing the radioactive microspheres with the suspension medium. The removal volume may be 2 mL, and the predetermined volume of suspension medium may be 5 mL. The first ratio of the transfer volume may be X / (X+Y) of the transfer volume, and the second ratio of the transfer volume is Y / (X+Y) of the transfer volume. The injection system may be a double-barrel syringe including a first barrel with a first compartment and a second barrel with a second compartment. The ratio of the cross-sectional area of ​​the first to the cross-sectional area of ​​the second may be 4:1. The first barrel may be pre-filled with a first substance, and the second barrel may be pre-filled with a second substance. The total volume of the first and second substances may be 2 mL. The total volume of the first and second substances may be 5 mL. The transfer volume may include activity levels in the range of 0.1 MBq to 250 MBq. Since residual activity exists within the syringe, the activity level can vary by up to ±30%, and therefore the transfer volume may include activity levels ranging from 0.1 MBq to 250 MBq ±30%. Preferably, the activity level varies by up to ±20%. The activity level may also be in the range of 0.3 MBq to 220 MBq, and the transfer volume may be in the range of 0.3 μL to 220 μL.The target size may be in the range of 1 mm to 50 mm in average diameter. The transfer volume may include activity levels in the range of 10 MBq to 200 MBq. The transfer volume may include activity levels in the range of 10 MBq to 300 MBq. The activity level may be in the range of 20 MBq to 150 MBq, and the transfer volume may be in the range of 100 μL to 750 μL. The target size may be in the range of 40 mm to 130 mm in average diameter. The first substance may contain albumin, and the second substance may contain glutaraldehyde. The radioactive microspheres may contain activity levels of 1.5 GBq or less, or 3 GBq or less, and the predetermined volume of the suspension medium may be 5 mL or less. Both mixing of the radioactive isotope microspheres and filling of the injection system can be performed by a shielded transfer syringe equipped with a needle in the range of 50 mm to 100 mm in length. The method may further include verifying the activity level of the transport capacity of the radioisotope microspheres by determining the activity level of the container after the injection system has been filled, or by determining the activity level of the injection system after the injection system has been filled. The method may further include placing the filled injection system in a radiation shielding container. The method may further include discarding each of the first and second materials in a volume ratio of X:Y, such that the sum of the two parts equals the transport capacity of the mixed microspheres.

[0021] In another embodiment, a method for treating a patient is provided, comprising delivering a therapeutic volume of mixed radioactive microspheres to a lesion, where the lesion includes a tumor lesion and / or a postoperative lesion site, and the delivery is made using a double-barrel syringe equipped with a mixing tip, where the first barrel of the syringe contains bovine serum albumin and a radioisotope, and the second barrel contains glutaraldehyde and a radioisotope. The method may further include filling each barrel of the double-barrel syringe with different amounts of radioactive microspheres based on the size of the lesion. In other variations, the method may include filling only one of the two barrels of a double-barrel syringe with radioactive microspheres, for example, the larger or smaller of the two barrels, or the barrel containing a highly viscous substance, such as the barrel containing bovine serum albumin. The double-barrel syringe may have a total injectable volume of 2.1–2.5 mL and an activity of 20–90 MBq before injection. The treatment site may have an average radius of 20–45 mm. The therapeutic volume injected may be the total injectable volume. This double-barrel syringe may contain a total injectable volume of 5.1–6 mL and 90–150 MBq of activity before injection. The therapeutic volume injected may be equal to the total injectable volume. The lesion may be a hepatocellular carcinoma lesion. As shown in Example 10, a dose of 150 Gy was well tolerated. The dose at the lesion may be at least 150 Gy. This double-barrel syringe may contain a total injectable volume of 2.0001–2.05 mL and 0.3–30 MBq of activity before injection. The lesion may have an average radius of 0.5–25 mm. The therapeutic volume delivered may be the total injectable volume. This barrel syringe may contain a total injectable volume of 5.01–5.5 mL and 20–250 MBq of activity before injection. This double-barrel syringe may contain a total injectable volume of 2.0001–2.05 mL and activity of 0.3±20%–30 MBq±20% before injection. The lesion may have an average radius of 0.5–25 mm. The therapeutic volume delivered may be the total injectable volume.This barrel syringe may contain a total injectable volume of 5.01–5.5 mL and an activity of 20±20%–250±20% MBq before injection. The lesion or resection site of ductal carcinoma in situ may have an average radius of 25–50 mm. The therapeutic volume injected may be equal to the total injectable volume. The concentration of bovine serum albumin may be between 30%–60% by weight. The concentration of glutaraldehyde may be between 5%–15% by weight.

[0022] In yet another embodiment, a method for treating a patient is provided, which includes removing a double-barrel syringe from a sealed sterile package, in which each barrel may be pre-filled with different substances in different volumes, the total volume of the different substances being 5 mL or less; determining the transfer volume of a radioactive microsphere suspension based on the size of the lesion; and transferring the different volume portions of the transfer volume of the radioactive suspension into each barrel of the double-barrel syringe. The total volume of the different substances may be 5 mL or less. The transfer volume of the radioactive microsphere suspension may be less than 300 μL, the activity level may be less than 300 MBq, and the lesion may have an average diameter of 25 mm to 50 mm. The method may further include treating the lesion with a total volume of 5.01 to 5.3 mL of different substances and a radioactive microsphere suspension. The total volume of the different substances may be 2 mL or less. The transfer volume of the radioactive microsphere suspension may be less than 30 μL, the activity level may be less than 30 MBq, and the lesion may have an average diameter of 0.3 mm to 30 mm. This method may further include treating the lesion with a total volume of different substances and radioactive microsphere suspensions, which may be greater than 2 mL and less than 2.1 mL.

[0023] In another embodiment, a lesion treatment system is provided comprising a double-barrel syringe, the double-barrel syringe comprising: a first barrel having a first sliding seal and a first cross-sectional area and containing a first glue component; a second barrel having a second sliding seal and a second cross-sectional area and containing a second glue component; a drive unit configured to dispense fixed ratios of the first and second glue components from the first and second barrels; a radioactive isotope mounted on at least one of the first and second barrels; and a plurality of lesion size indicators provided on the double-barrel syringe, the indicators corresponding to uniform size intervals over a size range but spatially arranged at non-uniform intervals along the double-barrel syringe. The drive unit may be a linked double plunger attached to the first and second sliding seals and may be configured to move the first and second sliding seals by an equal longitudinal distance. The first and second cross-sectional areas may be different. The first glue component may be bovine serum albumin, and the second glue component may be glutaraldehyde. The bovine serum albumin may be 45% by weight, and the glutaraldehyde may be 10% by weight. The radioactive isotope is 90 It is Y, and its activity level may be 10-250 MBq. The radioactive isotope has an activity level of 10-100 MBq. 90 It may be Y, where the indicators showing multiple lesion sizes may include lesion diameters in the range of 40 mm to 90 mm. The radioactive isotope has an activity level of 80 to 160 MBq. 90 It may be Y, where the indicators showing multiple lesion sizes may include lesion diameters in the range of 90 mm to 130 mm. The radioactive isotope has an activity level of 0.1 to 50 MBq. 90 This may be Y, where the indicators showing multiple lesion sizes may include lesion diameters ranging from 0.5 mm to 25 mm. The radioactive isotope has an activity level of 25 to 250 MBq. 90 Y may be the case, and the index indicating multiple lesion sizes here may include lesion diameters in the range of 25 mm to 50 mm.

[0024] In one embodiment, a method for treating a patient is provided, which is,

number

[0025] The target tissue radius may include one or more target tissue radii within the range of 0.5 cm to 2.0 cm. This method is based on the determined therapeutic dose. 90 This may further include filling a 2-chamber syringe with an amount of Y. 90The amount of Y may be further based on the syringe size, and further based on the syringe size and the dead space associated with the syringe size. Each of the two chambers of the syringe may hold one component of a two-component glue or carrier composition. The first chamber of the syringe contains albumin, and the second chamber contains glutaraldehyde. 90 Y can be filled into both the first and second chambers of the syringe. In other variations, 90 Y is filled into only one of either the first or second chamber of the syringe. This method is performed through a mixing tip attached to a two-chamber syringe. 90 The process may further include injecting Y with a glue or carrier composition, and the mixing tip comprises a shaft having a plurality of angled mixing structures. In another embodiment, a non-temporary computer-readable medium is provided, which includes a computer program product that, when the computer program product is executed on one or more processors, performs the therapeutic dose determination described above.

[0026] In another embodiment, a non-temporary computer-readable medium is provided, which contains the tumor uptake rate and average, correlated with tumor size. 90 Based on a Y-tissue penetration distance of 4 mm, 90 The computer instructions include one or more computer instructions, including determining a therapeutic dose of Y. The computer instructions are to be delivered to a syringe delivery device. 90 Command to output the first volume of Y, command to output the transfer syringe size, first volume 90 A command to optionally output the first chamber of a syringe delivery device for the transfer of Y, which should be transferred to the syringe delivery device. 90 An instruction to optionally determine the output of the second capacity of Y, and / or 90The computer-readable medium may further include instructions for optionally outputting a second chamber for the transfer of a second volume of Y. In another variant, the computer-readable medium may further include computer instructions for determining a target volume of the carrier composition, outputting the target volume of the carrier composition, and determining and outputting a waste volume of the carrier composition based on the transfer syringe size. The output may be provided on a display screen and may include a numerical output and / or a graphical output of the syringe with a graphical indicator of the numerical output. The computer program product may perform the above steps when the computer is running on one or more processors.

[0027] In yet another embodiment, a kit for performing radiotherapy procedures is provided. The kit may comprise two sterile 1 mL syringes, two Luer locks, two 22 G needles, two sterile 20 G × 70 mm needles, and two PMMA cylinders, each cylinder configured to hold a 1 mL or 2 mL syringe. In other variations, the two 20 G × 70 mm needles may be replaced with any needles having a diameter of 20 G or greater and including a length of at least 50 mm, and / or the PMMA cylinders may include non-circular cross-sectional shapes such as square or polygonal, and may include metal or polymer materials other than PMMA. In some further embodiments, the kit may optionally further include an additional lead pot. 90 It may include Y microspheres and / or empty vials for diluting and / or mixing water for injection. [Brief explanation of the drawing]

[0028] [Figure 1] Figure A shows examples of stylet, introduction device, and catheter components that can be used in the procedure of the embodiment. Figure B shows the catheter and introduction device of A, with the catheter inserted into the introduction device and the hubs of both locked together. [Figure 2] Figures A and B are front and rear views of a syringe cylinder filled with 90Y microspheres in a BIOGLUE® carrier. [Figure 3] A and B are PET / CT and CT scans, respectively, of a radioactive gel filled in a plastic sphere. [Figure 4] Figures A to C show the absorbed doses at volumes of 0.5 mL, 4.2 mL, and 11.4 mL, respectively, filled with the 90Y-matrix composition. [Figure 5] This graph shows the percentage of activity at different distances from the center of the three cavities in Figure 4A to C. [Figure 6] This graph shows the estimated Grays / Megabecquerel (MBq) values ​​for each distance from the center of the three cavities in Figure 4A to C. [Figure 7] This graph shows the estimated total absorbed dose for each distance from the center of the three cavities in Figure 4A to C. [Figure 8A] This is a cross-sectional CT image of a mouse with a thigh tumor. [Figure 8B] Figure 8A shows composite transverse CT / PET / SPECT images illustrating tumor activity in mice. [Figure 8C] Figure 8B shows the PET / SPECT image components. [Figure 8D] This is a cross-sectional CT image of another mouse with a tumor in its thigh. [Figure 8E] Figure 8D shows composite transverse CT / PET / SPECT images illustrating intratumoral activity in mice. [Figure 8F] Figure 8E shows the PET / SPECT image components. [Figure 9] A is a schematic cross-sectional view of a dual-lumen catheter shaft having concentric lumens. B is a schematic cross-sectional view of a dual-lumen catheter shaft having an eccentric lumen. C is a schematic cross-sectional view of a dual-lumen catheter shaft having an arc-shaped septum between the two lumens. D is a schematic cross-sectional view of a dual-lumen catheter shaft having a straight septum between the two lumens. [Figure 10A] This is a photograph of another example of the dual-lumen catheter delivery kit. [Figure 10B] This is a magnified photograph of the combination of the proximal end of the catheter, the insertion device, and the stylet. [Figure 10C] Figure 10A is a longitudinal cross-sectional view of the proximal end of the catheter. [Figure 10D] Figures 10A and 10B show longitudinal cross-sectional views of the proximal end of the introduction device. [Figure 11] A is a lateral CT view of the excised tumor, and B is a top-level CT view of the excised tumor. C is a composite lateral and top-level CT / PET / SPECT view of the excised tumor shown in A and B, and D is the top-level CT / PET / SPECT view of those images. E is a PET / SPECT image component from C, and F is a PET / SPECT image component from D. [Figure 12] A is a lateral CT view of another excised tumor, and B is a top-level CT view of another excised tumor. C is a composite lateral and top-level CT / PET / SPECT view of the excised tumors shown in A and B, and D is their top-level CT / PET / SPECT view. E is a PET / SPECT image component from C, and F is a PET / SPECT image component from D. [Figure 13] A is a lateral CT view of another excised tumor, and B is a top-level CT view of another excised tumor. C is a composite lateral and top-level CT / PET / SPECT view of the excised tumors shown in A and B, and D is their top-level CT / PET / SPECT view. E is a PET / SPECT image component from C, and F is a PET / SPECT image component from D. [Figure 14A] A 10x magnification tissue slide of the resection bed of an animal after intratumoral injection of 90Y-matrix, 7 days post-treatment, including a 20x magnified inset with arrows indicating the area of ​​necrosis. [Figure 14B] A 10x magnification tissue slide of the resection bed of an animal 14 days post-treatment after intratumoral injection of 90Y-matrix, including a 20x magnified inset with arrows indicating areas of necrosis. [Figure 14C]A 10x magnification tissue slide of the resection bed of an animal 21 days post-treatment after intratumoral injection of 90Y-matrix, including a 20x magnified inset with arrows indicating the area of ​​necrosis. [Figure 14D] This is a 10x magnification tissue slide taken 7 days post-treatment in the resection bed of an animal after 90Y intratumor injection without the use of any matrix, and includes a 20x magnification inset. [Figure 14E] This is a 10x magnification tissue slide taken 14 days post-treatment in the resection bed of an animal after 90Y intratumor injection without the use of any matrix, and includes a 20x magnification inset. [Figure 14F] This is a 10x magnification tissue slide taken 21 days post-treatment in the resection bed of an animal after 90Y intratumor injection without the use of any matrix, and includes a 20x magnification inset. [Figure 14G] This is a 10x magnification tissue slide taken 7 days post-treatment from the resection site of an animal in which matrix was injected into the tumor without the use of 90Y. [Figure 14H] This is a 10x magnification tissue slide taken 14 days post-treatment from the resection site of an animal in which matrix was injected into the tumor without the use of 90Y. [Figure 14I] This is a 10x magnification tissue slide from the resection site of an animal that underwent intratumoral injection of matrix without the use of 90Y, 21 days post-treatment. [Figure 14J] This graph shows the percentage of necrosis at weeks 1, 2, and 3 in each group of the study. [Figure 15] This figure shows Western blot analysis of p53 and β-tubulin expression in the 90Y-matrix group and the 90Y-monotherapy group. [Figure 16] This graph shows the tumor volume at the time of selection for the 90Y-matrix group, the 90Y-monotherapy group, and the localized carrier therapy group. [Figure 17A] This figure shows the in vivo distribution of 90Y microspheres and 90Y-matrix within organ systems. [Figure 17B] This figure shows the in vivo distribution of 90Y microspheres and 90Y-matrix within organ systems. [Figure 17C] This figure shows the in vivo distribution of individual organ systems on day 7 (90Y). [Figure 17D] This figure shows the in vivo distribution of the 90Y-matrix in organ systems on day 7. [Figure 17E] This figure shows the in vivo distribution of individual organ systems on day 14 (90Y). [Figure 17F] This figure shows the in vivo distribution of the 90Y-matrix in organ systems on day 14. [Figure 18] This graph shows the percentage of the 90Y dose absorbed by the tumor as a function of tumor size, accompanied by simulations performed for ρ = 1.00 g / cm³ (density of water) and ρ = 1.05 g / cm³ (liver density). [Figure 19] This is a graph of the 90Y beta spectrum implemented in the model used in Figure 18A. [Figure 20] This graph shows the delivery energy per unit activity, k(r), calculated using MCNP4c as a function of tumor diameter over 90 years. [Figure 21] This graph shows the residual as a function of tumor diameter. [Figure 22] This graph shows the absorbed dose per administered activity unit (GBq) for ρ = 1.05 g / cm³ (liver density), accompanied by an inset detailing the lesion diameter range from 0 cm to 1 cm. [Figure 23] This graph shows the absorbed dose per activity unit administered relative to ρ = 1.00 g / cm³ (density of water), accompanied by an inset detailing the lesion diameter range from 0 cm to 1 cm. [Figure 24A] This graph shows the in vivo distribution of 90Y between the 90Y-matrix group and the 90Y-monotherapy group during the first week. [Figure 24B] This graph shows the in vivo distribution of 90Y between the 90Y-matrix group and the 90Y-monotherapy group at week 3. [Figure 25]Graph A shows the in vivo distribution of 90Y between tumor and non-tumor sites in the 90Y-matrix treatment group. Graph B shows the in vivo distribution of 90Y between tumor and non-tumor sites in the 90Y-monotherapy group. [Figure 26] Image A is an axial MRI image of a patient with HCC nodules, and image B is a coronal MRI image of a patient with HCC nodules. [Figure 27] A is an ultrasound image of the targeting stage, B is an ultrasound image of the injection stage, and C is an ultrasound image of the post-injection stage of the treatment procedure. [Figure 28] A is an axial 90Y PET CT image of the patient shown in Figure 26A and B, showing the distribution of 90Y after injection of 90Y therapy, and B is a coronal 90Y PET CT image of the patient shown in Figure 26A and B, showing the distribution of 90Y after injection of 90Y therapy. [Figure 29] A is an axial MRI image of the patient shown in Figures 26A and B and Figures 28A and B, three weeks after injection, in which a complete response was recorded. B is a coronal MRI image of the patient shown in Figures 26A and B and Figures 28A and B, three weeks after injection, in which a complete response was recorded. [Modes for carrying out the invention]

[0029] As disclosed herein, embedded in surgical sealants and / or adhesives such as tissue glue materials 90Compositions providing specific radioactive doses of Y-coated microspheres are considered effective in the treatment of gastrointestinal cancers, preferably HCC, such as hepatocellular carcinoma (HCC) or metastatic lesions (mCRC) originating from primary colon cancer, and are thought to have a better safety / tolerability profile compared to transarterial radioembolization. Such radioactivity doses are selected from the group consisting of 0.48 MBq, 2.4 MBq, 7 MBq, 17 MBq, 28 MBq, 30 MBq, 48 MBq, 75 MBq, 114 MBq, 160 MBq, and 219 MBq, or 0.48 ± 30% MBq, 2.4 ± 30% MBq, 7 ± 30% MBq, 17 ± 30% MBq, 28 ± 30% MBq, 30 ± 30% MBq, 48 ± 30% MBq, 75 ± 30% MBq, 114 ± 30% MBq, 160 ± 30% MBq, and 219 ± 30% MBq. The composition may be selected from the group consisting of 0.48±20%MBq, 2.4±20%MBq, 7±20%MBq, 17±20%MBq, 28±20%MBq, 30±20%MBq, 48±20%MBq, 75±20%MBq, 114±20%MBq, 160±20%MBq, and 219±20%MBq, and may be in the range of 0.4 to 220 MBq ± 30%, where the tumor size may vary from 5 mm to 50 mm, and the dose may be adjusted according to the tumor size. Such a composition can be administered, for example, to patients who need it, for example, by intratumor injection. For use in the treatment of hepatocellular carcinoma (HCC) 90 The composition of the present invention, comprising Y, may be administered transdermally to provide brachytherapy to tumors.

[0030] Glue, tissue glue, or bioglue is defined in this context as a biomaterial used as a surgical sealant and / or adhesive. Surgical sealants and adhesives can be used as adjuncts to sutures to prevent air and fluid leakage. They can also be used as a substitute for sutures and staples for better closure, minimized blood loss, faster execution, and easier, less painful surgery that does not require removal. These are classified into three groups: natural polymer sealants (such as fibrin, collagen, and albumin sealants), synthetic polymer sealants (such as polyurethane, polyethylene glycol, and polyester adhesives), and cyanoacrylate sealants. Therefore, in one or more embodiments of the present invention, the terms “glue,” “tissue glue,” and “bioglue” are defined as surgical sealants and / or adhesives. In one or more embodiments of the present invention, the surgical sealant and / or adhesive is selected from the group consisting of natural polymer sealants (fibrin-based, collagen-based, albumin-based sealants, etc.), synthetic polymer sealants (polyurethane-based, polyethylene glycol-based, polyester-based adhesives, etc.), and cyanoacrylate-based sealants. In one or more embodiments of the present invention, the surgical natural polymer sealant of the present invention is selected from the group consisting of polyurethane-based, polyethylene glycol-based, and polyester-based adhesives. In one or more embodiments of the present invention, the synthetic polymer sealant of the present invention is selected from the group consisting of fibrin-based, collagen-based, and albumin-based sealants. In one or more embodiments of the present invention, the surgical sealant and / or adhesive of the present invention is an albumin-based sealant. In one or more embodiments of the present invention, the albumin-based sealant and / or adhesive of the present invention is BIOGLUE®. BIOGLUE® is 90It can be used as the glue component of a Y-glue matrix composition. BIOGLUE® is a mixture of bovine serum albumin (BSA; 45% by weight / volume in sterile water for injection) and glutaraldehyde (10% by weight / volume in sterile water for injection) in a 4:1 ratio. Therefore, the compositions described herein are 90 Y microspheres and albumin, or 90 It may contain Y microspheres and glutaraldehyde. In one or more embodiments of the present invention, the surgical sealant and / or adhesive of the present invention is selected from the group consisting of PEG + trilysine amine hydrogel (Duraseal, Integra), fibrin sealant (thrombin + fibrinogen, Tachosil, Nycomed), and human fibrin sealant (Tisseel, Ethicon).

[0031] In one embodiment, a kit for performing direct injection radiotherapy is provided. The kit comprises a venting needle, a radiation shielding syringe, and an elongated needle at least 50 mm to 100 mm in length. These components of the kit can be used to transfer radioisotope particles from their transport container to a matrix-containing syringe. The venting syringe can be inserted through the sealing portion of the transport container to relieve or release any vacuum that may form inside the transport container during the transfer process, and may be an 18G, 22G, 25G, 28G, 30G, 31G, or 32G subcutaneous injection needle. The venting needle may optionally remain in place for the remainder of the procedure or be removed immediately after insertion. The elongated needle is attached to the radiation shielding syringe either at the time of use or at the time of manufacture and is used to remove the liquid medium from the transport container.

[0032] In some variations, the kit may comprise an injector, a dual-lumen catheter, and a needle. The kit may further comprise a radiation-shielding syringe and an elongated needle and / or the aforementioned venting needle, at least 50 mm to 100 mm in length. In yet another variation, the kit may further comprise a glue or matrix and / or a radioisotope source, although in other embodiments, the glue / matrix and / or radioisotopes are procured separately from the kit. In these variations, the kit may further comprise adapters configured to connect the kit components to a third-party injector system of user choice. Alternatively, one or more of the kit components may be configured to connect to a third-party glue / matrix syringe or infusion system. Thus, radioisotopes, particularly 90 Compositions comprising Y and glue / matrix are also provided.

[0033] 90 The Y source may include vials of radiotherapy microspheres. The vials are made of clear, unshielded glass and may be removably housed in lead-lined pots or other containers. 3 GBq in 5 mL of water or other suspension. 90 A vial containing Y is provided. 90Y is a pure, high-energy (maximum energy 2.227 MeV, average 0.93 MeV) β-emitter isotope. Its half-life is 64.1 hours, and its maximum penetration depth in tissue is 11 mm, with an average of 2.5 mm. The vial may be placed in a lead pot or other shielding container. The vial or other packaging may include calibration or validation data and / or a code for online access to them, so that healthcare providers performing treatment can compensate for any radioactive decay that has occurred since the initial manufacturing and validation. However, in other embodiments, the activity level of the microspheres may vary, for example, to 100 MBq, 200 MBq, 300 MBq, 400 MBq, 500 MBq, 600 MBq, 700 MBq, 800 MBq, 900 MBq, 1 GBq, 2 GBq, 3 GBq, 4 GBq, 5 GBq, or a range between any two of these activity levels, and the number of microspheres per vial may vary, for example, to 10 million, 20 million, 30 million, 40 million, 50 million, 60 million, 70 million, 80 million, 90 million, 100 million, or a range between any two of these numbers of microspheres. In one particular embodiment, 90 Source Y may contain 2.4 GBq of particles in 3 mL of water.

[0034] In one particular embodiment, SIR-SPHERES® is 90 Y or 90 It can be used as a Y particle source. SIR-SPHERES® is a biocompatible microsphere solution containing approximately 40 to 80 million microspheres in 5 mL of water. These microspheres have a diameter of 20 to 60 microns (μm). 90It contains a non-biodegradable resin containing pure, high-energy (maximum energy 2.227 MeV, average 0.93 MeV) β-emitter isotope of Y. The half-life is 64.1 hours, and the maximum penetration depth in tissue is 11 mm, with an average of 2.5 mm. SIR-SPHERES® microspheres are permanent implants (i.e., the microspheres are not metabolized or excreted after implantation). 94% of the total radiation is delivered locally within 11 days. SIR-SPHERES® microspheres are supplied by the manufacturer in shielded (6.4 mm thick) vials with water for administration. Each vial contains approximately 3 GBq in a final volume of 5 mL. 90 Y, or alternatively, 2.4 GBq in a final volume of 3 mL 90 Y is contained in a range of 2-3 GBq per final volume of 2-5 mL or 2-3 mL. The number of microspheres is 40-80 × 10 per vial. 6 individual, or 32-64 x 10 6 This is within the range of individual items. SIR-SPHERES® vials must be stored at 15-25°C.

[0035] Potential adverse events associated with the use of SIR-SPHERES® include: • Fever • Transient decrease in hemoglobin • Mild to moderate abnormal liver function test results (e.g., mild elevation of ALT, AST, alkaline phosphatase, and / or bilirubin) ·abdominal pain ·nausea ·vomiting ·diarrhea

[0036] As mentioned above, the kit may optionally further include a glue or matrix source, although the glue or matrix source may also be sourced separately for use in the kit. In examples, such a glue or matrix may be a surgical sealant and / or adhesive such as a tissue glue comprising two components such as a non-crosslinked matrix material and a curable carrier, where the non-crosslinked matrix material and the curable carrier are mixed to induce curing of the surgical sealant and / or adhesive such as the tissue glue. In specific examples, the composition is 90 The Y microspheres and a curable surgical sealant and / or adhesive such as tissue glue are included, which is preferably a component of a two-component curable surgical sealant and / or adhesive such as tissue glue. In certain embodiments, BIOGLUE® is, 90 It can be used as the glue component of a Y-glue matrix composition. BIOGLUE® is a mixture of bovine serum albumin (BSA; 45% by weight / volume in sterile water for injection) and glutaraldehyde (10% by weight / volume in sterile water for injection) in a 4:1 ratio. Therefore, the compositions described herein are 90 Y microspheres and albumin, or 90It may contain Y microspheres and glutaraldehyde. Bovine serum is purified by thermal precipitation, chromatography, and gamma irradiation to eliminate the possibility of infectious disease. Glutaraldehyde exposure causes bovine serum albumin, extracellular matrix proteins, and lysine molecules on the cell surface to bind together, forming strong covalent bonds. This reaction is spontaneous and independent of the patient's clotting state. The glue begins polymerization within 20-30 seconds, reaching maximum strength in about 2 minutes, producing a solid implant. The degradation process takes about 2 years, after which the implant is replaced by fibrous granulation tissue. The adhesive solution (BSA and glutaraldehyde mixed in a 4:1 ratio) is mixed at the applicator tip of a dual-chamber syringe, where the cross-linking reaction is initiated. BIOGLUE® is not considered a true hemostatic agent because it does not promote the clotting process in the blood. However, BIOGLUE® functions as a sealant by tamponating the parenchymal tissue after complete hardening. It is generally used as an adjunct to more standard methods of achieving hemostasis, such as suturing or the use of topical hemostatic agents.

[0037] Potential adverse events associated with the use of BIOGLUE® include: • Non-adhesion of the product to the tissue • Application of adhesive to tissues unrelated to the procedure • Inflammation and immune response • Allergic reaction • Calcification of tissue • Local tissue necrosis ·Vascular occlusion • Obstruction of the bronchi or lumen • Thrombosis and / or thromboembolism • Pulmonary embolism • Injury or damage to normal blood vessels or tissues • Potential transmission of infectious agents from animal-derived materials.

[0038] In other embodiments, different alternative compositions having concentrations of BSA and glutaraldehyde components are provided at different concentrations or used in different ratios. For example: 1. 45% BSA and 40% glutaraldehyde in a 1:1 ratio. 2. 45% BSA and 20% glutaraldehyde in a 2:1 ratio. 3. 36% BSA and 8% glutaraldehyde in a 4:1 ratio. 4. 36% BSA and 12% glutaraldehyde in a 3:1 ratio.

[0039] In another embodiment, TISSEEL® sealant (Baxter Healthcare; Deerfield, IL) 90It can be used as a glue, matrix, or carrier component in composition Y. TISSEEL is a two-component fibrin sealant produced from pooled human plasma. When the two components, sealer protein and thrombin, are mixed, the composition is similar to the final stage of the blood component cascade. The sealer protein is a sterile, non-pyrogenic, steam-heated, and solvent / surfactant-treated preparation made from pooled human plasma. The sealer protein is supplied either as a lyophilized powder for reconstitution with a fibrinolysis inhibitor solution, or as a completed frozen solution pre-filled on one side of a dual-chamber syringe. The active ingredient of the sealer protein is fibrinogen. The sealer protein solution contains a fibrinolysis inhibitor, including synthetic aprotinin, which delays fibrinolysis. Aprotinin is produced by solid-phase synthesis from entirely non-human / non-animal-derived materials. The composition of the sealer protein solution is as follows: total protein level of 96–125 mg / mL, fibrinogen of 67–106 mg / mL, aprotinin of 2250–3750 KIU / mL, and further containing human albumin, trisodium citrate, histidine, niacinamide, polysorbate 80, and water for injection. The thrombin component is a sterile, non-pyrogenic, steam-heated, and solvent / surfactant-treated preparation made from pooled human plasma. Thrombin (human) is also provided either as a lyophilized powder for reconstitution with calcium chloride solution, or as a completed frozen solution pre-sealed on one side of a dual-chamber syringe. The thrombin solution contains 400–625 units / mL of thrombin, 36–44 μmol / mL of calcium chloride, and some human albumin, sodium chloride, and water for injection. The two components of TISSEEL, namely sealer protein and thrombin, may be supplied in dual-chamber syringes with total volumes of 2 mL, 4 mL, and 10 mL, with equal volumes in each chamber. For example, each chamber may be a dual chamber of 1 mL, 2 mL, and 5 mL, supplied in a 1:1 ratio. In other embodiments, the concentrations of the sealer protein solution and thrombin solution may differ, so that unequal ratios of sealer protein solution and thrombin solution are used.

[0040] Another dual-solution sealant that may be used is BOLHEAL® (Chemo-Sero Therapeutic Institute; Kumamoto, JP), which contains a first solution of 80 mg / mL human fibrinogen, 75 IU / mL human plasma-derived coagulation factor (XIII), and 1000 KIE of cow's oysteroprotinin, and a second solution of 250 IU / mL human thrombin and 5.9 mL / mL calcium chloride, which are mixed in a 1:1 ratio at the time of use.

[0041] 90 Another matrix that can be used in the Y-matrix system is SURGIFLO® (Ethicon, Inc; Somerville, NJ), which comprises 8 mL of fluid sterile gelatin as the first component and 2000 IU of lyophilized human thrombin powder, which is reconstituted using 2 mL of sterile water for injection as the second component.

[0042] In yet another embodiment, a multi-component polyethylene glycol sealant such as COSEAL® surgical sealant (Baxter Healthcare; Deerfield, IL) may be used. COSEAL® may include a pre-sealed applicator or syringe component having two liquid storage compartments and one dry powder compartment. One solution is a diluted HCl solution, and the other solution is a sodium phosphate / sodium carbonate solution. The dry powder syringe contains a 4-arm polyethylene glycol polymer with a molecular weight of 10 kDa (chain ends sealed with thiol groups) and pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate. The two solutions are provided in syringes of equal size. First, the dry powder is reconstituted with the buffer by vigorously moving it back and forth at least 20 times between the dry powder and the buffer until the dry powder appears to be dissolved.

[0043] In other embodiments, the glue component may include a single-component glue, sealant, or matrix, such as cyanoacrylate, alginate, polyvinyl alcohol, sodium polyacrylate, agarose, methylcellulose, carboxymethylcellulose, hyaluronic acid, etc.

[0044] During this procedure, one or more of the following may be recommended: - Keep surgical gloves, sterile gauze swabs / towels, and other surgical instruments away from the matrix to minimize the risk of the matrix adhering to these surfaces. - Use the syringe, applicator, and tip applicator extension for a single patient only. Do not re-sterilize. - Do not use if the packaging has been opened or damaged. - Be careful not to accidentally spill the contents of the syringe. - Do not press the syringe plunger while it is connected to the syringe. - Ensure that the material discharged from the applicator during priming does not come into contact with the fabric.

[0045] 90 The matrix components of Y-matrix compositions can polymerize rapidly. Priming must be performed quickly, and the compound must be applied immediately afterward. Pause between priming and application can cause polymerization within the tip applicator. The following are recommendations: - Extra from the surgical field 90 Do not use blood collection equipment while aspirating the Y-matrix composition. - Do not apply the matrix to an excessively moist surgical field, as this may reduce adhesion. - There is a risk of damaging the fabric, 90 Do not separate or peel off the Y-matrix composition from any area or surface it has come into contact with by mistake. - In closed anatomical areas located very close to nerve structures 90Do not embed the Y-matrix composition. - For pregnant or breastfeeding women 90 Caution should be exercised when using Y-matrix compositions. This is especially important for pregnant or breastfeeding women. 90 There are currently no studies on the efficacy or safety of using Y-matrix compositions. - This device contains radioactivity, and incorrect placement of the product can have serious consequences. Therefore, physicians should not implant this product without proper training in handling and implantation techniques. - All persons handling, dispensing, and implanting this device must understand and comply with all local and state regulatory requirements for the management of therapeutic radioactive materials. Approved radiation protection techniques should be used to protect workers when handling isotopes and patients. - 90 Some patients may experience gastric discomfort after treatment with a Y-matrix composition, but gastric complications can be reduced by using an H-2 blocker the day before implantation and continuing it as needed. - 90 The radioactive isotope components of the Y-matrix composition showed a slight possibility of sensitization when tested on the skin in animal models. - If workers are not properly protected (i.e., wearing gloves, masks, protective gear, and safety glasses, etc.), 90Y - Do not use the matrix composition. Unpolymerized glutaraldehyde can cause irritation to the eyes, nose, throat, and skin, difficulty breathing, and local tissue necrosis. Prolonged exposure to unpolymerized glutaraldehyde, an ingredient in BIOGLUE®, can cause cardiac or central nervous system damage. If contact occurs, immediately wash the affected area with plenty of water and seek medical attention. - If there is an infectious disease 90 Do not use Y-matrix compositions. Also, use with caution on contaminated areas of the body. - To the same patient 90Exercise caution when applying the Y-matrix composition multiple times for repeated exposure. Hypersensitivity reactions may occur during exposure to the matrix components. Sensitization has been observed in animals. - 90 Some components of the Y-matrix contain animal-derived materials that may transmit infectious pathogens.

[0046] Potential side effects of the procedures described herein may include: - Non-adhesion of the product to tissue or treatment site - Application of adhesive to tissues that are not the target of the procedure - Inflammation and immune response - Allergic reaction - Calcification of tissue - Necrosis of local tissue - Blood vessel occlusion - Obstruction of the bronchi or lumen - Thrombosis and / or thromboembolism - Pulmonary embolism - Damage to normal blood vessels or tissues - Potential transmission of infectious agents from animal-derived materials - Fever - Transient decrease in hemoglobin - Changes in biochemical test values ​​related to the liver (e.g., ALT, AST, alkaline phosphatase, bilirubin) (mild to moderate) - abdominal pain - Malice - vomiting - diarrhea

[0047] As shown in Example 10, the present disclosure 90 Administration of Y microspheres did not cause any of the same side effects expected from TARE. In particular, transient increases in liver enzymes or transient decreases in lymphocytes were not observed in the interim analysis. Therefore, in embodiments, the compositions and / or methods disclosed herein do not result in transient increases in liver enzymes or transient decreases in lymphocytes after administration.

[0048] Furthermore, radiation-embolism-induced liver disease (i.e., hyperbilirubinemia, hypoalbuminemia, ascites) or non-targeted irradiation (radiation gastritis, gastrointestinal ulcers, upper gastrointestinal bleeding, pancreatitis, radiation pneumonitis) was not observed in the clinical trials presented in Example 10. Therefore, in some embodiments, the treatments disclosed herein do not cause radiation-embolism-induced liver disease or non-targeted irradiation. Consequently, in some embodiments, the treatments provided herein result in fewer side effects and / or adverse events compared to TARE (Weber et al. EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds. European Journal of Nuclear Medicine and Molecular Imaging (2022) 49:1682-1699). This represents a remarkable and advantageous technical effect.

[0049] In some variants, the devices, kits, and methods described herein may be used to treat one or more target sites following surgical excision or ablation in order to treat residual tumor cells. However, in other variants, the target site is treated before excision, for example, in an attempt to reduce the stage of cancer in order to convert an unresectable tumor into a resectable tumor. In yet another variant, the target site may be treated even if there is no plan to perform a surgical or ablation procedure. In some variants, this treatment may be used to treat non-cancerous diseases or conditions, such as intra-articular injections to treat synovitis, intradermal injections to treat keloids and hypertrophic scars, and intravascular injections for hemangiomas.

[0050] In one exemplary embodiment, a method for treating small tumors utilizes a mixing injector configured to be connected to a glue supply injector and a source of radiotherapy particles. The vial is removed from its packaging, and a predetermined amount (e.g., 0.5 mL, 1 mL, 1.5 mL, 2 mL, or 2.5 mL, or 10%, 20%, 30%, 40%, or 50%) of the un-agitated or non-microsphere-containing suspension is first removed without reconstitution of the suspension of microspheres in water by shaking or other means. In other variants, the amount of liquid removed may vary, resulting in a suspension with an activity-to-volume ratio in the range of, for example, 0.5 GBq, 0.8 GBq, 1.0 GBq, 1.2 GBq, or 1.5 GBq per mL, or between any two of these ratios. After removing a portion of the suspension, the vial is reconstituted by shaking or other agitation. Based on the remaining concentration of the radiotherapy agent (e.g., 3 GBq in 4 mL of suspension), the desired amount of activity is withdrawn into a radiotherapy transfer syringe based on volume. In some embodiments, the radiotherapy transfer syringe is the same syringe used to remove a predetermined amount of unagitated liquid or non-microsphere suspension, while in other embodiments, a different syringe is used to remove the unagitated liquid or non-microsphere suspension.

[0051] Next, the cap of the matrix syringe is removed. In some embodiments, a predetermined volume of glue may be dispensed from the glue source syringe based on the calculated volume of microspheres / suspension to accommodate the volume of microsphere solution required to deliver microspheres at the desired activity level. In some variations, additional volume may be provided in the syringe by retracting the plunger mechanism. In other variations, it is not necessary to adjust the volume of the matrix syringe before adding the isotope solution, as the existing void in the matrix syringe is sufficient to hold the amount of radioactive isotope being transferred.

[0052] In some variants involving a two-component matrix, the radiotherapy matrix composition is delivered using a mixing tip. This mixing tip mixes the two components within a range of 1, 2, or 3 cm from the distal end of the chamber containing the components. The distal end of the mixing tip may include multiple distal openings that are generally linear in configuration along the transverse dimension of the mixing tip in order to increase the area of ​​application by a single operation of the mixing tip. For example, the mixing tip may include two, three, four, five, six, seven, or eight distal openings aligned along a transverse dimension that is at least 1 cm, 1.5 cm, 2 cm, 2.5 cm, or 3 cm wide.

[0053] In other variants, the delivery kit may include a dual-lumen tube, a dual-lumen needle, or a dual-lumen catheter, which ensures that the mixing or polymerization of the two components occurs more distally to prevent the polymerization of components within a single-lumen tube or catheter, thereby preventing obstruction before the matrix reaches the target site. These delivery components may be preferred when the distance from the skin surface to the target surface exceeds 2 cm, 3 cm, 4 cm, or 5 cm from the end of the chamber housing the matrix components.

[0054] In one embodiment, the delivery kit may include a dual-lumen injection needle or introduction needle. This needle may be 11G, 12G, 13G, 14G, 15G, or 16G in diameter, and the shaft length may include, for example, 100mm–200mm, 120mm–150mm, or 140mm–170mm. The needle may be made from AISI 302, 304, or 306L stainless steel and mounted to a proximal female Luer lock hub. The needle may include a stylet configured to be inserted through the lumen of the needle. The stylet includes a solid core protruding from the distal end of the needle, with or without a pointed or distal tip for puncture. This needle can be used with 12G, 13G, 14G, 15G, 16G, 17G, or 18G coaxial double-lumen catheters, with shaft lengths ranging, for example, 100mm–300mm, 150mm–250mm, or 170mm–200mm. The catheter may also have a proximal Luer lock hub. The catheter hub may be configured to engage with the proximal Luer lock hub of the introduction needle, for example, via a male Luer lock structure that can lock onto the introduction needle hub when the catheter is inserted through the needle hub and needle shaft, or, for example, via a deformable or biased clamp structure that is reversibly attached to the outer surface of the introduction needle hub. The diameters of the needle and catheter may be selected such that the catheter is removably inserted through the introduction needle and there is no significant leakage of bodily fluids between the outer wall of the catheter and the inner wall of the lumen of the introduction needle. For example, the catheter may be at least 1G or 2G smaller than the introduction needle.

[0055] As a specific example, the SVAS Biosana kit 10 shown in Figure 1A is available. This includes a 15G × 150mm coaxial introduction needle 12 and a 16G × 120mm coaxial catheter 14, which are configured to interact with each other. The proximal end of the introduction device is equipped with a male Luer lock hub 16, and therefore the distal end 18 of the catheter hub 20 is equipped with a female Luer lock hub that can engage with the male Luer lock hub 16 when the catheter 14 is inserted into the introduction device 12. The proximal end 22 of the catheter hub 20 further includes a connector configured to be attached to a matrix syringe or matrix infusion system. This could be, for example, a dedicated complementary female connector interface for BIOGLUE® infusion syringes, or a female Luer lock hub. The kit 10 also includes a stylet 24 that can be securely locked and inserted into the introduction device 12, and is used when inserting and positioning the introduction device 12 at the target site. The stylet 24 may have a solid proximal end 26 with a releaseable clamping mechanism for attachment to the proximal hub of the introducer 12, or in other embodiments, it may have a female Luer lock. Figure 1B shows the catheter 14 inserted into the introducer 12 with the male Luer lock hub 16 engaged with the female Luer lock hub 18.

[0056] In one embodiment, the vial or bottle containing the radioactive isotope microspheres is removed from its radiation shielding container and optionally placed in a lead or acrylic lidless box, if available. The seal of the vial is cleaned with an alcohol swab, and then a vent is formed by puncturing the seal with a needle. A needle, such as a 22G, 25G, 28G, 30G, 31G, or 32G subcutaneous injection needle, is optionally left in place. Next, a 5 mL syringe is attached to a 20 G or 22 G needle, which has a length in the range of 50 mm to 150 mm, 50 mm to 120 mm, or 70 mm to 100 mm. Then, the seal is punctured again using the syringe and the attached needle. Without agitating or mixing the microspheres that have settled at the bottom of the vial or bottle, the needle tip is positioned above the settled microspheres in the suspension, and preferably 2 mL of the suspension is removed and discarded without substantially removing the microspheres. Use a dose calibrator to test or confirm the activity remaining in the vial or bottle. Assuming the vial or bottle contained 3 GBq in 5 mL of suspension, at this point the vial or bottle will theoretically contain 3 GBq in 3 mL of suspension. In other variations, different amounts of suspension may be removed, or additional suspension, such as sterile water for injection or isotonic sodium chloride solution, may be added to the vial or bottle to change the concentration of activity per volume.

[0057] The target activity level and volume to be injected into the target lesion are determined based on the following, optionally taking into account: (a) the calibrated or nominal activity concentration in the vial, (b) the target activity level or absorbed dose to be delivered to or achieved to each target lesion, and (c) the residual volume of material that may remain in the injection system after maximum injection (e.g., in the syringe tip distal to the plunger or slide seal of the syringe, and in the mixing tip or injection catheter or needle). The target absorbed dose, also referred to herein as absorbed dose, may be, for example, 18 Gy or 20 Gy to the excision bed of an excised breast lesion, or up to 150 Gy for a liver lesion. Thus, one embodiment of the present invention relates to the composition of the present invention for use in the treatment of hepatocellular carcinoma (HCC), 90 The target absorbed dose of Y is in the range of 120 Gy to 150 Gy, for example, a dose of 150 Gy. Further embodiments of the present invention relate to compositions of the present invention used for the treatment of hepatocellular carcinoma (HCC) or metastatic lesions (mCRC) of the liver originating from primary colon cancer. 90 The target absorbed dose of Y is in the range of 120 Gy to 150 Gy. Further embodiments of the present invention relate to compositions of the present invention for use in the treatment of gastrointestinal tumors. Additional embodiments of the present invention relate to compositions of the present invention for use in the treatment of pancreatic cancer or pancreatic lesions. Additional embodiments of the present invention relate to compositions of the present invention for use in the treatment of liver lesions, such as primary or secondary liver lesions. Additional embodiments of the present invention relate to compositions of the present invention for use in the treatment of metastatic cancer and metastatic lesions. Preferably, when used in the treatment of lesions as described herein, 90The target absorbed dose of Y is in the range of 120 Gy to 150 Gy. The syringe and attached needle are then reinserted into the vial or bottle and used to agitate and resuspend the settled microspheres in the suspension by moving the syringe plunger multiple times, for example, around 10 to 20 times, and / or until sufficient mixing is visually confirmed by the suspension presenting a homogeneous appearance and the absence of visible settled microspheres. Next, the target activity volume is removed using the syringe. Then, the syringe cap of the hemostatic agent such as glue / matrix is ​​removed, and the target activity volume of the suspension containing the microspheres is then distributed between the two chambers of the hemostatic agent such as glue / matrix. The distribution ratio is 4:1 for the BSA:glutaraldehyde chamber, or a ratio corresponding to the cross-sectional area or volume of the matrix component chamber. For other syringe / infusion systems, for example, if the volume or cross-sectional area ratio between two chambers is 1:1, 1.5:1, or 2:1, the target volume is distributed in the ratios of 1:1, 1.5:1, and 2:1. For a three-chamber delivery system, for example, an infusion system with a ratio of 1:1:1, 4:1:1, or 4:2:1, the target volume is distributed in the same ratio as the three chambers.

[0058] In a preferred embodiment of the present invention, filling the dual-chamber syringe is required for the first chamber which contains only the BSA solution. 90 This further includes filling the syringe with Y-syringe activity level, minimizing radioactive loss within the syringe.

[0059] In another preferred embodiment of the present invention, filling the dual-chamber syringe fills the second chamber containing glutaraldehyde with an appropriate amount of WFI while simultaneously filling the first chamber containing the BSA solution with the necessary amount of WFI. 90 This further includes filling the syringe with Y-activity level, thereby minimizing radioactivity loss within the syringe. To maintain the desired ratio of BSA:glutaraldehyde, for example, a 4:1 ratio within the syringe, 90After the Y microspheres are filled only into the BSA chamber, WFI is added to the chamber containing glutaraldehyde to maintain the BSA:glutaraldehyde ratio. In this embodiment, the total volume of the syringe is 2 mL, and 250 μL 90 When Y microspheres are added to the BSA-containing chamber, the BSA:glutaraldehyde ratio can be maintained at 4:1 by adding 62.5 μL of WFI to the glutaraldehyde-containing chamber. In a further embodiment, the total volume of the syringe is 5 mL, and 500 μL 90 When Y microspheres are added to the BSA-containing chamber, the BSA:glutaraldehyde ratio can be maintained at 4:1 by adding 125 μL of WFI to the glutaraldehyde-containing chamber. In a further embodiment, the total volume of the syringe is 10 mL, and 1000 μL 90 When Y microspheres are added to a BSA-containing chamber, the BSA:glutaraldehyde ratio can be maintained at 4:1 by adding 250 μL of WFI to the glutaraldehyde-containing chamber.

[0060] After dispensing or filling the matrix syringe with the target activity volume, the syringe cap is returned to the matrix syringe. Commercially available dose calibrators, commonly used in radiopharmaceuticals, may be used to verify the expected activity in the syringe and, if necessary, to correct it. The filled matrix syringe is then returned to its radiation-shielded container for storage or for transport to the operating room or treatment facility.

[0061] In the operating room or treatment facility, the patient is prepared and draped using standard sterile methods, and anesthesia is achieved. The target lesion, e.g., a liver lesion, is identified based on imaging modalities such as ultrasound or fluoroscopy, or prior imaging studies. These imaging studies are performed with or without the use of contrast agents. A stylet is inserted into the introduction needle and then percutaneously into the target lesion, preferably under ultrasound or CT guidance. The pre-sealed syringe, pre-filled with radiotherapy particles, is removed from its radiation shielding container, and the syringe cap is removed by rotating the cap from side to side while the syringe is held upright. The double cap of the coaxial catheter is then aligned with the two openings of the dual-chamber syringe. Markings on the catheter may be provided to facilitate alignment with the syringe. The catheter can then be locked to the syringe using a locking collar or other locking mechanism. This is to prevent accidental separation of the syringe and catheter.

[0062] Optionally, after reconfirming the position of the injector / catheter combination, the plunger or actuator of the syringe / delivery system is activated to dispense the mixture. In some embodiments, the syringe plunger or delivery system actuator may be operated at a speed of approximately 0.5 mm to 1 mm per second, 0.5 mm to 2 mm per second, or approximately 0.5 mm to 1.5 mm per second. Once delivery is complete, the injector needle / catheter may be left for 30 to 60 seconds, or at least 5, 10, 15, 20, 30 seconds, and / or 30, 45, 60, 90, or 120 seconds. This may ensure polymerization at the target site. The injector needle / catheter may then be removed from the target site. Optionally, a twisting motion may be used to ensure sufficient separation of the matrix from the injector needle / catheter without seeding into the insertion path or pulling on the target site due to incomplete separation of the injection matrix and the injector needle / catheter. Subsequently, the insertion site of the guide needle / catheter is checked for fluid leakage and, optionally, sutured or sealed with non-radioactive bio-glue or matrix, followed by bandaging and treatment as needed. Radioactive materials or biohazardous components are disposed of appropriately.

[0063] After the desired amount of composition has been administered or delivered, the stylet is removed from the inserted introducer while maintaining the introducer's position. The syringe / catheter is then inserted through the introducer until the distal hub of the catheter locks into the proximal hub of the introducer.

[0064] In embodiments that do not require percutaneous access via needle or catheter, instead of attaching a needle and / or catheter after achieving access via the introducer in the above procedure, a mixing tool tip may be attached to the mixture syringe. After attaching the mixing tip, the syringe may be shaken to thoroughly mix the radioactive isotope suspension with hemostatic components such as glue or matrix components. The mixture may then be applied to the surface of the resection cavity by operating the syringe plunger or delivery system actuator at a speed of approximately 0.5 mm to 1 mm per second. After delivery is complete, the resection cavity may be left exposed for 30 to 60 seconds to ensure polymerization at the target site. The resection cavity is then closed and treated in a normal manner. Radioactive material or biohazardous components are disposed of appropriately.

[0065] In other embodiments, the radioactive isotope particles may be pre-mixed at the time of manufacture with one or both of the hemostatic components, such as the matrix or glue of the pre-filled syringe. For example, 90Y microspheres may be pre-mixed with BSA and / or glutaraldehyde components and filled into pre-sealed syringes. In some variant forms, different sizes of syringes with different therapeutic concentrations may be provided, as the required therapeutic concentrations may differ for specific lesion sizes or diseases. For example, 1 mL, 2 mL, 5 mL, or 10 mL pre-sealed syringe infusion systems may be provided, each having different activity per mL with the pre-mixed BSA component, but no activity within the glutaraldehyde component. Syringes may contain activity concentrations ranging from 5 MBq to 50 MBq per mL, 7 MBq to 45 MBq per mL, 7 MBq to 40 MBq per mL, 15 MBq to 40 MBq per mL, or 15 MBq to 30 MBq per mL. These concentrations may be used, for example, to treat breast cancer. In other embodiments, 1 mL or 2 mL syringes may contain activity concentrations ranging from 0.1 MBq to 20 MBq per mL, or from 0.2 MBq to 15 MBq per mL, and 5 mL or 10 mL syringes may contain activity concentrations ranging from 3 MBq to 30 MBq per mL, or from 5 MBq to 25 MBq per mL. These syringe concentrations can be used for more radiosensitive tumors or, for example, in HCC, where it is necessary to reduce the impact on surrounding normal tissue.

[0066] In other embodiments, the syringe may contain activity in the range of, for example, 0.7–250 MBq or 0.1–300 MBq before administration. This activity may include, for example, 0.68 MBq, 3.42 MBq, 10.01 MBq, 22.44 MBq, 42.48 MBq in a 2.5 mL injectable volume, or, for example, 33.43 MBq, 55.26 MBq, 86.09 MBq, 129.71 MBq, 182.57 MBq, or 249.59 MBq in a 6 mL injectable volume before administration. The activity may vary by up to ±30%, preferably up to ±20%. The injected effective activity may range from 0.4 to 250 MBq, for example, activities selected from the group consisting of 0.48 MBq, 2.4 MBq, 7 MBq, 17 MBq, 28 MBq, 30 MBq, 48 MBq, 75 MBq, 114 MBq, 160 MBq, and 219 MBq. Furthermore, the injected effective activity may range from 0.4 to 250 ± 30% MBq, for example, activities selected from the group consisting of 0.48 ± 30% MBq, 2.4 ± 30% MBq, 7 ± 30% MBq, 17 ± 30% MBq, 28 ± 30% MBq, 30 ± 30% MBq, 48 ± 30% MBq, 75 ± 30% MBq, 114 ± 30% MBq, 160 ± 30% MBq, and 219 ± 30% MBq. Furthermore, the effective activity injected may range from 0.4 to 250 ± 20% MBq, for example, selected from the group consisting of 0.48 ± 20% MBq, 2.4 ± 20% MBq, 7 ± 20% MBq, 17 ± 20% MBq, 28 ± 20% MBq, 30 ± 20% MBq, 48 ± 20% MBq, 75 ± 20% MBq, 114 ± 20% MBq, 160 ± 20% MBq, and 219 ± 20% MBq. The radioactive dose depends on the tumor size, with larger tumors requiring a greater dose of radioactivity for treatment. Due to residual activity in the syringe after administration, the dose administered may differ slightly from the dose proposed herein, with such a difference being up to 30%, but preferably 20% or less. This adjusted difference is important to prevent the delivered dose from being underestimated due to residual radioactivity in the syringe (see Example 11). Furthermore, 90The administered radioactivity dose of Y can be approximately 0.48 ± 20% MBq (when the average tumor size corresponds to a diameter of 5 mm or less), approximately 2.4 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 5 mm to 10 mm or less), approximately 7 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 10 mm to 15 mm or less), approximately 17 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 15 mm to 20 mm or less), approximately 28 - 30 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 20 mm to 25 mm or less), approximately 48 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 25 mm to 30 mm or less), approximately 75 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 30 mm to 35 mm or less), approximately 114 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 35 mm to 40 mm or less), approximately 160 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 40 mm to 45 mm or less), and 219 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 45 mm to 50 mm or less). Such doses are particularly suitable for the treatment of HCC. Exemplary 90 doses of Y administered to HCC patients are presented in Tables 3 and 4 of Example 9. Thus, in an embodiment, 90 the pharmaceutical composition disclosed herein comprising Y is for use in the treatment of hepatocellular carcinoma (HCC), and preferably, is a 90 radioactivity dose of Y as suggested above. Further, due to the handling of the composition prior to administration, the dose can vary slightly by about 1 - 30%. Thus, in an embodiment, the radioactivity dose varies by up to 30% from the above. In a further embodiment, the radioactivity dose varies by up to 20% from the above. Additionally, due to the handling of the composition prior to administration, the dose can vary slightly by about 1 - 15%. Thus, in an embodiment, the radioactivity dose varies by up to 10% from the above. 90 The radioactivity dose of Y can be prepared in the pharmaceutical composition. This composition can include microspheres and optionally a bioglu. 90The radioactive dose of Y can be prepared as a pharmaceutical composition ready for administration to a patient in need. Such a pharmaceutical composition may also be called an injectable composition. Treatment may include administering such a pharmaceutical composition, or injectable composition, to a patient in need. Specific examples of dose selection for liver cancer and breast cancer are provided in the following specific examples.

[0067] Dose measurement As mentioned earlier, hepatocellular carcinoma (HCC) is the most common primary malignant liver disease and the leading cause of cancer-related deaths worldwide. It is an advanced cancer that typically develops in the context of cirrhosis. Unfortunately, in many cases, it is discovered in an advanced stage when the patient is symptomatic and has some degree of liver dysfunction. In the United States, a total of 30,640 new cases of liver cancer and intrahepatic cholangiocarcinoma were reported in 2013, resulting in 21,670 deaths. HCC is more common in men than women (2.4:1) and has shown high incidence in East Asia / South Asia, Central / West Africa, Melanesia, and Micronesia / Polynesia. Despite significant advances in preventive technologies, new technologies, and screening methods (both diagnostic and therapeutic), incidence and mortality rates are increasing, and regardless of etiology, cirrhosis is the most important risk factor for the development of HCC. Currently, multiple treatment modalities exist. However, only orthotopic liver transplantation or surgical resection can be considered a curative treatment. Therefore, patients with HCC who are eligible for liver transplantation are particularly well-suited to treatment with the compositions disclosed herein. Other treatment modalities include transarterial chemoembolization, radioembolization, percutaneous ethanol injection, radiotherapy, and ablation therapy. In particular, percutaneous ablation is a promising approach for treating inoperable primary tumors or metastases of the liver. In fact, surgery is a candidate for less than 40% of patients with HCC, and the likelihood of recurrence after curative surgery is generally high. Therefore, it is preferable that patients treated with the compositions described herein are contraindicated for conventional transarterial radioembolization. Against this backdrop, percutaneous techniques are representative of highly successful treatment options and are now widely used for the treatment of metastatic and small primary tumors. Among these techniques, methods such as chemical ablation, cryoablation, and high-temperature ablation (e.g., radiofrequency, microwave, laser, and ultrasound) are widely accepted in the treatment of liver tumors, as they can serve as a bridge to transplant candidates, especially for small primary lesions. The choice of treatment modality is based on tumor size, location, extrahepatic metastasis, and underlying liver function.

[0068] Due to the lack of effective systemic therapies for HCC, researchers have been exploring the use of 90 local tumor control by yttrium radioembolization since the 1960s. Currently, radioembolization (also known as selective internal radiotherapy (SIRT) or transarterial radioembolization (TARE)) is 90 an established and effective treatment for liver malignancies based on the transarterial injection of yttrium - loaded microspheres. 90 The dosimetric distribution of radiation resulting from the intra - arterial injection of yttrium microspheres has been studied by many researchers in the past. Currently, 90 there are two clinically available microsphere devices incorporating yttrium. One uses glass microspheres (TheraSphere; MDS Nordion, Ottawa, Ontario, Canada), and the other uses resin microspheres (SIR - Spheres; Sirtex Medical, Sydney, Australia). The resin - based microsphere device consists of biocompatible 90 yttrium - loaded microspheres with diameters of 20 - 40 μm. When administered, the spheres remain in the liver as permanent implants. Brachytherapy is a type of internal radiation therapy where seeds, ribbons, or capsules containing a radiation source are placed inside the body, within the tumor, or near it. Brachytherapy is a local treatment that treats only a specific part of the body. The composition of the present invention containing 90 yttrium can be administered percutaneously to provide brachytherapy to the tumor.

[0069] In the conventional catheter - based approach, radioembolization involves the intra - arterial injection of microspheres. However, in recent years, numerous studies have addressed the dosimetric issues in therapies based on the use of 90 intratumoral injection of yttrium - labeled compounds by percutaneous puncture. In recent years, this technique has been used for 90 yttrium - labeled [DOTA 0 -D - Phe 1 -Tyr 3]Ocleotide ( 90 It has been successfully applied to patients treated with Y-DOTATOC.

[0070] Furthermore, based on clinical experience gained from liver radioembolization, appropriate activities 90 Percutaneous ablation of HCC by intratumoral injection of Y may significantly reduce the likelihood of local recurrence. In connection with this, in the form of microspheres mixed with biocompatible compounds... 90 There is growing interest in developing a new intratumor procedure for HCC involving the local administration of Y.

[0071] Generally, intratumoral administration of radionuclides allows for the selective treatment of tumors smaller than 1 centimeter, thus raising concerns about dose measurement for small lesions. To date, 90 There is no easy way to accurately assess the absorbed dose to tumors and normal liver tissue when Y is administered. 90 This is because Y emits only pure beta rays, and its penetration range within tissue is limited. As a result, the delivered dose depends heavily on the distribution of microspheres and tumor mass. In particular, current analytical methods used to evaluate the absorbed dose to the liver and the absorbed dose to tumor masses within the liver parenchyma are insufficient within a given organ. 90 This approach is based on the assumption that all particles emitted from Y are completely absorbed by the organ. However, if the tumor size is small, this assumption may no longer hold, and the current analytical approach, when used for dose assessment of small target areas, is likely to provide inaccurate dose results.

[0072] therefore, 90 The current analytical format used to evaluate the absorbed dose after Y microsphere administration is based on the assumption that all β particle energy is completely absorbed by the treated mass, and therefore may provide inaccurate results when used to calculate doses in small target areas. In this study, we examine the effects in lesions of various sizes. 90We evaluate the absorbed dose in a scenario of intratumor injection of Y and propose dose regimens that take into account the partial absorption of β particle energy by the target tissue.

[0073] In one embodiment, into the tumor 90 Assuming selective delivery of Y (i.e., in a scenario of percutaneous ablation of HCC via intratumor injection of radionuclide), absorbed dose in small lesions was evaluated. A simplified model of the tumor mass was implemented in the MCNP4C Monte Carlo (MC) code, and the tumor mass was 90 The objective was to determine the absorbed dose to the lesion when the area was uniformly filled with Y.

[0074] In some variant forms, the absorbed dose per unit of administered activity was evaluated using Monte Carlo calculations with spheres of different sizes (0.5–20 cm in diameter). The spheres represented tumor regions. 90 It is assumed that Y is uniformly filled. Monte Carlo's results were compared with well-established analytical approaches.

[0075] Initial results indicate that the current analytical model leads to a dose overestimation of less than 10% for lesions with a diameter greater than approximately 2 cm. However, for lesions with a diameter less than 2 cm, the analytical model can deviate significantly from Monte Carlo's results (by more than 10%), resulting in a dose overestimation of more than 50% for lesions with a diameter of 0.5 cm. An alternative formula for calculating absorbed dose in small target regions was provided.

[0076] 90 Y is primarily stable (99.983%) through beta decay. 90 It decays down to the ground state level of Y. A weak beta bifurcation occurs at the 1760 keV excited level, which decays via the E0 gamma transition. + -0 + The transition is followed by the emission of two gamma rays or electron-positron pairs, or internal conversion. 90The adopted half-life for the Y ground state is 64.041 hours or 2.6684 days.

[0077] Among the radionuclides used in clinical practice, 90 Y possesses attractive physical and radiobiological characteristics that make this radionuclide suitable as a localized treatment option. Its high-energy beta particles (maximum energy 2278.7 keV, average energy 926.7 keV) and their penetration depth (maximum particle range within tissue 11 mm, tissue range where 50% of the energy is delivered 4 mm) allow for the selective delivery of high doses to the target area while simultaneously preserving surrounding tissues and healthy organs. In particular, the penetration depth of high-energy beta particles is a key factor in the success of this radionuclide in radioembolization, enabling high-dose deposition in the tissue between embolusted capillaries. Conventional dose calculation formulas ( 90 After local administration of Y, two important simplification assumptions are commonly made. • Within a given organ 90 Beta radiation emitted from Y is completely absorbed by the organ. In most cases, this assumption is valid for an average of 4 mm within the tissue. 90 This is supported by the Yβ range. · 90 The retention of Y in the area where it was delivered (i.e., no migration of the radiopharmaceutical outside the tumor area).

[0078] By combining these two assumptions, it becomes possible to easily calculate the average absorbed dose to the organ of interest on a macroscopic scale. This calculation is performed as follows: 90 This was performed using the latest nuclear data for Y, as shown below, and is commonly referred to as the MIRD (Medical Internal Radiation Dose) approach:

number

[0079] Assuming that all the energy of a beta decay is absorbed by the volume in which the decay occurs, the constant term k can be calculated considering a given physical value and its statistical uncertainty:

number

[0080] The constant coefficient 49.38 (J / GBq) is, 90 This is the energy released per unit activity of Y. Due to the uncertainty in the nuclear data reported in the following equation, a relative standard uncertainty of 0.1% is introduced into the constant term, i.e., 49.38(5)(J / GBq), which is consistent with the recommendations of the American Association of Physicists in Medicine.

[0081] Finally, the absorbed dose D (expressed in Gy) is equal to the delivered energy E. tot It is obtained by dividing by the mass m (expressed in kg) of the target region.

number

[0082] Notably, the same formula with a slightly different constant k has been reported in other literature (e.g., 49.98, 49.67).

[0083] According to the partition model, the tumor uptake rate (FU) is used to calculate the absorbed dose within the tumor. tumor The following formula can be used when (i.e., the percentage of administered activity accumulated in the tumor) is known.

number

[0084] Equations (4) and (5) above are, 90 It must be emphasized again that this is only valid for Y-type radioembolization and represents only the average absorbed dose in an organ or large lesion, i.e., the average absorbed dose on a macroscopic scale. In this specification, it is hypothesized that these formulas may not apply to very small tumor masses, since the assumption that the energy released during decay is completely absorbed by the target mass m no longer holds true. In particular, when the size of the lesion is very small (especially in areas less than 1 centimeter), 90 The energy released per unit activity of Y can be significantly reduced. Therefore, below, the constant term k in equation (3) is treated as a function of the lesion radius (r) and is denoted as k(r).

[0085] In this study, the absorbed dose per administered activity unit was evaluated using Monte Carlo calculations in a simplified geometric configuration. The MC code MCNP4C was used for this purpose. MCNP is a general-purpose, continuous-energy, generalized-geometry, time-dependent, coupled neutron / photon / electron Monte Carlo transport code. For photon transport, the code takes into account photoelectric absorption, coherent scattering, incoherent scattering, and pair production, with the possibility of K-shell and L-shell fluorescence emission or Auger electron emission. Photoelectric cross-sections are based on Storm and Israel, and scattering cross-sections are obtained from the ENDF table. A continuous-deceleration approximate energy loss model is used for electron transport.

[0086] Spherical lesions of different sizes (diameter range of 0.5 to 20 cm) were examined at two different densities: ρ = 1.00 g / cm³. 3 (Density of water) and ρ = 1.05 g / cm³ 3 The simulation was performed using (liver density). In both scenarios, it was assumed that the sphere was immersed in a semi-infinite medium of the same density as the sphere. This sphere represents the tumor region. 90While it is assumed to be uniformly filled with Y, it is assumed that the surrounding medium does not contain radioactivity.

[0087] The calculations were performed in the coupled electron-photon mode [MODE P E] using the el03 electron interaction data library (ELIB = 03E) and the mcnplip2 photon interaction data library (PLIB = 02P). The simulation was carried out considering all available advanced options such as electron generation by photons, bremsstrahlung effects, and knock-on electron generation. The MCNP simulation was performed over an appropriate time to make the statistical uncertainty regarding the absorbed dose less than 0.01%.

[0088] Figure 18 shows, as a function of tumor size, 90 the fraction of the absorbed dose in the tumor of Y obtained from the MCNP simulation. The 90 β - ray spectrum of Y implemented in this model is also shown in Figure 19. The calculations were performed in both a sphere of water (ρ = 1.00 g / cm 3 ) and a sphere of liver tissue (ρ = 1.05 g / cm 3 ). In both cases, when the lesion diameter is less than 2 cm, more β - particle energy is delivered outside the sphere, and the first assumption mentioned above (radiation emitted from a microsphere within a given organ is completely absorbed by that organ) does not hold. Consistently, the delivered energy per unit activity k(r) shows the same trend while confirming that such terms deviate significantly from its constant value of 49.38 (J / GBq) considered in Equation (4) when the tumor size is small (Figure 20). To utilize the information reported in Figure 20 at the clinical level, the k(r) data obtained from the MC calculations were fitted using the following function.

Equation

[0089]

Table 1

[0090] For both the density of water and the liver, from the fit r 2 = 0.999 was obtained. Furthermore, the goodness of fit was also evaluated through the analysis of residuals (Figure 21). This analysis shows that the maximum deviation between the calculated data and the fitted data is less than 0.2, and this result supports the accuracy of the fit. Based on the fitting function described in Equation (6), Equation (4) can be rewritten in the following form:

Equation

[0091] For a given activity A0, using Equation (7), the absorbed dose for very small lesions (up to 0.5 cm in diameter) can be accurately calculated. The absorbed dose to the lesions calculated using Equation (7) shows good agreement (maximum deviation less than 0.5%) with the MC calculation results. As expected, ideally when r → ∞, Equation (7) reduces to Equation (4). It should be noted that the energy per activity k(r) obtained in the case of the limit x → ∞ from Equation (6) is 49.35 (J / GBq), which is compared with the accepted value of 49.38 (J / GBq) (deviation 0.06%) derived from Equation (4).

[0092] Figure 22 compares the absorbed dose per activity (Gy / GBq) calculated by Monte Carlo for spherical lesions of different sizes and for ρ = 1.05 g / cm 3 with that obtained using the MIRD analytical approach. For ρ = 1.00 g / cm 3Similar results are shown in Figure 23. In addition, Figure 23 reports the absorbed dose calculated using the established Olinda / EXM code developed by the Society of Nuclear Medicine's Radiation Dose Assessment Resource (RADAR) Task Group. As shown in Figure 23, the absorbed dose values ​​calculated using the MC approach agree well with the values ​​obtained using Olinda / EMX. When the lesion diameter was less than 2 cm, a significant discrepancy was found between the MC-calculated dose values ​​and the values ​​obtained using the MIRD analytical approach (Figure 23, inset).

[0093] Finally, Tables 2 and 3 below show the MC calculation (D MCNP ) and MIRD analytical approach (D MIRD Compare the absorbed dose values ​​per 1 GBq of administered activity obtained in ). 100·(D MCNP -D MIRD ) / D MIRD The percentage difference between the two methods (the last column in both tables, Δ), calculated as follows, is also reported. As long as the lesion diameter exceeds 2 cm, the difference in absorbed dose values ​​remains within approximately 10%. When the lesion size is less than 2 cm, the two calculation approaches diverge significantly due to the pronounced energy deposition outside the sphere. This is because, 90 This coincides with the maximum particle range of Y within the tissue (approximately 11 mm). In this case, at water (liver) density, the MC calculation shows absorbed doses that are 9.3% (9.6%), 27.8% (26.7%), and 56.7% (55.4%) lower than the MIRD analysis approach for tumor diameters of 2 cm, 1 cm, and 0.5 cm, respectively (Tables 2 and 3).

[0094] [Table 2]

[0095] [Table 3]

[0096] 90Dose measurement using Y has attracted considerable attention over the past 20 years. However, few researchers have addressed the problem of dose measurement in very small liver lesions. 90 The maximum range of Y-type beta particles within a tissue is 11 mm, while the range of average-energy beta particles is approximately 4 mm. 90 It should be noted that the penetration depth of high-energy β-particles of Y is an essential component for the success of this radionuclide in hepatic radioembolization, enabling high-dose delivery to the tissue between embolusted capillaries.

[0097] This study was conducted in lesions of various sizes. 90 The objective is to evaluate the absorbed dose per activity unit in a scenario of percutaneous ablation of HCC via intratumor injection of Y. 90 A simplified model tumor region was implemented in the MCNP4C MC code to determine the absorbed dose to the lesion when uniformly filled with Y. Two different densities: ρ = 1.00 g / cm³. 3 (Density of water) and ρ = 1.05 g / cm³ 3 Regarding liver density, spherical lesions of different sizes (ranging from 0.5 to 20 cm in diameter) were simulated. In both scenarios, it was assumed that the lesions were immersed in a semi-infinite medium of the same density as the lesion. As long as the lesion diameter exceeds 2 cm, the MIRD analytical approach and MCNP calculations provide results within 10%, regardless of the lesion density. When the lesion diameter is less than 2 cm, a significant difference (i.e., a deviation of more than 10%) was obtained between the MC calculations and the MIRD approach. As a general conclusion, the MIRD approach tends to overestimate the absorbed dose in small lesions because the basic assumption of the model is that β radiation is completely absorbed by the tumor or tissue where decay occurs. If the radius of the tumor is smaller than the maximum range of β radiation in the medium, a considerable amount of energy is delivered outside the lesion, resulting in a smaller absorbed dose.

[0098] Despite the availability of different dose algorithms, the MIRD analysis algorithm described in equation (4) remains widely used at the clinical level to assess absorbed doses within tumors and liver compartments. For larger liver lesions, equation (4) can provide accurate dose estimates (provided that accurate input parameters, including target uptake rates, are introduced). However, applying this approach to assess absorbed doses to small tumor masses (i.e., less than approximately 2 cm in diameter) may yield inaccurate dose estimates.

[0099] In addition, the MIRD analysis algorithm is safely used in treatment planning using glass microspheres. The basic principle is based on equation (4), which calculates the average dose within the tissue volume. 90 This is described as a function of Y activity. During treatment planning, equation (4) can be solved for treatment activity A0. The results obtained in this embodiment suggest that a MIRD analytical approach can be used to achieve a given tumor cell death endpoint in small liver lesions. 90 This raises the question of whether or not Y's activities should be evaluated. 90 This applies when Y is injected into the tumor. For example, in the case of HCC, 120 Gy is usually considered a reasonable minimum target dose. Therefore, 90 When treating HCC patients with Y beta particles, D tumor It is desirable to set it to a minimum of 120 Gy. Equation (5) can be rearranged to derive the prescribed therapeutic activity: A(GBq)=D tumor xm tumor (kg) / 49.38(J / GBq)×FU tumor

[0100] For example, tumor mass m tumor However, 0.52 mg (1 cm in diameter), FU tumor =1, and D tumor Assuming = 120 Gy, equation (5) becomes (ρ = 1.05 g / cm³). 3(Considering this), this would result in a therapeutic activity of 1.21 MBq. On the other hand, if equation (7) is used instead of equation (4), a therapeutic activity of 1.62 MBq is obtained. As outlined earlier, the reason for this difference is the significant energy deposition outside the sphere (approximately 26% of the β-particle energy is delivered outside the sphere, as reported in Figure 18A). As a result, a therapeutic activity of 1.21 MBq would actually correspond to an absorbed dose of approximately 90 Gy, far below the therapeutic endpoint.

[0101] As mentioned above, 90 Intratumoral injection of Y may present certain treatment planning challenges related to its potential to highly selectively treat extremely small lesions. In his paper, Ariel discusses the treatment of rhabdomyosarcoma. 90 The first use of Y microspheres in the interstitial space was reported (Ariel I 1978: Cure of an embryonal rhabdomyosarcoma of the nose of an infant by interstitial space). 90 Yttrium microspheres: A case report (International Journal of Nuclear Medicine and Biology 5 37-41). A nodule measured 1.5 cm in diameter was successfully treated by injecting 185 MBq microspheres into the interstitial space. Another study (Tian JH, Xu BX, Zhang JM, Dong BW, Liang P, Wang XD 1996 Ultrasound-guided internal radiotherapy using yttrium-90-glass microspheres for liver malignancies Journal of Nuclear Medicine 37 958-63) showed that, 90 Y-glass microspheres were injected into designated tumor sites using ultrasound-guided techniques. Tumor sizes ranged from 1.9 to 8.8 cm, with most lesions less than 5 cm in diameter. More recently, Ferrari and collaborators have investigated localized...90 The absorbed dose to the neocauses and surrounding tissues of a small volume after Y-DOTATOC injection was evaluated (Ferrari M, Cremonesi M, Bartolomei M, Bodei L, Chinoll M, Fiorenza M, Tosi G, Paganelli G. Dosimetric model for locoregional treatments of brain tumors with 90 Y-conjugates:clinical application with 90 Y-DOTATOC, J Nucl Med. 2006 Jan;47(1):105-12.). The latest literature review on intratumoral treatment with radioactive beta-emitting microparticles can be found in Bakker R, Lam M, van Nimwegen S, Rosenberg A, van Es R and Nijsen J 2017 Intratumoral treatment with radioactive beta-emitting microparticles: a systematic review Journal of Radiation Oncology 6 323-341.

[0102] This specification describes the delivery system described herein, which is used to deliver (a biocompatible matrix) 90 A procedure is described in which Y microspheres are delivered to a target by direct, image-guided intratumoral injection. This procedure, also known as percutaneous radioablation, is a minimally invasive treatment for patients with small (less than approximately 3 cm) liver tumors. The treatment is performed using the following combination of components: i) a 4:1 ratio mixture of bovine serum albumin and glutaraldehyde, FDA approved for use in soft tissue repair or sealing damaged parenchyma, BIOGLUE® (Cryolife, Atlanta, US), ii) 90coated with Y, approved for administration into liver tumors via the hepatic artery, SIR-SPHERES® (Sirtex Medical, Sydney, Australia), and iii) hemostatic agent components such as glue, 90 a dedicated coaxial dual-lumen catheter, MIPP-KIT® (Svas Biosana, Naples, Italy), for directly injecting a Y microsphere mixture and glue into tumors under image guidance. The findings of this study suggest that care should be taken when planning treatment with Y for 90 very small lesions using standard analytical approaches. This is 90 especially true when performing intratumoral administration of Y, as this approach enables selective treatment of tumors less than 1 centimeter in size. In such scenarios, the use of analytical approaches to calculate the treatment activity required to achieve a given tumor cell death endpoint can lead to significant underestimation of the dose.

[0103] In some embodiments, the alternative algorithm presented by Equation (7) can be usefully utilized in treatment planning for intratumoral injection of microspheres, and results in close agreement with Monte Carlo calculations (maximum deviation less than 0.5%).

[0104] In conclusion, given a given activity A0, the analytical formula (Equation 4) proposed by the MIRD model is likely to overestimate the absorbed dose in lesions smaller than 2 cm. Conversely, when prescribing using an analytical approach 90Evaluating Y activity can lead to underestimation of activity. This is because the fundamental assumption used to derive equation (4) (complete absorption of β particles within the target volume) no longer applies to small lesions. However, for lesions with a diameter greater than approximately 2 cm, the overestimation is less than 10%. In principle, the larger the lesion size, the better the agreement between the MIRD model and the Monte Carlo calculation. Below 2 cm in lesion size, the two calculation approaches diverge significantly, and the analysis algorithm can overestimate dose by up to 57% (for lesions with a diameter of 0.5 cm). Therefore, caution is needed when using equation (4) to determine absorbed dose in very small lesions. In particular, the use of equation (7) rather than equation (4) is recommended for evaluating absorbed dose in small tumor areas.

[0105] Example 1: Non-clinical study In one embodiment, 90 In a series of experiments in which Y microspheres were mixed with hydrogels such as tissue glue or surgical sealants and / or adhesives, 90 The uniform distribution of Y-labeled particles is demonstrated. By coagulating during injection or implantation procedures, the radioactive glue or gel can be uniformly distributed and undesirable effects such as gravity, dispersion, leakage into blood or lymphatic vessels, and hematoma can be prevented. Figures 2A and 2B show the contents of BIOGLUE®. 90 The image shows a gamma camera image of a Y microsphere at 1 mCi (37 MBq), which is a mixture of 45 vol / wt% bovine serum albumin and 10 vol / wt% glutaraldehyde mixed in a 4:1 ratio in a 2.5 mL syringe cylinder. Additional tests were performed using a 5 mL plastic sphere. This sphere was tested using a dual-lumen coaxial catheter at activity levels ranging from 370 to 740 MBq. 90The Y microspheres were filled with a gel carrier or a matrix material such as BIOGLUE, COSEAL (PEG / HCl / NaPhos / NaCO3; Baxter Healthcare, Hayward, CA) or BERIPLAST (fibrinogen / thrombin; CSL Behring GmbH; Marburg, Germany). In these tests, gamma camera and PET / CT imaging were performed using 4 mm slices to more accurately assess the distribution of radioactivity in the solidified carrier, as shown in Figures 3A and B. Figure 3A also showed that PET / CT imaging did not separate the liquid used to suspend the microspheres in the solid carrier material within the cavity after mixing, and that there were no changes in the uniform distribution within the cavity or other changes in the solidification process, even at larger sizes.

[0106] Regarding the use of gamma cameras and PET / CT imaging examinations, 90 The dose measurement distribution of the Y microspheres and the solidified matrix was also used in the evaluation. Figures 4A-C show the relative absorbed doses in cavities with spherical volumes of 0.5 mL, 4.2 mL, and 11.4 mL, with radii of 0.5 cm, 1 cm, and 1.5 cm, respectively. These are the values ​​measured from the center of each corresponding volume and in a shell volume 1 mm thick from the surface of the sphere.

[0107] Figure 5 shows the respective volumes described above in Figures A to C. 90This shows the percentage of activity of the Y Microsphere-BIOGLUE® composition. For volumes with radii of 0.5 cm, 1 cm, and 1.5 cm, the percentage of activity drops substantially to less than 50% within 0.5 cm of the volume surface or within 150% of the radius from the center of the volume. For a 0.5 cm radius volume, the percentage of activity drops to less than 10% or 5% within 0.5 cm of its surface (i.e., within 1 cm of its center) and drops to zero within 1 cm of its surface (i.e., within 1.5 cm of its center). For a 1 cm radius volume, the percentage of activity drops to less than 10% or 5% within 0.5 cm of its surface (i.e., within 1.5 cm of its center) and drops to less than 1% within 1 cm of its surface (i.e., within 2 cm of its center). For a volume with a radius of 1.5 cm, the percentage of activity decreases to less than 10% or 5% within 0.5 cm from the surface (i.e., within 2 cm from the center), and to less than 1% within 1 cm from the surface (i.e., within 2.5 cm from the center). The estimated absorbed doses for these volumes are shown below:

[0108] [Table 4]

[0109] [Table 5]

[0110] [Table 6]

[0111] Figure 6 shows the absorbed dose per activity unit (Gy / MBq) for adjacent shell volumes for these three volumes. These plots show that the absorbed dose decreases by at least 95%, or one to two orders of magnitude, within a distance of 0.5 cm from the surface of the volume, and by at least 90% within 150% of the radius.

[0112] Figure 7 shows the total absorbed dose (in gray) in adjacent shell volumes for these three volumes. In a volume with a radius of 0.5 cm, the absorbed dose within 0.5 cm of the surface (1 cm from the center) is reduced by approximately 90%. In a volume with a radius of 1 cm, the absorbed dose within 0.5 cm of the surface (1.5 cm from the center) is reduced by more than 90%. In a volume with a radius of 1.5 cm, the absorbed dose within 0.5 cm of the surface (2 cm from the center) is reduced by more than 90%.

[0113] Example 2: Test using mice In one study, the applicant used human MIA-Paca-2 RFP cells in the thigh of CD1 nude mice in an animal model of pancreatic cancer. Subsequently, in the site of the induced tumor, 90 A novel matrix was applied that acts as a carrier for the Y sphere. 90 Intratumoral application of a novel matrix containing Y spheres enabled the achievement of effective doses for tumor treatment by increasing the levels of compounds in tissue through their uniform distribution, reducing diffusion rates, and avoiding and minimizing systemic side effects of the treatment.

[0114] The experimental protocol involved localized treatment that influenced tumor shrinkage, resulting in tangible benefits for the host. The results from this study and other studies described herein suggest that, given that the majority of pancreatic cancers are inoperable due to locally advanced lesions, a transition to clinical practice could yield significant benefits.

[0115] The radioactive isotopes and matrix used in this test were SIR-SPHERES® and BIOGLUE®, respectively. This composition is thought to perform the following: - It can be administered intratumorally to completely necrotize the tumor tissue surrounding the injection site, thereby enabling the treatment of malignant tumor masses that cannot be surgically removed; - Following surgical excision or ablation of malignant tumor masses, it can be applied as a coating or filling material for surgical wounds to completely necrotize any remaining tumor cells located along the edges of these wounds; - By improving the effectiveness of anticancer substances and increasing the concentration of such substances within the treated tumor mass or within the surgical wound resulting from surgical removal or ablation of the tumor, it is possible to achieve a beneficial increase in the local administration and duration of action of such substances; - To prevent or delay the free dispersion of anticancer substances within the patient's body, thereby limiting systemic exposure to their toxic components; and / or - To avoid or mitigate some of the side effects associated with the application of alternative treatment methods to surgical removal of malignant tumor masses.

[0116] In a suitable viscous material capable of capturing microspheres, 90 A radioisotope-matrix composition containing a substance with suitable anticancer activity, such as Y or other types similar to holmium, is thought to provide a uniform distribution and act as a carrier for the aforementioned substance. Necrosis of target tumor cells is as described above. 90 This is induced by appropriate internal electron beam radiotherapy (IER), determined by the localized emission of radioactive particles from Y-labeled microspheres. This has been demonstrated through studies of gamma camera and PET / CT / SPECT imaging shown in Figures 8A-8F. 90Y However, due to the viscosity of the matrix-forming components, it was found to be dispersed in a nearly uniform manner within the tumor mass into which it is injected, or within the surgical wound to which it is applied, and this uniform distribution proved to be very useful in the necrosis of tumor cells located in these areas.

[0117] Tumors were induced in mice after injection of human MIA-Paca-2 RFP cells. Figures 8A and 8D show the results. 90 Figures 8B and 8E illustrate PET / SPECT images of matrices that do not contain Y spheres, while Figures 8B and 8E illustrate combined 90Figures 8C and 8F show PET images of mice injected with a Y-matrix composition. Figures 8C and 8F are SPECT images corresponding to the mice in Figures 8B and 8D. 90 This confirms that none of the Y spheres leaked or dispersed from the injection site, and that the distribution of radioisotopes within the tumor was uniform.

[0118] These results also demonstrate that by using a hydrogel or matrix with a sufficient coagulation rate as a carrier for radiolabeled microspheres, the potential dispersion of microspheres within the patient's body, potentially caused by factors such as gravity, circulation in the blood and / or lymphatic vessels, and the presence of hematomas, can be substantially limited, thus avoiding or significantly reducing potential side effects resulting from the potential leakage of radioactive material in the patient.

[0119] The material forming the hydrogel or matrix is ​​a viscous gel or matrix designed for direct intratumoral injection or application to the surface of the tumor resection site. This matrix, due to its size and composition (e.g., resin or glass), is trapped within the gel matrix and localized for an extended period at the tumor or resection site to increase or maximize the local dose level and irradiation duration. 90 It is configured to contain a Y-sphere. 90 As an overall effect of a matrix with Y microspheres, local 90 The concentration of Y microspheres increases, limiting or reducing peak exposure to the whole body.

[0120] Example 3: Development of a matrix injector Because the two solutions forming a hemostatic gel, sealant, or hydrogel have different densities and viscosities, one solution may flow into the catheter in a larger volume than the other, which can lead to the following problems: - Waste of compounds; - The operator needs to apply considerable force to the syringe with both hands, making it difficult to apply the compound; - The operator is unable to hold the catheter in place with one hand during injection, leading to misapplication of the compound due to displacement of the catheter end; such displacement forces the operator to use a larger amount of compound to ensure that the compound reaches and covers the entire target volume.

[0121] Furthermore, if the flow rate of either of the two compounds decreases, the activation of the compound is accelerated near the end of the catheter where mixing takes place to activate the compound, i.e., near the exit point of the two substances. This can lead to catheter occlusion, and therefore the operator is forced to apply greater force to overcome the resistance of the two solutions to injection. Moreover, the greater the force required from the operator, the more difficult it becomes to hold the end of the catheter in place near the target. This necessitates continuous monitoring of the catheter's correct positioning using ultrasound or X-ray and any necessary repositioning.

[0122] Due to these potential problems, various glues and matrices have so far been used only during surgery. Furthermore, dual-lumen catheters, designed and developed for other purposes, cannot deliver two solutions to the relevant areas simultaneously, resulting in obvious waste of compounds or drugs and inadequate therapeutic outcomes, and posing significant difficulties in percutaneous or laparoscopic administration.

[0123] Therefore, the technical challenge is to ensure that the flow rates of two solutions with different viscosities and densities are the same, meaning they must flow in and out of the distal end or outlet of the catheter simultaneously.

[0124] Therefore, the career matrix and 90It is beneficial to deliver the compound to the target region in a desired ratio using a device that can deliver the compound in combination with a microsphere equipped with Y, while preferably avoiding all the conventional drawbacks in percutaneous image-guided therapy, laparoscopic therapy, and intraoperative therapy.

[0125] In one embodiment, a dual-lumen catheter was developed for the injection of a two-component compound, particularly a glue or drug containing thrombin and fibrinogen. The catheter comprises a first lumen for a first solution of the first component and a second lumen for a second solution of the second component. The aforementioned lumens form a first area and a second area, respectively, in the cross-section of the catheter, and the ratio of these areas is proportional to the viscosity ratio of the respective fluids. According to a further aspect of the present invention, it is preferable that the aforementioned ratio of the aforementioned areas is greater than the square root of the viscosity ratio of the fluids passing through each lumen.

[0126] In particular, the aforementioned ratio of the areas is preferably approximately equal to the square of the viscosity ratio of the fluid passing through each lumen. The above ratio values ​​take into account another aspect, namely that viscosity changes with temperature.

[0127] In some examples, the lumens have a circular cross-section and are concentric, with the first lumen enclosing the second lumen, as shown in Figure 9A. In this case, the first lumen is preferably configured and sized to accommodate a more viscous solution, thereby potentially exposing the solution to heating induced by contact between the catheter and the patient's tissue during injection.

[0128] Therefore, modifications of the catheter that enable better utilization of heat transfer from the outside require that the two lumens have a circular cross-section and be concentric, and that the more viscous solution flows through the outer lumen, thus the outer lumen has a larger cross-section than the inner lumen.

[0129] The aforementioned catheters are used in the medical / clinical field whenever necessary for administering anticancer compounds, in minimally invasive percutaneous procedures, surgical procedures, laparoscopic procedures, or interventional radiological procedures.

[0130] As a result of the present invention, it is possible for two solutions to have the same flow rate and therefore move along the catheter simultaneously, i.e., to be discharged from the catheter in equal volumes and to ensure accurate activation of the drug when injected in close proximity to the patient's target tissue. Advantages include the ability to minimize injection time and the amount of force required by the operator during injection, as well as minimizing the amount of compound injected.

[0131] The features of the catheter according to the present invention are indeed remarkable. This is because, as anyone skilled in the art will see, Poiseuille's law is applied, which stipulates that the constant velocity motion of a viscous, incompressible fluid in a tube having a certain cross-section is laminar flow, that is, composed of the relative sliding of an infinite number of cylinders coaxial with the tube axis.

[0132] As a result, the pressure difference Δp between two points located at the inlet and outlet of the tube is given by the following:

number

[0133] To minimize the force applied by the operator to the body of the dual-chamber syringe, the two solutions along the catheter must have the same flow rate and the same pressure difference. Therefore,

number

[0134] In the equation, S1 and S2 represent the cross-sectional areas of the lumens, respectively. In other words, by applying Poiseuille's law, the ratio of the cross-sectional areas of the two lumens should be proportional to the square root of their respective viscosity ratios.

[0135] More precisely, the present invention defines a preferred ratio between the ratio of areas and the ratio of cross-sectional areas, which is considered to contradict the predictions of the aforementioned physical laws.

number

[0136] In fact, the aforementioned physical laws cannot predict the behavior of the two solutions forming the hemostatic agent when the temperature changes, especially when the catheter is inserted into the patient's body. Indeed, under the circumstances described above, the temperatures of the two solutions change from approximately 18°C, the ambient temperature, to approximately 37°C, the body temperature.

[0137] The above-described formulas can be modified to account for different positions in the relationship between the inner and outer lumens, for example, when the lumen axes coincide (Figure 9A), when they do not coincide but are parallel (Figure 9B), or when the two lumens are separated by a curved or straight partition (Figure 9C and D, respectively).

[0138] However, in some modified forms, the catheter properties are obtained according to the following relationship when the area ratio of the lumen cross-section is slightly greater than the square root of each viscosity ratio.

number

[0139] One embodiment has an outer diameter of 16G, which corresponds to an outer diameter of approximately 1.6mm. Furthermore, since the two lumens are concentric: - The first lumen has a diameter of 0.022 inches, or 0.56 mm. - The second lumen has a diameter of 0.010 inches, or 0.25 mm.

[0140] Therefore, the cross-sectional area of ​​the second lumen is π × 0.125 2 = 0.04906 mm 2 Therefore, the total area of ​​the first lumen is π × 0.28 2 = 0.24617 mm 2 Therefore, the net area is 0.24617 - 0.04906 = 0.19711 mm². 2 This means that the area ratio of the first lumen to the second lumen is approximately 4. Therefore, it is suitable for solutions having a viscosity ratio of approximately the square root of 4, i.e., about 2. Externally, other embodiments of the catheter may have standardized cross-sections, for example 20G, 18G, 16G, or 14G.

[0141] Preferably, the catheter is made of a radiopaque material that is visible under fluoroscopy and / or other imaging modalities. Its suitable length for use is about 20 cm, and the aforementioned material is preferably semi-rigid, but in other embodiments it may be flexible or rigid. Preferably, the catheter includes a rigid connector that can be connected to a special syringe for injecting a two-component compound. In other embodiments, the catheter may have a shaft length in the range of 10 cm to 100 cm, about 20 cm to 70 cm, or 30 cm to 60 cm. It may include a rigid Y-connector dedicated to the two components, or a standard Luer lock end connector. Finally, the catheter body preferably has specific markings spaced at predetermined intervals, for example, 1-centimeter intervals, i.e., spaced in centimeters for at least a portion of the catheter.

[0142] The kit may further include an introducer that is the same length as the catheter, e.g., 20 cm, and has a cross-section compatible with one of the possible cross-sections of the catheter. In some variations, the distal tip of the catheter may be coplanar with the distal tip of the introducer. In other embodiments, the catheter tip may extend outward from the distal tip of the introducer by 1 mm to 10 mm, or 1 mm to 5 mm, or 2 mm to 4 mm, or may be positioned at a distance proximal to the introducer. The introducer may also be divided into sections in centimeters, i.e., markings at regular intervals may be made from radiopaque material. Furthermore, it may include a removable steel core (e.g., 210 mm in total length) that is slightly longer than the introducer and has a sharp tip, and may include a Luer lock connector. A preferred material for the catheter body is GRILFLEX® ELG6260 (PEBA). Finally, the catheter terminates with a cross-section perpendicular to the axis.

[0143] Figure 10A shows a catheter 1002, an introduction device 1004, an introduction device core (not shown), and a needle 1006. 90 This is a photograph of another exemplary kit 1000 that may be used for the delivery of a Y-matrix composition. To perform the procedure, the introducer 1004, along with its core, is positioned using ultrasound, CT, or MR imaging guidance. After removing the core of the introducer 1004, the needle 1006 is inserted through the introducer 1004. Any biopsy or other ablation procedure may be performed through the needle 1006. After the diagnostic and / or therapeutic procedure is performed, the needle 1006 is removed, the catheter 1002 is inserted into the introducer 1004, and a multi-chamber sealant injector (not shown) is attached to the catheter 1002. The injector-catheter combination is then withdrawn from the tissue pathway while the sealant is injected along the tissue pathway.

[0144] The distal end 1008 of the needle 1006 has a sharply angled tip and is preferably visible under ultrasound. For example, the needle cross-section may be 16G, i.e., corresponding to an outer diameter of 1.60 mm and an inner diameter of 1.20 mm, and the tip may be made of AISI304 and be visible under ultrasound. The proximal hub 1010 of the needle 1006 may have an attached Luer lock distal connector 1012 with, for example, transparent ABS TERLUX® TR2812. The preferred length of the needle shaft 1014 is 200 mm, and the shaft 1014 is configured to be inserted into the introducer 1004. The introducer 1004 may have a GRILAMID® L25 shaft with an optional tapered distal tip. The inner diameter of the introducer 1004 is approximately 1.70 mm, while the length of the introducer 1004 is preferably slightly longer than the needle 1006, for example, 210 mm, or 1 mm to 20 mm, 5 mm to 10 mm, or 5 mm to 15 mm longer than the needle 1006. In other embodiments, the inner diameter of the introducer may be in the range of 0.8 mm to 2.2 mm, or 1 mm to 2.2 mm, or it may be able to accommodate catheters or needle shafts of 12 G to 18 G size.

[0145] Figure 10B shows magnified images of the catheter 1002, the inlet 1004, and the proximal hubs 1016, 1018, and 1010 of the needle 1006, respectively, with the needle 1006 inserted into the inlet 1004 so that the proximal needle hub 1010 engages with the proximal inlet hub 1018 via complementary Luer locks 1012, 1022. The proximal hub 1016 of the catheter 1002 has two ports 1024, 1026 configured to attach to the two ends of a dual-chamber syringe (not shown). Figures 10C and 10D show longitudinal cross-sections of the catheter 1002 with a male Luer lock connector 1028 compatible with the female Luer lock connector 1022 of the inlet 1004, respectively. This configuration allows both the needle 1006 and the catheter 1002 to be releasably locked to the introducer 1004 when inserted into the introducer 1004. The introducer 1004 may also include a shaft 1030 having a distance scale 1032 visible along its longitudinal length, the shaft 1030 preferably being radiopaque and, for example, filled with 30% barium sulfate and inserted into a protective polyethylene tube. The catheter 1002 and introducer 1004 are also illustrated with optional handles 1034, 1036 for easier handling during use.

[0146] Before performing minimally invasive treatment, the kit is prepared so that the introducer is first inserted with a diameter corresponding to the catheter selected according to the procedure to be performed, and placed under ultrasound guidance, CT, or MRI scanning. After the core of the introducer is removed, a coaxial double-lumen catheter is then inserted to fill the treatment area and, if necessary, the area reached by the introducer, and the compound is administered as needed. The introducer is then gradually removed to release the compound, including through the introducer's pathway. This ensures effective function, ease of administration, drug conservation, and avoidance of additional invasive procedures for delivering anticancer drugs from outside. The above elements and features can be combined in various preferred embodiments without departing from the scope.

[0147] Example 4: Test using pigs In another animal study, eight large white sows weighing 75±5 kg, selected from special farms that were free of infection and pre-immunized, were subjected to in vivo glue-injection into three different liver segments or lobes under ultrasound guidance. 90 Y microspheres were injected. In these procedures, 60 / 80 mCi 90 24 mL of glutaraldehyde-crosslinked albumin (BIOGLUE®) containing Y microspheres was administered to the left lobe, right lobe, and right perineal lobe of the inferior vena cava. The veterinarian examined all animals to assess their health status and ensure there were no disease-related symptoms. The animals then underwent 8 hours of preoperative fasting, anesthesia, and blood sampling. Blood samples were taken from the jugular vein a) preoperatively (T0), b) postoperatively, before awakening (T1), and c) before hepatectomy (T2). All pigs were divided into four groups of two animals each, and under general anesthesia, at different times, underwent midline laparotomy, approximately 3.5 cm. 2 The ablation areas were subjected to intraoperative ultrasound identification, treatment of three different liver segments with anticancer compounds, organ removal, and euthanasia. Group 1 was euthanized 7 days after treatment, Group 2 14 days later, Group 3 21 days later, and Group 4 28 days later. The removed livers were then used for macroscopic and microscopic evaluation.

[0148] After treatment, all the pigs were moved to an animal facility and monitored daily. The facility environment complied with current regulations, and all animals were allowed to move around freely and "free-feed."

[0149] Figures 11A-F, 12A-F, and 13A-F are PET / SPECT images of three different pig livers excised at 7 days, respectively. Blood samples taken from the pigs according to the timing indicated in the protocol showed no significant abnormalities in blood coagulation parameters. The results of the anatomical and pathological evaluations of the excised livers are shown in the table below. 90 This shows the characteristics of the ablation region at different post-injection periods for the Y-matrix composition.

[0150] [Table 7]

[0151] [Table 8]

[0152] [Table 9]

[0153] [Table 10]

[0154] [Table 11]

[0155] [Table 12]

[0156] [Table 13]

[0157] [Table 14]

[0158] The above analysis shows the stable ablation area at each treatment site and each evaluation time point. The mean ± SD area of ​​necrosis (cm²) was evaluated histopathologically. 2 )teeth, 90 The values ​​were 18.8±3.7, 20.5±2.8, 19.2±2.1, and 20.5±2.0 one, two, three, and four weeks after injection of the Y-matrix composition, respectively.

[0159] Acute systemic toxicity tests, intradermal reactivity tests, and delayed-type hypersensitivity tests were performed on the test animals. 90The safety of administering the Y-matrix composition was investigated. The results observed in test animals were very similar to those of the control group. No symptoms were detected in the acute systemic toxicity test. No erythema or mild erythema was detected in the intradermal reactivity test, and no visible changes were observed in the delayed hypersensitivity test.

[0160] moreover, 90 Partial non-biodegradability of Y-matrix compositions and 90 Considering the decay time of Y, subcutaneous in male albino rats 90 The local and systemic effects of the Y-matrix composition were evaluated 26 and 52 weeks after implantation. Regarding local effects, no abnormalities were detected in macroscopic evaluation or autopsy at all transplanted sites. The mean final response index for the treatment and control groups was calculated using histological evaluation. At 26 weeks, the indices were 1.5 and 1.8, respectively (0.0–2.9 indicates minimal or no response), and at 52 weeks, they were 3.5 and 4.2, respectively (3.0–8.9 indicates a mild response).

[0161] Regarding the effects on the whole body, 90 The Y-matrix composition did not produce any significant difference compared to the control when the following parameters were evaluated: tissue structure, cell hypertrophy, necrosis, inflammatory cell population, atrophy, edema, congestion, fibrosis, and vasocongestion.

[0162] No significant abnormalities in blood or liver parameters were observed in blood samples collected from the test animals at different time points. 90 No effects of radioactivity were detected in complete blood cell counts (CBC) after administration of the Y-matrix composition.

[0163] Based on the above results, and considering that the ablation size is in the range of 3.7–5.3 cm in length and 4.0–5.0 cm in width, and there are no side effects on organs or bone marrow, the use of a local approach to the treatment of liver lesions is suggested to be potentially useful and appropriate in human treatment.

[0164] Example 5: Test using rabbits In other animal studies, for the treatment of unresectable primary or secondary solid tumors, and / or to prevent or delay local recurrence after resection with positive margins, and to confirm the efficacy and safety of the procedure, 90 Intratumoral injection and / or intraoperative local application of a hydrogel matrix containing Y was used. In one study, 90 Seventy New Zealand rabbits with induced pararenal tumors were treated with the Y Microsphere-BIOGLUE® composition. For the tumor transplantation procedure, the rabbits underwent laparotomy from the xiphoid process to the umbilicus. Blunt dissection was used to expose the peritoneum through the avascular linea alba. Careful incision of the peritoneum allowed exploration to the right renal fossa of the peritoneal cavity, where a single VX2 tumor (approximately 5 mm) was found. 3 Transplantation was performed using these cells. The VX2 tumor cells originated from skin cancer in cottontail rabbits, but it was later found that these cells could be transplanted into all strains of domestic rabbits and were used in human cancer trials for various solid tumors, including lung, bladder, mammary gland, kidney, and liver.

[0165] Paranephroma progression was tolerated for two weeks, and repeated renal ultrasonography, initiated one week after tumor cell transplantation, was used to monitor the tumor diameter until it reached approximately 2 cm. At the end of this period, a right nephrectomy was performed via a second laparotomy. The tumor derived from the VX2 transplant was excised, leaving a residual tumor mass less than 1 cm thick. At autopsy, after complete removal of the residual tumor mass, the area was marked with a small surgical clip to facilitate tissue identification. At the end of the two-week tumor graft growth period and after the partial tumor resection described above, 46 animals were randomly assigned to one of the following groups to evaluate the safety, efficacy, and biodistribution of each treatment. a) 22 rabbits 90 Group A, treated with Y-matrix composition: Of these animals, 6 were euthanized under general anesthesia after 1 week, 8 after 2 weeks, and 8 after 3 weeks. b) 15 rabbits 90Y- was assigned to monotherapy (Group B). Here, 185 MBq was administered with each dose. 90 Y microspheres (in 1 mL of physiological saline) were used. Five of these animals were euthanized under general anesthesia after one week, and the remaining ten were euthanized after two and three weeks, respectively. c) Nine rabbits were assigned to treat localized carriers alone (Group C). Here, 0.3 mL of a bovine serum albumin / glutaraldehyde mixture (in 1 mL of saline) was used. Three of these animals were euthanized under general anesthesia after one week, and the remaining six were euthanized after two and three weeks, respectively.

[0166] Tumors were injected with their randomly assigned compositions and observed over time. They were collected 1, 2, and 3 weeks after treatment. 90 Y-matrix composition, 90 Residual neoplastic lesions were excised from all animals treated with either Y- monotherapy or a localized carrier monotherapy, and examined macroscopically and microscopically. The volume of the excised tumor mass was calculated as volume = 1 / 2 (length × width). 2 The calculations were performed according to the formula ). The collected specimens were fixed with 4% PFA solution after PET / CT scanning (described in more detail below), cut by cryostat (slice to a thickness of 5 μm), stained using the standard hematoxylin and eosin method, and analyzed by a blinded pathologist to confirm necrosis of the target tissue against the original treatment. For residual tumors in groups A and B 90 To evaluate Y-induced necrosis, p53 protein (necrosis marker) expression was detected by Western blot (WB) analysis of protein lysates collected from animals sacrificed at each time point. β-tubulin was used as a control marker. Liver enzymes (ALT, AST, GGT, alkaline phosphatase), bilirubin, and complete blood count (CBC) were performed at baseline. Subsequently, blood tests were performed every 7 days before the animals were euthanized, and blood was collected from the hearts of anesthetized animals.

[0167] As mentioned above, one week and three weeks after the surgery, 90 Y-matrix composition and 90 Animals treated with Y- alone were sacrificed under general anesthesia and immediately subjected to PET / CT imaging. These evaluations checked not only the diffusion and uniform distribution of the radioactive material within the target lesion, but also the potential for dispersion of the injected compound in the rest of the target organ and other areas of the body. In fact, after the PET scan, selected organs were removed from the animals. 90 A detailed in vivo distribution analysis of Y was performed. The organs removed included the brain, thyroid gland, muscles, trachea, bronchi, right lung, heart wall, lymph nodes, liver, gallbladder, spleen, small intestine, colon, pancreas, peritoneum, right adrenal gland, testes, left kidney, right kidney, bladder, skin, bone, and tumor lesions. The weight of the above organs was measured and expressed as counts per minute (CPM) in the β-release absorption spectrum. 90 Activity Y was detected for each of these via a Geiger-Müller counter.

[0168] The data was stored in a Microsoft Excel 14.1.0 database. GraphPad Prism6 was used for mean ± SD graph plotting. Descriptive statistics were used for baseline variables, and statistical significance was confirmed using the unpaired Mann-Whitney test. Where shown, the coefficient of variation, expressed as a percentage, was calculated as the ratio of the standard deviation to the mean, by multiplying the result by 100.

[0169] The antitumor effect is, 90 It was found that the necrosis of treated tumors was directly proportional to the exposure time to the Y Microsphere-BIOGLUE® composition, with an average of 10% necrosis on day 7, an average of 30% necrosis on day 14, and an average of 90% necrosis on day 21. The results of this study were found to be beneficial after nephrectomy. 90 Histological examination of the margins of resected tissue treated with a Y-microsphere hydrogel mixture showed that nearly complete necrosis of viable VX2 cancer tumor cells was observed 21 days later.

[0170] Figures 14A, 14B, and 14C show the hydrogel matrix and after nephrectomy. 90 Figure 14A shows the histological analysis of resected tissue with positive margins treated with Y-microspheres at 7, 14, and 21 days, respectively. Figure 14A shows that the percentage of necrotic cells was 70% 7 days after treatment, while Figure 14B shows that the percentage of necrotic cells was 90% 14 days after treatment, with arrows indicating the area of ​​necrosis.

[0171] In comparison, hydrogel or 90 Tissue from the resection site of animals treated with Y microspheres alone showed palpable macroscopic tumor growth, and histological examination revealed the presence of viable VX2 cancer cells at 7, 14, and 21 days. Figures 14D-14F show nephrectomy and 90 Figures 14G to 14I show tissue with positive margins from tumor beds treated with Y microspheres alone at 7, 14, and 21 days, respectively. Figures 14D to 14F show tissue with positive margins from tumor beds treated with hydrogel alone after nephrectomy at 7, 14, and 21 days, respectively. 90 This shows that the percentage of necrotic cells at 7, 14, and 21 days after injection of Y microspheres alone was 20%. Histological slides in Figures 14G to 14I show that the necrotic area after hydrogel treatment was less than 5%, and viable tumor cells were observed. The percentage of necrosis was quantified by histological evaluation performed after H&E staining of the collected residual tumor. In Figure 14J, 90 The group treated with the Y-matrix composition and 90 Both the Y- monotherapy group and the matrix monotherapy group were statistically significantly more effective than the matrix monotherapy group in inducing necrosis at each time point (*=p<0.05, **=p<0.005, ***=p<0.0005, ***=p<0.0005, Mann-Whitney test). Furthermore, after 3 weeks, 90 Rabbits treated with the Y-matrix composition showed higher necrosis than any of the other treatment groups (***=p<0.0005, Mann-Whitney test).

[0172] The Western blot analysis shown in Figure 15 further indicates an increase in the expression of the p53 protein, a marker of tumor necrosis, which was detected particularly at the 3-week observation period and is consistent with the increase in necrosis detected by histological evaluation in the test group.

[0173] Tumor volume was also compared at the point of selection, as shown in Figure 16. This comparison was used to evaluate the ability of each treatment group to slow or inhibit tumor growth. 90 Y-matrix composition and 90 Both Y- monotherapy groups were significantly more effective than matrix monotherapy in inhibiting tumor growth at 2 weeks (**=p<0.005, Mann-Whitney test). However, even more surprisingly, at 3 weeks, 90 Rabbits treated with the Y-matrix composition showed a statistically significant reduction in tumor volume compared to any of the other treatment groups (*=p<0.05, Mann-Whitney test). 90 Y-matrix composition therapy 90 It was not expected that this treatment would outperform Y- alone.

[0174] 90 Y-matrix composition and 90 In excised tissue of rabbits treated with Y-alone (without matrix) 90 The total level of Y is as follows: [Table 15]

[0175] moreover, 90 The system described in this study for administering the composition to the excision bed by applying a hydrogel matrix containing Y microspheres, using the same activity level, 90 This represents a multimodal approach to treating solid tumors that is expected to achieve higher counts than Y injection alone.

[0176] Depending on the viscosity and density of the hydrogel matrix (hydrogel), the hydrogel mixture can be injected directly into the excision site or applied in layers for uniform distribution. 90 Increased local concentration of radioactive Y agent, prolonged retention in situ, and 90 Ensuring that Y-sphere dispersion is minimal or nonexistent, and therefore potentially limiting systemic side effects.

[0177] Through this examination, 90 High concentration in a matrix equipped with Y 90 Y level is, 90 Compared to the treatment of rabbits injected with Y-spheres alone, the effects lasted longer at the injection site and achieved complete destruction of residual tumor cells (with positive margins) in our animal model.

[0178] These results 90 The use of a combination of Y microspheres and hydrogels 90 Compared to administration of Y microspheres alone, high concentrations over a long period of time 90 Achieve Y and a uniform distribution, thereby treating tumor cells in animal models. 90 Compared to animals that received Y-single, 90 This study demonstrates that Y-matrix therapy may potentially reduce the relative risk of local recurrence in animals treated with it. Furthermore, 90 Evaluations performed on animals treated with Y-matrix showed that, compared to controls, blood radioactivity levels, bone marrow suppression, renal, cardiac, and pulmonary toxicity, and 90Y No intestinal perforation or bleeding associated with the diffusion of microspheres was observed. 90 This is in contrast to the findings observed in animals that received Y-single therapy.

[0179] In the initial evaluation, three rabbits 90 Y microspheres are injected into the target site, and a beta counter is used to measure the whole body. 90The distribution of Y was quantified. Figure 17A shows that there was little residual activity at the target site in each rabbit, and that some activity was detected in all organ sites, but significant activity was concentrated in the spleen, small intestine, peritoneum, and adrenal gland of at least some animals. In contrast, as shown in Figure 17B, at the same site... 90 In rabbits injected with Y-matrix, activity was detected only at the target site, while activity was negligible or not detected at all in other organ sites.

[0180] Further analysis of the rabbits registered in this study revealed that 90 Y-single group and 90 In the Y-matrix group, in the selected organs 90 The distribution of Y was evaluated on day 7 and day 14. The results are shown in Figures 17C to 17F. As shown in Figure 17C, on day 7, additional 90 Significant activity was detected in the tumor site of a single rabbit, but significant activity was also detected in the bronchi and pancreas of a single rabbit, as well as in other sites such as lymph nodes, liver, gallbladder, small intestine, colon, peritoneum, and bladder. In contrast, as shown in Figure 17D, on day 7... 90 Y-matrix rabbits showed significantly higher activity at tumor sites, while other selected organ sites showed minimal or no detectable activity. Day 14, 90 In Y-matrix rabbits, activity at tumor sites was reduced but still significant, while activity at other selected sites remained minimal or undetectable (Figure 17F). On the other hand, on day 14... 90 In rabbits with Y-isolated chromosomes, activity at the tumor site was significantly reduced, 90 Y was further redistributed to other organ sites. This included areas where no activity was detected on day 7 (Figure 17E), including the brain, thyroid, muscles, trachea, right lung, spleen, right adrenal gland, testes, right kidney, skin, and bone. This data, 90This suggests that the Y-matrix not only achieves a higher level of treatment at the tumor site, but also significantly suppresses delayed in vivo distribution to non-target organs that can occur between days 7 and 14.

[0181] The presence of radioactive isotopes within the tumor region was analyzed by PET / CT imaging at 1 week and 3 weeks. 90 Y activity was assessed in the injection area and in other anatomical compartments using a Geiger-Müller counter. 90 The radiation intensity results for Y are shown in Figures 24A and 24B, respectively, at both 1 week and 3 weeks. 90Y -Compared to rabbits treated alone, 90 Rabbits treated with the Y-matrix composition showed reproducible high levels at the tumor injection site (p<0.05, Mann-Whitney test). The same analysis was performed on pre-identified distal organs at both 1 and 3 weeks (Figures 24A and 24B, p<0.05, Mann-Whitney test). 90 Compared to rabbits treated with Y-alone, 90 In rabbits treated with the Y-matrix composition, a much lower, almost undetectable signal was observed. Detection was observed in distal non-target organs (non-tumor). 90 Based on the total amount of Y signal, 90 Y-matrix composition therapy was effective at all time points evaluated within the tumor injection site. 90 It was shown to be very effective in retaining the Y signal (Figure 25A and B, p<0.0005, Mann-Whitney test). As expected, at 3 weeks 90 The tumor injection site signal for Y-matrix composition therapy was significantly lower than the same signal one week after compound injection. 90 Y-monotherapy in the target injection site 90 The effects on retaining Y activity were far from equivalent. A comparison of the coefficient of variation (CoV) of activity levels detected in tumors and non-tumor target areas showed that both approaches were incompatible at both time points. 90 Compared to Y-monotherapy, 90We confirmed significantly lower variability (i.e., higher reproducibility) in Y-matrix composition therapy. 90 In the Y-matrix composition treatment group, the incidence of CoV in tumor sites was 5.69% and in non-tumor sites was 14.33% at 1 week. At 3 weeks, the incidence of CoV in tumor sites was 1.89% and in non-tumor sites was 29.56%. 90 In the Y-monotherapy group, at 1 week, CoV in tumor sites was 136% and in non-tumor sites was 156.18%. At 3 weeks, CoV in tumor sites was 199.87% and in non-tumor sites was 175.38%.

[0182] These results 90 Y-matrix composition therapy can not only significantly reduce the incidence of side effects or serious adverse events by localizing the effects of radiotherapy and reducing or minimizing local and distant leakage through the shunt, but also, via the same pathway, 90 Compared to patients treated with Y-monotherapy or transarterial radioembolization, 90 This suggests that the Y-matrix composition may potentially increase disease-free progression and / or survival rates in patients treated with it. Furthermore, 90 In the treatment of human patients, where a wide range of pre-treatment workflows and assessments are required before Y radiation therapy can be administered, 90 Y-matrix composition therapy can reliably reduce the risks associated with hepatopulmonary shunts or other extratarget shunts. As a result, some or all of the pre-treatment workflow may be unnecessary or not performed. For example, in other variations, 90 Y-matrix composition therapy may be provided without requiring any shunts to the liver or lungs, or prior therapeutic imaging (e.g., technetium-99 scans) to evaluate sites other than the target site associated with varicose veins or arteriovenous malformations. This is achieved via a shunt localized by a localization carrier. 90This is due to the reduction or minimization of Y leakage. As a result, prior treatment imaging is not required to evaluate shunts, and therefore prior treatment procedures to treat potential shunts are also not required. This may shorten the time to initiation of treatment by one, two, three, four, five, six, or even seven days or more, because treatment is not delayed by prior treatment shunt imaging, prior treatment shunt reduction procedures, and prior treatment rescans to evaluate the effectiveness of shunt reduction procedures. Shunt procedures that may no longer be required or performed may include arterial embolization, hepatic vein balloon occlusion, and varicose vein and AVM occlusion. Since dose adjustments to account for shunts are no longer required, dose calculations can also be simplified, for example, by eliminating the need for adjustments based on shunt percentage and / or pulmonary dose limits. Patients with a high percentage of hepatic, pulmonary, or hepatopulmonary shunts no longer need to be excluded from treatment. One or more of these features may be included in the various treatments described herein in tumor treatment protocols.

[0183] Example 6: Breast cancer With the increasing incidence of microscopic, asymptomatic lesions detectable radiologically, several research teams in the 1990s began to consider most DCIS diagnoses as potentially being a "slowly progressive disease," arguing that mastectomy alone could be the first-line treatment for patients with solitary, small-diameter DCIS lesions. Until a few years ago, the standard treatment involved irradiating the entire breast with 50 Gy in 25 fractions over five weeks. However, the publication of long-term results from important randomized controlled trials in the UK and Canada demonstrated the effectiveness and efficiency of shorter treatment plans (smaller fractionation radiotherapy). DCIS is usually undetectable by palpation. With the widespread use of screening mammography, the number of DCIS diagnoses has increased, and it now accounts for 20-30% of all breast cancers detected by mammography.

[0184] More than two-thirds of women diagnosed with DCIS are treated with breast-conserving surgery (BCS), with or without adjuvant therapy. The ipsilateral recurrence rate for women who undergo BCS for DCIS is 1-3% per year, and while the long-term local recurrence rate can exceed 35% with surgery alone, adding external beam radiation therapy significantly reduces the recurrence rate (15% at 10 years). Several factors contribute to an increased risk of local recurrence after BCS, the strongest of which is whether the DCIS was completely excised.

[0185] 1. The risk is much lower for surgical margins that are free of cancer or more than 1 mm away from the cancer. If cancer is found at the margin, the patient should undergo a new surgery to achieve curative treatment. This can occur in about 20% of patients.

[0186] 2. Intraoperative radiotherapy (IORT) is an alternative to postoperative whole breast irradiation, involving a single dose of 16-20 Gy of radiation after surgical excision, allowing the treatment to be completed on the same day.

[0187] 3. Recent trials, such as the ELIOT trial comparing intraoperative electron beam radiotherapy with external beam radiotherapy for early-stage breast cancer, and the TARGIT-A trial comparing targeted intraoperative radiotherapy with whole breast irradiation for breast cancer, have demonstrated that IORT in specific selected groups of low-risk early-stage breast cancer patients yields acceptable outcomes in terms of local lesion control and therefore can serve as a viable alternative to conventional WBRT, representing a good compromise between treating all patients with external beam radiotherapy and treating all patients without treatment.

[0188] In a 2017 consensus statement on accelerated partial breast irradiation issued by the American Society for Radiation Oncology (ASTRO), several recommendations were provided regarding the selection criteria for “appropriate” low-risk DCIS patients. 90 Based on 15 years of clinical experience accumulated through transarterial injection of Y-coated microspheres, appropriate treatment of the excision site of the excised breast tissue. 90It is reasonable to assume that the administration of Y activity overcomes some of the limitations of WBRT and IORT and should dramatically reduce the likelihood of local recurrence occurring at the resection site in most cases. Based on the data available in the literature, a target dose of 20 Gy (≥18 Gy) appears to be sufficient to effectively ablate the tissue surrounding the resection site of the resected DCIS lesion.

[0189] In one embodiment, 90 Clinical trials were conducted regarding the use of Y-matrix compositions. 90 The Y-matrix composition includes a combination of BIOGLUE® and SIR-SPHERES® equipped with Yttrium-90. In this test, 90 Microspheres pre-loaded with Y were mixed with surgical glue for radioablation of surgical margins after mastectomy of DCIS. This study was a multicenter, non-inferiority, pre-market, first-in-human pilot study in patients with biopsy-diagnosed mastectomy of DCIS who were eligible for breast-conserving surgery. The primary objective of this study was to evaluate the ability to reach the resection bed for DCIS resection as planned and to deliver a specified dose without clinical complications that limit the treatment. Alternatively, the primary objective was to evaluate the ability to deliver an absorbed dose of 20 Gy (≥18 Gy) for radioablation of surgical margins after DCIS resection. 90 The performance of the Y-matrix composition may also be evaluated. A secondary objective of this study is to evaluate the performance of the Y-matrix composition through imaging diagnostic procedures (PET-CT and DW-MRI). 90 The objectives were to evaluate the performance of the Y-matrix composition, assess local and systemic toxicity, and evaluate the quality of life of registered patients after DCIS resection. 90After radioablation of surgical margins with a Y-matrix composition, subjects will be followed up for 1 to 3 months. However, this study will be considered complete for each subject after magnetic resonance-diffusion-weighted imaging or mammography. The total study period per patient is 15 weeks, and the enrollment period is 6 months. The primary endpoint of this study is the ability to reach the resection bed for DCIS resection as planned and to deliver the prescribed dose without clinical complications that limit the treatment. Secondary endpoints include (1) surgical resection of the segment containing the lesion, 90 (1) the volume / extent of surgical margin tissue ablated by the use of the Y-glue matrix composition (measured by PET-CT (positron emission tomography-computed tomography) 2–6 hours and 24 hours postoperatively, as well as mammography or (if available) magnetic resonance-diffusion weighted imaging (MRI-DW, day 30)); (2) the safety of the procedure, determined by vital signs, clinical examinations, the type and severity of adverse events and / or device malfunctions or usability associated with the postoperative radioablation procedure; and (3) the quality of life of enrolled patients, measured by the EORTC QLQ-C30 and BR23 questionnaires.

[0190] The sample size is 10 to 20 subjects. In a further embodiment, with a sample size of 20 subjects, a one-sided (alpha=0.025) one-sample test can be used to achieve 80% power to detect the non-inferiority primary endpoint. This FIH trial is 90 We are exploring the performance and safety of Y-matrix compositions. 90 The effect of 20 Gy delivered locally by the Y-matrix composition is considered reasonable by examining the results of similar studies. Non-inferiority margins of 18 Gy have been assessed as clinically significant, and a standard deviation of 3 Gy has been assumed. Sample size estimation was performed using SAS version 9.4.

[0191] The inclusion criteria for this study are as follows: - Female subjects, aged 50 and over - Subjects who have breast DCIS diagnosed by biopsy, are eligible to undergo BCS, and are "appropriate" for partial breast irradiation according to the latest ASTRO guidelines (age 50 years or older, low to moderate nuclear typia, excised with negative margins of 3 mm or more, Tis, size ≤ 25 mm). - Subjects who may receive subsequent external beam radiation therapy (EBRT) if deemed appropriate by the treating physician; - Subjects with evidence of DCIS by mammography or contrast-enhanced magnetic resonance imaging; - Subjects with localized DCIS (3 mm or larger and 25 mm or smaller) located in a position accessible for percutaneous ablation; - Subjects with clinically negative axillary lymph nodes and no clinical findings suggestive of invasive breast cancer.

[0192] The exclusion criteria for this examination are as follows: - Female subjects, aged 50 and over - Subjects with a histological type different from carcinoma; - Subjects with Paget's cancer; - Subjects with lesions (15 mm or less) located in the axillary region or near the skin region; - Subjects with the presence of microcalcifications extending beyond 30 mm; - Subjects who are pregnant or breastfeeding; - Subjects with a history of positive tumors (excluding some carcinoma in situ or skin cancers that have been surgically removed without signs of disease progression in the past 15 years, and contralateral breast cancer).

[0193] Each subject underwent imaging tests, and DCIS lesions were diagnosed and the disease stage determined as follows: - Following the resection of the target lesion, the resection site is treated with radiation ablation using an experimental device; - To achieve ablation, an appropriate absorbed dose of 20 Gy (18 Gy or more) is administered to the excision site following DCIS resection; - Within 7 days after the surgical procedure, the patient should have a resection site. 90The patient will visit the facility for evaluation of the volumetric effects of administering the Y-matrix composition, as well as for evaluation of its cosmetic properties and toxicity; - 30 (±5) days later, the excision site treated with radioablation is examined using magnetic resonance diffusion-weighted imaging or mammography to assess the extent of ablated tissue.

[0194] Optionally, additional patient evaluations and clinical clearance will be conducted for the first five patients. Clinical clearance will include review of follow-up data for at least one week if there are no complications, and four weeks if complications are present. This will include review of unplanned contact with patients, if conducted.

[0195] Once a DCIS diagnosis is confirmed and the inclusion / exclusion criteria are met, subjects will be enrolled in the study and admitted to the hospital the day before the scheduled surgery, following standard clinical practice. On the day of surgery, subjects will undergo DCIS resection in addition to other procedures requiring collaboration between surgeons and nuclear medicine specialists. 90 The subject will undergo excision bed ablation using a Y-matrix composition. After the treatment, the subject will return to the surgical ward and be discharged the day after the surgery / ablation procedure. The subject will be followed up at 7, 30, and 90 days after surgery to assess their local and general condition. At the end of the follow-up, if the treating physician deems it appropriate, the subject may receive additional external beam radiation therapy.

[0196] Participants will be informed of the purpose of the study, the procedure, and the potential risks, and will be required to sign an informed consent form. Each screened participant will be identified by a sequential screening number. Participants will only be enrolled after signing an informed consent form and before any other study procedure. All patients followed up at the study site will be checked for compliance with the inclusion and exclusion criteria. One or more of the following information will be collected, but the information does not need to be collected in the same exemplary schedule. [Table 16-1] [Table 16-2]

[0197] If all inclusion criteria are met, the patient will be seen one week after screening. 90 Ablation procedures using a Y-matrix composition are planned. Each patient will be followed up for adverse events and adverse effects throughout the entire trial period from the date of informed consent signing. Blood samples will be collected at each trial visit for the following hematological and biochemical tests: - Complete blood count including white blood cell differential - Protein electrophoresis fractionation - APTT - INR - Fibrinogen - Blood sugar - Blood urea nitrogen (BUN) - Creatinine - AST, ALT, total bilirubin and fractionated bilirubin, GGT, LDH, alkaline phosphatase - Serum ions: sodium, calcium, potassium, chloride - Tumor marker (AFP)

[0198] V0 90 Blood sampling to detect early blood disorders 1, 3, 6, and 12 hours after delivery of the Y-matrix composition: - Complete blood count including white blood cell differential - AST, ALT, total bilirubin and fractionated bilirubin, GGT, LDH, alkaline phosphatase

[0199] All data concerning study subjects will be presented appropriately using descriptive statistics such as mean, standard deviation, median, minimum, maximum, or frequency table. For the primary endpoint, a 5% confidence interval (CI) will be estimated, and non-inferiority will be tested by comparing the lower limit of the CI to the non-inferiority margin. Secondary endpoints include assessment of quality of life (measured by the EORTC QLQ-C30 and BR23 questionnaires), assessment of the volume / degree of ablated surgical margin tissue (measured by PET-CT and mammography or magnetic resonance-diffusion-weighted imaging), and 90 This includes demonstrating the safety profile of the Y-matrix composition. Quality of life questionnaire scores, the volume / degree of ablated surgical stump tissue, and their changes over time are assessed using descriptive statistics. 90 The incidence of adverse events, considering their relationship to Y-matrix composition, is calculated for all patients, along with their severity and severity. Safety assessment consists of recording and summarizing all adverse events, as well as analyzing changes in vital signs and clinical laboratory parameters. Descriptive statistics are provided for safety variables.

[0200] In one example procedure, a BIOGLUE® syringe size of 2 mL or 5 mL is selected based on the tumor size(s) or total volume(s) determined in a pre-procedure workup. 90 The Y-matrix composition is prepared during pre-procedure setup as follows: 1. Unpack the SIR-SPHERES® microspheres and leave the transport vials in the lead pot. 2. If available, place it in a lead or acrylic shielded box and put it on the benchtop. 3. Remove the vial for transporting SIR-SPHERES® microspheres from the lead pot and shake vigorously to disperse the SIR-SPHERES® microspheres. 4. Determine the activity inside the transport vial using a dose calibrator such as a gamma camera, and return it to the lead pot. 5. Determine the volume to be withdrawn to provide the patient with the required radiation dose. The table below shows the activity values ​​of SIR-SPHERES® injected into 2 mL or 5 mL BIOGLUE® syringes, depending on the radius of the tumor bed. To calculate the activity, a vial of SIR-SPHERES® containing a dose of 3 GBq / 5 mL was considered. Furthermore, it was assumed that 300 microliters of residue would remain in the BIOGLUE® syringe at the end of treatment for the patient. The table also shows the volume of SIR-SPHERES® to be added to the BIOGLUE® syringe in a 1:4 (glutaraldehyde:bovine albumin) ratio, using 2 mL / 5 mL syringes, respectively. For tumor sizes with a radius of less than 50 mm, assuming a 2 mL syringe is selected, SIR-SPHERES® and BIOGLUE® are uniformly mixed, the maximum volume of mixture is dispensed, and a nominal 300 μL of mixture residue remains in the syringe, the following applies: [Table 17]

[0201] For tumor sizes of 50mm to 70mm or larger in radius, assuming a 5mL syringe is selected, SIR-SPHERES® and BIOGLUE® are uniformly mixed, the maximum volume of mixture is dispensed, and a nominal 300μL of mixture residue remains in the syringe, the following applies: [Table 18] 6. Partially remove the aluminum seal from the SIR-SPHERES® microsphere transport vial and clean it with an alcohol swab. 7. Insert a 25-gauge needle into the partition of the transport vial to create a vent, ensuring that the needle is sufficiently far from the contents of the transport vial. 8. Using a shielded 5 mL syringe equipped with a 20-22 gauge spinal needle at least 70 mm in length, puncture the septum of the SIR-SPHERES microsphere transport vial and quickly pull and push back to thoroughly mix the SIR-SPHERES microspheres. 9. Rapidly withdraw the patient's pre-calculated radioactive dose and transfer it to the two chambers of the BIOGLUE® syringe as described in items 10-13 below. 10. Remove the cap from the double-chamber syringe containing the glue ingredients. 11. Dispense the microspheres into the glue double-chamber syringe, adhering to a 4:1 ratio (80% into the BSA chamber and 20% into the glutaraldehyde chamber), as reported in the previous table. 12. Reinsert the cap into the syringe. 13. Verify the patient's dose by remeasuring the activity in the transport vial using a dose calibrator, and adjust it if necessary. 14. Place the syringe in a radiation-shielded container suitable for transport to the operating room / radiology room. 15. In the operating room / radiology room, 90 A prepared syringe / injector system equipped with Y is removed from the radiation shielding container. 16. The sterile package containing the mixing tip is opened. 17. Hold the syringe upright and tap it until the air bubbles in the liquid rise to the top of the syringe. 18. Connect the sterile mixing tip applicator contained in the glue package. 19. Shake the syringe briefly. 20. Press the plunger of the syringe against the resection cavity to apply the compound. 21. Wait for the compound to polymerize (for example, wait a few seconds). 22. Proceed to suturing the area in question.

[0202] The actual amount injected is determined by the nuclear medicine specialist performing the radiation ablation procedure, according to the size of the surgical resection area (tumor bed) to be ablated and their clinical judgment.

[0203] For the ablation procedure, the patient undergoes preparation according to the standard procedures of the treatment facility. The patient is prepared, draped, and anesthesia is achieved using standard sterile methods. The target area is identified by the surgeon during the procedure using appropriate markers / inks.

[0204] For dose assessment, assuming negligible or absent leakage of radioactive tracers, two PET / CT scans of the breast region are taken. The first scan is performed between 2 and 6 hours after injection (pi), and the second scan is performed 24 hours after injection. These two scans allow confirmation that the time-time radioactivity curve follows physical decay according to preclinical data. Dose calculations are performed using MIRD formalism (OLINDA / EXM software). In particular, for dose to lesions, the unit density sphere model available in OLINDA / EXM is used, assuming a disc-shaped morphology and uniform distribution.

[0205] To confirm the in vivo distribution of the radioactive tracer, the patient will undergo a single whole-body scan acquired using a SPECT / CT device. This scan will be performed between 16 and 24 hours after injection. This information is useful in confirming that the radioactive tracer remains in the tumor bed.

[0206] After discharge, patients will be followed up for 90 days. Following the post-ablation evaluation (V3), the study will be considered complete for each subject. However, during the follow-up, information on any adverse events that may be related to the radiation ablation procedure will be collected and included in the case report form.

[0207] Adverse events are classified according to established classification systems such as the Common Terminology Criteria for Adverse Events v5.0.

[0208] At the end of the procedure, the needle, syringe, and other components must be disposed of according to the standard operating procedures of the facility for handling biohazardous materials and / or radioactive materials.

[0209] In some of the other variations of breast cancer treatment techniques, 90 Y-matrix composition therapy may be provided without requiring prior therapeutic imaging (e.g., technetium-99 scans) to evaluate other sites besides the target site, including any shunts to the liver or lungs, varicose veins, or AVMs. In some variant forms, prior therapeutic imaging to evaluate shunts is not required, and therefore prior therapeutic procedures to treat potential shunts are also not required. This can shorten the time to initiation of treatment by one, two, three, four, five, six, or seven days or more, as treatment is not delayed by prior therapeutic shunt imaging, prior therapeutic shunt reduction procedures, and prior therapeutic rescans to evaluate the effectiveness of the shunt reduction procedures. Shunt procedures that may no longer be required or performed may include arterial embolization, hepatic vein balloon occlusion, and varicose vein and AVM occlusion. Since dose adjustments to account for shunts are no longer required, dose calculations can also be simplified, for example, by eliminating adjustments based on shunt percentage and / or pulmonary dose limits. Patients with a high proportion of liver, lung, or hepatopulmonary shunts no longer need to be excluded from treatment.

[0210] Example 7: Breast cancer In other exemplary study designs or treatment schemes, patient selection, monitoring, and follow-up are as disclosed with respect to Example 6 above, but the procedure, kit, and / or dosage may differ. In this example, the product is a surgical glue which is itself a combination of bovine serum albumin and glutaraldehyde in a 4:1 ratio, and β-radioactive 90 This includes combinations with microspheres coated with the Y isotope. The kit may further include one or more syringe shielding devices to protect the user from accidental radiation exposure.

[0211] This kit may be indicated for ablation of surgical margins after breast-conserving surgery. However, it is contraindicated in patients with known hypersensitivity to bovine-derived materials or other glue components. An example of a dose regimen using a 2 mL BIOGLUE® syringe in combination with SIR-SPHERES® to achieve a dose of 20 Gy or 18 Gy or more in the tumor bed is as follows: [Table 19]

[0212] In some further embodiments, 90 Filled into a Y-matrix syringe 90 The volume of the Y microsphere solution may be adjusted as follows, based on the nominal decay time (x:00 to x:59 per x-hour) and tumor size. [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26]

[0213] The kits that may be used include: - Two sterile Luer-lock syringes (1 mL each) are provided. - Two sterile 22G needles are provided. - Sterilized needles (e.g., 20G x 70mm), for example, two STERICAN® needles made by B. Braun. - Two radiation-protective syringe holders, e.g., for polymethyl methacrylate (PMMA) cylinders: • One 2mL glue syringe cylinder (Cylinder "A") • One 1mL syringe cylinder (Cylinder "B") - One sterilized radiation shielding box (for transport in OR). Not manufactured by BetaGlue.

[0214] The kit may optionally include the following components, but in other embodiments, these components may be sourced separately: - SIR-SPHERES®, etc., containing 3 GBq+ / -10% in 5 mL of water for injection (WFI), supplied in a lead pot. 90 One vial of Y microspheres - One bottle of two-component glue in a capped dual-chamber syringe (2mL), such as the BIOGLUE® 2mL syringe, provided in a box and other packaging.

[0215] In addition to the kits mentioned above, healthcare providers or facilities authorized or approved to provide radiation therapy may also have the following items available for use during the procedure: - 90 Sterile radiation-shielded boxes or containers for transporting Y microsphere vials - Radiation-protected waste receptacle - 90 Forceps or tongs used to handle Y microsphere vials - Dose calibrator for measuring radioactivity, such as gamma cameras. - Alcohol pads

[0216] As initial preparations for the use of radiation therapy: 1. Open the box containing the glue syringe packaging. 2. Open the packaging containing the glue syringe using a sterile method. 3. Remove the cap from the glue syringe. 4. Place the glue syringe inside the PMMA cylinder (cylinder "A"). 5. 90 Open the lead pot containing the Y microsphere vial and use forceps to remove the vial from the pot. 6. Using a dose calibrator, 90 Measure the radioactivity of the Y microsphere vial and confirm its presence (the measured value should show 3 GBq + / - 10%). 7. Place the vial back into the lead pot. 8. Partially remove any protective material from around the vial and clean the vial with an alcohol pad. 9. 90 Place one 20G needle inside the vial so that it reaches the Y microsphere, and insert one 22G needle into the vial for ventilation. 10. Place the 1 mL syringe into the PMMA cylinder (cylinder "B"). 11. Shake the lead pot in a circular motion for at least 10 seconds. 12. Connect a 1 mL syringe to a 20 G needle and, for a 2 mL glue syringe, add the amount of glutaraldehyde to the glutaraldehyde chamber of the glue syringe according to the amount reported below. 90 Extract the capacity from the Y microsphere. 13. 90 The Y microsphere is injected into the glutaraldehyde component chamber of the glue syringe, and the empty 1 mL syringe is disposed of in the radioactive protective waste box without discarding the PMMA cylinder (cylinder "B") that contained the 1 mL syringe. 14. Place the second 1 mL syringe inside the PMMA cylinder (cylinder "B") and connect the second 20 G × 70 mm needle. 15. Stir or shake the lead pot in a circular motion for at least 10 seconds. 16. Using a 1 mL syringe, prepare the bovine serum albumin (BSA) chamber of the two-component glue syringe according to the amount reported in the table above (for a 2 mL two-component glue syringe). 90Y Extract the amount of microspheres. 90 Adjust the damping component of Y. 17. 90 Inject the Y microsphere into the BSA component chamber of the two-component glue syringe, and dispose of the empty 1 mL syringe with a 20 G x 70 mm needle in the radioactive waste receptacle. Do not dispose of the cylinder shield. 18. Connect the mixing tip to the two-component glue syringe. This will allow you to mix the pre-filled glue and 90 The Y microspheres are contained within the BSA component chamber. 19. Using a dose calibrator such as a gamma camera, 90 Measure the radioactivity of the Y-matrix syringe and place the syringe in a radiation shielding box. 90 The Y-matrix syringe is ready to be moved to the operating room or treatment room.

[0217] The actual amount injected is determined by the nuclear medicine specialist performing the radioablation procedure and may depend on the size of the surgical resection area (tumor bed) to be ablated and clinical judgment. Prior to delivery of the treatment, the system may be further assembled using the exemplary mixing tips described below. 1. Prepared 90 Remove the radiation-shielding PMMA cylinder containing the Y-matrix syringe from the radiation-shielding box, and hold the syringe upright within the PMMA cylinder to maintain an air bubble at the top of the syringe throughout the dispensing procedure. 2. Open the sterile packaging containing the mixing tip and remove the mixing tip from the packaging. Check the color of the mixing tip and ensure that the pointer on the color is directly above the larger of the two connection openings. If the pointer on the color is not above the larger opening, rotate the locking collar on the tip body until the pointer is above the larger connection opening. 3. With the syringe tip held upright, remove the cap. Align the mixing tip with the syringe and attach it. 4. Press the mixing tip firmly into the syringe and lock it in place by rotating the lock collar on the mixing tip. 5. With the syringes upright, align the dual plunger heads with the corresponding larger and smaller syringes. Insert the plunger into the back of the syringe and push until you feel resistance, then optionally recap the syringe.

[0218] 90 Once the Y-matrix syringe is assembled, 90 Y radiation therapy can be administered via the following exemplary procedure. 1. 90Y- With the matrix syringe still inserted into the PMMA cylinder, 90 Stir the Y-matrix syringe for at least 5 seconds. 2. If necessary, 90 Remove the cap from the Y-matrix syringe. 3. Press the plunger to remove air bubbles. 4. Press the plunger and immediately 90 Apply the Y-matrix to the resection cavity. 5. Wait for a predetermined time, for example, 60 seconds, 90 seconds, or 120 seconds, or use an imaging modality such as fluoroscopy, CT, ultrasound, or endoscopy. 90 By observing the phase changes of the Y-matrix, 90 Confirm that the Y-matrix has polymerized. 6. Close the surgical site by suturing, stapling, or bonding. 7. 90 Place the Y-matrix syringe in a radiation shielding container and dispose of it, regardless of whether or not it contains a PMMA cylinder.

[0219] In some of the other variations of breast cancer treatment techniques, 90 Y-matrix composition therapy may be provided without requiring prior therapeutic imaging (e.g., technetium-99 scans) to evaluate other sites besides the target site, including any shunts to the liver or lungs, varicose veins, or AVMs. In some variant forms, prior therapeutic imaging to evaluate shunts is not required, and therefore prior therapeutic procedures to treat potential shunts are also not required. This can shorten the time to initiation of treatment by one, two, three, four, five, six, or seven days or more, as treatment is not delayed by prior therapeutic shunt imaging, prior therapeutic shunt reduction procedures, and prior therapeutic rescans to evaluate the effectiveness of the shunt reduction procedures. Shunt procedures that may no longer be required or performed may include arterial embolization, hepatic vein balloon occlusion, and varicose vein and AVM occlusion. Since dose adjustments to account for shunts are no longer required, dose calculations can also be simplified, for example, by eliminating adjustments based on shunt percentage and / or pulmonary dose limits. Patients with a high proportion of liver, lung, or hepatopulmonary shunts no longer need to be excluded from treatment.

[0220] Example 8: Hepatocellular carcinoma In another test, 90 Microspheres pre-loaded with Y are mixed with a surgical glue matrix for radioablation of primary liver lesions, which are then excised. However, in other variations of the experiment, excision is not necessarily performed after delivery of the radioactive isotope particles. 90 Percutaneous ablation of liver lesions using Y-matrix compositions may be a more effective treatment method that minimizes local or systemic side effects. The use of this novel localized approach is considered appropriate for human treatment based on the following: - Application time: 2-5 minutes, with or without ultrasound guidance; - Ablation size: in the range of 3.8-5.3 cm in length and 4.0-5.0 cm in width; and - No systemic side effects were observed.

[0221] Subjects selected for this study are both ablable (i.e., suitable for percutaneous ablation) and resectable (i.e., determined to be so by a liver surgeon), as indicated in the inclusion criteria. Subjects will be offered surgical resection of early hepatocellular carcinoma (HCC) within the normally expected timeframe (35-40 days after diagnosis / staging). However, by enrolling in this study, they will also be offered minimally invasive percutaneous β-ablation of the lesion 5-10 days after diagnosis. Liver surgery will then be performed approximately 30 days later, but at this point... 90 All Y activities have already disappeared. 90 The half-life of Y is 64.1 hours. Surgical resection removes the entire liver segment containing the ablated lesion, thus allowing for a far more accurate and complete histological examination than any type of imaging currently available for evaluating the outcome of ablation procedures. This type of trial is commonly known as an "ablate-resect" trial and has numerous applications in the medical field. Subjects are, 90 Patients undergo HCC radiation ablation using a Y-matrix composition and are followed up for 2-3 months. The total study period for each patient is 14 weeks, with a registration period of 6 months.

[0222] The primary objective of this study is to evaluate the feasibility of this new technique, while histological evaluation of the resected specimens will provide valuable information regarding its potential efficacy. If the hypothesis that peri-HCC necrosis occurs more completely is supported, it will lead to improved efficacy of the percutaneous ablation technique in early-stage HCC patients. Furthermore, since HCC is a complication of cirrhosis, completely curing one such lesion may impact the outcomes of cirrhotic patients, given the frequent appearance of new HCC lesions in other anatomical areas of the liver. The secondary objectives of this study are (1) 90 (2) To demonstrate effective tumor mass necrosis after ablation with a Y-matrix composition. 90 (3) Evaluate the histological response after ablation with a Y-matrix composition in the target tissue 90 This includes (4) evaluating the dose measurement of the Y-matrix composition, and (5) evaluating the quality of life of registered patients, and (6) evaluating the local and systemic toxicity of the procedure.

[0223] This is a single-center, premarket, first-in-human pilot study in patients undergoing ablation-resection for primary HCC. The primary endpoint of this study is the delivery of a pre-determined dose into the tumor without reaching the HCC lesion as planned and without clinical complications that limit treatment. 90 The ability to deliver the Y-matrix composition. Secondary test endpoints were (1) the necrosis rate of tumor tissue and the presence of viable cells at the treatment site by histological evaluation after surgical resection of the segment containing the lesion, and (2) confirmation by PET scan 24 to 48 hours after the procedure. 90 (3) correct anatomical delivery of the Y-matrix composition, (4) effective delivery of the prescribed radiation dose to the target tissue (measured in Gy), (5) quality of life of enrolled patients as measured by the EORTC QLQ C-30 / HCC18 questionnaire, and (6) safety: vital signs, clinical tests, adverse events related to the radiation ablation procedure and surgical resection, as well as the type and severity of adverse events occurring during the period between the two treatments.

[0224] The patient population will consist of 10 adult male and female patients with early-stage HCC. Inclusion criteria include: - Individuals with liver lesions diagnosed as early-stage HCC; - Patients with up to seven non-subcapsular lesions, with a maximum diameter of 50 mm, who are deemed surgically resectable according to local criteria; - Subjects having at least one of the above-mentioned lesions (maximum diameter 50 mm) that are considered suitable for percutaneous ablation; - Adult men and women (18 years of age or older) - Persons who are able to read, understand, and sign an informed consent form.

[0225] The exclusion criteria for this examination are as follows: - Pregnant women, women who may be pregnant, or breastfeeding women; - Those who have taken another exam within the past three months; - Individuals unsuitable for general anesthesia and abdominal surgery; - 90 Persons with a known allergy to any of the components of the Y-matrix composition or to any anesthetic; - Individuals for whom the procedure is contraindicated due to co-existing medical problems; - Individuals with other concomitant malignant tumors; - Individuals with clinical or laboratory abnormalities that may be contraindicated for enrollment in the study at the discretion of the principal investigator.

[0226] The test procedure will include the following: Each subject will undergo imaging tests including diffusion-weighted magnetic resonance imaging (DW-MRI) or abdominal computed tomography, along with contrast-enhanced ultrasound (and biopsy), to diagnose and determine the stage of HCC lesions. - One of the lesions (percutaneous ablation and 90 The Y-matrix composition is considered to meet the criteria for intratumoral administration, but is treated with radioablation using an experimental device. - 90 The appropriate and effective delivery of a predetermined dose of the Y-matrix composition is evaluated by PET 24–48 hours after the ablation procedure. - The degree of necrosis of the treated lesion is evaluated by DW-MRI 21 days after the ablation procedure. - 7-9 days after DW-MRI, the entire tumor mass is surgically removed. - The excised lesion (which has been previously treated with radiation ablation) will be sent for histological examination according to the procedures outlined in the treatment plan. - Follow-up will be conducted two months after the surgery.

[0227] The collected data are summarized using descriptive statistics. Continuous variables are expressed as the number of cases, mean, and standard deviation, and the median, minimum, and maximum values ​​of the interquartile range. Categorical variables are summarized using the number of subjects and percentages. For the primary endpoint, a 5% confidence interval (CI) is estimated for the mean and standard deviation of the delivered dose. Secondary endpoints are summarized using descriptive statistics and 95% confidence intervals. Surgical specimens are processed by a pathologist for evaluation of the surgical margins and observed for macroscopic changes due to necrosis. Safety assessments include recording all adverse events (AEs) classified using the Common Terminology Criteria for Adverse Events v5.0, as well as changes in vital signs and laboratory parameters.

[0228] Each participant will be informed of the purpose, procedure, and potential risks of the study and will be required to sign an informed consent form. Each screened participant will be identified by a sequential screening number. Participants will only be enrolled after signing an informed consent form before any study procedure. All patients observed at the study site will be checked for compliance with the inclusion and exclusion criteria.

[0229] The following information will be collected: - Demographic data - Height and weight - Vital signs (e.g., blood pressure (BP), heart rate (HR), respiratory rate (RR)) - ECG - General and physical examination - Medical history and surgical history - Confirmation of alcohol consumption - Urine analysis containing Bence Jones protein - Pregnancy urine testing for women of childbearing age - Concomitant medications / treatments - Tumor evaluation using contrast-enhanced ultrasound and tissue biopsy (if applicable) - Imaging of the liver using magnetic resonance imaging (MRI) or computed tomography (CT) - Imaging of tumors using PET scans - In addition to the mRECIST criteria, tumor staging is performed using the TNM classification and the Barcelona clinical staging algorithm. - A quality of life questionnaire (EORTC-QLQ C-30) and HCC18 are distributed to patients.

[0230] If any adverse events occur during the period from the initial screening to the day of the ablation procedure, the patient will be instructed to immediately contact the research team. 90 On the day of treatment with the Y-matrix composition, each patient will undergo a pre-procedure review including the following: - Vital signs (e.g., BP; HR; RR) - General physical examination - Tumor evaluation - PET imaging (within 24-48 hours after ablation) - Dose measurement evaluation - Concomitant medications - Confirmation of adverse events - 90 Anesthesia for injection of Y-matrix composition - Contrast-enhanced ultrasound examination - 90 Ablation using a Y-matrix composition

[0231] If all registration criteria are met and the patient signs the informed consent form, 7 days after these screening tests, 90 A β-ablation procedure using a Y-matrix composition is scheduled. Each patient will be followed up for adverse events and adverse effects throughout the entire study period from the date of informed consent signing. Blood samples will be collected for the following determinations: - Complete blood count including white blood cell differential - Protein electrophoresis fractionation - Activated partial thromboplastin time (APTT) - International Ratio of Standardization (INR) - Fibrinogen - Blood sugar - Blood urea nitrogen (BUN) - Creatinine - Serum glutamate-oxaloacetate transaminase (AST / SGOT), alanine aminotransferase (ALT / SGPT), total bilirubin and fractionated bilirubin, gamma glutamyltransferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP). - Serum ions: sodium, calcium, potassium, chloride - Tumor markers (alpha-fetoprotein, AFP)

[0232] Before performing the ablation procedure, the following pre-procedure checks will be performed: - Compliance with inclusion and exclusion criteria - Vital signs (BP; HR; RR) - General and physical examination - Concomitant medications / treatments

[0233] 90 The Y-matrix kit is a radioisotope and matrix source as described elsewhere in this specification, for example, Sirtex Medical (SIRSPHERES®). 90The kit includes Y microspheres and BIOGLUE® manufactured by Cryolife. Furthermore, the kit includes a dual-lumen catheter configured to be attached to a BIOGLUE® dual-chamber syringe to facilitate the separate delivery of two matrix components via the catheter. This prevents the matrix from gelling or solidifying inside the catheter during delivery. The catheter features, along with its introduction needle and stylet, are as described above.

[0234] For the procedure, a BIOGLUE® syringe in 2mL or 5mL size is selected based on the tumor size(s) or total volume(s) determined in the pre-procedure workup. 90 The Y-matrix composition is prepared during pre-procedure preparation as follows: 1. Open the box containing the microsphere vials and leave the vials inside the lead container. 2. If available, place it in a lead or acrylic box and put it on the bench. 3. Partially remove the aluminum seal from the SIR-SPHERES® vial and clean it with an alcohol swab. 4. Insert the 25G needle into the vial septum to form an opening, and ensure that the needle is securely positioned within the vial contents. 5. Using a shielded 5 mL syringe equipped with a 20-22 G spinal needle at least 70 mm in length, puncture the septum of the SIR-SPHERES® microsphere ampoule. 6. Remove and discard 2 mL of the suspension. 7. Use a dose calibrator to determine the radioactivity in the transport vial and place it in a lead container. 8. Determine the volume to be extracted to obtain the necessary radiation dose for the liver lesion, depending on the size of the tumor bed.

[0235] In the activity calculation, the SIR-SPHERES® vial was assumed to contain a radioactivity concentration of 3 GBq / 3 mL after removing a volume equivalent to 2 mL of supernatant. It was also considered that 158 ​​μL of volume would remain in the dual-lumen catheter at the end of in-patient use. However, in other variants, the amount of supernatant removed or added may differ, or remain unchanged at all. For tumor sizes less than 30 mm in diameter, assuming a 2 mL syringe is selected, SIR-SPHERES® and BIOGLUE® are uniformly mixed, the maximum volume of mixture is dispensed, and a nominal 158 μL of mixture residue remains in the catheter, the following applies: [Table 27]

[0236] For tumor sizes of 50mm to 70mm or larger in radius, assuming a 5mL syringe is selected, SIR-SPHERES® and BIOGLUE® are uniformly mixed, the maximum volume of mixture is dispensed, and a nominal 300μL of mixture residue remains in the syringe, the following applies: [Table 28] 9. Return the syringe to the vial and move the plunger back and forth to thoroughly mix the SIR-SPHERES® beads. Quickly withdraw the pre-calculated radioactive dose and continue transferring it to the BIOGLUE® chamber as described below. 10. Remove the cap from the double-chamber syringe containing the glue. 11. Dispense the microspheres into the glue double-chamber syringe, adhering to a 4:1 ratio (80% into the BSA chamber and 20% into the glutaraldehyde chamber). 12. Put the cap back on the syringe. 13. Confirm the patient's dose by re-evaluating the activity in the syringe using a dose calibrator and adjust it if necessary. 14. Place the syringe in a radiation-shielded container suitable for transport to the operating room / radiology room.

[0237] For percutaneous ablation 90 To administer the Y-matrix composition, the MIPP kit from SVAS Biosana Systems, shown in Figures 1A and 1B, is used. This kit is specifically designed for optimal use with the transdermal application of BIOGLUE® and is used with components of the following sizes: - Insertion needle: 15G diameter, 150mm length - Injector catheter: 16G diameter and 120mm length

[0238] The procedure continues as follows: 15. Percutaneous access must be ensured to facilitate the insertion of a needle catheter into the liver parenchyma. 16. Appropriate anesthesia must be used in accordance with the standard operating approach at the center. 17. Place the kit's introducer and stylet onto the liver lesion with the assistance of an ultrasound scanner, or under CT guidance or other imaging modalities. 18. 90 Remove the sterile syringe containing the Y-matrix composition components from the radiation shielding container. 19. 90 Remove the syringe cap containing the Y-matrix composition components. 20. Holding the syringe firmly with the pin facing upwards, rotate the cap 90° counterclockwise and shake it from side to side to remove the cap. Align the kit's dual-lumen catheter with the syringe using the corresponding notches, and position the end of the kit's dual-lumen catheter on the syringe. Be careful not to accidentally spill the solution from the syringe during assembly. 21. Secure the double catheter in the kit by firmly pushing the catheter towards the syringe and rotating the catheter collar 90° clockwise. 22. Keep the syringe straight and align the large and small storage sections of the solution syringe over the corresponding syringe plunger heads. Slide the plunger backwards on the syringe until resistance is encountered. This assembles the dispensing device. 23. Remove the stylet from the kit's introduction device. 24. Insert the catheter into the insertion device and secure it via the Luer lock connector. 25. Press the plunger to dispense the mixture. 26. The plunger should be pushed at a speed in the range of 0.5 to 1.0 mm / s. 27. Wait at least 30 seconds before retracting the device, rotating it slightly to prevent it from sticking to the tissue with glue. 28. At the end of the procedure, the needle catheter and syringe must be disposed of according to the standard operating procedures of the biohazard disposal center. 29. The insertion site must be properly closed and protected with a bandage. 30. If deemed appropriate, topical antibiotics may be administered.

[0239] Preparation and implantation procedures must be considered as significant risks of potential radiation hazards and contamination to personnel. Local guidelines regarding the use of radiation during implantation and post-implantation care must be followed.

[0240] Using a PET scan 24-48 hours after the procedure, 90 The delivery of the Y-matrix composition will be evaluated. Dosage measurements will be performed by mathematical analysis of data acquired from PET scans.

[0241] Furthermore, prior to surgical resection, each patient will be re-evaluated 21 days later for tumor assessment, including contrast-enhanced ultrasound, MRI and / or CT imaging, and clinical evaluation. Dosimetry will be re-evaluated using PET scans with mathematical analysis of the data. The insertion site and liver tissue will be monitored for changes over time between radiation ablation and resection. Any observed pathological conditions and / or complications must be recorded in the CRF. Additional evaluations will include: - Vital signs (e.g., BP; HR; RR) - General physical examination - Complete set of clinical tests (e.g., blood chemistry and hematological parameters) - mRECIST criteria - Concomitant medications - Confirmation of adverse events - EORTC-30 / HCC18 questionnaire

[0242] Seven to nine days after re-evaluation, i.e., 28 to 30 days after the ablation procedure, the patient will return to the hospital for surgical excision of the target lesion. The surgical excision will be performed according to the standard procedures of the study site. The surgical procedure will include: - Vital signs (BP; HR; RR) - General physical examination - Tumor evaluation - Anesthesia for surgical purposes - surgery - Histological evaluation - Concomitant medications - Confirmation of adverse events

[0243] From a radiation protection standpoint, the surgery is radiologically safe for the surgeon and all supporting personnel because during the radiation ablation procedure... 90 This is because residual radioactivity decreases to 10 MBq 20 days after an injection of a 2 GBq dose of Y. The effect at 1 meter is approximately 3 mSv / h in vitro and approximately 1 mSv / h in vivo (in the human body), both of which are below the ambient background radiation levels.

[0244] If surgery becomes contraindicated on the scheduled date, the subject will be excluded from the study. However, they will undergo the same evaluations described for postoperative assessment and will be monitored for any safety issues.

[0245] The resected liver tissue is sent to the pathology department for evaluation. The specimen is processed by a pathologist for evaluation of the surgical margins and observed for macroscopic changes due to necrosis. The percentage of necrosis in the tumor mass is measured, and the presence of any viable cells in the treated lesion is histologically assessed. 90 The radial distribution of Y microspheres is also evaluated and measured. Specimen orientation is performed using appropriate systems such as color inking. Resection margins are evaluated macroscopically and microscopically, with imaging (where appropriate). Liver specimens containing treated liver tissue are processed and evaluated for microscopic examination. After specimen orientation, the specimens are observed for macroscopic changes due to necrosis, and then the tissue within the treated area is examined microscopically for induced tissue necrosis. The extent of necrosis is determined using hematoxylin / eosin staining techniques, which rely on visual examination of the state of the cell membrane and structure to assess cell viability, and standard immunohistochemistry.

[0246] For the same reasons that surgery is radiologically safe, histopathological evaluation is also safe for pathologists and all supporting personnel.

[0247] Postoperative patient management will follow local standard procedures and practices, including (if necessary) admission to the intensive care unit for 24-48 hours post-surgery. After being transferred to a regular ward, the patient will undergo the following evaluations before discharge: - Vital signs (e.g., BP; HR, RR) - ECG - Physical examination - Blood chemistry (including liver function assessment: AST, ALT, total bilirubin and fractionated bilirubin, gamma GT, LDH, alkaline phosphatase) and hematology - Surgical downstaging criteria - Concomitant medications / treatments - Tumor evaluation using contrast-enhanced ultrasound - Confirmation of adverse events and adverse effects

[0248] After discharge, patients will be followed up for two months. This study will be considered completed for each subject after the two-month follow-up period. During the follow-up, information on any adverse events that may be related to the radiation ablation procedure or surgical resection will be collected and included in the CRF.

[0249] During follow-up visits for post-discharge checkups, which take place 28 days after surgery and 56 days after ablation, patients will undergo the following experimental procedures: - Vital signs (e.g., BP; HR; RR) - General physical examination, weight measurement - Complete set of clinical tests (e.g., blood chemistry and hematological parameters) - Tumor evaluation - Imaging evaluation (e.g., PET scan) - Concomitant medications - Confirmation of adverse events

[0250] In some of the other variations of liver tumor treatment techniques, 90Y-matrix composition therapy may be provided without requiring prior therapeutic imaging (e.g., technetium-99 scans) to evaluate other sites besides the target site, including any shunts to the liver or lungs, varicose veins, or AVMs. In some variant forms, prior therapeutic imaging to evaluate shunts is not required, and therefore prior therapeutic procedures to treat potential shunts are also not required. This can shorten the time to initiation of treatment by one, two, three, four, five, six, or seven days or more, as treatment is not delayed by prior therapeutic shunt imaging, prior therapeutic shunt reduction procedures, and prior therapeutic rescans to evaluate the effectiveness of the shunt reduction procedures. Shunt procedures that may no longer be required or performed may include arterial embolization, hepatic vein balloon occlusion, and varicose vein and AVM occlusion. Since dose adjustments to account for shunts are no longer required, dose calculations can also be simplified, for example, by eliminating adjustments based on shunt percentage and / or pulmonary dose limits. Patients with a high proportion of liver, lung, or hepatopulmonary shunts no longer need to be excluded from treatment.

[0251] To evaluate the primary endpoint, a 5% confidence interval (CI) is estimated for the mean dose delivered. Furthermore, the standard deviation of the mean dose delivered and its 95% confidence interval are calculated to quantify the variability and dynamic range of the novel technology's performance. Secondary endpoints are summarized, as appropriate, using descriptive statistics and 95% confidence intervals. Quality of life is measured using the EORTC QLQ C30 and HCC18 questionnaires and assessed at screening visits (V-1) and visit 1 (V1). Descriptive statistics for single-item scores at each trial visit, as well as the change in score between visit 1 (V1) and screening visit (V-1), are provided. Surgical specimens are processed by a pathologist for evaluation of surgical margins and observed for macroscopic changes due to necrosis. Safety assessment consists of recording and summarizing all adverse events, as well as analysis of changes in vital signs and clinical laboratory parameters. 90The incidence of adverse events, considering their relationship to Y-matrix composition, is calculated for all patients, along with their severity and severity. Severity assessment of adverse or serious adverse events must be performed using NCI-CTCAE version 5. Clinical laboratory data are summarized by type of clinical laboratory. For each clinical laboratory measurement, descriptive statistics at baseline, as well as observed values ​​and changes from baseline at each scheduled time point, are calculated. A list of subjects whose clinical laboratory results are outside the normal range is also provided. Parameters with predefined NCI-CTCAE toxicity grades are summarized. Descriptive statistics for vital sign values ​​and changes from baseline are summarized. Descriptive statistics are provided for safety variables.

[0252] Example 9: Hepatocellular carcinoma In another embodiment, the treatment of hepatocellular carcinoma is provided by a different mixing procedure and kit than those used and included in Example 8 above. 90 A therapeutic kit for performing direct, image-guided intratumor injection of Y bioglue or curable carrier material may include: - Items included in the kit or to be procured separately: - 90 Lead pot for containing Y microsphere vials, - 1.5 GBq in a total of 5 cc of water for injection (WFI) at the time of calibration. - Two-component bio-glue or curable carrier kit, e.g., a 2 mL or 5 mL kit. - Optional local applicators for syringes(s)(s)(s)(s)(s)(s) - Injection needle (length 15-18 cm) - Connector - Additional lead pot - Empty vials (for example) 90 (For diluting Y microspheres) - 1mL syringes with Luer lock (multiple available) - 22G needle - 20G x 70mm needle - Three PMMA cylindrical radiation shields: - 2 mL syringe for bioglue (e.g., cylinder "A") - 5 mL syringe for biological glue (e.g., cylinder "B") - Cylinder for 1 mL syringe (e.g., cylinder "C")

[0253] In addition, the following components are included in the kit or must be sourced separately: - Sterilized radiation shielding box; - Non-sterile radiation-protected waste boxes; and - 90 Forceps or tongs for handling Y microsphere vials

[0254] In some embodiments, 90 The treatment kit for performing direct, image-guided intratumor injection of Y bio-glue or hardening carrier material is divided into three stages: - Preparation of materials - 90 Dilution of Y microsphere vials - Diluted 90 Addition of Y microspheres to bio-glues or curing carrier kits

[0255] Preparation of materials: - Open the bio-glue or curing carrier kit. - Open the packaging of the bio-glue or curable carrier syringe using a sterilization method. - Remove the cap from the syringe. - Place the syringe inside the corresponding cylinder shield (for example, cylinder "A" or "B"). - Open the lead pot containing the microsphere vial and use tongs to remove the vial from the pot. - Using a dose calibrator, 90 Measure the radioactivity of the Y microsphere vial (the measured value should show 1.5 GBq + / - 10%). - If the dosage is outside the prescribed range, the concentration can be adjusted as follows: - If the dose is too low, WFI needs to be removed to bring it within the appropriate concentration range. ■ Firstly, the microspheres are allowed to settle to the bottom of the vial, enabling the removal of a portion of the WFI. ■ Once the microspheres have settled or separated from the WFI, remove the WFI using a 1 mL syringe with a 22 G needle attached to a cylinder shield (e.g., cylinder "C") to achieve the desired microsphere concentration. ■ The amount of WFI removed (mL) is calculated as follows: Removed WFI (mL) = (Measured dose (GBq) / 0.300). - If the dose is too high, WFI (Whole Fibre Injection) may need to be added to bring it within the appropriate concentration range. ■ Inject WFI using a 1 mL syringe fitted with a 22 G needle to achieve the desired microsphere concentration. ■ The amount of WFI (mL) to be injected or added is calculated as follows: Additional WFI (mL) = (Measured dose (GBq) / 0.300) - 5. - 90 Place the Y microsphere vial into a lead pot. - 90 Place the additional empty vials needed for diluting the Y microspheres into a lead pot.

[0256] 90 Dilution of Y microspheres - Using tumor measurements, the user: ■ Choose whether to use a small syringe (e.g., 2 mL) or a large syringe (e.g., 5 mL), and ■ Use 90 Determine the capacity of the Y microsphere. - 90 Partially remove the radiation protection from the Y vial and clean the vial with an alcohol pad. - One sterile needle 90 Place it inside a Y vial so that it reaches the microsphere. -90 During the removal of Y, a 22G needle 90 Insert it into the Y vial and allow air to circulate to release the vacuum inside the vial. - Insert a 22G needle into the empty vial. - Place the 1 mL syringe into its corresponding cylinder (cylinder "C"). - Shake the lead pot in a circular motion for a predetermined time, for example, 5 seconds, 10 seconds, 15 seconds, 20 seconds, or 30 seconds. - Connect a 1 mL syringe to a sterile needle, and depending on the tumor size measurement and the selected corresponding syringe size, proceed as follows: 90 The volume of the Y microsphere mixture is withdrawn. If the volume exceeds 1 mL, multiple withdrawals are made. [Table 29] [Table 30] - Selected capacity 90 For volumes exceeding 1 mL, the Y microsphere mixture is injected into additional empty vials using multiple withdrawal and injection steps. - Based on the amount in the fourth column heading "WFI volume," withdraw sterile water for injection into another 1 mL syringe. ■ Inject the specified amount of water that was removed into the dilution vial in the same manner. ■ If the volume exceeds 1 mL, several injections may be necessary. - Gently swirl the diluted solution in the dilution vial to mix it thoroughly. - Use a dose calibrator to measure the radioactivity of the microspheres in the diluted vial. ■ This measurement must match within ±10% of the quantity in the fifth column of Table 1 or Table 2. ■ This results in the diluted contents of the dilution vial 90 The Y microspheres are ready to be mixed into the bio-glue.

[0257] To the bioglue injector 90Addition of Y microspheres. - Diluted 90 Shake the lead pot containing the diluted vial with the Y microsphere by moving it in a circular motion for at least 10 seconds. - Connect a 1 mL syringe to a sterile needle and add the diluted glutaraldehyde for the glutaraldehyde chamber (clear) of the bioglue syringe according to the amount shown in Table 3 or 4. 90 In the diluted vial of Y microspheres 90 Extract the amount of Y microspheres (for a 2 mL or 5 mL bioglue syringe, respectively). [Table 31] [Table 32]

[0258] As described above, the total preparation volumes of 2.5 mL and 6.0 mL are for 2 mL and 5 mL syringes, respectively, taking into account the dead space in the mixing tip and injector. The amount of radioactivity after injection is listed as “residual activity” in Tables 3 and 4. The actual injected activity (last column in Tables 3 and 4) is the activity delivered to the tumor itself and coincides with the target dose (first column in Tables 1 and 2), assuming that the entire syringe or injector barrel is injected and no material remains in the syringe or barrel.

[0259] The amount applied will be determined by the nuclear medicine specialist performing the radioablation procedure, according to the size of the tumorous lesion to be ablated and their clinical judgment. If the entire amount of the product is not applied, the activity applied to the tumor will be correspondingly lower.

[0260] The dosage preparation procedure described above is based on a single-use coaxial needle (e.g., a 17G needle with a length of 15 cm and a lumen volume of 745 microliters). Depending on the depth of the HCC lesion, longer single-use coaxial needles (e.g., a 17G needle with a length of 18 cm and a lumen volume of 806 microliters) may be used, as well as needles of other gauges and / or lengths with different lumen volumes.

[0261] Injection procedure

[0262] This infusion procedure may utilize components included in additional infusion kits or dose preparation kits. These components may include: - Prepared according to the preparation procedure 90 One Y Microsphere multi-barrel syringe - One non-sterile, radiation-protected waste box (included or sourced separately) - Insertion kit 3000 shown in Figure 30A: - Single-use introduction needle 3002 (e.g., 17G needles with lengths of 15cm, 18cm or other) - Connector 3004 with cap - Mixer 3006 (e.g., MEDMIX, Switzerland); and - Distal Luer Lock 3008

[0263] The patient is positioned on the operating table, and the insertion site is prepared and draped according to standard sterile procedures. Local anesthesia is administered from the insertion site to the target area of ​​the liver. - The insertion needle 3002 of the insertion kit 3000 is inserted into the liver to the desired target site under CT, fluoroscopy, or ultrasound guidance, as shown in Figures 27A-C. - Prepared 90 Remove the multi-barrel syringe equipped with a Y microsphere from the radiation shielding box. - Remove the cap from the multi-barrel syringe. - The cap of connector 3004 is attached to the syringe. As shown in Figure 30B, marker 3010 on cap 3004 is aligned with the corresponding marker 3012 on syringe 3014 with syringe 3014 inside shield cylinder 3016. Next, as shown in Figure 30C, rotate the cap 3004 clockwise relative to the syringe 3014 and the corresponding marker 3012. - Referring to Figure 30D, plungers 3018A and 3018B are fitted into syringe 3014. - Remove the inner needle from the guide needle. - The multi-barrel syringe is shaken in the shielded cylinder for at least 5 seconds. - As shown in Figure 30E, the Luer lock 3008 of the connector 3004 attached to the multi-barrel syringe 3014 is connected to the proximal end 3020 of the introduction needle 3002. - Press the plunger of the syringe, 90 Deliver the Y microsphere. - The plunger should be pushed using a constant injection speed or injection rate. - Examples: 0.5 and 1.0 mm / second Wait 120 seconds, then withdraw the syringe and guide needle. - Place the syringe and insertion needle inside the radiation shielding box. - The insertion site must be properly closed and protected with a bandage. - Topical antibiotics may be applied to the insertion site at the discretion of the patient if clinically indicated. - As shown in Figures 28A and 28B, 90 A PET-CT scan should be obtained within 24 hours and can be used to confirm tumor coverage by the injector. - An FDG PET scan may also be performed approximately 21 days or 3 weeks later to evaluate residual tumor at the injection site. - Diffusion-weighted MRI may be performed at 21 days or 3 weeks, 56 days or 8 weeks, and / or 90 days, 12 weeks, or 3 months to assess the response and / or disease progression in the immediate phase.

[0264] Five patients with morphologically proven unresectable HCC had tumors with an average diameter of 2cm to 5cm. 90 Bio-glue Y was injected percutaneously. Pre-procedure imaging included ultrasound, MRI (e.g., images of lesion 2600 in Figures 26A and 26B), and fluorodeoxyglucose (FDG) PET-CT. Intratumoral injection was performed using a catheter with real-time ultrasound imaging or step-by-step CT guidance. In Figures 27A-C, for example, the HCC lesion 2600 identified by pre-procedure imaging was re-identified during ultrasound imaging, and the needle insertion route 2602 was directed from the surface 2604 to the lesion 2600 (Figure 27A). Then, using ultrasound imaging, the needle 2606 was inserted and guided into the lesion 2600 via the insertion route 2602, and the desired amount was injected. 90 Inject Y's bioglue 2608 until it reaches the lesion 2600 (Figure 27C) (Figure 27B). Figures 28A and B show the tumor 2600 90The images show axial and coronal views of the patient, confirming that the lesion is covered with Y's bioglue 2608. Activity levels ranging from 78.56 MBq to 115.25 MBq were injected into the lesions of five patients. In other embodiments, doses ranging from 70 MBq to 120 MBq are injected into tumors ranging from 2 cm to 5 cm. In yet another embodiment, higher doses of 140 MBq to 240 MBq, or 210 MBq to 360 MBq, or up to 280 MBq to 480 MBq, are possible for the same tumor size range. In some patients, the entire injection volume is delivered to the center of each tumor mass, while in other variant forms, the injection volume may be distributed to multiple different sites within the tumor mass. For example, the dose may be distributed by three injections between the deep / distal, central / intermediate, and superficial / proximal regions of the tumor mass, with relative volume ratios of 25% / 50% / 25% or 20% / 60% / 20% of the total injection volume. In other variants, at least 50% of the dose is injected into the center of the tumor mass, and the remainder or at least a portion of the dose is injected into one or more off-center sites of the tumor mass. After injection, when removing the injection needle, a bio-glue or other hemostatic agent may be injected along the needle's path as the needle is withdrawn.

[0265] For example, within 12, 24, or 38 hours after the procedure, the injected 90 To confirm the localization and activity level of Y bioglue, 90 YPET-CT may be performed. FDG PET and / or diffusion-weighted MRI may be performed one week, two weeks, three weeks, four weeks, eight weeks, and / or twelve weeks after treatment, or 30 days, 60 days, and / or 90 days after treatment, to evaluate the response to treatment, e.g., no response, partial response, or complete response. Figures 29A and 29B show axial and coronal MRI images, respectively, of the patients from Figures 26A and 29B taken three weeks after treatment, showing residual tumor or 90No activity was observed in Y, indicating a complete response to treatment. No procedure-related adverse events were reported in this patient or any other patient treated in this study. All patients enrolled in the study were 90 The injection of bio-glue into Y was well tolerated.

[0266] At the end of the trial, 3 out of 5 patients achieved a complete response (60%), and 2 out of 5 patients achieved a partial response (40%). There were no patients who did not respond to the treatment.

[0267] Regarding adverse events, the following events were observed in at least one patient: - Abdominal pain (1 case): However, it was classified as unrelated to treatment. - Mild pain (1 case): Classified as an adverse event. - Fever (2 cases): However, these were classified as unrelated to treatment. - Localized tissue necrosis (all patients): However, it occurred only in the treated area. - Portal vein thrombosis (1 case - pre-existing condition): However, it was classified as unrelated to treatment. - Vomiting (1 case): However, it was classified as having little correlation with treatment.

[0268] None of the following adverse events were observed in any of the five patients; however, in other variants, the proportion of patients experiencing any one of these adverse events may be 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or less than 5%. - fatigue - Malice - diarrhea - Transient elevation of liver enzymes - Mild to moderate abnormal liver function test values ​​(ALT / AST, alkaline phosphatase, bilirubin) - Transient reduction of hemoglobin - Transient lymphocyte decrease - Radiation-induced liver disease (e.g., hyperbilirubinemia, hypoalbuminemia, ascites) - Non-targeted radiation (e.g. radiation gastritis, gastrointestinal ulcer, upper gastrointestinal bleeding, pancreatitis, radiation pneumonitis) - Non-adhesion of therapeutic products to tissues - Application of adhesive to tissues unrelated to the procedure - Inflammation and immune response - Allergic reaction - Calcification of tissue - Vascular occlusion - Obstruction of the bronchi or lumen - Pulmonary embolism - Damage to normal blood vessels or tissues - Transmission of infectious agents from animal-derived materials - Severe hematoma - Severe bleeding - Vasovagal syncope

[0269] The results of the FIH trial indicate an appropriate activity level. 90 Direct, image-guided intratumoral injection of Y bioglue is effective and appears to have a superior safety / tolerability profile compared to transarterial radioembolization. In some variant forms, sclerosing 90 Percutaneous direct injection of Y material for radiotherapy can achieve response rates of, for example, at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, and 95%. Complete response rates may be, for example, at least 10%, 20%, 30%, 40%, 50%, or up to 60%, or 30-50%, 30-60%, 40-60%, or 50-60%. The percentage of patients with abnormal liver function tests may be, for example, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or less than 5%.

[0270] In other transformation forms, 90 Treatment with direct, image-guided intratumoral injection of Y bioglue or hardening carrier material can convert patients with unresectable HCC into resectable disease. In some variant forms, this alone is possible. 90The treatment may be carried out solely by direct, image-guided intratumoral injection of Y's bioglue or scalable carrier material, or as part of a multimodality therapy / conversion scheme. These multimodality therapy schemes may include, for example, angiogenesis inhibitors, anti-PD-1 antibodies (e.g., atezolizumab), kinase inhibitors (e.g., sorafenib, regorafenib, sunitinib, erlotinib), and systemic chemotherapy with FOLFOX4, GEMOX, XELOX, or GP chemotherapy schemes, transarterial chemoembolization (TACE), or hepatic artery infusion (HAIC) chemotherapy.

[0271] While the embodiments described above are described in some detail as examples and illustrations for the purpose of clarification and understanding, it is clear that certain changes and modifications may be made, and that they are intended to be included within the scope of the appended claims. Furthermore, it should be understood that the components and features of the devices and materials described herein may be used in any combination, and that the methods described herein may include all or some of the elements described herein. The description of a particular element or feature relating to a particular figure is not intended to be limiting, nor should it be construed to suggest that that element cannot be used in combination with other described elements.

[0272] Example 10: Interim analysis of clinical toxicology tests This embodiment helps illustrate the clinical application of BAT-90 as described herein in the treatment of HCC. Here, a group of HCC patients were treated with the composition disclosed herein at doses appropriate to tumor size. The clinical trial endpoints addressed the safety and tolerability of the treatment. This included addressing the toxic effects of the treatment and potential clinical complications associated with the treatment.

[0273] The primary objective of this embodiment is to evaluate the feasibility of the use of the compositions, methods, and devices disclosed herein as a potentially novel system enabling effective and safe radioablation of primary resectable and unresectable liver lesions (HCC), thereby providing a new technique as a novel means of local treatment for this disease.

[0274] This example is from the First-in-Human (FiH) Clinical Trial (ID BGT-HCC-AR / 2019 (RADIO-ABLATION OF MALIGNANT PRIMARY LIVER LESIONS (HEPATOCELLULAR) This study discloses CARCINOMA, HCC. As the RSI (Rating Standard Safety Information) of this study is based on common (and relatively rare) side effects associated with BAT-90 treatment, this study placed particular emphasis on known safety indicators associated with the TARE procedure (e.g., transient elevation of liver enzymes and transient decrease in lymphocytes, etc.), and / or the use of BioGlue®, and also considered (as a secondary objective) the evaluation of the local and systemic toxicity of the procedure. Accordingly, this study aims to highlight the therapeutic benefits presented herein: (1) providing treatment to HCC patients with multifocal disease, (2) providing treatment to HCC patients ineligible for TARE (due to vascular shunts, multisegment / multilobed disease, and / or hepatic impairment), and (3) providing a treatment option with fewer side effects compared to TARE.

[0275] Interim analysis The interim analysis was planned when 50% of the collected data had been reached. This was when the first five patients had been enrolled in the trial and received treatment. This was the first-in-human (FiH) analysis, and the purpose of this analysis was to explore the safety and feasibility data collected initially, and therefore, descriptive statistics would be provided. Special reporting requirements for interim analysis: • Descriptions and considerations of unexpected observations and equipment malfunctions; • A tabular list and discussion of AE, SAE, ADE, SADE, and USADE (not limited to SAEs that are reported); · 90 The dangers of Y microspheres;

[0276] Analysis of primary outcomes Key evaluation criteria The primary endpoint was the percentage of subjects who received an appropriate intratumor dose of BAT-90 without treatment-limiting clinical complications, and the associated 95% Clopper-Pearson confidence interval. None of the subjects from the PP (or ITT) population experienced any clinical complications that limited treatment 21 days after the surgical procedure. Clinical complications that limit treatment BAT-90 treatment-related adverse events and adverse events that limit the ability to place BAT-90 within HCC target lesions. [Table 33]

[0277] Safety and tolerability analysis Adverse events Thirty adverse events occurred during the interim analysis period.

[0278] Harmful device action / Unexpected harmful device action / Serious harmful device action / Serious unexpected harmful device action Only one adverse device effect was found to have a "probable" causal relationship with the device. The adverse event (ADE) was associated with an adverse event (AE) defined as "pain in the upper right abdomen (injection site)," and therefore related to the needle delivery device, which is part of the medical device delivery system. This was defined as mild and expected, and unrelated to treatment with BAT-90 itself, and no concomitant medications were offered. The pain resolved without complications. This AE was classified as an ADE because its delivery system is considered part of a BAT-90 medical device. [Table 34]

[0279] Up to the end of the interim analysis, there were no unexpected adverse device effects (UADE), serious adverse device effects (SADE), or serious unexpected adverse device effects (USADE). Serious adverse events There were five serious adverse events reported in two subjects. [Table 35] [Table 36]

[0280] Device malfunction No device malfunctions were reported.

[0281] Adverse events / harmful device effects that led to the discontinuation of the trial No adverse events or adverse device effects were observed in the interim analysis that led to the discontinuation of the trial.

[0282] Adverse events / harmful device effects resulting in death During the interim analysis period, there were two serious adverse events resulting in death (details are reported in the "Safety and Tolerability Analysis" section). Vital signs and clinical laboratory evaluation [Table 37] [Table 38] [Table 39-1] [Table 39-2]

[0283] 90 Risks of Yttrium Microspheres: A Comparison of Transdermal and Transarterial Administration Routes (TARE) Considering the specific administration route (transcutaneous) for BAT-90 (percutaneous) versus the administration route (intra-arterial) for TARE, the lack of migration of activity from the injection site recorded in this clinical trial ensures that the adverse events (AEs) reported with TARE do not apply to BAT-90. In fact, considering the safety profile obtained from the interim analysis of the FIH trial using BAT-90, and comparing it with the list of AEs reported in the EANM2022 guidelines for TARE, the inventors believe that not all adverse events reported in EANM (including those listed in the Instructions for Use (IFU) for 90 yttrium microspheres) apply to BAT-90. As shown in the comparison table below, the inventors chose to report the risks that are most likely to be associated with BAT-90 in their assessment, aiming to minimize similar risks associated with TARE. [Table 40] Weber et al. EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds.European Journal of Nuclear Medicine and Molecular Imaging(2022)49:1682-1699)

[0284] conclusion The purpose of the interim analysis conducted within this study was to evaluate the feasibility and safety profile of the treatment procedure using the BAT-90, a Class III investigational medical device. This was the first step in providing justification for continuing the current study without significant changes to the study design, and also providing preliminary suggestions for future clinical research.

[0285] For this purpose, the data was submitted for evaluation by an independent data monitoring committee (DMC). The DMC noted the following: 1. Each of the five patients included in the analysis (ITT population) was examined with particular emphasis on noted adverse events and / or adverse device effects. No serious adverse events and / or device effects related to the study treatment were observed (particularly in relation to the relevant RSI). Therefore, the treatment provided was judged to be well-tolerated by all patients enrolled in the study at the cutoff time for the interim analysis. 2. The DMC noted that the application of the investigational treatment is highly feasible and has not caused any specific delivery problems. This emphasizes that the treatment has high applicability and can be applied not only in highly specialized cancer centers but also in surrounding hospitals equipped with standard infrastructure for managing oncology patients. 3. The DMC prepared an outline of potential toxicity scenarios, paying particular attention to the following: • Device dispersion / leakage at the nearest boundary of the treated lesion (potentially causing destruction of surrounding healthy tissue), • and / or higher activity and related compared to what is defined in the actual approved version of the protocol. 90 This concerns the application of doses of Y (and therefore doses exceeding 150 Gy). In this regard, considering both the clinical practice followed by surgeons who resect entire hepatic lobes when targeting resectable indications and the specificity of the liver's regenerative capacity, the committee determined that the risks associated with “overtreatment” were acceptable compared to the benefits derived from avoiding potential complete ablation and lesion recurrence. The committee advised the sponsor to proceed with a pivotal trial with higher doses. 90 We suggested considering treatment with dose Y. 4. DMC demonstrated that the proposed experimental treatment is also applicable to liver metastatic lesions (mCRCs) originating from primary colon cancer. Since liver metastases undergo various waves of recurrence, sequential administration of the proposed treatment may be considered.

[0286] The conclusions from DMC also suggest that BAT-90 is suitable for use in other types of cancer, such as other oncogenic gastrointestinal cancers, including metastatic lesions (mCRCs) from primary colon cancer, primary and secondary liver lesions, pancreatic cancers such as pancreatic lesions, and gastrointestinal metastases.

[0287] Example 11: Reconstruction and correction coefficient of BAT-90 This embodiment serves to evaluate the amount of residual radioactivity in the syringe after administration. The amount of residual radioactivity in the delivery device is important for evaluating the dose delivered to the tumor. Knowing the amount of residual radioactivity in the device after administration allows for the addition of a correction factor to the calculation of the dose required in the syringe to deliver the intended amount of radioactivity to the tumor.

[0288] Therefore, the clinical outcomes obtained from the initial results of the FIH trial using BAT-90 presented in Example 10 of this specification provide important information on how to improve the efficacy of medical devices. Most importantly, special attention has been paid to the modality of the preparation of the BAT-90 syringe before administration to the patient.

[0289] In particular, the improvements focus on two important aspects. - Syringe reconstruction ( 90 (Process of adding Y microspheres to a syringe) - To achieve complete ablation of the lesion, it is administered to the tumor. 90 Add a specific correction factor to the Y activity.

[0290] Reconfiguration of BAT-90 syringe The reconstruction process, that is, a predetermined dose 90 The process of adding Y microspheres to a bioglue syringe is routinely performed in the Nuclear Medicine Department. The usual syringe preparation involves adding equal amounts of Y microspheres to each chamber of the bioglue syringe before administration. 90The Y microsphere is added. The usual process for preparing the syringe is to add it to both chambers. 90 This includes adding Y microspheres in a 4:1 ratio. This bioglue syringe is a dual-chamber syringe containing BSA in one chamber and glutaraldehyde in the other chamber, and these two components have different densities. Because the densities in the two chambers are different, in filling the dual chamber, the two chambers 90 The uneven distribution of Y microspheres, coupled with the water-like density within the glutaraldehyde chamber, led to microsphere precipitation at the bottom of the syringe in the glutaraldehyde chamber, increasing the uncertainty of the delivered dose.

[0291] Therefore, inside the bioglue syringe 90 To improve the uniformity distribution of Y microspheres, 90 The process was modified to fill the BSA chamber with Y microspheres and add only WFI (water for injection) to the glutaraldehyde chamber. This new preparation process is performed in the syringe. 90 This results in a more uniform distribution of Y microspheres, leading to more precise radiation delivery.

[0292] Correction coefficient To further improve the accuracy of the administration process and dosage, a "residual activity correction factor" was provided that measures the residual activity in the syringe and takes into account the residual activity in the syringe after administration. In fact, the process of reconfiguring the BAT-90 syringe before administering it to the patient involves: 90 The use of an intermediate syringe and needle is planned to be used to add Y microspheres to a bioglue syringe.

[0293] These components always contain intermediate steps and consumables used for injection. 90There is residual activity of Y, which needs to be corrected to determine the final dose administered to the tumor. To perform this calculation, the interim results from the FIH trial disclosed in Example 10 are used for a given dose. 90 A correction factor of 20% was established as the optimal ratio to ensure that Y microspheres are delivered into the tumor. [Table 41] The results shown in Table 13 indicate that, on average, 17% residual activity remained in the syringe, but the residual activity ranged from 12% to 30%. Therefore, when preparing syringes for administration, a specific correction factor of 20% in addition to the intended activity to be delivered is appropriate, although in some cases, a correction of up to 30% may be preferable. This 20% is incorporated into the algorithm for calculating the dose to be prepared in the nuclear medicine department before infusion to the patient. 20% is delivered to the tumor. 90 This improves the precision of the final dose of Y microspheres and ensures that the delivered dose is optimal for achieving complete tumor necrosis.

Claims

1. For use in the treatment of gastrointestinal cancer ９０ A composition containing Y, ９０ The composition wherein the radioactivity dose of Y is in the range of 0.4 to 220 MBq ± 30%, such as a dose selected from the group consisting of 0.48 MBq, 2.4 MBq, 7 MBq, 17 MBq, 28 MBq, 30 MBq, 48 MBq, 75 MBq, 114 MBq, 160 MBq, and 219 MBq, or a dose selected from the group consisting of 0.48 ± 30% MBq, 2.4 ± 30% MBq, 7 ± 30% MBq, 17 ± 30% MBq, 28 ± 30% MBq, 30 ± 30% MBq, 48 ± 30% MBq, 75 ± 30% MBq, 114 ± 30% MBq, 160 ± 30% MBq, and 219 ± 30% MBq.

2. For use in the treatment of gastrointestinal cancer ９０ A composition comprising Y, wherein the cancer comprises a tumor with a diameter of 5 mm to 5 cm.

3. The aforementioned ９０ The administered radioactive dose of Y is - 0.48 ± 20% MBq (when the average tumor size corresponds to a diameter of 5 mm or less); - 2.4 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 5 mm but less than or equal to 10 mm); - 7 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 10 mm but less than or equal to 15 mm); - 17 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 15 mm but less than or equal to 20 mm); - 28-30 ± 20% MBq (corresponding to an average tumor size of more than 20 mm in diameter but less than or equal to 25 mm); - 48 ± 20% MBq (corresponding to an average tumor size of more than 25 mm in diameter but less than or equal to 30 mm); - 75 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 30 mm but less than or equal to 35 mm); - 114 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 35 mm but less than or equal to 40 mm); - 160 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 40 mm but less than or equal to 45 mm) and - 219 ± 20% MBq (when the average tumor size corresponds to a diameter greater than 45 mm and less than or equal to 50 mm), for use according to claim 1 or 2 ９０ A composition containing Y.

4. For use in the treatment of gastrointestinal cancer as described in any of the prior claims, wherein the radioactivity dose is in the range of 0.4 to 220 MBq ± 30%, such as ±5%, ±10%, ±15%, ±20%, or ±25%, preferably ±20%. ９０ A composition containing Y.

5. A pharmaceutical composition, wherein the composition is ９０ A composition for use according to any of the prior claims, comprising Y microspheres and surgical sealants and / or adhesives such as tissue glue.

6. The composition is ９０ A composition for use according to any of the prior claims, comprising Y microspheres and components of a two-component curable surgical sealant and / or adhesive, such as tissue glue.

7. The composition for use according to claims 5 to 6, wherein the surgical sealant and / or adhesive is selected from the group consisting of natural polymer sealants (such as fibrin-based, collagen-based, and albumin-based sealants), synthetic polymer sealants (such as polyurethane-based, polyethylene glycol-based, and polyester-based adhesives), and cyanoacrylate-based sealants.

8. The composition for use according to claims 5 to 7, wherein the surgical sealant and / or adhesive is BIOGLUE®.

9. The composition is ９０ Y microspheres and albumin, or ９０ A composition for use according to any of the preceding claims, comprising Y microspheres and glutaraldehyde.

10. The composition for use according to any of the prior claims, wherein the composition has an activity of 0.1 to 300 MBq before administration.

11. A composition for use according to any of the prior claims, wherein the target absorbed dose is 120 Gy to 150 Gy, preferably 150 Gy.

12. The composition for use according to any of the prior claims, wherein the composition is administered to a patient in need thereof.

13. The composition for use according to any of the prior claims, wherein the composition is administered by image-guided intratumor injection.

14. The composition for use according to any of the prior claims, wherein the composition is prepared for transdermal administration to provide brachytherapy to a tumor.

15. A method for preparing a composition for use according to any of the prior claims. - To determine the average tumor size of the tumor lesion, - Using the above average tumor size ９０ Select the Y syringe activity level, - below ９０ Y syringe activity level, ○ 0.7 ± 20% MBq (when the average tumor size corresponds to a diameter of 5 mm or less); ○ 3 ± 20% MBq (corresponding to an average tumor size of more than 5 mm in diameter but less than or equal to 10 mm); ○ 10 ± 20% MBq (when the average tumor size is greater than 10 mm but less than or equal to 15 mm in diameter); ○ 22 ± 20% MBq (when the average tumor size is greater than 15 mm in diameter but less than or equal to 20 mm); ○ 33–42 ± 20% MBq (corresponding to an average tumor size of more than 20 mm in diameter but less than or equal to 25 mm); ○ 55 ± 20% MBq (corresponding to an average tumor size of more than 25 mm in diameter but 30 mm or less); ○ 86 ± 20% MBq (when the average tumor size is greater than 30 mm but less than or equal to 35 mm in diameter); ○ 130 ± 20% MBq (when the average tumor size is greater than 35 mm in diameter but less than or equal to 40 mm); ○ 183 ± 20% MBq (corresponding to an average tumor size of more than 40 mm in diameter but 45 mm or less) or, The method comprising providing a dual-chamber syringe having 250 ± 20% MBq (when the average tumor size corresponds to a diameter of more than 45 mm to 50 mm or less).

16. The dual-chamber syringe described above, - A first chamber pre-filled with a surgical sealant and / or adhesive (e.g., a tissue glue component such as bovine serum albumin), The method according to claim 15, comprising: a second chamber pre-filled with a curable carrier (e.g., glutaraldehyde).

17. The necessary to fill the dual-chamber syringe is the ９０ The method according to claim 15 or 16, further comprising filling the first chamber and / or the second chamber with Y syringe activity level.

18. The necessary to fill the dual-chamber syringe is the ９０ The method according to claim 15 or 16, further comprising filling the first chamber containing the BSA solution with a Y syringe activity level.

19. A method for treating gastrointestinal cancer, for patients suffering from gastrointestinal cancer. ９０ The method includes administering a dose of Y microspheres, wherein the dose is in the range of approximately 0.4 to 220 MBq ± 30%, such as approximately 0.48 MBq ± 30%, approximately 2.4 MBq ± 30%, approximately 7 MBq ± 30%, approximately 17 MBq ± 30%, approximately 28 MBq ± 30%, approximately 30 MBq ± 30%, approximately 48 MBq ± 30%, approximately 75 MBq ± 30%, approximately 114 MBq ± 30%, approximately 160 MBq ± 30%, or approximately 219 MBq ± 30%, or approximately 0.48 ± 30% MBq to approximately 218 ± 30% MBq. ９０ The method comprising the radioactive dose of Y.

20. The aforementioned ９０ Y is a hardening ９０ The treatment method according to claim 16, administered as adhesive Y.

21. The composition for use according to any one of claims 1 to 14, or the method according to any one of claims 15 to 20, wherein the gastrointestinal cancer is selected from the group consisting of hepatocellular carcinoma (HCC), metastatic lesions of the liver originating from primary colon cancer (mCRC), and / or pancreatic lesions.

22. The composition for use according to any one of claims 1 to 14, or the method according to any one of claims 15 to 20, wherein the gastrointestinal cancer is a tumorigenic carcinoma.

23. The composition for use according to any one of claims 1 to 14, or the method according to any one of claims 15 to 20, wherein the gastrointestinal cancer is a metastatic lesion (mCRC) of the liver derived from primary colon cancer.

24. The composition for use according to any one of claims 1 to 14, or the method according to any one of claims 15 to 20, wherein the gastrointestinal cancer is a pancreatic lesion.

25. The composition for use according to any one of claims 1 to 14, or the method according to any one of claims 15 to 20, wherein the gastrointestinal cancer is a pancreatic tumor.

26. The composition for use according to any one of claims 1 to 14, or the method according to any one of claims 15 to 20, wherein the gastrointestinal cancer is hepatocellular carcinoma (HCC).

27. A composition for use according to any one of claims 1 to 14 or 20 to 26, wherein the cancer comprises a tumor with a diameter of 5 mm to 5 cm, or the method according to any one of claims 15 to 20 or 21 to 26.

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