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

Abstract

The present invention relates to dose regimen of a radionuclide for use in the treatment of gastrointestinal cancer, such as hepatocellular carcinoma (HCC), via brachytherapy featuring a two-component surgical sealant and / or adhesive, such as a tissue glue and radioisotope loaded microspheres. The active dose to be administered is in the range of 0.4-220 MBq and is based on the size of the target tumor.

Description

COMPOSITIONS, DEVICES AND KITS FOR SELECTIVE INTERNAL RADIATION THERAPY OF HEPATOCELLULAR CARCINOMAFIELD

[0001] The present invention relates to dose regimen of a radionuclide for use in the treatment of gastrointestinal cancers, such as hepatocellular carcinoma (HCC), pancreatic lesions and liver metastatic lesions derived from primary colon cancers (mCRC) featuring a percutaneously administered two-component surgical sealant and / or adhesive and radioisotope loaded microspheres. The active dose to be administered is in the range of 0.4-220±30% MBq and is based on the size of the target tumor.BACKGROUND

[0002] The technologies and methods relate generally to radiation therapeutics, and more specifically to compositions, devices and methods for the use of compositions comprising a carrier matrix and radiotherapeutic particles for the treatment of various oncologic and proliferative diseases, including but not limited to breast cancer and liver cancer.

[0003] Ductal Carcinoma In-Situ (DCIS), or Stage 0 breast cancer, is a biologically and clinically heterogeneous disease with a natural history influenced by both tumor- and host- related factors. Consequently, DCIS treatment after breast conserving surgery (BCS) remains controversial. It has been estimated that nine patients have to be treated to prevent one local recurrence, but some trials have shown that use of intraoperative radiotherapy (IORT) in some selected groups of low-risk early breast cancer patients result in acceptable outcomes and could therefore serve as an alternative to conventional whole-breast irradiation.

[0004] External -beam radiotherapy of the breast after BCS reduces the local breast tumor recurrence rate from 25 - 30% to less than 10% at 10 years. However, it is still a problem to find the optimal therapy modality for the remaining 10% of breast cancer patients presenting with a tumor recurrence years after BCS and External-beam radiotherapy (EBRT). The normal tissue tolerance does not allow, even after years, a second full-dose course of radiotherapy to the entire breast after a second BCS. Especially for patients with small, localized recurrences, in whom a local excision would technically be possible, mastectomy is generally preferred over BCS forfear of worse outcome due to omission of radiotherapy. Until the 1980s, mastectomy was the reference treatment for DCIS patients, with an approximate 98% rate of local control. Based on not only the disease extension and / or multi-centricity, but also in consideration of the patient’s preferences, mastectomy continues to be performed after 2000 in at least one third of DCIS cases. Recent US data in early breast cancer (stage I and II) has shown that, due to poor access to radiation therapy and low patient compliance to treatment, up to 60% of patients may not receive any radiation therapy, and thus mastectomy is still used.

[0005] However, with increasing advances in diagnostic modalities and regular follow-up visits, recurrent breast tumors are often diagnosed at a very small tumor size. Furthermore, the most common and survival-limiting problem for these patients is usually not the local situation within the breast, but the increased risk of developing distant metastases. Finally, more than 90% of all ipsilateral breast tumor recurrences occur near the index tumor. A novel option is to treat these patients after re-resection of the recurrent tumor with partial breast irradiation. This approach is based on the hypothesis that re-irradiation to a limited volume will be effective and result in an acceptable frequency of side effects. IORT is one option to deliver high doses to a restricted area at risk, i.e. the adjacent tissue to the tumor cavity after tumor resection. IORT can be delivered with dedicated linear accelerators in the operation room or novel mobile devices using electrons or low-energy x-rays.

[0006] IORT, in which postoperative whole-breast irradiation is substituted for one session of radiotherapy with the same equivalent dose during surgery, allows treatment to be completed on the same day. Recent trials such as electron intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT trial) and targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial) have demonstrated that IORT in some selected groups of low-risk early breast cancer patients results in acceptable outcomes and could, therefore, serve as an alternative to conventional WBRT.

[0007] In the ELIOT trial, 1305 patients were randomized (654 to external radiotherapy and 651 to intraoperative radiotherapy) with a follow up of 5-8 years. Results from this trial showed that local recurrence in the intraoperative radiotherapy group was lower than that achieved after mastectomy in a previous study (the Milan I trial). The TARGIT-A trial was a randomized, noninferiority trial that compared risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (TARGIT) versus fractionated EBRT for breast cancer. The results at 5 years of3451 patients (1721 patients were randomized to TARGIT and 1730 to EBRT) demonstrated that TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer. This trial showed non-inferiority regarding local control after intraoperative radiotherapy (IORT) with 20 Gy which was followed by whole breast radiotherapy (WBRT) in patients with risk factors only in comparison to standard WBRT (50-56 Gy) after breast-conserving surgery in selected patients. The meta-analysis of Vaidya et al. showed that in women with breast cancer, there is a small but definite reduction in mortality when partial breast irradiation (PBI) is given instead of whole breast irradiation (WBI). On the basis of 2 statistical models used by Vaidya et al., the absolute difference in non-breast cancer mortality was 1.1% to 1.3% and was statistically significant (P=.O23 or P=.O11). The absolute difference in overall mortality was likely to be between 1.0% and 1.3%. The low P values of P=.15 or P=.O5 indicated the improbability of observing this difference if there was no real difference between PBI and WBI. Given that the total mortality was only 4.9% (207 of 4231), in relative terms, this was a 25% reduced mortality with PBI; thus it would also be clinically significant.

[0008] Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults, and is the most common cause of death in people with cirrhosis. It occurs in the setting of chronic liver inflammation, and is most closely linked to chronic viral hepatitis infection (hepatitis B or C) or exposure to toxins such as alcohol or aflatoxin. Certain diseases, such as hemochromatosis and alpha 1 -antitrypsin deficiency markedly increase the risk of developing HCC, while metabolic syndrome and non-alcoholic steato-hepatitis are increasingly recognized as risk factors for HCC. As with any cancer, the treatment and prognosis of HCC vary depending on the specifics of tumor histology, size, local / distant spread, and overall health. Outcomes are significantly improved if treatment is initiated earlier in the disease process. Subjects with early stage HCC are normally offered three types of therapy: (1) orthotopic liver transplantation, in selected cases; (2) surgical resection of the affected hepatic segment; (3) loco- regional therapy, which include percutaneous or catheter-based therapies. Most current forms of percutaneous ablation have been shown to be as effective as surgical resection. They are also less invasive and demanding for the patient and for the medical facilities. It is difficult, however, in many cases to achieve a negative “surgical” margin, for a number of reasons, including the size of the lesion and its anatomical location. This means that surrounding areas to the tumorallesion bearing satellite micro-metastases can be missed and not necrotized. This, in turn, makes recurrence of the tumor a clear possibility. The currently reported overall success rate is in fact 70-80% for thermal ablation (e.g. radio frequency, laser, microwave), 70-80% for cryo-ablation, and 60-80% for ethanol injection (data Mayo Clinic 2017). Therefore, at least 20% of tumoral lesions will be followed by local recurrence.

[0009] Percutaneous local ablation (PLA) techniques are currently considered as the best treatment option for patients with early-stage HCC who are not candidates for surgical resection. They are safe, minimally invasive, efficacious and cost-effective. Radiofrequency ablation is considered as the first-line treatment in some centers, though most of the guidelines recommend it for small HCCs, where surgical resection is not feasible. PLA is a relatively simple minimally invasive procedure that selectively targets the tumor and an additional intentional margin of healthy tissue from 0.5 to 1.0 cm. This additional margin helps to achieve complete ablation (A0) similar to R0 resection after surgery. Moreover, hepatic resection is not an ideal treatment for very small sized cases of HCC because of 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 of colorectal cancer liver metastases. A strong consensus level was achieved for the treatment of nodules up to 5 cm when well located (with easy access). Likewise, a strong level of consensus was achieved for combination strategies with respect to systemic treatments alone. The panel also agreed in considering PLA as potentially curative in resectable patients when used as a first-line treatment. The clinical effectiveness of selective internal radiation therapy (SIRT, also known as Trans Arterial Radio Embolization, TARE) using biradiolabelled lipiodol was first demonstrated in 1994 based on a randomized study in patients with portal vein thrombosis. In particular, one retrospective study has shown that glass microspheres are able to achieve a significantly improved rate of down-staging compared to chemoembolization, with significantly fewer side effects in patients with stage T3 HCC, while another study has shown that progression-free survival is significantly improved in patients with HCC who were treated with locoregional therapies, such as chemoembolization and radioembolization.90Y resin microspheres (SIR-SPHERES® — Sirtex Medical) is a CE-marked brachytherapy device, recommended through the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines for the treatment of chemo-refractory colorectal cancer liver metastases in selected patients with liver-only or liver-dominant disease.BRIEF SUMMARY

[0010] Because of the clinical experience accumulated in over 15 years of treatments based on trans-arterial infusion of90Y-coated microspheres, it is believed that the administration of the appropriate activity of90Y should reduce the chances of local recurrence, which occurs in the vast majority of cases in the surgical bed. As disclosed herein, specific active doses of90Y- coated microspheres e.g., embedded in a surgical sealant and / or adhesive such as a tissue glue material, is efficacious in the treatment of hepatocellular carcinoma (HCC) and appears to have a better safety / tolerability profile compared to transarterial radioembolization, such active doses may be in the range of 0.4-220 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, wherein the tumor size may vary from 5mm to 50 mm, and the dose may be adjusted according to the tumor size. In some variations, the active dose deviates with ±30%, such as ±5, 10, 15, 20 or ±25%, preferably ±20%. The treatment may also be suitable for different types of gastrointestinal cancers such as e.g., HCC or liver metastatic lesions derived from primary colon cancers (mCRC). In particular variations the gastrointestinal cancer is hepatocellular cancer (HCC) and / or liver metastatic lesions derived from primary colon cancers (mCRC). Additionally in some variations the treatment may also be suitable 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 mammal, e.g. a human, patient may be treated with a combination of90Y microspheres and a localizing carrier agent, including but not limited to a bioglue or hydrogel. The combination therapy may be injected directly into a tumor, post-surgical tumor site, or biopsy site. In some further variations, the combination therapy may be provided without requiring a pre-treatment imaging, e.g. a Technetium-99 scan, to assess for any shunting to the liver or lungs or other off-target locations, such as a variceal or arteriovenous malformation (AVM). This is due to the reduction, minimization or elimination of shunting effect of the localizing carrier. In turn, because pre-treatment imaging to assess shunting is not required, pretreatment procedures to treat potential shunting are also not required. This can potentially reduce the time-to-treatment by one, two, three, four, five, six or seven days or more, because treatment is not delayed by pre-treatment shunt imaging, pre-treatment shunt reduction procedures, and pre-treatment rescanning to assess the effectiveness of the shunt reduction procedures. The shunt procedures that would no longer be required or performed may include arterial embolization,hepatic vein balloon occlusion, and variceal and AVM occlusion procedures. Because dosing adjustments to account for the shunting are no longer required, dosing calculations may also be simplified, e.g. no longer requiring adjustments based on the shunt fraction and / or lung dosing limit. Patients with substantial liver, lung or hepatopulmonary shunt fractions also do not need to be excluded from therapy anymore. One or more of these features of tumor treatment protocols may be included in the various treatments described herein.

[0012] In one example, a method of treating a human patient is provided, comprising performing a90Y dose calculation to determining a therapeutically effective90Y dosage for a tumor site with the localizing carrier and delivering the90Y dosage to the tumor site with the localizing carrier, wherein treatment extends progression-free survival compared to delivering90Y dosage without the localizing carrier. In some further examples, pre-treatment imaging to assess shunting is not required. The treatment time may be reduced by at least one day by not performing pre-treatment imaging. The pre-treatment imaging scan may not be required or may be performed may be a Technetium-99m scan. The shunting may be hepatopulmonary shunting. The localizing carrier may be a combination of glutaraldehyde and bovine serum albumin. The tumor site is an unresected tumor or a resected tumor bed. In some examples, the calculation of the pre-procedure shunt fraction estimation and / or post-procedure biodistribution imaging is not performed. Pre-treatment with arterial embolization, hepatic vein balloon occlusion, and / or variceal or arteriovenous malformation occlusion is not required. In some embodiments, the90Y dose calculation does not include an adjustment based on the shunt fraction estimation and / or a lung dosing limit. The lung dosing limit may be 30 Gy or less in a single treatment procedure and 50 Gy or less with multiple procedures. The method may not exclude patients above a shunt fraction limit, e.g. a hepatopulmonary shunt fraction limit of 20% or more.

[0013] In another embodiment, a method of treating a patient with90Y without performing a pre-treatment Technetium-99m scan is provided, and in another embodiment, a method of treating a patient with90Y without determining shunt fraction. In still another embodiment, a method of treating a patient with90Y without performing any exclusion of patients above a hepatopulmonary shunt fraction limit is provided.

[0014] Exemplary devices, kits and methods are disclosed using a combined90Y-matrix and delivery system to treat patients with DCIS or other forms of early breast cancer, and to assess effectiveness and safety of radioactivity -based ablation of surgical margins following DCISresection. Exemplary devices, kits and methods are used to treat hepatocellular carcinoma, including but not limited to injection or administration into a lesion, or to a treatment site following resection of a lesion. The delivery kit comprising a coaxial dual-lumen catheter used to provide direct, imaging -guided intra-tumoral injection of the90Y microsphere-matrix combination.

[0015] In some variations, the patients selected for treatment may comprise patients with Stage 0 breast cancer (e.g., DCIS) who are treated with intra-tumoral or tumor bed injection. In other variations, the patients may have Stage I or II breast cancer who are treated by intra- tumoral injection or treatment of the tumor bed post-lumpectomy. This may also include Stage IIA and / or IIB patients and include intra-tumoral injection into one or more axillary lymph nodes.

[0016] The90Y-matrix and delivery system is believed to allow for an effective and safe radioablation of surgical margins following DCIS resection, thus offering a new procedure in the armamentarium of loco-regional treatments for early breast cancer, compared to90Y microsphere treatment alone.

[0017] In other variations, the patient selected for treatment may comprise patients with hepatocellular carcinoma, with metastatic liver tumors, whether resectable or unresectable. Patients with HCC may include those with Tl, Tla, Tib, T2, T3, or T4 primary tumors, as well as those with or without or unknown regional lymph nodes metastases involvement and / or distal metastases, including Stage IA, IB, II, IIIA, IIIB, IVA and IVB HCC patients. Treatment may include intra-tumoral administration or post-resection administration to the tumor bed in the liver, lymph node or distal metastasis site.

[0018] In one example, the90Y-matrix system is a combination of BIOGLUE® (CryoLife; Kennesaw, GA), a mixture of bovine serum albumin and glutaraldehyde in a 4: 1 ratio, and SIR- SPHERES® microspheres (Sirtex Medical; North Sydney, AU) coated with90Y, a pure P emitter isotope. The mixture is delivered using a dual-chamber syringe. Pre-loaded microspheres with90Y are then blended with glue components, and used to perform radio-ablation of the surgical margins of the treatment site.

[0019] In various examples, systems, kits and methods for preparing an injection system and / or treating target lesions with a selective internal radiation therapy includes a double-barrel syringe loaded with a two-component surgical sealant and / or adhesive, such as a tissue glue, andradioisotope loaded microspheres are provided. The microspheres are loaded into the syringe based on the size of the target location and are injected with a needle or dual-lumen catheter. Dosing regimens for treating breast cancer lesions up to 130 mm in diameter and hepatocellular carcinoma lesions up to 50 mm are included.

[0020] In one example, a method of preparing an implantable radiotherapeutic is provided, comprising mixing radioisotope microspheres with a suspension medium, wherein the microspheres are located in the suspension medium contained in a first container, determining a transfer volume of the mixed microspheres based on a target size, loading an injection system with the transfer volume, the injection system comprising a first compartment with a first cross- sectional area and a second compartment with a second cross-sectional area, the first and second cross-sectional areas having a ratio of XY, transferring a first proportion of the transfer volume to the first compartment, and transferring a second proportion of the transfer volume to the second compartment, wherein the first proportion and the second proportion have a proportion ratio of XY. The radioactive microspheres may be provided in a settled state in a container within a predetermined volume of the suspension medium. The method may further comprise removing a removal volume of the suspension medium from the pre-determined volume of the suspension medium before mixing the radioactive microspheres with the suspension medium. The removal volume may be 2 mL and the pre-determined volume of suspension medium may be 5 mL. The first proportion of the transfer volume may be X / (X±Y) of the transfer volume and wherein the second proportion of the transfer volume is Y / (X±Y) of the transfer volume. The injection system may be a double-barrel syringe, comprising a first barrel with the first compartment and a second barrel with the second compartment. The ratio of the first cross-sectional area to the second cross- sectional area may be 4: 1. The first barrel may be preloaded with a first substance and the second barrel may be preloaded 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 comprise an activity level in the range of 0.1 MBq to 250 MBq. Since residual activity is present in the syringe, the active level may deviate with up to ±30%, Accordingly, the transfer volume may comprise an activity level in the range of 0.1 MBq to 250 MBq±30%. Preferably, the activity level deviates with up to ±20%. The activity level may be in the range of 0.3 MBq to 220 MBq, and the transfer volume may be in a range of 0.3 pL to 220 pL. The target size may be in a range of 1 mm to 50 mm in average diameter. The transfer volume may comprisean activity level in the range of 10 MBq to 200 MBq. The transfer volume may comprise an activity level 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 a range of 100 pL to 750 pL. The target size may be in a range of 40 mm to 130 mm in average diameter. The first substance may comprise an albumin and the second substance may comprise glutaraldehyde. The radioactive microspheres may comprise an activity level of 1.5 GBq or less, or 3 GBq or less and the pre-determined volume of suspension medium may be 5 mL or less. The mixing of the radioisotope microspheres and the loading of the injection system may be both performed by a shielded transfer syringe with a needle with a length in the range of 50 mm to 100 mm. The method may further comprise verifying an activity level of the transfer volume of the radioisotope microspheres by determining an activity level of the container after loading the injection system, or determining an activity level of the injection system after loading the injection system. The method may further comprise placing the loaded injection system into a radioprotective vessel. The method may further comprise disposing of a portion each of the first and second substances in a volume ratio of XY and wherein the total of the two portions is equal to the transfer volume of the mixed microspheres.

[0021] In another example, a method of treating a patient is provided, comprising delivering a treatment volume of mixed radioactive microspheres to a lesion, wherein the lesion includes the tumor lesion and / or the post-surgical lesion site, using a double barrel syringe with a mixing tip, wherein the first barrel of the syringe contains bovine serum albumin and the radioactive isotope, and the second barrel of the syringe contains glutaraldehyde and the radioactive isotope. The method may further comprise loading each barrel of the double barrel syringe with different amounts of the radioactive microspheres based on a size of the lesion. In other variations, the method may comprise loading only one of the two barrels of the double barrel syringe with the radioactive microspheres, e.g. the larger or smaller of the two barrels, or the barrel containing the more viscous material, e.g. the barrel containing the bovine serum albumin. The double-barrel syringe, prior to injection, may comprise a total injectable volume between 2.1 and 2.5 mL and an activity of 20 to 90 MBq. The treatment location may have an average radius of 20 to 45 mm. The treatment volume injected may be the total injectable volume. The double-barrel syringe, prior to injection, may comprise a total injectable volume between 5.1 and 6 mL and an activity of 90 to 150 MBq. The treatment volume injected may be equal to the total injectable volume. The lesion may be a hepatocellular carcinoma lesion. As is shown in Example 10, doses of 150Gy were welltolerated. The dose at the lesion may be at least 150 Gy. The double-barrel syringe, prior to injection, may comprise a total injectable volume between 2.0001 and 2.05 mL and an activity of 0.3 to 30 MBq. The lesion may have an average radius of 0.5 to 25 mm. The treatment volume delivered may be the total injectable volume. The barrel syringe, prior to injection, may comprise a total injectable volume between 5.01 and 5.5 mL and an activity of 20 to 250 MBq. The doublebarrel syringe, prior to injection, may comprise a total injectable volume between 2.0001 and 2.05 mL and an activity of 0.3±20% to 30 MBq±20%. The lesion may have an average radius of 0.5 to 25 mm. The treatment volume delivered may be the total injectable volume. The barrel syringe, prior to injection, may comprise a total injectable volume between 5.01 and 5.5 mL and an activity of 20±20% to 250±20% MBq. The ductal carcinoma in situ lesion or resection site may have an average radius of 25 to 50 mm. The treatment volume injected may be equal to the total injectable volume. The concentration of bovine serum albumin may be between 30 and 60 percent by weight. The concentration of glutaraldehyde may be between 5 and 15 percent by weight.

[0022] In still another example, a method of treating a patient is provided, comprising removing from a sealed sterile package a double barrel syringe, wherein each barrel may be pre-loaded with a different volume of a different substance, the total volume of the different substances may be 5 mL or less, determining a transfer volume of a radioactive microsphere suspension based on a lesion size, and transferring different size portions of the transfer volume of the radioactive suspension to 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 pL and the activity level may be less than 300 MBq and the lesion may be between 25 mm and 50 mm in average diameter. The method may further comprise treating the lesion with a total volume of the different substances and radioactive microsphere suspension between 5.01 and 5.3 mL. 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 pL and the activity level may be less than 30 MBq and the lesion may be between 0.3 mm and 30 mm in average diameter. The method may further comprise treating the lesion with a total volume of the different substances and radioactive microsphere suspension that 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 comprising a first barrel with a first sliding seal and a first cross sectional area, and containing a first glue component, a second barrel with a second sliding seal and a second crosssectional area and containing a second glue component, a driver configured to dispense a fixed proportion of the first and the second glue components from the first and second barrels, a radioisotope loaded in at least one of the first and second barrels, a plurality of indicia of lesion sizes provided on the double barrel syringe, comprising uniform size intervals across a size range that are spatially located at non-uniform intervals along the double barrel syringe. The driver may be an interconnected double plunger attached to the first and second sliding seals and may be configured to move the first and second sliding seals at equal longitudinal distances. 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 radioisotope may be90Y with an activity level between 10 and 250 MBq. The radioisotope may be90Y with an activity level between 10 and 100 MBq and wherein the plurality of indicia of lesion sizes may include lesion diameters in the range of 40 mm to 90 mm. The radioisotope may be90Y with an activity level between 80 and 160 MBq and wherein the plurality of indicia of lesion sizes may include lesion diameters in the range of 90 mm to 130 mm. The radioisotope may be90Y with an activity level between 0.1 and 50 MBq and wherein the plurality of indicia of lesion sizes may include lesion diameters in the range of 0.5 mm to 25 mm. The radioisotope may be90Y with an activity level between 25 and 250 MBq and wherein the plurality of indicia of lesion sizes 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, comprising determining a treatment dosage using the target activity level Ao and mass of the target tissue using Davg(r = — — — , wherein the delivered energy per unit activity k(r) is based on the radius of the target tissue. In some variations, the k(r) value is 49.35 (J / GBq). In additional embodiments, a method for preparing a composition for use in treatment of HCC is provided, wherein the method e.g., comprises; determining an average tumor size of a tumor lesion; selecting a90Y syringe activity level using the average tumor size; and providing a dual chamber syringe with a90Y syringe activity level of; 0.7 MBq for an average tumor size corresponding to a diameter up to 5 mm; 3 MBq for an average tumor size corresponding to a diameter greater than 5 mm and up to 10 mm; 10 MBq for an average tumor size corresponding to a diameter greater than 10 mm and up to 15 mm; 22 MBq for an average tumor size corresponding to a diameter greater than 15 mm and up to 20 mm; 33-42 MBq for an average tumor size corresponding to a diameter greater than 20 mm andup to 25 mm; 55 MBq for an average tumor size corresponding to a diameter greater than 25 mm and up to 30 mm; 86 MBq for an average tumor size corresponding to a diameter greater than 30 mm and up to 35 mm; 130 MBq for an average tumor size corresponding to a diameter greater than 35 mm and up to 40 mm; 183 MBq for an average tumor size corresponding to a diameter greater than 40 mm and up to 45 mm; or 250 MBq for an average tumor size corresponding to a diameter greater than 45 mm and up to 50 mm. The activity levels may be 10 % lower to 10 % higher of the above-mentioned amounts. The activity levels may be 20 % lower to 20 % higher of the above-mentioned amounts. The activity levels may be 30 % lower to 30 % higher of the above- mentioned amounts. Preferably, said dual chamber syringe comprises; a first chamber is pre- loaded with surgical sealant and / or adhesive, such as a tissue glue component, such as bovine serum albumin; and a second chamber pre-loaded with a solidifying carrier, such as glutaraldehyde. In addition, the dual chamber syringe is preferably further loaded with the appropriate90Y syringe activity level into the first and / or second chambers.

[0025] The target tissue radius may include one or more target tissue radii in the range of 0.5 cm to 2.0 cm. The method may further comprise loading an amount of90Y into a two-chamber syringe, wherein the amount is based on the determined treatment dosage. The amount of90Y may be further based on syringe size, and may be further based on syringe size and dead space associated with the syringe size. The two chambers of the syringe may each hold one component of a two-component glue or carrier composition. A first chamber of the syringe comprises albumin and a second chamber comprises glutaraldehyde. The90Y may be loaded into both the first and the second chambers of the syringe. In other variations, the90Y is loaded only in one of either the first or second chamber of the syringe. The method may further comprise injecting the90Y and glue or carrier composition through a mixing tip attached to the two-chamber syringe, wherein the mixing tip comprises a shaft with a plurality of angle mixing structures. In another embodiment, a non-transitory computer-readable medium is provided, comprising a computer program product comprising one or more computer instructions to perform the determination of the treatment dosage as described above, when the computer program is run on one or more processors.

[0026] In another embodiment, a non-transitory computer-readable medium is provided, comprising one or more computer instructions, comprising determining a90Y treatment dosage based on a fractional tumor uptake correlated to tumor size and an average90Y tissue penetration distance of 4 mm. The computer instructions may further comprise instructions to output a firstvolume of90Y to be transferred into a syringe delivery device, to output a transfer syringe size, to optionally output a first chamber of the syringe delivery device for the transfer of the first volume of90Y, to optionally determine output of a second volume of90Y to be transferred into the syringe delivery device and / or to optionally output a second chamber for the transfer of the second volume of90Y. In another variation, the computer-readable medium may further comprise computer instructions to determine a target volume of a carrier composition, output the target volume of the carrier composition, and determine and output a waste volume of the carrier composition based on the transfer syringe size. Output may be provided on a display screen, and may include numerical output and / or pictoral output of a syringe with graphical indicator of the numerical output. The computer program product may perform the steps above when the computer is run on one or more processors.

[0027] In still another embodiment, a kit for performing radiotherapeutic procedures is provided. The kit may comprise two sterile 1 mL syringes, two Luer locks, two 22G needles, two sterile 20G x 70 mm needles and two PMMA cylinders, each configured to retain a 1 mL or 2 mL syringe. In other variations, the two 20G x 70 mm needles may be substituted with any needles that are 20G or larger in size and comprise a length of at least 50 mm, and / or the PMMA cylinders may comprise a non-circular cross-sectional shape, e.g. square or polygon shape, and may comprise a metal or polymeric material other than PMMA. In some further embodiments, the kit may optionally further include an additional lead pot, an empty vial for dilution and / or mixing of90Y microspheres and / or water for injection.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG. 1 A is an exemplary component view of the stylet, introducer and catheter that may be used with exemplary procedures; FIG. IB depicts the catheter and introducer of FIG. 1 A wherein the catheter is inserted into the introducer and their hubs are locked together;

[0029] FIGS. 2 A and 2B are anteroposterior and posteroanterior views of a syringe cylinder loaded with90Y microspheres in a BIOGLUE® carrier;

[0030] FIGS. 3A and 3B are PET / CT and CT scans, respectively, of a radiogel loaded in a plastic sphere;

[0031] FIGS. 4A to 4C depict the absorbed doses of 0.5 mL, 4.2 mL and 11.4 mL volumes, respectively, filled with a90Y-matrix composition;

[0032] FIG. 5 is a graphical plot of the percentage activity per distance from the center of the three cavities in FIGS. 4 A to 4C;

[0033] FIG. 6 is a graphical plot of the estimated Grays per MBq per distance from the center of the three cavities in FIGS. 4A to 4C;

[0034] FIG. 7 is a graphical plot of the estimated total absorbed dose per distance from the center of the three cavities in FIGS. 4 A to 4C;

[0035] FIG. 8A are transverse CT views of a mouse with a thigh tumor; FIG. 8B are composite transverse CT / PET / SPECT views of the mouse in FIG. 8A depicting tumor activity; FIG. 8C are the PET / SPECT image components from FIG. 8B; FIG. 8D are transverse CT views of another mouse with a thigh tumor; FIG. 8E are composite transverse CT / PET / SPECT views of the mouse in FIG. 8D depicting tumor activity; FIG. 8F are the PET / SPECT image components from FIG. 8E;

[0036] FIG. 9A is a schematic cross-sectional view of a dual-lumen catheter shaft with concentric lumens; FIG. 9B is a schematic cross-sectional view of a dual-lumen catheter shaft with eccentric lumens; FIG. 9C is a schematic cross-sectional view of a dual-lumen catheter shaft with an arcuate septum between the two lumens; FIG. 9D is a is a schematic cross-sectional view of a dual-lumen catheter shaft with a straight septum between the two lumens;

[0037] FIG. 10A is a photograph of another example of a dual -lumen catheter delivery kit; FIG. 10B is a close-up photograph of the proximal end of the catheter and the combined introducer and stylet; FIG. 10C is a longitudinal cross-sectional view of the proximal end of the catheter in FIGS. 10A and 10B; FIG. 10D is a longitudinal cross-sectional view of the proximal end of the introducer in FIGS. 10A and 10B;

[0038] FIGS. 11 A and 1 IB are side and superior cross-sectional CT views of an explanted tumor, respectively; FIGS. 11C and 11D are composite side and superior cross-sectional CT / PET / SPECT views of the explanted tumor in FIGS. 11 A and 1 IB, respectively; FIGS. 1 IE and 1 IF are the PET / SPECT image components from FIGS. 11C and 1 ID, respectively;

[0039] FIGS. 12A and 12B are side and superior cross-sectional CT views of another explanted tumor, respectively; FIGS. 12C and 12D are composite side and superior cross- sectional CT / PET / SPECT views of the explanted tumor in FIGS. 12A and 12B, respectively; FIGS. 12E and 12F are the PET / SPECT image components from FIGS. 12C and 12D, respectively;

[0040] FIGS. 13A and 13B are side and superior cross-sectional CT views of another explanted tumor, respectively; FIGS. 13C and 13D are composite side and superior cross- sectional CT / PET / SPECT views of the explanted tumor in FIGS. 13A and 13B, respectively; FIGS. 13E and 13F are the PET / SPECT image components from FIGS. 13C and 13D, respectively;

[0041] FIGS. 14A to 14C are lOx magnification histology slides with 20x magnificent insets at post-treatment 7, 14 and 21 days of a resection bed in an animal following intra-tumoral injection of a90Y-matrix, with arrows indicating the areas of necrosis; FIGS. 14D to 14F are lOx magnification histology slides with 20x magnificent insets at post-treatment 7, 14 and 21 days of a resection bed in an animal following intra-tumoral injection of90Y without any matrix; FIGS. 14G to 141 are lOx magnification histology slides post-treatment 7 and 14 days of a resection bed in an animal following intra-tumoral injection of matrix without any90Y; FIG. 14J is a graph of the percentage necrosis of each arm of the study at 1, 2 and 3 weeks;

[0042] FIG. 15 illustrates the Western Blot analyses of p53 and P-tubulin expression for the90Y matrix and90Y-only treatment groups;

[0043] FIG. 16 is a graph of the tumor volume at selected time-points for the90Y matrix,90Y- only and localizing carrier treatment groups;

[0044] FIGS. 17A and 17B depict the organ system biodistribution of90Y microspheres and90Y-matrix, respectively; FIGS. 17C and 17D depict the organ system biodistribution of90Y-only and90Y-matrix at 7 days, respectively, and FIGS. 17E and 17F depict the organ system biodistribution of90Y-only and90Y-matrix at 14 days, respectively;

[0045] FIG. 18 is a graph of the fraction of90Y absorbed dose into the tumor as a function of tumor size, with simulations performed for =1.00 g / cm3(water density) and p= .05 g / cm3(liver density);

[0046] FIG. 19 is a graph of the90Y beta spectrum implemented in the model used in FIG 18 A;

[0047] FIG. 20 is a graph of the delivered energy per unit activity of90Y, k(r), calculated with MCNP4c as a function of the tumor diameter;

[0048] FIG. 21 is a graph of the residuals as a function of the tumor diameter;

[0049] FIG. 22 is a graph of the absorbed dose per unit administered activity (GBq), for p= .05 g / cm3(liver density), with an inset depicting the detail in the range from 0 cm to 1 cm lesion diameter;

[0050] FIG. 23 is a graph of the absorbed dose per unit administered activity for =1.00 g / cm3(water density), with an inset depicting the detail in the range from 0 cm to 1 cm lesion diameter;

[0051] FIG. 24A and 24B are graphs of the90Y biodistribution between the90Y matrix and90Y-only treatment groups at 1 and 3 weeks, respectively; and

[0052] FIGS. 25A and 25B are graphs depicting the90Y biodistribution between tumor and non-tumor locations of the90Y matrix and90Y-only treatment groups, respectively.

[0053] FIGS. 26 A and 26B are axial and coronal MRI images, respectively, of a patient with a HCC nodule.

[0054] FIGS. 27A to 27C are ultrasound images of a treatment procedure during the targeting, injection and post-injection phases, respectively.

[0055] FIGS. 28 A and 28B are axial and coronal Y90 PET CT images, respectively, of the patient in FIGS. 26A and 26B depicting post-injection distribution of Y90 therapy.

[0056] FIGS. 29 A and 29B are axial and coronal MRI images, respectively, of the patient in FIGS. 26A-26B and 28A-28B, three weeks post-injection, documenting a complete response.DETAILED DESCRIPTION

[0057] As disclosed herein, compositions providing specific active doses of90Y-coated microspheres e.g., embedded in a surgical sealant and / or adhesive, such as a tissue glue material, is efficacious in the treatment of a gastrointestinal cancer, such as hepatocellular carcinoma (HCC) or liver metastatic lesions derived from primary colon cancers (mCRC), preferably HCC, and appears to have a better safety / tolerability profile compared to transarterial radioembolization, such active doses may be in the range of 0.4-220 ±30% 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, or 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, or 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 wherein the tumor size may vary from 5mm to 50 mm, and the dose may be adjusted according tothe tumor size. Such composition may e.g., be administered to a person in the need thereof e.g., via. intratumoral injection. The present composition comprising90Y for use in the treatment of hepatocellular carcinoma (HCC) can be performed by percutaneous administration in order to provide brachytherapy to the tumor.

[0058] A glue, tissue glue or bioglue is in the present context defined as biomaterials that are used as surgical sealants and / or adhesives. Surgical sealants and adhesives can be used as adjuncts to sutures to prevent air and liquid leakages. They can also potentially replace sutures and staples for better closure, minimized blood loss, faster implementation, and easy and less painful operation without the need for removal. They can be classified into three groups: natural polymer based sealants (such as fibrin-, collagen-, and albumin-based sealants), synthetic polymer based sealants (such as polyurethane-, polyethylene glycol-, and polyester-based adhesives), and cyanoacrylate sealants. Thus, 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 sealants and / or adhesives of the invention are selected from the group consisting of natural polymer based sealants (such as fibrin-, collagen-, and albuminbased sealants), synthetic polymer based sealants (such as polyurethane-, polyethylene glycol-, and polyester-based adhesives), and cyanoacrylate sealants. In one or more embodiments of the present invention, the surgical natural polymer-based sealant of the invention is selected from the group consisting of polyurethane-, polyethylene glycol-, and polyester-based adhesives. In one or more embodiments of the present invention, the synthetic polymer-based sealant of the invention is selected from the group consisting of fibrin-, collagen-, and albumin-based sealants. In one or more embodiments of the present invention, the surgical sealant and / or adhesive of the invention is an albumin-based sealant. In one or more embodiments of the present invention, the albuminbased sealant and / or adhesive of the invention is BIOGLUE®. BIOGLUE® may be used for the glue component of the90Y-glue matrix composition. BIOGLUE® is an admixture of bovine serum albumin (BSA; 45% weight / volume in sterile water for injection) and glutaraldehyde (10% weight / volume in sterile water for injection) in a 4: 1 ratio. Accordingly, a composition described herein may comprise90Y microspheres and albumin, or90Y microspheres and glutaraldehyde. In one or more embodiments of the present invention, the surgical sealants and / or adhesives of the invention are selected from the group consisting of PEG + Trilysine amine hydrogel (Duraseal,Integra), Fibrin sealant (thrombin + fibrinogen, Tachosil, Nycomed), and human fibrin sealant (Tisseel, Ethicon).

[0059] In one embodiment, a kit for performing direct injection radiotherapy is provided. The kit comprises a venting needle, a radio-shielded syringe, and an elongate needle of at least 50 mm to 100 mm in length. These components of the kit may be used to transfer radioisotope microparticles from their transport vessel to the matrix-containing syringe. The venting syringe may be inserted through the seal of the transport vessel to break or release any vacuum that may form in the transport vessel during the transfer process, and may be a 18G, 22G, 25G, 28G, 30G, 31G or 32G hypodermic needle. The venting needle may be optionally left in place during the remainder of the procedure, or removed immediately after insertion. The elongate needle is attached to the radio- shielded syringe at either the point-of-use or point-of-manufacture and is used to remove liquid media from the transport vessel.

[0060] In some variations, the kit may comprise an introducer, a dual-lumen catheter, and a needle. The kit may optionally further comprise a radio-shielded syringe, an elongate needle of at least 50 mm to 100 mm in length, and / or a venting needle as described above. In still other variations, the kit may further comprise a glue or matrix, and / or a radioisotope source, but in other examples, the glue / matrix, and / or the radioisotope are sourced separately from the kit. In these variations, the kit may further comprise adapters configured to couple the kit components to a third party injector system selected by the user, or one or more of the kit components may be configured to couple to a third party glue / matrix syringe or injection system. Accordingly, a composition comprising a radioisotope, in particular90Y, and a glue / matrix is also provided.

[0061] The90Y source may comprise a vial of radiotherapeutic microspheres. The vial may be a clear unshielded glass vial, that may be removably provided in a lead lined pot or other container. A vial containing 3 GBq of90Y in 5 mL of water or other suspension liquid are provided. The90Y is a pure, high energy (maximum energy 2.227 MeV, mean 0.93 MeV), P- emitter isotope. Its half-life is 64.1 hours; the maximum penetration in tissues is 11 mm with a mean of 2.5 mm. The vial may be provided in a lead pot or other shielded container. The vial or other packaging may contain calibration or validation data, and / or a code to access online regarding the same, so that the treating healthcare provider can compensate for any radioactive decay that has occurred since the initial manufacture and validation. In other examples, however, the amount of microsphere activity may be different, e.g. 100 MBq, 200, MBq, 300MBq, 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 of between any two of these activity levels, and the number of microspheres per vial may be different, e.g. 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 microsphere counts. In one specific example, the90Y source may comprise 2.4 GBq particles in 3 mL of water.

[0062] In one particular embodiment, SIR-SPHERES® may be used for the source of the90Y or90Y particles. SIR-SPHERES® is a solution of biocompatible microspheres containing about 40 to about 80 million microspheres in 5 mL water. The microspheres comprise a nonbiodegrading resin with diameters between 20 and 60 microns (pm), containing90Y, a pure, high energy (maximum energy 2.227 MeV, mean 0.93 MeV), P-emitter isotope. The half-life is 64.1 hours; the maximum penetration in tissues is 11 mm with a mean of 2.5 mm. SIR-SPHERES® microspheres are a permanent implant (e.g. the microspheres are not metabolized or excreted after implantation). 94% of total radiation is locally delivered in 11 days. SIR-SPHERES® microspheres are provided by the manufacturer in a shielded (6.4 mm of thickness) vial with water for the administration. Each vial contains approximatively 3 GBq of90Y in a final volume of 5 mL, or alternatively 2.4 GBq of90Y in a final volume of 3 mL, or in a range from 2-3 GBq in a final volume of 2-5 mL, or 2-3 mL; the number of microspheres ranges between 40-80 x 106 / vial, or 32-64 x 106 / vial. The SIR-SPHERES® vial should be stored at 15-25°C.

[0063] The potential adverse events associated with the use of SIR-SPHERES® include:• fever• transient decrease of hemoglobin• mild to moderate abnormality of liver function tests (e.g. mild increase in ALT, AST, alkaline phosphatase, and / or bilirubin)• abdominal pain• nausea• vomiting• diarrhea

[0064] As described previously, the kit may further optionally comprise a glue or matrix source, but the glue or matrix source may also be separately sourced for use with the kit. In examples, such 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 solidifying carrier, where mixing of the non-crosslinked matrix material and the solidifying carrier, induces solidification of the surgical sealant and / or adhesive, such as a tissue glue. In particular examples, the composition comprises90Y microspheres and a solidifying surgical sealant and / or adhesive, such as a tissue glue, preferable a component of a two-component solidifying surgical sealant and / or adhesive, such as a tissue glue. In one particular example, BIOGLUE® may be used for the glue component of the90Y-glue matrix composition. BIOGLUE® is an admixture of bovine serum albumin (BSA; 45% weight / volume in sterile water for injection) and glutaraldehyde (10% weight / volume in sterile water for injection) in a 4: 1 ratio. Accordingly, a composition described herein may comprise90Y microspheres and albumin, or90Y microspheres and glutaraldehyde. The bovine serum is purified by heat precipitation, chromatography, and gamma-irradiation to eradicate possible transmissible diseases. Glutaraldehyde exposure causes the lysine molecules of the bovine serum albumin, extracellular matrix proteins, and cell surfaces to bind to each other, creating a strong covalent bond. The reaction is spontaneous and independent of the coagulation status of the patient. The glue begins to polymerize within 20 to 30 seconds and reaches maximal strength in approximately 2 minutes, resulting in a solid implant. The degradation process takes approximately 2 years, and the implant is then replaced with fibrotic granulation tissue. The adhesive solutions (BSA and glutaraldehyde in a 4: 1 ratio) are mixed in the applicator tip of the dual-chamber syringe where cross-linking begins. BIOGLUE® is not believed to be a true hemostatic agent because it does not accelerate the clotting process in blood. However, BIOGLUE® acts as a sealant after it completely hardens, by tamponating parenchymal tissue. It is commonly used as an adjunct to more standard methods for gaining hemostasis, such as suturing or use of topical hemostatic agents.

[0065] The potential adverse events associated with the use of BIOGLUE® include:• non-adhesion of the product to tissue• application of the adhesive to tissue extraneous to procedure• inflammatory and immune reactions• allergic reaction• tissue mineralization• local tissue necrosis• vessel obstruction• bronchial or luminal obstruction• thrombosis and / or thromboembolism• pulmonary embolism• injury or damage to normal vessels or tissue• possible transmission of infectious agents from material of animal origin.

[0066] In other examples, alternate compositions with different concentrations of BSA and glutaraldehyde components may be provided at different concentrations and / or used with different ratios, e.g.:1. 45% BSA and 40% glutaraldehyde components in a 1 : 1 ratio2. 45% BSA and 20% glutaraldehyde components in a 2: 1 ratio3. 36% BSA and 8% glutaraldehyde components in a 4: 1 ratio4. 36% BSA and 12% glutaraldehyde components in a 3 : 1 ratio

[0067] In another example, TISSEEL® sealant (Baxter Healthcare; Deerfield, IL) may be used for the glue, matrix or carrier component of the90Y composition. TISSEEL is a two-component fibrin sealant that is manufactured from pooled human plasma. When the two components, the sealer protein and thrombin, are combined, the composition is similar to the final stage of the blood component cascade. The sealer protein is a sterile, non-pyrogenic, vapor heated and solvent / detergent treated preparation made from pooled human plasma. The sealer protein is provided either as a freeze-dried powder for reconstitution with a fibrinolysis inhibitor solution or as a finished frozen solution pre-filled into one side of a dual-chambered syringe. The active ingredient of the sealer protein is fibrinogen. The sealer protein solution contains a fibrinolysis inhibitor comprising synthetic aprotinin, that delays fibrinolysis. The aprotinin is manufactured by solid phase synthesis from materials completely of non-human / non-animal origin. The composition of the sealer protein solution has a total protein level of 96-125 mg / mL, fibrinogen 67-106 mg / mL, aprotinin 2250-3750 KIU / mL, and also human albumin, tri-sodium citrate, histidine, niacinamide, polysorbate 80 and water for injection. The thrombin component is a sterile, non-pyrogenic, vapor heated and solvent / detergent treated preparation made from pooled human plasma. Thrombin (human) is also provided either as a freeze-dried powder for reconstitution with calcium chloride solution or as a finished frozen solution pre-filled into one side of a dual-chambered syringe. The thrombin solution contains 400-625 units of thrombin / mL, 36-44 pmol / mL of calcium chloride, and also some human albumin, sodiumchloride and water for injection. The two components of TISSEEL, the sealer protein and thrombin, can be provided in dual-chamber syringes with 2mL, 4 mL, and 10 mL total volume, of equal chamber sizes, e.g. dual chambers of 1 mL, 2 mL and 5 mL per chamber, and are provided in a 1 :1 ratio. In other examples, the concentrations of the sealer protein solution and the thrombin solution may be different such that a non-equal ratio of sealer protein solution and the thrombin solution is used.

[0068] Another dual solution sealant that may be used is BOLHEAL® (Chemo-Sero Therapeutic Institute; Kumamoto, JP), which comprises a first solution of 80 mg / mL human fibrinogen, 75 lU / mL of human plasma-derived coagulation factor (XIII) and 1000 KIE bovine aprotinin, and a second solution of 250 HJ / mL of human thrombin and 5.9 ml / mL of calcium chloride, which are mixed at the point of use in a 1 : 1 ratio.

[0069] Another matrix that may be used in the90Y-matrix system is SURGIFLO® (Ethicon, Inc; Somerville, NJ), which comprises a first component of 8 mL of flowable sterile gelatin and a second component of 2000 IU of lyophilized human thrombin powder that is reconstituted using 2 ml of sterile water for injection.

[0070] In still another example, a multi-component polyethylene glycol sealant, such as COSEAL® surgical sealant (Baxter Healthcare; Deerfield, IL), may be used. The COSEAL® may comprise a pre-filled applicator or syringe components, with two liquid storage compartments and one dry powder compartment. One solution is a dilute HC1 solution and the other is a sodium phosphate / sodium carbonate solution. The dry powder syringe contains a 4- arm polyethylene glycol polymer of 10 kDa molecular weight, where the arms are capped with thiol groups, and pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate. The two solutions are provided in equal size syringes. The dry powder is first reconstituted with the buffer liquid solution by forceful transfer back and forth at least 20 times between the dry powder and the buffer solution until the dry powder appears to be dissolved.

[0071] In other examples, the glue component may comprise a single component glue, sealant or matrix, e.g. a cyanoacrylate, alginate, polyvinyl alcohols, sodium polyacrylate, agarose, methylcellulose, carboxymethylcellulose, hyaluronic acid, etc.

[0072] During the procedure, one or more of the following may be recommended:- Maintain the position of surgical gloves, sterile gauze swab / towels and other surgical instruments separate from the matrix to minimize the potential and inadvertent adhesion of the matrix to these surfacesThe syringes, applicators and tip-applicator extensions are to be used exclusively for a single patient. Do not re-sterilize.- Do not use if the packaging is open or damaged.- Be careful not to accidentally spill the contents of the syringe- Do not press the syringe plunger while connecting to the syringe.Avoid contact of fabrics with material expelled from the applicator during priming.

[0073] The matrix component of90Y-matrix composition can polymerize quickly. Priming must take place quickly and it should be followed immediately by application of the compound. A pause between priming and application can cause polymerization in the tip-applicator. It is recommended:- Do not use blood collection devices while aspirating excess90Y-matrix composition from the surgical field- Do not apply matrix in an excessively wet surgical field. This may cause poor grip.- Do not detach or peel the90Y-matrix composition from a point or surface where it has come into contact inadvertently, as this may cause damage to the fabric.- Do not implant90Y-matrix composition in closed anatomical sites that are in the immediate vicinity of nerve structures.- Use caution when using the90Y-matrix composition in pregnant or lactating women. There are currently no efficacy or safety studies concerning90Y-matrix composition use in pregnant or lactating women.- Due to the radioactivity of this device and the significant consequences of incorrect product placement, physicians should not implant this product without proper training on the handling and implant technique.All persons who handle, dispense and implant this device must know and comply with all local and state regulatory requirements governing therapeutic radioactive materials. The accepted radiation protection techniques should be used to protect personnel when handling both the isotope and the patient.Some patients may experience gastric problems after treatment with90Y-matrix composition, but H-2 blocking agents can be used the day before the implant and continued, if necessary, to reduce gastric complications.The radioisotope component of the90Y-matrix composition showed a slight potential for sensitization when tested on skin in an animal model.- Do not use the90Y-matrix composition if personnel are not adequately protected (i.e., wear gloves, mask, protective clothing and safety glasses). Unpolymerized glutaraldehyde can cause irritation to eyes, nose, throat or skin, as well as breathing difficulties and local tissue necrosis. Prolonged exposure to unpolymerized glutaraldehyde, which is a component of BIOGLUE®, can cause heart or central nervous system disorders. In the event of contact, immediately rinse the affected areas with plenty of water and seek medical attention.- Do not use the90Y-matrix composition in the presence of infections and use cautiously in contaminated areas of the body.- Exercise caution in repeatedly exposing the same patient to multiple applications of the90Y-matrix composition. Reactions due to hypersensitivity are possible during exposure to the matrix component. Sensitization phenomena have been observed in animals.Some of the90Y-matrix components contain a material of animal origin that may be able to transmit infectious agents.

[0074] Potential side effects of the procedures described herein may include: failure of the product to adhere to the tissue or treatment side, application of the adhesive to a tissue not subject to the procedure, inflammatory and immune reaction allergic reaction- tissue mineralization necrosis of local tissue obstruction of the vessels- bronchial or luminal obstruction thrombosis or thrombo-embolism pulmonary embolismdamage to normal vessels or tissues possible transmission of infectious agents from the material of animal origin, fever- temporary reduction of hemoglobin altered biochemical tests (mild to moderate) concerning the liver (e.g. ALT, AST, alkaline phosphatase, bilirubin) abdominal pain nausea- vomiting diarrhea

[0075] As is shown in example 10, the administration of the 90Y microspheres according to the present disclosure, did not lead to all the same side effects as would be expected from TARE. In particular no transitory elevation of liver enzymes or transitory decline in lymphocytes was observed in the interim analysis. Accordingly, in embodiments the composition and / or methods as disclosed herein does not results in a transitory elevation of liver enzymes or transitory decline in lymphocytes after administration.

[0076] Additionally, no radioembolization-induced liver disease (i.e. hyperbilirubinemia, hypoalbuminemia, ascites) or non-target irradiation (radiation gastritis, gastrointestinal ulceration, upper gastrointestinal bleeding, pancreatitis, radiation pneumonitis) was observed in the clinical study presented in Example 10. Accordingly, in embodiments the treatment as disclosed herein do not result in radioembolization-induced liver disease or non-target irradiation. Accordingly, in some embodiments, the treatment provided herein results in fewer side effects and / or adverse events when compared with 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 is a surprising and advantageous technical effect.

[0077] In some variations, the devices, kits and methods described herein may be used to treat one or more target locations following surgical resection or ablation, in order to treat any residual tumor cells, but in other variations, the target locations may be treated prior to resection, e.g. to attempt to downgrade the cancer stage in order to convert an unresectable tumor to a resectable tumor. In still other variations, the target locations may be treated without any plans to performa surgical or ablative procedure. In some variations, the therapy may be used to treat non- cancerous disease or symptoms, e.g. intra-articular injection to treat synovitis, intradermal injection to treat keloids and hypertrophic scars, intravascular injection for hemangioma, etc.

[0078] In one exemplary embodiment, a method for treatment of a small tumor utilizes a mixing injector configured to be connected to a supply injector of glue and to a supply of radiotherapeutic particles. The vial is removed from its packaging and, without shaking or otherwise reconstituting the suspension of the microspheres in the water, a predetermined amount of non-agitated or non-microsphere containing suspension liquid is first removed, e.g. 0.5 mL, 1 mL, 1.5 mL, 2 mL, or 2.5 mL, or 10%, 20%, 30%, 40% or 50%. In other variations, the amount of liquid removed can vary, but results in a suspension liquid that has an activity to volume ratio that is 0.5 GBq, 0.8 GBq, 1.0 GBq, 1.2 GBq, or 1.5 GBq per 1 mL, for example, or in a range between any two of these ratios. After removal of some of the suspension liquid, the vial is reconstituted via shaking or other agitation. Based on the remaining concentration of the radiotherapeutic, e.g. 3 GBq in 4 ml suspension liquid, the desired amount of activity is withdrawn, based on the volume, into the radiotherapy transfer syringe. In some examples, the radiotherapy transfer syringe is the same syringe used to remove the predetermined volume of non-agitated or non-microsphere suspension liquid, but in other examples, a different syringe is used for non-agitated or non-microsphere suspension liquid removal.

[0079] The matrix syringe is then uncapped. In some examples, a predetermined volume of glue from the glue source syringe may be dispensed, based on the calculated volume of microspheres / suspension liquid, in order to accommodate the volume of microsphere solution that is needed to deliver the desired activity level of microspheres. In some variations, additional volume may be provided in the syringe by pulling back the plunger mechanism. In other variations, no volume adjustment to the matrix syringe is needed before adding the isotope solution, because of existing air gaps provided in the matrix syringe are sufficient to hold the amount of radioisotope to be transferred.

[0080] In some variations comprising a two-component matrix, the radiotherapeutic-matrix composition is delivered using a mixing tip that may mix the two components within 1, 2 or 3 cm of the distal ends of the chambers containing the components. The distal end of the mixing tip may comprise multiple distal openings that may comprise a generally linear configuration across a transverse dimension of the mixing tip, in order to increase the single-pass coverage areaof the mixing tip. For the example, the mixing tip may comprise 2, 3, 4, 5, 6, 7 or 8 distal openings that are aligned along a transverse dimension that is at least 1, 1.5, 2, 2.5 or 3 cm wide.

[0081] In other variations, the delivery kit may comprise dual-lumen tubing, dual-lumen needle or a dual-lumen catheter so that the mixing or polymerization of the two components occurs more distally, in order to avoid polymerization of the components within a single-lumen tubing or catheter, which may result in clogging before the matrix reaches the target location. These delivery components may be preferred when the distance from the skin surface to the target surface is more than 2, 3, 4 or 5 cm from the ends of the chambers containing the matrix components.

[0082] In one example, the delivery kit may include a dual -lumen injection needle or introducer needle. The needle may be a needle measuring 11G, 12G, 13G, 14G, 15G, or 16G, and comprise a shaft length in the range of 100 mm to 200 mm, 120 mm to 150 mm, or 140 mm to 170 mm, for example. The needle may be made from AISI 302, 304, or 306L stainless steel, and attached to a proximal female Luer lock hub. The needle may also include a stylet configured for insertion through the lumen of the needle, the stylet comprising a solid core with or without a pointed or piercing distal tip that extends out of the distal end of the needle. The needle may be used with a coaxial double-lumen catheter with a diameter of 12G, 13G, 14G, 15G, 16G, 17G or 18G, and comprise a shaft length in the range of 100 mm to 300 mm, 150 mm to 250 mm, or 170 mm to 200 mm, for example. The catheter may also comprise a proximal Luer lock hub. The hub of the catheter may also be configured to lock with the proximal Luer lock hub of the introducer needle, e.g. via a male Luer lock structure that can lock to the introducer needle hub when the catheter is inserted through the needle hub and needle shaft, or a deformable or biased clamp structure that reversibly attaches to the exterior surface of the introducer needle hub, for example. The needle and catheter diameters may be selected such that the catheter is configured to be removably inserted through the introducer needle without significant leakage of bodily fluid between the outer wall of the catheter and the inner lumen wall of the introducer needle, e.g. the catheter may be at least 1G or 2G smaller in size than the introducer needle.

[0083] In one specific example, the kit 10 from SVAS Biosana, depicted in FIG. 1 A, may be used, which includes a 15G x 150 mm coaxial introducer needle 12 and a 16G x 120 mm coaxial catheter 14, configured to work with each other. The proximal end of the introducer comprises amale Luer lock hub 16, such that the distal end 18 of the catheter hub 20 comprises a female Luer lock hub that can engage the male Luer lock hub 16 when the catheter 14 is inserted into the introducer 12. The proximal end 22 of the catheter hub 20 further comprises a connector configured to attach to a matrix syringe or matrix injection system. This may be, for example, a proprietary complementary female connector interface to a BIOGLUE® injection syringe, or a female Luer lock hub. The kit 10 may also comprise a stylet 24 that is reliably lockable and insertable into the introducer 12, and is used during insertion and positioning of the introducer 12 to the target location. The stylet 24 may include a solid proximal end 26 that comprises a releasable clamp mechanism to attach to the proximal hub of the introducer 12, or may comprise a female Luer lock in other examples. FIG. IB depicts the catheter 14 inserted into the introducer 12, with the male Luer lock hub 16 engaged with the female Luer lock hub 18.

[0084] In one example, the vial or bottle with the radioisotope microspheres is retrieved from its radioprotective container, and optionally placed in a lead or acrylic open-top box, if available. The seal on the vial is cleaned with an alcohol swab, and then an air opening is formed in the seal by puncturing the seal with a needle. The needle, such as a 22G, 25G, 28G, 30G, 31G or 32G hypodermic needle is optionally left in place. A 5 mL syringe is then attached to a 20G or 22G needle with a length in the range of 50 mm to 150 mm, 50 mm to 120 mm, or 70 mm to 100 mm. The syringe and attached needle are then used to re-puncture the seal. Without agitating or mixing the settled microspheres at the bottom of the vial or bottle, the needle tip is positioned within the suspension liquid but above the settled microspheres, and 2 mL of suspension liquid is removed and discarded, preferably without significant removal of any microspheres. Using a dose calibrator, the activity remaining in the vial or bottle is checked or confirmed. Assuming that the vial or bottle contained 3 GBq in 5 mL of suspension liquid, the vial or bottle should now nominally contain 3 GBq in 3 mL of suspension liquid. In other variations, a different amount of suspension liquid may be removed, or additional suspension liquid, such as Water For Injection or isotonic sodium chloride solution, may be added to the vial or bottle to alter the concentration of the activity per volume.

[0085] The target activity level and volume to be injected into the target lesion is then determined or based on (a) the calibrated or nominal activity concentration in the vial, (b) the target activity level or absorbed dose to be delivered to or achieved in the target lesion(s) respectively, and (c) optionally accounting for the residual volume of material that may be in thesyringe injection system after a full or maximum injection, e.g. residual volume in the syringe tip distal to the plunger or sliding seal of the syringe, and in the mixing tip or injection catheter or needle. The target-absorbed dose, also referred to as absorbed dose herein, may be, for example, 18 Gy or 20 Gy to the surgical beds from resected breast lesions, and up to 150 Gy for hepatic lesions. Thus, an embodiment of the present invention relates to the composition of the present invention for use in the treatment of hepatocellular carcinoma (HCC), wherein the target- absorbed dose of90Y is in the range of 120Gy to 150 Gy, such as a dose of 150 Gy. Further embodiments of the present invention relate to the composition of the present invention for use in the treatment of hepatocellular carcinoma (HCC) or liver metastatic lesions derived from primary colon cancers (mCRC), wherein the target-absorbed dose of90Y is in the range of 120Gy to 150 Gy. Further embodiments of the present invention relate to the composition of the present invention for use in the treatment of gastrointestinal tumors. Additional embodiments of the present invention relate to the composition of the present invention for use in the treatment of pancreatic cancers or pancreatic lesions. Additional embodiments of the present invention relate to the composition 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 the composition of the present invention for use in the treatment of metastatic cancers and metastatic lesions. Preferably, when used in the treatment of lesions as described herein the target-absorbed dose of90Y is in the range of 120Gy to 150 Gy The syringe and attached needle is then reinserted into the vial or bottle and is used to agitate and suspend the settled microspheres in the suspension liquid by moving the plunger of the syringe back and forth several times, e.g. 10 to 20 times, and / or until sufficient mixing is visually confirmed by the homogenous appearance of the suspension liquid and without any visibly settled microspheres. The target activity volume is then removed using the syringe. The syringe cap of the hemostatic agent, such as a glue / matrix, syringe is then removed, and the target activity volume of the suspension liquid with microspheres is then distributed between the two chambers of the hemostatic agent, such as a glue / matrix, syringe in a 4:1 ratio to the BSA:glutaraldehyde chambers, or in a ratio corresponding to their cross-sectional areas or volumes of the matrix component chambers. For other syringe / inj ection systems, for example, where there is a 1 : 1, 1.5: 1 or 2: 1 volume or cross- sectional area ratio between the two chambers, the target volume will be distributed in a 1 : 1, 1.5: 1 and 2: 1 ratio. For a three-chamber delivery system, e.g. a 1 : 1 :1 or 4: 1 : 1 or 4:2: 1 ratioinjection system, the target volume would be distributed by the same ratio to the three chambers, respectively.

[0086] In a preferred embodiment of the present invention, the loss of radioactivity in the syringe is minimized because the loading of the dual chamber syringe further comprises loading the required90Y syringe activity level into the first chamber containing the BSA solution only.

[0087] In an additional preferred embodiment of the present invention, the loss of radioactivity in the syringe is minimized because the loading of the dual chamber syringe further comprises loading the required90Y syringe activity level into the first chamber containing the BSA solution while loading a suitable amount of WFI into the second chamber containing the glutaraldehyde. To maintain the desired ratio of BSA:glutaraldehyde, such as a ratio in the syringe of 4:1, once the90Y microspheres are loaded into the BSA chamber only, WFI may be added to the chamber containing the glutaraldehyde to maintain the BSA:glutaraldehyde ratio. In embodiments, when the total syringe volume is 2 ml, and 250 pL of90Y microspheres is added to the BSA containing chamber, 62,5 pL of WFI may be added to the glutaraldehyde containing chamber to maintain the BSA:glutaraldehyde ratio at 4: 1. In further embodiments, when the total syringe volume is 5 ml, and 500 pL of90Y microspheres is added to the BSA containing chamber, 125 pL of WFI may be added to the glutaraldehyde containing chamber to maintain the BSA:glutaraldehyde ratio at 4: 1. In further embodiments, when the total syringe volume is 10 ml, and 1000 pL of90Y microspheres is added to the BSA containing chamber, 250 pL of WFI may be added to the glutaraldehyde containing chamber to maintain the BSA:glutaraldehyde ratio at 4: 1.

[0088] After distributing or loading the target activity volume into the matrix syringe, the syringe cap is placed back on the matrix syringe. A commercially available dose calibrator commonly used in a radio-pharmacy may be used to confirm the expected activity in the syringe, and correct it, if needed. The loaded matrix syringe is then placed back in its radioprotective container for storage or transport to the operating room or procedure facility.

[0089] At the operating room or procedure facility, the patient is prepped and draped in the usual sterile fashion, and anesthesia is achieved. The target lesion, e.g. hepatic lesion, is identified using an imaging modality such as ultrasound or fluoroscopy or based on prior imaging, the imaging performed with or without the use of any contrast agent. A stylet is inserted into the introducer needle, and is then percutaneously inserted into the target lesion, preferably with ultrasound or CT guidance. The pre-filled syringe previously loaded with theradiotherapeutic particles is removed from its radioprotective container and the syringe cap is removed by holding the syringe upright and rotating the cap from side to side. The bilateral cap of the coaxial catheter is then aligned with the two openings of the dual-chamber syringe. Indicia on the catheter may be provided to facilitate the alignment with the syringe. The catheter may then be locked onto the syringe using a locking collar or other locking mechanism, such as to resist inadvertent separation of the syringe and catheter.

[0090] Upon optionally reconfirming the position of the introducer / catheter combination, the plunger or actuator of the syringe / delivery system is actuated to dispense the mixture. In some examples, the syringe plunger or delivery system actuator may be actuated at a rate of approximately 0.5 mm to 1 mm per second, 0.5 mm to 2 mm per second, or 0.5 mm to 1.5 mm per second. Once delivery is completed, the introducer needle / catheter may be left in place for 30 to 60 seconds, or at least 5 seconds, 10 seconds, 15 seconds, 20 seconds or 30 seconds, and / or no more than 30 seconds, 45 seconds, 60 seconds, 90 seconds, or 120 seconds. This may ensure polymerization at the target location, after which the introducer needle / catheter may be removed from the target location, using an optional twisting motion to ensure adequate separation of the matrix from the introducer needle / catheter without seeding of the insertion tract or pulling of the target location due to incomplete separation of the injected matrix and the introducer needle / catheter. The introducer needle / catheter insertion site may then be checked for any fluid leakage and optionally stitched or sealed with non-radioactive bioglue or matrix, and then bandaged and dressed as needed. Any radioactive or biohazardous components are disposed as appropriate.

[0091] After the desired amount of the composition has been administered or delivered, the stylet is then removed from the inserted introducer while maintaining the position of the introducer. The syringe / catheter is then inserted through the introducer until the distal hub of the catheter locks with the proximal hub of the introducer.

[0092] In embodiments that do not require percutaneous access with a needle or catheter, in the procedure above a mixing tool tip may be attached to the mixture syringe instead of achieving access with the introducer followed by attachment of a needle and / or catheter. After attachment of the mixing tip, the syringe may be shaken to sufficiently mix the radioisotope suspension with the hemostatic agent component, such as a glue or matrix components. The syringe plunger or delivery system actuator may then be actuated at a rate of approximately 0.5mm to 1 mm per second to apply the mixture to the surface of the surgical cavity. Once delivery is completed, the surgical cavity may be left exposed for 30 to 60 seconds to ensure polymerization at the target location. The surgical cavity may then be closed and dressed in the usual fashion. Any radioactive or biohazardous components are disposed as appropriate.

[0093] In other examples, the radioisotope microparticles may be premixed at the point of manufacture with one or both components of the hemostatic agent component, such as a matrix or glue, of a prefilled syringe. For example, the90Y microspheres may be pre-mixed and loaded with the BSA and / or glutaraldehyde component of the prefilled syringe. In some variations, because of potentially different treatment concentrations that are necessary for particular lesion sizes or diseases, different sized syringes with different treatment concentrations may be provided. For example, 1 mL, 2 mL, 5 mL or 10 mL prefilled syringe injection systems may be provided but with different activities per mL pre-mixed with the BSA component but with no activity in the glutaraldehyde components. The syringes may comprise an activity concentration in the range of 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, in the treatment of breast cancers. In other examples, the 1 or 2 mL syringes may comprise an activity concentration in the range of 0.1 MBq to 20 MBq per mL, or 0.2 MBq to 15 MBq per mL, and the 5 mL or 10 mL syringes may comprise an activity concentration in the range of 3 MBq to 30 MBq per mL, or 5 MBq to 25 MBq per mL. The concentrations of these syringes may be used with more radiosensitive tumors or where effects on the surrounding normal tissue need to be reduced, e.g. HCC.

[0094] In other examples, the syringes may comprise an activity concentration in the range of may comprise an activity in the range of 0.1-300 MBq e.g., 0.7-250 MBq prior to administration, such as an activity of e.g., 0.68 MBq, 3.42 MBq, 10.01 MBq, 22.44 MBq, 42.48 MBq, in an injectable volume of 2.5 mL, or 33.43 MBq, 55.26 MBq, 86.09 MBq, 129.71 MBq, 182.57 MBq or 249.59 MBq in an injectable volume of e.g., 6 mL prior to administration. The activity may differ with up to ±30%, preferably up to ±20%. The injected active activity may be in the range of 0.4-250 MBq, such as an activity 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. Additionally, the injected active activity may be in the range of 0.4-250±30% MBq, such as an activity 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. Additionally, the injected active activity may be in the range of 0.4-250±20% MBq, such as an activity 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 dose to be administered depends on the tumor size, where a larger tumor correlates with a higher active dose needed in the treatment. Due to residual activity in the syringe after administration the dose to be administered may differ slightly from the dose proposed herein, such difference may be up to 30%, but should preferably be no more than 20%. The adjusted difference is important because it will ensure that the delivered dose is not underestimated due to leftover radioactivity that remaining in the syringe (see example 11). Accordingly, the active administered dose of90Y may be, about 0.48±20% MBq for an average tumor size corresponding to a diameter up to 5 mm; about 2.4±20% MBq for an average tumor size corresponding to a diameter greater than 5 mm and up to 10 mm; about 7±20% MBq for an average tumor size corresponding to a diameter greater than 10 mm and up to 15 mm; about 17±20% MBq for an average tumor size corresponding to a diameter greater than 15 mm and up to 20 mm; about 28-30±20% MBq for an average tumor size corresponding to a diameter greater than 20 mm and up to 25 mm; about 48±20% MBq for an average tumor size corresponding to a diameter greater than 25 mm and up to 30 mm; about 75±20% MBq for an average tumor size corresponding to a diameter greater than 30 mm and up to 35 mm; about 114±20% MBq for an average tumor size corresponding to a diameter greater than 35 mm and up to 40 mm; about 160±20% MBq for an average tumor size corresponding to a diameter greater than 40 mm and up to 45 mm; and about 219±20% MBq for an average tumor size corresponding to a diameter greater than 45 mm and up to 50 mm. Such doses are in particular suitable for treatment of HCC. Exemplary90Y doses administered to HCC patients are presented in table 3 and 4 in example 9. Accordingly, in embodiments, the pharmaceutical composition as disclosed herein comprising90Y is for use in the treatment of hepatocellular carcinoma (HCC), with a preferred active dose of90Y as suggested above. Additionally, doses may vary slightly, such as with 1-30% due to handling of the compositions prior to administration. Thus in embodiments, the active dose varies from the above with at the most 30%. In additional embodiments, the active dose varies from the above with at the most 20%. Additionally, doses may vary slightly, such as with 1-15% due to handling of the compositions prior to administration. Thus in embodiments, the active dose varies from theabove with at the most 10%. The active dose of90Y can be prepared in a pharmaceutical composition. This composition can comprise microspheres and optionally a bioglue. The active dose of90Y can be prepared as a pharmaceutical composition that is ready for the administration to an individual in need thereof. Such pharmaceutical composition can also be referred to as an injectable composition. The treatment may comprise administration of such a pharmaceutical composition, or injectable composition, to a person in the need thereof.Specific examples of dose selection for hepatic and breast cancers are provided in certain examples later below.Dosimetry

[0095] As noted previously, hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. It is an aggressive cancer typically occurring in the setting of cirrhosis. Unfortunately, it commonly presents in advanced stages, when patients have become symptomatic and have some degree of liver impairment. In the United States, a total of 30,640 new liver and intrahepatic bile duct cancers occurred in 2013, in addition to 21,670 deaths. HCC occurred more often in males than females (2.4:1), with a higher incidence in Eastern and Southern Asia, Middle and Western Africa, Melanesia, and Micronesia / Polynesia. Despite major advances in prevention techniques, new technologies and screening procedures (in both diagnosis and treatment), incidence and mortality are increasing, with cirrhosis being the most important risk factor for the development of HCC regardless of etiology. Today, multiple treatment modalities exist. However, only orthotopic liver transplantation or surgical resection may be regarded as curative. As such, patients suffering from HCC, who are otherwise eligible for liver transplant are especially suitable for treatment with a composition as disclosed herein. Other treatment modalities include transarterial chemoembolization, radioembolization, percutaneous ethanol injection, radiation therapy, and ablation therapies. In particular, percutaneous ablation is a promising approach to treating inoperable primary tumors or metastases in the liver. In fact, in the treatment of HCC, fewer than 40% of patients are candidates for surgery, and the possibility of recurrence after curative surgery is generally high Accordingly, the patients to treat with a composition as described herein are preferably ineligible for traditional transarterial radioembolization. Against this backdrop, percutaneous techniques represent a successful therapeutic option and are widely used today for the treatment of metastatic and small primary tumors. Among these techniques, methods such aschemical ablation, cryoablation, high temperature ablation (e.g. radiofrequency, microwave, laser, and ultrasound) have gained wide acceptance for the treatment of liver tumors as they may serve as a bridge for transplant candidates, especially in relation to small primary lesions. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function.

[0096] Due to the lack of effective systemic therapies for HCC, researchers have been investigating the use of locoregional tumor control with90Y radioembolization since the 1960s. Today radioembolization (or Selective Internal Radio Therapy, SIRT, also known as Trans Arterial Radio Embolization, TARE) is an established and effective treatment for liver malignancies based on trans-arterial infusion of90Y-laden microspheres. Radiation dose distributions arising from intrahepatic arterial infusion of90Y microspheres have been investigated by a number of authors in the past. At present, there are two clinically available microsphere devices in which90Y is incorporated: one with microspheres made of glass (TheraSphere; MDS Nordion, Ottawa, Ontario, Canada) and the other with microspheres made of resin (SIR-Spheres; Sirtex Medical, Sydney, Australia). The resin microsphere device consists of biocompatible90Y-bearing microspheres with diameters of 20-40 pm. Once administered, the spheres remain in the liver as a permanent implant. Brachytherapy is a type of internal radiation therapy in which seeds, ribbons, or capsules that contain a radiation source are placed in the body, in or near the tumor. Brachytherapy is a local treatment and treats only a specific part of the body. The present composition comprising90Y for use in the treatment of hepatocellular carcinoma (HCC) can be performed by percutaneous administration in order to provide brachytherapy to the tumor.

[0097] In the traditional catheter-based approach, radioembolization involves intra-arterial infusion of microspheres. However, in recent years a number of studies have addressed the problem of dosimetry in therapies based on the use of intratumoral administration of90Y- conjugates by percutaneous puncture. In recent years, this technique has been successfully applied to patients treated with90Y-labeled [DOTA°-D-Phe1-Tyr3] octreotide (90Y-DOTATOC) for malignant gliomas.

[0098] Furthermore, based on the clinical experience gained in liver radioembolization, percutaneous ablation of HCC through the intratumoral injection of an appropriate activity of90Y has the potential to reduce drastically the chances of local recurrence. In this context, there isgrowing interest in the development of new intratumoral procedures for HCC throughout a localized administration of90Y in the form of microspheres mixed with biocompatible compounds.

[0099] As a rule, intratumoral administration of radionuclides raises questions about the dosimetry of small lesions as this approach allows sub-centimeters tumors to be selectively treated. To date, there is no simple way to assess exactly the absorbed dose to tumors and normal liver tissue when90Y is administered. This is because90Y only emits pure beta radiation with limited penetration range in tissue. Consequently, the delivered dose is highly dependent on the distribution of microspheres and the tumor mass. In particular, the current analytic formalism used to assess the absorbed dose to the liver and to the tumor masses inside the liver parenchyma is based on the assumption that all particles released from90Y within a given organ are fully absorbed by that organ. However, when the tumor size is small this assumption may no longer be true and the current analytic approach is likely to provide inaccurate dose results when used to assess the dose in small target regions.

[0100] Thus, the current analytic formalism used to assess the absorbed dose after the administration of90Y-microspheres may provide inaccurate results when used to calculate the dose in small target regions, as it is based on the assumption that all P-particle energy is fully absorbed by the treated mass. The present work assesses the absorbed dose in a scenario of intratumoral injection of90Y in lesions of varying size, and provides a dosing regimen that accounts for partially absorbed P-particle energy that is fully absorbed by the treated mass.

[0101] In one example, the absorbed dose in small lesions are assessed, assuming a selective delivery of90Y into the tumor (i.e. in a scenario of percutaneous ablation of HCC through the intratumoral injection of the radionuclide). A simplified model for tumor masses was implemented into MCNP4C Monte Carlo (MC) code with the aim to determine the absorbed dose to the lesion when the tumor mass is uniformly filled with90Y.

[0102] In some variations, the absorbed dose-per-unit administered activity was assessed using Monte Carlo calculation in spheres of different size (diameter 0.5-20 cm). The spheres are representative of tumor regions and are intended to be uniformly filled with90Y. Monte Carlo results were compared with the well-established analytic approach.

[0103] The initial results indicate that the use of the current analytic model provides dose overestimations below 10% for lesions with a diameter larger than approximately 2 cm. However, for lesions with a diameter smaller than 2 cm, the analytic model is likely to deviate significantly(>10%) from Monte Carlo results, providing dose overestimations larger than 50% for lesions of 0.5 cm diameter. An alternative equation is provided for the calculation of the absorbed dose in small target regions.

[0104] 90Y disintegrates by P emission mainly (99.983%) to the stable90Y ground state level. A weak beta branch occurs to the 1760 keV excited level that decays by an E0 gamma transition. This 0+-0+transition is followed by the emission of two gammas, or an electron-positron pair, or internal conversion. The adopted half-life of90Y ground state is 64.041 hours or 2.6684 days.

[0105] Among the radionuclides used in clinical practice,90Y has attractive physical and radiobiologic features that make this radionuclide suitable for a loco-regional therapeutic option. The high-energy P-particles (maximum energy 2278.7 keV, average energy 926.7keV) and their penetration depth (maximum particle range in tissue, 11 mm; range in tissue after which 50% of the energy particles is transferred, 4 mm) allows high radiation doses to be selectively delivered to the target area, while sparing surrounding tissues and normal organs. In particular, the penetration depth of the high-energy P-particles is a key element of this radionuclide’s success in radioembolization, allowing for high-dose deposition into the tissues between embolized capillaries. In the traditional dose calculation formalism (after locoregional administration of90Y), two important simplifying assumptions are generally made:• P radiation released from90Y within a given organ is fully absorbed by that organ. In most cases, this assumption is supported by the average 4 mm90Y P range in tissue.• permanence of90Y in the area where they have been delivered (i.e. no migration of the radiopharmaceutical outside the tumor region).

[0106] Combining these two assumptions allows for easy calculation of average absorbed dose to an organ of interest on a macroscopic scale. The calculation, carried out using most up-to-date nuclear data for90Y, is illustrated below and it is generally referred to as the MIRD (Medical Internal Radiation Dose) approach:where Eavgis the average energy released per decay of90Y based on the probability density function ^?(E) for emission, is the90Y decay constant based on the half-life of 64.041 hours,and k a constant term. Ao is the activity present in the organ in GBq and Etotis the total energy released by Ao from the time that it is infused until it has fully decayed.

[0107] Assuming that all of the energy of the P-decay is absorbed in the volume where the decay occurs, the constant term, k, can be calculated taking the given physical values and their statistical uncertainties:109dis1.487 ■ 10-13 / 1.487 ■ 10“13 / - 230547s >= 49.38 (J / GBq) (3)0.69315 GBq

[0108] The constant factor 49.38(J / GBq) is the energy released per unit activity of90Y. The adopted uncertainties on the nuclear data reported in the equation below lead to a relative standard uncertainty of 0.1% on the constant term, i.e. 49.38(5) (J / GBq), in line with recommendations from the American Association of Physicists in Medicine.

[0109] Finally, the absorbed dose D (expressed in Gy) can be obtained by dividing the delivered energy, Efof, by the mass of the target region m (expressed in kg)

[0110] Of note, the same formula with a slightly different constant term, k, has been reported in other publications (e.g. 49.98, 49.67).

[0111] According to the partition model, the equation above can be used to calculate the absorbed dose in the tumor, once the fractional tumor uptake FUfMmor(i.e. the fraction of the administered activity accumulated in the tumor) is known:

[0112] It must be reiterated that equations (4) and (5) above are only valid for90Y radioembolization and only representative of average absorbed dose in an organ or a large lesion, i.e. on a macroscopic scale. It is hypothesized herein that these equations may not hold for very small tumor masses, as the assumption that the energy emitted during decay is totally absorbed by the mass of interest m is no longer true. In particular, when the size of the lesion is very small (especially in the sub-centimeter region), the energy released per unit activity of90Y may decrease significantly. Therefore, hereafter the constant term k in equation (3) will be treated as a function of the lesion radius (r) and indicated as k(r).

[0113] In the present study, the absorbed dose-per-unit administered activity was assessed using Monte Carlo calculations in a simplified geometry. MC code MCNP4C has been 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, with the possibility of K- and L-shell fluorescent emission or Auger electron, coherent and incoherent scattering and pair production. The photoelectric cross sections are based on Storm and Israel whereas the scattering cross sections are taken from ENDF tabulations. The continuous slowing down approximation energy loss model is used for electron transport.

[0114] Spherical lesions of different size (diameters in the range 0.5-20 cm) were simulated for two different densities: p = 1.00 g / cm3(water density) and p = 1.05 g / cm3(liver density). In both scenarios, spheres were assumed to be immersed in a semi-infinite medium with the same density of the sphere. The spheres are representative of tumor regions and are supposed to be uniformly filled with90Y, while the surrounding medium is assumed to contain no radioactivity.

[0115] Calculations were performed in 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). Simulations were carried out taking into account all the available advanced options, such as electron production by photons, Bremsstrahlung effect and knock-on electron production. MCNP simulations were run for an adequate time to get a statistical uncertainty on the absorbed dose below 0.01%.

[0116] FIG. 18 shows the fraction of90Y absorbed dose into the tumor as a function of the tumor size, obtained from MCNP simulations. The90Y beta spectrum implemented in the model is also reported in the FIG. 19. Calculations were performed both for water spheres (p = 1.00 g / cm3) and for spheres made of liver tissue (p = 1.05 g / cm3). In both cases, when the lesion diameter drops below 2 cm, a greater amount of the P particle energy is delivered outside the sphere and the first of the above mentioned assumptions (radiation released from microspheres within a given organ is fully absorbed by that organ) does not hold. Consistently, the delivered energy per unit activity, k(r), shows the same trend (FIG. 20) confirming that when the tumor size is small, such term deviates significantly from its constant value of 49.38 (J / GBq), considered in equation (4). In order to use information reported in FIG. 20 at the clinical level, k(r) data obtained from MC calculations were fitted with the following function:where r is the lesion radius in cm (assuming spherical tumors) and ko, A, a, B, b are parameters determined by the fit, as reported in Table 1 below for both for water and liver density:

[0117] Table 1 : Fitting parameters of equation (6) with relative standard uncertainties, for water and liver density (denoted with superscriptswandL, respectively). R2=0.999 in both cases.

[0118] An r2=0.999 was obtained from the fit, both for water and liver density. Furthermore, goodness-of-fit was also assessed through the analysis of residuals (FIG. 21), which shows maximum deviations below 0.2 between calculated and fitted data, confirming the accuracy of the fit. Based on the fitting function described in equation (6), equation (4) can be rewritten in the following form:

[0119] For a given activity Ao, equation (7) can be used to accurately calculate the absorbed dose for very small lesions (down to 0.5 cm diameter). The absorbed dose to lesions calculated using equation (7) provides results in good agreement with MC calculations (maximum deviation below 0.5%). As expected, when ideally r — > co equation (7) reduces to equation (4). Of note, the energy per unit activity, k(r), obtained from equation (6) when x — > co is 49.35 (J / GBq), against the accepted value of 49.38 (J / GBq) derived from equation (4) (0.06% deviation).

[0120] FIG. 22 compares absorbed doses per unit activity (Gy / GBq) calculated with Monte Carlo with those obtained using the MIRD analytic approach, for spherical lesions of different size and for = 1.05 g / cm3. The same results for / ) = 1.00 g / cm3are shown in FIG. 23. In addition, FIG. 23 reports absorbed doses calculated using the well-established Olinda / EXM code, developed bythe Radiation Dose Assessment Resource (RADAR) Task Group of the Society of Nuclear Medicine. As illustrated in FIG. 23, absorbed dose values calculated with the MC approach concur well with those obtained using Olinda / EMX. Significant deviations were found between MC calculated dose values and those obtained using the MIRD analytic approach when the lesion diameter drops below 2 cm (FIG. 23, inset).

[0121] Ultimately, Tables 2 and 3 below compare absorbed dose values per GBq of administered activity obtained with MC calculations (DMCV ) and with the MIRD analytic approach ( MIRD). The percentage differences between the two methods (last column of both tables, A) is also reported, calculated as 100 • (D CNP - DMIRD)(DMIRD. The difference in absorbed dose values is within -10% as long as the diameter of the lesion exceeds 2 cm. The two calculation approaches deviate significantly when the lesion size drops below 2 cm, due to significant energy deposition outside the sphere. This is consistent with the maximum particle range in tissue for90Y (about 11 mm). In this case, for water (liver) density, the MC calculations provide absorbed doses -9.3% (-9.6%), -27.8% (-26.7%), -56.7% (-55.4%) lower than the MIRD analytic approach for tumor diameter of 2 cm, 1 cm and 0.5 cm, respectively (Tables 2 and 3).

[0122] Table 2: Dose per unit activity calculated with MCNP4C for spherical lesions of different size uniformly filled with90Y. The lesions are assumed to have a density of p = 1.05 g / cm3(liver density). The same quantity (dose-per-unit activity) has been calculated using the MIRD analytic approach described by equation (4). The last column of the table (A) shows the percentage deviation between the two methods, calculated as 100 • (DMCNP - MIRD) / MIRD.

[0123] Table 3: Dose per unit activity calculated with MCNP for spherical lesions of different size uniformly filled with90Y. The lesions are assumed to have a density of p = 1 g / cm3(water density). The same quantity (dose per unit activity) has been calculated using the MIRD analytic approach described by equation (4). The last column of the table (A) shows the percentage deviation between the two methods, calculated as 100 • (DMCNP - DMIRDYDMIRD.

[0124] Dosimetry with90Y has received much attention in the past two decades. However, few researchers have addressed the problem of dosimetry in very small liver lesions. The maximum range of90Y ^-particles is 11 mm in tissue, while average energy ^-particles have a range of about 4 mm. It is worth noting that the penetration depth of the high-energy90Y ^-particles is a critical component of this radionuclide’s success in liver radioembolization, allowing for high dose delivery into the tissue between embolized capillaries.

[0125] The present work aims to assess the absorbed dose per unit activity in a scenario of percutaneous ablation of HCC through the intratumoral injection of90Y in lesions of varying size. A simplified model tumor area was implemented into MCNP4C MC code with the aim to determine the absorbed dose to the lesion when the tumor mass is uniformly filled with90Y. Spherical lesions of different size (diameter in the range 0.5-20 cm) were simulated for two different densities: p = 1.00 g / cm3(water density) and p = 1.05 g / cm3(liver density). In bothscenarios, lesions were assumed to be immersed in a semi-infinite medium with the same density of the lesion. The MIRD analytic approach and MCNP calculations provide results within 10%, no matter the density of the lesion, as long as the lesion diameter exceeds 2 cm. When the lesion diameter drops below 2 cm, significant differences were obtained between MC calculations and the MIRD approach (i.e. deviations >10%). As a general conclusion, the MIRD approach tends to overestimate the absorbed dose in small lesions, as the basic assumption of the model is that fl radiation is fully absorbed by the tumor or tissue where the decay occurs. When the radius of the tumor is smaller than the maximum range of the fl radiation in the medium, a significant amount of the energy is delivered out of the lesion, thus providing smaller absorbed dose values.

[0126] Presently, despite the availability of different dose algorithms, the MIRD analytic algorithm described by equation (4) is still widely used to assess the absorbed dose in tumor and in the liver compartment at the clinical level. For liver lesions that are larger, equation (4) may provide accurate dose estimates (provided that accurate input parameters are introduced, among which the fractional uptake of the target). However, when this approach is applied to assess the absorbed dose to small tumor masses (i.e. approximately below 2 cm diameter) inaccurate dose estimates may be obtained.

[0127] In addition, the MIRD analytic algorithm has been safely used for treatment planning with glass microspheres. The foundational principle is based on equation (4), which describes the average dose in a tissue volume as a function of90Y activity. During treatment planning, equation (4) can be solved for the treatment activity Ao. The results obtained in the present example raise questions as to whether the MIRD analytic approach should be used to assess the prescribed90Y activity in order to achieve a given tumoricidal endpoint in small liver lesions. This is especially true when intratumoral injection of90Y is performed. For example, for HCC, 120 Gy is typically considered a reasonable minimum target dose. Therefore, when treating an HCC patient with90Y 1-particles, one may wish to set Dz, to a minimum of 120 Gy. Equation (5) can be rearranged to derive the prescribed treatment activity:A(GBq) = D tumor mtumor(kg) / 49.38(J / GBq) ■ F Utumor

[0128] Assuming, for example, a tumor mass, mtumor, of 0.52 mg (diameter 1 cm), FUtumor = 1 and Dtumor = 120 Gy, equation (5) would yield a treatment activity of 1.21 MBq (considering p = 1.05 g / cm3). On the other hand, if equation (7) is used instead of equation (4), a prescribed activity of 1.62 MBq is obtained. As previously outlined, the cause of this difference is a result of asignificant energy deposition outside the sphere (about 26% of the / i-particles energy is delivered outside the sphere, as reported in FIG. 18 A). Consequently, a therapeutic activity of 1.21 MBq would actually correspond to an absorbed dose of about 90 Gy, well below the therapeutic endpoint.

[0129] As mentioned, the intratumoral injection of90Y is likely to pose specific treatment planning issues related to the possibility of treating very small lesions very selectively. In his paper, Ariel reported the first interstitial use of90Y microspheres for the treatment of a rhabdomyosarcoma (Ariel I 1978 Cure of an embryonal rhabdomyosarcoma of the nose of an infant by interstitial90Yttrium microspheres : A case report International Journal of Nuclear Medicine and Biology 5 37-41'). A nodule measuring 1.5 cm in diameter was successfully treated with interstitial injection of 185 MBq of microspheres. In 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 37958-63),90Y -glass microspheres were injected into predetermined tumor sites using an ultrasound-guided procedure. Tumor size ranged from 1.9 to 8.8 cm, with most lesions being less than 5 cm in diameter. More recently, Ferrari and co-workers assessed the absorbed doses to small-volume brain neocavities and surrounding tissues after local90Y-DOTATOC injection (Ferrari M, Cremonesi M, Bartolomei M, Bodei L, Chinol M, Fiorenza M, Tosi G, Paganelli G. Dosimetric model for locoregional treatments of brain tumors with90Y -conjugates: clinical application with90Y- DOTATOC, J Nucl Med. 2006 Jan;47(l): 105-12.). A recent review of the literature on the 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.

[0130] Described herein is a procedure whereby microspheres are delivered to the target using a direct, image-guided intratumoral injection of90Y microspheres (embedded in a biocompatible matrix) using a delivery system as described herein. This procedure is also known as percutaneous radioablation and is a minimally invasive treatment for patients with small (below approximately 3 cm) liver tumors performed using a combination of the following components: i) BIOGLUE® (Cryolife, Atlanta, US), a FDA-approved mixture of bovine serum albumin and glutaraldehyde in a 4: 1 ratio, approved for use in soft tissue repair or to seal damaged parenchyma ii) SIR-SPHERES® coated with90Y (Sirtex Medical, Sydney, Australia) approved for implantation into hepatic tumors via the hepatic artery and the iii) MIPP-KIT® (Svas Biosana, Naples, Italy) a dedicated coaxial dual-lumen catheter for the direct, imaging-guided intra-tumoral injection of the hemostatic agent component, such as a glue, and90Y microsphere mixture. The evidence from this study suggests that caution must be taken when planning the treatment of very small lesions with90Y, implementing the standard analytic approach. This is particularly true when intratumoral administration of90Y is performed, as this approach allows sub-centimeters tumors to be selectively treated. In such a scenario, the use of the analytic approach to calculate the therapeutic activity needed to achieve a given tumoricidal endpoint may result in important dose underestimations.

[0131] In some embodiments, the alternative algorithm presented by equation (7) can be usefully employed in treatment planning for intratumoral injection of microspheres, providing results in close agreement with Monte Carlo calculations (maximum deviation below 0.5%).

[0132] In conclusion, for a given activity Ao, the analytic equation proposed by the MIRD model (equation 4) is likely to overestimate the absorbed dose in lesions below 2 cm. Conversely, activity underestimations can be obtained if the analytic approach is used to assess the prescribed90Y activity. This is because the basic assumption made to derive equation (4) (full absorption of the fl particle into the target volume) is no longer true for small lesions. However, overestimations are below 10% for lesions with a diameter larger than approximately 2 cm. As a rule, the larger the lesion size, the better the agreement of the MIRD model with Monte Carlo calculations. When the lesion size drops below 2 cm the two calculation approaches deviate significantly, with the analytic algorithm providing dose overestimations up to 57% (for lesions of 0.5 cm diameter). Therefore, caution is advised when using equation (4) for absorbed dose determination in very small lesions. In particular, for the assessment of the absorbed dose in small tumor regions the use of equation (7) is suggested instead of equation (4).Example 1 : Pre-Clinical Study

[0133] In one example, a homogeneous distribution of90Y-labelled particles is demonstrated in a set of experiments using90Y microspheres mixed with a hydrogel or surgical sealant and / or adhesive, such as a tissue glue. By solidifying during the injection or implantation process, the radioactive glue or gel can be distributed uniformly, and it can resist undesired effects from gravity, dispersion or leakage into the blood or lymph vessels, hematomas, etc. FIGS. 2A and2B depict gamma camera views of ImCi (37 MBq) of90Y microspheres in BIOGLUE®, which is a mixture of 45% wt / vol bovine serum albumin and 10% wt / vol glutaraldehyde, in a 4: 1 ratio in a 2.5 mL syringe cylinder. Additional studies were performed using 5 mL plastic spheres which were filled with90Y microspheres and a gel carrier or matrix material, such as BIOGLUE, COSEAL (PEG / HCl / NaPhos / NaCO3; Baxter Healthcare, Hayward, CA) or BERIPLAST (fibrinogen / thrombin; CSL Behring GmbH; Marburg, German), at activity levels in the range of 370 to 740 MBq, filled using a dual-lumen coaxial catheter. In these studies, gamma camera and PET / CT imaging was performed using 4 mm slices to more precisely assess the distribution of radioactivity in the solidified carrier, as shown in FIGS. 3A and 3B. The PET / CT imaging in FIG. 3 A also demonstrated that there was no separation of the liquid used to suspend the microspheres in the solid carrier material in the cavities after mixing, and that there were no changes in the homogenous distribution or other changes to the solidification process within the cavities at the larger sizes.

[0134] The use of the gamma camera and PET / CT imaging was also used to evaluate the dosimetry distribution of the90Y microspheres and solidified matrix. FIGS. 4A to 4C depict the relative absorbed doses in cavities of 0.5 mL, 4.2 mL and 11.4 mL spherical volumes (0.5 cm, 1 cm and 1.5 cm radii, respectively), as measured from the center of each corresponding volume and shell volumes 1 mm thick from the sphere surface.

[0135] FIG. 5 depicts the percent activity of the90Y microsphere-BIOGLUE® composition in each of the volumes described hereabove in FIGS. 4A to 4C. For each of the 0.5, 1 cm and 1.5 cm radii volumes, the percentage of activity effectively falls to less than 50% activity within a 0.5 cm distance of the radius from the volume surface, or within a 150% radius distance from the center of the volume. For the 0.5 cm radius volume, the percentage activity falls to less than 10% or 5% within 0.5 cm from its surface and to zero within 1 cm of its surface, or 1 cm from its center and 1.5 cm from its center, respectively. For the 1 cm radius volume, the percentage activity falls to less than 10% or 5% within 0.5 cm from its surface and to less than 1% within 1 cm from its surface, or 1.5 cm from its center and 2 cm from its center, respectively. For the 1.5 cm radius volume, the percentage activity falls to less than 10% or 5% within 0.5 cm from its surface and to less than 1% within 1 cm from its surface, or 2 cm from its center and 2.5 cm from its center, respectively. The estimated absorbed doses for these volumes are provided below:

[0136] 0.5 mL volume with 0.5 cm radius and activity of 185 MBq:

[0137] 4.2 mL volume with 1 cm radius and activity of 370 MBq:

[0139] FIG. 6 depicts the absorbed dose per unit (Gy / MBq) in adjacent shell volumes for the three volumes. These plots show that there is a decrease of at least 95%, or 1 to 2 orders of magnitude decrease in the absorbed dose within a 0.5cm distance from the surface of the volume, and at least a 90% decrease within 150% of the radius.

[0140] FIG. 7 depicts the total absorbed dose in Grays in adjacent shell volumes for the three volumes. For the 0.5 cm radius volume, the absorbed dose within 0.5 cm from the surface (1 cm from the center) decreases by about 90%. For the 1 cm radius volume, the absorbed dose within 0.5 cm from the surface (1.5 cm from the center) decreases by more than 90%. For the 1.5 cm radius volume, the absorbed dose within 0.5 cm from the surface (2 cm from the center) decreases by more than 90%.Example 2: Mice Study

[0141] In one study, an animal model of pancreatic cancer applicant used with human MIA- Paca-2 RFP cells in the thigh of CD1 nude mice to then apply the new matrix, which will act as a carrier for the90Y spheres, in the site of the induced tumor. Intra-tumoral application of the new matrix with90Y spheres led to increased levels of the compound in the tissues through its homogeneous distribution and made it possible to achieve effective doses for the treatment of the tumor by reducing the rate of spreading and avoiding and minimizing the systemic side effects of therapy.

[0142] The experimental protocol involved a locoregional treatment affecting tumor shrinkage with tangible benefits for the host. The results obtained from this and other studies herein can be translated into clinical practice, introducing significant benefits, as in the majority of cases pancreatic cancer is inoperable for locally advanced disease.

[0143] The radioisotope and matrix used for this study were the SIR-SPHERES® and the BIOGLUE® as described above. It is believed that the composition: can be administered intra-tumorally in order to cause complete necrosis of the tumor tissue surrounding the injection site, thus allowing the treatment of malignant tumor masses which cannot be surgically removed; can be applied as a coating or filling material for surgical wounds, following surgical resection or ablative treatments of malignant tumor masses in order to cause complete necrosis of any remaining tumor cells localized along the edges of these wounds; can lead to the increased efficacy of anticancer substances, producing a beneficial increase in the administration and dosing times of said substances at a local level, through increased concentration of the substances inside the treated tumor masses, or inside surgical wounds from surgical removal, or ablative treatments, of tumors; prevents or slows anticancer substances from freely dispersing in the patient's body, thereby limiting systemic exposure to their toxic components; and / or avoids or reduces some of the side effects from application of methods of treatment alternative to surgical resection of malignant tumor masses.

[0144] It is believed that the radioisotope-matrix composition including a substance with adequate anticancer capacity, such as90Y or other similar type to Holmium, in a suitable viscous material capable of entrapping the microspheres, may provide homogenous distribution and act as a carrier of said substance. Necrosis of the tumor cells of interest is induced by adequate internal electron radiotherapy (IER) determined by localized emission of radioactive particles by the above-mentioned microspheres radiolabeled with90Y. Through gamma camera and PET / CT / SPECT imaging studies, depicted in FIGS. 8A to 8F, it was found that the90Y is dispersed in an almost homogeneous manner inside the tumor mass into which it is injected or inside the surgical wound on which it is applied, on account of the viscous nature of the components forming the matrix, and that this homogeneous distribution is highly instrumental in the necrosis of the tumor cells located in these areas.

[0145] Tumors were induced in mice following injection of the human MIA-Paca-2 RFP cells. FIGS. 8A and 8D depict PET / SPECT images of the matrix that did not contain any90Y spheres, while FIGS. 8B and 8E depict PET images of the mice injected with the combined90Y-matrix composition. FIGS. 8C and 8F are corresponding SPECT images of the mice in FIGS. 8B and8D, confirming that none of the90Y spheres had leaked or dispersed from the injection site, and that there is a homogenous distribution of the radioisotope within the tumor.

[0146] The results also show that, by using a hydrogel or matrix with a sufficient solidification rate as a carrier for the radiolabeled-microspheres, the possible dispersion of said microspheres in the patient's body potentially caused by factors such as gravity, circulation in the blood and / or lymphatic vessels, the presence of hematomas, etc. may be substantially limited, thus avoiding or greatly reducing possible side effects from potential leakage of the radioactive material in the patient.

[0147] The material forming the hydrogel or matrix is a viscous gel or matrix designed for direct intra-tumoral injection or for application of a surface of a tumor resection site. This matrix is configured to contain the90Y spheres, which, on account of their size and composition, (e.g. resin or glass), are trapped in the gel matrix and thus localized at the tumor or resection site for an extended period of time in order to increase or maximize the local dose level and duration of exposure. The overall effect of the matrix with90Y microspheres results in an increase in local90Y microspheres concentrations, limiting or reducing peak systemic exposure.Example 3: matrix-injector development

[0148] Due to the different densities and viscosities of the two solutions forming a hemostatic gel, sealant or hydrogel, one solution may flow into the catheter in greater quantity than the other, whereby the following problems may occur: compound wastage; difficulty applying the compound on account of the considerable force the operator has to apply to the syringe with both hands; misapplication of the compound due to dislodgement of the end portion of the catheter because the operator is unable to use just one hand to hold said catheter in place during infusion; such dislodgement requires the operator to use a greater quantity of the compound in order to be sure that it has reached and covered the entire the target volume.

[0149] Moreover, the reduced flow rate of either of the two compounds facilitates activation of the compound near the end portion of the catheter where mixing takes place to activate the compound, i.e., near the outlet of the two substances, which causes the obstruction of said catheter, thus causing the operator to apply more force in order to overcome the resistance of thetwo solutions to the infusion. In addition, the greater the force required of the operator, the more difficult it is to hold the end portion of the catheter near the target in place; this involves the need to perform continuous ultrasound or X-ray monitoring of the correct positioning of the catheter and any repositioning that may be required.

[0150] Due to these potential problems, and until now, the various glues and matrices have only been used intraoperatively. Further there have been great difficulties with percutaneous administration or during laparoscopy due to the use of double-lumen catheters which are designed and developed for other purposes and are unable to convey the two solutions to the area concerned at the same time, resulting in obvious wastage of compounds or drugs and poor therapeutic results.

[0151] Therefore, the technical issue consists of ensuring that the two solutions with different viscosities and densities have the same flow rate, meaning that they must flow in and out from the distal end or outlet of the catheter at the same time.

[0152] Thus, it is beneficial to deliver a combination of a carrier matrix and90Y-loaded microspheres with a device capable of transporting the compound to the target area in the desired ratio, and while preferably avoiding all the disadvantages existing thus far both in the case of percutaneous image-guided treatments and laparoscopic and intraoperative treatments.

[0153] In one example, a double-lumen catheter was developed for the infusion of a two- component compound, particularly for glues or agents containing thrombin and fibrinogen. The catheter comprises a first lumen intended for a first solution of a first component and a second lumen intended for a second solution of a second component. Said lumens respectively form, as per a catheter cross-section, a first area and a second area, with the ratio of said areas being proportional to the viscosity ratio of the respective fluids. According to a further aspect of the invention, it is preferable for said ratio of said areas to be greater than the square root of the ratio of the viscosities of the fluids passing through the respective lumens.

[0154] In particular, it is preferable for said ratio of said areas to be approximately equal to the square of the ratio of the viscosities of the fluids passing through the respective lumens. Said ratio value takes another aspect into account, namely that the viscosity varies according to the temperature.

[0155] In some examples, the lumens have a circular cross section and are concentric, and that the first lumen incorporates the second lumen, as depicted in FIG. 9A. In this case, it ispreferable for the first lumen to be configured and sized so as to receive the higher viscosity solution so that said solution might be more exposed to warming induced by contact of the catheter with the patient's tissues during infusion.

[0156] Therefore, the variant of the catheter allowing for better use of the penetration of warmth coming from outside requires the two lumens to have a circular cross-section and to be concentric and for the higher viscosity solution to flow in the outer lumen and therefore the outer lumen to have a larger cross-section than the inner lumen.

[0157] The catheter described above is applied in the medical / clinical field in minimally invasive percutaneous procedures, surgical, laparoscopic or interventional radiology procedures whenever necessary to administer the anticancer compound.

[0158] As a result of the present invention, it becomes possible to ensure that the two solutions have the same flow rate and so move along the catheter at the same time, i.e. exit the catheter in equal amounts so as to ensure the correct activation of the agent when infused in proximity to the patient's target tissues. As an advantage, it is possible to minimize infusion times and the amount of effort the operator is required to use during the infusion and it is also possible to minimize the quantities of the compound injected.

[0159] The features of a catheter according to the present invention prove to be very surprising because a technician in the field would have clearly applied Poiseuille's law, which states that the motion at constant speed of a viscous and incompressible fluid in a pipe having a constant cross section is laminar, i.e., consists of the relative sliding of an infinite number of cylinders coaxial to the tube axis.

[0160] Consequently, a pressure variation Ap between two points located respectively at the inlet and outlet of the tube is given by:Where L is the length of the tube, r is the diameter of the tube, Qvis the flow rate of the viscous fluid in the tube and q is the viscosity of the fluid.

[0161] Since it is required for the two solutions to have the same flow rate and the same pressure variation along the catheter in order to minimize the effort applied by the operator on the body of the dual-chamber syringe, therefore:

[0162] Where Si and S2 respectively represent the lumen cross-section areas. In other words, by applying Poiseuille's law, the result should be for the ratio of the cross sections of the two lumens to be proportional to the square root of the ratio of the respective viscosities.

[0163] To be more precise, the present invention stipulates a preferred proportion between the ratios of the areas and the ratios of the cross-sections, expressed using the following formula, which seems to go against the predicted said law of physics: h=i hS2

[0164] In fact, said law of physics is unable to contemplate the behavior of the two solutions forming the hemostatic agent when the temperature varies and particularly when the catheter is inserted in the patient’s body. In fact, under said circumstances, the temperature of the two solutions varies from an ambient temperature of approximately 18 °C to approximately 37 °C, the temperature of the human body.

[0165] Variations of the formula described above may be made in order to contemplate different positions of the inner lumen in relation to the outer lumen, for example with the axes of the lumens coincident (FIG. 9A), not coincident but parallel (FIG. 9B), or with the two lumens divided by a curved or straight septum (FIGS. 9C and 9D, respectively).

[0166] However, in some variations, the properties of the catheter are obtained according to the following relation, when the ratio between the areas of the lumen cross-sections is slightly greater than the square root of the ratio of the respective viscosities:

[0167] One embodiment has an external diameter of 16G, corresponding to an external diameter of approximately 1.6 mm. In addition, the two lumens are concentric, therefore: the first lumen has a diameter of 0.022 inches, i.e. 0.56 mm the second lumen has a diameter of 0.010 inches, i.e. 0.25 mm

[0168] Therefore, the cross-sectional area of the second lumen is it x 0.1252= 0.04906 mm2, the gross area of the first lumen is itx0.282= 0.24617 mm2, while the net area is 0.24617 - 0.04906 = 0.19711 mm2. This means that the ratio between the areas of the first and second lumen is approximately 4; therefore, it is suitable for solutions with a viscosity ratio of approximately the square root of 4, i.e. approximately 2. Externally, other embodiments of the catheter may have a standardized cross-section, for example 20G, 18G, 16G, or 14G.

[0169] Preferably, the catheter is made of a radiopaque material that is visible during x-rays and / or other imaging modalities. A length compatible with its use is approximately 20 cm and it is preferable for said material to make it semi-rigid, but in other examples may be flexible or rigid. Preferably, it comprises a rigid connector that can be connected to special syringes for injecting the two-component compound. In other examples, 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 comprise a rigid Y-connector specific to the two components, with a Luer-lock end connector that is a standard connector. Lastly, it is preferable for the catheter body to have specific markings at a set distance apart, for example at a distance of one centimeter apart, i.e. divided into centimeters for at least part of the catheter.

[0170] The kit may further comprise an introducer the same length as the catheter, for example 20 cm, and 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 flush with the distal tip of the introducer. In other examples, the catheter tip may extend out or be spaced proximally from the distal end of the introducer by 1 mm to 10 mm, or 1 mm to 5 mm, or 2 mm to 4 mm. The introducer may also be divided into centimeters, i.e. markings a set distance apart and made of radiopaque material. Furthermore, it may have a removable steel core with a sharp tip slightly longer than the introducer, for example, 210 mm long, and may include a Luer-lock connector. The preferred material for the body of the catheter is GRILFLEX® ELG 6260 (PEBA). Lastly, the catheter ends with an orthogonal cut along the axis.

[0171] FIG. 10A is a photograph of another exemplary kit 1000 that may be used for delivery of the90Y-matrix composition, comprising a catheter 1002, an introducer 1004, an introducer core (not shown), and a needle 1006. To perform the procedure, the introducer 1004 together 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 biopsyor other ablation procedure may be performed through the needle 1006. After the diagnostic and / or therapeutic procedure is performed, the needle 1006 is removed and the catheter 1002 is inserted into the introducer 1004 and the multi-chamber sealant injector (not shown) is attached to the catheter 1002. The sealant is then injected along the tissue tract as the combined injector and catheter are withdrawn from the tissue tract.

[0172] The distal end 1008 of the needle 1006 has a sharp, beveled tip and is preferably visible on ultrasound. For example, a cross-section of the needle could be 16G, that is, equivalent to an outer diameter of 1.60 mm and an inner diameter of 1.20 mm, made of AISI 304 with the tip being visible on ultrasound. The proximal hub 1010 of the needle 1006 may have an attached Luer-lock distal connector 1012, for example, comprising transparent ABS TERLUX® TR2812. The preferred length of the needle shaft 1014 is 200 mm, and shaft 1014 is configured to be inserted into the introducer 1004. The introducer 1004 may comprise 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 should be preferably slightly longer than the needle 1006, e.g. 210 mm, or a length that is 1 mm to 20 mm, 5 mm to 10 mm, or 5 mm to 15 mm longer than the needle 1006. In other examples, 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 otherwise to accept a catheter or needle shaft with a size from 12G to 18G.

[0173] FIG. 10B is a close-up photograph of the proximal hubs 1016, 1018, 1010 of the catheter 1002, introducer 1004, and needle 1006, respectively, with needle 1006 inserted into the introducer 1004 such that the proximal needle hub 1010 is engaged to the proximal introducer hub 1018 via complementary Luer locks 1012, 1022. The proximal hub 1016 of the catheter 1002 comprises two ports 1024, 1026 that are configured to attach to dual tips of a dual-chamber syringe (not shown). FIGS. 10C and 10D depict longitudinal cross-sections of the catheter 1002 with a male Luer-lock connector 1028 compatible with a female Luer-lock connector 1022 of the introducer 1004, respectively. This configuration permits 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 comprise a shaft 1030 with distance markings 1032 visible along its longitudinal length, and wherein the shaft 1030 is preferably radiopaque, e.g., loaded with 30% barium sulfate and inserted into a protective polythene tube. The catheter 1002 and introducer 1004 are also depicted with optional handles 1034, 1036 to facilitate handling during use.

[0174] Before a minimally invasive treatment takes place, the kit is prepared so that the introducer is inserted first, with the diameter corresponding to the catheter chosen according to the procedure to be performed, and it will be placed under ultrasound guidance, CT or MRI scanning. Once the core of the introducer is removed, the coaxial double-lumen catheter is then inserted and the compound is administered as needed, in order to fill the treatment area and if necessary the distance covered by the introducer, which is then slowly removed in order to release the compound including along the course of the introducer. This ensures effective functioning, ease of administration, conservation of drugs, and avoiding of additional invasive procedures for externally conveying the anticancer agent. The elements and features described above, in their various preferred embodiments, may be combined without departing from the scope.Example 4: Pi Study

[0175] In another animal study, eight large white female pigs weighing 75 ± 5 kg, selected from special farms, free of infection and previously immunized, underwent injection of bioglue-90Y microspheres under ultrasound guidance of three different liver segments or lobes. For these procedures, 24 ml of glutaraldehyde crosslinked albumin (BIOGLUE®) containing 60 / 80mCi of90Y microspheres was used in the left lobe, the right lobe, and the right lower paracaval lobe.The veterinarian examined all animals in order to assess their state of health and the absence of symptoms related to any disease and then underwent eight-hour preoperative fasting, anesthesia, and blood sampling. Blood samples taken from the jugular vein were performed: a) before surgery (TO), b) after surgery, before awakening (T 1), and c) before explantation of the liver (T2). All pigs, divided into four groups of 2 animals each, after general anesthesia were subjected at different times to: median laparotomy, intraoperative ultrasound identification of an ablation area approximately 3.5 cm2, treatment of 3 different liver segments with the anti-cancer compound, organ explantation and euthanasia: the first group was sacrificed 7 days after treatment, the second after 14 days, the third after 21 days and the fourth after 28 days. The explanted liver was then used for macroscopic and microscopic evaluation.

[0176] After treatment, all pigs were transferred to the animal facility and monitored daily; facility conditions were compliant with applicable current legislation as all animals were free to roam and feed "ad libitum".

[0177] FIGS. 11 A to 1 IF, 12A to 12F, and 13A to 13F are PET / SPECT images of three different porcine livers, respectively, that were explanted after 7 days. The blood samples taken from the pigs, according to the timings indicated in the protocol, did not document any significant abnormalities in blood coagulation parameters. The results of the anatomical and pathological evaluation of the explanted livers, shown in the tables below, characterize the area of ablation at different post-injection time periods of the90Y matrix composition.

[0178] 75 kg pig #1:

[0179] 80 kg pig #2:

[0180] 85 kg pig #3:

[0181] 75 kg pig #4:

[0182] 85 kg pig #5:

[0183] 100 kg pig #6:

[0184] 90 kg pig #7:

[0185] 80 kg pig #8:

[0186] The analysis above demonstrates a stable ablation area at each treatment site and at each evaluated time point. The necrotic mean ± SD area (cm2), as assessed at histo-pathology, was 18.8± 3.7, 20.5±2.8, 19.2 ± 2.1 and 20.5 ± 2.0, after 1, 2, 3, and 4 weeks from90Y matrix composition injection, respectively.

[0187] Acute systemic toxicity tests, intracutaneous reactivity tests, and delayed hypersensitivity tests were performed to verify the safety of90Y matrix composition administration to experimental animals. The results observed in the treated animals were very similar to the controls: no symptoms were detected in the acute systemic toxicity test; and no erythema nor slight erythema were detected in the intracutaneous reactivity test and no visible changes were observed in the delayed hypersensitivity test.

[0188] Moreover, considering the partial non-bioabsorbable nature of90Y matrix composition and the90Y decay time, the local and systemic effects of subcutaneous90Y matrix composition in male albino rats were assessed after 26 and 52 weeks from implantation. Considering the local effects, no abnormality was detected after macroscopic evaluation and necropsy in all implanted sites. The histological evaluation was used to calculate a Mean Final Index of reaction for the treated and control groups, which were 1.5 and 1.8 respectively at 26 weeks (values from 0.0 to 2.9 mean minimal or no reaction), 3.5 and 4.2 respectively at 52 weeks (values from 3.0 to 8.9 mean slight reaction).

[0189] As far as the systemic effects,90Y matrix composition did not cause significantly different effects, when compared to the control, when the following parameters were evaluated: tissue architecture; cell hypertrophy; necrosis; inflammatory population; atrophy; edema; hyperemia; fibrosis; and vascular congestion.

[0190] Blood samples collected from the test animals at the different timepoints did not document any significant abnormalities of the hematic and liver parameters; no radioactivity effects were detectable on the CBC blood counts after90Y matrix composition administration.

[0191] Based on the results above, the use of a locoregional approach to treatment of hepatic lesions appears to be potentially useful and appropriate for human treatment, based on ablationsizes ranging from 3.7 to 5.3 cm in length and 4.0 to 5.0 cm in width, and absence of side effects on organs and bone marrow.Example 5: Rabbit Study

[0192] In another animal study, intra-tumoral injection of a90Y-loaded hydrogel matrix was used for the treatment of unresectable primary or secondary solid tumors and / or intraoperative local application to prevent or delay local recurrence after resection with positive margins and to confirm efficacy and safety of the procedure. In one study, a90Y microsphere-BIOGLUE® composition was used to treat seventy New Zealand rabbits with induced para-renal tumors. For the tumor implant procedure, the rabbits underwent a xipho-umbilical laparotomy. A blunt dissection was used to expose the peritoneum through the avascular linea alba. Careful dissection of the peritoneum allowed for the exploration of the peritoneal cavity up to the right renal lodge, where one implant of VX2 tumor (about 5 mm3) was performed. Although VX2 tumor cells originated from skin cancer of cottontail rabbits, it was later found to be transplantable to all strains of domestic rabbits and used to study a variety of solid tumor human cancers, including the lung, bladder, breast, kidney and liver.

[0193] Para-renal tumor progression was allowed for 2 weeks and monitored by ultrasound until its mass reached approximately 2 cm in diameter, as checked by repeated renal ultrasonography, starting 1 week after tumor cell implantation. At the end of this period a right nephrectomy was performed, through a second laparotomy. The tumor originating from the VX2 implant was excised leaving an in-situ residual mass / l cm thick. The area was marked with a small surgical clip to facilitate tissue identification at the time of necropsy, when the residual tumor mass was completely removed. At the end of the 2-week tumor implant growth and after partial tumor excision as described above, 46 animals were randomly assigned to one of the following groups, to assess the safety, efficacy and biodistribution of each treatment: a) 22 rabbits were treated with 1 ml of90Y matrix composition (group A): 6 of these animals were euthanized under general anesthesia after 1 week, 8 after 2 weeks and 8 after 3 weeks; b) 15 rabbits were assigned to90Y-only treatment (group B), where 185 MBq of90Y microspheres (in 1 ml saline solution) were used for each administration; 5 of these animalswere euthanized under general anesthesia at 1 week, and 10 more at 2 and 3 weeks, respectively; c) 9 rabbits were assigned to localizing carrier-only treatment (group C), where 0.3 ml of combined bovine serum albumin / glutaraldehyde (in 1 ml of saline solution) were used; 3 of these animals were euthanized under general anesthesia at 1 week, and 6 more at 2 and 3 weeks, respectively.

[0194] The tumors were injected with their randomly assigned composition and monitored over time. The residual tumoral lesion of all animals (treated with either90Y matrix composition,90Y-only or localizing carrier-only), collected after 1, 2 and 3 weeks from treatment, were harvested and examined macroscopically and microscopically. The explanted tumor mass was calculated according to the formula volume=l / 2(length x width2). The collected specimens were fixed with a 4% PFA solution after PET / CT scanning (described in greater detail below), cut by a cryostat (sliced at 5-um thickness), stained using routine hematoxylin and eosin methods, and finally analyzed to ascertain the target tissue necrosis by a pathologist blinded to the original treatment. To assess90Y-induced necrosis on the residual tumors in groups A and B, the expression of p53 protein (a necrotic marker) was detected by western blot analysis (WB) on protein lysates collected from animals sacrificed at each time point; B-tubulin was used as a control marker. Liver enzymes (ALT, AST, GGT, alkaline phosphatase), bilirubin and complete blood counts (CBC) were performed at baseline; blood tests were then performed every 7 days before animals were euthanized, collecting blood from the heart of anesthetized animals.

[0195] As noted above, at 1 and 3 weeks post-surgery, the animals treated with90Y matrix composition and90Y-only were sacrificed under general anesthesia and immediately subjected to PET / CT imaging. These assessments checked not only the diffusion of the radioactive material within the target lesions and its homogeneous distribution, but also the possible dispersion of the injected compound in the rest of the target organ, as well as in other areas of the body. In fact, after the PET scan, selected organs were explanted from the animals to perform a thorough90Y biodistribution analysis. The explanted organs included the brain, thyroid, muscle, trachea, bronchi, right lung, heart wall, lymph nodes, liver, gallbladder, spleen, small intestine, colon, pancreas, peritoneum, right adrenal, testicle, left kidney, right kidney, bladder, skin, bone and tumor lesion.The above organs were weighed and the activity of90Y, expressed as counts per minute (CPM) in the absorption spectrum of B emissions, was detected through a Geiger-Muller counter for each of them.

[0196] Data were included in a Microsoft Excel 14.1.0 database. GraphPad Prism 6 was used for mean ± SD graph plots. Descriptive statistics were used for baseline variables, and statistical significance was checked using unpaired Mann-Whitney test. Where indicated, the coefficient of variation, expressed as percentage, was calculated as the ratio between SD and mean, multiplying the result by 100.

[0197] The antineoplastic effect was found to be directly proportional to the time of exposure to the90Y microsphere-BIOGLUE® composition, with treated tumors exhibiting 10% average necrosis at day 7, 30% average necrosis at day 14, and 90% average necrosis at day 21. The results of this study showed that the histological examination of the positive resection margin of the bed after nephrectomy and treatment with90Y- microspheres hydrogel mixture demonstrated almost total necrosis of viable VX2 carcinoma tumor cells after 21 days.

[0198] FIGS. 14A, 14B and 14C depict the histological tissue analysis of the positive resection margin of the bed after nephrectomy and treatment with a hydrogel matrix and90Y microspheres after 7, 14 and 21 days, respectively. FIG. 14A shows that 7 days after treatment, the percentage of necrotic cells is 70%, while FIG. 14B shows that after 14 days, the percentage of necrotic cells is 90%, with the arrows indicating areas of necrosis.

[0199] In comparison, the tissue in the resection bed of the animals treated with hydrogel or90Y-microspheres alone showed a palpable macroscopic tumor growth and a histological examination showed the presence of viable VX2 carcinoma cells after 7, 14 and 21 days. FIGS. 14D to 14F depict the histology of a positive resection margin of the tumor bed after nephrectomy and treatment with a90Y microspheres -only after 7, 14 and 21 days, respectively, and FIGS. 14G to 141 depict the histology of a positive resection margin of the tumor bed after nephrectomy and treatment with hydrogel-only after 7, 14 and 21 days, respectively. FIGS. 14D to 14F show that the percentage of necrotic cells 7, 14 and 21 days post- injection of90Y microspheres-only is 20%. In FIGS. 14G to 141 histology slides, viable tumor cells can be seen, within a 5% area of necrosis after treatment with a hydrogel. The percentage necrosis was quantified in the histological evaluations performed on the harvested residual tumors after H&E staining. As shown in graph of FIG. 14 J, both the groups treated with90Y matrix compositionand90Y-only were significantly more effective (*=p<0.05; **=p<O.OO5;***=p<O.OOO5; ***= p < 0.0005, Mann-Whitney test) than the matrix-only treatment group, to induce necrosis at each time points. Moreover, after three weeks, the rabbits treated with90Y matrix composition showed a higher necrosis than any of the other treated groups (***=p<0.0005. Mann-Whitney test).

[0200] The Western Blot analyses depicted in FIG. 15 further show an increase in p53 protein expression, a marker of tumor necrosis, which was detected especially at the 3 week observation point and is consistent with the increase of necrosis detected by histological evaluation in the study groups.

[0201] Tumor volume was also compared at selected time-points, as depicted in FIG. 16. This comparison was used to assess the ability of each treatment group to slow or impair tumor growth. Both the90Y matrix composition and90Y-only treatment group were significantly more effective (**=p<0.005; Mann-Whitney test) than the matrix-only group to inhibit tumor growth after two weeks. More surprisingly, however, after three weeks, rabbits treated with the90Y matrix composition showed a statically significant tumor volume inhibition larger than any of the other treated groups (*=p<0.05. Mann-Whitney test). It was not expected that the90Y matrix composition therapy could outperform90Y-only therapy.

[0202] The total levels of90Y in the resected tissue in the rabbits treated with a90Y- matrix composition and90Y-only (without matrix) are included below:

[0203] Furthermore, due to the application of the hydrogel matrix containing90Y microspheres, the system described in this study for administering the composition in the resection bed represents a multimodal approach to the treatment of solid tumors that appears to achieve higher counts than90Y injection alone, using the same activity level.

[0204] The viscosity and density of the hydrogel matrix (hydrogel) allows the hydrogel mixture to be directly injected or layered within the resection site, ensuring homogeneous distribution, an increase in the local concentration of the90Y radiation agent, longer retention in situ and low or no dispersion of the90Y spheres, thus potentially limiting systemic side effects.

[0205] Through this study, a high concentration of90Y levels in the90Y-loaded matrix persisted at the administration site for a longer period of time, when compared to the treatment of rabbits injected with90Y spheres alone, achieving complete destruction of residual tumor cells (positive margins) created in our animal model.

[0206] These results demonstrate that use of the90Y microspheres and hydrogel combination achieves a high concentration of90Y for a prolonged period compared to the administration of90Y microspheres alone, and also achieves homogeneous distribution, thus treating tumor cells in the animal model and potentially reducing the relative risk of local recurrence in the animals who received treatment with90Y-matrix compared to those receiving90Y alone. In addition, the evaluations carried out in animals treated with90Y-matrix, compared to the controls, revealed no levels of radioactivity in the blood, no myelosuppression, no renal, cardiac or pulmonary toxicityand no intestinal perforations or bleeding related to the spread of the90Y microspheres, as opposed to the findings observed in the animals receiving90Y alone.

[0207] In an initial assessment, three rabbits were injected with90Y microspheres at a target location and a beta counter was used to quantify the distribution of90Y throughout the body. FIG. 17A illustrates that little activity remained at the target locations of each rabbit, and some activity was detected at every organ location, but with substantial activity concentrated at the spleen, small intestine, peritoneum and adrenal glands of at least some of the animals. In contrast, for the rabbits which underwent injection with the90Y-matrix at the same location, as depicted in FIG. 17B, activity was detected only at the target locations, with negligible or no activity detected at any of the other organ locations.

[0208] In a further analysis of the rabbits enrolled in the study, the distribution of90Y in selected organs was assessed at 7 days and 14 days, in the90Y-only and90Y-matrix groups, as illustrated in FIGS. 17C to 17F. As depicted in FIG. 17C, at 7 days, significant activity was detected at the tumor site for the additional90Y-only rabbits, but also significant activity in one rabbit at the bronchi and pancreas, as well as detectable activity at other sites such as the lymph nodes, liver, gallbladder, small intestine, colon, peritoneum and bladder. In contrast, the90Y- matrix rabbits at 7 days had significantly higher activity detected at the tumor site and minimal or no detectable activity in the other selected organ sites, as illustrated in FIG. 17D. At 14 days, the90Y-matrix rabbits still had lower but still significant activity at the tumor site, and still minimal or no detectable activity at the other selected sites (FIG. 17F), while the90Y-only rabbits at 14 days had substantially reduced activity at the tumor sites, but the90Y had further redistributed to the other organ sites, even those without detectable activity at 7 days (FIG. 17E), including the brain, thyroid, muscle, trachea, right lung, spleen, right adrenal, testicle, right kidney skin and bone. This data suggests that the90Y-matrix not only achieves higher therapeutic levels at the tumor sites, but also substantially resists delayed biodistribution to off- target organs that may occur between 7 and 14 days.

[0209] The radioisotope presence in the tumor area was analyzed at 1 and 3 week-time points by PET / CT imaging. The90Y activity was assessed in the injection area, as well as in other anatomical districts, by a Geiger-Muller counter. The results of90Y radiation intensity showed a reproducible and elevated level in the tumor injection site for90Y matrix composition treated rabbits, as compared with90Y-only treated rabbits, both at 1 week and 3 -week time-points(p<0.05, Mann-Whitney test), as depicted in FIGS. 24A and 24B, respectively. The same analysis, when carried-out in the pre-specified distant organs, showed a much lower, almost undetectable signal in90Y matrix composition treated rabbits, as compared to the90Y-only treated rabbits, both at 1 week and 3-week time-points (FIGS. 24A and 24B, p<0.05, Mann- Whitney test).Based on the total amount of90Y signal detected in the distant non-target organs (non-tumor),90Y matrix composition therapy was shown to be very effective in retaining the90Y signal within the tumor injection site at all assessed time-points (FIGS. 25A and 25B, p<0.0005, Mann-Whitney test). As expected, the tumor injection site signal of90Y matrix composition therapy at 3 weeks was much lower than the same signal after 1 week of the compound injection. The free90Y-only treatment was far from being equally effective in the retention of the 90 Y activity in the target injection site. The comparison of the coefficient of variation (CoV) of the activity levels detected in the tumor vs. non-tumor target areas confirmed a much lower variability of90Y matrix composition therapy when compared to90Y-only treatment (i.e., a higher repeatability) at both time-points. In the90Y matrix composition therapy group, at 1 week, the CoV was 5.69% for tumor and 14.33% for non-tumor sites, and at 3 weeks, the CoV was 1.89% for tumor and 29.56% for non-tumor sites. In the90Y-only therapy group, at 1 week, the CoV was 136% for tumor and 156.18% for non-tumor sites, and at 3 weeks, the CoV was 199.87% for tumor and 175.38% for non-tumor sites.

[0210] These results suggest that not only can90Y matrix composition therapy reduce sizably the rate of side effects or serious adverse events by localizing the radiotherapeutic effect and reducing or minimizing their escape locally and distantly through shunting, but may potentially increase the duration of disease-free progression and / or survival in patients treated with90Y matrix composition when compared to patients treated with90Y-only therapies by the same route, or by transarterial radioembolization. Furthermore, in the treatment of human patients, where there is an extensive pre-treatment workflow and assessment that is required before90Y radiotherapy can be performed,90Y matrix composition therapy may reliably reduce the risk associated with hepatopulmonary shunting or other off-target shunting such that portions or all of the pre-treatment workflow is not required or otherwise not performed. For example, in some further variations,90Y matrix composition therapy may be provided without requiring a pretreatment imaging, e.g. a Technetium-99 scan, to assess for any shunting to the liver or lungs or other off-target locations, such as the ones associated with variceal or arteriovenousmalformation. This is due to the reduction or minimization of90Y leakage via shunting, achieved by the localizing carrier. In turn, because pre-treatment imaging to assess shunting is not required, pre-treatment procedures to treat potential shunting are also not required. This can potentially reduce the time-to-treatment by one, two, three, four, five, six or seven days or more, because treatment is not delayed by pre-treatment shunt imaging, pre-treatment shunt reduction procedures, and pre-treatment rescanning to assess the effectiveness of the shunt reduction procedures. The shunt procedures that would no longer be required or performed may include arterial embolization, hepatic vein balloon occlusion, and variceal and AVM occlusion procedures. Because dosing adjustments to account for the shunting are no longer required, dosing calculations may also be simplified, e.g. no longer requiring adjustments based on the shunt fraction and / or lung dosing limit. Patients with substantial liver, lung or hepatopulmonary shunt fractions also do not need to be excluded from therapy anymore. One or more of these features of tumor treatment protocols may be included in the various treatments described herein.Example 6 Breast Cancer

[0211] With the increasing occurrence of very small, radiologically detected subclinical lesions, several teams started considering, in the 1990’s, most DCIS diagnoses as a possibly “indolent disease” and claimed that lumpectomy alone could be the treatment of choice in patients presenting with small size unifocal DCIS. The administration of 50 Gy in 25 fractions over 5 weeks to the whole breast was considered the standard until a few years ago, when the publication of the long-term results of important British and Canadian randomized studies proved the effectiveness and efficiency of schemes administered over shorter times (hypo- fractionated radiotherapy). DCIS is not normally palpable; the widespread use of screening mammography has allowed the diagnosis of increasing numbers of patients with DCIS, who now account for 20-30% of all mammographically detected breast cancers.

[0212] Women diagnosed with DCIS are treated with breast-conserving surgery (BCS) in more than 2 / 3 of the cases, with or without adjuvant therapy. The ipsilateral recurrence rate for women operated on by BCS for DCIS is 1-3% per year; long-term local recurrence rates can be higher than 35% for women operated by surgery alone and are much lower (15% at 10 yrs.) if external beam is added to surgery. Several factors are associated with the increased risk of localrecurrence after BCS, among which the strongest one is whether DCIS has been fully excised or not:

[0213] 1. Margins that are clear from cancer or are more than 1 mm away from cancer have a much lower risk. If margins are not clear from cancer, patients should undergo new surgery to achieve a radical treatment; this can occur in around 20% of patients.

[0214] 2. Intraoperative radiotherapy (IORT), in which postoperative whole-breast irradiation is substituted by one session of radiotherapy with a dose of 16-20 Gy after surgical resection, allows the treatment to be completed on the same day.

[0215] 3. Recent trials such as electron intraoperative radiotherapy versus external beam radiotherapy for early breast cancer (ELIOT trial) and targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial) have demonstrated that IORT in selected groups of low-risk early breast cancer patients results in acceptable outcomes in terms of local disease control and could, therefore, serve as an alternative to conventional WBRT, representing a good compromise between treating all patients with external beam radio-therapy and not treating patients at all.

[0216] In the Consensus Statement regarding Accelerated Partial Breast Irradiation published on 2017 by American Society for Radiation Oncology (ASTRO), were provided some recommendations on selection criteria for “suitable” patients with low-risk DCIS. On the basis of the clinical experience accumulated in over 15 years of treatments based on trans-arterial infusion of90Y-coated microspheres, it is reasonable to assume that the administration of the appropriate activity of90Y in the surgical bed of the resected mammary gland should overcome some limitations of WBRT and IORT, and reduce drastically the chances of local recurrence which occurs in the vast majority of cases in the surgical bed. From data available in literature, a target dose of 20 Gy (>18 Gy) is believed to be sufficient to effectively ablate the tissue surrounding the surgical bed of a resected DCIS lesion.

[0217] In one example, a clinical study on the use of a90Y-matrix composition was performed. The90Y-matrix composition comprised a combination of BIOGLUE® with SIR-SPHERES® loaded with Yttrium-90. In the study, microspheres pre-loaded with90Y were blended with a surgical glue for the radio-ablation of surgical margins following the resection of breast DCIS. The study was a multi-center, non-inferiority, pre-market, First-In-Human pilot study for patients with biopsy-proven breast DCIS, eligible to receive breast-conserving surgery. The primaryobjectives of this study are to assess the ability to reach the surgical bed of a DCIS resection as planned, and to deliver a pre-determined dose without treatment-limited clinical complications. Alternatively, the primary objective may be to assess the performance of the90Y-matrix composition in the delivery of an absorbed dose of 20 Gy (>18 Gy) for the radio-ablative procedure of surgical margins following DCIS resection. The secondary objectives of this study were to evaluate the performance of the90Y-matrix composition through imaging procedures (PET-CT and DW-MRI), to assess local and systemic toxicity, and to assess quality of life of enrolled patients. The subjects will be followed up for 1 to 3 months after radio-ablation of surgical margins with the90Y-matrix composition following DCIS resection. The study, however, will be considered concluded for each subject after the examination of the Magnetic Resonance-Diffusion Weighted Imaging or mammography. The total study duration per patient is of 15 weeks, with an enrollment period of 6 months. The primary endpoint of the study will be the ability to reach the surgical bed of the DCIS resection as planned, and to deliver a predetermined dose without treatment-limiting clinical complications. The secondary endpoints will be (1) the volume / extent of surgical margin tissue ablated by the use of the90Y-glue matrix composition, following surgical resection of the segment containing the lesion, as measured by PET-CT (Positron Emission Tomography-Computerized Tomography) 2-6 hours after surgery and 24 hours after surgery, and by mammography or (if available) Magnetic Resonance- Diffusion Weighted Imaging (MRI-DW, Day 30); (2) the safety of the procedure, as determined by vital signs, laboratory tests, type and severity of any adverse events and / or device deficiency or usability associated with the procedure of radio-ablation following surgical resection; and (3) the quality of life of the enrolled patients, as measured by the EORTC QLQ-C30 and BR23 Questionnaires.

[0218] A sample size of 10 to 20 subjects will be enrolled. In further embodiments, a sample size of 20 subjects can achieve an 80% power to detect a non-inferiority primary endpoint using a one-side (alpha=0.025), one sample test. Because this FIH study explores the performance and safety of the90Y-matrix composition, an effect of 20 Gy delivered locally by the90Y-matrix composition has been deemed plausible by looking at results of similar studies. The noninferiority margin of 18 Gy has been evaluated as clinically significant and the standard deviation has been assumed to be 3 Gy. Sample size estimation has been performed using SAS version 9.4.

[0219] The inclusion criteria for the study will be:Female, Age > 50;Subjects with biopsy-proven breast DCIS, eligible to receive BCS and “suitable” for partial breast irradiation as per the latest ASTRO guidelines (Age > 50; low to intermediate nuclear grade; resected with margins negative at >3 mm; Tis; Size < 25 mm).Subjects may undergo subsequent External Beam Radiotherapy (EBRT) if deemed appropriate by the treating physician;Subjects with mammographic or Contrast-Enhanced Magnetic Resonance Imaging evidence of DCIS;Subjects with a localized DCIS (> 3 mm and < 25 mm), with a location accessible to percutaneous ablation;Clinically negative axillary lymph nodes and no clinical findings suggestive of invasive breast cancer.

[0220] The exclusion criteria for the study will be: Female, Age > 50;- Histotype different from carcinoma;- Paget carcinoma;- Lesions located near to axilla region or cutaneous areas (< 15 mm); Presence of microcalcifications extending for more than 30 mm;- Pregnancy or breast-feeding ongoing;- Positive history for neoplasia (with the exclusion of carcinoma in situ of a portion or skin cancer surgically removed and contra lateral breast cancer without any sign of disease progression in the last 15 years).

[0221] Each subject will undergo imaging and have the DCIS lesion diagnosed and staged as follows:The surgical bed following resection of the target lesion will be treated with radioablation using the experimental device;An appropriate absorbed dose of 20 Gy (> 18 Gy) will be administered to the surgical bed following DCIS resection in order to achieve ablation;- Within 7 days after the surgical procedure, the patients will return at site for the assessment of the volume of the effect of the administration of90Y-matrix composition on the surgical bed, as well as for its cosmetic and toxicity evaluation; 30 (± 5) days later the surgical bed treated with radio-ablation will be assessed using Magnetic Resonance Diffusion Weighted Imaging or mammography in order to evaluate the extent of the ablated tissue.

[0222] Optionally, for the first five patients, additional patient assessment and clinical clearance will be performed. The clinical clearance will include validations of the follow-up data for at least 1 week, if no complications occurred, or 4 weeks, in case of complications. This will include validation of unscheduled contacts with the patient, if performed.

[0223] Once the diagnosis of DCIS is confirmed and the inclusion / exclusion criteria met, subjects will be enrolled in the study and admitted to the hospital the day before their scheduled surgery, according to the normal clinical practice. On the day of the surgery, subjects will undergo DCIS excision plus surgical bed ablation with a90Y-matrix composition, through a procedure that will require collaboration between the surgeon and the nuclear medicine specialist. Once the treatment is performed, subjects will return to the surgical ward and be discharged the day after the surgery / ablation procedure. Subjects will be followed-up 7, 30 and 90 days after surgery to assess their local and general conditions; at the end of follow-up, they may undergo subsequent external beam radiotherapy if deemed appropriate by the treating physician.

[0224] The subjects will be informed about the aims, procedures and possible risks of the study and will be asked to sign the informed consent form. Each screened subject will be identified by a progressive screening number. Subjects will be enrolled only after having signed the informed consent form before any other study procedure. All the patients followed by the investigational center will be checked for adherence to the inclusion and exclusion criteria. One or more of the following information will be collected, though the collection of the information need not be collected on the same exemplary schedule:

[0225] If all the entry criteria are fulfilled, patients will be planned for the ablation procedure by using the90Y-matrix composition 1 week after screening. Each patient will be followed-up for any adverse events or adverse effects from the informed consent signature date, during the whole study duration. A blood sample will be collected for the following hematological and biochemical determinations at each study visit:Complete blood count with differential- Electrophoretic protein pattern- APTT- INRFibrinogen- Blood glucose- Blood urea nitrogen (BUN)CreatinineAST, ALT, total and fractionated bilirubin, GGT, LDH, alkaline phosphatase Serum ions: sodium, calcium, potassium, chlorideTumor marker (AFP)

[0226] Blood sampling to detect early blood disorders at 1, 3, 6 and 12 hours after90Y-matrix composition delivery at Vo:Complete blood count with differentialAST, ALT, total and fractionated bilirubin, GGT, LDH, alkaline phosphatase

[0227] All data for the study subjects will be presented using descriptive statistics as mean, standard deviation, median, minimum, maximum or frequency tables, as appropriate. For the primary endpoint a confidence interval (CI) with a significance level of 5% will be estimated andthe lower boundary of the CI will be compared to the non-inferiority margin in order to test the non-inferiority. Secondary endpoints involve the evaluation of quality of life (as measured by the EORTC QLQ-C30 and BR23 Questionnaires), the evaluation of the volume / extent of surgical margin tissue ablated (as measured by PET-CT and by Mammography or Magnetic Resonance- Diffusion Weighted Imaging) and the demonstration of the safety profile of90Y-matrix composition. Scores of quality of life questionnaires, volume / extent of surgical margin tissue ablated and their change over time will be evaluated by descriptive statistics. Incidence of adverse events, with regards also to the relationship with the90Y-matrix composition, will be calculated for all patients, along with their severity and the seriousness. Safety assessments will consist of recording and tabulating all adverse events, as well as with an analysis of changes in vital signs and laboratory parameters. Descriptive statistics will be provided for safety variables.

[0228] For one exemplary procedure, a syringe size, 2 mL or 5 mL, of the BIOGLUE® will be selected based on the size(s) or total volume(s) of the tumor as determined on the pre-procedure work-up.90Y-matrix composition is prepared during the pre-procedure set-up as follows:1. Unpack SIR-SPHERES® microspheres, leaving shipping vial in lead pot.2. Place on the bench top in a lead or acrylic shielded box if available.3. Remove the SIR-SPHERES® microspheres shipping vial from the lead pot and shake vigorously to disperse the SIR-SPHERES® microspheres.4. Using a dose calibrator, such as a gamma camera, to determine the activity in the shipping vial and return it to the lead pot.5. Determine the volume to be withdrawn to provide the required patient radiation dose. The following tables show the activity values of SIR-SPHERES® to be inserted into the 2 ml or 5ml BIOGLUE® syringe, depending on the radius of the tumor bed. In order to calculate the activity, a vial of SIR-SPHERES® containing a 3 GBq / 5 ml dose was considered. Moreover, it has been considered a residual of 300 microliters will remain in the BIOGLUE® syringe at the end of the treatment on the patient. The table also shows the volumes of SIR-SPHERES® to be placed into the BIOGLUE® syringe in ratios of 1 :4 (glutaraldehyde: bovine albumin) using the 2ml / 5ml syringe respectively. For tumor sizes less than 50 mm radius, a 2 mL syringe is selected, and assuming that the SIR-SPHERES® and BIOGLUE® are uniformly mixed and the maximum amount of the mixture is dispensed, leaving a nominal 300 pL residual of the mixture in the syringe:

[0229] For tumor sizes from 50 mm radius to 70 mm radius or higher, a 5 mL syringe is selected, and assuming that the SIR-SPHERES® and BIOGLUE® are uniformly mixed and the maximum amount of the mixture is dispensed, leaving a nominal 300 pL residual of the mixture in the syringe:6. Partially remove the aluminum seal of the SIR-SPHERES® microspheres shipping vial, clean with alcohol swab.7. Insert a 25-gauge needle through the septum of the shipping vial to create a vent, ensuring the needle is well clear of the contents in the shipping vial.8. Use a shielded 5ml syringe with a 20-22 gauge spinal needle at least 70mm long to puncture the septum of the SIR-Spheres microspheres shipping vial, and quickly draw back and forth several times in order to mix the SIR-Spheres microspheres thoroughly.9. Quickly withdraw the pre-calculated patient radiation dose and transfer in the two chambers of the BIOGLUE® syringe as described in the following points 10-13.10. Remove the double-chamber syringe cap containing the glue components.11. Distribute the microspheres in the double chamber syringe of the glue respecting the ratio of 4: 1 (80% in the BSA chamber, 20% in the glutaraldehyde chamber), as reported in the tables before.12. Reinsert the cap on the syringe.13. Verify the patient dose by re-measuring the activity in the shipping vial with the dose calibrator, and correct, if necessary.14. Place the syringe in a radioprotective container suitable for the transport into the operating room / radiology procedure room.15. At the operating room / radiology procedure room, the prepared syringe / injector system with the90Y is removed from the radioprotective container.16. The sterile package containing the mixing-tip is opened.17. Hold the syringe upright, and tap the syringe until any air bubbles in the liquids rise to the top of the syringe18. Connect the sterile mixing-tip applicator contained in the glue package.19. Briefly shake the syringe.20. Apply the compound in the surgical cavity pushing on the pistons of the syringe21. Wait for the compound to polymerize (e.g. wait a few seconds).22. Proceed to suture the area.

[0230] The actual amount to be injected will be decided by the nuclear medicine specialist performing the procedure of radio-ablation, depending on the size of the surgical resection area (tumor bed) to be ablated and on his / her clinical judgement.

[0231] For the ablation procedure, the patient will undergo preparation for ablation procedure as per standard procedure of the treating facility. The patient will be prepped and draped in the usual sterile fashion, and anesthesia will be achieved. The target area will be identified by the surgeon intra-operatively, also using an appropriate marker / ink.

[0232] For the dosimetric evaluation, assuming that the radiotracer leakage is negligible / absent, two PET / CT scans of the breast region will be acquired, the first one between 2 / 6 hours post injection (p.i.) and the second one 24 hours p.i. These two scans will enable us to confirm that the time-activity curve follows a physical decay, accordingly to the preclinical data. The dose calculation will be performed by using the MIRD formalism (OLINDA / EXM software). In particular, for the lesion dose, the unit-density sphere model available in OLINDA / EXM will be used, assuming a discoid morphology and a uniform distribution.

[0233] In order to confirm the radiotracer biodistribution, the patients will undergo one wholebody scan acquired by SPECT / CT device: the acquisition will be performed between 16-24 hours p.i. This information is useful to confirm that the radiotracer remains confined in the tumor bed.

[0234] After discharge, patients will be followed up for 90 days. The study will be considered concluded for each subject after the post-ablation evaluation (V3); during the follow-up, however, information will be collected on any adverse event that might be related with the radioablation procedure and included in the clinical research form.

[0235] Adverse events will be classified according to established classification systems, such as the Common Terminology Criteria for Adverse Events v5.0.

[0236] At the conclusion of the procedure, the needle, the syringe and any other components must be disposed of, following the institution’s standard operating procedure for handling biohazardous and / or radioactive materials.

[0237] In some further variations of the breast cancer treatment procedures,90Y matrix composition therapy may be provided without requiring a pre-treatment imaging, e.g. a Technetium-99 scan, to assess for any shunting to the liver or lungs or other off-target locations,including varices and AVMs. In some variations, because pre-treatment imaging to assess shunting is not required, pre-treatment procedures to treat potential shunting are also not required. This may result in reducing the time-to-treatment by one, two, three, four, five, six or seven days or more, because treatment is not delayed by pre-treatment shunt imaging, pretreatment shunt reduction procedures, and pre-treatment rescanning to assess the effectiveness of the shunt reduction procedures. The shunt procedures that would no longer be required or performed may include arterial embolization, hepatic vein balloon occlusion, and variceal and AVM occlusion procedures. Because dosing adjustments to account for the shunting are no longer required, dosing calculations may also be simplified, e.g. no longer requiring adjustments based on the shunt fraction and / or lung dosing limit. Patients with substantial liver, lung or hepatopulmonary shunt fractions also do not need to be excluded from therapy anymore.Example 7: Breast Cancer

[0238] In another exemplary study design or treatment regimen, the patient selection, monitoring and follow-up are as disclosed for Example 6 above, but the procedure, kit and / or dosing may be different. In this example, the product comprises the combination of a surgical glue, itself a combination of bovine serum albumin and glutaraldehyde in a 4: 1 ratio, and microspheres covered with |3-emitting90Y isotope. The kit may further comprise one or more syringe shielding devices to protect the user from inadvertent radioactivity exposure.

[0239] The kit may be indicated for the ablation of surgical margins after conservative breast surgery, and is contraindicated in patients with known sensitivity to materials of bovine origin or other glue components. One example of a dosing regimen that utilizes a 2 mL BIOGLUE® syringe along with SIR-SPHERES® to achieve a dose at the tumor bed of 20 Gy or >18 Gy is:

[0240] In some further embodiments, the volume of90Y microsphere solution that is loaded into the90Y-matrix syringe may be adjusted based on the nominal decay hour period (x:00 to x:59 per x hour) and tumor size as follows:Tumor Bed Radius: 20 mm to 24 mmTumor Bed Radius: 25 mm to 29 mmTumor Bed Radius: 30 mm to 34 mmTumor Bed Radius: 35 mm to 39 mmTumorBedRadius: 40 mm to 44 mmTumorBedRadius: 45 mm to 49 mmTumor Bed Radius: 50 mm to 54 mm

[0241] The kit that may be used includes:- two syringes (1 ml.) with Luer-lock, provided sterile- two 22G needles provided sterile- two sterile needles ( e.g. 20G x 70mm), e.g. STERICAN® needles by B. Braun- two radioprotective syringe holders, e.g. polymethylmethacrylate (PMMA) cylinders:■ one cylinder for the 2 ml. glue syringe (Cylinder “A”)■ one cylinder for the for 1 ml. syringe (Cylinder “B”)1 sterile radio-protected box (for the transport in OR) not provided by BetaGlue;

[0242] The kit may optionally comprise the following components, though in other examples, these components may be provided sourced separately: one vial of90Y microspheres, such as SIR-SPHERES®, containing 3 GBq+ / - 10% in5ml. of Water For Injection (WFI), provided in a lead pot one syringe of two-component glue in a capped dual-chamber syringe (2ml.), such as a 2mL syringe of BIOGLUE®, provided in a box and / or other packaging

[0243] In addition, to the above kit, healthcare providers or sites licensed or authorized to provide radiotherapy will also have available and will use during the procedure: a sterile radio-protected box or container for transport of the vial of90Y microspheres a radio-protected waste receptacle forceps or tongs used to handle the vial of90Y microspheres a dose calibrator to measure radioactivity, such as a gamma camera alcohol pad

[0244] To initially prepare the radiotherapy for use:1. Open the box containing the glue syringe packaging2. Open the packaging containing the glue syringe in sterile fashion3. Remove the cap of the glue syringe4. Place the syringe of glue in its PMMA cylinder (Cylinder “A”)5. Open the lead pot containing the vial of90Y microspheres and remove the vial from the pot using the forceps6. Using a dose calibrator, measure the radioactivity of the90Y microspheres vial and confirm the radioactivity (measurement should report 3GBq+ / -10%)7. Place the vial back in the lead pot8. Partially remove any protective materials from around the vial and clean the vial with an alcohol pad9. Place one of the 20G needles into the vial to reach the90Y microspheres and insert one of the 22G needles in the vial for ventilation10. Place a 1 mL syringe into its PMMA cylinder (Cylinder “B”)11. Shake the lead pot with circulating movements for at least 10 seconds.12. Connect the 1 mL syringe to the 20G needle and draw the amount of90Y microspheres for the glutaraldehyde chamber of the glue syringe according to the quantity reported in the below, for a glue syringe of 2 mL13. Inject the90Y microspheres into the glutaraldehyde component chamber of the glue syringe and dispose of the empty 1 mL syringe in a radio-protected waste box, without disposing the PMMA cylinder (Cylinder “B”) that contained the 1 mL syringe14. Place the second 1 mL syringe into the PMMA cylinder (Cylinder “B”) and connect the second 20G x 70 mmm needle15. Agitate or shake the lead pot with circulating movements for at least 10 seconds16. With the 1 mL syringe, draw the amount of90Y microspheres for the bovine serum albumin (BSA) chamber of the two-component glue syringe according to the quantity reported in tables above (for a two-component glue syringe of 2 mL). Adjust for any90Y decay17. Inject the90Y microspheres into the BSA component chamber of the two- component glue syringe and dispose of the empty 1 mL syringe with the 20G x 70 mm needle in a radio-protected waste receptacle. Do not dispose of the cylinder shield.18. Connect the mixing tip to the two-component glue syringe, now contains the pre- loaded glue and the90Y microspheres in the BSA component chamber19. Using the dose calibrator, measure the radioactivity of the90Y-matrix syringe using a gamma camera and place the syringe in the radio-protected box. The90Y-matrix syringe is now ready to be transported to the operating or procedure room.

[0245] The actual amount to be injected will be decided by the nuclear medicine specialist performing the procedure of radio-ablation, and may depend on the size of the surgical resection area (tumor bed) to be ablated and on clinical judgment. Before the delivery of therapy, the system may be further assembled with an exemplary mixing tip as described below:1. Remove the radio-protective PMMA cylinder containing the prepared90Y-matrix syringe from the radio-protective box, holding the syringe in the PMMA cylinder upright through the entire dispensing process to maintain any air bubbles in the upper part of the syringe2. Open the sterile packaging containing the mixing tip and remove the mixing tip from the packaging, checking the mixing tip collar to ensure that the pointer on the collar is directly above the largest of the two connection openings. If the pointer of the collar is not at the largest opening, rotate the locking collar on the tip body until the pointer is above the largest connection opening.3. With the syringe tip in the upright position, remove the cap. Align and attach the mixing tip to the syringe4. Lock the mixing tip by pushing the mixing tip firmly onto the syringe and rotating the mixing tip locking collar.5. Keeping the syringe upright, align the dual plunger heads to the corresponding large and small syringe. Insert and push the plunger into the back of the syringe until resistance is met, and then optionally recap the syringe.

[0246] Once the90Y-matrix syringe is assembled, the90Y radiotherapy may be administered via the following exemplary procedure:1. Agitate the90Y-matrix syringe for at least 5 seconds, while the90Y-matrix syringe remains inserted in its PMMA cylinder2. Remove the cap from the90Y-matrix syringe if needed3. Push the plunger to remove any air bubbles4. Apply the90Y-matrix immediately to the surgical cavity, by pushing the plunger5. Confirm that the90Y-matrix has polymerized, by either waiting for a predetermined amount of time, e.g. 60, 90, or 120 seconds, or by observing for phase changes in90Y-matrix via an imaging modality, e.g. fluoroscopy, CT, ultrasound or endoscopy.6. Close the surgical site by suturing, stapling or gluing7. Place the90Y-matrix syringe into the radio-protected container and dispose of it, with or without the PMMA cylinder

[0247] In some further variations of the breast cancer treatment procedures,90Y matrix composition therapy may be provided without requiring a pre-treatment imaging, e.g. a Technetium-99 scan, to assess for any shunting to the liver or lungs or other off-target locations, including varices and AVMs. In some variations, because pre-treatment imaging to assess shunting is not required, pre-treatment procedures to treat potential shunting are also not required. This may result in reducing the time-to-treatment by one, two, three, four, five, six or seven days or more, because treatment is not delayed by pre-treatment shunt imaging, pretreatment shunt reduction procedures, and pre-treatment rescanning to assess the effectiveness of the shunt reduction procedures. The shunt procedures that would no longer be required orperformed may include arterial embolization, hepatic vein balloon occlusion, and variceal and AVM occlusion procedures. Because dosing adjustments to account for the shunting are no longer required, dosing calculations may also be simplified, e.g. no longer requiring adjustments based on the shunt fraction and / or lung dosing limit. Patients with substantial liver, lung or hepatopulmonary shunt fractions also do not need to be excluded from therapy anymore.Example 8: Hepatocellular Carcinoma

[0248] In another study, microspheres pre-loaded with90Y will be mixed with a surgical glue matrix for the radio-ablation of primary liver lesions, followed by their resection. In other variations of the study, however, resection is not necessarily performed after delivery of the radioisotope particles. Percutaneous ablation of hepatic lesions with a90Y-matrix composition may be a more effective therapy, minimizing local or systemic side effects. The use of this novel loco-regional approach seems to be appropriate for human treatment based on:- time for application, with or without ultrasound guidance, in a range between 2 to 5 min; size of ablation, range between 3.8 to 5.3 cm in length and 4.0 to 5.0 cm in width; and absence of systemic side effects.

[0249] The subjects selected for the study will be both ablatable (i.e., amenable to percutaneous ablation) and resectable (i.e., judged such by the liver surgeon), as shown in the inclusion criteria. They will be offered surgical resection for early stage hepato-cellular carcinoma (HCC) within the usually expected time frame (35-40 days after diagnosis / staging), but by enrolling in the study they will also be offered a minimally -invasive procedure of percutaneous P-ablation of their lesion 5-10 days after diagnosis, to be then followed by hepatic surgery around 30 days afterwards, when all activity of90Y has long ceased (the half-life of90Y is 64.1 hours). The surgical resection will remove the whole liver segment containing the ablated lesion, thus allowing for a complete histological examination which is, in fact, much more accurate than any type of currently available imaging to assess the outcome of the ablation procedure. This type of study is normally known as “ablate-resecf ’ study, and there are numerous examples of its use in medicine. The subjects will be followed up for 2-3 months after surgery, following the HCC radio-ablation with the90Y-matrix composition. The total study duration for each patient is about 14 weeks, with an enrollment period of 6 months.

[0250] The primary objective of this study is the assessment of the feasibility of this novel procedure, while the histological assessment of the resected specimen will offer useful information about its possible efficacy. If the hypothesis of a much more complete peri-HCC necrosis is supported, it will provide a more efficacious procedure of percutaneous ablation to the Early-Stage HCC population. In addition, since HCC is a complication of liver cirrhosis, the complete cure of one such lesion will have a possible impact on the outcome of cirrhotic patients, given the frequent appearance of new HCC lesions in other anatomical areas of the liver. The secondary objectives of this study include (1) to demonstrate an effective tumor mass necrosis after ablation with the90Y-matrix composition, (2) to evaluate the histological response after ablation with the90Y-matrix composition, (3) to evaluate the dosimetry of the90Y-matrix composition in the target tissue, (4) to assess quality of life of enrolled patients, and (5) to assess the local and systemic toxicity of the procedure.

[0251] This is a single-center, pre-market, pilot First-In-Human study for patients who will undergo an ablate-resect procedure for primary HCC. The primary study endpoint will be the ability to reach the HCC lesion as planned and to deliver an intra-tumoral pre-determined dose of the90Y-matrix composition without treatment-limiting clinical complications. The secondary study endpoints will be (1) the percentage of tumor mass necrosis and presence of viable cells in the treated lesion, assessed histologically after surgical resection of the segment containing the lesion, (2) the correct anatomical delivery of the90Y-matrix composition, as confirmed by PET- scan 24-48 hours after the procedure, (3) effective delivery of a pre-determined radioactivity dose to the target tissue (measured in Gy), (4) quality of life of the enrolled patients, as measured by the EORTC QLQ C-30 / HCC 18 questionnaires, and (5) safety: vital signs, laboratory tests, type and severity of any adverse events associated with the procedure of radio-ablation, with the surgical resection, and occurring in the period between the two treatments.

[0252] The patient population size will be 10 adult patients, male and female, with early stage HCC. The inclusion criteria will include:Subjects with hepatic lesions diagnosed as HCC - Early Stage;Subjects with a maximum of 7 non-subscapsular lesions with a maximum diameter of 50 mm, considered surgically resectable according to local standards;Subjects with at least one of the upper above mentioned lesions considered amenable to percutaneous ablation (maximum diameter 50 mm);Adult male and female subjects (aged over 18 years)Able to read, comprehend and willing to sign the informed consent form

[0253] The exclusion criteria for the study will be:- Female subject who is pregnant or likely to become pregnant, or is breastfeeding; Subjects who have participated in another study within the past 3 months;Subjects not suitable for general anesthesia and abdominal surgery;Subjects with any known allergy to the90Y-matrix composition components, or the anesthetics;Subjects with contraindications to the procedure because of concomitant medical problems.Subjects with other concomitant malignanciesAny clinical or laboratory disorder which in the investigator’s opinion might contraindicate the subject’s participation in the study.

[0254] The study procedures will include:- Each subject will undergo imaging with Contrast-Enhanced Ultrasound (plus Histology), together with Diffusion-Weighted Magnetic Resonance Imaging (DW- MRI) or Computerized Tomography of the abdomen, in order to have the HCC lesions diagnosed and staged;One of the lesions (considered meeting the criteria for percutaneous ablation and intra-tumoral administration of the90Y-matrix composition) will be treated with radio-ablation using the experimental device;The proper and effective delivery of a pre-determined dose of the90Y-matrix composition will be assessed by PET 24-48 hrs. after the ablative procedure;The degree of necrosis of the treated lesion will be assessed by DW-MRI 21 days after the ablative procedure;7 - 9 days after DW-MRI, the whole tumor mass will be surgically resected;The resected lesion (pre-treated with radio-ablation) will be sent for histological examination, in accordance with the procedures described in the protocol; and- Follow-up will occur 2 months after surgery.

[0255] Collected data will be summarized by descriptive statistics. Continuous variables will be presented as number of cases, mean, and standard deviation, median with interquartile range,minimum and maximum. Categorical variables will be summarized using counts of subjects and percentages. For the primary endpoint, a confidence interval (CI) for the mean delivered dose and for the standard deviation with a significance level of 5% will be estimated. Secondary endpoints will be summarized by descriptive statistics and 95% confidence intervals. Surgical specimens will be processed by the pathologist for evaluation of surgical margins and will be observed for gross changes due to necrosis. Safety assessments will include recording of all adverse events (AEs) as classified using Common Terminology Criteria for Adverse Events v5.0, as well as of changes in vital signs and laboratory parameters.

[0256] Each subject will be informed about the aims, procedures and possible risks of the study and will be asked to sign the informed consent form. Each screened subject will be identified by a progressive screening number. Subjects will be enrolled only after having signed the informed consent form before any study procedure. All the patients monitored at the investigational center will be checked for adherence to the study inclusion and exclusion criteria.

[0257] The following information will be collected:- Demographic data- Height and weightVital signs (e.g. blood pressure (BP); heart rate (HR); respiratory rate (RR))- ECGGeneral and physical examination- Medical and surgical history Alcohol consumption check- Urine analysis, including Bence-Jones protein- Pregnancy urine test for women in fertile ageConcomitant medications / treatmentsTumor evaluation using contrast-enhanced ultrasound plus histology (if applicable) Imaging of the liver will be made using Magnetic Resonance Imaging (MRI) or Computerized Tomography (CT)Imaging of the tumor will be performed using a PET scan The tumor will be staged using the TNM classification and the Barcelona Clinic staging algorithm, in addition to the mRECIST criteriaQuality of life questionnaires (EORTC-QLQ C-30) and HCC18, will be administered to the patients

[0258] Patients will be instructed to contact immediately the research team in case of appearance of any adverse events, which might appear in the timeframe between initial screening and the day of the ablation procedure. On the day of the treatment with the90Y-matrix composition, each patient will undergo a pre-procedure review that will include:Vital signs (e g. BP; HR; RR) General physical examination Tumor evaluation- PET imaging (within 24-48 hours after ablation)- Dosimetry assessmentConcomitant medicationsAdverse events checkAnesthesia for the injection of the90Y-matrix composition Contrast-enhanced ultrasonographyAblation by using the90Y-matrix composition

[0259] If all the entry criteria are fulfilled and the patients have signed the Informed Consent form, they will be scheduled for the P-ablation procedure using the90Y-matrix composition seven days after these screening tests. Each patient will be followed-up for any adverse events or adverse effects from the informed consent signature date, during the whole study duration. A blood sample will be collected for the following determinations:Complete blood count with differential- Electrophoretic protein patternActivated Partial Thromboplastin Time (APTT) International Normalized Ratio (INR) Fibrinogen- Blood glucose- Blood urea nitrogen (BUN)CreatinineSerum glutamic-oxaloacetic transaminase (AST / SGOT), alanine aminotransferase (ALT / SGPT), total and fractionated bilirubin, gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP).Serum ions: sodium, calcium, potassium, chloride Tumor marker (alpha-fetoprotein, AFP)

[0260] Pre-procedure checks will be performed before the performance of the ablative procedure, as follows:Adherence to inclusion and exclusion criteriaVital signs (BP; HR; RR)General and physical examinationConcomitant medications / treatments

[0261] The90Y-matrix kit will include a radioisotope source and matrix source as described elsewhere herein, e.g.90Y microspheres from Sirtex Medical (SIRSPHERES®) and BIOGLUE® from Cryolife. In addition, the kit will include a dual-lumen catheter configured to attach to the dual-chamber syringe of the BIOGLUE® to facilitate delivery of the two matrix components separately through the catheter, so that the matrix does not gel or solidify inside the catheter during delivery. The catheter features are described above, along with its introducer needle and its stylet.

[0262] For the procedure, the syringe size, 2 mL or 5 mL, of the BIOGLUE® will be selected based on the size(s) or total volume(s) of the tumor as determined on the pre-procedure work-up. The90Y-matrix composition is prepared during the pre-procedure set-up as follows:1. Open the box containing the vial of microspheres, leaving the vial in the lead container2. Place on the bench in a lead or acrylic box if available3. Partially remove the aluminum seal from the SIR-SPHERES® vial and clean with an alcohol swab4. Insert a 25G needle into the vial septum to create an opening, making sure the needle is clearly in the contents of the vial5. Use a 5 ml syringe screened with a 20-22G spinal needle at least 70 mm long to pierce the septum of the SIR-SPHERES® microspheres ampoule6. Take 2ml of suspension liquid and dispose of it7. Using a dose calibrator, determine activity in the shipping vial and place it in the lead container8. Determine the volume to be withdrawn to provide the required radiation dose to the hepatic lesion, depending on the size of the tumor bed.

[0263] For the calculation of the activity, a vial of SIR-SPHERES® was considered containing a concentration dose of 3 GBq / 3 ml, after removal of a volume equal to 2 ml of supernatant and it was taken into account that in the dual-lumen catheter, at the end of use in patients, a volume of 158 pL remains. In other variations, however, a different amount of supernatant may be removed or added, or not changed at all. For tumor sizes less than 30 mm diameter, a 2 mL syringe is selected, and assuming that the SIR-SPHERES® and BIOGLUE® are uniformly mixed and the maximum amount of the mixture is dispensed, leaving a nominal 158 pL residual of the mixture in the catheter:

[0264] For tumor sizes from 50 mm radius to 70 mm radius or higher, a 5 mL syringe is selected, and assuming that the SIR-SPHERES® and BIOGLUE® are uniformly mixed and the maximum amount of the mixture is dispensed, leaving a nominal 300 pL residual of the mixture in the syringe:9. Insert the syringe back into the vial and move the plunger back and forth to thoroughly mix the SIR- SPHERES® beads. Rapidly withdraw the pre-calculated radiation dose and proceed with the transfer to the BIOGLUE® chambers as described below.10. Remove the cap of the double-chamber syringe containing the glue components.11. Distribute the microspheres in the double-chamber syringe respecting the 4: 1 ratio (80% in the BSA chamber, 20% in the glutaraldehyde chamber).12. Put the cap back on the syringe.13. Check the patient's dose by re-evaluating the activity in the syringe with the dose calibrator and correct if necessary.14. Place the syringe in a radioprotected container suitable for transport in the operating room / radiology suite.

[0265] For the administration of90Y-matrix composition for percutaneous ablation, the use of the MIPP-Kit by SVAS Biosana system, depicted in FIGS. 1 A and IB, are used as it is specifically designed for optimal use with BIOGLUE® for percutaneous application, with the following sized components:Introducer needle: 15G diameter and 150 mm lengthInjector catheter: 16G diameter and 120 mm length

[0266] The procedure would continue as follows:15. Percutaneous access should be achieved to facilitate insertion of the needle catheter into the hepatic parenchyma.16. Appropriate anesthesia should be used, as per the standard operational approach at the Center.17. Place the kit’s introducer and stylet in the liver lesion with the aid of an ultrasound scanner or under CT guidance or other imaging modality.18. Remove sterile syringe containing the90Y-matrix composition components from the radio-protected container.19. Remove the syringe cap containing the90Y-matrix composition components.20. Holding the syringe firmly with the pin facing up, rotate the cap 90° counterclockwise and remove the cap by swinging it from side to side. Align the dual-lumen catheter of the kit with the syringe using the corresponding notches on each and place the end of the dual-lumen catheter of the kit on the syringe. Take care not to accidentally spill the solution from the syringe during assembly.21. Lock the bilateral catheter of the kit in place by pushing the catheter firmly towards the syringe and rotating the catheter collar 90° clockwise.22. Keeping the syringe straight, align the large and small reservoirs of the solution syringe over the corresponding syringe plunger heads. Slide the plunger towards the back of the syringe until it meets resistance. The dispensing device is thus assembled.23. Remove the stylet of the introducer of the kit.24. Insert the catheter into the introducer and lock it through the Luer-lock fitting.25. Press the plunger to dispense the mixture.26. The plunger should be pressed at a speed in the range of 0.5 and 1.0 mm / s27. Wait at least 30 seconds before retracting the introducer while providing a slight rotation to prevent the glue from adhering the introducer with the tissue.28. At the end of the procedure, the needle catheter and syringe should be disposed of following the standard operating procedure of the biohazard handling center.29. The insertion site must be properly closed and protected by bandaging30. It is possible to administer topical antibiotics, if deemed appropriate.

[0267] The preparation and implantation procedure must be considered as a potential radiation hazard for personnel and a serious risk of contamination. Local guidelines on the use of radiation with regard to implantation and post-implant care should be followed.

[0268] The delivery of the90Y-matrix composition will be evaluated using PET scanning 24- 48 hours after the procedure. Dosimetry will be analyzed through mathematical analysis of the data acquired from the PET scan.

[0269] Each patient will also be re-evaluated after 21 days for tumor evaluation, prior to surgical resection, which will include contrast enhanced ultrasound, MRI and / or CT imaging, and a clinical evaluation. Dosimetry will be re-assessed using a PET scan with mathematical analysis of the data. The site of insertion and the liver tissue will be monitored for changes during the time between radio-ablation and excision. Any morbidity and / or complications observed must be recorded on the CRFs. Additional evaluation will include:Vital signs (e g. BP; HR; RR) General physical examination Complete lab tests (e.g. blood chemistry and hematology parameters) mRECIST criteriaConcomitant medicationsAdverse events check- EORTC-30 / HCC18 questionnaires

[0270] Seven to nine days after the re-evaluation, i.e. 28-30 days after the ablation procedure, the patient will return to hospital for the target lesion surgical resection, which will be performed as per standard procedure of the investigation site. The surgery procedure will include:Vital signs (BP; HR; RR)General physical examinationTumor evaluationAnesthesia for surgery purpose Surgery- Histological assessmentConcomitant medications Adverse events check

[0271] From a radioprotection perspective, the surgery is radiologically safe for the surgeon and all the ancillary personnel, because after 20 days, the residual emission after a 2GBq dose of90Y injected during the procedure of radio-ablation is reduced to 10 MBq. The effect at 1 meter is approximately 3mSv / h in vitro, and approximately 1 mSv / h in vivo (in the human body), both below the background environmental radiation level.

[0272] In case surgery becomes contraindicated at the due date, the subject will be withdrawn from the study, but will undergo the same assessments as described for the post-surgery evaluation and followed up for any safety issues.

[0273] The resected liver tissue will be sent to the Pathology Department for assessment. Specimens will be processed by the pathologist for evaluation of surgical margins and will be observed for gross changes due to necrosis. The percentage of tumor mass necrosis will be measured, and the presence of any viable cells in the treated lesion will be assessed histologically. The radial distribution of the90Y microspheres will also be assessed and measured. Sample orientation will be performed using an appropriate system, such as color inking. Resection margins will be assessed through imaging (when appropriate), grossly, and microscopically. The liver specimen, including the treated liver tissue, will be processed for and evaluated by microscopic examination. After sample orientation, the specimen will be observed for gross changes due to the necrosis, and then tissue within the treated region will be microscopically examined for induced tissue necrosis. The extent of necrosis will be determined using Hematoxylin / Eosin staining technique, which relies on visual examination of the condition of cell membranes and structures in order to assess the viability of cells, and standard immunohi stochemi stry .

[0274] For the same reasons that the surgery is radiologically safe, the histopathological assessment is also safe for the pathologist and all the ancillary personnel.

[0275] The patient care following surgery will follow the local standard routine and practices, involving (where appropriate) admission to the intensive care unit for 24-48 h after surgery, before being transferred to the hospital regular ward, where patients will undergo the following assessments before discharge:Vital signs (e g. BP, HR, RR)- ECG- Physical examination- Blood chemistry (including liver function assessments: AST, ALT, total and fractionated bilirubin, Gamma GT, LDH, alkaline phosphatase) and hematology Surgical down staging criteria Concomitant medications / treatmentsTumor evaluation using contrast-enhanced ultrasound Adverse events and adverse effects check

[0276] After discharge, patients will be followed up for 2 months. The study will be considered concluded for each subject after the 2 months follow-up period; during the follow-up period, information will be collected on any adverse events which might be related with the radio-ablation procedure or the surgical resection and included in the CRFs.

[0277] During the post-discharge follow-up visit, which will occur 28 days after the surgery, 56 days after ablation, the patients will undergo the following study procedures:Vital signs (e g. BP, HR; RR) General physical examination, weight Complete lab tests (e.g. blood chemistry and hematology parameters) Tumor evaluationImaging evaluation (e.g. PET scan) Concomitant medications Adverse events check

[0278] In some further variations of the liver tumor treatment procedures,90Y matrix composition therapy may be provided without requiring a pre-treatment imaging, e.g. a Technetium-99 scan, to assess for any shunting to the liver or lungs or other off-target locations, including varices and AVMs. In some variations, because pre-treatment imaging to assess shunting is not required, pre-treatment procedures to treat potential shunting are also not required. This may result in reducing the time-to-treatment by one, two, three, four, five, six or seven days or more, because treatment is not delayed by pre-treatment shunt imaging, pretreatment shunt reduction procedures, and pre-treatment rescanning to assess the effectiveness of the shunt reduction procedures. The shunt procedures that would no longer be required or performed may include arterial embolization, hepatic vein balloon occlusion, and variceal and AVM occlusion procedures. Because dosing adjustments to account for the shunting are no longer required, dosing calculations may also be simplified, e.g. no longer requiring adjustmentsbased on the shunt fraction and / or lung dosing limit. Patients with substantial liver, lung or hepatopulmonary shunt fractions also do not need to be excluded from therapy anymore.

[0279] In order to evaluate the primary endpoint, a confidence interval (CI) for the mean delivered dose with a significance level of 5% will be estimated. In addition, standard deviation of the mean value of delivered dose and its 95% confidence interval will be calculated in order to quantify the dispersion and the dynamic range of the performance of the new technology. Secondary endpoints will be summarized by descriptive statistics and 95% confidence intervals, as appropriate. Quality of life, as measured by the EORTC QLQ C30 and HCC18 questionnaires, will be evaluated at screening visit (V-l) and Visit 1 (VI). Descriptive statistics of single item score at each study visit and change of scores at VI versus scores at screening visit (V-l) will be provided. Surgical specimens will be processed by the pathologist for evaluation of surgical margins and will be observed for gross changes due to necrosis. Safety assessments will consist of recording and tabulating all adverse events, as well as with an analysis of changes in vital signs and laboratory parameters. Incidence of adverse events, with regards also to the relationship with the90Y-matrix composition, will be calculated for all patients, along with their severity and the seriousness. The severity assessment for an adverse event or serious adverse event should be completed using the NCI CTCAE Version 5. Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be calculated for each laboratory analyte at baseline and for observed values and changes from baseline at each scheduled time point. A listing of subjects with any laboratory results outside the reference ranges will be provided. Parameters with predefined NCI-CTCAE toxicity grades will be summarized. Descriptive statistics of vital signs values and changes from baseline will be summarized. Descriptive statistics will be provided for safety variables.Example 9: Hepatocellular Carcinoma

[0280] In another example, treatment of hepatocellular carcinoma is provided with a different mixing procedure and kit than used and included with Example 8 above. The treatment kits for performing direct, image-guided, intra-tumoral injection of90Y biological glue or solidifying carrier material may include: either supplied with the kit or provisioned separately: a lead pot containing a vial of90Y microspheres, 1.5 GBq at the time of calibration in a total of 5 cc water for injection (WFI)a two-component biological glue or solidifying carrier kit, e.g. a 2 ml or 5 ml kit an optional topical applicator(s) for the syringe(s) an injection needle (15 to 18 cm length) connector an additional lead pot an empty vial, e.g. for dilution of90Y microspheres a 1 mL syringe(s) with Luer-lock22G needles20G x70 mm needles- three PMMA cylinder radiographic shields:- cylinder for use with the 2 ml biological glue syringe (e.g. Cylinder “A”).- cylinder for use with a 5 ml biological glue syringe (e.g., Cylinder “B”).- cylinder for use with a 1 ml syringe (e.g., Cylinder “C”).

[0281] In addition, provided with the kit or provided separately are: a sterile radio-protected box; a non-sterile radio-protected waste box; and forceps or tongs to handle90Y microspheres vial.

[0282] In some examples, the treatment kits for performing direct, image-guided, intra-tumoral injection of90Y biological glue or solidifying carrier material may be provided in three phases:- Preparation of the materialDilution of the vial of90Y microspheres.Addition of diluted90Y microspheres to the biological glue or solidifying carrier kit.

[0283] Preparation of the material:Open the biological glue or solidifying carrier kit.Open the packaging of the biological glue or solidifying carrier syringe in a sterile manner.- Remove the cap of the syringe.- Place the syringe in its corresponding cylinder shield (e.g. Cylinder “A” or “B”). Open the lead pot containing the microsphere vial and remove the vial from the pot using forceps or tongs.- Using a dose calibrator, measure the radioactivity of the90Y microspheres vial (the measurement should report 1.5 GBq ± 10%).If the dose is outside the prescribed range, the concentration can be adjusted as follows: If the dose is too low, WFI should be removed to bring it into the proper concentration range.■ First allow the microspheres to settle to the bottom of the vial, to allow for removal of some of the WFI.■ Once the microspheres have settled or separated from the WFI, use a 1 ml syringe with a 22G needle on the cylinder shield (e.g. Cylinder “C”) to remove WFI to achieve the desired concentration of microspheres.■ The amount of WFI to remove (in mL) may be calculated as mL WFI to be removed = (Measured Dose in GBq / 0.300).If the dose is too high, WFI should be added to bring it into the proper concentration range.■ Use a 1 mL syringe with a 22G needle to inject WFI to achieve the desired concentration of microspheres.■ The amount of WFI to inject or add (in mL) may be calculated as mL WFI to be added = (Measured Dose in GBq / 0.300)-5- Place the90Y microspheres vial in the lead pot.- Place the extra, empty vial required for dilution of the90Y microspheres into a lead pot.

[0284] Dilution of the90Y microspheres- Using the measurement of the tumor, the user will:■ Select whether to use the smaller or larger syringe, e.g. 2 mL or 5 mL syringe; and■ Identify a volume of the90Y microspheres to be used.- Partially remove the radio-protection of the90Y vial and clean the vial with an alcohol pad.- Place one sterile needle into the90Y vial, reaching down to the microspheres. Insert a 22G needle into the90Y vial, to provide ventilation and break any vacuum in the vial during90Y removal.Insert a 22G needle into the empty vial.- Place a 1 mL syringe into its corresponding cylinder (Cylinder “C”).Shake the lead pot with circulating movements for at pre-specified period of time, e.g. 5, 10, 15, 20 or 30 seconds.Connect the 1 mL syringe to the sterile needle and draw the volume of90Y microsphere mixture per below, depending on measurement of tumor size and selected corresponding syringe size. Multiple draws will be used for volumes greater than 1 mL.Table 1 : 2 mL syringe of Biological GlueTable 2: 5 mL syringe of Biological GlueInj ect the selected volume of90Y microsphere mixture into the extra empty vial, placed into the extra lead container, using multiple draws and injections for volumes greater than 1 mL.- Withdraw Water for Inj ection into a separate 1 mL syringe, based on the amount in the fourth column titles “Volume of WFI”.■ Inject the specified water amount into the dilution vial as well.■ Several injections may be required for volumes greater than 1 mL. Gently swirl the diluted solution in the dilution vial to mix it well.- Using a dose calibrator, measure the radioactivity of the microspheres in the dilution vial.■ The measurement should match the amount in Table 1 or 2, column 5 ± 10%.■ The diluted90Y microspheres in the dilution vial are now ready to be mixed into the biological glue.

[0285] Addition of the90Y microspheres into the biological glue injectorShake the lead pot containing the dilution vial with the diluted 90 Y microspheres with circulating movements for at least 10”Connect the 1 mL syringe to the sterile needle and draw the amount of90Y microspheres in the dilution vial of diluted90Y microspheres for the glutaraldehyde chamber (transparent) of the biological glue syringe according to the quantity listed in Table 3 or 4, for biological glue syringes of 2ml or 5 ml, respectively.Table 3: 2 mL biological glueTable 4: 5 mL biological glue

[0286] As noted above, the total prepared volume of 2.5 mL and 6.0 mL for the 2 mL and 5 mL syringes, but account for dead space in the mixing tip and the introducer. The amount of radioactivity post-injection is listed as “Residual Activity in Tables 3 and 4. The Actual Activity injected (last column in Tables 3 and 4) is the activity delivered into the tumor itself, and matches the target dose (first column in Tables 1 and 2), but assumes that the entire syringe or injector barrel has been injected and no material remains in the syringe or barrel.

[0287] The amount applied will be decided by the nuclear medicine specialist performing the procedure of radio-ablation, depending on the size of the tumoral lesion to be ablated and on his / herclinical judgement. If the full volume of product is not applied, the activity applied to the tumor will be correspondingly lower.

[0288] The dose preparation procedures described above are based on a single-use coaxial introducer needle, e.g. 17G needle with a 15 cm length that has a lumen holding a volume of 745 microliters. Depending on the HCC lesion depth, a longer single-use coaxial introducer needle, e.g. 17G needle with an 18 cm length and 806 microliter lumen volume, may be used, in additional to other needles with other gauges and / or lengths, which may have different lumen volumes.

[0289] Injection procedure

[0290] The injection procedure may utilize an additional injection kit or components included with the dose preparation kit. The components may include:1 multi-barrel syringe of the prepared90Y microspheres, from the preparation procedure1 non-sterile radio-protected waste box, included or provided separately insertion kit 3000, depicted in FIG. 30 A:Single-use introducer needle 3002, e.g. 17G with a 15 cm, 18 cm or other length.Connector 3004 with a cap.Mixing structure 3006 (e.g. MEDMIX, Switzerland); andDistal Luer -lock 3008.

[0291] The patient is positioned on the procedure table, and the insertion site is prepped and draped in the usual sterile fashion. Local anesthesia achieved at the insertion site to the target site in the liver.The introducer needle 3002 of the insertion kit 3000 is inserted into the liver, under CT, fluoroscopy, or ultrasound guidance to the desired target location, as depicted in FIGS. 27A to 27C.The multi-barrel syringe with the prepared90Y microspheres is removed from its radioprotected box.The cap of the multi-barrel syringe is removed.The cap of the connector 3004 is attached to the syringe. As depicted in FIG. 30B, a marker 3010 on the cap 3004 is aligned with a corresponding marker 3012 on the syringe 3014 as it resides in the shield cylinder 3016.The cap 3004 is then rotated clockwise relative to the syringe 3014 and its corresponding marker 3012, as shown in FIG. 30C.- Referring to FIG. 30D, the plungers 3018A and 3018B are then engaged to the syringe 3014.The inner needle of the introducer needle is removed.The multi-barrel syringe is shaken while in the shield cylinder for at least 5 seconds.The Luer-lock 3008 of connector 3004 attached to the multi-barrel syringe 3014 is then connected to the proximal end 3020 of the introducer needle 3002, as illustrated in FIG. 30E.- Push the plungers of the syringe to deliver the 90Y microspheres.The plunger should be pushed using a constant rate or speed of injection. Example: 0.5 and 1.0 mm / s- Wait 120 seconds before withdrawing the syringe and introducer needle.- Place the syringe and the introducer needs into the radio-protected box.The insertion site should be properly closed and protected by bandagingTopical antibiotics may be optionally applied to the insertion site, as clinically indicated.A 90 Y PET-CT scan should be obtained within 24 hours, as depicted in FIGS. 28 A and 28B, which may be used to confirm tumor coverage by the injectate.A FDG PET scan may also be performed at around 21 days or 3 weeks to assess for residual tumor at the injection site.- Diffusion-weighted MRI may also be performed at 21 days or 3 weeks, 56 days or 8 weeks, and / or 90 days or 12 week or 3 months to assess near-term response and / or disease progression.

[0292] Five patients with morphologically proven unresectable HCC underwent percutaneous injection of Y90 biological glue into tumors between 2 cm to 5 cm in average diameter. Preprocedure imaging included ultrasound, MRI (e.g. imaging of lesion 2600 in FIGS. 26A and 26B) and fluorodeoxy glucose (FDG) PET-CT. Intra-tumoral injection was performed by acatheter using real-time ultrasound imaging or step-by-step CT guidance. In FIGS. 27 A to 27C, for example, the HCC lesion 2600 identified by pre-procedure imaging is re-identified during ultrasound imaging and the needle insertion path 2602 is directed from the surface 2604 to the lesion 2600 (FIG. 27A). The needle 2606 is then inserted and guided by the insertion path 2602 to the lesion 2600 with ultrasound imaging and is injected (FIG. 27B) until the desired amount of90Y biological glue 2608 is delivered to the lesion 2600 (FIG. 27C). FIGS. 28A and 28B are axial and coronal views of the patient confirming the coverage of the tumor 2600 by the90Y biological glue 2608. Activity levels in the range of 78.56 MBq to 115.25 MBq were injected into the lesions of the 5 patients. In other embodiments, dosages in the range of 70 MBq to 120 MBq are injected into tumors in the range of 2 cm to 5 cm. In still other embodiments, higher dosages can be injected into the same range of tumor sizes, from 140 MBq to 240 MBq, or 210 MBq to 360 MBq, or up to 280 MBq to 480 MBq. In some patients, the entire injected volume is delivered to the center of each tumoral mass, but in other variations, the injected volume may be distributed to different locations within the tumor mass. For example, the dosage may be distributed via three injections of 25% / 50% / 25% or 20% / 60% / 20% relative volumes of the total injected volume between the deep / distal, center / middle, and superficial / proximal regions of the tumor mass. In other variations, at least 50% of the dosage is injected into the center of the tumor mass, and the remainder or at least some of the dosage is injected in one or more off- center locations in the tumor mass. Following injection, the injection needle is removed and a biological glue or other hemostasis agent may be injected along the needle tract as the needle is withdrawn, to facilitate hemostasis.

[0293] Post-procedurally within 12, 24 or 38 hours, for example,90Y PET-CT may be performed to confirm the localization and activity level of the injected90Y biological glue. After 1, 2, 3, 4, 8, and / or 12 weeks, or at 30, 60 and / or 90 days following treatment, FDG PET and / or diffusion-weighted MRI may be performed to assess the response to therapy, e.g. no response, partial response, or complete response. FIGS. 29A and 29B, are axial and coronal MRI images, respectively, of the patient from FIGS. 26 A and 26B three weeks after treatment, showing a complete response to the therapy, with no residual tumor or90Y activity in the tumor bed 2610. No procedure-related adverse events were reported with this or other patients treated in the study. All patients in the study tolerated the injection of the90Y biological glue well.

[0294] At the completion of the trial, three of five patients had a complete response (60%), with two of five patients having partial responses (40%). There were no non-responders to treatment.

[0295] With respect to adverse events, the following were observed in at least one patient: Abdominal pain (1 case), but classified as not related to therapy- Mild pain (1 case), classified as adverse event- Fever (2 cases), but classified as not related to therapy- Local tissue necrosis (all patients), but only in the treated area- Portal vein thrombosis (1 case - preexisting condition), but classified as not related to therapyVomiting (1 case) but classified as unlikely related to therapy

[0296] None of the following adverse events were observed in any of the five patients, though in other variations, the percentage of patients experience any one of the adverse events may be less than 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%,- Fatigue- NauseaDiarrheaTransitory elevation of liver enzymes- Mild to moderate abnormality of liver function tests (ALT / AST, alkaline phosphatase, bilirubin)Transitory reduction in hemoglobinTransitory decline in lymphocytes- Radioembolization-induced liver disease (e.g. hyperbilirubinemia, hypoalbuminemia, ascites)- Non-target irradiation (e.g. radiation gastritis, gastrointestinal ulceration, upper gastrointestinal bleeding, pancreatitis, radiation pneumonitis)- Non-adhesion of therapeutic product to tissueApplication of adhesive to tissue extraneous to procedureInflammatory and immune reactionsAllergic reactionsTissue mineralizationVessel obstructionBronchial or luminal obstructionPulmonary embolism- Damage to normal vessels or tissuesTransmission of infectious agents from material of animal origin- Major hematoma- Major bleedingVasovagal episode

[0297] The results of the FIH study showed that direct, image-guided, intra-tumoral injection of an appropriate activity level of90Y biological glue is efficacious and appears to have a better safety / tolerability profile compared to transarterial radioembolization. In some variations, percutaneous direct injection of radiotherapy with solidifying90Y material can achieve response rates of at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% and 95%, for example. The complete response rates may be at least or up to 10%, 20%, 30%, 40%, 50% or 60%, or in the range of 30-50%, 30-60%, 40-60%, or 50-60%, for example. The percentage of patients with liver function test abnormalities may be less than 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%, for example.

[0298] In other variations, treatment with direct, image-guided, intra-tumoral injection of90Y biological glue or solidifying carrier material may be used to convert patients with unresectable HCC to resectable disease. In some variations, this may be done solely with direct, image-guided, intra-tumoral injection of90Y biological glue or solidifying carrier material, or in a multi -modality treatment / conversion regimen. These multi-modal treatment regimens may include, for example, angiogenesis inhibitors, anti-PD-1 antibodies (e.g. atezolizumab), kinase inhibitors (e.g. sorafenib, regorafenib, sunitinib, erlotinib) and systemic, transarterial chemo-embolizaton (TACE) or hepatic arterial infusion (HAIC) chemotherapy with FOLFOX4, GEMOX, XELOX, or GP chemotherapy regimens, for example.

[0299] Although the foregoing implementations has, for the purposes of clarity and understanding, been described in some detail by the use of illustration and example, it will be apparent that certain changes and modifications may be practiced, and are intended to fall within the scope of the appended claims. Additionally, it should be understood that the components andcharacteristics of the devices and materials described herein may be used in any combination, and the methods described herein may comprise all or a portion of the elements described herein. The description of certain elements or characteristics with respect to a specific figure are not intended to be limiting or nor should they be interpreted to suggest that the element cannot be used in combination with any of the other described elements.Example 10: Interim analysis of clinical toxicological study

[0300] The present examples serve to illustrate the clinical application of BAT-90, as described herein, in the treatment of HCC, where a group of patients with HCC were treated with a composition as disclosed herein, at a dose fitting to the tumor size. The endpoints of the clinical study were to address the Safety and Tolerability of the treatment, which also addressing the toxicological effects of the treatment, and potential clinical complications associated with the treatment.

[0301] The primary objective of the present example to assess the feasibility of the use of compositions, method and devices as disclosed herein as a potential novel system allowing for an effective and safe radio-ablation of primary resectable and unresectable hepatic lesions (HCC), thus offering a new procedure in the armamentarium of loco-regional treatments for this disease.

[0302] The present examples discloses an First in Human (FiH) clinical study (ID BGT- HCC- AR / 2019 (RADIO-ABLATION OF MALIGNANT PRIMARY LIVER LESIONS (HEPATOCELLULAR CARCINOMA, HCC), the assessment of local and systemic toxicity of the procedure has been also addressed (as a secondary objective) paying particular attention to any of the safety indicators known to be related with the TARE procedure (such as, but not limited to the transitory elevation of liver enzymes and the transitory decline of lymphocytes) and / or the use of the BioGlue®, since the RSI (Reference Safety Information) for the present study is based on the common (and less common) side effects related to BAT-90 treatment. Accordingly, the present study aims to underline the benefits of the treatment presented herein, which are to 1) to provide treatment to HCC patients that present with multi-focal disease, 2) to provide treatment to those HCC patients ineligible to TARE (due to vascular shunts, multi-segment / multi-lobe disease and / or due to impaired liver function) and 3) provide a therapy option with reduced side effects compared to TARE.I l lInterim analysis

[0303] The Interim Analysis was planned after reaching 50% of collected data, when the first 5 patients were enrolled into the study and treated. Being this a First in Human study (FiH), the aim of the analysis is to explore the first collected safety and feasibility data and therefore a descriptive statistics is provided.Special Reporting Requirements for the Interim Analysis:• Description and discussion of all unexpected observations and device deficiencies;• Tabular list and discussion of AE,SAE, ADE, SADE, USADE (not limited to reportable SAE);• Hazards of 90Y microspheres;Analysis of Primary OutcomesPrimary Endpoint

[0304] Primary endpoint was the percentage and the associated 95% Clopper-Pearson confidence interval of the subjects with an appropriate intra-tumoral pre-determined dose of BAT- 90 without treatment-limiting clinical complications.None of the subjects from the PP (or ITT) population had any treatment-limiting clinical complications after 21 days from surgical procedure.Treatment limiting clinical complications:BAT-90 treatment related AEs and ADEs limiting the ability to deploy BAT-90 into the HCC target lesion.Table 5 Proportion of Subjects with / wo Treatment-limiting Clinical Complications After 21 Days from Surgical Procedure - Primary Endpoint - ITT PopulationSafety and Tolerability analysesAdverse Events

[0305] There were 30 adverse events in the period of the Interim Analysis.Adverse Device Effects / Unanticipated Adverse Device Effect / Serious Adverse Device Effect / Serious Unanticipated Adverse Device Effect

[0306] There was only 1 adverse device effect which has “Probable” causal relationship with the device.The ADE was related to an AE defined as “Pain in the right upper part of the abdomen (injection site)”, therefore related to the introducer of the needle, which is part of the medical device delivery system It was defined as mild, expected, not related to the treatment of BAT-90 itself and no concomitant medication was provided. It resolved without sequelae.The reason why this AE was classified as ADE is because the delivery system is considered as part of BAT-90 Medical Device.Table 6 Summary of Adverse Device Effects- Safety Population

[0307] There was no unanticipated adverse device effect (UADE), serious adverse device effect (SADE) and unanticipated serious adverse device (USADE) effect by the end of Interim Analysis.Serious Adverse EventsThere were 5 serious adverse events which affected 2 subjects.Table 7. Listing: Serious Adverse Events- Safety Population*GRADE 3: Extreme distress, causing significant impairment of functioning or incapacitation.Prevents normal everyday activities**GRADE 5: Death related to the adverse eventTable 8 Summary of serious adverse events-Safety PopulationDevice deficiencies

[0308] There was no device deficiency reported.Adverse Events / Adverse Device Effects Leading to Withdrawal

[0309] No adverse events / adverse device effects led to withdrawal in the Interim Analysis.Adverse Events / Adverse Device Effects Leading to Death

[0310] There were 2 cases of Serious Adverse Events leading to death that were included in the Interim Analysis (details are reported in in section ’’Safety and Tolerability analyses”).Vital signs and Clinical Laboratory EvaluationTable 9 Statistical Characteristics of Vital Signs by Visits - Secondary Endpoint, Safety PopulationTable 10 Statistical Characteristics of Laboratory Parameters (Hematology) by Visits - Secondary Endpoint, ITT PopulationTable 11 Statistical Characteristics of Laboratory Parameters (Chemistry) by Visits - Secondary Endpoint, Safety Population.Hazards with "Yttrium Microspheres: Route of Administration Percutanous vs Transarterial (TARE)

[0311] Given the specific route of administration of BAT-90 (percutaneous) vs. TARE (intraarterial), the lack of activity migration from its site of injection documented in our clinical study, seems to ensure that the AE’s reported for TARE are not applicable to BAT-90.Indeed considering the safety profile coming from the Interim analysis of the FIH study with BAT-90 and comparing the list of AE’s reported in the EANM 2022 guidelines for TARE , we believe that not all of the adverse events reported in the EANM, which also include the adverseevents listed in the IFUs of the 90Yttrium microspheres, are applicable to BAT-90, as shown in the following comparison table we have elected to report the risks that, in our evaluation, are likely to be associated with BAT-90, so as to minimize the similar risks associated with TARE.Table 12. Adverse Events with TARE in EANM 2022Weber 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- 1699Conclusion

[0312] The objective of the Interim Analysis, conducted within the present study was to evaluate the feasibility and safety profile of the treatment procedure with BAT-90, a class III investigational medical device, providing as a first instance the possible confirmation to continue the actual study with no need of major modifications to the study design, but also preliminary suggestions to be implemented in further clinical investigations.

[0313] To this purpose the data were submitted to the evaluation of an independent Data Monitoring Committee (DMC). The DMC noted the following:1. A special focus has been dedicated to all the annotated adverse events and / or adverse device effects of each of the five patients included in the Analysis (ITT population). No major adverse events and / or device effects related to the study treatment have been evidenced (with specific reference to the applicable RSI). Thus, the proposed treatment has been judged to be well tolerated from all patients enrolled in the study, as per the interim analysis cut-off.2. The DMC noted that the application of the study treatment is highly feasible and did not cause any specific delivering problems. This emphasized the high applicative potential of this treatment not only in highly specialized cancer centers but also in peripheral hospitals, having standard infrastructures for the management of oncological patients.3. The DMC has made an overview of potential scenarios of toxi cities, with particular attention to:• the dispersion / leakage of the device in the nearest boundaries of the lesion treated, possibly causing the destruction of surrounding healthy tissues• and / or the application of higher activities and related dosages of Y90 compared to the ones defined in the actual approved version of the protocol (therefore doses higher than 150 Gy) and considering both the practice followed by surgeons who proceed with entire lobar liver resection when targeting the resectable indication and the peculiarity of liver capacity of regeneration, the risk related to “overtreatment" has been judged by the Committee to be affordable compared to the advantagecoming from potential total ablation and avoiding of lesion recurrence.The Committee suggested to the Sponsor to take in consideration the treatment with higher90Y90 doses when rolling over to pivotal studies.4. The DMC has evidenced that the proposed study treatment could also be applied for liver metastatic lesions derived from primary colon cancers (mCRC). Since liver mets undergo diverse waves of insurgence, sequential administration of the proposed treatment could be envisaged.

[0314] The conclusion from the DMC also suggest that BAT-90 is suitable for use in other types of cancers, such as e.g., other tumorigenic gastrointestinal cancers, such as e.g., liver metastatic lesions derived from primary colon cancers (mCRC), primary and secondary liver lesions, pancreatic cancer such as pancreatic lesions, and gastrointestinal metastatic lesions.Example 11 : Reconstitution of BAT-90 and Correction factor

[0315] The present example serves to evaluate the amount of residual radiation in the syringes after administration. The amount of residual radiation in the delivery device is important to be able to evaluate the dose delivered to the tumor. Knowing the residual radiation in the device after administration will allow the additional of a correction factor to the calculation of the dose which is needed in the syringe in order to administer the intended amount of radiation to the tumor.

[0316] Accordingly, the clinical outcomes coming from the initial result of FH4 study with BAT-90 presented in Example 10 herein, provides important information to how to improve the efficacy of the medical device. Most importantly a special attention has been given to the modalities of preparation of the BAT-90 syringes before the administration into the patient.

[0317] In particular the improvements are focused on two important aspects:- Reconstitution of the syringes (process to add90Y microspheres to the syringes) Add a specific correction factor on top to the activity of90Y to be administer to the tumor to reach full ablation of the lesion.Reconstitution of BAT-90 Syringes

[0318] The process of reconstitution, i.e., the process to add a pre-determined dose of 90Y microspheres to the Bio glue syringes, is routinely done in Nuclear Department. The routine preparation of the syringe is to add an equal amount of 90Y microspheres to each chamber of the Bioglue syringe before administration. The normal process for preparing the syringe comprises addition of the 90Y microspheres in both chambers at a 4: 1 ratio. The Bioglue syringe is a dual chamber syringe containing BSA in one chamber and Glutaraldehyde in the second one; these two components have different density. Due to the different densities in the two chambers, the dual chamber loading led to an uneven distribution of the 90Y microspheres, in the two chambers, which lead to higher uncertainty in the delivered dose, due to settling of the microspheres in the bottom of the syringe in Glutaraldehyde chamber due to its water like density.

[0319] Thus, to improve the homogeneity distribution of 90Y microsphere within the BioGlue syringe, the process was changed such that all the 90 Y microspheres were loaded into the BSA chamber while only WFI (Water for Injection) was added into the Glutaraldehyde chamber. This new preparation process leads to a more homogenous distribution of the 90Y microspheres in the syringe, and leads to a more accurate radiation dosing.Correction Factor

[0320] To further improve the administration process and dosing accuracy, the residual radiation in the syringe was measured in order to provide a “residual activity correction factor”, which accounts for the residual activity in the syringe after administration.Indeed, the process of reconstitution of BAT-90 syringes before the administration into the patient foresees the use of intermediate syringe and needles used to add Y90 microspheres into the Bioglue Syringes.

[0321] Due to the intermediate steps and consumables used to make the injection, there is always a residual activity of90Y in these components which must be corrected for in order to evaluate the final dose that is administered into the tumor. To make this calculation the intermediate results coming from FIH study disclosed in example 10 established a 20% as correction factor as the optimal percentage to guarantee that predetermined dose of90Y microspheres is delivered into the tumor.Table 13: Residual activity after administration.From the results provided in table 13, it can be seen that on average there was a residual activity in the syringe of 17%, but that the residual activity ranged from 12-30%. Accordingly, a specific correction factor of 20%, on top of the indented activity to be delivered is suitable when preparing the syringe for administration but up to 30% correction may also be preferable in some instances. This 20% has be inserted into the algorithm for the calculation of the dose to be prepared in Nuclear Department before the injection into the patient. The 20% improves the accuracy of the final dose of90Y microspheres delivered into the tumor and ensures that the delivered dose is optimal to reach full tumor necrosis.

Claims

WHAT IS CLAIMED IS:

1. A composition comprising90Y for use in the treatment of a gastrointestinal cancer, wherein the active dose of90Y in the range of 0.4-220 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 such as 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=1=30% MBq, 160±30% MBq and 219±30% MBq.

2. A composition comprising90Y for use in the treatment of a gastrointestinal cancer, wherein the cancer comprises tumor between 5 mm and 5 cm in diameter.

3. The composition comprising90Y for use according to claim 1 or 2, wherein the active administered dose of90Y is0.48±20%, MBq for an average tumor size corresponding to a diameter up to 5 mm;2.4±20%, MBq for an average tumor size corresponding to a diameter greater than 5 mm and up to 10 mm;7±20%, MBq for an average tumor size corresponding to a diameter greater than 10 mm and up to 15 mm;17±20%, MBq for an average tumor size corresponding to a diameter greater than 15 mm and up to 20 mm;28-30±20%, MBq for an average tumor size corresponding to a diameter greater than 20 mm and up to 25 mm;48±20%, MBq for an average tumor size corresponding to a diameter greater than 25 mm and up to 30 mm;75±20%, MBq for an average tumor size corresponding to a diameter greater than 30 mm and up to 35 mm;114±20%, MBq for an average tumor size corresponding to a diameter greater than 35 mm and up to 40 mm;160±20%, MBq for an average tumor size corresponding to a diameter greater than 40 mm and up to 45 mm; and219±20%, MBq for an average tumor size corresponding to a diameter greater than 45 mm and up to 50 mm.

4. The composition comprising90Y for use in the treatment of a gastrointestinal cancer according to any of the preceding claims, wherein the active dose is in the range of 0.4-220 MBq ± 30%, such as ±5%, ±10%, ±15%, ±20% or such as ±25%, preferably ±20%.

5. The composition for use according to any of the preceding claims, which is a pharmaceutical composition, wherein the composition comprises90Y microspheres and a surgical sealant and / or adhesive, such as a tissue glue.

6. The composition for use according to any of the preceding claims, wherein the composition comprises90Y microspheres and a component of a two-component solidifying surgical sealant and / or adhesive, such as a tissue glue.

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

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

9. The composition for use according to any of the preceding claims, wherein the composition comprises90Y microspheres and albumin, or90Y microspheres and glutaraldehyde.

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

11. The composition for use according to any of the preceding claims, wherein the target- absorbed dose is between 120Gy and 150 Gy, preferably 150 Gy.

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

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

14. The composition for use according to any of the preceding claims, wherein the composition is prepared for percutaneous administration in order to provide brachytherapy to the tumor.

15. A method for preparing a composition for use according to any of the preceding claims, wherein the method comprises determining an average tumor size of a tumor lesion; selecting a90Y syringe activity level using the average tumor size; and providing a dual chamber syringe with a90Y syringe activity level of o 0.7±20% MBq for an average tumor size corresponding to a diameter up to 5 mm; o 3±20% MBq for an average tumor size corresponding to a diameter greater than 5 mm and up to 10 mm; o 10±20% MBq for an average tumor size corresponding to a diameter greater than 10 mm and up to 15 mm; o 22±20% MBq for an average tumor size corresponding to a diameter greater than 15 mm and up to 20 mm; o 33-42±20% MBq for an average tumor size corresponding to a diameter greater than 20 mm and up to 25 mm; o 55±20% MBq for an average tumor size corresponding to a diameter greater than 25 mm and up to 30 mm; o 86±20% MBq for an average tumor size corresponding to a diameter greater than 30 mm and up to 35 mm;o 130±20% MBq for an average tumor size corresponding to a diameter greater than 35 mm and up to 40 mm; o 183±20% MBq for an average tumor size corresponding to a diameter greater than 40 mm and up to 45 mm; or o 250±20% MBq for an average tumor size corresponding to a diameter greater than 45 mm and up to 50 mm.

16. The method according to claim 15, wherein the dual chamber syringe comprises a first chamber pre-loaded with a surgical sealant and / or adhesive, such as a tissue glue component, such as bovine serum albumin, and a second chamber pre-loaded with a solidifying carrier, such as glutaraldehyde.

17. The method according to claim 15 or 16, wherein loading the dual chamber syringe further comprises loading the required90Y syringe activity level into the first and / or second chambers.

18. The method according to claim 15 or 16, wherein loading the dual chamber syringe further comprises loading the required90Y syringe activity level into the first chamber containing the BSA solution.

19. A method of treatment for a gastrointestinal cancer, comprising; administering a dose of 90Y microspheres to a patient suffering from a gastrointestinal cancer, wherein said dose comprises about an active dose of90Y in the range of 0.4-220 MBq±30%, such as a dose of about 0.48 MBq±30%„ about 2.4 MBq±30%„ about 7 MBq±30%„ about 17 MBq±30%,, about 28 MBq±30%„ about 30 MBq±30%„ about 48 MBq±30%„ about 75 MBq±30%,, about 114 MBq±30%„ about 160 MBq±30%,, or about 219 MBq±30%,, or about 0.48±30%, MBq to about 218±30%, MBq.

20. The method of treatment according to claim 16, wherein the90Y is administered as a solidifying90Y adhesive.

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

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

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

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

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

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

27. The composition for use according to any of claims 1-14 or 20-26, or the method according to any of claims 15-20 or 21-26, wherein the cancer comprises a tumor between 5 mm and 5 cm in diameter.

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