Device for treating cancer

Abstract

A device and method of treating cancerous tissue from a blood vessel, such as a blood vessel proximate a pancreas having pancreatic cancer. The device includes a disruption apparatus and a fixation element fixing a position of the disruption apparatus within the blood vessel. The disruption apparatus is configured to disrupt cancer cells of the pancreatic cancer from within the blood vessel. The method includes delivering the device through the blood vessel to a position adjacent to the cancerous tissue, and disrupting the cancerous tissue by delivering heat or energy to the cancer. Other embodiments are described and claimed.

Description

DEVICE FOR TREATING CANCERRELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 516,803, filed on July 31, 2023, titled “DEVICE AND METHOD OF TREATING CANCER,” which is incorporated herein by reference in its entirety to provide continuity of disclosure.TECHNICAL FIELD

[0002] The subject matter of the present disclosure generally relates to devices and methods for treating cancer. More particularly, the subject matter of the present disclosure relates to devices and methods for treating pancreatic cancer.BACKGROUND

[0003] Pancreatic cancer is the seventh leading cause of cancer-related death in both males and females worldwide, and it is predicted to become the second leading cause of cancer death in western countries by 2030, surpassing lung, colon, hepatocellular, stomach, and breast cancer. Standard of care surgical treatments also introduce problems, including dislodgement of cancer cells into the blood and / or lymph systems, which results in the opportunity for cancer cells to metastasize to other sites in the body and cause additional tumors to form.

[0004] The main treatment for pancreatic cancer is surgical removal of a tumor or cancerous tissue; however, the tumor or the cancerous tissue typically spreads beyond the pancreas by the time of a pancreatic cancer diagnosis. Using currently available techniques, removing all the cancerous tissue is difficult. As a result, only about 9% of patients are alive five years after a pancreatic cancer diagnosis.

[0005] Referring to FIG. 1, this diagram illustrates the general anatomical structure of a pancreas 100 along with related anatomical structures, such as a spleen 102, a duodenum 104, and at least one vascular structure, such as an aorta 106, a splenic vein 108, a splenic artery 110, a portal vein 112, a superior mesenteric vein 114, a superior mesenteric artery 115, a celiac trunk 116 or a celiac vein, and an hepatic artery 118. Typically, diagnostic techniques involve using a high-definition three-dimensional computerized tomography (CT) scan (not shown) to determine whether cancerous tissue (not shown) has invaded any of the major blood vessels near the pancreas 100. A cancer (not shown) in the head of the pancreas 100 is said to be locally advanced when the cancerous tissue has invaded a superior mesenteric artery 115 or a superior mesenteric vein 114. Pancreatic cancer cells typically attach to, or wrap around, a portal vein112 or a superior mesenteric vein 114, e.g.. a vein that drains blood (not shown) from the duodenum 104 or other part of the intestines to the liver (not shown), a superior mesenteric artery 115, e.g., an artery that supplies blood to the duodenum 104 or other part of the intestines, a celiac artery, and an hepatic artery 118, e.g., an artery that supplies blood from the heart to the liver. They then spread along a length of the blood vessel before invading into the vessel itself. Next, the cancer cells destroy the endothelial cell lining of blood vessels and replace those endothelial cells with tumor-lined structures and eventually fill the lumen with tumors.

[0006] Pancreatic tumor cells are driven by an interaction between a protein receptor, such as but not limited to CD44, an activin A receptor (“ALK7”), and a protein activin in pancreatic cancer cells. While chemotherapy may not cure the pancreatic cancer, chemotherapy may slow its growth, thereby allowing the patient to live longer. Still referring to FIG. 1, if the cancerous tissue extensively involves major blood vessels, the pancreatic cancer may be surgically unresectable, even if concurrently using available cancer treatments, such as radiation and chemotherapy. These types of pancreatic cancers are unresectable due to the local extent of the diseased tissue. In some cases, at least one of chemotherapy and radiation is used to shrink locally advanced tumors to render them resectable. However, if the cancerous tissue has developed around the artery or the vein, successful resection is less likely, even after chemotherapy, by using related art treatments.

[0007] Regional chemotherapy involves delivering chemotherapeutic treatment in proximity to, adjacent to, and / or intratumorally to the tumor to avoid systemic side effects. However, cancer cells are highly resistant to penetration by chemotherapy agents, pancreatic cancer cells even more so. Typically, a pancreatic tumor is referred to as “hard,” mostly comprising connective tissue and non-cancerous immune cells. A pancreatic tumor's micro-environment is highly stromal, e.g., invading connective tissue below a surface of an affected organ. Stroma refers to a type of connective tissue that provides other tissue with strength and shape. Stromal cells are referred to as fibroblasts. In pathology, these fibroblasts are referred to as “spindle” cells having a thin elongated shape. Stroma also refers to blood vessels that deliver nutrients to an organ and to lymphatic channels that deliver excess fluid and waste from the organ. Stroma also develops via a body’s natural scarring process, such as scar formation, e.g., keloids. Scar formation then leads to formation of a large amount of hyaluronic acid (“HA”), a carbohydrate polymer, in a matrix, e.g., an HA matrix, that densifies the pancreatic cancer cells by attracting and retaining large amounts of water. This water retention increases pressure in the pancreas 100 that can be at least 10-fold that of a normal pancreas 100. Surrounding blood vesselscollapse under the pressure caused by the HA, thereby impeding or stopping blood flow; however, the pancreatic cancer cells remain viable due to a supply of sugar from the HA.

[0008] Because of the lack of blood flow to the pancreas caused by the HA matrix and the infiltration of cancer cells into the arteries supplying blood to the pancreas, pancreatic cancer cells insidiously actively function as obstacles to the only routes for delivering cancer treatment drugs to the pancreas 100, thereby effectively preventing cancer treatment drugs, either systemic or regional, from reaching and destroying pancreatic tumors. Endothelial cells that are in direct contact with the cancer cells undergo apoptosis (cell death), thereby leading to a blood vessel channel exclusively having cancer cells.

[0009] In animal models, breakdown of the HA matrix with a therapeutic hyaluronidase, e.g., a pegvorhyaluronidase (PEGPH20), reduces intra- tumoral pressure, thereby restoring circulation, facilitating drug delivery, and improving response to chemotherapy (Provenzano et al., 2012; Jacobetz et al., 2013). However, PEGPH20 was the subject of a recent unsuccessful clinical trial which sought to degrade HA and release pressure on the tumors to allow the vasculature structure to expand and deliver drugs. Reduction in the HA content of tumors is thought to facilitate T-cell penetration (Sharma et al., 2020); however, an HA matrix may also be necessary to restrain tumor dissemination (Helms et al., 2020; Lee et al., 2014; Ozdemir et al., 2015; Rhim et al., 2014); and HA degradation may actually enhance tumor metabolism and growth via growth-factor, signaling dependent pathways (Sullivan et al., 2018) as well as signaling independent pathways, such as the N-Acetylglucosamine (GlcNAc) salvage pathways. As such, the findings in the related art are conflicting, suggesting that other treatment modalities may be more effective.

[0010] Additionally, in other related studies, an activin inhibitor reduced the replacement of healthy blood vessel tissue with cancer cells, wherein the interaction between ALK7 and activin may be the major driver of pancreatic cancer’s growth and metastasis. This conjecture has been confirmed by eliminating the ALK7 expression in cancer cells and then by implanting these cancer cells into mice, thereby resulting in slower-growing in vivo tumors with higher blood vessel density and fewer apoptotic endothelial cells.

[0011] HF10 is an attenuated strain of Herpes Simplex Virus type 1 (HSV-1), an oncolytic virus which in clinical trials to date has demonstrated antitumor activity when injected into cancerous areas. Oncolytic viruses, which rarely proliferate in normal cells, destroy cancer cells directly by proliferating inside them.

[0012] Currently, patients with pancreatic cancer not only experience high mortality rates and an average of only three and a half years from diagnosis to death, but also experience severe andongoing pain. Cancer cells and the HA matrix can press against nerves in proximity to the pancreas, and / or can press on the spine and spinal nerves, causing severe pain. Morphine or other opiates are frequently prescribed, due to the severity of the pain. For patients who do not tolerate opiates well, or who wish to remain more lucid during ongoing treatment or hospice care, other treatments would be desirable.

[0013] In view of the challenges experienced in the related art, a long-felt need exists for technologies capable of removing pancreatic cancer cells that are growing into, around, and / or lining the lumen of, blood vessels proximate the pancreas without harming the blood vessels. Further, in view of the challenges experienced in the related art, a long-felt need exists for technologies capable of delivering cancer treatment drugs to, and into, the pancreatic cancer cells. Additionally, in view of the challenges experienced in the related art, a long-felt need exists for technologies capable of alleviating pancreatic cancer pain without the use of opiates.SUMMARY

[0014] The present invention is defined in the independent claims. Further embodiments of the invention are defined in the dependent claims.

[0015] A catheter is provided herein. The catheter is configured for insertion into one or more blood vessels proximate a pancreas having pancreatic cancer. The catheter includes a disruption apparatus configured to disrupt cancer cells of the pancreatic cancer from within the blood vessel and a fixation element configured to fix a position of the disruption apparatus within the blood vessel.

[0016] A method is provided herein. The method is for treating a patient diagnosed with cancer. The method includes delivering a device through a blood vessel of the patient to a position adjacent to cancerous tissue proximate a cancerous organ. The method includes disrupting the cancerous tissue.

[0017] A method is provided herein. The method is for treating a patient having pancreatic cancer. The method includes intravascularly positioning an catheter within a blood vessel of the patient and adjacent to a cancer of the patient. The method includes ablating cancer cells of the cancer by delivering energy to the cancer via the catheter.

[0018] A method is provided herein. The method is for treating cancer. The method includes delivering a balloon delivery catheter to treatment sites in a plurality of blood vessels adjacent to a pancreas. The method includes inflating the balloon delivery catheter at each of the treatment sites. The method includes delivering one or more of heat or energy to a vessel wall at each of the treatment sites. An amount of the delivered heat or energy is effective to disrupt cancer cellsadjacent to the treatment sites. The method includes deflating the balloon delivery catheter at each of the treatment sites. The method includes withdrawing the balloon delivery catheter from the body lumen.

[0019] The above summary does not include an exhaustive list of all aspects of the present invention. It is contemplated that the invention can be practiced from all suitable combinations of the various aspects summarized above, as well as those disclosed in the Detailed Description below and particularly pointed out in the claims. Such combinations have particular advantages not specifically recited in the above summary.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings.

[0021] FIG. 1 is a diagram of an anatomical structure of a pancreas.

[0022] FIG. 2 is a perspective view of a cancer treatment system, in accordance with an embodiment.

[0023] FIG. 3 is a side view of selected components of the cancer treatment system, in accordance with an embodiment.

[0024] FIG. 4 is a side view of selected components of the cancer treatment system, in accordance with an embodiment.

[0025] FIG. 5 is a perspective view of selected components of the cancer treatment system inserted into a body lumen, in accordance with an embodiment.

[0026] FIG. 6 is a side view of a cancer treatment system having a compliant balloon inflated to a first inflation diameter, in accordance with an embodiment.

[0027] FIG. 7 is a side view of a cancer treatment system having a compliant balloon inflated to a second inflation diameter, in accordance with an embodiment.

[0028] FIG. 8 is a perspective view of selected components of the cancer treatment system having a flexible feature between several transducers, in accordance with an embodiment.

[0029] FIG. 9 is a perspective view of selected components of the cancer treatment system having a flexible feature between several transducers, in accordance with an embodiment.

[0030] FIG. 10 is a side view of selected components of the cancer treatment system having a flexible feature between several transducers, in accordance with an embodiment.

[0031] FIG. 11 is a side view of selected components of the cancer treatment system having an imaging transducer, in accordance with an embodiment.

[0032] FIG. 12 is a side view of selected components of the cancer treatment system having cavitation electrodes, in accordance with an embodiment.

[0033] FIG. 13 is a flowchart of a method of disrupting cancerous tissue, in accordance with an embodiment.

[0034] FIG. 14 is a flowchart of a method of disrupting cancer cells, in accordance with an embodiment.

[0035] FIG. 15 is a flowchart of a method of disrupting cancer cells, in accordance with an embodiment.

[0036] FIG. 16 is a side view of a distal end of a cancer treatment system having an exposed ablation transducer, in accordance with an embodiment.

[0037] FIG. 17 is a side view of a distal end of a cancer treatment system having an exposed ablation transducer and an occlusion balloon distal thereto, in accordance with an embodiment.

[0038] The illustrated embodiments are merely examples and are not intended to limit the disclosure. The schematics are drawn to illustrate features and concepts and are not necessarily drawn to scale.DETAILED DESCRIPTION

[0039] The foregoing is a summary, and thus, necessarily limited in detail. The above- mentioned aspects, as well as other aspects, features, and advantages of the present technology will now be described in connection with various embodiments. The inclusion of the following embodiments is not intended to limit the disclosure to these embodiments, but rather to enable any person skilled in the art to make and use the contemplated invention(s). Other embodiments may be utilized, and modifications may be made without departing from the spirit or scope of the subject matter presented herein. Aspects of the disclosure, as described and illustrated herein, can be arranged, combined, modified, and designed in a variety of different formulations, all of which are explicitly contemplated and form part of this disclosure.

[0040] To address at least the foregoing challenges experienced in the related art, the present disclosure generally involves a device and methods for treating pancreatic cancer cells that are growing into, around, and / or lining the lumen of blood vessels proximate the pancreas, whereby the blood vessels are substantially unharmed. In certain embodiments, the pancreatic cancer cells, which have attached to, wrapped around, and / or spread along a length of one or more blood vessels, e.g., one or more portal vein, superior mesenteric vein, superior mesenteric artery,celiac artery, and / or hepatic artery, are disrupted. As used in this document, the word “disrupt” and its verb tenses refer to causing damage and / or death to cancer cells or components thereof, where that damage includes the collapse of cancer cells. For example, the pancreatic cancer tumor or tumors can be ablated such as to denature the pancreatic cancer cells and / or form a thickened residue. The denatured cells and / or thickened residue can then be removed from the one or more blood vessels, e.g., by using a surgical or harmonic scalpel to peel the cells / residue off of the exterior of the one or more blood vessels. In certain embodiments, physical removal of the denatured cancer cells is not necessary, and the cancer cells may be carried away by the blood supply within the blood vessel(s).

[0041] In certain embodiments, ablation of the pancreatic cancer cells serves to open up the tissue of the vessel so that other therapies may successfully reach other tumor cells in proximity to or within the pancreas.

[0042] Further, the present disclosure involves a device and methods for delivering cancer treatment drugs to, and into, the pancreatic cancer cells that are growing into, around, and / or lining the lumen of, blood vessels proximate the pancreas. Ultrasound may optionally be used to introduce small cracks in the blood vessel wall in order to make it easier to delivery chemotherapy to the remaining cancer cells, facilitating delivery of chemotherapy to the pancreatic cancer cells.

[0043] In an embodiment, an intravascular means of ablating pancreatic cancer cells growing into and around blood vessels and the lining the lumen of blood vessels proximate the pancreas without harming the blood vessels (including inner walls) is provided. In an embodiment, an unfocused ultrasound ablation catheter is provided that includes a flexible post separating ablation transducers to permit the catheter to navigate a tortuous path and fit into the portal vein / superior mesenteric vein, superior mesenteric artery, celiac artery, and / or hepatic artery. A balloon catheter may be used to ablate the cancer cells attached to, wrapped around, spread along a length of and / or invading one or more blood vessels.

[0044] In certain embodiments, an ultrasound balloon catheter can be used to ablate the cancer cells attached to, wrapped around, spread along a length of and / or invading one or more blood vessels without substantially harming, e.g., causing stenosis of, the blood vessel. In certain embodiments, the balloon is used to occlude the blood vessel, and circulation of a cooling fluid is used to prevent damage to the blood vessel wall (inner wall) during ablation. In certain embodiments, an ultrasound catheter having a positioning element other than balloon can be used. For example the ultrasound catheter having expandable leaflets for positioning the ultrasound transducer can be used.

[0045] In an embodiment, a second transducer unit, e.g. , a cavitation transducer unit, optimized for causing cavitation, e.g., a focused transducer having a frequency of 50-200 kHz, is configured to aid in the collapse of cancer cells around blood vessels, trigger a specific cellular anticancer immune response, and / or facilitate chemotherapy, e.g., delivery of an activin inhibitor and / or PEGPH20, to the blood vessels and pancreatic tumors, while preserving the blood vessel wall. In an embodiment, cavitation electrodes are used in lieu of a second transducer unit. In an embodiment, the catheter also comprises an imaging transducer unit, optimized for imaging. For example, a part of the first transducer unit or a separate unit from the first transducer unit includes piezoelectric material having a frequency of, e.g., 20MHz, which can be used to identify cancer cells.

[0046] In certain embodiments, a balloon catheter may be used to both ablate the cancer cells attached to, wrapped around, spread along a length of, and / or invading one or more blood vessels and deliver drug therapy. In certain embodiments, the balloon includes apertures that permit a drug therapy to weep out of the balloon, e.g., after ablation of the cancer cells opens the blood vessel up and / or creates cracks in the blood vessel wall.

[0047] Any system, apparatus, device, product-by-process, composition of matter, process, technique, or method, herein described, is useful in the health, medical, or surgical fields, including oncological care, procedures, and surgeries; however, the subject matter of the present disclosure may extend, or apply, to other conditions or fields of health, medicine, or surgery; and such extensions or implementations are encompassed by the present disclosure. Any system, apparatus, device, product-by-process, composition of matter, process, technique, or method, herein described, encompasses technologies that are applicable to health, medical, or surgical procedures for any other anatomical region that will benefit from the use of a catheter to facilitate access to an interior of an animal body, such as a human body.

[0048] Various systems, apparatuses, devices, products-by-process, compositions of matter, processes, techniques, or methods may be below-described; and when described, provide examples thereof, in accordance with embodiments of the present disclosure. None of the below-described embodiments limit any claimed embodiment; and any claimed embodiment may also encompass systems, apparatuses, devices, products-by-process, compositions of matter, processes, techniques, or methods which may differ from below-described examples but are also encompassed by the present disclosure. The claimed embodiments are not limited to any one or any combination of any below-described system, apparatus, device, product-by- process, composition of matter, process, technique, or method.

[0049] Furthermore, this Detailed Description sets forth numerous specific details to provide a thorough understanding of the various embodiments described throughout the present disclosure; however, the herein described embodiments may be practiced without these specific details. In other instances, well-known methods, techniques, procedures, or components have not been described in detail so as not to obscure the herein described embodiments.

[0050] The present disclosure provides a method of treating a cancer of an organ, e.g., pancreatic cancer, that has metastasized into blood vessels that surround the organ. The method involves ablating, e.g., by chemical or thermal means, the cancer cells surrounding or otherwise in proximity to a blood vessel, cancer cells that have invaded the blood vessel wall, and / or cancer cells within the lumen of the blood vessel. After ablating, the ablated cancer cells may be removed by blood flow and / or through surgical means. For example, the method may harden or thicken the cancer cells so that they can be removed, e.g., using a surgical scalpel or harmonic scalpel. The method may further include codelivery of one or more therapeutic agents, before and / or after the cancer cells have been fully or partially removed. In an embodiment, the method may include enhancing the porosity of the blood vessel wall to facilitate delivery of one or more therapeutic agents to the blood vessel and / or through the blood stream to the organ, e.g., pancreas. In an embodiment, e.g., HF10 is injected into the one or more blood vessel walls.Ultrasound may then be used to enhance delivery of the HF10. The method may further include systemic or local administration of an immunotherapeutic agent. The method may remove the remaining cancer cells surrounding the vessel walls, cancer cells that have replaced the endothelium lining, and / or cancer cells filling the lumen. In addition, the method may enable therapeutic agents to travel in the blood stream to tumors within the cancerous organ.

[0051] By ablating and then removing the cancer cells, the effectiveness of intracellular penetration enhancing agents may be significantly improved to result in an increase in drug permeability of a therapeutic agent into any remaining cancer cells. The absorbance rate of locally, regionally, or systemically delivered immune stimulating agents, e.g., cancer vaccine, CD4 and / or NKT cell stimulating agents, may also be improved. As used in this document, the terms “anticancer agent” and “therapeutic agent” refer to any agent effective, at least in part, to treat cancer, regardless of its chemical or biochemical structure, as set forth in more detail below.

[0052] In certain embodiments, the side-effect profile of a therapeutic agent and / or an intracellular permeation enhancing agent is improved. By removing cancer cells surrounding, inside the wall of, and within the lumen of blood vessels proximate a cancerous organ, less of atherapeutic agent and / or an intracellular permeation enhancing agent may be used to treat remaining cancer cells, with improved efficacy and reduced side effects.

[0053] In some embodiments, the therapeutic agent is administered intratumorally. In some embodiments, the therapeutic agent is administered systemically. The therapeutic agent can be an anticancer agent.

[0054] In some embodiments, the anticancer agent is a chemotherapeutic agent, such as Abirateron cetate, Afatinib, Aldesleukin, Alemtuzumab, Alitretinoin, Altretamine, Amifostine, Aminoglutethimide Anagrelide, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, Azathioprine, Bendamustine, Bevacizumab, Bexarotine, Bicalutamide, Bleomycin, Bortezomib, Busulfan, Capecitabine, Carboplatin, Carmustine, Cetuximab, Chlorambucil, Cisplatin, Cladribine, Crizotinib, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Dasatinib, Daunorubicin, Denileukin diftitox, Decitabine, Docetaxel, Dexamethasone, Doxifluridine, Doxorubicin, Epirubicin, Epoetin Alpha, Epothilone, Erlotinib, Estramustine, Etinostat, Etoposide, Everolimus, Exemestane, Filgrastim, Floxuridine, Fludarabine, Fluorouracil, Fluoxymesterone, Flutamide, folate linked alkaloids, Gefitinib, Gemcitabine, Gemtuzumab ozogamicin, GM-CT-01, Goserelin, Hexamethylmelamine, Hydroxyureas, Ibritumomab, Idarubicin, Ifosfamide, Imatinib, Interferon alpha, Interferon beta, Irinotecan, Ixabepilone, Lapatinib, Leucovorin, Leuprolide, Lenalidomide, Letrozole, Lomustine, Mechlorethamine, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitoxantrone, Nelarabine, Nilotinib, Nilutamide, Octreotide, Ofatumumab, Oprelvekin, Oxaliplatin, Paclitaxel, Panitumumab, Pemetrexed, Pentostatin, polysaccharide galectin inhibitors, Ponatonib, Procarbazine, Raloxifene, Retinoic acids, Rituximab, Romiplostim, Sargramostim, Sorafenib, Streptozocin, Sunitinib, Tamoxifen, Temsirolimus, Temozolamide, Teniposide, Thalidomide, Thioguanine, Thiotepa, Tioguanine, Topotecan, Toremifene, Tositumomab, Trametinib, Trastuzumab, Tretinoin, Valrubicin, VEGF inhibitors and traps, Vinblastine, Vincristine, Vindesine, Vinorelbine, Vintafolide (EC 145), Vorinostat, a salt thereof, or any combination of the foregoing.

[0055] In other embodiments, the therapeutic agent is a therapeutic antibody or a combination of two or more therapeutic antibodies, such as Abagovomab, Alacizumabpegol, Alemtuzumab, Altumomab pentetate (Hybri-ceaker), Amatuximab, Anatumomab mafenatox, anti-PD-I antibodies, Apolizumab, Arcitumomab (CEA-Scan), Belimumab, Bevacizumab, Bivatuzumab mertansine, Blinatumomab, Brentuximab vedotin, Cantuzumab mertansine, antuzumabravtansine, Capromab pendetide (Prostascint), Catumaxomab (Removab ), Cetuximab (Erbitux), Citatuzumab bogatox, Cixutumumab, Clivatuzumab tetraxetan (hPAM4-Cide), Conatumumab, Dalotuzumab, Denosumab, Drozitumab, Edrecolomab (Panorex), Enavatuzumab, Gemtuzumab, Ibritumomab tiuxetan, Ipilimumab (MDX-101), Ofatumumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab, antibodies targeting CD44 such as sulfasalazine, or any combination thereof.

[0056] In yet another embodiment, the therapeutic agent is a nucleic acid molecule. For example, the nucleic acid molecule can be an interfering RNA, e.g., RN Ai or shRNA, a gene therapy expression vector, or a gene silencing vector.

[0057] In certain embodiments, the therapeutic agent is a radioisotope.

[0058] In certain embodiments, the therapeutic agent is a thymidylate synthase inhibitor. In certain embodiments, the therapeutic agent is a platinum compound.

[0059] In certain embodiments, the therapeutic agent is a vinca alkaloid agent. In certain embodiments, the therapeutic agent is cisplatin or other platinum agent e.g., satraplatin, pcioplatin, nedaplatin, triplatin, carboplatin or oxaplatin). In embodiments, the above methods further involve administering a therapeutically effective amount of an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is a cancer vaccine, hormone, epitope, cytokine, tumor antigen, CD4 cell stimulator, NKT cell agonist, or adjuvant. For example, the immunotherapeutic agent can be an interferon, interleukin, tumor necrosis factor, ovalabumin, Neuvenge®, Oncophage, CimaVaxEGF, Mobilan, a-Gal glycolipid, a-Galactosylceramide (a- GalCer), β-mannosylceramide ( β-ManCer), adenovirus delivered vaccines, Celldex's CDX1307 and CDX1401; GRNVAC1, viral based vaccines, MVA-BN, PROSTVAC®, Advaxis'; ADXS11- 001, ADXS31-001, ADXS31-164, BiovaxID, folate binding protein (E39), Granulocyte macrophage colony stimulating factor (GM-CSF) with and without E75 (Neu Vax) or OncoVEX, trastuzumab, Ae-37, IMA901, SC1B1, Stimuvax, peptides that can elicit cytotoxic lymphocyte response, peptides such as PEP-1 and / or other therapeutic agents that reduce or eliminate CD44 expression, peptide vaccines including telomerase peptide vaccine (GV1001), survivin peptide, MU Cl peptide, ras peptide, TARP 29-37-9V Peptide epitope enhanced peptide, DNA Vector pPRA-PSM with synthetic peptides E-PRA and E-PSM; Ad.p53 DC vaccine, NY-ESO-1 Plasmid DNA (pPN7611), genetically modified allogeneic (human) tumor cells for the expression of IL-1, IL-7, GM-CSF, CDS0 or CD154, HyperAcute(R)-Pancreatic cancer vaccine (HAPa-1 and HAPa-2 components), Melaxin (autologous dendritoma vaccine) and BCG, GV AX (CG8123), CD40 ligand and IL-2 gene modified autologous skin fibroblasts and tumor cells, ALVAC-hB7.1, Vaximm Gmbh's VXM01, Immunovative Therapies' AlloStim-7, ProstAtak™, TG4023 (MVA-FCU1), Antigenic's HSPPC-96, Immunovaccine Technologies' DPX-0907 which consists of specific HLA-A2 -restricted peptides, a universal THelper peptide, a polynucleotide adjuvant, a liposome and Montanide (ISA51 VG), GSK2302032A, Memgen's ISF35, Avax's OVax: Autologous, DNP-Modified Ovarian vaccine, Theratope®, Adl00-gp96Ig-HLA Al, Bioven's recombinant Human rEGF-P64K / Montanide vaccine, TARP 29-37, or Dendreon's DN24-02.

[0060] In certain embodiments, the immunotherapeutic agent is an a-Gal glycolipid.

[0061] In certain embodiments, the immunotherapeutic agent is a β-ManCer comprising a sphingosine moiety and a fatty acid moiety comprising a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 49 carbon atoms. In related embodiments, the fatty acid moiety comprises a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 8 to about 15 carbon atoms. In other related embodiments, the fatty acid moiety comprises a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having from about 18 to about 30 carbon atoms. In the above embodiments, the immunotherapeutic agent enhances the therapeutic effects of the therapeutic agent. For example, the immunotherapeutic agent further reduces the growth of the tumor or further shrinks the tumor.

[0062] In some embodiments, the immunotherapeutic agent is administered after ablating the cancer cells and / or removing the cancer cells, and / or after permeating the blood vessel wall, and / or after administration of the therapeutic agent. In other embodiments, the immunotherapeutic agent is administered simultaneously with the administration of the therapeutic agent.

[0063] In embodiments, the immunotherapeutic agent is administered locally, regionally, or systemically. For example, the immunotherapeutic agent can be administered intraperitoneally. The immunotherapeutic agent can also be administered intratumorally.

[0064] As described in detail herein, a cancer therapy includes ablating cancer cells surrounding, inside the wall of, and / or within the lumen of blood vessels proximate a cancerous organ, e.g., a pancreas, such as to either disintegrate at least some cancer cells so that they are removed by blood flow or char at least some cancer cells so that they become surgically excisable.

[0065] The disclosed methods are believed to overcome limitations associated with current treatment methods. Some therapeutic methods involve ablating locally or regionally, coadministering a therapeutic agent and an intracellular penetration enhancing agent to a subject, thereby achieving high concentrations of the therapeutic agent in the tumor cells. The delivery methods of the present invention minimize exposure of the rest of the body to the cytotoxic therapeutic agent. The therapeutic methods also involve administration of an immunotherapyagent. The immunotherapy agent, which is administered before, during, or after delivery of the therapeutic and intracellular penetration enhancing agents, stimulates the immune system and enhances the anti-cancer effects of the therapeutic agent and the intracellular penetration enhancing agent.

[0066] Delivering short, intense electrical pulses to cell populations or tissues in vivo results in transient permeabilisation of cell membranes and this has provided the basis for what has become known as electrochemotherapy (Heller et al., (1999) Advanced Drug Delivery Rev. 35: 119). Electrochemotherapy can facilitate the passage of chemotherapeutic drugs into cancer cells which had become impermeable to those drugs. In certain embodiments, cancer cells surrounding blood vessels may first be ablated, while preserving the blood vessel wall, and electrical pulses may then be administered to the blood vessel wall to facilitate administration of anti-cancer treatment to the blood vessel wall, e.g., cancer cells that have invaded the blood vessel wall.

[0067] In certain embodiments, lasers, ultrasound, iontophoresis and electroporation, microneedles, thermophoresis, and / or magnetophoresis may be used to provide physical permeation enhancement to deliver a range of therapeutics, including genetic materials and vaccines to treat the cancer. For example, ultrasound may be used to facilitate delivery of macromolecules into tissue by causing micron-scale disruptions in the tissue of the blood vessel. Chemotherapy agents and / or other therapeutic agents may then more easily pass into the tissue of the blood vessel to treat the cancer cells therein.

[0068] In certain embodiments, microbubbles may be additionally or alternatively used to enhance local delivery of therapeutic agents (i.e., genes or drugs) through a process known as sonoporation, in which ultrasound forms small pores in cell membranes for the transfer of nucleic acid materials, microbubbles, and / or drugs. A variety of methods for drug / gene loading of microbubbles have been adapted to incorporate different therapeutic agents (e.g., plasmid DNA, lipophilic drug, hydrophilic drug) according to solubility which can be used to penetrate the ablated cancer cells to neutralize any remaining viable cancer.

[0069] Hyperthermia, ablation, histotripsy, and microbubble stable / inertial cavitation can alter the tumor microenvironment to enhance immuno activation to inhibit tumor growth. In certain embodiments, immunotherapy may be provided using microbubbles loaded with therapeutic gases. Microbubble cavitation can increase vessel permeability and thereby improve the delivery of immune cells, cytokines, antigens, and antibodies to tumors. Violent microbubble cavitation can disrupt tumor cells and efficiently expose them to numerous antigens so as to promote the maturity of antigen-presenting cells and subsequent adaptive immune-cell activation.

[0070] Ultrasound and hyperthermia may also be combined to trigger antitumor immune responses. In an embodiment, a temperature of about 43° C may be maintained after the ablative therapy for about 30-60 min.

[0071] The application of ultrasound in the presence of microbubbles and therapeutic agent simultaneously increases cell permeability and releases therapeutic agent at the precise location of disease, achieving enhanced therapeutic agent delivery relative to treatment with ultrasound and therapeutic agent without microbubbles. Increasing acoustic pressure promotes unstable microbubble cavitation which enhances cell permeabilization but decreases cell viability. Incorporation of a therapeutic agent into a molecular-targeted microbubble produces a microbubble capable of molecular targeting and therapy.

[0072] Acoustic radiation force (ARF) may be applied to produce a pressure gradient that displaces the microbubbles away from the acoustic source, enhances microbubble localization and accumulation near the treatment area, and is thereby believed to overcome flow and flotation limitations. For enhanced ARF application, ultrasound transducers that generate acoustic radiation may be configured to stimulate lipid-shelled microbubbles at the microbubble's resonance frequency (typically less than 5 MHz) and image at higher frequencies. In certain embodiments, an acoustic radiation force IVUS (ARFIVUS) transducer, having a center frequency of 3.3 MHz to operate closer to the resonance frequencies of the 1.4- to 2.6- pm-diameter microbubbles, pushes microbubbles toward the vessel wall and may be used to enhance intravascular microbubble binding efficiency and drug delivery.

[0073] Referring to FIG. 2, a perspective view of a cancer treatment system is shown in accordance with an embodiment. A cancer treatment system 200 may be a catheter-based system. More particularly, the system can include a catheter 202 that can be delivered intraluminally, e.g.. intravascularly, through a vascular access site and through the vasculature to a target anatomical region of a subject. When so placed, a disruption apparatus 310 of the system (FIG. 3), located at or in proximity to the distal end of the catheter 202, can be positioned within a target anatomy, e.g., within a body lumen such as a blood vessel. As described below, the disruption apparatus 310 can include one or more ultrasound transducers that may be disposed within a medical balloon 204. The transducer(s) can be activated to deliver mechanical ultrasound energy radially outwardly so as to suitably heat, disrupt, and thus treat, cancer cells within the target anatomical region. The disruption apparatus 310 may be configured to deliver RF energy, pulse field energy, microwave energy, and / or cryoablation to tissue, in addition to or instead of ultrasound energy.

[0074] The cancer treatment system 200 may include the catheter 202, a controller 206, and a connection cable 208. In certain embodiments, the cancer treatment system 200 optionally further includes the balloon 204 (or other suitable expandable member), a reservoir 210, a cartridge 212, and a control mechanism, such as a handheld remote control. In certain embodiments, the controller 206 is connected to the catheter 202 through the cartridge 212 and the connection cable 208. In certain embodiments, the controller 206 interfaces with the cartridge 212 to provide a cooling fluid 214 stored in the reservoir 210 to the catheter 202 for inflating and deflating the balloon 204 and / or for cooling tissue immediately adjacent to a treatment site.

[0075] In an embodiment, a balloon catheter 202 can include a compliant balloon 204 configured to accommodate a range of target vessel sizes. For example, the compliant balloon 204 may be configured to treat a blood vessel having a vessel lumen diameter between 3 to 9 mm in diameter. Thus, the compliant balloon 204 can mitigate the need to use several different balloon catheters per procedure. Accordingly, the balloon 204 can reduce procedure times and complexity.

[0076] Referring to FIG. 3, a side view of selected components of the cancer treatment system is shown in accordance with an embodiment. The cancer treatment catheter 202 can include a distal region 302 and a proximal region 304. The catheter 202 may have a length that depends on a treatment application. For example, in certain embodiments suitable for, e.g., accessing the blood vessels around the pancreas 100 through a femoral access delivery method, the catheter 202 can have a working length (measured from a distal tip of the catheter 202 to a proximal hub 306 of the catheter 202) of 80 to 90 cm, e.g., 85 cm, in the femoral access delivery method. In embodiments suitable for, e.g., accessing the blood vessels around the pancreas 100 through a radial access delivery method, the catheter 202 can have a working length of a comparatively longer length. More particularly, the working length can be 150 to 160 cm, e.g., 155 cm. Furthermore, an overall length of the catheter 202 for such application, including a length of electrical cabling 316 extending to an electrical coupling 318, can be longer. More particularly, the electrical cabling 316 can have a length of about 305 cm from the proximal hub 306 to the electrical coupling 318.

[0077] The catheter 202 can have a profile that is suitable to be inserted into a body lumen, e.g., a blood vessel proximate the pancreas 100, through the femoral and radial access locations. For example, the catheter 202 may be 4 to 6 French in diameter, e.g., 5 French. The profile is facilitated in part by a catheter shaft 308 having an outer diameter in a range of 0.050 to 0.060 inch, e.g., 0.057 inch.

[0078] The distal region 302 of the cancer treatment system 200 may be a portion of the device that is advanced through the vasculature into a target anatomy, e.g., a target vessel having a vessel wall, to treat the target vessel or tissue adjacent to the target vessel. The distal region 302 can include the balloon 204 mounted on a catheter shaft 308. The balloon 204 can be a compliant balloon having the characteristics described in detail below. For example, the balloon 204 can have a cylindricity that supports and centers a disruption apparatus 310 within the balloon 204 and within a range of vessel diameters, and thus, contributes to uniform energy delivery.

[0079] The catheter shaft 308 can be an elongated tubular structure that extends longitudinally from a proximal end to a distal end. The balloon 204 can be mounted and supported on the catheter shaft 308 at the distal end. Furthermore, the disruption apparatus 310 can be mounted on the catheter shaft 308 and contained within the balloon 204.

[0080] The catheter shaft 308 can include one or more lumens that may be used as fluid conduits, electrical cabling passageways, guidewire lumens 312, and / or the like. In an embodiment, the catheter shaft 308 can include a guidewire lumen 312 that is shaped, sized and otherwise configured to receive a guidewire. A guidewire may be utilized to place the distal end 302 of the catheter 202 at the desired location in the vasculature, in a standard manner known to one skilled in the art. In an embodiment, the guidewire lumen 312 is an over-the-wire type guidewire lumen, extending from a distal tip of the catheter 202 through an entire length of the catheter shaft 308 to an exit port 314 in the proximal hub 306 of the catheter 202. As described below, the lumen(s) of the catheter shaft 308 may also communicate inflation / cooling fluid 214 from the proximal region 304 to the balloon 204 during balloon expansion. In an embodiment, the guide wire lumen 312 is a rapid exchange type guidewire lumen, as described in greater detail below.

[0081] In an embodiment, the disruption apparatus 310 is mounted on the catheter shaft 308 at the distal region 302 of the catheter 202, within the interior of the balloon 204. The disruption apparatus 310 is configured to emit one or more of heat energy or other energy toward a blood vessel wall. For example, the disruption apparatus 310 can include an ablation unit 902 configured to transmit ablation energy to ablate cancer cells. Similarly, the disruption apparatus 310 can include a cavitation unit 904 configured to transmit cavitation energy to collapse the cancer cells. The ablation unit 902 may be an ablation transducer 902, and / or the cavitation unit 904 may be a cavitation transducer 904. In certain embodiments, the ultrasound transducer(s) 902, 904 may be ultrasound transducer(s) configured to emit ultrasound energy circumferentially, partially circumferentially, or in another shape. In certain embodiments, theultrasound transducer(s) 902, 904 can simultaneously emit ultrasound energy in more than a 270-degree arc to the blood vessel (e.g., as measured relative to a longitudinal axis of the transducer(s)), e.g., a 360-degree arc around the vessel wall. In some embodiments, cavitation is not performed, and the cavitation unit 904 may be omitted from the catheter 202. In such embodiments, a single ablation unit 902 may be utilized, or more than one ablation unit 902 may be utilized. Where more than one ablation unit 902 is utilized, this description of this document may be read to replace the cavitation unit 904 with a second ablation unit 902. In many applications, ablation alone is sufficient to treat tissue and damage and / or kill cancer cells. Further, the cavitation unit 904 may require more power than the ablation unit 902, such that omission of the cavitation unit 904 simplifies power delivery to the distal region 302 of the catheter 202, and may make the electrical cabling 316 lighter, more flexible, and / or smaller in diameter. In an embodiment, electrical cabling 316 extends from the proximal region 304 to the distal region 302 and is connected to the disruption apparatus 310 to generate energy for emission to target tissue.

[0082] In some embodiments, the disruption apparatus 310 is configured to ablate one or more nerves at a treatment site, in order to relieve at least some of the pain associated with pancreatic cancer or other disease or disorder. In such embodiments, at least one treatment site may be located where one or more nerves are ablated for pain relief may be free from cancer. Ablation of one or more nerves associated with the celiac trunk may be helpful to relieve pain, in at least some patients, that is caused by or associated with pancreatic cancer. Ablation of nerves at other locations in proximity to the pancreas also may be helpful to relieve the patient’ s pain. The disruption apparatus 310 is movable intravascularly to different treatment sites in the vasculature. Consequently, as the catheter 202 is moved in order to move the disruption apparatus 310 among different treatment sites, at least one of those treatment sites may be a treatment site for nerve ablation for pain relief.

[0083] One or more transducers 902, 904 of the disruption apparatus 310 may include first and second electrodes that are arranged on either side of a cylindrical piezoelectric material, such as lead zirconate titanate (PZT). To energize the one or more transducers 902, 904, a voltage is applied across the first and the second electrodes at frequencies selected to cause the piezoelectric material to resonate, thereby generating ultrasound energy that is emitted radially outward from the one or more transducers 902, 904. Each transducer 902, 904 is designed to provide a generally uniform and predictable emission profile, to inhibit damage to surrounding non-target tissue. In addition, the cooling fluid 214 is circulated through the balloon 204, prior to, during, and after activation of the disruption apparatus 310, so as to reduce heating of aninner lining of the body lumen and to cool, e.g., one or more of the ablation unit 902, the cavitation unit 904, and / or other functional units of the disruption apparatus 310. In this manner, the peak temperatures achieved by tissue within the cooling zone (that is, tissue in contact with or in proximity to the balloon 204 through which the cooling fluid 214 is circulated) remain lower than for tissue located outside the cooling zone.

[0084] In some embodiments, heating of an inner lining of the body lumen, such as a blood vessel, with an ultrasound transducer 902, 904 is desirable, in order to damage or kill cancer cells in the endothelial lining, the intima, and / or the media of the blood vessel. To do so, as one example, cooling fluid 214 may be circulated through the interior of the balloon 204 at a lower flow rate, or may not be circulated through the balloon 204 at all. As another example, referring to FIG. 16, the balloon 204 may be omitted altogether, and the ablation transducer 902 may be placed in the blood vessel in direct contact with blood. As another example, referring to FIG. 17, the blood vessel to be treated may be occluded downstream of the treatment site, such as by a balloon distally spaced apart from the ultrasound transducer. Such occlusion causes heat from the ultrasound energy applied to tissue to build in tissue, without cooling fluid 214 or blood to carry the heat away from that tissue.

[0085] The proximal region 304 may include one or more connectors or couplings. The connectors or couplings can be electrically connected to the transducer via the electrical cabling 316. For example, the proximal region 304 may include one or more electrical coupling(s) 318 that connect to a proximal end of the electrical cabling 316. A distal end of the electrical cabling 316 can be connected to the disruption apparatus 310.

[0086] The catheter 202 may be coupled to the controller 206 by connecting the electrical coupling 318 to the connection cable 208. The connection cable 208 may be removably connected to the controller 206 and / or the catheter 202 via a port on the controller 206 and / or the catheter 202. Accordingly, the controller 206 can be used with several catheters during a procedure by disconnecting the coupling of a first catheter 202, exchanging the first catheter 202 with a second catheter, and connecting a coupling of the second catheter to the controller 206. In certain embodiments, e.g., where only one catheter 202 needs to be used during a procedure, the connection cable 208 may be permanently connected to the controller 206.

[0087] In certain embodiments, the proximal region 304 of the catheter 202 may further include one or more fluidic ports. For example, the proximal hub 306 can include a fluidic inlet port 320 and a fluidic outlet port 322, via which an expandable member, e.g., the balloon 204, may be fluidly coupled to the reservoir 210. The reservoir 210 can therefore supply cooling fluid 214 to the balloon 204 through the fluidic inlet port 320, and receive spent cooling fluid214 (that is, cooling fluid 214 that has been heated by proximity to the disruption apparatus 310 during its energization) from the fluidic outlet port 322. The reservoir 210 optionally may be included with the controller 206, e.g., attached to the outer housing of the controller 206 as shown in FIG. 2. Alternatively, the reservoir 210 may be provided separately. In some embodiments, the balloon 204 may be configured as a weeping balloon 204, or may otherwise allow escape of spent cooling fluid 322 therefrom, into the bloodstream distal to the balloon 204. In such embodiments, the fluidic outlet port 322 may be omitted.

[0088] Referring to FIG. 4, a side view of selected components of the cancer treatment system 200 is shown in accordance with an embodiment. In an embodiment, the catheter 202 may be configured for use with a rapid-exchange type guidewire lumen 312. More particularly, the guidewire lumen 312 can extend from the distal tip 311 of the catheter 202 through a partial length of the catheter shaft 308 to an exit port 402 in the distal region 302 of the catheter 202. For example, a distance from the distal tip 311 of the catheter 202 to the rapid exchange exit port 402 may be in a range of 20 to 30 cm, e.g., 23 cm. The proximal hub 306 illustrated in FIG. 4 may differ from the proximal hub 306 illustrated in FIG. 3, given that the exit port 402 may be moved from the proximal portion to the distal portion. Other components of rapid exchange version of the catheter 202 may be similar to those of an over-the-wire version of the catheter 202, and thus, the descriptions of the components illustrated in FIG. 3 can apply to similarly numbered components illustrated in FIG. 4. According to other embodiments, any other configuration of catheter 202 and guidewire lumen 312 may be utilized as long as such catheter 202 allows for access to the treatment location, and as long as such catheter 202 allows for the performance of the method described herein.

[0089] Referring to FIG. 5, a perspective view of selected components of the cancer treatment system 202 inserted into a body lumen is shown in accordance with an embodiment. The cancer treatment system 200 can be inserted into a body lumen of a subject through a conventional vascular access method, such as via femoral access or radial access. For example, a distal region 302 of the catheter 202 of the cancer treatment system 200 can be advanced through the vasculature into a target vessel 500, e.g., a blood vessel such as the superior mesenteric artery 115. The target vessel 500 can have target tissue 502 associated therewith. The target tissue 502 may, for example, include nerves or cancer cells. The target tissue 502 can be located around and / or in proximity to the target vessel 500, e.g., in an outer layer (an adventitia layer) of the target vessel 500, or radially outward from the adventitia of the target vessel 500. The target tissue 502 may be cancerous tissue on an inner surface of the lumen of the target vessel 500, and / or extending into the tissue of the target vessel 500. In an embodiment, the cancer treatmentsystem 200 includes a guidewire support tip 504 having a lumen that connects to the guidewire lumen 312 of the catheter shaft 308. The support tip 504 can receive the guidewire 506 to allow the device to be tracked over a guidewire 506 to the target anatomy associated with the target vessel 500.

[0090] When the distal region 302 of the catheter 202 is disposed in the vessel lumen of the target vessel 500, the disruption apparatus 310 and the balloon 204 (or another suitable expandable member) are positioned radially inward from the target tissue 502, e.g., the cancer cells. The disruption apparatus 310 may be located or disposed partially or completely in an interior 507 of the balloon 204. The balloon 204 can be filled with an inflation fluid, e.g., the cooling fluid 214, to expand the balloon 204. When the balloon 204 is inflated with the inflation fluid, the balloon 204 can contact an interior surface, e.g., an intima, of the target vessel 500. The expanded balloon 204 may therefore have an inflated diameter substantially equal to a lumen diameter of the target vessel 500, and appose the target vessel 500 and substantially center the transducer within the target vessel 500.

[0091] In certain embodiments, the disruption apparatus 310 may be programmed to output acoustic energy, such as ultrasonic energy, when the balloon 204 fully occludes the target lumen. The balloon 204 may substantially center the disruption apparatus 310 within the target lumen. In certain embodiments, e.g., suitable for cancer treatment, the balloon 204 may be a compliant balloon 204, as described below, which may be inflated in the patient during a procedure at a working pressure of about 1.4 to 2 atm using the inflation fluid. The balloon 204 is sized for insertion in the target lumen; in the case of insertion into one or more of the blood vessels around the pancreas 100, for example, the balloon 204 may be selected to have expansion sizes including outer diameters of one or more of 3.5 mm, 4.2 mm, 5 mm, 6 mm, 7 mm, 8 mm, or 9 mm. The balloon 204 may have a burst strength of greater than 45 psi.

[0092] In some embodiments, when inflated by being filled with the inflation fluid under the control of the controller 206 within the target vessel 500, a balloon wall of the balloon 204 may be generally parallel with an outer surface of the disruption apparatus 310. Optionally, the balloon 204 may be inflated sufficiently as to be in apposition with the target vessel 500. For example, when inflated, the balloon 204 may at least partially contact, and thus be in apposition with, the inner wall of the target vessel 500. In other embodiments, the balloon 204 is configured not to substantially contact the target vessel 500 when expanded. The balloon 204 may be maintained at a specified size by pushing fluid into, e.g., via the inlet port, and pulling fluid out of, e.g. , via the outlet port, the balloon at a particular flow rate. More particularly, the inflation fluid 306 can circulate at one flow rate within the balloon 204 to expand the balloon, ata second flow rate to contract the balloon 204, and / or at a third flow rate to maintain the balloon 204 at substantially the same diameter.

[0093] In certain embodiments, the catheter shaft 308 may be about 1.8 mm in diameter. In certain embodiments, the catheter shaft 308 is between 5 and 6 French in diameter. The catheter shaft 308 includes one or more fluid conduits, passageways for electrical cabling 316 or the guidewire 506, etc. For example, the catheter shaft 308 may include the guidewire lumen 312 that is shaped, sized and otherwise configured to receive the guidewire 506. The catheter shaft 308 may include a cable lumen (extending through a same shaft as the guidewire lumen 312) for receiving the electrical cabling 316, and / or fluid lumens for transferring the inflation / cooling fluid 214, e.g., water, sterile water, saline, 5% dextrose (D5W), other liquids or gases, etc., from and to a fluid source, e.g., the reservoir 210, at the proximal region 304 of the catheter 202 external to the patient. Referring also to FIGS. 8-9, the catheter shaft 308 can include one or more fluid channels 330, 332, e.g., interior fluid passages, in fluid communication with the interior 507 of the balloon 204, and the fluid channel(s) can be used to move fluid into or out of the interior 507 of the balloon 204. For example, the fluid channel(s) can include an inlet channel 330 to deliver the inflation fluid from the inlet port 320 of the catheter 202 to the interior 507 of the balloon 204 under control of the controller 206. Similarly, the fluid channel(s) can include an outlet channel 332 to remove fluid from the interior 507 of the balloon 204 to the outlet port 322 of the catheter 202. Accordingly, the inlet channel 330 and the outlet channel 332 are in fluid communication with the interior 507 of the balloon 204 to circulate fluid through the interior of the balloon 204 at a flow rate selected to inflate the balloon 204.The flow rate also controls heat transfer between the balloon 204 and a vessel wall 508 to reduce a likelihood of overheating tissue during treatment. For example, the flow rate through the interior of the balloon 507 can provide for active cooling of about the first millimeter of tissue to preserve the integrity of, e.g., the blood vessel wall 508 around the pancreas 100.

[0094] Referring to FIG. 6, a side view of a cancer treatment system having a compliant balloon 204 inflated to a first inflation diameter is shown in accordance with an embodiment. In certain embodiments, the balloon 204 is compliant and configured to be deployed in a wide range of lumen, blood vessel, or artery sizes. For example, the balloon 204 may be capable of adapting to arteries with an inner diameter of 3 mm to 8 mm. Accordingly, using the compliant balloon 204 permits a single catheter 202 to be used during a procedure, advantageously decreasing operating time, particularly where multiple treatment sites are treated in blood vessels of different diameters. In certain embodiments, the use of a compliant balloon 204advantageously decreases the complexity, and thereby the rate of complications, of the procedure.

[0095] In certain embodiments, the cancer treatment system 200 is configured to measure the lumen, blood vessel, or artery sizes, and since the balloon 204 is configured to accommodate a wide range of lumen sizes, the controller 206 can be programmed to automatically inflate the balloon 204 to the appropriate diameter. Such automation advantageously provides improvements to the complexity of the procedure and mitigates a risk of user error. In certain embodiments, the cancer treatment system 200 having a compliant balloon 204 does not require the user to choose a size of balloon 204 and / or switch out catheters 202 to provide multiple sized balloons 204 during a single procedure.

[0096] The compliant medical balloon 204 can include a balloon wall 602, which at any longitudinal location, may have a generally annular cross-section. More particularly, the balloon wall 602 can have an outer surface that expands into contact with the target tissue 502, and an inner surface that defines the interior 507 of the balloon 204. As described above, the disruption apparatus 310 can be mounted on the catheter shaft 308, either directly or indirectly (e.g., via the electrical cabling 316).

[0097] The disruption apparatus 310 can be positioned within the interior 507 of the balloon 204. More particularly, the balloon 204 can have a balloon body 604, and the balloon body 604 can radially surround the disruption apparatus 310. For example, the balloon body 604 can be a generally cylindrical portion of the balloon wall 602 that extends radially around the disruption apparatus 310 relative to a longitudinal axis of the catheter shaft 308. The balloon body 604 can extend longitudinally between a plurality of corners 606. For example, a distal comer 606 can define a distal extent of the balloon body 604, and a proximal corner 606 can define a proximal extent of the balloon body 604. In an embodiment, a distance between the corners 606, which defines a length of the balloon body 604, can be equal to or greater than a length of the disruption apparatus 310. More particularly, the balloon body 604 length may be, at a minimum, the length of the disruption apparatus 310. Accordingly, the disruption apparatus 310 can be positioned such that a proximal end of the disruption apparatus 310 is distal to the proximal comer 606 of the balloon 204, and a distal end of the dismption apparatus 310 is proximal to the distal comer 606 of the balloon 204. The comers 606 can transition the balloon body 604 into a plurality of shoulders 608. Furthermore, in addition to transitioning the balloon 204 sections, the shape of the comers 606 can have a primary impact on the ability of the balloon 204 to center the transducer within the target vessel 500.

[0098] In an embodiment, the plurality of shoulders 608 include a distal shoulder (distal to the balloon body 604) that connects the balloon body 604 to a distal mounting section 610 of the balloon wall 602. Similarly, a proximal shoulder (proximal to the balloon body 604) can connect the balloon body 604 to a proximal mounting section 610 of the balloon wall 602. Accordingly, the shoulders 608 transition the portions of the balloon wall 602 that connect the balloon 204 to the catheter shaft 308 with the portion of the balloon wall 602 that interacts with the target tissue 502 during expansion.

[0099] The disruption apparatus 310 can be mounted on an isolation tube and / or the backing member 612. In this case the proximal mounting section 610 can be mounted on the catheter shaft 308 proximal to the disruption apparatus 310, but the distal mounting section 610 can be mounted on the disruption apparatus 310, backing member 612 or support tip 504. The mounting sections 610 may be connected to the catheter shaft 308 via thermal, adhesive, or mechanical joints that hermetically seal the balloon 204 to the catheter shaft 308. Accordingly, the interior 507 of the balloon 204, which is between the mounting sections 610, can surround the disruption apparatus 310 and provide a space for the inflation / cooling fluid 214 to circulate around the disruption apparatus 310 during treatment.

[0100] It will be appreciated that, as opposed to compliant balloons that primarily function to occlude a target anatomy, the balloon 204 of the cancer treatment system 200 also functions to substantially center the disruption apparatus 310 within the target vessel 500. The flexibility of the balloon 204 required to achieve the inflation methodologies described below, however, may lead to the disruption apparatus 310 becoming eccentric with the vessel lumen if particular features are not implemented in the balloon 204. More particularly, a shape and material of the balloon 204 can be provided as described below to provide a compliant balloon 204 that is also supportive enough to center the disruption apparatus 310 within the target vessel 500 during use.

[0101] The shape of the balloon 204 can contribute to optimally centering the disruption apparatus 310 within the target vessel 500. In an embodiment, the balloon body 604 and the plurality of shoulders 608 meet at rounded comers 606. The corners 606 may be considered rounded because, rather than the transition between the shoulder 608 and the balloon body 604 being sharp or angular, the transition has a smooth, arcuate profile. The profile can be described as having a full radius, as opposed to a discrete change in radius that would be apparent, for example, in medical balloons 204 typically used for angioplasty procedures. It has been shown that, as compared to balloon shapes having sharp comers 606, the rounded comers 606 of the balloon 204 provide that, when the balloon 204 is inflated within the target vessel 500, thecatheter shaft 308 (and the disruption apparatus 310 mounted on the catheter shaft 308) remains substantially centered in the target vessel 500.

[0102] The material of the balloon 204 can contribute to optimally centering the disruption apparatus 310 within the target vessel 500. In certain embodiments, the balloon 204 may comprise nylon, polyether block amide (PEBAX®), or other suitable polymers. In an embodiment, the balloon wall 602 is formed from an elastomeric material. For example, the elastomeric material can include a urethane material, such as a thermoplastic polyurethane (TPU). The TPU can be a poly ether-based TPU, such as Pellethane®. Alternatively, the balloon wall 602 may be formed from another medical grade polyether-based TPU, such as Isothane®.

[0103] Isothane® is a urethane material having a material specification that is closely controlled. As compared to other types of urethane, Isothane® may be particularly useful because variations in material properties between lots of material are low. More particularly, from lot to lot, Isothane® may have fewer gels and more consistent block chains as compared to other materials. Accordingly, in an embodiment, the raw material used to form the balloon 204 is Isothane®.

[0104] A hardness of the material from which the balloon 204 is made can contribute to the compliance of the balloon 204, e.g., the ability of the balloon 204 to expand and conform to different vessel lumen diameters. The hardness of that material can also contribute to the ability of the balloon 204 to supportively center the disruption apparatus 310 in a blood vessel lumen. Accordingly, the material used to form the balloon wall 602 may have a Shore durometer between about 95A and about 55D. More particularly, the balloon wall 602 material can have a Shore D durometer in a range of 50 to 60. For example, the balloon 204 may be formed from Pellethane® having a Shore D durometer of 55, or Isothane® such as 5095A, 7195A, or 5055D having a shore durometer of 55. In a particular embodiment, it has been shown that the balloon wall 602 formed from Isothane® having a Shore D durometer of 55 can provide excellent results in balancing the performance goals of compliant expansion with supportive strength.

[0105] Whereas non-compliant balloon 204 inflation is limited by the balloon 204 itself, i.e., the balloon diameter is generally fixed when inflated at different pressures within the expected operating range, and therefore can accommodate a limited range of vessel sizes, compliant balloon 204 expansion can employ multiple methods of inflation that allow the compliant balloon 204 to accommodate a larger range of vessel sizes. The compliant medical balloon 204 of the cancer treatment system 200 described above can be deployed in the target vessel 500using any of several inflation methodologies. Such methodologies can be termed a “pressure limiting approach,” an “arterial limiting approach,” and a “hybrid approach.”

[0106] The pressure limiting approach uses specific inflation pressures to attain specific balloon 204 diameters to gain apposition to various vessel sizes. The arterial limiting approach uses a fixed inflation pressure regardless of arterial diameter. The hybrid approach is a combination of the arterial limiting and pressure limiting approaches. The hybrid approach uses a fixed inflation pressure to gain apposition to smaller arterial diameters, but uses alternate (higher) inflation pressures to gain apposition to larger arterial diameters. The strength of the artery effectively determines the size of the balloon 204 at low pressures, and at higher pressures the balloon pressure determines the size of the balloon 204. These inflation paradigms are described in further detail below.

[0107] Still referring to FIG. 6, the balloon 204 is shown in a first state and, more particularly, at a first inflation diameter. The inflation diameter can be an outer dimension of the balloon body 604. In an embodiment, the balloon wall 602 has a shape and stiffness (as described herein) such that, when the compliant balloon 204 is inflated to a first inflation pressure of 10 psi, the balloon body 604 of the balloon wall 602 has a cylindrical profile and a first inflation diameter of 3.5 mm to 6 mm. The inflation pressure can correspond to a flow rate of fluid circulated through the interior 507 of the balloon 204 between the inlet channel 403 and the outlet channel 405. For example, the fluid may be circulated at a flow rate of 15 to 35 mL / min e.g., 25 to 35 mL / min) to inflate the balloon 204 to the inflation pressure of 10 psi, which results in the first inflation diameter of 3 to 6 mm (e.g., 3.5 to 6 mm). The balloon body 604 of the balloon 204 can have the first inflation diameter of 3.5 mm at a first inflation pressure of 10 psi and a flow rate of 30 mL / min.

[0108] In certain embodiments used for the pressure limiting approach, a single balloon 204 can have an inflation diameter that is directly related to the pressure in the balloon 204. More particularly, the outer diameter of the balloon 204 is directly related to the pressure in the balloon 204. According to this embodiment, the higher the pressure, the bigger the balloon 204. It is contemplated that the balloon 204 may have an expansion range of 3.5 to 9 mm. More particularly, the balloon 204 may have a nominal size of 3.5 mm when inflated to the state shown in FIG. 5, however, as the inflation pressure is increased, the inflation diameter may also increase.

[0109] Referring to FIG. 7, a side view of a cancer treatment system 200 having a compliant balloon 204 inflated to a second inflation diameter is shown in accordance with an embodiment. When the medical balloon 204 is inflated to a second inflation diameter, e.g., 8 mm, the balloonwall 602 can have essentially the same sections described above. More particularly, the medical balloon 204 can include the mounting sections 610, shoulders 608, and balloon body 604. The comers 606, which transition the balloon body 604 into the shoulders 608, can be rounded. In an embodiment, the rounded corners 606 can have a same radius as the balloon body 604 and the shoulders 608 such that the balloon wall 602 has a single, arcuate profile of a same radius between the distal mounting section 610 and the proximal mounting section 610. As in FIG. 7, the balloon body 604 can be longer than, and surround, the disruption apparatus 310 mounted on the catheter shaft 308.

[0110] Although the corners 606 may be rounded, the balloon 204 may have angular corners 606 instead. More particularly, angular corners 606 may be incorporated in the shape of the balloon 204. Angular corners 606 have been shown to center and support the disruption apparatus 310.

[0111] In an embodiment, the balloon wall 602 has a shape and stiffness (as described herein) such that, when the compliant balloon 204 is inflated to a second inflation pressure of 30 psi, the balloon body 604 of the balloon wall 602 has a cylindrical profile and a second inflation diameter of 8 mm to 9 mm. The inflation pressure can correspond to a flow rate of fluid circulated through the interior 507 of the balloon 204 between the fluid inlet channel and the fluid outlet channel. As one example, the fluid may be circulated through the interior 507 of the balloon 204 at a flow rate of 35 to 50 mL / min (e.g., 40 to 45 mL / min) to inflate the balloon 204 to the inflation pressure of 30 psi, which results in the first inflation diameter of 8 to 9 mm. As another example, the balloon body 604 of the balloon 204 can have the second inflation diameter of 8 mm at a second inflation pressure of 30 psi and a flow rate of 40 to 45 mL / min.

[0112] The catheter 202 is configured for insertion into one or more blood vessels that extend through or in proximity to the pancreas 100. More particularly, the catheter 202 can be configured to treat cancerous tissue from a blood vessel such as a blood vessel proximate the pancreas 100 having pancreatic cancer. To affect such treatment, the disruption apparatus 310 may be configured to disrupt cancer cells of the pancreatic cancer.

[0113] The disruption apparatus 310 can include one or more of an ablation unit 902 or a cavitation unit 904. More particularly, although the disruption apparatus 310 is illustrated as a single tubular body in FIGS. 2-7, it will be appreciated that the apparatus may be composed of several units having respective functions. For example, the ablation unit 902 may be configured to transmit ablation energy to ablate cancer cells. Similarly, the cavitation unit 904 may be configured to transmit cavitation energy to collapse the cancer cells. Ablation energy and cavitation energy may be used alone or in combination to disrupt the cancer cells so that thecells can damaged or killed, and / or so that a therapeutic agent may be more easily delivered to the cancer cells. As described above, removal of dead or damaged cancer cells after ablation and / or cavitation, whether performed surgically or intravascularly, may be beneficial for the patient.

[0114] In an embodiment, the ablation unit 902 is an ablation ultrasound transducer 902. Similarly, in an embodiment, the cavitation unit 904 is a cavitation ultrasound transducer 904. The transducers 902, 904, whether used for ablation or cavitation, can emit acoustic energy. For example, the ablation energy can be unfocused acoustic energy or focused acoustic energy. Similarly, cavitation energy can be focused acoustic energy or unfocused acoustic energy. For example, the cavitation energy can include focused acoustic energy having a frequency in a range of 50 kHz to 200 kHz. Accordingly, the disruption apparatus 310 may be configured to operate either or both ultrasound transducers in a focused mode or an unfocused mode.

[0115] Using the ablation unit 902 and or cavitation unit 904, the disruption apparatus 310 can ablate and / or collapse cancer cells. Thermal ablation of cancer cells is achieved by raising the temperature of the cancer cells between 56 and 100 °C, or by exposing cancer cells to extremely cold temperatures, such as induced by the delivery of extremely cold liquid or gas to cancer cells or tissue in proximity to cancer cells, for a long enough time to ablate the cancer cells, but not to necrose the blood vessels. Thermal ablation may be accomplished with unfocused ultrasound, focused ultrasound, radiofrequency energy, laser energy, microwave energy, and cryoablation, which can selectively destroy cancer cells, while leaving the vessel wall 508 and organs intact. Unfocused ultrasound may be used to ablate cancer cells without damaging the blood vessels or organs. Cooling fluid 214 may be delivered via a balloon 204 or other mechanism, at the same time as ablation energy and / or cavitation energy, to cool and thereby protect the inner lumen of the blood vessel to avoid, e.g. stenosis.

[0116] Heat may be applied to the cancer cells encircling a blood vessel such as to char them so that they can be removed from the blood vessel wall 508 by surgical or minimally invasive means. Cancer cells may ablate faster than healthy tissue cells because of the lack of blood flow within the cancer cells.

[0117] Cavitation may be used to cause membranous organelles, such as mitochondria, endoplasmic reticuli, and nuclear membranes, within cancer cells to collapse. Cavitation can be used to break cancer cells lining blood vessel lumens into small pieces, leaving the tumor antigen intact or leading to exposure of an immunogenic moiety hidden within the tumor antigens, stimulating the patient’s antitumor immune system. A standard embolic protection system may be utilized in the blood vessel, downstream of the treatment site, to capture thosesmall pieces, in order to protect against metastasis and stroke. Cavitation can be used to aid in the collapse of cancer cells around blood vessels, and / or trigger a specific cellular anticancer immune response, while preserving the blood vessel wall 508.

[0118] Cavitation close to cell membranes can lead to an increase in membrane permeability to enhance the delivery of therapeutic agents, e.g., chemotherapy (e.g., an activin inhibitor and / or PEGPH20), from drug carriers through the cell membrane. In addition, cavitation may sensitize cancer cells to radiation therapy via tumor oxygenation and DNA repair inhibition.

[0119] Suitable materials for the ablation ultrasound transducer 902 or the cavitation ultrasound transducer 904 to achieve the desired cell disruption include, but are not limited to, piezoelectric materials. Piezoelectric materials can include piezoelectric ceramics, crystalline and polymers, acoustic micro-electromechanical systems (MEMS) transducers such as piezoelectric micromachined ultrasonic transducers (PMUT) and capacitive micromachined ultrasonic transducer (CMUT). Examples of suitable piezoelectric materials include, but are not limited to, lead zirconate titanate (PZT), CMUT, and PMUT. In certain embodiments, the materials for the transducer 34 includes or consists of lead zirconate titanate 8 (PZT8), which is also known as Navy III Piezo Material. Raw PZT transducers may be plated with layers of copper, nickel and / or gold to create an inner electrode and an outer electrode. Application of alternating current across the inner and outer electrodes causes the piezoelectric material to vibrate transverse to the longitudinal direction of the cylindrical tube and radially emit ultrasonic waves.

[0120] One or more of the ablation ultrasound transducer 902 or cavitation ultrasound transducer 904 is generally supported via the backing member 612 or isolation tube. For example, the ablation ultrasound transducer 902and the cavitation ultrasound transducer 904can surround the backing member 612. In certain embodiments, backing member 612 comprises stainless steel coated with nickel and gold, wherein nickel is used as a bonding material between the stainless steel and gold plating. In certain embodiments, an outer diameter of the ablation ultrasound transducer 902or the cavitation ultrasound transducer 904is about 1.5 mm, the inner diameter is about 1 mm, and the ablation ultrasound transducer 902 or the cavitation ultrasound transducer 904has a length, for example, in a range of 3 to 9 mm, such as 6 mm. The backing member 612 may extend from the distal end of the catheter shaft 308 to the support tip 504. For example, the distal end of the backing member 612 may be positioned within an adjacent opening in the support tip 504, and the proximal end of the backing member 612 may be moveably coupled to the distal end of the catheter shaft 308 via the electrical cabling 316. In other embodiments, there is a gap between the distal end of the catheter shaft 308 and thebacking member 612 supporting the transducer, and / or a gap between the backing member 612 and the support tip 504.

[0121] Referring to FIG. 8, a perspective view of selected components of the cancer treatment system having a flexible feature between several ultrasonic transducers is shown in accordance with an embodiment. In an embodiment, the disruption apparatus 310 can include several ultrasonic transducers. For example, an ablation unit 902 of the disruption apparatus 310, which may include an ultrasound transducer, may be longitudinally separated from a cavitation unit 904 of the disruption apparatus 310. In certain embodiments, the ablation unit 902 and the cavitation unit 904 can be positioned in one or more balloons, e.g., the balloon 204, on the catheter 202. Although two transducer assemblies, one for the ablation unit 902 and one for the cavitation unit 904, are depicted in FIG. 8, the catheter 202 may include more transducer assemblies, e.g., without limitation, three, four, five, or more, e.g., twenty. The use of multiple smaller transducers, each longitudinally shorter than a single ablation transducer 902 or cavitation transducer 904, within a single balloon 204 increases the flexibility of the catheter 202. The increased flexibility may provide access to smaller diameter body lumens, such as blood vessels around the pancreas 100 and / or having a diameter that is less than 3 mm. The flexibility-enhanced catheter 202 can therefore be delivered through small diameter and / or tortuous anatomies, and / or can reduce de-centering of a transducer assembly of the disruption apparatus 310 due to placement of the transducer assembly at a curve in a body lumen. As another example, as described below, the catheter 202 may include an imaging unit (FIG. 11) located in the interior 507 of the balloon 204, and the imaging unit can include an imaging transducer.

[0122] The device can include a flexible feature 906 connecting the ablation unit 902 to the cavitation unit 904. More particularly, one or more flexible features 906 may connect adjacent transducers within the interior 507 of the balloon 204. For example, the flexible feature 906 can be a flexible post separating and located between the ablation unit 902 and the cavitation unit 904. The flexible feature 906 can include a bridge portion of the backing member 612 extending between adjacent transducer assemblies and can serve as the backing member 612 for multiple transducer assemblies and in the same balloon 204. The ablation unit 902 and the cavitation unit 904 can surround the backing member 612, and the flexible feature 906 can spiral about the backing member 612 between the units.

[0123] An enhanced flexibility region of the flexible feature 906 can include an opening 910 that extends through the wall of the backing member 612 to make the flexibility feature 906 flexible. As one example, opening 910 can spiral around the longitudinal axis of the backingmember 612 along at least part of the length of the flexible feature 906. The opening 910 can make a portion of the backing member 612 located between adjacent transducer assemblies more flexible than portions of the backing member 612 within the transducers. As a result, at least one flexibility enhanced portion of the backing member 612 has a helical or substantially helical configuration for a portion of the longitudinal length of the backing member 612. In some instances, the enhanced flexibility region does not extend into any of the transducer assemblies in the balloon 204.

[0124] The spiral rate can be used to measure the number of degrees that the helix turns around the longitudinal axis of the backing member 612 per unit length of the longitudinal axis. The spiral rate can determine the degree of flexibility of the flexibility enhanced portion of the backing member 612. For instance, increasing the spiral rate can provide a more flexible backing member 612 while decreasing the spiral rate can provide a more rigid backing member 612. Suitable spiral rates (pitch counts) include, but are not limited to, rates greater than or equal to 0° / mm, extending over more than 360° or more than 720°.

[0125] Referring to FIG. 9, a perspective view of selected components of the cancer treatment system having a flexible feature 906 between several transducers is shown in accordance with an embodiment. In an embodiment, bridge portions having enhanced flexibility do not extend under the transducer assemblies; however, all of a portion of the bridge portions in a catheter 202 can each include more of enhanced flexibility regions that extend from between transducer assemblies under one or more transducer assemblies. The flexible feature 906 can include a connecting portion of the backing member 612 extending from a transducer assembly to the catheter shaft 308. The illustrated connecting portions are shown as excluding one or more enhanced flexibility regions, however, the connecting portion can optionally include one or more enhanced flexibility regions.

[0126] The flexible feature 906 may be a flexible boot, as illustrated in FIG. 9. More particularly, the flexible feature 906 can have a solid tubular structure including an end coupled to the ablation transducer 902 and an end coupled to the cavitation transducer 904. The boot may be formed, for example, from a elastomeric material such as silicone. Accordingly, the boot, although solid, may be flexible enough to bend and allow the transducers move relative to each other. Where more than two transducers 902, 904 are utilized, a flexible feature 906 may be provided between each pair of transducers 902, 904 to enhance flexibility of the disruption apparatus 310 as a whole.

[0127] Increasing a separation distance between the transducers 902, 904 of the device, such as a distance between the ablation unit 902 and the cavitation unit 904, can increase theflexibility of the catheter 202 in some embodiments. In some instances, the separation distance is greater than or equal to 0 mm or 2 mm and / or less than 6 mm to reduce spatial acoustic intensity between the operation of adjacent transducer assemblies. For example, the ablation unit 902 and the cavitation unit 904 can have respective active regions spaced apart by a separation distance. The active regions can be regions of the units configured to output energy. In an embodiment, the separation distance between the active regions is less than 5 mm, e.g., 3 mm.

[0128] Referring to FIG. 10, a side view of selected components of the cancer treatment system having a flexible feature 906 between several transducers is shown in accordance with an embodiment. In an embodiment, the ultrasound transducers 902, 904 of the disruption apparatus 310 are longitudinally separated within the balloon 204 by the flexible feature 906. The flexible feature 906 can be configured to facilitate navigating the device through blood vessels, e.g., to the target vessel 500 around the pancreas 100. The flexible feature 906 can have a proximal end coupled to one of the ultrasound transducers, e.g., the ablation unit 902, and another and coupled to another ultrasound transducer, e.g., the cavitation unit 904. The flexible feature 906 can have an annular structure including a central channel through which the backing member 612 extends. The ultrasound transducers 902, 904 can be mounted on the backing member 612. Accordingly, the ultrasound transducers 902, 904 of the disruption apparatus 310 can be stabilized by both the backing member 612 and the flexible feature 906 of the catheter 202. As shown in FIG. 10, in some embodiments, both the ablation transducer 902 and cavitation transducer 904 are air- backed ultrasonic transducers. In such an embodiment, the ultrasonic transducers 902, 904 each include a cylindrical electrode 920 as described above. The cylindrical electrode 920 is spaced radially outward from the backing member 612, and is attached to the backing member 612 by one or more posts 922 extending radially outward from the backing member 612 to an inner surface of the cylindrical electrode 920. Spaced radially between the backing member 612 and the inner surface of the cylindrical electrode 920 is an air gap 924.

[0129] Referring to FIG. 11, a side view of selected components of the cancer treatment system 200 having an imaging unit 1102 associated with the catheter 202 is shown in accordance with an embodiment. The imaging unit 1102 may, for example, include a functional unit configured to transmit and / or receive an imaging signal to detect cancer cells, which may be an imaging transducer 1102. The imaging transducer 1102 can be located in the interior 507 of the balloon 204. The illustrated portion of the device in FIG. 11 includes the imaging unit 1102, and it will be appreciated that other functional units, such as the ablation unit 902 and / or thecavitation unit 904, may also be located within the interior 507 of the balloon 204 adjacent to the imaging transducer 1102.

[0130] In an embodiment, the imaging transducer 1102 includes a piezoelectric material. The piezoelectric material, or another material forming the imaging transducer 1102, can generate the imaging signal when excited. For example, the imaging transducer 1102 may be configured to transmit the imaging signal at a predetermined frequency. The predetermined frequency can be a frequency used to detect cancer cells. For example, the imaging signal can have a frequency of 20 MHz.

[0131] The imaging transducer 1102 can include one or more elements. For example, the imaging transducer 1102 can include several elements arranged in an array. The array may be a single cylindrical array. Alternatively, the array can be a multi-row cylindrical array. Alternatively, the elements may be arranged in any other suitable manner.

[0132] In an embodiment, the imaging unit 1102 may be a portion of the ablation unit 902, and the imaging transducer 1102 may be a portion of the ablation transducer 902. More particularly, a single transducer may be operated in a manner that provides both ablation and imaging. Such a single ablation and imaging transducer can have several steps in diameter along its longitudinal dimension. More particularly, the single ablation and imaging transducer can have a composite cylindrical structure in which the first section of the cylinder has a first diameter, and a second section of the cylinder has a second, different diameter. One section of the cylinder may be the ablation unit 902, and the other section of the cylinder may be the imaging unit 1102. Accordingly, the catheter 202 can include the imaging unit 1102, the ablation unit 902, and the cavitation unit 904 within the balloon interior 507.

[0133] Referring to FIG. 12, a side view of selected components of the cancer treatment system 200 having cavitation electrodes 1202 is shown in accordance with an embodiment. The disruption apparatus 310 may include at least one ablation transducer 902, configured to generate ultrasound energy and direct that energy radially outward into tissue. Transducers and / or the electrodes of the disruption apparatus 310 can provide certain functionality as described below.

[0134] In an embodiment, an ablation catheter 202 includes cavitation electrodes 1202. For example, cavitation electrodes 1202 may include a distal cavitation electrode 1204 positioned distal to the ablation transducer 902, and a proximal cavitation electrode 1206 positioned proximal to the ablation transducer 902. The distal cavitation electrode 1204 can be separated from the proximal cavitation electrode 1206 by at least 5 mm. In an embodiment, each of thecavitation electrodes 1202 are spaced apart from the ablation transducer 902 by about 7 mm, e.g., 6.7 mm.

[0135] The voltage applied to the cavitation electrodes 1202 to achieve the desired functionality may be between about 100 to 10,000 volts. The voltage can depend on the gap between the electrodes. In an embodiment, the electrodes comprise stainless steel, tungsten, nickel, iron, steel, etc., such that they are configured to withstand operational loads. For example, in the case of cavitation electrodes 1202, high voltage levels and intense mechanical forces, e.g., about 1000-2000 psi or 20-200 ATM in a few microseconds, are generated during use. The cavitation electrodes 1202 can have a small surface area, such as to have a higher current density and therefore generate steam bubbles upon application of a high voltage. The generation, growth and collapse of these bubbles can produce cavitations and shock waves to break and denature the cancer cells. The direction of the resultant pressure pulse waves produced by the cavitation may be controlled based on the circumferential orientation of the electrode where cavitation is to occur. In an embodiment, the cavitation electrodes 1202 comprise two ring electrodes, each comprising an inner electrode, an insulating layer disposed over the inner electrode such that an opening in the insulating layer is aligned with the inner electrode, and an outer electrode sheath disposed over the insulating layer such that an opening in the outer electrode sheath is coaxially aligned with the opening in the insulating layer.

[0136] In certain embodiments, the cavitation electrodes 1202 comprise two simple electrodes (+ and -), one distal to and the other proximal to the ablation unit 902. The cavitation electrodes 1202 may comprise one or more ring electrodes 1204, 1206 attached to the catheter 202 distal and proximal to the transducer units and within an insulated (to protect patient from electric shock) balloon 204. In an embodiment, the cavitation electrodes 1202 are located on the ablation transducer 902 itself, e.g., on one or more steps of the ablation transducer 902. In an embodiment, one electrode 1202 could be distal or proximal an ablation transducer 902 and one electrode 1202 could be between spaced-apart ablation transducers 902. The catheter 202 may include two ablation transducers 902, and the cavitation electrodes 1202 may be distributed in various configurations around the ablation transducers 902.

[0137] The transducer and electrode configurations described above are illustrative. Other configurations are contemplated. For example, the catheter 202 can include RF ablation electrodes, instead of or in addition to an ablation transducer 902. The ablation unit 902 may include a telescoping transducer slidable over the one or more cavitation electrodes 1202. The slidable transducer can protect the electrodes after the cavitation therapy is administered.

[0138] The ablation unit 902 and / or the cavitation unit 904 may have structures that differ from those discussed above. As one example, the ablation unit 902 may be configured to provide cryothermal ablation to tissue. In such case, the disruption apparatus 310 may include a cryoprobe in addition to, or instead of, an ablation transducer 902. The cryoprobe can deliver liquid nitrogen, other cryogenic liquid, or supercooled gas to rapidly cool and ablate the cancer cells. As another example, the ablation unit 902 may be configured to deliver microwave energy to tissue. In such case, the ablation unit 902 includes a microwave antenna that receives power from the connection cable 208, converts that power to microwave energy, then directs that microwave energy toward the cancer cells to ablate them with heat. As another example, the ablation unit 902 may be configured to deliver laser energy to tissue. In such case, the ablation unit 902 may be an optical diffuser that receives laser energy via an optical fiber extending through the catheter shaft 308, and directs that laser energy toward the cancer cells to ablate them with heat. It will be appreciated, therefore, that the ablation unit 902, the cavitation unit 904, the imaging unit 1102, and other functional units of the disruption apparatus 310 may be embodied by different functional units having the intended effect on the cancer cells.

[0139] Ablation techniques and functional units are therefore not restrictive. As described above, the ablation unit 902 can be configured to use thermal ablation techniques, such as unfocused ultrasound, focused ultrasound, radio-frequency, laser, microwave, and cryo-ablation, which selectively destroy cancer cells, while leaving the vessel wall 508 and organs intact, by example only. Unfocused ultrasound may be used to ablate cancer cells without damaging the vascular structure, e.g., the blood vessels, or organs. Cooling fluid 214 can be delivered via a balloon 204 or other mechanism to protect an inner lumen of the vascular structure, e.g., the blood vessel, to avoid damage, e.g., stenosis. Heat may be applied to the cancer cells that encircle a vascular structure, e.g., a blood vessel, to char the cancer cells so that the cancer cells are releasable from the vascular structure, e.g., a blood vessel wall 508, by using a surgical or minimally invasive technique. Cancer cells may ablate faster than healthy tissue cells due to an absence of blood flow within the cancer cells.

[0140] In an embodiment, the catheter 202 can include a balloon 204 configured to deliver a therapeutic agent to the cancer cells. For example, a user may deliver the therapeutic agent after cavitation. In some embodiments of the present disclosure, the cancer treatment system 200 is configured to facilitate delivering the chemotherapy medication or another therapeutic agent. For example, the balloon 204 can include one or more perforations to deliver the therapeutic agent of the cancer cells. The therapeutic agent can include an anti-cancer drug such an activin- inhibitor or a pegvorhyaluronidase (PEGPH20). Drug delivery can include delivery of anytherapeutic agent or cancer agent to the cancer cells by the cancer treatment system 200, or in conjunction with the cancer treatment system 200, such as by injection or by IV drip, before, during, and / or after treatment of cancer cells by the cancer treatment system 200.

[0141] Drug delivery can include nanoparticle (NP)-based gemcitabine drug delivery. By nanoparticle encapsulation and targeted delivery of chemotherapeutic drugs, an encapsulated nanoparticle carrier can pass through the cell membrane without being affected by cell surface NTs. Such encapsulated nanoparticle carrier is believed to both overcome various pathological and pharmacological barriers, and also greatly enhance drug activity and utilization, which can contribute to reducing the chemoresistance of pancreatic cancer. The therapeutic agent can include human serum albumin nanoparticles (GEM-HSA-NP) loaded with gemcitabine. Nanoparticles loaded with GEM may inhibit cell proliferation, arrest cell cycle, and induce apoptosis of chemoresistant cancer cells. Such nanoparticles may also be equally effective in patients with low expression of hENTl, and without increasing biotoxicity of GEM-HSA-NP compared with gemcitabine.

[0142] Drug delivery can also include combination therapy. A therapeutic agent, which covalently pre-conjugates two or more therapeutic agents via hydrolyzable ligands, can make it possible for various drugs to be loaded onto the same nanocarrier. Paclitaxel-gemcitabine conjugated dual-drug nanocarrier delivery system may significantly improve the intracellular efficacy of gemcitabine compared with the free drug conjugates. In many phases II or III clinical trials, the combination of gemcitabine plus nanoparticle bound paclitaxel (nab-paclitaxel) has higher activity and stronger cytotoxicity than GEM alone. Patients with pancreatic cancer receiving gemcitabine combined with nanoparticles may have a better survival advantage and higher median overall survival duration and progression-free survival duration.

[0143] Referring to FIG. 13, a flowchart of a method of disrupting cancerous tissue is shown in accordance with an embodiment. At operation 1302, a device is delivered through a blood vessel of the patient to a position adjacent to cancerous tissue. Accordingly, catheter 202 can be delivered into a portal vein 112, a superior mesenteric vein 114, a superior mesenteric artery 115, a celiac artery, celiac trunk 116, or a hepatic artery 118. In some embodiments, the hepatic artery 118 or the splenic artery 110 are preferred as blood vessels through which the catheter 202 is delivered to a position adjacent to cancerous tissue. Cancerous tissue may be located within a blood vessel proximate a cancerous organ. In some embodiments, the device is the disruption apparatus 310. The delivery of the device in operation 1302 may be performed in any suitable manner, such as advancement through an arterial access port guided by fluoroscopy.

[0144] In other embodiments, the imaging unit 1102 of the device can be used to check for cancer cells within and / or surrounding the blood vessel as the device is advanced. When cancer cells are found, the balloon 204 may be inflated to enable balloon- vessel wall apposition. Imaging the blood vessel may be performed during treatment. The imaging unit 1102, located at the distal end of the device, can be used to perform the imaging.

[0145] At operation 1304, the device disrupts cancerous tissue. More particularly, the ablation unit 902 and / or the cavitation unit 904 may be used to ablate, break, or denature the cancer cells. Disruption of the cancer cells may occur circumferentially about the blood vessel.

[0146] Disrupting the cancerous tissue can include ablating the cancer cells. Ablation can occur through thermal ablation. Thermal ablation may be achieved by delivering energy to the cancerous tissue until the cancer cells are damaged or necrotized. For example, the ablation unit 902 may be activated to emit unfocused ultrasound to provide thermal ablation. Alternatively, the ablation unit 902 may be activated to emit focused ultrasound to provide thermal ablation. Alternatively, the ablation unit 902 may be activated to emit radiofrequency energy to heat and char the cancer cells. Ablation of the cancer cells can raise a temperature of the cancerous tissue to a temperature in the range of 56 °C to 100°C. For example, ablation of cancer cells can be achieved by heating the cancer cells to a temperature range of approximately 48 °C to approximately 85 °C for a sufficient time duration to ablate the cancer cells, while avoiding necrotizing vascular structure or any other healthy tissue. The treatment temperature is dependent on the treatment time.

[0147] Alternative means of thermal ablation may be used. For example, the ablation unit 902 can be activated to emit cold gas. The cold gas can thermally ablate the cancer cells.

[0148] Disrupting the cancerous tissue can include collapsing the cancerous tissue using cavitation. The cavitation unit 904 may be the device, which can be activated to generate cavitation, resulting in substantial pressure fluctuations in the region of the cancerous tissue. The pressure fluctuations can collapse membranous organelles within the cancerous tissue. As a result, the cancerous tissue may be disrupted and / or killed. More particularly, the cavitation may break cancer cells into smaller pieces. Furthermore, the cavitation can leave a tumor antigen intact, and / or expose an immunogenic moiety within the tumor antigen to stimulate an antitumor immune system of the patient.

[0149] Following ablation and / or cavitation, a therapeutic agent may be delivered to the blood vessel. For example, an anticancer agent or drug can be delivered to the cancerous tissue. The anticancer agent can be a chemotherapy drug such as described above, which may be delivered to the blood vessel around the pancreas 100.

[0150] A user may check whether the cancer cells have been successfully disrupted. For example, after ablating and / or cavitating the cancer cells, the balloon 204 may be expanded to apply a high pressure to the cancer cells within the blood vessel. The expansion can break up the cancer cells. The imaging unit 1102 may be used to determine whether cancer cells are broken successfully. Disruption of the cancer cells can introduce cracks and gaps between fragmented cancer cells. Such gaps can provide acoustic pathways to facilitate ablation. Similarly, perforations within the cancerous tissue can provide treatment paths for a therapeutic agent to propagate into the cancerous tissue.

[0151] Referring to FIG. 14, a flowchart of a method of disrupting cancer cells is shown in accordance with an embodiment. The method may be similar to the method illustrated in FIG. 13. At operation 1402, a catheter 202 is intravascularly positioned within a target blood vessel of the patient. More particularly, the catheter 202 can be positioned adjacent to the cancer of the patient. The cancer may be pancreatic cancer.

[0152] At operation 1404, cancer cells of the cancer can be disrupted by delivering energy to the cancer via the catheter 202. Ablation of the cancer cells may include damaging or necrotizing the cancer cells to ease removal of the cancer cells from the blood vessel.

[0153] It will be appreciated that ablation and / or cavitation may be applied in various sequences. For example, ablation may be applied first, and then cavitation therapy may be applied in order to break remaining cancer cells on the lumen of the vessel wall 508 circumferentially. Alternatively, cavitation therapy may be applied first so that the cancerous cells surrounding the lumen do not interfere with the sonication of the ablation unit 902. In some embodiments, cavitation is not used, and only thermal ablation is used to damage or necrotize cancer cells surrounding the blood vessels. Accordingly, ablation or cavitation may be used individually or in tandem to disrupt the cancer cells. Alternatively, ablation and cavitation may be performed at the same time or at overlapping times. It will be appreciated that disruption of the cancerous tissue can trigger a specific cellular anti-cancer immune response, as described above.

[0154] After disruption, cancer cells and / or the cancerous tissue can be excised from the blood vessel. Excising the cancer may include scraping disrupted cancerous tissue from the blood vessel with a scraping unit. In an embodiment, the catheter 202 includes a scraping unit configured to remove cancer cells. The scraping unit may be a scalpel. For example, the scalpel can be a harmonic scalpel. In an embodiment, a scraping unit is located on the device, and is utilized intravascularly. For example, the scraping unit can have a structure such as a rotatingblade, a rotating burr, or another feature that can shave or excise cells from the inner wall of the blood vessel.

[0155] The scraped cancer cells can be collected. In an embodiment, the catheter 202 includes a collection unit configured to collect the cancer cells. The collection unit may, for example, include a mesh basket. Whereas the scraping unit can scrape the disrupted cancer cells from the blood vessel, the collection unit may be positioned proximate to the disruption apparatus 310 and / or the scraping unit to capture the scraped cancer cells. Cancer cells may be stored in the collection unit for retrieval from the patient when the catheter 202 is removed from the patient.

[0156] Referring to FIG. 15, a flowchart of a method of disrupting cancer cells is shown in accordance with an embodiment. The device, e.g., a balloon delivery catheter 202, can be used to treat several treatment sites similar to the manner described above with respect to a single treatment site. At operation 1502, a balloon delivery catheter 202 is delivered to treatment sites in several blood vessels adjacent to the pancreas 100. The balloon delivery catheter 202 can be inflated at each of the treatment sites.

[0157] At operation 1506, heat and / or energy is delivered to a vessel wall 508 at each of the treatment sites. More particularly, a wall of the body lumen adjacent to the cancer cells can be targeted by the delivered heat and / or energy to disrupt the cancer cells at each of the treatment sites. An amount of the delivered heat or energy is effective to disrupt cancer cells adjacent to the treatment sites. For example, the delivered heat or energy can be effective to ablate the cancer cells. Similarly, the delivered heat or energy can be effective to collapse the cancer cells. As described above, at least one or more of the treatment sites may be associated with pain relief, instead of cancer cell ablation or damage. Thus, at operation 1506, heat and / or energy may be delivered to nerves at one or more treatment sites, in order to reduce the pain experienced by the patient that is caused by their cancer.

[0158] In an embodiment, the balloon delivery catheter 202 is used to infuse a formulation to one or more of the treatment sites. For example, the formulation can be infused from the inflated balloon delivery catheter 202 to the vessel wall 508 adjacent to nerves or nerve Indians at each of the treatment sites. The infused formulation can include one or more therapeutic agents, as set forth above, to treat the cancer cells and / or nerves or nerve endings.

[0159] At operation 1508, the balloon delivery catheter 202 can be deflated at each of the treatment sites. The balloon delivery catheter 202 can be moved from one treatment site to another while deflated. Accordingly, the operations of FIG. 15 can be used repeatedly to treat each of the several treatment sites.

[0160] At operation 1510, the device can be removed from the blood vessel. More particularly, the balloon delivery catheter 202 can be withdrawn from the body lumen through the vascular access site through which the catheter was originally inserted into the patient’s vasculature. The cancer treatment using the balloon delivery catheter 202 is then complete.

[0161] The device and method described above provides several advantages. The device can remove cancer cells from blood vessels that may otherwise be inoperable. Disruption of the cancer cells can make it easier for a surgeon to peel away, excise, or otherwise remove cancer cells. Furthermore, the effect of the ablation and cavitation can improve an anti-cancer immune response of patients. More particularly, the treatment can sensitize cancer cells to radiation therapy via tumor oxygenation and DNA repair inhibition. Finally, although the cancer cells are disrupted, the blood vessels can be spared to more safely remove the cancerous tissue from the patient.

[0162] In some embodiments of the present disclosure, thermal ablation by the ablation unit 902 may be first applied; and scraping of, or other interventional or surgical removal of, the treated tissue may be subsequently applied in order to remove the remaining cancer cells from the lumen of the blood vessel. The scraped treated tissue may be collected by the tissue collection unit.

[0163] As used in the description and claims, the singular form “a”, “an,” and “the” include both singular and plural references unless the context clearly dictates otherwise. For example, the term “unit” may include, and is contemplated to include, a plurality of units. At times, the claims and disclosure may include terms such as “a plurality,” “one or more,” or “at least one;” however, the absence of such terms is not intended to mean, and should not be interpreted to mean, that a plurality is not conceived.

[0164] The term “about” or “approximately,” when used before a numerical designation or range (e.g., to define a length or pressure), indicates approximations which may vary by ( + ) or ( - ) 5%, 1% or 0.1%. All numerical ranges provided herein are inclusive of the stated start and end numbers. The term “substantially” indicates mostly (i.e., greater than 50%) or essentially all of a device, substance, or composition.

[0165] As used herein, the term “comprising” or “comprises” is intended to mean that the devices, systems, and methods include the recited elements, and may additionally include any other elements. “Consisting essentially of’ shall mean that the devices, systems, and methods include the recited elements and exclude other elements of essential significance to the combination for the stated purpose. Thus, a system or method consisting essentially of the elements as defined herein would not exclude other materials, features, or steps that do notmaterially affect the basic and novel characteristic(s) of the claimed disclosure. “Consisting of’ shall mean that the devices, systems, and methods include the recited elements and exclude anything more than a trivial or inconsequential element or step. Embodiments defined by each of these transitional terms are within the scope of this disclosure.

[0166] The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. Other embodiments may be utilized and derived therefrom, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is in fact disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.

[0167] The following numbered clauses define further embodiments of the present disclosure.

[0168] 1. A catheter configured for insertion into one or more blood vessels proximate a pancreas to treat pancreatic cancer, the catheter comprising:

[0169] a disruption apparatus being configured to disrupt cancer cells of the pancreatic cancer from within the blood vessel; and

[0170] a fixation element fixing a position of the disruption apparatus within the blood vessel.

[0171] 2. A catheter configured for insertion into one or more blood vessels proximate a pancreas having pancreatic cancer, the catheter comprising:

[0172] a disruption apparatus configured to disrupt cancer cells of the pancreatic cancer.

[0173] 3. The catheter of clauses 1 or 2, wherein the disruption apparatus includes an ablation unit configured to emit ablation energy to ablate the cancer cells.

[0174] 4. The catheter of clause 3, wherein the ablation unit is an ablation transducer.

[0175] 5. The catheter of clause 4, wherein the ablation transducer comprises lead zirconate titanate.

[0176] 6. The catheter of clause 4, wherein the ablation transducer comprises a capacitive micromachined ultrasonic transducer.

[0177] 7. The catheter of clause 4, wherein the ablation transducer comprises a piezoelectric micromachined ultrasonic transducer.

[0178] 8. The catheter of clause 3, wherein the ablation unit includes one or more ablation electrodes.

[0179] 9. The catheter of any one of clauses 4-7, wherein the ablation transducer is configured to emit ultrasound energy simultaneously in more than 270 degrees arc to the blood vessel.

[0180] 10. The catheter of clause 9, wherein the ablation transducer is configured to emit the ultrasound energy simultaneously in a 360 degrees arc to the blood vessel.

[0181] 11. The catheter of any one of clauses 1-10, wherein the disruption apparatus is configured to disrupt cancer cells attached to, wrapped around, and / or spread along a length of the blood vessel.

[0182] 12. The catheter of clause 3, wherein the ablation energy includes unfocused acoustic energy.

[0183] 13. The catheter of clause 3, wherein the disruption apparatus further comprises a cavitation unit configured to emit cavitation energy to disrupt the cancer cells.

[0184] 14. The catheter of clause 13, wherein the cavitation unit is a cavitation transducer.

[0185] 15. The catheter of any one of clauses 13-14, wherein the cavitation unit includes one or more cavitation electrodes.

[0186] 16. The catheter of clause 15, wherein the one or more cavitation electrodes include a distal cavitation electrode distal to the ablation unit and a proximal cavitation electrode proximal to the ablation unit.

[0187] 17. The catheter of clause 16, wherein the distal cavitation electrode and the proximal cavitation electrode are separated from one another by at least 5 mm.

[0188] 18. The catheter of any one of clauses 13-17, wherein the ablation unit includes a telescoping transducer slidable over the one or more cavitation electrodes.

[0189] 19. The catheter of any one of clauses 13-18, wherein the cavitation energy includes focused acoustic energy.

[0190] 20. The catheter of clause 19, wherein the focused acoustic energy has a frequency in a range of 50 kHz to 200 kHz.

[0191] 21. The catheter of any one of clauses 13-20, wherein the ablation unit and the cavitation unit have respective active regions configured to output energy and a separation distance between the active regions is less than 5 mm.

[0192] 22. The catheter of any one of clauses 13-21, further comprising a flexible feature located between the ablation unit and the cavitation unit.

[0193] 23. The catheter of clause 22, wherein the ablation unit and the cavitation unit each are attached to a backing member, and wherein the flexible feature comprises a portion of the backing member with an opening that spirals around that portion of the backing member.

[0194] 24. The catheter of clause 23, wherein the flexible feature comprises a flexible boot between and connected to the ablation unit and the cavitation unit.

[0195] 25. The catheter of any one of clauses 1-24, further comprising an imaging unit configured to transmit an imaging signal to detect the cancer cells.

[0196] 26. The catheter of clause 25, wherein the imaging unit includes an imaging transducer.

[0197] 27. The catheter of clause 26, wherein the imaging transducer comprises a piezoelectric material.

[0198] 28. The catheter of any one of clauses 25-27, wherein the imaging signal has a frequency of 20 MHz.

[0199] 29. The catheter any one of clauses 25-28, wherein the imaging unit is a portion of an ablation unit of the disruption apparatus.

[0200] 30. The catheter of any one of clauses 1-29, wherein the fixation element comprises:

[0201] a balloon having an interior; and

[0202] a catheter shaft having a fluid channel, wherein the interior of the balloon is in fluid communication with the fluid channel.

[0203] 31. The catheter of clause 30, wherein the balloon is compliant and includes a balloon body having a balloon wall radially surrounding the disruption apparatus.

[0204] 32. The catheter of clause 31, wherein the compliant balloon is formed from polyether-based thermoplastic polyurethane having a Shore D durometer in a range of 50 to 60.

[0205] 33. The catheter of clause 32, wherein the poly ether-based thermoplastic polyurethane is Pellethane having a Shore D durometer of 55.

[0206] 34. The catheter of any one of clauses 30-33, wherein the balloon includes one or more perforations to deliver a therapeutic agent to the cancer cells.

[0207] 35. The catheter of any one of clauses 1-34, wherein the catheter further comprises a scraping unit configured to remove the cancer cells.

[0208] 36. The catheter of any one of clauses 1-35, wherein the catheter further comprises a collection unit configured to collect the cancer cells.

[0209] 37. A device configured to treat cancerous tissue from a blood vessel comprising:

[0210] a catheter shaft having a distal end, a proximal end, and an interior fluid passage; and

[0211] a disruption apparatus located in the interior, wherein the disruption apparatus is configured to disrupt cancer cells of the cancerous tissue, and wherein the disruption apparatus includes a plurality of transducers connected by a flexible feature configured to facilitate navigating the device through the blood vessel.

[0212] 38. The device of clause 37, wherein the plurality of transducers include an ultrasound transducer.

[0213] 39. The device of clause 37 or 38, wherein the disruption apparatus further comprises a cryoprobe.

[0214] 40. The device of any one of clauses 37-39, wherein the disruption apparatus is configured to operate in a focused mode.

[0215] 41. The device of any one of clauses 37-39, wherein the disruption apparatus is configured to operate in an unfocused mode.

[0216] 42. The device of any one of clauses 37-41 further comprising an imaging unit located in the interior.

[0217] 43. The device of clause 42, wherein the imaging unit includes an imaging transducer.

[0218] 44. The device of clause 43, wherein the imaging transducer includes one or more elements.

[0219] 45. The device of clause 44, wherein the one or more elements include a plurality of elements arranged in an array.

[0220] 46. The device of clause 45, wherein the array is a single cylindrical array.

[0221] 47. The device of clause 45, wherein the array is a multi-row cylindrical array.

[0222] 48. The device of any one of clauses 37-47, further comprising a balloon having an interior in fluid communication with the interior fluid passage, wherein the balloon is configured to receive a cooling fluid circulating through the interior via the interior fluid passage of the device when the disruption apparatus is activated.

[0223] 49. The device of any one of clauses 37-48, further comprising a scraping unit configured to scrape the disrupted cancer cells from the blood vessel.

[0224] 50. The device of any one of clauses 37-49, further comprising a collection unit positioned proximate to the disruption apparatus.

[0225] 51. A method of treating a patient with cancer, comprising:

[0226] delivering a device through a blood vessel of the patient to a position to cancerous tissue proximate a cancerous organ; and

[0227] disrupting the cancerous tissue.

[0228] 52. The method of clause 51, wherein disrupting the cancerous tissue includes ablating cancer cells.

[0229] 53. The method of clause 52, wherein disrupting the cancerous tissue includes charring the cancer cells.

[0230] 54. The method of any one of clauses 51-53, wherein ablating the cancer cells includes activating an ablation unit of a catheter to emit unfocused ultrasound energy.

[0231] 55. The method of any one of clauses 51-53, wherein ablating the cancer cells includes activating an ablation unit of a catheter to emit focused ultrasound energy.

[0232] 56. The method of any one of clauses 51-53, wherein ablating the cancer cells includes activating an ablation unit of a catheter to emit radio frequency energy.

[0233] 57. The method of any one of clauses 51-53, wherein ablating the cancer cells includes activating an ablation unit of a catheter to emit cold fluid.

[0234] 58. The method of any one of clauses 51-56, wherein ablating the cancer cells includes raising a temperature of the cancerous tissue to a temperature between 56°C to 100°C.

[0235] 59. The method of any one of clauses 51-58, wherein disrupting the cancerous tissue comprises collapsing the cancerous tissue using cavitation.

[0236] 60. The method of clause 59, wherein collapsing the cancerous tissue comprises collapsing membranous organelles within the cancerous tissue.

[0237] 61. The method of clause 59, wherein the cavitation breaks cancer cells of the cancerous tissue into smaller pieces and one or more of leaves a tumor antigen intact or exposes an immunogenic moiety within the tumor antigen to stimulate an antitumor immune system of the patient.

[0238] 62. The method of clause 61, further comprising capturing the smaller pieces that enter the bloodstream.

[0239] 63. The method of any one of clauses 51-62, wherein the blood vessel comprises one or more of a portal vein, a superior mesenteric vein, a superior mesenteric artery, a celiac artery, a celiac trunk, a splenic artery, or a hepatic artery.

[0240] 64. The method of any one of clauses 51-63, further comprising excising the cancerous tissue from the blood vessel.

[0241] 65. The method of any one of clauses 51-64, further comprising delivering chemotherapy to the blood vessel.

[0242] 66. The method of any one of clauses 51-65, further comprising scraping disrupted cancerous tissue from the blood vessel with a scraping unit.

[0243] 67. The method of clause 66, wherein the scraping unit is a scalpel.

[0244] 68. The method of clause 67, wherein the scalpel is a harmonic scalpel.

[0245] 69. The method of any one of clauses 66-68, wherein the scraping unit is located on the device.

[0246] 70. The method of any one of clauses 51-69, further comprising discarding disrupted cancerous tissue with a collection unit by moving the device through the blood vessel in a longitudinal direction.

[0247] 71. The method of clause 70, wherein the collection unit is positioned proximate to an ablation unit used to disrupt the cancerous tissue.

[0248] 72. The method of any one of clauses 51-71, further comprising imaging the blood vessel during the treatment.

[0249] 73. The method of clause 72, wherein imaging the blood vessel is done by an imaging unit located at a distal end of the device.

[0250] 74. The method of any one of clauses 51-73, further comprising delivering an anti- cancerous drug to the cancerous tissue.

[0251] 75. The method of clause 74, wherein the anti-cancerous drug includes an activin inhibitor.

[0252] 76. The method of clause 75, wherein the anti-cancerous drug includes pegvorhyaluronidase (PEGPH20).

[0253] 77. The method of any one of clauses 51-76, wherein disrupting the cancerous tissue includes triggering a specific cellular anti-cancer immune response.

[0254] 78. A method of treating a patient having pancreatic cancer, comprising:

[0255] intravascularly positioning a catheter within a blood vessel of the patient and adjacent to a cancer of the patient; and

[0256] ablating cancer cells of the cancer by delivering energy to the cancer via the catheter.

[0257] 79. The method of clause 78, wherein ablating the cancer cells includes charring the cancer cells to ease removal of the cancer cells from the blood vessel.

[0258] 80. The method of clause 78, wherein the catheter comprises a balloon having an interior, the balloon in proximity to a distal end of the catheter, and an ablation unit inside the balloon; wherein said ablation comprises actuating the ablation unit to emit energy; the method further comprising circulating cooling fluid through the interior of the balloon to inflate theballoon into contact with the walls of the blood vessel, and circulating cooling fluid through the interior of the balloon during the ablating to protect the walls of the blood vessel from heat generated during the ablating.

[0259] 81. The method of clause 78, wherein the cancer cells are located in the walls of the blood vessel; wherein the catheter comprises a balloon having an interior, the balloon in proximity to a distal end of the catheter, and an ablation unit inside the balloon; wherein the ablating comprises actuating the ablation unit to emit energy; the method further comprising circulating cooling fluid through the interior of the balloon to inflate the balloon an amount that does not bring the balloon into contact with the walls of the blood vessel, and circulating cooling fluid through the interior of the balloon during the ablating.

[0260] 82. The method of clause 78, wherein the cancer cells are located in the walls of the blood vessel; wherein the catheter comprises an ablation unit in proximity to a distal end thereof; wherein the ablating comprises placing the ablation unit in the blood vessel in contact with blood flowing therethrough, and actuating the ablation unit to emit energy.

[0261] 83. The method of clause 78, wherein the cancer cells are located in the walls of the blood vessel; wherein the catheter comprises a balloon having an interior, the balloon in proximity to a distal end of the catheter, and an ablation unit proximal to and outside of the balloon; the method further comprising circulating through the interior of the balloon to inflate the balloon into contact with the walls of the blood vessel to occlude the blood vessel before the ablating; and wherein the ablating comprises actuating the ablation unit to emit energy.

[0262] 84. A method for treating cancer, comprising:

[0263] delivering a balloon delivery catheter to treatment sites in a plurality of blood vessels adjacent to a pancreas;

[0264] inflating the balloon delivery catheter at each of the treatment sites;

[0265] delivering energy at each of the treatment sites, wherein an amount of the delivered energy is effective to disrupt cancer cells adjacent to the treatment sites;

[0266] deflating the balloon delivery catheter at each of the treatment sites; and

[0267] withdrawing the balloon delivery catheter from the body lumen.

[0268] 85. The method of clause 84, wherein the delivered heat or energy is effective to ablate the cancer cells.

[0269] 86. The method of clause 84, wherein the delivered heat or energy is effective to collapse the cancer cells.

[0270] 87. The method of clause 84, wherein the method comprises infusing a formulation from the inflated balloon delivery catheter to the vessel wall adjacent to nerves or nerve endings at each of the treatment sites.

[0271] 88. The method of clause 84, wherein the energy is acoustic energy.

[0272] 89. The method of clause 84, wherein the energy is RF energy.

[0273] 90. The method of clause 84, wherein the energy is microwave energy.

[0274] 91. The method of clause 84, wherein the energy is heat energy.

[0275] 92. A treatment system comprising a catheter of any of clauses 1-36, and a reservoir containing a therapeutic agent for use in a method of treating cancer in a patient, wherein the catheter delivers the therapeutic agent to the cancerous tissue, such as one or more selected from anticancer agents, therapeutic antibodies, immunotherapeutic agents, nucleic acid molecules, radioisotopes, thymidylate synthase inhibitors, vinca alkaloid agents, cisplatin or other platinum agents and other therapeutic agents described herein.

[0276] 93. The system for use according to clause 92, wherein microbubbles are used to enhance local delivery of therapeutic agents.

[0277] 94. The system for use according to clause 92 or 93, wherein the method of treating cancer in a patient includes the method as defined in any of clauses 50-82 or as defined in any combination of clauses 50-82.

[0278] 95. The system for use according to any of clauses 92-94, wherein the cancer is pancreatic cancer.

[0279] 96. The system for use according to any of clauses 92-94, wherein the therapeutic agent is contained in the reservoir in dissolved form in a treatment solution, wherein treatment solution is delivered to the cancerous tissue.

[0280] 97. A catheter system comprising: the catheter of any one of clauses 1 to 36, wherein the catheter has a guidewire lumen; and a guidewire configured to be accommodated in the guidewire lumen of the catheter.

[0281] 98. A method for treating cancer, comprising:

[0282] delivering a balloon delivery catheter to treatment sites in a plurality of blood vessels adjacent to a pancreas, wherein at least one of the treatment sites is a cancer treatment site and at least one of the treatment sites is a pain treatment site;

[0283] inflating the balloon delivery catheter at each of the treatment sites;

[0284] delivering energy at each of the cancer treatment sites, wherein an amount of the delivered energy is effective to disrupt cancer cells adjacent to each cancer treatment site, anddelivering energy at each of the pain treatment sites, wherein an amount of the delivered energy is effective to ablate at least one nerve adjacent to each pain treatment site;

[0285] deflating the balloon delivery catheter at each of the treatment sites; and

[0286] withdrawing the balloon delivery catheter from the body lumen.

Claims

CLAIMSWhat is claimed is:

1. A catheter configured for insertion into one or more blood vessels proximate a pancreas to treat pancreatic cancer, the catheter comprising: a disruption apparatus being configured to disrupt cancer cells of the pancreatic cancer from within the blood vessel; and a fixation element fixing a position of the disruption apparatus within the blood vessel.

2. A catheter configured for insertion into one or more blood vessels proximate a pancreas having pancreatic cancer, the catheter comprising: a disruption apparatus configured to disrupt cancer cells of the pancreatic cancer.

3. The catheter of claims 1 or 2, wherein the disruption apparatus includes an ablation unit configured to emit ablation energy to ablate the cancer cells.

4. The catheter of claim 3, wherein the ablation unit is an ablation transducer.

5. The catheter of claim 4, wherein the ablation transducer comprises lead zirconate titanate.

6. The catheter of claim 4, wherein the ablation transducer comprises a capacitive micromachined ultrasonic transducer.

7. The catheter of claim 4, wherein the ablation transducer comprises a piezoelectric micromachined ultrasonic transducer.

8. The catheter of claim 3, wherein the ablation unit includes one or more ablation electrodes.

9. The catheter of any one of claims 4-7, wherein the ablation transducer is configured to emit ultrasound energy simultaneously in more than 270 degrees arc to the blood vessel.

10. The catheter of claim 9, wherein the ablation transducer is configured to emit the ultrasound energy simultaneously in a 360 degrees arc to the blood vessel.

11. The catheter of any one of claims 1-10, wherein the disruption apparatus is configured to disrupt cancer cells attached to, wrapped around, and / or spread along a length of the blood vessel.

12. The catheter of claim 3, wherein the ablation energy includes unfocused acoustic energy.

13. The catheter of claim 3, wherein the disruption apparatus further comprises a cavitation unit configured to emit cavitation energy to disrupt the cancer cells.

14. The catheter of claim 13, wherein the cavitation unit is a cavitation transducer.

15. The catheter of any one of claims 13-14, wherein the cavitation unit includes one or more cavitation electrodes.

16. The catheter of claim 15, wherein the one or more cavitation electrodes include a distal cavitation electrode distal to the ablation unit and a proximal cavitation electrode proximal to the ablation unit.

17. The catheter of claim 16, wherein the distal cavitation electrode and the proximal cavitation electrode are separated from one another by at least 5 mm.

18. The catheter of any one of claims 13-17, wherein the ablation unit includes a telescoping transducer slidable over the one or more cavitation electrodes.

19. The catheter of any one of claims 13-18, wherein the cavitation energy includes focused acoustic energy.

20. The catheter of claim 19, wherein the focused acoustic energy has a frequency in a range of 50 kHz to 200 kHz.

21. The catheter of any one of claims 13-20, wherein the ablation unit and the cavitation unit have respective active regions configured to output energy and a separation distance between the active regions is less than 5 mm.

22. The catheter of any one of claims 13-21, further comprising a flexible feature located between the ablation unit and the cavitation unit.

23. The catheter of claim 22, wherein the ablation unit and the cavitation unit each are attached to a backing member, and wherein the flexible feature comprises a portion of the backing member with an opening that spirals around that portion of the backing member.

24. The catheter of claim 23, wherein the flexible feature comprises a flexible boot between and connected to the ablation unit and the cavitation unit.

25. The catheter of any one of claims 1-24, further comprising an imaging unit configured to transmit an imaging signal to detect the cancer cells.

26. The catheter of claim 25, wherein the imaging unit includes an imaging transducer.

27. The catheter of claim 26, wherein the imaging transducer comprises a piezoelectric material.

28. The catheter of any one of claims 25-27, wherein the imaging signal has a frequency of 20 MHz.

29. The catheter any one of claims 25-28, wherein the imaging unit is a portion of an ablation unit of the disruption apparatus.

30. The catheter of any one of claims 1-29, wherein the fixation element comprises: a balloon having an interior; and a catheter shaft having a fluid channel, wherein the interior of the balloon is in fluid communication with the fluid channel.

31. The catheter of claim 30, wherein the balloon is compliant and includes a balloon body having a balloon wall radially surrounding the disruption apparatus.

32. The catheter of claim 31, wherein the compliant balloon is formed from polyether-based thermoplastic polyurethane having a Shore D durometer in a range of 50 to 60.

33. The catheter of claim 32, wherein the polyether-based thermoplastic polyurethane is Pellethane having a Shore D durometer of 55.

34. The catheter of any one of claims 30-33, wherein the balloon includes one or more perforations to deliver a therapeutic agent to the cancer cells.

35. The catheter of any one of claims 1-34, wherein the catheter further comprises a scraping unit configured to remove the cancer cells.

36. The catheter of any one of claims 1-35, wherein the catheter further comprises a collection unit configured to collect the cancer cells.

37. A device configured to treat cancerous tissue from a blood vessel comprising: a catheter shaft having a distal end, a proximal end, and an interior fluid passage; and a disruption apparatus located in the interior, wherein the disruption apparatus is configured to disrupt cancer cells of the cancerous tissue, and wherein the disruption apparatus includes a plurality of transducers connected by a flexible feature configured to facilitate navigating the device through the blood vessel.

38. The device of claim 37, wherein the plurality of transducers include an ultrasound transducer.

39. The device of claim 37 or 38, wherein the disruption apparatus further comprises a cryoprobe.

40. The device of any one of claims 37-39, wherein the disruption apparatus is configured to operate in a focused mode.

41. The device of any one of claims 37-39, wherein the disruption apparatus is configured to operate in an unfocused mode.

42. The device of any one of claims 37-41, further comprising an imaging unit located in the interior.

43. The device of claim 42, wherein the imaging unit includes an imaging transducer.

44. The device of claim 43, wherein the imaging transducer includes one or more elements.

45. The device of claim 44, wherein the one or more elements include a plurality of elements arranged in an array.

46. The device of claim 45, wherein the array is a single cylindrical array.

47. The device of claim 45, wherein the array is a multi-row cylindrical array.

48. The device of claim any one of claims 37-47, further comprising a balloon having an interior in fluid communication with the interior fluid passage, wherein the balloon is configured to receive a cooling fluid circulating through the interior via the interior fluid passage of the device when the disruption apparatus is activated.

49. The device of any one of claim 37-48, further comprising a scraping unit configured to scrape the disrupted cancer cells from the blood vessel.

50. The device of any one of claim 37-49, further comprising a collection unit positioned proximate to the disruption apparatus.

51. A method of treating a patient with cancer, comprising: delivering a device through a blood vessel of the patient to a position to cancerous tissue proximate a cancerous organ; and disrupting the cancerous tissue.

52. The method of claim 51, wherein disrupting the cancerous tissue includes ablating cancer cells.

53. The method of claim 52, wherein disrupting the cancerous tissue includes charring the cancer cells.

54. The method of any one of claims 51-53, wherein ablating the cancer cells includes activating an ablation unit of a catheter to emit unfocused ultrasound energy.

55. The method of any one of claims 51-53, wherein ablating the cancer cells includes activating an ablation unit of a catheter to emit focused ultrasound energy.

56. The method of any one of claims 51-53, wherein ablating the cancer cells includes activating an ablation unit of a catheter to emit radio frequency energy.

57. The method of any one of claims 51-53, wherein ablating the cancer cells includes activating an ablation unit of a catheter to emit cold fluid.

58. The method of any one of claims 51-56, wherein ablating the cancer cells includes raising a temperature of the cancerous tissue to a temperature between 56°C to 100°C.

59. The method of any one of claims 51-58, wherein disrupting the cancerous tissue comprises collapsing the cancerous tissue using cavitation.

60. The method of claim 59, wherein collapsing the cancerous tissue comprises collapsing membranous organelles within the cancerous tissue.

61. The method of claim 59, wherein the cavitation breaks cancer cells of the cancerous tissue into smaller pieces and one or more of leaves a tumor antigen intact or exposes an immunogenic moiety within the tumor antigen to stimulate an antitumor immune system of the patient.

62. The method of claim 61, further comprising capturing the smaller pieces that enter the bloodstream.

63. The method of any one of claims 51-62, wherein the blood vessel comprises one or more of a portal vein, a superior mesenteric vein, a superior mesenteric artery, a celiac artery, a celiac trunk, a splenic artery, or a hepatic artery.

64. The method of any one of claims 51-63, further comprising excising the cancerous tissue from the blood vessel.

65. The method of any one of claims 51-64, further comprising delivering chemotherapy to the blood vessel.

66. The method of any one of claims 51-65, further comprising scraping disrupted cancerous tissue from the blood vessel with a scraping unit.

67. The method of claim 66, wherein the scraping unit is a scalpel.

68. The method of claim 67, wherein the scalpel is a harmonic scalpel.

69. The method of any one of claims 66-68, wherein the scraping unit is located on the device.

70. The method of any one of claims 51-69 further comprising discarding disrupted cancerous tissue with a collection unit by moving the device through the blood vessel in a longitudinal direction.

71. The method of claim 70, wherein the collection unit is positioned proximate to an ablation unit used to disrupt the cancerous tissue.

72. The method of any one of claims 51-71, further comprising imaging the blood vessel during the treatment.

73. The method of claim 72, wherein imaging the blood vessel is done by an imaging unit located at a distal end of the device.

74. The method of any one of claims 51-73, further comprising delivering an anti-cancerous drug to the cancerous tissue.

75. The method of claim 74, wherein the anti-cancerous drug includes an activin inhibitor.

76. The method of claim 75, wherein the anti-cancerous drug includes pegvorhyaluronidase (PEGPH20).

77. The method of any one of claims 51-76, wherein disrupting the cancerous tissue includes triggering a specific cellular anti-cancer immune response.

78. A method of treating a patient having pancreatic cancer, comprising: intravascularly positioning a catheter within a blood vessel of the patient and adjacent to a cancer of the patient; and ablating cancer cells of the cancer by delivering energy to the cancer via the catheter.

79. The method of claim 78, wherein ablating the cancer cells includes charring the cancer cells to ease removal of the cancer cells from the blood vessel.

80. The method of claim 78, wherein the catheter comprises a balloon having an interior, the balloon in proximity to a distal end of the catheter, and an ablation unit inside the balloon; wherein said ablation comprises actuating the ablation unit to emit energy; the method further comprising circulating cooling fluid through the interior of the balloon to inflate the balloon into contact with the walls of the blood vessel, and circulating cooling fluid through the interior of the balloon during the ablating to protect the walls of the blood vessel from heat generated during the ablating.

81. The method of claim 78, wherein the cancer cells are located in the walls of the blood vessel; wherein the catheter comprises a balloon having an interior, the balloon in proximity to a distal end of the catheter, and an ablation unit inside the balloon; wherein the ablating comprises actuating the ablation unit to emit energy; the method further comprising circulating cooling fluid through the interior of the balloon to inflate the balloon an amount that does not bring the balloon into contact with the walls of the blood vessel, and circulating cooling fluid through the interior of the balloon during the ablating.

82. The method of claim 78, wherein the cancer cells are located in the walls of the blood vessel; wherein the catheter comprises an ablation unit in proximity to a distal end thereof; wherein the ablating comprises placing the ablation unit in the blood vessel in contact with blood flowing therethrough, and actuating the ablation unit to emit energy.

83. The method of claim 78, wherein the cancer cells are located in the walls of the blood vessel; wherein the catheter comprises a balloon having an interior, the balloon in proximity to a distal end of the catheter, and an ablation unit proximal to and outside of the balloon; the method further comprising circulating through the interior of the balloon to inflate the balloon into contact with the walls of the blood vessel to occlude the blood vessel before the ablating; and wherein the ablating comprises actuating the ablation unit to emit energy.

84. A method for treating cancer, comprising: delivering a balloon delivery catheter to treatment sites in a plurality of blood vessels adjacent to a pancreas; inflating the balloon delivery catheter at each of the treatment sites; delivering energy at each of the treatment sites, wherein an amount of the delivered energy is effective to disrupt cancer cells adjacent to the treatment sites; deflating the balloon delivery catheter at each of the treatment sites; and withdrawing the balloon delivery catheter from the body lumen.

85. The method of claim 84, wherein the delivered heat or energy is effective to ablate the cancer cells.

86. The method of claim 84, wherein the delivered heat or energy is effective to collapse the cancer cells.

87. The method of claim 84, wherein the method comprises infusing a formulation from the inflated balloon delivery catheter to the vessel wall adjacent to nerves or nerve endings at each of the treatment sites.

88. The method of claim 84, wherein the energy is acoustic energy.

89. The method of claim 84, wherein the energy is RF energy.

90. The method of claim 84, wherein the energy is microwave energy.

91. The method of claim 84, wherein the energy is heat energy.

92. A treatment system comprising a catheter of any of claims 1-36, preferably according to claim 33, and a reservoir containing a therapeutic agent for use in a method of treating cancer in a patient, wherein the catheter delivers the therapeutic agent to the cancerous tissue, such as one or more selected from anticancer agents, therapeutic antibodies, immunotherapeutic agents, nucleic acid molecules, radioisotopes, thymidylate synthase inhibitors, vinca alkaloid agents, cisplatin or other platinum agents and other therapeutic agents described herein.

93. The system for use according to claim 92, wherein microbubbles are used to enhance local delivery of therapeutic agents.

94. The system for use according to claim 92 or 93, wherein the method of treating cancer in a patient includes the method as defined in any of claims 50-82 or as defined in any combination of claims 50-82.

95. The system for use according to any of claims 92-94, wherein the cancer is pancreatic cancer.

96. The system for use according to any of claims 92-94, wherein the therapeutic agent is contained in the reservoir in dissolved form in a treatment solution, wherein treatment solution is delivered to the cancerous tissue.

97. A catheter system comprising: the catheter of any one of claims 1 to 36, wherein the catheter has a guidewire lumen; and a guidewire configured to be accommodated in the guidewire lumen of the catheter.

98. A method for treating cancer, comprising:delivering a balloon delivery catheter to treatment sites in a plurality of blood vessels adjacent to a pancreas, wherein at least one of the treatment sites is a cancer treatment site and at least one of the treatment sites is a pain treatment site; inflating the balloon delivery catheter at each of the treatment sites; delivering energy at each of the cancer treatment sites, wherein an amount of the delivered energy is effective to disrupt cancer cells adjacent to each cancer treatment site, and delivering energy at each of the pain treatment sites, wherein an amount of the delivered energy is effective to ablate at least one nerve adjacent to each pain treatment site; deflating the balloon delivery catheter at each of the treatment sites; and withdrawing the balloon delivery catheter from the body lumen.

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