COMPOSITIONS, DEVICES AND KITS FOR SELECTIVE INTERNAL RADIATION THERAPY

Abstract

Systems, kits and methods for preparing an injection system and/or treating target lesions with a selective internal radiation therapy which includes a double-barrel syringe loaded with a two-component tissue glue and radioisotope loaded microspheres. The microspheres are loaded into the syringe based on the size of the target location and are administered with a needle or dual-lumen catheter. Dosing regimens for treating breast cancer lesions or surgical beds up to 130 mm in diameter and hepatocellular carcinoma lesions up to 50 mm are included.

Claims

1-40. (canceled)

41. A method of preparing cancer therapy, comprising: determining an average tumor size of a cancer lesion; selecting a .sup.90Y syringe activity level and a .sup.90Y treatment activity level using the average tumor size, wherein the .sup.90Y treatment activity level is: a. 15 MBq to 20 MBq for the tumor size corresponding to a radius in the range of 20 mm to 24 mm; b. 20 MBq to 25 MBq for the tumor size corresponding to a radius in the range of 25 mm to 29 mm; c. 25 MBq to 35 MBq for the tumor size corresponding to a radius in the range of 30 mm to 34 mm; d. 40 MBq to 50 MBq for the tumor size corresponding to a radius in the range of 35 mm to 39 mm; e. 55 MBq to 65 MBq for the tumor size corresponding to a radius in the range of 40 mm to 44 mm; f. 75 MBq to 85 MBq for the tumor size corresponding to a radius in the range of 45 mm to 49 mm; g. 90 MBq to 100 MBq for the tumor size corresponding to a radius in the range of 50 mm to 54 mm; and loading a dual chamber syringe with the selected .sup.90Y syringe activity level, wherein the dual chamber syringe comprises a first chamber pre-loaded with bovine serum albumin and a second chamber pre-loaded with glutaraldehyde.

42. The method of claim 41, wherein the .sup.90Y syringe activity level is: a. 20 MBq for the tumor size corresponding to a radius in the range of 20 mm to 24 mm; b. 25 MBq for the tumor size corresponding to a radius in the range of 25 mm to 29 mm; c. 35 MBq for the tumor size corresponding to a radius in the range of 30 mm to 34 mm; d. 50 MBq for the tumor size corresponding to a radius in the range of 35 mm to 39 mm; e. 70 MBq for the tumor size corresponding to a radius in the range of 40 mm to 44 mm; f. 90 MBq for the tumor size corresponding to a radius in the range of 45 mm to 49 mm; and g. 110 MBq for the tumor size corresponding to a radius in the range of 50 mm to 54 mm.

43. The method of claim 41, further comprising: a. adjusting a concentration of a .sup.90Y source before withdrawing the selected .sup.90Y syringe activity level, wherein adjusting the concentration comprises: i. adding 5 mL of water to the .sup.90Y source; or ii. adjusting the concentration of the .sup.90Y source to 3 GBq/10 mL; and b. withdrawing the selected .sup.90Y syringe activity level from the .sup.90Y source.

44. The method of claim 41, further comprising determining a volume of the .sup.90Y syringe activity level for withdrawal based on .sup.90Y decay and the average tumor size.

45. The method of claim 41, wherein loading the dual chamber syringe comprises loading the .sup.90Y syringe activity level into the first and second chambers of the dual chamber syringe in a 1:4 ratio.

46. The method of claim 41, further comprising: placing the dual chamber syringe into a first radio-protective container before loading the dual chamber syringe with the selected .sup.90Y syringe activity level; placing a transfer syringe into a second radio-protective container; and using the transfer syringe to load the dual chamber syringe.

47. The method of claim 46, wherein the first and second radio-protective containers comprise PMMA cylinders.

48. The method of claim 41, further comprising: confirming a source activity level of a .sup.90Y source; withdrawing the .sup.90Y syringe activity level from the .sup.90Y source; and confirming the syringe activity level of the dual chamber syringe after loading the dual chamber syringe.

49. The method of claim 41, further comprising confirming a residual activity level of the dual chamber syringe after injecting the treatment site.

50. The method of claim 41, wherein the cancer lesion is a breast cancer lesion.

51. The method of claim 50, wherein the breast cancer lesion is ductal carcinoma in situ.

52. The method of claim 50, wherein the treatment site is a post-resection treatment site of the breast cancer lesion.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG. 1A is an exemplary component view of the stylet, introducer and catheter that may be used with exemplary procedures; FIG. 1B depicts the catheter and introducer of FIG. 1A wherein the catheter is inserted into the introducer and their hubs are locked together;

[0030] FIGS. 2A and 2B are anteroposterior and posteroanterior views of a syringe cylinder loaded with .sup.90Y microspheres in a BIOGLUE® carrier;

[0031] FIGS. 3A and 3B are PET/CT and CT scans, respectively, of a radiogel loaded in a plastic sphere;

[0032] FIGS. 4A to 4C depict the absorbed doses of 0.5 mL, 4.2 mL and 11.4 mL volumes, respectively, filled with a .sup.90Y-matrix composition;

[0033] FIG. 5 is a graphical plot of the percentage activity per distance from the center of the three cavities in FIGS. 4A to 4C;

[0034] FIG. 6 is a graphical plot of the estimated Grays per MBq per distance from the center of the three cavities in FIGS. 4A to 4C;

[0035] FIG. 7 is a graphical plot of the estimated total absorbed dose per distance from the center of the three cavities in FIGS. 4A to 4C;

[0036] FIG. 8A are transverse CT views of a mouse with a thigh tumor; FIG. 8B are composite transverse CT/PET/SPECT views of the mouse in FIG. 8A depicting tumor activity; FIG. 8C are the PET/SPECT image components from FIG. 8B; FIG. 8D are transverse CT views of another mouse with a thigh tumor; FIG. 8E are composite transverse CT/PET/SPECT views of the mouse in FIG. 8D depicting tumor activity; FIG. 8F are the PET/SPECT image components from FIG. 8E;

[0037] FIG. 9A is a schematic cross-sectional view of a dual-lumen catheter shaft with concentric lumens; FIG. 9B is a schematic cross-sectional view of a dual-lumen catheter shaft with eccentric lumens; FIG. 9C is a schematic cross-sectional view of a dual-lumen catheter shaft with an arcuate septum between the two lumens; FIG. 9D is a is a schematic cross-sectional view of a dual-lumen catheter shaft with a straight septum between the two lumens;

[0038] FIG. 10A is a photograph of another example of a dual-lumen catheter delivery kit; FIG. 10B is a close-up photograph of the proximal end of the catheter and the combined introducer and stylet; FIG. 10C is a longitudinal cross-sectional view of the proximal end of the catheter in FIGS. 10A and 10B; FIG. 10D is a longitudinal cross-sectional view of the proximal end of the introducer in FIGS. 10A and 10B;

[0039] FIGS. 11A and 11B are side and superior cross-sectional CT views of an explanted tumor, respectively; FIGS. 11C and 11D are composite side and superior cross-sectional CT/PET/SPECT views of the explanted tumor in FIGS. 11A and 11B, respectively; FIGS. 11E and 11F are the PET/SPECT image components from FIGS. 11C and 11D, respectively;

[0040] FIGS. 12A and 12B are side and superior cross-sectional CT views of another explanted tumor, respectively; FIGS. 12C and 12D are composite side and superior cross-sectional CT/PET/SPECT views of the explanted tumor in FIGS. 12A and 12B, respectively; FIGS. 12E and 12F are the PET/SPECT image components from FIGS. 12C and 12D, respectively;

[0041] FIGS. 13A and 13B are side and superior cross-sectional CT views of another explanted tumor, respectively; FIGS. 13C and 13D are composite side and superior cross-sectional CT/PET/SPECT views of the explanted tumor in FIGS. 13A and 13B, respectively; FIGS. 13E and 13F are the PET/SPECT image components from FIGS. 13C and 13D, respectively;

[0042] FIGS. 14A to 14C are 10× magnification histology slides with 20× magnificent insets at post-treatment 7, 14 and 21 days of a resection bed in an animal following intra-tumoral injection of a .sup.90Y-matrix, with arrows indicating the areas of necrosis; FIGS. 14D to 14F are 10× magnification histology slides with 20× magnificent insets at post-treatment 7, 14 and 21 days of a resection bed in an animal following intra-tumoral injection of .sup.90Y without any matrix; FIGS. 14G to 14I are 10× magnification histology slides post-treatment 7 and 14 days of a resection bed in an animal following intra-tumoral injection of matrix without any .sup.90Y; FIG. 14J is a graph of the percentage necrosis of each arm of the study at 1, 2 and 3 weeks;

[0043] FIG. 15 illustrates the Western Blot analyses of p53 and β-tubulin expression for the .sup.90Y matrix and .sup.90Y-only treatment groups;

[0044] FIG. 16 is a graph of the tumor volume at selected time-points for the .sup.90Y matrix, .sup.90Y-only and localizing carrier treatment groups;

[0045] FIGS. 17A and 17B depict the organ system biodistribution of .sup.90Y microspheres and .sup.90Y-matrix, respectively; FIGS. 17C and 17D depict the organ system biodistribution of .sup.90Y-only and .sup.90Y-matrix at 7 days, respectively, and FIGS. 17E and 17F depict the organ system biodistribution of .sup.90Y-only and .sup.90Y-matrix at 14 days, respectively;

[0046] FIG. 18 is a graph of the fraction of .sup.90Y absorbed dose into the tumor as a function of tumor size, with simulations performed for ρ=1.00 g cm.sup.3 (water density) and ρ=1.05 g/cm.sup.3 (liver density);

[0047] FIG. 19 is a graph of the .sup.90Y beta spectrum implemented in the model used in FIG. 18A;

[0048] FIG. 20 is a graph of the delivered energy per unit activity of .sup.90Y, k(r), calculated with MCNP4c as a function of the tumor diameter;

[0049] FIG. 21 is a graph of the residuals as a function of the tumor diameter;

[0050] FIG. 22 is a graph of the absorbed dose per unit administered activity (GBq), for ρ=1.05 g/cm.sup.3 (liver density), with an inset depicting the detail in the range from 0 cm to 1 cm lesion diameter;

[0051] FIG. 23 is a graph of the absorbed dose per unit administered activity for ρ=1.00 g cm.sup.3 (water density), with an inset depicting the detail in the range from 0 cm to 1 cm lesion diameter;

[0052] FIGS. 24A and 24B are graphs of the .sup.90Y biodistribution between the .sup.90Y matrix and .sup.90Y-only treatment groups at 1 and 3 weeks, respectively; and

[0053] FIGS. 25A and 25B are graphs depicting the .sup.90Y biodistribution between tumor and non-tumor locations of the .sup.90Y matrix and .sup.90Y-only treatment groups, respectively.

DETAILED DESCRIPTION

[0054] In one embodiment, a kit for performing direct injection radiotherapy is provided. The kit comprises a venting needle, a radio-shielded syringe, and an elongate needle of at least 50 mm to 100 mm in length. These components of the kit may be used to transfer radioisotope microparticles from their transport vessel to the matrix-containing syringe. The venting syringe may be inserted through the seal of the transport vessel to break or release any vacuum that may form in the transport vessel during the transfer process, and may be a 22 G, 25 G, 28 G, 30 G, 31 G or 32 G hypodermic needle. The venting needle may be optionally left in place during the remainder of the procedure, or removed immediately after insertion. The elongate needle is attached to the radio-shielded syringe at either the point-of-use or point-of-manufacture and is used to remove liquid media from the transport vessel.

[0055] In some variations, the kit may comprise an introducer, a dual-lumen catheter, and a needle. The kit may optionally further comprise a radio-shielded syringe, an elongate needle of at least 50 mm to 100 mm in length, and/or a venting needle as described above. In still other variations, the kit may further comprise a glue or matrix, and/or a radioisotope source, but in other examples, the glue/matrix and/or the radioisotope are sourced separately from the kit. In these variations, the kit may further comprise adapters configured to couple the kit components to a third party injector system selected by the user, or one or more of the kit components may be configured to couple to a third party glue/matrix syringe or injection system.

[0056] The .sup.90Y source may comprise a vial of radiotherapeutic microspheres. The vial may be a clear unshielded glass vial, that may be removably provided in a lead lined pot or other container. A vial containing 3 GBq of .sup.90Y in 5 mL of water or other suspension liquid are provided. The .sup.90Y is a pure, high energy (maximum energy 2.227 MeV, mean 0.93 MeV), β-emitter isotope. Its half-life is 64.1 hours; the maximum penetration in tissues is 11 mm with a mean of 2.5 mm. The vial may be provided in a lead pot or other shielded container. The vial or other packaging may contain calibration or validation data, and/or a code to access online regarding the same, so that the treating healthcare provider can compensate for any radioactive decay that has occurred since the initial manufacture and validation. In other examples, however, the amount of microsphere activity may be different, e.g. 100 MBq, 200, MBq, 300 MBq, 400 MBq, 500 MBq, 600 MBq, 700 MBq, 800 MBq, 900 MBq, 1 GBq, 2 GBq, 3 GBq, 4 GBq, 5 GBq, or a range of between any two of these activity levels, and the number of microspheres per vial may be different, e.g. 10 million, 20 million, 30 million, 40 million, 50 million, 60 million, 70 million, 80 million, 90 million, 100 million, or a range between any two of these microsphere counts. In one specific example, the .sup.90Y source may comprise 2.4 GBq particles in 3 mL of water.

[0057] In one particular embodiment, SIR-SPHERES® may be used for the source of the .sup.90Y or .sup.90Y particles. SIR-SPHERES® is a solution of biocompatible microspheres containing about 40 to about 80 million microspheres in 5 mL water. The microspheres comprise a non-biodegrading resin with diameters between 20 and 60 microns (μm), containing .sup.90Y, a pure, high energy (maximum energy 2.227 MeV, mean 0.93 MeV), β-emitter isotope. The half-life is 64.1 hours; the maximum penetration in tissues is 11 mm with a mean of 2.5 mm. SIR-SPHERES® microspheres are a permanent implant (e.g. the microspheres are not metabolized or excreted after implantation). 94% of total radiation is locally delivered in 11 days. SIR-SPHERES® microspheres are provided by the manufacturer in a shielded (6.4 mm of thickness) vial with water for the administration. Each vial contains approximatively 3 GBq of .sup.90Y in a final volume of 5 mL, or alternatively 2.4 GBq of .sup.90Y in a final volume of 3 mL, or in a range from 2-3 GBq in a final volume of 2-5 mL, or 2-3 mL; the number of microspheres ranges between 40-80×10.sup.6/vial, or 32-64×10.sup.6/vial. The SIR-SPHERES® vial should be stored at 15-25° C.

[0058] The potential adverse events associated with the use of SIR-SPHERES® include: [0059] fever [0060] transient decrease of hemoglobin [0061] mild to moderate abnormality of liver function tests (e.g. mild increase in ALT, AST, alkaline phosphatase, and/or bilirubin) [0062] abdominal pain [0063] nausea [0064] vomiting [0065] diarrhea

[0066] As described previously, the kit may further optionally comprise a glue or matrix source, but the glue or matrix source may also be separately sourced for use with the kit. In one particular example, BIOGLUE® may be used for the glue component of the .sup.90Y-glue matrix composition. BIOGLUE® is an admixture of bovine serum albumin (BSA; 45% weight/volume in sterile water for injection) and glutaraldehyde (10% weight/volume in sterile water for injection) in a 4:1 ratio. The bovine serum is purified by heat precipitation, chromatography, and gamma-irradiation to eradicate possible transmissible diseases. Glutaraldehyde exposure causes the lysine molecules of the bovine serum albumin, extracellular matrix proteins, and cell surfaces to bind to each other, creating a strong covalent bond. The reaction is spontaneous and independent of the coagulation status of the patient. The glue begins to polymerize within 20 to 30 seconds and reaches maximal strength in approximately 2 minutes, resulting in a solid implant. The degradation process takes approximately 2 years, and the implant is then replaced with fibrotic granulation tissue. The adhesive solutions (BSA and glutaraldehyde in a 4:1 ratio) are mixed in the applicator tip of the dual-chamber syringe where cross-linking begins. BIOGLUE® is not believed to be a true hemostatic agent because it does not accelerate the clotting process in blood. However, BIOGLUE® acts as a sealant after it completely hardens, by tamponating parenchymal tissue. It is commonly used as an adjunct to more standard methods for gaining hemostasis, such as suturing or use of topical hemostatic agents.

[0067] The potential adverse events associated with the use of BIOGLUE® include: [0068] non-adhesion of the product to tissue [0069] application of the adhesive to tissue extraneous to procedure [0070] inflammatory and immune reactions [0071] allergic reaction [0072] tissue mineralization [0073] local tissue necrosis [0074] vessel obstruction [0075] bronchial or luminal obstruction [0076] thrombosis and/or thromboembolism [0077] pulmonary embolism [0078] injury or damage to normal vessels or tissue [0079] possible transmission of infectious agents from material of animal origin.

[0080] In other examples, alternate compositions with different concentrations of BSA and glutaraldehyde components may be provided at different concentrations and/or used with different ratios, e.g.: [0081] 1. 45% BSA and 40% glutaraldehyde components in a 1:1 ratio [0082] 2. 45% BSA and 20% glutaraldehyde components in a 2:1 ratio [0083] 3. 36% BSA and 8% glutaraldehyde components in a 4:1 ratio [0084] 4. 36% BSA and 12% glutaraldehyde components in a 3:1 ratio

[0085] In another example, TISSEEL® sealant (Baxter Healthcare; Deerfield, Ill.) may be used for the glue, matrix or carrier component of the .sup.90Y composition. TISSEEL is a two-component fibrin sealant that is manufactured from pooled human plasma. When the two components, the sealer protein and thrombin, are combined, the composition is similar to the final stage of the blood component cascade. The sealer protein is a sterile, non-pyrogenic, vapor heated and solvent/detergent treated preparation made from pooled human plasma. The sealer protein is provided either as a freeze-dried powder for reconstitution with a fibrinolysis inhibitor solution or as a finished frozen solution pre-filled into one side of a dual-chambered syringe. The active ingredient of the sealer protein is fibrinogen. The sealer protein solution contains a fibrinolysis inhibitor comprising synthetic protinin, that delays fibrinolysis. The aprotinin is manufactured by solid phase synthesis from materials completely of non-human/non-animal origin. The composition of the sealer protein solution has a total protein level of 96-125 mg/mL, fibrinogen 67-106 mg/mL, aprotinin 2250-3750 KIU/mL, and also human albumin, tri-sodium citrate, histidine, niacinamide, polysorbate 80 and water for injection. The thrombin component is a sterile, non-pyrogenic, vapor heated and solvent/detergent treated preparation made from pooled human plasma. Thrombin (human) is also provided either as a freeze-dried powder for reconstitution with calcium chloride solution or as a finished frozen solution pre-filled into one side of a dual-chambered syringe. The thrombin solution contains 400-625 units of thrombin/mL, 36-44 μmol/mL of calcium chloride, and also some human albumin, sodium chloride and water for injection. The two components of TISSEEL, the sealer protein and thrombin, can be provided in dual-chamber syringes with 2 mL, 4 mL, and 10 mL total volume, of equal chamber sizes, e.g. dual chambers of 1 mL, 2 mL and 5 mL per chamber, and are provided in a 1:1 ratio. In other examples, the concentrations of the sealer protein solution and the thrombin solution may be different such that a non-equal ratio of sealer protein solution and the thrombin solution is used.

[0086] Another dual solution sealant that may be used is BOLHEAL® (Chemo-Sero Therapeutic Institute; Kumamoto, JP), which comprises a first solution of 80 mg/mL human fibrinogen, 75 IU/mL of human plasma-derived coagulation factor (XIII) and 1000 KIE bovine aprotinin, and a second solution of 250 IU/mL of human thrombin and 5.9 ml/mL of calcium chloride, which are mixed at the point of use in a 1:1 ratio.

[0087] Another matrix that may be used in the .sup.90Y-matrix system is SURGIFLO® (Ethicon, Inc; Somerville, N.J.), which comprises a first component of 8 mL of flowable sterile gelatin and a second component of 2000 IU of lyophilized human thrombin powder that is reconstituted using 2 ml of sterile water for injection.

[0088] In still another example, a multi-component polyethylene glycol sealant, such as COSEAL® surgical sealant (Baxter Healthcare; Deerfield, Ill.), may be used. The COSEAL® may comprise a pre-filled applicator or syringe components, with two liquid storage compartments and one dry powder compartment. One solution is a dilute HCl solution and the other is a sodium phosphate/sodium carbonate solution. The dry powder syringe contains a 4-arm polyethylene glycol polymer of 10 kDa molecular weight, where the arms are capped with thiol groups, and pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate. The two solutions are provided in equal size syringes. The dry powder is first reconstituted with the buffer liquid solution by forceful transfer back and forth at least 20 times between the dry powder and the buffer solution until the dry powder appears to be dissolved.

[0089] In other examples, the glue component may comprise a single component glue, sealant or matrix, e.g. a cyanoacrylate, alginate, polyvinyl alcohols, sodium polyacrylate, agarose, methylcellulose, carboxymethylcellulose, hyaluronic acid, etc.

[0090] During the procedure, one or more of the following may be recommended: [0091] Maintain the position of surgical gloves, sterile gauze swab/towels and other surgical instruments separate from the matrix to minimize the potential and inadvertent adhesion of the matrix to these surfaces [0092] The syringes, applicators and tip-applicator extensions are to be used exclusively for a single patient. Do not re-sterilize. [0093] Do not use if the packaging is open or damaged. [0094] Be careful not to accidentally spill the contents of the syringe [0095] Do not press the syringe plunger while connecting to the syringe. [0096] Avoid contact of fabrics with material expelled from the applicator during priming.

[0097] The matrix component of .sup.90Y-matrix composition can polymerize quickly. Priming must take place quickly and it should be followed immediately by application of the compound. A pause between priming and application can cause polymerization in the tip-applicator. It is recommended: [0098] Do not use blood collection devices while aspirating excess .sup.90Y-matrix composition from the surgical field [0099] Do not apply matrix in an excessively wet surgical field. This may cause poor grip. [0100] Do not detach or peel the .sup.90Y-matrix composition from a point or surface where it has come into contact inadvertently, as this may cause damage to the fabric. [0101] Do not implant .sup.90Y-matrix composition in closed anatomical sites that are in the immediate vicinity of nerve structures. [0102] Use caution when using the .sup.90Y-matrix composition in pregnant or lactating women. There are currently no efficacy or safety studies concerning .sup.90Y-matrix composition use in pregnant or lactating women. [0103] Due to the radioactivity of this device and the significant consequences of incorrect product placement, physicians should not implant this product without proper training on the handling and implant technique. [0104] All persons who handle, dispense and implant this device must know and comply with all local and state regulatory requirements governing therapeutic radioactive materials. The accepted radiation protection techniques should be used to protect personnel when handling both the isotope and the patient. [0105] Some patients may experience gastric problems after treatment with .sup.90Y-matrix composition, but H-2 blocking agents can be used the day before the implant and continued, if necessary, to reduce gastric complications. [0106] The radioisotope component of the .sup.90Y-matrix composition showed a slight potential for sensitization when tested on skin in an animal model. [0107] Do not use the .sup.90Y-matrix composition if personnel are not adequately protected (i.e., wear gloves, mask, protective clothing and safety glasses). Unpolymerized glutaraldehyde can cause irritation to eyes, nose, throat or skin, as well as breathing difficulties and local tissue necrosis. Prolonged exposure to unpolymerized glutaraldehyde, which is a component of BIOGLUE®, can cause heart or central nervous system disorders. In the event of contact, immediately rinse the affected areas with plenty of water and seek medical attention. [0108] Do not use the .sup.90Y-matrix composition in the presence of infections and use cautiously in contaminated areas of the body. [0109] Exercise caution in repeatedly exposing the same patient to multiple applications of the .sup.90Y-matrix composition. Reactions due to hypersensitivity are possible during exposure to the matrix component. Sensitization phenomena have been observed in animals. [0110] Some of the .sup.90Y-matrix components contain a material of animal origin that may be able to transmit infectious agents.

[0111] Potential side effects of the procedures described herein may include: [0112] failure of the product to adhere to the tissue or treatment side, [0113] application of the adhesive to a tissue not subject to the procedure, [0114] inflammatory and immune reaction [0115] allergic reaction [0116] tissue mineralization [0117] necrosis of local tissue [0118] obstruction of the vessels [0119] bronchial or luminal obstruction [0120] thrombosis or thrombo-embolism [0121] pulmonary embolism [0122] damage to normal vessels or tissues [0123] possible transmission of infectious agents from the material of animal origin. [0124] fever [0125] temporary reduction of hemoglobin [0126] altered biochemical tests (mild to moderate) concerning the liver (e.g. ALT, AST, alkaline phosphatase, bilirubin) [0127] abdominal pain [0128] nausea [0129] vomiting [0130] diarrhea

[0131] In some variations, the devices, kits and methods described herein may be used to treat one or more target locations following surgical resection or ablation, in order to treat any residual tumor cells, but in other variations, the target locations may be treated prior to resection, e.g. to attempt to downgrade the cancer stage in order to convert an unresectable tumor to a resectable tumor. In still other variations, the target locations may be treated without any plans to perform a surgical or ablative procedure. In some variations, the therapy may be used to treat non-cancerous disease or symptoms, e.g. intra-articular injection to treat synovitis, intradermal injection to treat keloids and hypertrophic scars, intravascular injection for hemangioma, etc.

[0132] In one exemplary embodiment, a method for treatment of a small tumor utilizes a mixing injector configured to be connected to a supply injector of glue and to a supply of radiotherapeutic particles. The vial is removed from its packaging and, without shaking or otherwise reconstituting the suspension of the microspheres in the water, a predetermined amount of non-agitated or non-microsphere containing suspension liquid is first removed, e.g. 0.5 mL, 1 mL, 1.5 mL, 2 mL, or 2.5 mL, or 10%, 20%, 30%, 40% or 50%. In other variations, the amount of liquid removed can vary, but results in a suspension liquid that has an activity to volume ratio that is 0.5 GBq, 0.8 GBq, 1.0 GBq, 1.2 GBq, or 1.5 GBq per 1 mL, for example, or in a range between any two of these ratios. After removal of some of the suspension liquid, the vial is reconstituted via shaking or other agitation. Based on the remaining concentration of the radiotherapeutic, e.g. 3 GBq in 4 ml suspension liquid, the desired amount of activity is withdrawn, based on the volume, into the radiotherapy transfer syringe. In some examples, the radiotherapy transfer syringe is the same syringe used to remove the predetermined volume of non-agitated or non-microsphere suspension liquid, but in other examples, a different syringe is used for non-agitated or non-microsphere suspension liquid removal.

[0133] The matrix syringe is then uncapped. In some examples, a predetermined volume of glue from the glue source syringe may be dispensed, based on the calculated volume of microspheres/suspension liquid, in order to accommodate the volume of microsphere solution that is needed to deliver the desired activity level of microspheres. In some variations, additional volume may be provided in the syringe by pulling back the plunger mechanism. In other variations, no volume adjustment to the matrix syringe is needed before adding the isotope solution, because of existing air gaps provided in the matrix syringe are sufficient to hold the amount of radioisotope to be transferred.

[0134] In some variations comprising a two-component matrix, the radiotherapeutic-matrix composition is delivered using a mixing tip that may mix the two components within 1, 2 or 3 cm of the distal ends of the chambers containing the components. The distal end of the mixing tip may comprise multiple distal openings that may comprise a generally linear configuration across a transverse dimension of the mixing tip, in order to increase the single-pass coverage area of the mixing tip. For the example, the mixing tip may comprise 2, 3, 4, 5, 6, 7 or 8 distal openings that are aligned along a transverse dimension that is at least 1, 1.5, 2, 2.5 or 3 cm wide.

[0135] In other variations, the delivery kit may comprise dual-lumen tubing, dual-lumen needle or a dual-lumen catheter so that the mixing or polymerization of the two components occurs more distally, in order to avoid polymerization of the components within a single-lumen tubing or catheter, which may result in clogging before the matrix reaches the target location. These delivery components may be preferred when the distance from the skin surface to the target surface is more than 2, 3, 4 or 5 cm from the ends of the chambers containing the matrix components.

[0136] In one example, the delivery kit may include a dual-lumen injection needle or introducer needle. The needle may be a needle measuring 11 G, 12 G, 13 G, 14 G, 15 G, or 16 G, and comprise a shaft length in the range of 100 mm to 200 mm, 120 mm to 150 mm, or 140 mm to 170 mm, for example. The needle may be made from AISI 302, 304, or 306L stainless steel, and attached to a proximal female Luer lock hub. The needle may also include a stylet configured for insertion through the lumen of the needle, the stylet comprising a solid core with or without a pointed or piercing distal tip that extends out of the distal end of the needle. The needle may be used with a coaxial double-lumen catheter with a diameter of 12 G, 13 G, 14 G, 15 G, 16 G, 17 G or 18 G, and comprise a shaft length in the range of 100 mm to 300 mm, 150 mm to 250 mm, or 170 mm to 200 mm, for example. The catheter may also comprise a proximal Luer lock hub. The hub of the catheter may also be configured to lock with the proximal Luer lock hub of the introducer needle, e.g. via a male Luer lock structure that can lock to the introducer needle hub when the catheter is inserted through the needle hub and needle shaft, or a deformable or biased clamp structure that reversibly attaches to the exterior surface of the introducer needle hub, for example. The needle and catheter diameters may be selected such that the catheter is configured to be removably inserted through the introducer needle without significant leakage of bodily fluid between the outer wall of the catheter and the inner lumen wall of the introducer needle, e.g. the catheter may be at least 1 G or 2 G smaller in size than the introducer needle.

[0137] In one specific example, the kit 10 from SVAS Biosana, depicted in FIG. 1A, may be used, which includes a 15 G×150 mm coaxial introducer needle 12 and a 16 G×120 mm coaxial catheter 14, configured to work with each other. The proximal end of the introducer comprises a male Luer lock hub 16, such that the distal end 18 of the catheter hub 20 comprises a female Luer lock hub that can engage the male Luer lock hub 16 when the catheter 14 is inserted into the introducer 12. The proximal end 22 of the catheter hub 20 further comprises a connector configured to attach to a matrix syringe or matrix injection system. This may be, for example, a proprietary complementary female connector interface to a BIOGLUE® injection syringe, or a female Luer lock hub. The kit 10 may also comprise a stylet 24 that is reliably lockable and insertable into the introducer 12, and is used during insertion and positioning of the introducer 12 to the target location. The stylet 24 may include a solid proximal end 26 that comprises a releasable clamp mechanism to attach to the proximal hub of the introducer 12, or may comprise a female Luer lock in other examples. FIG. 1B depicts the catheter 14 inserted into the introducer 12, with the male Luer lock hub 16 engaged with the female Luer lock hub 18.

[0138] In one example, the vial or bottle with the radioisotope microspheres is retrieved from its radioprotective container, and optionally placed in a lead or acrylic open-top box, if available. The seal on the vial is cleaned with an alcohol swab, and then an air opening is formed in the seal by puncturing the seal with a needle. The needle, such as a 22 G, 25 G, 28 G, 30 G, 31 G or 32 G hypodermic needle is optionally left in place. A 5 mL syringe is then attached to a 20 G or 22 G needle with a length in the range of 50 mm to 150 mm, 50 mm to 120 mm, or 70 mm to 100 mm. The syringe and attached needle are then used to re-puncture the seal. Without agitating or mixing the settled microspheres at the bottom of the vial or bottle, the needle tip is positioned within the suspension liquid but above the settled microspheres, and 2 mL of suspension liquid is removed and discarded, preferably without significant removal of any microspheres. Using a dose calibrator, the activity remaining in the vial or bottle is checked or confirmed. Assuming that the vial or bottle contained 3 GBq in 5 mL of suspension liquid, the vial or bottle should now nominally contain 3 GBq in 3 mL of suspension liquid. In other variations, a different amount of suspension liquid may be removed, or additional suspension liquid, such as Water For Injection or isotonic sodium chloride solution, may be added to the vial or bottle to alter the concentration of the activity per volume.

[0139] The target activity level and volume to be injected into the target lesion is then determined or based on (a) the calibrated or nominal activity concentration in the vial, (b) the target activity level or absorbed dose to be delivered to or achieved in the target lesion(s) respectively, and (c) optionally accounting for the residual volume of material that may be in the syringe injection system after a full or maximum injection, e.g. residual volume in the syringe tip distal to the plunger or sliding seal of the syringe, and in the mixing tip or injection catheter or needle. The target-absorbed dose may be, for example, 18 Gy or 20 Gy to the surgical beds from resected breast lesions, and 150 Gy for hepatic lesions. The syringe and attached needle is then reinserted into the vial or bottle and is used to agitate and suspend the settled microspheres in the suspension liquid by moving the plunger of the syringe back and forth several times, e.g. 10 to 20 times, and/or until sufficient mixing is visually confirmed by the homogenous appearance of the suspension liquid and without any visibly settled microspheres. The target activity volume is then removed using the syringe. The syringe cap of the glue/matrix syringe is then removed, and the target activity volume of the suspension liquid with microspheres is then distributed between the two chambers of the glue/matrix syringe in a 4:1 ratio to the BSA:glutaraldehyde chambers, or in a ratio corresponding to their cross-sectional areas or volumes of the matrix component chambers. For other syringe/injection systems, for example, where there is a 1:1, 1.5:1 or 2:1 volume or cross-sectional area ratio between the two chambers, the target volume will be distributed in a 1:1, 1.5:1 and 2:1 ratio. For a three-chamber delivery system, e.g. a 1:1:1 or 4:1:1 or 4:2:1 ratio injection system, the target volume would be distributed by the same ratio to the three chambers, respectively.

[0140] After distributing or loading the target activity volume into the matrix syringe, the syringe cap is placed back on the matrix syringe. A commercially available dose calibrator commonly used in a radio-pharmacy may be used to confirm the expected activity in the syringe, and correct it, if needed. The loaded matrix syringe is then placed back in its radioprotective container for storage or transport to the operating room or procedure facility.

[0141] At the operating room or procedure facility, the patient is prepped and draped in the usual sterile fashion, and anesthesia is achieved. The target lesion, e.g. hepatic lesion, is identified using an imaging modality such as ultrasound or fluoroscopy or based on prior imaging, the imaging performed with or without the use of any contrast agent. A stylet is inserted into the introducer needle, and is then percutaneously inserted into the target lesion, preferably with ultrasound or CT guidance. The pre-filled syringe previously loaded with the radiotherapeutic particles is removed from its radioprotective container and the syringe cap is removed by holding the syringe upright and rotating the cap from side to side. The bilateral cap of the coaxial catheter is then aligned with the two openings of the dual-chamber syringe. Indicia on the catheter may be provided to facilitate the alignment with the syringe. The catheter may then be locked onto the syringe using a locking collar or other locking mechanism, such as to resist inadvertent separation of the syringe and catheter.

[0142] Upon optionally reconfirming the position of the introducer/catheter combination, the plunger or actuator of the syringe/delivery system is actuated to dispense the mixture. In some examples, the syringe plunger or delivery system actuator may be actuated at a rate of approximately 0.5 mm to 1 mm per second, 0.5 mm to 2 mm per second, or 0.5 mm to 1.5 mm per second. Once delivery is completed, the introducer needle/catheter may be left in place for 30 to 60 seconds, or at least 5 seconds, 10 seconds, 15 seconds, 20 seconds or 30 seconds, and/or no more than 30 seconds, 45 seconds, 60 seconds, 90 seconds, or 120 seconds. This may ensure polymerization at the target location, after which the introducer needle/catheter may be removed from the target location, using an optional twisting motion to ensure adequate separation of the matrix from the introducer needle/catheter without seeding of the insertion tract or pulling of the target location due to incomplete separation of the injected matrix and the introducer needle/catheter. The introducer needle/catheter insertion site may then be checked for any fluid leakage and optionally stitched or sealed with non-radioactive bioglue or matrix, and then bandaged and dressed as needed. Any radioactive or biohazardous components are disposed as appropriate.

[0143] After the desired amount of the composition has been administered or delivered, the stylet is then removed from the inserted introducer while maintaining the position of the introducer. The syringe/catheter is then inserted through the introducer until the distal hub of the catheter locks with the proximal hub of the introducer.

[0144] In embodiments that do not require percutaneous access with a needle or catheter, in the procedure above a mixing tool tip may be attached to the mixture syringe instead of achieving access with the introducer followed by attachment of a needle and/or catheter. After attachment of the mixing tip, the syringe may be shaken to sufficiently mix the radioisotope suspension with the glue or matrix components. The syringe plunger or delivery system actuator may then be actuated at a rate of approximately 0.5 mm to 1 mm per second to apply the mixture to the surface of the surgical cavity. Once delivery is completed, the surgical cavity may be left exposed for 30 to 60 seconds to ensure polymerization at the target location. The surgical cavity may then be closed and dressed in the usual fashion. Any radioactive or biohazardous components are disposed as appropriate.

[0145] In other examples, the radioisotope microparticles may be premixed at the point of manufacture with one or both components of the matrix or glue of a prefilled syringe. For example, the .sup.90Y microspheres may be pre-mixed and loaded with the BSA and/or glutaraldehyde component of the prefilled syringe. In some variations, because of potentially different treatment concentrations that are necessary for particular lesion sizes or diseases, different sized syringes with different treatment concentrations may be provided. For example, 1 mL, 2 mL, 5 mL or 10 mL prefilled syringe injection systems may be provided but with different activities per mL pre-mixed with the BSA component but with no activity in the glutaraldehyde components. The syringes may comprise an activity concentration in the range of 5 MBq to 50 MBq per mL, 7 MBq to 45 MBq per mL, 7 MBq to 40 MBq per mL, 15 MBq to 40 MBq per mL, or 15 MBq to 30 MBq per mL. These concentrations may be used, for example, in the treatment of breast cancers. In other examples, the 1 or 2 mL syringes may comprise an activity concentration in the range of 0.1 MBq to 20 MBq per mL, or 0.2 MBq to 15 MBq per mL, and the 5 mL or 10 mL syringes may comprise an activity concentration in the range of 3 MBq to 30 MBq per mL, or 5 MBq to 25 MBq per mL. The concentrations of these syringes may be used with more radiosensitive tumors or where effects on the surrounding normal tissue need to be reduced, e.g. HCC. Specific examples of dose selection for hepatic and breast cancers are provided in certain examples later below.

Dosimetry

[0146] As noted previously, hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. It is an aggressive cancer typically occurring in the setting of cirrhosis. Unfortunately, it commonly presents in advanced stages, when patients have become symptomatic and have some degree of liver impairment. In the United States, a total of 30,640 new liver and intrahepatic bile duct cancers occurred in 2013, in addition to 21,670 deaths. HCC occurred more often in males than females (2.4:1), with a higher incidence in Eastern and Southern Asia, Middle and Western Africa, Melanesia, and Micronesia/Polynesia. Despite major advances in prevention techniques, new technologies and screening procedures (in both diagnosis and treatment), incidence and mortality are increasing, with cirrhosis being the most important risk factor for the development of HCC regardless of etiology. Today, multiple treatment modalities exist. However, only orthotopic liver transplantation or surgical resection may be regarded as curative. Other treatment modalities include transarterial chemoembolization, radioembolization, percutaneous ethanol injection, radiation therapy, and ablation therapies. In particular, percutaneous ablation is a promising approach to treating inoperable primary tumors or metastases in the liver. In fact, in the treatment of HCC, fewer than 40% of patients are candidates for surgery, and the possibility of recurrence after curative surgery is generally high. Against this backdrop, percutaneous techniques represent a successful therapeutic option and are widely used today for the treatment of metastatic and small primary tumors. Among these techniques, methods such as chemical ablation, cryoablation, high temperature ablation (e.g. radiofrequency, microwave, laser, and ultrasound) have gained wide acceptance for the treatment of liver tumors as they may serve as a bridge for transplant candidates, especially in relation to small primary lesions. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function.

[0147] Due to the lack of effective systemic therapies for HCC, researchers have been investigating the use of locoregional tumor control with .sup.90Y radioembolization since the 1960s. Today radioembolization (or Selective Internal Radio Therapy, SIRT, also known as Trans Arterial Radio Embolization, TARE) is an established and effective treatment for liver malignancies based on trans-arterial infusion of .sup.90Y-laden microspheres. Radiation dose distributions arising from intrahepatic arterial infusion of .sup.90Y microspheres have been investigated by a number of authors in the past. At present, there are two clinically available microsphere devices in which .sup.90Y is incorporated: one with microspheres made of glass (TheraSphere; MDS Nordion, Ottawa, Ontario, Canada) and the other with microspheres made of resin (SIR-Spheres; Sirtex Medical, Sydney, Australia). The resin microsphere device consists of biocompatible .sup.90Y-bearing microspheres with diameters of 20-40 μm. Once administered, the spheres remain in the liver as a permanent implant.

[0148] In the traditional catheter-based approach, radioembolization involves intra-arterial infusion of microspheres. However, in recent years a number of studies have addressed the problem of dosimetry in therapies based on the use of intratumoral administration of .sup.90Y-conjugates by percutaneous puncture. In recent years, this technique has been successfully applied to patients treated with .sup.90Y-labeled [DOTA.sup.0-D-Phe.sup.1-Tyr.sup.3] octreotide (.sup.90Y-DOTATOC) for malignant gliomas.

[0149] Furthermore, based on the clinical experience gained in liver radioembolization, percutaneous ablation ofHCC through the intratumoral injection of an appropriate activity of .sup.90Y has the potential to reduce drastically the chances of local recurrence. In this context, there is growing interest in the development of new intratumoral procedures for HCC throughout a localized administration of .sup.90Y in the form of microspheres mixed with biocompatible compounds.

[0150] As a rule, intratumoral administration of radionuclides raises questions about the dosimetry of small lesions as this approach allows sub-centimeters tumors to be selectively treated. To date, there is no simple way to assess exactly the absorbed dose to tumors and normal liver tissue when .sup.90Y is administered. This is because .sup.90Y only emits pure beta radiation with limited penetration range in tissue. Consequently, the delivered dose is highly dependent on the distribution of microspheres and the tumor mass. In particular, the current analytic formalism used to assess the absorbed dose to the liver and to the tumor masses inside the liver parenchyma is based on the assumption that all particles released from .sup.90Y within a given organ are fully absorbed by that organ. However, when the tumor size is small this assumption may no longer be true and the current analytic approach is likely to provide inaccurate dose results when used to assess the dose in small target regions.

[0151] Thus, the current analytic formalism used to assess the absorbed dose after the administration of .sup.90Y-microspheres may provide inaccurate results when used to calculate the dose in small target regions, as it is based on the assumption that all β-particle energy is fully absorbed by the treated mass. The present work assesses the absorbed dose in a scenario of intratumoral injection of .sup.90Y in lesions of varying size, and provides a dosing regimen that accounts for partially absorbed β-particle energy that is fully absorbed by the treated mass.

[0152] In one example, the absorbed dose in small lesions are assessed, assuming a selective delivery of .sup.90Y into the tumor (i.e. in a scenario of percutaneous ablation of HCC through the intratumoral injection of the radionuclide). A simplified model for tumor masses was implemented into MCNP4C Monte Carlo (MC) code with the aim to determine the absorbed dose to the lesion when the tumor mass is uniformly filled with .sup.90Y

[0153] In some variations, the absorbed dose-per-unit administered activity was assessed using Monte Carlo calculation in spheres of different size (diameter 0.5-20 cm). The spheres are representative of tumor regions and are intended to be uniformly filled with .sup.90Y. Monte Carlo results were compared with the well-established analytic approach.

[0154] The initial results indicate that the use of the current analytic model provides dose overestimations below 10% for lesions with a diameter larger than approximately 2 cm. However, for lesions with a diameter smaller than 2 cm, the analytic model is likely to deviate significantly (>10%) from Monte Carlo results, providing dose overestimations larger than 50% for lesions of 0.5 cm diameter. An alternative equation is provided for the calculation of the absorbed dose in small target regions.

[0155] .sup.90Y disintegrates by R emission mainly (99.983%) to the stable .sup.90Y ground state level. A weak beta branch occurs to the 1760 keV excited level that decays by an E0 gamma transition. This 0.sup.+-0.sup.+ transition is followed by the emission of two gammas, or an electron-positron pair, or internal conversion. The adopted half-life of .sup.90Y ground state is 64.041 hours or 2.6684 days.

[0156] Among the radionuclides used in clinical practice, .sup.90Y has attractive physical and radiobiologic features that make this radionuclide suitable for a loco-regional therapeutic option. The high-energy β-particles (maximum energy 2278.7 keV, average energy 926.7 keV) and their penetration depth (maximum particle range in tissue, 11 mm; range in tissue after which 50% of the energy particles is transferred, 4 mm) allows high radiation doses to be selectively delivered to the target area, while sparing surrounding tissues and normal organs. In particular, the penetration depth of the high-energy β-particles is a key element of this radionuclide's success in radioembolization, allowing for high-dose deposition into the tissues between embolized capillaries. In the traditional dose calculation formalism (after locoregional administration of .sup.90Y), two important simplifying assumptions are generally made: [0157] β radiation released from .sup.90Y within a given organ is fully absorbed by that organ. In most cases, this assumption is supported by the average 4 mm .sup.90Y β range in tissue. [0158] permanence of .sup.90Y in the area where they have been delivered (i.e. no migration of the radiopharmaceutical outside the tumor region).

[0159] Combining these two assumptions allows for easy calculation of average absorbed dose to an organ of interest on a macroscopic scale. The calculation, carried out using most up-to-date nuclear data for .sup.90Y, is illustrated below and it is generally referred to as the MIRD (Medical Internal Radiation Dose) approach:

[00002]$\begin{array}{cc}{E}_{\mathrm{avg}}={\int }_0^{\infty }E\phi \left(E\right)dE=926.7\mathrm{keV}=1.485.Math.{10}^{-13}J& \left(1\right)\end{array}$$\begin{array}{cc}{E}_{\mathrm{tot}}=A_0{E}_{\mathrm{avg}}{\int }_0^{\infty }{e}^{-\lambda t}dt=\frac{A_0}{\lambda }\left(1.487.Math.{10}^{-13}J\right)=A_0.Math.k& \left(2\right)\end{array}$

where E.sub.avg is the average energy released per decay of .sup.90Y based on the probability density function φ(E) for emission, λ is the .sup.90Y decay constant based on the half-life of 64.041 hours, and k a constant term. A.sub.0 is the activity present in the organ in GBq and E.sub.tot is the total energy released by A.sub.0 from the time that it is infused until it has fully decayed.

[0160] Assuming that all of the energy of the β-decay is absorbed in the volume where the decay occurs, the constant term, k, can be calculated taking the given physical values and their statistical uncertainties:

[00003]$\begin{array}{cc}k=\frac{1.487.Math.{10}^{-13}J}{\lambda }=\frac{1.487.Math.{10}^{-13}J.Math.230547s}{0.69315}.Math.\frac{\frac{{10}^9\mathrm{dis}}{s}}{GBq}=49.38\left(J/GBq\right)& \left(3\right)\end{array}$

[0161] The constant factor 49.38(J/GBq) is the energy released per unit activity of .sup.90Y. The adopted uncertainties on the nuclear data reported in the equation below lead to a relative standard uncertainty of 0.1% on the constant term, i.e. 49.38(5) (J/GBq), in line with recommendations from the American Association of Physicists in Medicine.

[0162] Finally, the absorbed dose D (expressed in Gy) can be obtained by dividing the delivered energy, E.sub.tot, by the mass of the target region m (expressed in kg):

[00004]$\begin{array}{cc}{D}_{\mathrm{avg}}\left(Gy\right)=\frac{A_0\left(GBq\right).Math.49.38\left(J/GBq\right)}{m\left(\mathrm{kg}\right)}& \left(4\right)\end{array}$

[0163] Of note, the same formula with a slightly different constant term, k, has been reported in other publications (e.g. 49.98, 49.67).

[0164] According to the partition model, the equation above can be used to calculate the absorbed dose in the tumor, once the fractional tumor uptake FU.sub.tumor (i.e. the fraction of the administered activity accumulated in the tumor) is known:

[00005]$\begin{array}{cc}{D}_{\mathrm{tumor}}\left(Gy\right)=\frac{A_0\left(GBq\right).Math.49.38\left(J/GBq\right).Math.F{U}_{\mathrm{tumor}}}{m\left(\mathrm{kg}\right)}& \left(5\right)\end{array}$

[0165] It must be reiterated that equations (4) and (5) above are only valid for .sup.90Y radioembolization and only representative of average absorbed dose in an organ or a large lesion, i.e. on a macroscopic scale. It is hypothesized herein that these equations may not hold for very small tumor masses, as the assumption that the energy emitted during decay is totally absorbed by the mass of interest m is no longer true. In particular, when the size of the lesion is very small (especially in the sub-centimeter region), the energy released per unit activity of .sup.90Y may decrease significantly. Therefore, hereafter the constant term k in equation (3) will be treated as a function of the lesion radius (r) and indicated as k(r).

[0166] In the present study, the absorbed dose-per-unit administered activity was assessed using Monte Carlo calculations in a simplified geometry. MC code MCNP4C has been used for this purpose. MCNP is a general-purpose, continuous-energy, generalized-geometry, time-dependent, coupled neutron/photon/electron Monte Carlo transport code. For photon transport, the code takes into account photoelectric absorption, with the possibility of K- and L-shell fluorescent emission or Auger electron, coherent and incoherent scattering and pair production. The photoelectric cross sections are based on Storm and Israel whereas the scattering cross sections are taken from ENDF tabulations. The continuous slowing down approximation energy loss model is used for electron transport.

[0167] Spherical lesions of different size (diameters in the range 0.5-20 cm) were simulated for two different densities: ρ=1.00 g/cm.sup.3 (water density) and ρ=1.05 g/cm.sup.3 (liver density). In both scenarios, spheres were assumed to be immersed in a semi-infinite medium with the same density of the sphere. The spheres are representative of tumor regions and are supposed to be uniformly filled with .sup.90Y, while the surrounding medium is assumed to contain no radioactivity.

[0168] Calculations were performed in coupled electron-photon mode [MODE P E] using the e103 electron interaction data library (ELIB=03E) and the mcnplip2 photon interaction data library (PLIB=02P). Simulations were carried out taking into account all the available advanced options, such as electron production by photons, Bremsstrahlung effect and knock-on electron production. MCNP simulations were run for an adequate time to get a statistical uncertainty on the absorbed dose below 0.01%.

[0169] FIG. 18 shows the fraction of .sup.90Y absorbed dose into the tumor as a function of the tumor size, obtained from MCNP simulations. The .sup.90Y beta spectrum implemented in the model is also reported in the FIG. 19. Calculations were performed both for water spheres (ρ=1.00 g/cm.sup.3) and for spheres made of liver tissue (ρ=1.05 g cm.sup.3). In both cases, when the lesion diameter drops below 2 cm, a greater amount of the β particle energy is delivered outside the sphere and the first of the above mentioned assumptions (radiation released from microspheres within a given organ is fully absorbed by that organ) does not hold. Consistently, the delivered energy per unit activity, k(r), shows the same trend (FIG. 20) confirming that when the tumor size is small, such term deviates significantly from its constant value of 49.38 (J/GBq), considered in equation (4). In order to use information reported in FIG. 20 at the clinical level, k(r) data obtained from MC calculations were fitted with the following function:

[00006]$\begin{array}{cc}k\left(r\right)=k_0+A.Math.\left(1-\exp \left(-\frac{r}{a}\right)\right)+B.Math.\left(1-\exp \left(-\frac{r}{b}\right)\right)& \left(6\right)\end{array}$

where r is the lesion radius in cm (assuming spherical tumors) and k.sub.0, A, a, B, b are parameters determined by the fit, as reported in Table 1 below for both for water and liver density:

TABLE-US-00001 TABLE 1 Fitting parameters of equation (6) with relative standard uncertainties, for water and liver density (denoted with superscripts .sup.w and .sup.L, respectively). R.sup.2 = 0.999 in both cases. Parameter Value.sup.w U.sub.rel.sup.w/% Value.sup.L U.sub.rel.sup.L/% k.sub.0 −11.883 1.10 −12.999 1.00 A 4.416 1.15 4.654 1.10 a 2.190 0.90 1.909 1.00 B 56.820 0.05 57.701 0.05 b 0.290 0.15 0.271 0.10

[0170] An r.sup.2=0.999 was obtained from the fit, both for water and liver density. Furthermore, goodness-of-fit was also assessed through the analysis of residuals (FIG. 21), which shows maximum deviations below 0.2 between calculated and fitted data, confirming the accuracy of the fit. Based on the fitting function described in equation (6), equation (4) can be rewritten in the following form:

[00007]$\begin{array}{cc}{D}_{\mathrm{avg}}\left(r\right)=\frac{A_0.Math.k\left(r\right)}{m}& \left(7\right)\end{array}$

[0171] For a given activity A.sub.0, equation (7) can be used to accurately calculate the absorbed dose for very small lesions (down to 0.5 cm diameter). The absorbed dose to lesions calculated using equation (7) provides results in good agreement with MC calculations (maximum deviation below 0.5%). As expected, when ideally r.fwdarw.∞ equation (7) reduces to equation (4). Of note, the energy per unit activity, k(r), obtained from equation (6) when x.fwdarw.∞ is 49.35 (J/GBq), against the accepted value of 49.38 (J/GBq) derived from equation (4) (0.06% deviation).

[0172] FIG. 22 compares absorbed doses per unit activity (Gy/GBq) calculated with Monte Carlo with those obtained using the MIRD analytic approach, for spherical lesions of different size and for ρ=1.05 g/cm.sup.3. The same results for ρ=1.00 g/cm.sup.3 are shown in FIG. 23. In addition, FIG. 23 reports absorbed doses calculated using the well-established Olinda/EXM code, developed by the Radiation Dose Assessment Resource (RADAR) Task Group of the Society of Nuclear Medicine. As illustrated in FIG. 23, absorbed dose values calculated with the MC approach concur well with those obtained using Olinda/EMX. Significant deviations were found between MC calculated dose values and those obtained using the MIRD analytic approach when the lesion diameter drops below 2 cm (FIG. 23, inset).

[0173] Ultimately, Tables 2 and 3 below compare absorbed dose values per GBq of administered activity obtained with MC calculations (D.sub.MCNP) and with the MIRD analytic approach (D.sub.MIRD). The percentage differences between the two methods (last column of both tables, Δ) is also reported, calculated as 100.Math.(D.sub.MCNP−D.sub.MIRD)/D.sub.MIRD. The difference in absorbed dose values is within ˜10% as long as the diameter of the lesion exceeds 2 cm. The two calculation approaches deviate significantly when the lesion size drops below 2 cm, due to significant energy deposition outside the sphere. This is consistent with the maximum particle range in tissue for .sup.90Y (about 11 mm). In this case, for water (liver) density, the MC calculations provide absorbed doses −9.3% (−9.6%), −27.8% (−26.7%), −56.7% (−55.4%) lower than the MIRD analytic approach for tumor diameter of 2 cm, 1 cm and 0.5 cm, respectively (Tables 2 and 3).

TABLE-US-00002 TABLE 2 Dose per unit activity calculated with MCNP4C for spherical lesions of different size uniformly filled with .sup.90Y. The lesions are assumed to have a density of p = 1.05 g/cm.sup.3 (liver density). The same quantity (dose-per-unit activity) has been calculated using the MIRD analytic approach described by equation (4). The last column of the table (Δ) shows the percentage deviation between the two methods, calculated as 100 .Math. (D.sub.MCNP − D.sub.MIRD)/D.sub.MIRD. Lesion Dose/particle MCNP MIRD diameter Mass (kg) (Gy/p) Gy/GBq Gy/GBq Δ  20 cm 4.40 3.38 .Math. 10.sup.−14 1.12 .Math. 10.sup.1 1.14 .Math. 10.sup.1 -1.8%  10 cm 5.50 .Math. 10.sup.−1 2.68 .Math. 10.sup.−13 8.91 .Math. 10.sup.1 9.10 .Math. 10.sup.1 -2.1% 8.0 cm 2.81 .Math. 10.sup.−1 5.21 .Math. 10.sup.−13 1.73 .Math. 10.sup.2 1.78 .Math. 10.sup.2 -2.8% 6.0 cm 1.19 .Math. 10.sup.−1 1.23 .Math. 10.sup.−12 4.08 .Math. 10.sup.2 4.21 .Math. 10.sup.2 -3.1% 5.0 cm 6.87 .Math. 10.sup.−2 2.11 .Math. 10.sup.−12 7.01 .Math. 10.sup.2 7.28 .Math. 10.sup.2 -3.7% 4.0 cm 3.52 .Math. 10.sup.−2 4.08 .Math. 10.sup.−12 1.36 .Math. 10.sup.3 1.42 .Math. 10.sup.3 -4.2% 3.0 cm 1.47 .Math. 10.sup.−2 9.51 .Math. 10.sup.−12 3.16 .Math. 10.sup.3 3.34 .Math. 10.sup.3 -6.2% 2.0 cm 4.40 .Math. 10.sup.−3 3.09 .Math. 10.sup.−11 1.03 .Math. 10.sup.4 1.14 .Math. 10.sup.4 -9.6% 1.0 cm 5.50 .Math. 10.sup.−4 2.01 .Math. 10.sup.−10 6.67 .Math. 10.sup.4 9.10 .Math. 10.sup.4 -26.7% 0.5 cm 6.87 .Math. 10.sup.−5 9.77 .Math. 10.sup.−10 3.25 .Math. 10.sup.5 7.28 .Math. 10.sup.5 -55.4%

TABLE-US-00003 TABLE 3 Dose per unit activity calculated with MCNP for spherical lesions of different size uniformly filled with .sup.90Y. The lesions are assumed to have a density of ρ = 1 g/cm.sup.3 (water density). The same quantity (dose per unit activity) has been calculated using the MIRD analytic approach described by equation (4). The last column of the table (Δ) shows the percentage deviation between the two methods, calculated as 100 .Math. (D.sub.MCNP − D.sub.MIRD)/D.sub.MIRD. Lesion Dose/particle MCNP MIRD diameter Mass (kg) (Gy/p) Gy/GBq Gy/GBq Δ  20 cm 4.19 3.54 .Math. 10.sup.−14 1.18 .Math. 10.sup.1 1.18 .Math. 10.sup.1 -0.0%  10 cm 5.23 .Math. 10.sup.−1 2.81 .Math. 10.sup.−13 9.33 .Math. 10.sup.1 9.44 .Math. 10.sup.1 -1.21% 8.0 cm 2.68 .Math. 10.sup.−1 5.47 .Math. 10.sup.−13 1.81 .Math. 10.sup.2 1.84 .Math. 10.sup.2 -1.5% 6.0 cm 1.13 .Math. 10.sup.−1 1.29 .Math. 10.sup.−12 4.27 .Math. 10.sup.2 4.37 .Math. 10.sup.2 -2.3% 5.0 cm 6.54 .Math. 10.sup.−2 2.20 .Math. 10.sup.−12 7.31 .Math. 10.sup.2 7.55 .Math. 10.sup.2 -3.2% 4.0 cm 3.35 .Math. 10.sup.−2 4.27 .Math. 10.sup.−12 1.42 .Math. 10.sup.3 1.47 .Math. 10.sup.3 -3.4% 3.0 cm 1.41 .Math. 10.sup.−2 9.95 .Math. 10.sup.−12 3.30 .Math. 10.sup.3 3.49 .Math. 10.sup.3 -5.4% 2.0 cm 4.17 .Math. 10.sup.−3 3.22 .Math. 10.sup.−11 1.07 .Math. 10.sup.4 1.18 .Math. 10.sup.4 -9.3% 1.0 cm 5.23 .Math. 10.sup.−4 2.05 .Math. 10.sup.−10 6.82 .Math. 10.sup.4 9.44 .Math. 10.sup.4 -27.8% 0.5 cm 6.54 .Math. 10.sup.−5 9.86 .Math. 10.sup.−10 3.27 .Math. 10.sup.5 7.55 .Math. 10.sup.5 -56.7%

[0174] Dosimetry with .sup.90Y has received much attention in the past two decades. However, few researchers have addressed the problem of dosimetry in very small liver lesions. The maximum range of .sup.90Y β-particles is 11 mm in tissue, while average energy β-particles have a range of about 4 mm. It is worth noting that the penetration depth of the high-energy .sup.90Y β-particles is a critical component of this radionuclide's success in liver radioembolization, allowing for high dose delivery into the tissue between embolized capillaries.

[0175] The present work aims to assess the absorbed dose per unit activity in a scenario of percutaneous ablation of HCC through the intratumoral injection of .sup.90Y in lesions of varying size. A simplified model tumor area was implemented into MCNP4C MC code with the aim to determine the absorbed dose to the lesion when the tumor mass is uniformly filled with .sup.90Y. Spherical lesions of different size (diameter in the range 0.5-20 cm) were simulated for two different densities: ρ=1.00 g/cm.sup.3 (water density) and ρ=1.05 g/cm.sup.3 (liver density). In both scenarios, lesions were assumed to be immersed in a semi-infinite medium with the same density of the lesion. The MIRD analytic approach and MCNP calculations provide results within 10%, no matter the density of the lesion, as long as the lesion diameter exceeds 2 cm. When the lesion diameter drops below 2 cm, significant differences were obtained between MC calculations and the MIRD approach (i.e. deviations >10%). As a general conclusion, the MIRD approach tends to overestimate the absorbed dose in small lesions, as the basic assumption of the model is that β radiation is fully absorbed by the tumor or tissue where the decay occurs. When the radius of the tumor is smaller than the maximum range of the β radiation in the medium, a significant amount of the energy is delivered out of the lesion, thus providing smaller absorbed dose values.

[0176] Presently, despite the availability of different dose algorithms, the MIRD analytic algorithm described by equation (4) is still widely used to assess the absorbed dose in tumor and in the liver compartment at the clinical level. For liver lesions that are larger, equation (4) may provide accurate dose estimates (provided that accurate input parameters are introduced, among which the fractional uptake of the target). However, when this approach is applied to assess the absorbed dose to small tumor masses (i.e. approximately below 2 cm diameter) inaccurate dose estimates may be obtained.

[0177] In addition, the MIRD analytic algorithm has been safely used for treatment planning with glass microspheres. The foundational principle is based on equation (4), which describes the average dose in a tissue volume as a function of .sup.90Y activity. During treatment planning, equation (4) can be solved for the treatment activity A.sub.0. The results obtained in the present example raise questions as to whether the MIRD analytic approach should be used to assess the prescribed .sup.90Y activity in order to achieve a given tumoricidal endpoint in small liver lesions. This is especially true when intratumoral injection of .sup.90Y is performed. For example, for HCC, 120 Gy is typically considered a reasonable minimum target dose. Therefore, when treating an HCC patient with .sup.90Y β-particles, one may wish to set D.sub.tumor to a minimum of 120 Gy. Equation (5) can be rearranged to derive the prescribed treatment activity:

A(GBq)=D.sub.tumor.Math.m.sub.tumor(kg)/49.38(J/GBq).Math.F U.sub.tumor

[0178] Assuming, for example, a tumor mass, m.sub.tumor, of 0.52 mg (diameter 1 cm), FU.sub.tumor=1 and D.sub.tumor=120 Gy, equation (5) would yield a treatment activity of 1.21 MBq (considering ρ=1.05 g/cm.sup.3). On the other hand, if equation (7) is used instead of equation (4), a prescribed activity of 1.62 MBq is obtained. As previously outlined, the cause of this difference is a result of a significant energy deposition outside the sphere (about 26% of the β-particles energy is delivered outside the sphere, as reported in FIG. 18A). Consequently, a therapeutic activity of 1.21 MBq would actually correspond to an absorbed dose of about 90 Gy, well below the therapeutic endpoint.

[0179] As mentioned, the intratumoral injection of .sup.90Y is likely to pose specific treatment planning issues related to the possibility of treating very small lesions very selectively. In his paper, Ariel reported the first interstitial use of .sup.90Y microspheres for the treatment of a rhabdomyosarcoma (Ariel I 1978 Cure of an embryonal rhabdomyosarcoma of the nose of an infant by interstitial .sup.90Yttrium microspheres: A case report International Journal of Nuclear Medicine and Biology 5 37-41). A nodule measuring 1.5 cm in diameter was successfully treated with interstitial injection of 185 MBq of microspheres. In another study (Tian J H, Xu B X Zhang J M, Dong B W Liang P, Wang X D 1996 Ultrasound-guided internal radiotherapy using yttrium-90-glass microspheres for liver malignancies Journal of Nuclear Medicine 37 958-63), .sup.90Y-glass microspheres were injected into predetermined tumor sites using an ultrasound-guided procedure. Tumor size ranged from 1.9 to 8.8 cm, with most lesions being less than 5 cm in diameter. More recently, Ferrari and co-workers assessed the absorbed doses to small-volume brain neocavities and surrounding tissues after local .sup.90Y-DOTATOC injection (Ferrari M, Cremonesi M, Bartolomei M, Bodei L, Chinol M, Fiorenza M, Tosi G, Paganelli G. Dosimetric model for locoregional treatments of brain tumors with .sup.90Y-conjugates: clinical application with .sup.90Y-DOTATOC, J Nucl Med. 2006 January; 47(1):105-12.). A recent review of the literature on the intratumoral treatment with radioactive beta-emitting microparticles can be found in Bakker R, Lam M, van Nimwegen S, Rosenberg A, van Es R and Nijsen J 2017Intratumoral treatment with radioactive beta-emitting microparticles: a systematic review Journal of Radiation Oncology 6 323-341.

[0180] Described herein is a procedure whereby microspheres are delivered to the target using a direct, image-guided intratumoral injection of .sup.90Y microspheres (embedded in a biocompatible matrix) using a delivery system as described herein. This procedure is also known as percutaneous radioablation and is a minimally invasive treatment for patients with small (below approximately 3 cm) liver tumors performed using a combination of the following components: i) BIOGLUE® (Cryolife, Atlanta, US), a FDA-approved mixture of bovine serum albumin and glutaraldehyde in a 4:1 ratio, approved for use in soft tissue repair or to seal damaged parenchyma ii) SIR-SPHERES® coated with .sup.90Y (Sirtex Medical, Sydney, Australia) approved for implantation into hepatic tumors via the hepatic artery and the iii) MIPP-KIT® (Svas Biosana, Naples, Italy) a dedicated coaxial dual-lumen catheter for the direct, imaging-guided intra-tumoral injection of the glue and .sup.90Y microsphere mixture. The evidence from this study suggests that caution must be taken when planning the treatment of very small lesions with .sup.90Y, implementing the standard analytic approach. This is particularly true when intratumoral administration of .sup.90Y is performed, as this approach allows sub-centimeters tumors to be selectively treated. In such a scenario, the use of the analytic approach to calculate the therapeutic activity needed to achieve a given tumoricidal endpoint may result in important dose underestimations.

[0181] In some embodiments, the alternative algorithm presented by equation (7) can be usefully employed in treatment planning for intratumoral injection of microspheres, providing results in close agreement with Monte Carlo calculations (maximum deviation below 0.5%).

[0182] In conclusion, for a given activity A.sub.0, the analytic equation proposed by the MIRD model (equation 4) is likely to overestimate the absorbed dose in lesions below 2 cm. Conversely, activity underestimations can be obtained if the analytic approach is used to assess the prescribed .sup.90Y activity. This is because the basic assumption made to derive equation (4) (full absorption of the f particle into the target volume) is no longer true for small lesions. However, overestimations are below 10% for lesions with a diameter larger than approximately 2 cm. As a rule, the larger the lesion size, the better the agreement of the MIRD model with Monte Carlo calculations. When the lesion size drops below 2 cm the two calculation approaches deviate significantly, with the analytic algorithm providing dose overestimations up to 57% (for lesions of 0.5 cm diameter). Therefore, caution is advised when using equation (4) for absorbed dose determination in very small lesions. In particular, for the assessment of the absorbed dose in small tumor regions the use of equation (7) is suggested instead of equation (4).

Example 1: Pre-Clinical Study

[0183] In one example, a homogeneous distribution of .sup.90Y-labelled particles is demonstrated in a set of experiments using .sup.90Y microspheres mixed with a hydrogel or tissue glue. By solidifying during the injection or implantation process, the radioactive glue or gel can be distributed uniformly, and it can resist undesired effects from gravity, dispersion or leakage into the blood or lymph vessels, hematomas, etc. FIGS. 2A and 2B depict gamma camera views of 1 mCi (37 MBq) of .sup.90Y microspheres in BIOGLUE®, which is a mixture of 45% wt/vol bovine serum albumin and 10% wt/vol glutaraldehyde, in a 4:1 ratio in a 2.5 mL syringe cylinder. Additional studies were performed using 5 mL plastic spheres which were filled with .sup.90Y microspheres and a gel carrier or matrix material, such as BIOGLUE, COSEAL (PEG/HCl/NaPhos/NaCO.sub.3; Baxter Healthcare, Hayward, Calif.) or BERIPLAST (fibrinogen/thrombin; CSL Behring GmbH; Marburg, German), at activity levels in the range of 370 to 740 MBq, filled using a dual-lumen coaxial catheter. In these studies, gamma camera and PET/CT imaging was performed using 4 mm slices to more precisely assess the distribution of radioactivity in the solidified carrier, as shown in FIGS. 3A and 3B. The PET/CT imaging in FIG. 3A also demonstrated that there was no separation of the liquid used to suspend the microspheres in the solid carrier material in the cavities after mixing, and that there were no changes in the homogenous distribution or other changes to the solidification process within the cavities at the larger sizes.

[0184] The use of the gamma camera and PET/CT imaging was also used to evaluate the dosimetry distribution of the .sup.90Y microspheres and solidified matrix. FIGS. 4A to 4C depict the relative absorbed doses in cavities of 0.5 mL, 4.2 mL and 11.4 mL spherical volumes (0.5 cm, 1 cm and 1.5 cm radii, respectively), as measured from the center of each corresponding volume and shell volumes 1 mm thick from the sphere surface.

[0185] FIG. 5 depicts the percent activity of the .sup.90Y microsphere-BIOGLUE® composition in each of the volumes described hereabove in FIGS. 4A to 4C. For each of the 0.5, 1 cm and 1.5 cm radii volumes, the percentage of activity effectively falls to less than 50% activity within a 0.5 cm distance of the radius from the volume surface, or within a 150% radius distance from the center of the volume. For the 0.5 cm radius volume, the percentage activity falls to less than 10% or 5% within 0.5 cm from its surface and to zero within 1 cm of its surface, or 1 cm from its center and 1.5 cm from its center, respectively. For the 1 cm radius volume, the percentage activity falls to less than 10% or 5% within 0.5 cm from its surface and to less than 1% within 1 cm from its surface, or 1.5 cm from its center and 2 cm from its center, respectively. For the 1.5 cm radius volume, the percentage activity falls to less than 10% or 5% within 0.5 cm from its surface and to less than 1% within 1 cm from its surface, or 2 cm from its center and 2.5 cm from its center, respectively. The estimated absorbed doses for these volumes are provided below:

[0186] 0.5 mL volume with 0.5 cm radius and activity of 185 MBq:

TABLE-US-00004 Distance from Gy/ Center (cm) MBq Gy 0.5 62.9 11640 0.6 35.0 6467 0.7 14.0 2587 0.8 5.6 1035 0.9 2.1 388 1 0.559 103 1.2 0.070 13 1.5 0.0002 0.04

[0187] 4.2 mL volume with 1 cm radius and activity of 370 MBq:

TABLE-US-00005 Distance from Gy/ Center (cm) MBq Gy 1 10.1 3732.3 1.1 6.7 2488.2 1.2 2.2 829.4 1.3 1.0 373.2 1.4 0.6 207.4 1.5 0.112 41.5 1.6 0.004 1.7 1.7 0.001 0.4

[0188] 14.1 mL volume with 1.5 cm radius and activity of 1110 MBq:

TABLE-US-00006 Distance from Gy/ Center (cm) MBq Gy 1.5 3.46 3843.2 1.6 1.15 1281.1 1.7 0.81 896.7 1.8 0.35 384.3 1.9 0.12 128.1 2 0.06 64.1 2.1 0.0092 10.2 2.3 0.0012 1.3

[0189] FIG. 6 depicts the absorbed dose per unit (Gy/MBq) in adjacent shell volumes for the three volumes. These plots show that there is a decrease of at least 95%, or 1 to 2 orders of magnitude decrease in the absorbed dose within a 0.5 cm distance from the surface of the volume, and at least a 90% decrease within 150% of the radius.

[0190] FIG. 7 depicts the total absorbed dose in Grays in adjacent shell volumes for the three volumes. For the 0.5 cm radius volume, the absorbed dose within 0.5 cm from the surface (1 cm from the center) decreases by about 90%. For the 1 cm radius volume, the absorbed dose within 0.5 cm from the surface (1.5 cm from the center) decreases by more than 90%. For the 1.5 cm radius volume, the absorbed dose within 0.5 cm from the surface (2 cm from the center) decreases by more than 90%.

Example 2: Mice Study

[0191] In one study, an animal model of pancreatic cancer applicant used with human MIA-Paca-2 RFP cells in the thigh of CD1 nude mice to then apply the new matrix, which will act as a carrier for the .sup.90Y spheres, in the site of the induced tumor. Intra-tumoral application of the new matrix with .sup.90Y spheres led to increased levels of the compound in the tissues through its homogeneous distribution and made it possible to achieve effective doses for the treatment of the tumor by reducing the rate of spreading and avoiding and minimizing the systemic side effects of therapy.

[0192] The experimental protocol involved a locoregional treatment affecting tumor shrinkage with tangible benefits for the host. The results obtained from this and other studies herein can be translated into clinical practice, introducing significant benefits, as in the majority of cases pancreatic cancer is inoperable for locally advanced disease.

[0193] The radioisotope and matrix used for this study were the SIR-SPHERES® and the BIOGLUE® as described above. It is believed that the composition: [0194] can be administered intra-tumorally in order to cause complete necrosis of the tumor tissue surrounding the injection site, thus allowing the treatment of malignant tumor masses which cannot be surgically removed; [0195] can be applied as a coating or filling material for surgical wounds, following surgical resection or ablative treatments of malignant tumor masses in order to cause complete necrosis of any remaining tumor cells localized along the edges of these wounds; [0196] can lead to the increased efficacy of anticancer substances, producing a beneficial increase in the administration and dosing times of said substances at a local level, through increased concentration of the substances inside the treated tumor masses, or inside surgical wounds from surgical removal, or ablative treatments, of tumors; [0197] prevents anticancer substances from freely dispersing in the patient's body, thereby limiting systemic exposure to their toxic components; and/or [0198] avoids some of the side effects from application of methods of treatment alternative to surgical resection of malignant tumor masses.

[0199] It is believed that the radioisotope-matrix composition including a substance with adequate anticancer capacity, such as .sup.90Y or other similar type to Holmium, in a suitable viscous material capable of entrapping the microspheres, may provide homogenous distribution and act as a carrier of said substance. Necrosis of the tumor cells of interest is induced by adequate internal electron radiotherapy (IER) determined by localized emission of radioactive particles by the above-mentioned microspheres radiolabeled with .sup.90Y. Through gamma camera and PET/CT/SPECT imaging studies, depicted in FIGS. 8A to 8F, it was found that the .sup.90Y is dispersed in an almost homogeneous manner inside the tumor mass into which it is injected or inside the surgical wound on which it is applied, on account of the viscous nature of the components forming the matrix, and that this homogeneous distribution is highly instrumental in the necrosis of the tumor cells located in these areas.

[0200] Tumors were induced in mice following injection of the human MIA-Paca-2 RFP cells. FIGS. 8A and 8D depict PET/SPECT images of the matrix that did not contain any .sup.90Y spheres, while FIGS. 8B and 8E depict PET images of the mice injected with the combined .sup.90Y-matrix composition. FIGS. 8C and 8F are corresponding SPECT images of the mice in FIGS. 8B and 8D, confirming that none of the .sup.90Y spheres had leaked or dispersed from the injection site, and that there is a homogenous distribution of the radioisotope within the tumor.

[0201] The results also show that, by using a hydrogel or matrix with a sufficient solidification rate as a carrier for the radiolabeled-microspheres, the possible dispersion of said microspheres in the patient's body potentially caused by factors such as gravity, circulation in the blood and/or lymphatic vessels, the presence of hematomas, etc. may be substantially limited, thus avoiding or greatly reducing possible side effects from potential leakage of the radioactive material in the patient.

[0202] The material forming the hydrogel or matrix is a viscous gel or matrix designed for direct intra-tumoral injection or for application of a surface of a tumor resection site. This matrix is configured to contain the .sup.90Y spheres, which, on account of their size and composition, (e.g. resin or glass), are trapped in the gel matrix and thus localized at the tumor or resection site for an extended period of time in order to increase or maximize the local dose level and duration of exposure. The overall effect of the matrix with .sup.90Y microspheres results in an increase in local .sup.90Y microspheres concentrations, limiting or reducing peak systemic exposure.

Example 3: Matrix-Injector Development

[0203] Due to the different densities and viscosities of the two solutions forming a hemostatic gel, sealant or hydrogel, one solution may flow into the catheter in greater quantity than the other, whereby the following problems may occur: [0204] compound wastage; [0205] difficulty applying the compound on account of the considerable force the operator has to apply to the syringe with both hands; [0206] misapplication of the compound due to dislodgement of the end portion of the catheter because the operator is unable to use just one hand to hold said catheter in place during infusion; such dislodgement requires the operator to use a greater quantity of the compound in order to be sure that it has reached and covered the entire the target volume.

[0207] Moreover, the reduced flow rate of either of the two compounds facilitates activation of the compound near the end portion of the catheter where mixing takes place to activate the compound, i.e., near the outlet of the two substances, which causes the obstruction of said catheter, thus causing the operator to apply more force in order to overcome the resistance of the two solutions to the infusion. In addition, the greater the force required of the operator, the more difficult it is to hold the end portion of the catheter near the target in place; this involves the need to perform continuous ultrasound or X-ray monitoring of the correct positioning of the catheter and any repositioning that may be required.

[0208] Due to these potential problems, and until now, the various glues and matrices have only been used intraoperatively. Further there have been great difficulties with percutaneous administration or during laparoscopy due to the use of double-lumen catheters which are designed and developed for other purposes and are unable to convey the two solutions to the area concerned at the same time, resulting in obvious wastage of compounds or drugs and poor therapeutic results.

[0209] Therefore, the technical issue consists of ensuring that the two solutions with different viscosities and densities have the same flow rate, meaning that they must flow in and out from the distal end or outlet of the catheter at the same time.

[0210] Thus, it is beneficial to deliver a combination of a carrier matrix and .sup.90Y-loaded microspheres with a device capable of transporting the compound to the target area in the desired ratio, and while preferably avoiding all the disadvantages existing thus far both in the case of percutaneous image-guided treatments and laparoscopic and intraoperative treatments.

[0211] In one example, a double-lumen catheter was developed for the infusion of a two-component compound, particularly for glues or agents containing thrombin and fibrinogen. The catheter comprises a first lumen intended for a first solution of a first component and a second lumen intended for a second solution of a second component. Said lumens respectively form, as per a catheter cross-section, a first area and a second area, with the ratio of said areas being proportional to the viscosity ratio of the respective fluids. According to a further aspect of the invention, it is preferable for said ratio of said areas to be greater than the square root of the ratio of the viscosities of the fluids passing through the respective lumens.

[0212] In particular, it is preferable for said ratio of said areas to be approximately equal to the square of the ratio of the viscosities of the fluids passing through the respective lumens. Said ratio value takes another aspect into account, namely that the viscosity varies according to the temperature.

[0213] In some examples, the lumens have a circular cross section and are concentric, and that the first lumen incorporates the second lumen, as depicted in FIG. 9A. In this case, it is preferable for the first lumen to be configured and sized so as to receive the higher viscosity solution so that said solution might be more exposed to warming induced by contact of the catheter with the patient's tissues during infusion.

[0214] Therefore, the variant of the catheter allowing for better use of the penetration of warmth coming from outside requires the two lumens to have a circular cross-section and to be concentric and for the higher viscosity solution to flow in the outer lumen and therefore the outer lumen to have a larger cross-section than the inner lumen.

[0215] The catheter described above is applied in the medical/clinical field in minimally invasive percutaneous procedures, surgical, laparoscopic or interventional radiology procedures whenever necessary to administer the anticancer compound.

[0216] As a result of the present invention, it becomes possible to ensure that the two solutions have the same flow rate and so move along the catheter at the same time, i.e. exit the catheter in equal amounts so as to ensure the correct activation of the agent when infused in proximity to the patient's target tissues. As an advantage, it is possible to minimize infusion times and the amount of effort the operator is required to use during the infusion and it is also possible to minimize the quantities of the compound injected.

[0217] The features of a catheter according to the present invention prove to be very surprising because a technician in the field would have clearly applied Poiseuille's law, which states that the motion at constant speed of a viscous and incompressible fluid in a pipe having a constant cross section is laminar, i.e., consists of the relative sliding of an infinite number of cylinders coaxial to the tube axis.

[0218] Consequently, a pressure variation Δp between two points located respectively at the inlet and outlet of the tube is given by:

[00008]$\Delta p=\frac{8\eta L}{\pi r^4}{Q}_v$

Where L is the length of the tube, r is the diameter of the tube, Q.sub.v is the flow rate of the viscous fluid in the tube and η is the viscosity of the fluid.

[0219] Since it is required for the two solutions to have the same flow rate and the same pressure variation along the catheter in order to minimize the effort applied by the operator on the body of the dual-chamber syringe, therefore:

[00009]$\frac{{\eta }_1}{\pi .Math.r_1^4}=\frac{{\eta }_2}{\eta .Math.r_1^4},\mathrm{or}$$\frac{{\eta }_1}{S_1^2}=\frac{S_1^2}{S_2^2},\mathrm{therefore}$$\frac{{\eta }_1}{{\eta }_2}=\frac{S_1^2}{S_2^2}$

[0220] Where S.sub.1 and S.sub.2 respectively represent the lumen cross-section areas. In other words, by applying Poiseuille's law, the result should be for the ratio of the cross sections of the two lumens to be proportional to the square root of the ratio of the respective viscosities.

[0221] To be more precise, the present invention stipulates a preferred proportion between the ratios of the areas and the ratios of the cross-sections, expressed using the following formula, which seems to go against the predicted said law of physics:

[00010]$\frac{{\eta }_1^2}{{\eta }_2^2}=\frac{S_1}{S_2}$

[0222] In fact, said law of physics is unable to contemplate the behavior of the two solutions forming the hemostatic agent when the temperature varies and particularly when the catheter is inserted in the patient's body. In fact, under said circumstances, the temperature of the two solutions varies from an ambient temperature of approximately 18° C. to approximately 37° C., the temperature of the human body.

[0223] Variations of the formula described above may be made in order to contemplate different positions of the inner lumen in relation to the outer lumen, for example with the axes of the lumens coincident (FIG. 9A), not coincident but parallel (FIG. 9B), or with the two lumens divided by a curved or straight septum (FIGS. 9C and 9D, respectively).

[0224] However, in some variations, the properties of the catheter are obtained according to the following relation, when the ratio between the areas of the lumen cross-sections is slightly greater than the square root of the ratio of the respective viscosities:

[00011]$\sqrt{\frac{{\eta }_1}{{\eta }_2}}<\frac{S_1}{S_2}$

[0225] One embodiment has an external diameter of 16 G, corresponding to an external diameter of approximately 1.6 mm. In addition, the two lumens are concentric, therefore: [0226] the first lumen has a diameter of 0.022 inches, i.e. 0.56 mm [0227] the second lumen has a diameter of 0.010 inches, i.e. 0.25 mm

[0228] Therefore, the cross-sectional area of the second lumen is π×0.125.sup.2 0.04906 mm.sup.2, the gross area of the first lumen is π×0.28.sup.2=0.24617 mm.sup.2, while the net area is 0.24617−0.04906=0.19711 mm.sup.2. This means that the ratio between the areas of the first and second lumen is approximately 4; therefore, it is suitable for solutions with a viscosity ratio of approximately the square root of 4, i.e. approximately 2. Externally, other embodiments of the catheter may have a standardized cross-section, for example 20G, 18 G, 16 G, or 14 G.

[0229] Preferably, the catheter is made of a radiopaque material that is visible during x-rays and/or other imaging modalities. A length compatible with its use is approximately 20 cm and it is preferable for said material to make it semi-rigid, but in other examples may be flexible or rigid. Preferably, it comprises a rigid connector that can be connected to special syringes for injecting the two-component compound. In other examples, the catheter may have a shaft length in the range of 10 cm to 100 cm, about 20 cm to 70 cm, or 30 cm to 60 cm. It may comprise a rigid Y-connector specific to the two components, with a Luer-lock end connector that is a standard connector. Lastly, it is preferable for the catheter body to have specific markings at a set distance apart, for example at a distance of one centimeter apart, i.e. divided into centimeters for at least part of the catheter.

[0230] The kit may further comprise an introducer the same length as the catheter, for example 20 cm, and a cross-section compatible with one of the possible cross-sections of the catheter. In some variations, the distal tip of the catheter may be flush with the distal tip of the introducer. In other examples, the catheter tip may extend out or be spaced proximally from the distal end of the introducer by 1 mm to 10 mm, or 1 mm to 5 mm, or 2 mm to 4 mm. The introducer may also be divided into centimeters, i.e. markings a set distance apart and made of radiopaque material. Furthermore, it may have a removable steel core with a sharp tip slightly longer than the introducer, for example, 210 mm long, and may include a Luer-lock connector. The preferred material for the body of the catheter is GRILFLEX® ELG 6260 (PEBA). Lastly, the catheter ends with an orthogonal cut along the axis.

[0231] FIG. 10A is a photograph of another exemplary kit 1000 that may be used for delivery of the .sup.90Y-matrix composition, comprising a catheter 1002, an introducer 1004, an introducer core (not shown), and a needle 1006. To perform the procedure, the introducer 1004 together with its core is positioned using ultrasound, CT or MR imaging guidance. After removing the core of the introducer 1004, the needle 1006 is inserted through the introducer 1004. Any biopsy or other ablation procedure may be performed through the needle 1006. After the diagnostic and/or therapeutic procedure is performed, the needle 1006 is removed and the catheter 1002 is inserted into the introducer 1004 and the multi-chamber sealant injector (not shown) is attached to the catheter 1002. The sealant is then injected along the tissue tract as the combined injector and catheter are withdrawn from the tissue tract.

[0232] The distal end 1008 of the needle 1006 has a sharp, beveled tip and is preferably visible on ultrasound. For example, a cross-section of the needle could be 16 G, that is, equivalent to an outer diameter of 1.60 mm and an inner diameter of 1.20 mm, made of AISI 304 with the tip being visible on ultrasound. The proximal hub 1010 of the needle 1006 may have an attached Luer-lock distal connector 1012, for example, comprising transparent ABS TERLUX® TR2812. The preferred length of the needle shaft 1014 is 200 mm, and shaft 1014 is configured to be inserted into the introducer 1004. The introducer 1004 may comprise a GRILAMID® L25 shaft, with an optional tapered distal tip. The inner diameter of the introducer 1004 is approximately 1.70 mm, while the length of the introducer 1004 should be preferably slightly longer than the needle 1006, e.g. 210 mm, or a length that is 1 mm to 20 mm, 5 mm to 10 mm, or 5 mm to 15 mm longer than the needle 1006. In other examples, the inner diameter of the introducer may be in the range of 0.8 mm to 2.2 mm, or 1 mm to 2.2 mm, or otherwise to accept a catheter or needle shaft with a size from 12 G to 18 G.

[0233] FIG. 10B is a close-up photograph of the proximal hubs 1016, 1018, 1010 of the catheter 1002, introducer 1004, and needle 1006, respectively, with needle 1006 inserted into the introducer 1004 such that the proximal needle hub 1010 is engaged to the proximal introducer hub 1018 via complementary Luer locks 1012, 1022. The proximal hub 1016 of the catheter 1002 comprises two ports 1024, 1026 that are configured to attach to dual tips of a dual-chamber syringe (not shown). FIGS. 10C and 10D depict longitudinal cross-sections of the catheter 1002 with a male Luer-lock connector 1028 compatible with a female Luer-lock connector 1022 of the introducer 1004, respectively. This configuration permits both the needle 1006 and the catheter 1002 to be releasably locked to the introducer 1004 when inserted into the introducer 1004. The introducer 1004 may comprise a shaft 1030 with distance markings 1032 visible along its longitudinal length, and wherein the shaft 1030 is preferably radiopaque, e.g., loaded with 30% barium sulfate and inserted into a protective polythene tube. The catheter 1002 and introducer 1004 are also depicted with optional handles 1034, 1036 to facilitate handling during use.

[0234] Before a minimally invasive treatment takes place, the kit is prepared so that the introducer is inserted first, with the diameter corresponding to the catheter chosen according to the procedure to be performed, and it will be placed under ultrasound guidance, CT or MRI scanning. Once the core of the introducer is removed, the coaxial double-lumen catheter is then inserted and the compound is administered as needed, in order to fill the treatment area and if necessary the distance covered by the introducer, which is then slowly removed in order to release the compound including along the course of the introducer. This ensures effective functioning, ease of administration, conservation of drugs, and avoiding of additional invasive procedures for externally conveying the anticancer agent. The elements and features described above, in their various preferred embodiments, may be combined without departing from the scope.

Example 4: Pig Study

[0235] In another animal study, eight large white female pigs weighing 75±5 kg, selected from special farms, free of infection and previously immunized, underwent injection of bioglue-.sup.90Y microspheres under ultrasound guidance of three different liver segments or lobes. For these procedures, 24 ml of glutaraldehyde crosslinked albumin (BIOGLUE®) containing 60/80 mCi of .sup.90Y microspheres was used in the left lobe, the right lobe, and the right lower paracaval lobe. The veterinarian examined all animals in order to assess their state of health and the absence of symptoms related to any disease and then underwent eight-hour preoperative fasting, anesthesia, and blood sampling. Blood samples taken from the jugular vein were performed: a) before surgery (T0), b) after surgery, before awakening (T1), and c) before explantation of the liver (T2). All pigs, divided into four groups of 2 animals each, after general anesthesia were subjected at different times to: median laparotomy, intraoperative ultrasound identification of an ablation area approximately 3.5 cm.sup.2, treatment of 3 different liver segments with the anti-cancer compound, organ explantation and euthanasia: the first group was sacrificed 7 days after treatment, the second after 14 days, the third after 21 days and the fourth after 28 days. The explanted liver was then used for macroscopic and microscopic evaluation.

[0236] After treatment, all pigs were transferred to the animal facility and monitored daily; facility conditions were compliant with applicable current legislation as all animals were free to roam and feed “ad libitum”.

[0237] FIGS. 11A to 11F, 12A to 12F, and 13A to 13F are PET/SPECT images of three different porcine livers, respectively, that were explanted after 7 days. The blood samples taken from the pigs, according to the timings indicated in the protocol, did not document any significant abnormalities in blood coagulation parameters. The results of the anatomical and pathological evaluation of the explanted livers, shown in the tables below, characterize the area of ablation at different post-injection time periods of the .sup.90Y matrix composition.

[0238] 75 kg pig #1:

TABLE-US-00007 Trial Outside Outside Inside Inside # Location Length Width Length Width Size 1 Left lobe 5.0 4.8 4.6 4.0 4.4 × 3.8 3 Right lobe 5.2 4.6 4.3 4.0 4.3 × 3.8 4 Inferior 5.4 4.4 5.0 4.6 4.7 × 4.2 right lobe

[0239] 80 kg pig #2:

TABLE-US-00008 Trial Outside Outside Inside Inside # Location Length Width Length Width Size 1 Left lobe 4.0 5.0 4.5 4.2 4.3 × 4.0 second position 3 Left lobe 4.0 4.0 4.1 4.2 4.0 × 4.1 3 Lateral 5.8 5.5 5.5 5.0 5.2 × 5.0 right lobe

[0240] 85 kg pig #3:

TABLE-US-00009 Trial Outside Outside Inside Inside # Location Length Width Length Width Size 1 Medial 4.5 4.2 4.9 4.5 4.7 × 4.5 right lobe 2 Lateral 4.5 4.0 4.6 4.2 4.3 × 4.0 right lobe 3 Medial 5.0 4.9 4.3 5.0 4.1 × 4.7 left lobe

[0241] 75 kg pig #4:

TABLE-US-00010 Trial Outside Outside Inside Inside # Location Length Width Length Width Size 1 Medial 5.4 5.1 5.1 4.1 5.0 × 4.0 left lobe 2 Medial 6.0 5.2 5.5 4.9 5.3 × 4.8 right lobe 3 Lateral 5.4 5.0 5.0 4.2 5.0 × 4.0 right lobe

[0242] 85 kg pig #5:

TABLE-US-00011 Trial Outside Outside Inside Inside # Location Length Width Length Width Size 1 Medial 5.5 4.5 5.2 4.2 5.0 × 4.0 left lobe 2 Deep 5.2 4.3 4.2 4.0 4.0 × 4.0 right lobe 3 Lateral 6.0 5.0 5.1 4.2 5.0 × 4.0 right lobe

[0243] 100 kg pig #6:

TABLE-US-00012 Trial Outside Outside Inside Inside # Location Length Width Length Width Size 1 Medial left lobe 6.2 5.1 5.4 4.2 5.3 × 4.2 2 Medial right 5.5 4.1 5.0 4.0 4.8 × 4.0 lobe 3 Lateral right 5.0 4.6 4.6 4.2 4.5 × 4.0 lobe

[0244] 90 kg pig #7:

TABLE-US-00013 Trial Outside Outside Inside Inside # Location Length Width Length Width Size 1 Medial left lobe 5.1 4.5 4.8 4.5 4.8 × 4.5 2 Medial right 5.0 4.5 4.0 4.0 4.5 × 4.0 lobe 3 Lateral left lobe 6.0 5.0 5.0 4.5 5.0 × 4.5

[0245] 80 kg pig #8:

TABLE-US-00014 Trial Outside Outside Inside Inside # Location Length Width Length Width Size 1 Medial right 5.2 4.5 5.0 4.5 5.0 × 4.5 lobe 2 Medial right 5.7 4.8 4.7 4.2 4.7 × 4.0 lobe 3 Lateral right 5.0 5.0 4.5 4.5 4.5 × 4.3 lobe

[0246] The analysis above demonstrates a stable ablation area at each treatment site and at each evaluated time point. The necrotic mean±SD area (cm.sup.2), as assessed at histo-pathology, was 18.8±3.7, 20.5±2.8, 19.2±2.1 and 20.5±2.0, after 1, 2, 3, and 4 weeks from .sup.90Y matrix composition injection, respectively.

[0247] Acute systemic toxicity tests, intracutaneous reactivity tests, and delayed hypersensitivity tests were performed to verify the safety of .sup.90Y matrix composition administration to experimental animals. The results observed in the treated animals were very similar to the controls: no symptoms were detected in the acute systemic toxicity test; and no erythema nor slight erythema were detected in the intracutaneous reactivity test and no visible changes were observed in the delayed hypersensitivity test.

[0248] Moreover, considering the partial non-bioabsorbable nature of .sup.90Y matrix composition and the .sup.90Y decay time, the local and systemic effects of subcutaneous .sup.90Y matrix composition in male albino rats were assessed after 26 and 52 weeks from implantation. Considering the local effects, no abnormality was detected after macroscopic evaluation and necropsy in all implanted sites. The histological evaluation was used to calculate a Mean Final Index of reaction for the treated and control groups, which were 1.5 and 1.8 respectively at 26 weeks (values from 0.0 to 2.9 mean minimal or no reaction), 3.5 and 4.2 respectively at 52 weeks (values from 3.0 to 8.9 mean slight reaction).

[0249] As far as the systemic effects, .sup.90Y matrix composition did not cause significantly different effects, when compared to the control, when the following parameters were evaluated: tissue architecture; cell hypertrophy; necrosis; inflammatory population; atrophy; edema; hyperemia; fibrosis; and vascular congestion.

[0250] Blood samples collected from the test animals at the different timepoints did not document any significant abnormalities of the hematic and liver parameters; no radioactivity effects were detectable on the CBC blood counts after .sup.90Y matrix composition administration.

[0251] Based on the results above, the use of a locoregional approach to treatment of hepatic lesions appears to be potentially useful and appropriate for human treatment, based on ablation sizes ranging from 3.7 to 5.3 cm in length and 4.0 to 5.0 cm in width, and absence of side effects on organs and bone marrow.

Example 5: Rabbit Study

[0252] In another animal study, intra-tumoral injection of a .sup.90Y-loaded hydrogel matrix was used for the treatment of unresectable primary or secondary solid tumors and/or intraoperative local application to prevent or delay local recurrence after resection with positive margins and to confirm efficacy and safety of the procedure. In one study, a .sup.90Y microsphere-BIOGLUE® composition was used to treat seventy New Zealand rabbits with induced para-renal tumors. For the tumor implant procedure, the rabbits underwent a xipho-umbilical laparotomy. A blunt dissection was used to expose the peritoneum through the avascular linea alba. Careful dissection of the peritoneum allowed for the exploration of the peritoneal cavity up to the right renal lodge, where one implant of VX2 tumor (about 5 mm.sup.3) was performed. Although VX2 tumor cells originated from skin cancer of cottontail rabbits, it was later found to be transplantable to all strains of domestic rabbits and used to study a variety of solid tumor human cancers, including the lung, bladder, breast, kidney and liver.

[0253] Para-renal tumor progression was allowed for 2 weeks and monitored by ultrasound until its mass reached approximately 2 cm in diameter, as checked by repeated renal ultrasonography, starting 1 week after tumor cell implantation. At the end of this period a right nephrectomy was performed, through a second laparotomy. The tumor originating from the VX2 implant was excised leaving an in-situ residual mass≤1 cm thick. The area was marked with a small surgical clip to facilitate tissue identification at the time of necropsy, when the residual tumor mass was completely removed. At the end of the 2-week tumor implant growth and after partial tumor excision as described above, 46 animals were randomly assigned to one of the following groups, to assess the safety, efficacy and biodistribution of each treatment: [0254] a) 22 rabbits were treated with 1 ml of .sup.90Y matrix composition (group A): 6 of these animals were euthanized under general anesthesia after 1 week, 8 after 2 weeks and 8 after 3 weeks; [0255] b) 15 rabbits were assigned to .sup.90Y-only treatment (group B), where 185 MBq of .sup.90Y microspheres (in 1 ml saline solution) were used for each administration; 5 of these animals were euthanized under general anesthesia at 1 week, and 10 more at 2 and 3 weeks, respectively; [0256] c) 9 rabbits were assigned to localizing carrier-only treatment (group C), where 0.3 ml of combined bovine serum albumin/glutaraldehyde (in 1 ml of saline solution) were used; 3 of these animals were euthanized under general anesthesia at 1 week, and 6 more at 2 and 3 weeks, respectively.

[0257] The tumors were injected with their randomly assigned composition and monitored over time. The residual tumoral lesion of all animals (treated with either .sup.90Y matrix composition, .sup.90Y-only or localizing carrier-only), collected after 1, 2 and 3 weeks from treatment, were harvested and examined macroscopically and microscopically. The explanted tumor mass was calculated according to the formula volume=½(length×width.sup.2). The collected specimens were fixed with a 4% PFA solution after PET/CT scanning (described in greater detail below), cut by a cryostat (sliced at 5-um thickness), stained using routine hematoxylin and eosin methods, and finally analyzed to ascertain the target tissue necrosis by a pathologist blinded to the original treatment. To assess .sup.90Y-induced necrosis on the residual tumors in groups A and B, the expression of p53 protein (a necrotic marker) was detected by western blot analysis (WB) on protein lysates collected from animals sacrificed at each time point; β-tubulin was used as a control marker. Liver enzymes (ALT, AST, GGT, alkaline phosphatase), bilirubin and complete blood counts (CBC) were performed at baseline; blood tests were then performed every 7 days before animals were euthanized, collecting blood from the heart of anesthetized animals.

[0258] As noted above, at 1 and 3 weeks post-surgery, the animals treated with .sup.90Y matrix composition and .sup.90Y-only were sacrificed under general anesthesia and immediately subjected to PET/CT imaging. These assessments checked not only the diffusion of the radioactive material within the target lesions and its homogeneous distribution, but also the possible dispersion of the injected compound in the rest of the target organ, as well as in other areas of the body. In fact, after the PET scan, selected organs were explanted from the animals to perform a thorough .sup.90Y bio-distribution analysis. The explanted organs included the brain, thyroid, muscle, trachea, bronchi, right lung, heart wall, lymph nodes, liver, gallbladder, spleen, small intestine, colon, pancreas, peritoneum, right adrenal, testicle, left kidney, right kidney, bladder, skin, bone and tumor lesion. The above organs were weighed and the activity of .sup.90Y expressed as counts per minute (CPM) in the absorption spectrum of B emissions, was detected through a Geiger-Muller counter for each of them.

[0259] Data were included in a Microsoft Excel 14.1.0 database. GraphPad Prism 6 was used for mean±SD graph plots. Descriptive statistics were used for baseline variables, and statistical significance was checked using unpaired Mann-Whitney test. Where indicated, the coefficient of variation, expressed as percentage, was calculated as the ratio between SD and mean, multiplying the result by 100.

[0260] The antineoplastic effect was found to be directly proportional to the time of exposure to the .sup.90Y microsphere-BIOGLUE® composition, with treated tumors exhibiting 10% average necrosis at day 7, 30% average necrosis at day 14, and 90% average necrosis at day 21. The results of this study showed that the histological examination of the positive resection margin of the bed after nephrectomy and treatment with .sup.90Y-microspheres hydrogel mixture demonstrated almost total necrosis of viable VX2 carcinoma tumor cells after 21 days.

[0261] FIGS. 14A, 14B and 14C depict the histological tissue analysis of the positive resection margin of the bed after nephrectomy and treatment with a hydrogel matrix and .sup.90Y microspheres after 7, 14 and 21 days, respectively. FIG. 14A shows that 7 days after treatment, the percentage of necrotic cells is 70%, while FIG. 14B shows that after 14 days, the percentage of necrotic cells is 90%, with the arrows indicating areas of necrosis.

[0262] In comparison, the tissue in the resection bed of the animals treated with hydrogel or .sup.90Y-microspheres alone showed a palpable macroscopic tumor growth and a histological examination showed the presence of viable VX2 carcinoma cells after 7, 14 and 21 days. FIGS. 14D to 14F depict the histology of a positive resection margin of the tumor bed after nephrectomy and treatment with a .sup.90Y microspheres—only after 7, 14 and 21 days, respectively, and FIGS. 14G to 14I depict the histology of a positive resection margin of the tumor bed after nephrectomy and treatment with hydrogel-only after 7, 14 and 21 days, respectively. FIGS. 14D to 14F show that the percentage of necrotic cells 7, 14 and 21 days post-injection of .sup.90Y microspheres-only is 20%. In FIGS. 14G to 14I histology slides, viable tumor cells can be seen, within a 5% area of necrosis after treatment with a hydrogel. The percentage necrosis was quantified in the histological evaluations performed on the harvested residual tumors after H&E staining. As shown in graph of FIG. 14J, both the groups treated with .sup.90Y matrix composition and .sup.90Y-only were significantly more effective (*=p<0.05; **=p<0.005;***=p<0.0005; ***=p<0.0005, Mann-Whitney test) than the matrix-only treatment group, to induce necrosis at each time points. Moreover, after three weeks, the rabbits treated with .sup.90Y matrix composition showed a higher necrosis than any of the other treated groups (***=p<0.0005. Mann-Whitney test).

[0263] The Western Blot analyses depicted in FIG. 15 further show an increase in p53 protein expression, a marker of tumor necrosis, which was detected especially at the 3 week observation point and is consistent with the increase of necrosis detected by histological evaluation in the study groups.

[0264] Tumor volume was also compared at selected time-points, as depicted in FIG. 16. This comparison was used to assess the ability of each treatment group to slow or impair tumor growth. Both the .sup.90Y matrix composition and .sup.90Y-only treatment group were significantly more effective (**=p<0.005; Mann-Whitney test) than the matrix-only group to inhibit tumor growth after two weeks. More surprisingly, however, after three weeks, rabbits treated with the .sup.90Y matrix composition showed a statically significant tumor volume inhibition larger than any of the other treated groups (*=p<0.05. Mann-Whitney test). It was not expected that the .sup.90Y matrix composition therapy could outperform .sup.90Y-only therapy.

[0265] The total levels of .sup.90Y in the resected tissue in the rabbits treated with a .sup.90Y-matrix composition and .sup.90Y-only (without matrix) are included below:

TABLE-US-00015 .sup.90Y # Days post- Treatment (CPM) Organ treatment type 75727 Injection site 7 .sup.90Y + matrix 10106 Injection site 14 .sup.90Y + matrix 287 Liver 7 .sup.90Y + matrix 176 Liver 14 .sup.90Y + matrix 351 Lung 7 .sup.90Y + matrix 282 Lung 14 .sup.90Y + matrix 411 Heart 7 .sup.90Y + matrix 216 Heart 14 .sup.90Y + matrix 400 Right kidney 7 .sup.90Y + matrix 280 Right kidney 14 .sup.90Y + matrix 6000 Injection site 7 .sup.90Y only 4000 Injection site 14 .sup.90Y only 200 Liver 7 .sup.90Y only 150 Liver 14 .sup.90Y only 200 Lung 7 .sup.90Y only 130 Lung 14 .sup.90Y only 197 Heart 7 .sup.90Y only 106 Heart 14 .sup.90Y only 300 Right kidney 7 .sup.90Y only 120 Right kidney 14 .sup.90Y only

[0266] Furthermore, due to the application of the hydrogel matrix containing .sup.90Y microspheres, the system described in this study for administering the composition in the resection bed represents a multimodal approach to the treatment of solid tumors that appears to achieve higher counts than .sup.90Y injection alone, using the same activity level.

[0267] The viscosity and density of the hydrogel matrix (hydrogel) allows the hydrogel mixture to be directly injected or layered within the resection site, ensuring homogeneous distribution, an increase in the local concentration of the .sup.90Y radiation agent, longer retention in situ and low or no dispersion of the .sup.90Y spheres, thus potentially limiting systemic side effects.

[0268] Through this study, a high concentration of .sup.90Y levels in the .sup.90Y-loaded matrix persisted at the administration site for a longer period of time, when compared to the treatment of rabbits injected with .sup.90Y spheres alone, achieving complete destruction of residual tumor cells (positive margins) created in our animal model.

[0269] These results demonstrate that use of the .sup.90Y microspheres and hydrogel combination achieves a high concentration of .sup.90Y for a prolonged period compared to the administration of .sup.90Y microspheres alone, and also achieves homogeneous distribution, thus treating tumor cells in the animal model and potentially reducing the relative risk of local recurrence in the animals who received treatment with .sup.90Y-matrix compared to those receiving .sup.90Y alone. In addition, the evaluations carried out in animals treated with .sup.90Y-matrix, compared to the controls, revealed no levels of radioactivity in the blood, no myelosuppression, no renal, cardiac or pulmonary toxicity and no intestinal perforations or bleeding related to the spread of the .sup.90Y microspheres, as opposed to the findings observed in the animals receiving .sup.90Y alone.

[0270] In an initial assessment, three rabbits were injected with .sup.90Y microspheres at a target location and a beta counter was used to quantify the distribution of .sup.90Y throughout the body. FIG. 17A illustrates that little activity remained at the target locations of each rabbit, and some activity was detected at every organ location, but with substantial activity concentrated at the spleen, small intestine, peritoneum and adrenal glands of at least some of the animals. In contrast, for the rabbits which underwent injection with the .sup.90Y-matrix at the same location, as depicted in FIG. 17B, activity was detected only at the target locations, with negligible or no activity detected at any of the other organ locations.

[0271] In a further analysis of the rabbits enrolled in the study, the distribution of .sup.90Y in selected organs was assessed at 7 days and 14 days, in the .sup.90Y-only and .sup.90Y-matrix groups, as illustrated in FIGS. 17C to 17F. As depicted in FIG. 17C, at 7 days, significant activity was detected at the tumor site for the additional .sup.90Y-only rabbits, but also significant activity in one rabbit at the bronchi and pancreas, as well as detectable activity at other sites such as the lymph nodes, liver, gallbladder, small intestine, colon, peritoneum and bladder. In contrast, the .sup.90Y-matrix rabbits at 7 days had significantly higher activity detected at the tumor site and minimal or no detectable activity in the other selected organ sites, as illustrated in FIG. 17D. At 14 days, the .sup.90Y-matrix rabbits still had lower but still significant activity at the tumor site, and still minimal or no detectable activity at the other selected sites (FIG. 17F), while the .sup.90Y-only rabbits at 14 days had substantially reduced activity at the tumor sites, but the .sup.90Y had further redistributed to the other organ sites, even those without detectable activity at 7 days (FIG. 17E), including the brain, thyroid, muscle, trachea, right lung, spleen, right adrenal, testicle, right kidney skin and bone. This data suggests that the .sup.90Y-matrix not only achieves higher therapeutic levels at the tumor sites, but also substantially resists delayed biodistribution to off-target organs that may occur between 7 and 14 days.

[0272] The radioisotope presence in the tumor area was analyzed at 1 and 3 week-time points by PET/CT imaging. The .sup.90Y activity was assessed in the injection area, as well as in other anatomical districts, by a Geiger-Muller counter. The results of .sup.90Y radiation intensity showed a reproducible and elevated level in the tumor injection site for .sup.90Y matrix composition treated rabbits, as compared with .sup.90Y-only treated rabbits, both at 1 week and 3-week time-points (p<0.05, Mann-Whitney test), as depicted in FIGS. 24A and 24B, respectively. The same analysis, when carried-out in the pre-specified distant organs, showed a much lower, almost undetectable signal in .sup.90Y matrix composition treated rabbits, as compared to the .sup.90Y-only treated rabbits, both at 1 week and 3-week time-points (FIGS. 24A and 24B, p<0.05, Mann-Whitney test). Based on the total amount of .sup.90Y signal detected in the distant non-target organs (non-tumor), .sup.90Y matrix composition therapy was shown to be very effective in retaining the .sup.90Y signal within the tumor injection site at all assessed time-points (FIGS. 25A and 25B, p<0.0005, Mann-Whitney test). As expected, the tumor injection site signal of .sup.90Y matrix composition therapy at 3 weeks was much lower than the same signal after 1 week of the compound injection. The free .sup.90Y-only treatment was far from being equally effective in the retention of the 90Y activity in the target injection site. The comparison of the coefficient of variation (CoV) of the activity levels detected in the tumor vs. non-tumor target areas confirmed a much lower variability of .sup.90Y matrix composition therapy when compared to .sup.90Y-only treatment (i.e., a higher repeatability) at both time-points. In the .sup.90Y matrix composition therapy group, at 1 week, the CoV was 5.69% for tumor and 14.33% for non-tumor sites, and at 3 weeks, the CoV was 1.89% for tumor and 29.56% for non-tumor sites. In the .sup.90Y-only therapy group, at 1 week, the CoV was 136% for tumor and 156.18% for non-tumor sites, and at 3 weeks, the CoV was 199.87% for tumor and 175.38% for non-tumor sites.

[0273] These results suggest that not only can .sup.90Y matrix composition therapy reduce sizably the rate of side effects or serious adverse events by localizing the radiotherapeutic effect and reducing or minimizing their escape locally and distantly through shunting, but may potentially increase the duration of disease-free progression and/or survival in patients treated with .sup.90Y matrix composition when compared to patients treated with .sup.90Y-only therapies by the same route, or by transarterial radioembolization. Furthermore, in the treatment of human patients, where there is an extensive pre-treatment workflow and assessment that is required before .sup.90Y radiotherapy can be performed, .sup.90Y matrix composition therapy may reliably reduce the risk associated with hepatopulmonary shunting or other off-target shunting such that portions or all of the pre-treatment workflow is not required or otherwise not performed. For example, in some further variations, .sup.90Y matrix composition therapy may be provided without requiring a pre-treatment imaging, e.g. a Technetium-99 scan, to assess for any shunting to the liver or lungs or other off-target locations, such as the ones associated with variceal or arteriovenous malformation. This is due to the reduction or minimization of .sup.90Y leakage via shunting, achieved by the localizing carrier. In turn, because pre-treatment imaging to assess shunting is not required, pre-treatment procedures to treat potential shunting are also not required. This can potentially reduce the time-to-treatment by one, two, three, four, five, six or seven days or more, because treatment is not delayed by pre-treatment shunt imaging, pre-treatment shunt reduction procedures, and pre-treatment rescanning to assess the effectiveness of the shunt reduction procedures. The shunt procedures that would no longer be required or performed may include arterial embolization, hepatic vein balloon occlusion, and variceal and AVM occlusion procedures. Because dosing adjustments to account for the shunting are no longer required, dosing calculations may also be simplified, e.g. no longer requiring adjustments based on the shunt fraction and/or lung dosing limit. Patients with substantial liver, lung or hepatopulmonary shunt fractions also do not need to be excluded from therapy anymore. One or more of these features of tumor treatment protocols may be included in the various treatments described herein.

Example 6 Breast Cancer

[0274] With the increasing occurrence of very small, radiologically detected subclinical lesions, several teams started considering, in the 1990's, most DCIS diagnoses as a possibly “indolent disease” and claimed that lumpectomy alone could be the treatment of choice in patients presenting with small size unifocal DCIS. The administration of 50 Gy in 25 fractions over 5 weeks to the whole breast was considered the standard until a few years ago, when the publication of the long-term results of important British and Canadian randomized studies proved the effectiveness and efficiency of schemes administered over shorter times (hypo-fractionated radiotherapy). DCIS is not normally palpable; the widespread use of screening mammography has allowed the diagnosis of increasing numbers of patients with DCIS, who now account for 20-30% of all mammographically detected breast cancers.

[0275] Women diagnosed with DCIS are treated with breast-conserving surgery (BCS) in more than ⅔ of the cases, with or without adjuvant therapy. The ipsilateral recurrence rate for women operated on by BCS for DCIS is 1-3% per year; long-term local recurrence rates can be higher than 35% for women operated by surgery alone and are much lower (15% at 10 yrs.) if external beam is added to surgery. Several factors are associated with the increased risk of local recurrence after BCS, among which the strongest one is whether DCIS has been fully excised or not:

[0276] 1. Margins that are clear from cancer or are more than 1 mm away from cancer have a much lower risk. If margins are not clear from cancer, patients should undergo new surgery to achieve a radical treatment; this can occur in around 20% of patients.

[0277] 2. Intraoperative radiotherapy (IORT), in which postoperative whole-breast irradiation is substituted by one session of radiotherapy with a dose of 16-20 Gy after surgical resection, allows the treatment to be completed on the same day.

[0278] 3. Recent trials such as electron intraoperative radiotherapy versus external beam radiotherapy for early breast cancer (ELIOT trial) and targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial) have demonstrated that IORT in selected groups of low-risk early breast cancer patients results in acceptable outcomes in terms of local disease control and could, therefore, serve as an alternative to conventional WBRT, representing a good compromise between treating all patients with external beam radio-therapy and not treating patients at all.

[0279] In the Consensus Statement regarding Accelerated Partial Breast Irradiation published on 2017 by American Society for Radiation Oncology (ASTRO), were provided some recommendations on selection criteria for “suitable” patients with low-risk DCIS. On the basis of the clinical experience accumulated in over 15 years of treatments based on trans-arterial infusion of .sup.90Y-coated microspheres, it is reasonable to assume that the administration of the appropriate activity of .sup.90Y in the surgical bed of the resected mammary gland should overcome some limitations of WBRT and IORT, and reduce drastically the chances of local recurrence which occurs in the vast majority of cases in the surgical bed. From data available in literature, a target dose of 20 Gy (≥18 Gy) is believed to be sufficient to effectively ablate the tissue surrounding the surgical bed of a resected DCIS lesion.

[0280] In one example, a clinical study on the use of a .sup.90Y-matrix composition was performed. The .sup.90Y-matrix composition comprised a combination of BIOGLUE® with SIR-SPHERES® loaded with Yttrium-90. In the study, microspheres pre-loaded with .sup.90Y were blended with a surgical glue for the radio-ablation of surgical margins following the resection of breast DCIS. The study was a multi-center, non-inferiority, pre-market, First-In-Human pilot study for patients with biopsy-proven breast DCIS, eligible to receive breast-conserving surgery. The primary objectives of this study are to assess the ability to reach the surgical bed of a DCIS resection as planned, and to deliver a pre-determined dose without treatment-limited clinical complications. Alternatively, the primary objective may be to assess the performance of the .sup.90Y-matrix composition in the delivery of an absorbed dose of 20 Gy (≥18 Gy) for the radio-ablative procedure of surgical margins following DCIS resection. The secondary objectives of this study were to evaluate the performance of the .sup.90Y-matrix composition through imaging procedures (PET-CT and DW-MRI), to assess local and systemic toxicity, and to assess quality of life of enrolled patients. The subjects will be followed up for 1 to 3 months after radio-ablation of surgical margins with the .sup.90Y-matrix composition following DCIS resection. The study, however, will be considered concluded for each subject after the examination of the Magnetic Resonance-Diffusion Weighted Imaging or mammography. The total study duration per patient is of 15 weeks, with an enrollment period of 6 months. The primary endpoint of the study will be the ability to reach the surgical bed of the DCIS resection as planned, and to deliver a pre-determined dose without treatment-limiting clinical complications. The secondary endpoints will be (1) the volume/extent of surgical margin tissue ablated by the use of the .sup.90Y-glue matrix composition, following surgical resection of the segment containing the lesion, as measured by PET-CT (Positron Emission Tomography-Computerized Tomography) 2-6 hours after surgery and 24 hours after surgery, and by mammography or (if available) Magnetic Resonance-Diffusion Weighted Imaging (MRI-DW, Day 30); (2) the safety of the procedure, as determined by vital signs, laboratory tests, type and severity of any adverse events and/or device deficiency or usability associated with the procedure of radio-ablation following surgical resection; and (3) the quality of life of the enrolled patients, as measured by the EORTC QLQ-C30 and BR23 Questionnaires.

[0281] A sample size of 10 to 20 subjects will be enrolled. In further embodiments, a sample size of 20 subjects can achieve an 80% power to detect a non-inferiority primary endpoint using a one-side (alpha=0.025), one sample test. Because this FIH study explores the performance and safety of the .sup.90Y-matrix composition, an effect of 20 Gy delivered locally by the .sup.90Y-matrix composition has been deemed plausible by looking at results of similar studies. The non-inferiority margin of 18 Gy has been evaluated as clinically significant and the standard deviation has been assumed to be 3 Gy. Sample size estimation has been performed using SAS version 9.4.

[0282] The inclusion criteria for the study will be: [0283] Female, Age ≥50; [0284] Subjects with biopsy-proven breast DCIS, eligible to receive BCS and “suitable” for partial breast irradiation as per the latest ASTRO guidelines (Age ≥50; low to intermediate nuclear grade; resected with margins negative at ≥3 mm; Tis; Size ≤25 mm). [0285] Subjects may undergo subsequent External Beam Radiotherapy (EBRT) if deemed appropriate by the treating physician; [0286] Subjects with mammographic or Contrast-Enhanced Magnetic Resonance Imaging evidence of DCIS; [0287] Subjects with a localized DCIS (≥3 mm and ≤25 mm), with a location accessible to percutaneous ablation; [0288] Clinically negative axillary lymph nodes and no clinical findings suggestive of invasive breast cancer.

[0289] The exclusion criteria for the study will be: [0290] Female, Age ≥50; [0291] Histotype different from carcinoma; [0292] Paget carcinoma; [0293] Lesions located near to axilla region or cutaneous areas (≤15 mm); [0294] Presence of microcalcifications extending for more than 30 mm; [0295] Pregnancy or breast-feeding ongoing; [0296] Positive history for neoplasia (with the exclusion of carcinoma in situ of a portion or skin cancer surgically removed and contra lateral breast cancer without any sign of disease progression in the last 15 years).

[0297] Each subject will undergo imaging and have the DCIS lesion diagnosed and staged as follows: [0298] The surgical bed following resection of the target lesion will be treated with radio-ablation using the experimental device; [0299] An appropriate absorbed dose of 20 Gy (≥18 Gy) will be administered to the surgical bed following DCIS resection in order to achieve ablation; [0300] Within 7 days after the surgical procedure, the patients will return at site for the assessment of the volume of the effect of the administration of .sup.90Y-matrix composition on the surgical bed, as well as for its cosmetic and toxicity evaluation; [0301] 30 (±5) days later the surgical bed treated with radio-ablation will be assessed using Magnetic Resonance Diffusion Weighted Imaging or mammography in order to evaluate the extent of the ablated tissue.

[0302] Optionally, for the first five patients, additional patient assessment and clinical clearance will be performed. The clinical clearance will include validations of the follow-up data for at least 1 week, if no complications occurred, or 4 weeks, in case of complications. This will include validation of unscheduled contacts with the patient, if performed.

[0303] Once the diagnosis of DCIS is confirmed and the inclusion/exclusion criteria met, subjects will be enrolled in the study and admitted to the hospital the day before their scheduled surgery, according to the normal clinical practice. On the day of the surgery, subjects will undergo DCIS excision plus surgical bed ablation with a .sup.90Y-matrix composition, through a procedure that will require collaboration between the surgeon and the nuclear medicine specialist. Once the treatment is performed, subjects will return to the surgical ward and be discharged the day after the surgery/ablation procedure. Subjects will be followed-up 7, 30 and 90 days after surgery to assess their local and general conditions; at the end of follow-up, they may undergo subsequent external beam radiotherapy if deemed appropriate by the treating physician.

[0304] The subjects will be informed about the aims, procedures and possible risks of the study and will be asked to sign the informed consent form. Each screened subject will be identified by a progressive screening number. Subjects will be enrolled only after having signed the informed consent form before any other study procedure. All the patients followed by the investigational center will be checked for adherence to the inclusion and exclusion criteria. One or more of the following information will be collected, though the collection of the information need not be collected on the same exemplary schedule:

TABLE-US-00016 Surgery and Radio- Screening ablation Follow up Follow up Follow up V-1 V0 V1 V2 V3 Days -15 to 0 Day 0 Day 7 ± 2 Day 30 ± 5 Day 90 ± 7 Informed Consent X Demographic data and/or X Medical History Vital Signs and physical X X X X X measurements (e.g. BP, HR, height and weight) Inclusion and X Exclusion Criteria General and X X X X X Physical Examination ECG evaluation X DCIS Diagnosis − X Mammography + Ultrasound Mammary Ultrasound X Urinary pregnancy test X EORTC QLQ-C30 and X X X X BR23 Questionnaires Concomitant Medications X X X X X Hematology and X X X X X blood chemistry DCIS Surgery and BAT-90 X Delivery (preparation and administration to patients) Surgical Bed Evaluation X Blood Sampling (1, 3, 6 X and 12 hours after BAT-90 Implant Card X PET-CT (breast gland) 2/6/24 hours after surgery Whole body scintigraphy 16/24 hours after surgery Dosimetry X X MRI-Diffusion Weighted X X or (breast gland) mammography Safety and Tolerability X X X X Assessment/ Local Device Deficiencies X Cosmetic Evaluation X X X

[0305] If all the entry criteria are fulfilled, patients will be planned for the ablation procedure by using the .sup.90Y-matrix composition 1 week after screening. Each patient will be followed-up for any adverse events or adverse effects from the informed consent signature date, during the whole study duration. A blood sample will be collected for the following hematological and biochemical determinations at each study visit: [0306] Complete blood count with differential [0307] Electrophoretic protein pattern [0308] APTT [0309] INR [0310] Fibrinogen [0311] Blood glucose [0312] Blood urea nitrogen (BUN) [0313] Creatinine [0314] AST, ALT, total and fractionated bilirubin, GGT, LDH, alkaline phosphatase [0315] Serum ions: sodium, calcium, potassium, chloride [0316] Tumor marker (AFP)

[0317] Blood sampling to detect early blood disorders at 1, 3, 6 and 12 hours after .sup.90Y-matrix composition delivery at V.sub.0: [0318] Complete blood count with differential [0319] AST, ALT, total and fractionated bilirubin, GGT, LDH, alkaline phosphatase

[0320] All data for the study subjects will be presented using descriptive statistics as mean, standard deviation, median, minimum, maximum or frequency tables, as appropriate. For the primary endpoint a confidence interval (CI) with a significance level of 5% will be estimated and the lower boundary of the CI will be compared to the non-inferiority margin in order to test the non-inferiority. Secondary endpoints involve the evaluation of quality of life (as measured by the EORTC QLQ-C30 and BR23 Questionnaires), the evaluation of the volume/extent of surgical margin tissue ablated (as measured by PET-CT and by Mammography or Magnetic Resonance-Diffusion Weighted Imaging) and the demonstration of the safety profile of .sup.90Y-matrix composition. Scores of quality of life questionnaires, volume/extent of surgical margin tissue ablated and their change over time will be evaluated by descriptive statistics. Incidence of adverse events, with regards also to the relationship with the .sup.90Y-matrix composition, will be calculated for all patients, along with their severity and the seriousness. Safety assessments will consist of recording and tabulating all adverse events, as well as with an analysis of changes in vital signs and laboratory parameters. Descriptive statistics will be provided for safety variables.

[0321] For one exemplary procedure, a syringe size, 2 mL or 5 mL, of the BIOGLUE® will be selected based on the size(s) or total volume(s) of the tumor as determined on the pre-procedure work-up. .sup.90Y-matrix composition is prepared during the pre-procedure set-up as follows:

[0322] 1. Unpack SIR-SPHERES® microspheres, leaving shipping vial in lead pot.

[0323] 2. Place on the bench top in a lead or acrylic shielded box if available.

[0324] 3. Remove the SIR-SPHERES® microspheres shipping vial from the lead pot and shake vigorously to disperse the SIR-SPHERES® microspheres.

[0325] 4. Using a dose calibrator, such as a gamma camera, to determine the activity in the shipping vial and return it to the lead pot.

[0326] 5. Determine the volume to be withdrawn to provide the required patient radiation dose. The following tables show the activity values of SIR-SPHERES® to be inserted into the 2 ml or 5 ml BIOGLUE® syringe, depending on the radius of the tumor bed. In order to calculate the activity, a vial of SIR-SPHERES® containing a 3 GBq/5 ml dose was considered. Moreover, it has been considered a residual of 300 microliters will remain in the BIOGLUE® syringe at the end of the treatment on the patient. The table also shows the volumes of SIR-SPHERES® to be placed into the BIOGLUE® syringe in ratios of 1:4 (glutaraldehyde: bovine albumin) using the 2 ml/5 ml syringe respectively. For tumor sizes less than 50 mm radius, a 2 mL syringe is selected, and assuming that the SIR-SPHERES® and BIOGLUE® are uniformly mixed and the maximum amount of the mixture is dispensed, leaving a nominal 300 μL residual of the mixture in the syringe:

TABLE-US-00017 Sub-volumes of Amount .sup.90Y suspension .sup.90Y loaded into Ex- suspen- each syringe Com- pected sion chamber bined Tumor Syringe with- Glutar- Vol- Injected Residual radius Activity drawn BSA aldehyde ume Activity Activity (mm) (MBq) (μL) (μL) (μL) (μL) (MBq) (MBq) 20 20 100 20 80 2.100 17.1 2.9 25 25 125 25 100 2.125 21.5 3.5 30 35 175 35 140 2.175 30.2 4.8 35 50 250 50 200 2.250 43.3 6.7 40 70 350 70 280 2.350 61.1 8.9 45 90 450 90 360 2.450 79.0 11.0

[0327] For tumor sizes from 50 mm radius to 70 mm radius or higher, a 5 mL syringe is selected, and assuming that the SIR-SPHERES® and BIOGLUE® are uniformly mixed and the maximum amount of the mixture is dispensed, leaving a nominal 300 μL residual of the mixture in the syringe:

TABLE-US-00018 Sub-volumes of Amount .sup.90Y suspension .sup.90Y loaded into Ex- suspen- each syringe Com- pected sion chamber bined Tumor Syringe with- Glutar- Vol- Injected Residual radius Activity drawn BSA aldehyde ume Activity Activity (mm) (MBq) (μL) (μL) (μL) (μL) (MBq) (MBq) 45 90 450 90 360 5.450 85.0 5.0 50 110 550 110 440 5.550 104.1 5.9 55 130 650 130 520 5.650 123.1 6.9 60 140 700 140 560 5.700 132.6 7.4 65 150 750 150 600 5.750 142.2 7.8

[0328] 6. Partially remove the aluminum seal of the SIR-SPHERES(R) microspheres shipping vial, clean with alcohol swab.

[0329] 7. Insert a 25-gauge needle through the septum of the shipping vial to create a vent, ensuring the needle is well clear of the contents in the shipping vial.

[0330] 8. Use a shielded 5 ml syringe with a 20-22 gauge spinal needle at least 70 mm long to puncture the septum of the SIR-Spheres microspheres shipping vial, and quickly draw back and forth several times in order to mix the SIR-Spheres microspheres thoroughly.

[0331] 9. Quickly withdraw the pre-calculated patient radiation dose and transfer in the two chambers of the BIOGLUE® syringe as described in the following points 10-13.

[0332] 10. Remove the double-chamber syringe cap containing the glue components.

[0333] 11. Distribute the microspheres in the double chamber syringe of the glue respecting the ratio of 4:1 (80% in the BSA chamber, 20% in the glutaraldehyde chamber), as reported in the tables before.

[0334] 12. Reinsert the cap on the syringe.

[0335] 13. Verify the patient dose by re-measuring the activity in the shipping vial with the dose calibrator, and correct, if necessary.

[0336] 14. Place the syringe in a radioprotective container suitable for the transport into the operating room/radiology procedure room.

[0337] 15. At the operating room/radiology procedure room, the prepared syringe/injector system with the .sup.90Y is removed from the radioprotective container.

[0338] 16. The sterile package containing the mixing-tip is opened.

[0339] 17. Hold the syringe upright, and tap the syringe until any air bubbles in the liquids rise to the top of the syringe

[0340] 18. Connect the sterile mixing-tip applicator contained in the glue package.

[0341] 19. Briefly shake the syringe.

[0342] 20. Apply the compound in the surgical cavity pushing on the pistons of the syringe

[0343] 21. Wait for the compound to polymerize (e.g. wait a few seconds).

[0344] 22. Proceed to suture the area.

[0345] The actual amount to be injected will be decided by the nuclear medicine specialist performing the procedure of radio-ablation, depending on the size of the surgical resection area (tumor bed) to be ablated and on his/her clinical judgement.

[0346] For the ablation procedure, the patient will undergo preparation for ablation procedure as per standard procedure of the treating facility. The patient will be prepped and draped in the usual sterile fashion, and anesthesia will be achieved. The target area will be identified by the surgeon intra-operatively, also using an appropriate marker/ink.

[0347] For the dosimetric evaluation, assuming that the radiotracer leakage is negligible/absent, two PET/CT scans of the breast region will be acquired, the first one between 2/6 hours post injection (p.i.) and the second one 24 hours p.i. These two scans will enable us to confirm that the time-activity curve follows a physical decay, accordingly to the preclinical data. The dose calculation will be performed by using the MIRD formalism (OLINDA/EXM software). In particular, for the lesion dose, the unit-density sphere model available in OLINDA/EXM will be used, assuming a discoid morphology and a uniform distribution.

[0348] In order to confirm the radiotracer biodistribution, the patients will undergo one whole-body scan acquired by SPECT/CT device: the acquisition will be performed between 16-24 hours p.i. This information is useful to confirm that the radiotracer remains confined in the tumor bed.

[0349] After discharge, patients will be followed up for 90 days. The study will be considered concluded for each subject after the post-ablation evaluation (V3); during the follow-up, however, information will be collected on any adverse event that might be related with the radio-ablation procedure and included in the clinical research form.

[0350] Adverse events will be classified according to established classification systems, such as the Common Terminology Criteria for Adverse Events v5.0.

[0351] At the conclusion of the procedure, the needle, the syringe and any other components must be disposed of, following the institution's standard operating procedure for handling biohazardous and/or radioactive materials.

[0352] In some further variations of the breast cancer treatment procedures, .sup.90Y matrix composition therapy may be provided without requiring a pre-treatment imaging, e.g. a Technetium-99 scan, to assess for any shunting to the liver or lungs or other off-target locations, including varices and AVMs. In some variations, because pre-treatment imaging to assess shunting is not required, pre-treatment procedures to treat potential shunting are also not required. This may result in reducing the time-to-treatment by one, two, three, four, five, six or seven days or more, because treatment is not delayed by pre-treatment shunt imaging, pre-treatment shunt reduction procedures, and pre-treatment rescanning to assess the effectiveness of the shunt reduction procedures. The shunt procedures that would no longer be required or performed may include arterial embolization, hepatic vein balloon occlusion, and variceal and AVM occlusion procedures. Because dosing adjustments to account for the shunting are no longer required, dosing calculations may also be simplified, e.g. no longer requiring adjustments based on the shunt fraction and/or lung dosing limit. Patients with substantial liver, lung or hepatopulmonary shunt fractions also do not need to be excluded from therapy anymore.

Example 7: Breast Cancer

[0353] In another exemplary study design or treatment regimen, the patient selection, monitoring and follow-up are as disclosed for Example 6 above, but the procedure, kit and/or dosing may be different. In this example, the product comprises the combination of a surgical glue, itself a combination of bovine serum albumin and glutaraldehyde in a 4:1 ratio, and microspheres covered with 3-emitting .sup.90Y isotope. The kit may further comprise one or more syringe shielding devices to protect the user from inadvertent radioactivity exposure.

[0354] The kit may be indicated for the ablation of surgical margins after conservative breast surgery, and is contraindicated in patients with known sensitivity to materials of bovine origin or other glue components. One example of a dosing regimen that utilizes a 2 mL BIOGLUE® syringe along with SIR-SPHERES® to achieve a dose at the tumor bed of 20 Gy or ≥18 Gy is:

TABLE-US-00019 Volumes of .sup.90Y suspension Loaded into Each Syringe Combined .sup.90Y Chamber .sup.90Y-Glue Matrix micro- Bovine Concen- Tumor Nominal sphere Glutar- serum tration Residual Injected radius Activity volume aldehyde albumin Vol. (MBq/ Activity Activity (mm) (MBq) (μL) (μL) (μL) (mL) mL) (MBq) (MBq) 20-24 20 66.7 13.3 53.3 2.1 9.7 2.9 17.1 25-29 25 83.3 16.7 66.7 2.1 12.0 3.6 21.4 30-34 35 116.7 23.3 93.3 2.1 16.5 5.0 30.0 35-39 50 166.7 33.3 133.3 2.2 23.1 6.9 43.1 40-44 70 233.3 46.7 186.7 2.2 31.3 9.4 60.6 45-49 90 300.0 60.0 240.0 2.3 39.1 11.7 78.3 50-54 110 366.7 73.3 293.3 2.4 46.5 13.9 96.1

[0355] In some further embodiments, the volume of .sup.90Y microsphere solution that is loaded into the .sup.90Y-matrix syringe may be adjusted based on the nominal decay hour period (x:00 to x:59 per×hour) and tumor size as follows:

TABLE-US-00020 Tumor Bed Radius: 20 mm to 24 mm Volumes of .sup.90Y suspension Loaded into Each Syringe Combined Chamber .sup.90Y-Glue Matrix .sup.90Y micro- Bovine Concen- Nominal sphere Glutar- serum tration Residual Injected Time Activity volume aldehyde albumin Vol. (MBq/ activity activity (h) (MBq) (μL) (μL) (μL) (mL) mL) (MBq) (MBq)  0:00 20.0 66.7 13.3 53.3 2.1 9.7 2.9 17.1  1:00 20.0 67.4 13.5 53.9 2.1 9.7 2.9 17.1  2:00 20.0 68.1 13.6 54.5 2.1 9.7 2.9 17.1  3:00 20.0 68.9 13.8 55.1 2.1 9.7 2.9 17.1  4:00 20.0 69.6 13.9 55.7 2.1 9.7 2.9 17.1  5:00 20.0 70.4 14.1 56.3 2.1 9.7 2.9 17.1  6:00 20.0 71.1 14.2 56.9 2.1 9.7 2.9 17.1  7:00 20.0 71.9 14.4 57.5 2.1 9.7 2.9 17.1  8:00 20.0 72.7 14.5 58.2 2.1 9.6 2.9 17.1  9:00 20.0 73.5 14.7 58.8 2.1 9.6 2.9 17.1 10:00 20.0 74.3 14.9 59.4 2.1 9.6 2.9 17.1 11:00 20.0 75.1 15.0 60.1 2.1 9.6 2.9 17.1 12:00 20.0 75.9 15.2 60.7 2.1 9.6 2.9 17.1 13:00 20.0 76.7 15.3 61.4 2.1 9.6 2.9 17.1 14:00 20.0 77.6 15.5 62.1 2.1 9.6 2.9 17.1 15:00 20.0 78.4 15.7 62.7 2.1 9.6 2.9 17.1 16:00 20.0 79.3 15.9 63.4 2.1 9.6 2.9 17.1 17:00 20.0 80.1 16.0 64.1 2.1 9.6 2.9 17.1 18:00 20.0 81.0 16.2 64.8 2.1 9.6 2.9 17.1 19:00 20.0 81.9 16.4 65.5 2.1 9.6 2.9 17.1 20:00 20.0 82.8 16.6 66.2 2.1 9.6 2.9 17.1 21:00 20.0 83.7 16.7 66.9 2.1 9.6 2.9 17.1 22:00 20.0 84.6 16.9 67.7 2.1 9.6 2.9 17.1 23:00 20.0 85.5 17.1 68.4 2.1 9.6 2.9 17.1

TABLE-US-00021 Tumor Bed Radius: 25 mm to 29 mm Volumes of .sup.90Y suspension Loaded into Each Syringe Combined Chamber .sup.90Y-Glue Matrix .sup.90Y micro- Bovine Concen- Nominal sphere Glutar- serum tration Residual Injected Time Activity volume aldehyde albumin Volume (MBq/ activity activity (h) (MBq) (μL) (μL) (μL) (mL) mL) (MBq) (MBq)  0:00 25.0 83.3 16.7 66.7 2.1 12.0 3.6 21.4  1:00 25.0 84.2 16.8 67.4 2.1 12.0 3.6 21.4  2:00 25.0 85.2 17.0 68.1 2.1 12.0 3.6 21.4  3:00 25.0 86.1 17.2 68.9 2.1 12.0 3.6 21.4  4:00 25.0 87.0 17.4 69.6 2.1 12.0 3.6 21.4  5:00 25.0 88.0 17.6 70.4 2.1 12.0 3.6 21.4  6:00 25.0 88.9 17.8 71.1 2.1 12.0 3.6 21.4  7:00 25.0 89.9 18.0 71.9 2.1 12.0 3.6 21.4  8:00 25.0 90.9 18.2 72.7 2.1 12.0 3.6 21.4  9:00 25.0 91.9 18.4 73.5 2.1 12.0 3.6 21.4 10:00 25.0 92.9 18.6 74.3 2.1 11.9 3.6 21.4 11:00 25.0 93.9 18.8 75.1 2.1 11.9 3.6 21.4 12:00 25.0 94.9 19.0 75.9 2.1 11.9 3.6 21.4 13:00 25.0 95.9 19.2 76.7 2.1 11.9 3.6 21.4 14:00 25.0 97.0 19.4 77.6 2.1 11.9 3.6 21.4 15:00 25.0 98.0 19.6 78.4 2.1 11.9 3.6 21.4 16:00 25.0 99.1 19.8 79.3 2.1 11.9 3.6 21.4 17:00 25.0 100.2 20.0 80.1 2.1 11.9 3.6 21.4 18:00 25.0 101.2 20.2 81.0 2.1 11.9 3.6 21.4 19:00 25.0 102.4 20.5 81.9 2.1 11.9 3.6 21.4 20:00 25.0 103.5 20.7 82.8 2.1 11.9 3.6 21.4 21:00 25.0 104.6 20.9 83.7 2.1 11.9 3.6 21.4 22:00 25.0 105.7 21.1 84.6 2.1 11.9 3.6 21.4 23:00 25.0 106.9 21.4 85.5 2.1 11.9 3.6 21.4

TABLE-US-00022 Tumor Bed Radius: 30 mm to 34 mm Volumes of .sup.90Y suspension Loaded into Each Syringe Combined Chamber .sup.90Y-Glue Matrix .sup.90Y micro- Bovine Concen- Nominal sphere Glutar- serum tration Residual Injected Time Activity volume aldehyde albumin Volume (MBq/ activity activity (h) (MBq) (μL) (μL) (μL) (mL) mL) (MBq) (MBq)  0:00 35.0 116.7 23.3 93.3 2.1 16.5 5.0 30.0  1:00 35.0 117.9 23.6 94.4 2.1 16.5 5.0 30.0  2:00 35.0 119.2 23.8 95.4 2.1 16.5 5.0 30.0  3:00 35.0 120.5 24.1 96.4 2.1 16.5 5.0 30.0  4:00 35.0 121.8 24.4 97.5 2.1 16.5 4.9 30.1  5:00 35.0 123.2 24.6 98.5 2.1 16.5 4.9 30.1  6:00 35.0 124.5 24.9 99.6 2.1 16.5 4.9 30.1  7:00 35.0 125.9 25.2 100.7 2.1 16.5 4.9 30.1  8:00 35.0 127.2 25.4 101.8 2.1 16.5 4.9 30.1  9:00 35.0 128.6 25.7 102.9 2.1 16.4 4.9 30.1 10:00 35.0 130.0 26.0 104.0 2.1 16.4 4.9 30.1 11:00 35.0 131.4 26.3 105.1 2.1 16.4 4.9 30.1 12:00 35.0 132.8 26.6 106.3 2.1 16.4 4.9 30.1 13:00 35.0 134.3 26.9 107.4 2.1 16.4 4.9 30.1 14:00 35.0 135.8 27.2 108.6 2.1 16.4 4.9 30.1 15:00 35.0 137.2 27.4 109.8 2.1 16.4 4.9 30.1 16:00 35.0 138.7 27.7 111.0 2.1 16.4 4.9 30.1 17:00 35.0 140.2 28.0 112.2 2.1 16.4 4.9 30.1 18:00 35.0 141.8 28.4 113.4 2.1 16.3 4.9 30.1 19:00 35.0 143.3 28.7 114.6 2.1 16.3 4.9 30.1 20:00 35.0 144.9 29.0 115.9 2.1 16.3 4.9 30.1 21:00 35.0 146.4 29.3 117.1 2.1 16.3 4.9 30.1 22:00 35.0 148.0 29.6 118.4 2.1 16.3 4.9 30.1 23:00 35.0 149.6 29.9 119.7 2.1 16.3 4.9 30.1

TABLE-US-00023 Tumor Bed Radius: 35 mm to 39 mm Volumes of .sup.90Y suspension Loaded into Each Syringe Combined Chamber .sup.90Y-Glue Matrix .sup.90Y micro- Bovine Concen- Nominal sphere Glutar- serum tration Residual Injected Time Activity volume aldehyde albumin Vol. (MBq/ activity activity (h) (MBq) (μL) (μL) (μL) (mL) mL) (MBq) (MBq)  0:00 50.0 166.7 33.3 133.3 2.2 23.1 69.2 43.1  1:00 50.0 168.5 33.7 134.8 2.2 23.1 6.9 43.1  2:00 50.0 170.3 34.1 136.3 2.2 23.0 6.9 43.1  3:00 50.0 172.2 34.4 137.7 2.2 23.0 6.9 43.1  4:00 50.0 174.0 34.8 139.2 2.2 23.0 6.9 43.1  5:00 50.0 175.9 35.2 140.7 2.2 23.0 6.9 43.1  6:00 50.0 177.9 35.6 142.3 2.2 23.0 6.9 43.1  7:00 50.0 179.8 36.0 143.8 2.2 22.9 6.9 43.1  8:00 50.0 181.7 36.3 145.4 2.2 22.9 6.9 43.1  9:00 50.0 183.7 36.7 147.0 2.2 22.9 6.9 43.1 10:00 50.0 185.7 37.1 148.6 2.2 22.9 6.9 43.1 11:00 50.0 187.7 37.5 150.2 2.2 22.9 6.9 43.1 12:00 50.0 189.8 38.0 151.8 2.2 22.8 6.9 43.1 13:00 50.0 191.8 38.4 153.5 2.2 22.8 6.8 43.2 14:00 50.0 193.9 38.8 155.1 2.2 22.8 6.8 43.2 15:00 50.0 196.0 39.2 156.8 2.2 22.8 6.8 43.2 16:00 50.0 198.2 39.6 158.5 2.2 22.7 6.8 43.2 17:00 50.0 200.3 40.1 160.3 2.2 22.7 6.8 43.2 18:00 50.0 202.5 40.5 162.0 2.2 22.7 6.8 43.2 19:00 50.0 204.7 40.9 163.8 2.2 22.7 6.8 43.2 20:00 50.0 206.9 41.4 165.6 2.2 22.7 6.8 43.2 21:00 50.0 209.2 41.8 167.4 2.2 22.6 6.8 43.2 22:00 50.0 211.5 42.3 169.2 2.2 22.6 6.8 43.2 23:00 50.0 213.8 42.8 171.0 2.2 22.6 6.8 43.2

TABLE-US-00024 Tumor Bed Radius: 40 mm to 44 mm Volumes of .sup.90Y suspension Loaded into Each Syringe Combined Chamber .sup.90Y-Glue Matrix .sup.90Y micro- Bovine Concen- Nominal sphere Glutar- serum tration Residual Injected Time Activity volume aldehyde albumin Vol. (MBq/ activity activity (h) (MBq) (μL) (μL) (μL) (mL) mL) (MBq) (MBq)  0:00 70.0 233.3 46.7 186.7 2.2 31.3 9.4 60.6  1:00 70.0 235.9 47.2 188.7 2.2 31.3 9.4 60.6  2:00 70.0 238.4 47.7 190.7 2.2 31.3 9.4 60.6  3:00 70.0 241.0 48.2 192.8 2.2 31.2 9.4 60.6  4:00 70.0 243.7 48.7 194.9 2.2 31.2 9.4 60.6  5:00 70.0 246.3 49.3 197.0 2.2 31.2 9.3 60.7  6:00 70.0 249.0 49.8 199.2 2.2 31.1 9.3 60.7  7:00 70.0 251.7 50.3 201.4 2.3 31.1 9.3 60.7  8:00 70.0 254.4 50.9 203.5 2.3 31.0 9.3 60.7  9:00 70.0 257.2 51.4 205.8 2.3 31.0 9.3 60.7 10:00 70.0 260.0 52.0 208.0 2.3 31.0 9.3 60.7 11:00 70.0 262.8 52.6 210.3 2.3 30.9 9.3 60.7 12:00 70.0 265.7 53.1 212.5 2.3 30.9 9.3 60.7 13:00 70.0 268.6 53.7 214.9 2.3 30.9 9.3 60.7 14:00 70.0 271.5 54.3 217.2 2.3 30.8 9.2 60.8 15:00 70.0 274.5 54.9 219.6 2.3 30.8 9.2 60.8 16:00 70.0 277.4 55.5 221.9 2.3 30.7 9.2 60.8 17:00 70.0 280.5 56.1 224.4 2.3 30.7 9.2 60.8 18:00 70.0 283.5 56.7 226.8 2.3 30.7 9.2 60.8 19:00 70.0 286.6 57.3 229.3 2.3 30.6 9.2 60.8 20:00 70.0 289.7 57.9 231.8 2.3 30.6 9.2 60.8 21:00 70.0 292.9 58.6 234.3 2.3 30.5 9.2 60.8 22:00 70.0 296.0 59.2 236.8 2.3 30.5 9.1 60.9 23:00 70.0 299.3 59.9 239.4 2.3 30.4 9.1 60.9

TABLE-US-00025 Tumor Bed Radius: 45 mm to 49 mm Volumes of .sup.90Y suspension Loaded into Each Syringe Combined Chamber .sup.90Y-Glue Matrix .sup.90Y micro- Bovine Concen- Nominal sphere Glutar- serum tration Residual Injected time Activity volume aldehyde albumin Vol. (MBq/ activity activity (h) (MBq) (μL) (μL) (μL) (mL) mL) (MBq) (MBq)  0:00 90.0 300.0 60.0 240.0 2.3 39.1 11.7 78.3  1:00 90.0 303.3 60.7 242.6 2.3 39.1 11.7 78.3  2:00 90.0 306.6 61.3 245.3 2.3 39.0 11.7 78.3  3:00 90.0 309.9 62.0 247.9 2.3 39.0 11.7 78.3  4:00 90.0 313.3 62.7 250.6 2.3 38.9 11.7 78.3  5:00 90.0 316.7 63.3 253.3 2.3 38.8 11.7 78.3  6:00 90.0 320.1 64.0 256.1 2.3 38.8 11.6 78.4  7:00 90.0 323.6 64.7 258.9 2.3 38.7 11.6 78.4  8:00 90.0 327.1 65.4 261.7 2.3 38.7 11.6 78.4  9:00 90.0 330.7 66.1 264.5 2.3 38.6 11.6 78.4 10:00 90.0 334.3 66.9 267.4 2.3 38.6 11.6 78.4 11:00 90.0 337.9 67.6 270.3 2.3 38.5 11.5 78.5 12:00 90.0 341.6 68.3 273.3 2.3 38.4 11.5 78.5 13:00 90.0 345.3 69.1 276.3 2.3 38.4 11.5 78.5 14:00 90.0 349.1 69.8 279.3 2.3 38.3 11.5 78.5 15:00 90.0 352.9 70.6 282.3 2.4 38.3 11.5 78.5 16:00 90.0 356.7 71.3 285.4 2.4 38.2 11.5 78.5 17:00 90.0 360.6 72.1 288.5 2.4 38.1 11.4 78.6 18:00 90.0 364.5 72.9 291.6 2.4 38.1 11.4 78.6 19:00 90.0 368.5 73.7 294.8 2.4 38.0 11.4 78.6 20:00 90.0 372.5 74.5 298.0 2.4 37.9 11.4 78.6 21:00 90.0 376.5 75.3 301.2 2.4 37.9 11.4 78.6 22:00 90.0 380.6 76.1 304.5 2.4 37.8 11.3 78.7 23:00 90.0 384.8 77.0 307.8 2.4 37.7 11.3 78.7

TABLE-US-00026 Tumor Bed Radius: 50 mm to 54 mm Volumes of .sup.90Y suspension Loaded into Each Syringe Combined Chamber .sup.90Y-Glue Matrix .sup.90Y micro- Bovine Concentr Nominal sphere Glutar- serum Vol- ation Residual Injected time Activity volume aldehyde albumin ume (MBq/ activity activity (h) (MBq) (μL) (μL) (μL) (mL) mL) (MBq) (MBq)  0:00 110.0 366.7 73.3 293.3 2.4 46.5 13.9 96.1  1:00 110.0 370.7 74.1 296.5 2.4 46.4 13.9 96.1  2:00 110.0 374.7 74.9 299.8 2.4 46.3 13.9 96.1  3:00 110.0 378.8 75.8 303.0 2.4 46.2 13.9 96.1  4:00 110.0 382.9 76.6 306.3 2.4 46.2 13.8 96.2  5:00 110.0 387.1 77.4 309.6 2.4 46.1 13.8 96.2  6:00 110.0 391.3 78.3 313.0 2.4 46.0 13.8 96.2  7:00 110.0 395.5 79.1 316.4 2.4 45.9 13.8 96.2  8:00 110.0 399.8 80.0 319.9 2.4 45.8 13.8 96.2  9:00 110.0 404.2 80.8 323.3 2.4 45.8 13.7 96.3 10:00 110.0 408.6 81.7 326.9 2.4 45.7 13.7 96.3 11:00 110.0 413.0 82.6 330.4 2.4 45.6 13.7 96.3 12:00 110.0 417.5 83.5 334.0 2.4 45.5 13.7 96.3 13:00 110.0 422.1 84.4 337.6 2.4 45.4 13.6 96.4 14:00 110.0 426.6 85.3 341.3 2.4 45.3 13.6 96.4 15:00 110.0 431.3 86.3 345.0 2.4 45.2 13.6 96.4 16:00 110.0 436.0 87.2 348.8 2.4 45.2 13.5 96.5 17:00 110.0 440.7 88.1 352.6 2.4 45.1 13.5 96.5 18:00 110.0 445.5 89.1 356.4 2.4 45.0 13.5 96.5 19:00 110.0 450.4 90.1 360.3 2.5 44.9 13.5 96.5 20:00 110.0 455.3 91.1 364.2 2.5 44.8 13.4 96.6 21:00 110.0 460.2 92.0 368.2 2.5 44.7 13.4 96.6 22:00 110.0 465.2 93.0 372.2 2.5 44.6 13.4 96.6 23:00 110.0 470.3 94.1 376.2 2.5 44.5 13.4 96.6

[0356] The kit that may be used includes: [0357] two syringes (1 ml.) with Luer-lock, provided sterile [0358] two 22 G needles provided sterile [0359] two sterile needles (e.g. 20 G×70 mm), e.g. STERICAN® needles by B. Braun [0360] two radioprotective syringe holders, e.g. polymethylmethacrylate (PMMA) cylinders: [0361] one cylinder for the 2 ml. glue syringe (Cylinder “A”) [0362] one cylinder for the for 1 ml. syringe (Cylinder “B”) [0363] 1 sterile radio-protected box (for the transport in OR) not provided by BetaGlue;

[0364] The kit may optionally comprise the following components, though in other examples, these components may be provided sourced separately: [0365] one vial of .sup.90Y microspheres, such as SIR-SPHERES®, containing 3 GBq+/−10% in 5 ml. of Water For Injection (WFI), provided in a lead pot [0366] one syringe of two-component glue in a capped dual-chamber syringe (2 ml.), such as a 2 mL syringe of BIOGLUE®, provided in a box and/or other packaging

[0367] In addition, to the above kit, healthcare providers or sites licensed or authorized to provide radiotherapy will also have available and will use during the procedure: [0368] a sterile radio-protected box or container for transport of the vial of .sup.90Y microspheres [0369] a radio-protected waste receptacle [0370] forceps or tongs used to handle the vial of .sup.90Y microspheres [0371] a dose calibrator to measure radioactivity, such as a gamma camera [0372] alcohol pad

[0373] To initially prepare the radiotherapy for use:

[0374] 1. Open the box containing the glue syringe packaging

[0375] 2. Open the packaging containing the glue syringe in sterile fashion

[0376] 3. Remove the cap of the glue syringe

[0377] 4. Place the syringe of glue in its PMMA cylinder (Cylinder “A”)

[0378] 5. Open the lead pot containing the vial of .sup.90Y microspheres and remove the vial from the pot using the forceps

[0379] 6. Using a dose calibrator, measure the radioactivity of the .sup.90Y microspheres vial and confirm the radioactivity (measurement should report 3 GBq+/−10%)

[0380] 7. Place the vial back in the lead pot

[0381] 8. Partially remove any protective materials from around the vial and clean the vial with an alcohol pad

[0382] 9. Place one of the 20 G needles into the vial to reach the .sup.90Y microspheres and insert one of the 22 G needles in the vial for ventilation

[0383] 10. Place a 1 mL syringe into its PMMA cylinder (Cylinder “B”)

[0384] 11. Shake the lead pot with circulating movements for at least 10 seconds.

[0385] 12. Connect the 1 mL syringe to the 20 G needle and draw the amount of .sup.90Y microspheres for the glutaraldehyde chamber of the glue syringe according to the quantity reported in the below, for a glue syringe of 2 mL

[0386] 13. Inject the .sup.90Y microspheres into the glutaraldehyde component chamber of the glue syringe and dispose of the empty 1 mL syringe in a radio-protected waste box, without disposing the PMMA cylinder (Cylinder “B”) that contained the 1 mL syringe

[0387] 14. Place the second 1 mL syringe into the PMMA cylinder (Cylinder “B”) and connect the second 20 G×70 mmm needle

[0388] 15. Agitate or shake the lead pot with circulating movements for at least 10 seconds

[0389] 16. With the 1 mL syringe, draw the amount of .sup.90Y microspheres for the bovine serum albumin (BSA) chamber of the two-component glue syringe according to the quantity reported in tables above (for a two-component glue syringe of 2 mL). Adjust for any .sup.90Y decay

[0390] 17. Inject the .sup.90Y microspheres into the BSA component chamber of the two-component glue syringe and dispose of the empty 1 mL syringe with the 20 G×70 mm needle in a radio-protected waste receptacle. Do not dispose of the cylinder shield.

[0391] 18. Connect the mixing tip to the two-component glue syringe, now contains the pre-loaded glue and the .sup.90Y microspheres in the BSA component chamber

[0392] 19. Using the dose calibrator, measure the radioactivity of the .sup.90Y-matrix syringe using a gamma camera and place the syringe in the radio-protected box. The .sup.90Y-matrix syringe is now ready to be transported to the operating or procedure room.

[0393] The actual amount to be injected will be decided by the nuclear medicine specialist performing the procedure of radio-ablation, and may depend on the size of the surgical resection area (tumor bed) to be ablated and on clinical judgment. Before the delivery of therapy, the system may be further assembled with an exemplary mixing tip as described below:

[0394] 1. Remove the radio-protective PMMA cylinder containing the prepared .sup.90Y-matrix syringe from the radio-protective box, holding the syringe in the PMMA cylinder upright through the entire dispensing process to maintain any air bubbles in the upper part of the syringe

[0395] 2. Open the sterile packaging containing the mixing tip and remove the mixing tip from the packaging, checking the mixing tip collar to ensure that the pointer on the collar is directly above the largest of the two connection openings. If the pointer of the collar is not at the largest opening, rotate the locking collar on the tip body until the pointer is above the largest connection opening.

[0396] 3. With the syringe tip in the upright position, remove the cap. Align and attach the mixing tip to the syringe

[0397] 4. Lock the mixing tip by pushing the mixing tip firmly onto the syringe and rotating the mixing tip locking collar.

[0398] 5. Keeping the syringe upright, align the dual plunger heads to the corresponding large and small syringe. Insert and push the plunger into the back of the syringe until resistance is met, and then optionally recap the syringe.

[0399] Once the .sup.90Y-matrix syringe is assembled, the .sup.90Y radiotherapy may be administered via the following exemplary procedure: [0400] 1. Agitate the .sup.90Y-matrix syringe for at least 5 seconds, while the .sup.90Y-matrix syringe remains inserted in its PMMA cylinder [0401] 2. Remove the cap from the .sup.90Y-matrix syringe if needed [0402] 3. Push the plunger to remove any air bubbles [0403] 4. Apply the .sup.90Y-matrix immediately to the surgical cavity, by pushing the plunger [0404] 5. Confirm that the .sup.90Y-matrix has polymerized, by either waiting for a pre-determined amount of time, e.g. 60, 90, or 120 seconds, or by observing for phase changes in .sup.90Y-matrix via an imaging modality, e.g. fluoroscopy, CT, ultrasound or endoscopy. [0405] 6. Close the surgical site by suturing, stapling or gluing [0406] 7. Place the .sup.90Y-matrix syringe into the radio-protected container and dispose of it, with or without the PMMA cylinder

[0407] In some further variations of the breast cancer treatment procedures, .sup.90Y matrix composition therapy may be provided without requiring a pre-treatment imaging, e.g. a Technetium-99 scan, to assess for any shunting to the liver or lungs or other off-target locations, including varices and AVMs. In some variations, because pre-treatment imaging to assess shunting is not required, pre-treatment procedures to treat potential shunting are also not required. This may result in reducing the time-to-treatment by one, two, three, four, five, six or seven days or more, because treatment is not delayed by pre-treatment shunt imaging, pre-treatment shunt reduction procedures, and pre-treatment rescanning to assess the effectiveness of the shunt reduction procedures. The shunt procedures that would no longer be required or performed may include arterial embolization, hepatic vein balloon occlusion, and variceal and AVM occlusion procedures. Because dosing adjustments to account for the shunting are no longer required, dosing calculations may also be simplified, e.g. no longer requiring adjustments based on the shunt fraction and/or lung dosing limit. Patients with substantial liver, lung or hepatopulmonary shunt fractions also do not need to be excluded from therapy anymore.

Example 8: Hepatocellular Carcinoma

[0408] In another study, microspheres pre-loaded with .sup.90Y will be mixed with a surgical glue matrix for the radio-ablation of primary liver lesions, followed by their resection. In other variations of the study, however, resection is not necessarily performed after delivery of the radioisotope particles. Percutaneous ablation of hepatic lesions with a .sup.90Y-matrix composition may be a more effective therapy, minimizing local or systemic side effects. The use of this novel loco-regional approach seems to be appropriate for human treatment based on: [0409] time for application, with or without ultrasound guidance, in a range between 2 to 5 min; [0410] size of ablation, range between 3.8 to 5.3 cm in length and 4.0 to 5.0 cm in width; and [0411] absence of systemic side effects.

[0412] The subjects selected for the study will be both ablatable (i.e., amenable to percutaneous ablation) and resectable (i.e., judged such by the liver surgeon), as shown in the inclusion criteria. They will be offered surgical resection for early stage hepato-cellular carcinoma (HCC) within the usually expected time frame (35-40 days after diagnosis/staging), but by enrolling in the study they will also be offered a minimally-invasive procedure of percutaneous β-ablation of their lesion 5-10 days after diagnosis, to be then followed by hepatic surgery around 30 days afterwards, when all activity of .sup.90Y has long ceased (the half-life of .sup.9Y is 64.1 hours). The surgical resection will remove the whole liver segment containing the ablated lesion, thus allowing for a complete histological examination which is, in fact, much more accurate than any type of currently available imaging to assess the outcome of the ablation procedure. This type of study is normally known as “ablate-resect” study, and there are numerous examples of its use in medicine. The subjects will be followed up for 2-3 months after surgery, following the HCC radio-ablation with the .sup.90Y-matrix composition. The total study duration for each patient is about 14 weeks, with an enrollment period of 6 months.

[0413] The primary objective of this study is the assessment of the feasibility of this novel procedure, while the histological assessment of the resected specimen will offer useful information about its possible efficacy. If the hypothesis of a much more complete peri-HCC necrosis is supported, it will provide a more efficacious procedure of percutaneous ablation to the Early-Stage HCC population. In addition, since HCC is a complication of liver cirrhosis, the complete cure of one such lesion will have a possible impact on the outcome of cirrhotic patients, given the frequent appearance of new HCC lesions in other anatomical areas of the liver. The secondary objectives of this study include (1) to demonstrate an effective tumor mass necrosis after ablation with the .sup.90Y-matrix composition, (2) to evaluate the histological response after ablation with the .sup.90Y-matrix composition, (3) to evaluate the dosimetry of the .sup.90Y-matrix composition in the target tissue, (4) to assess quality of life of enrolled patients, and (5) to assess the local and systemic toxicity of the procedure.

[0414] This is a single-center, pre-market, pilot First-In-Human study for patients who will undergo an ablate-resect procedure for primary HCC. The primary study endpoint will be the ability to reach the HCC lesion as planned and to deliver an intra-tumoral pre-determined dose of the .sup.90Y-matrix composition without treatment-limiting clinical complications. The secondary study endpoints will be (1) the percentage of tumor mass necrosis and presence of viable cells in the treated lesion, assessed histologically after surgical resection of the segment containing the lesion, (2) the correct anatomical delivery of the .sup.90Y-matrix composition, as confirmed by PET-scan 24-48 hours after the procedure, (3) effective delivery of a pre-determined radioactivity dose to the target tissue (measured in Gy), (4) quality of life of the enrolled patients, as measured by the EORTC QLQ C-30/HCC18 questionnaires, and (5) safety: vital signs, laboratory tests, type and severity of any adverse events associated with the procedure of radio-ablation, with the surgical resection, and occurring in the period between the two treatments.

[0415] The patient population size will be 10 adult patients, male and female, with early stage HCC. The inclusion criteria will include: [0416] Subjects with hepatic lesions diagnosed as HCC—Early Stage; [0417] Subjects with a maximum of 7 non-subscapsular lesions with a maximum diameter of 50 mm, considered surgically resectable according to local standards; [0418] Subjects with at least one of the upper above mentioned lesions considered amenable to percutaneous ablation (maximum diameter 50 mm); [0419] Adult male and female subjects (aged over 18 years) [0420] Able to read, comprehend and willing to sign the informed consent form

[0421] The exclusion criteria for the study will be: [0422] Female subject who is pregnant or likely to become pregnant, or is breastfeeding; [0423] Subjects who have participated in another study within the past 3 months; [0424] Subjects not suitable for general anesthesia and abdominal surgery; [0425] Subjects with any known allergy to the .sup.90Y-matrix composition components, or the anesthetics; [0426] Subjects with contraindications to the procedure because of concomitant medical problems. [0427] Subjects with other concomitant malignancies [0428] Any clinical or laboratory disorder which in the investigator's opinion might contraindicate the subject's participation in the study.

[0429] The study procedures will include: [0430] Each subject will undergo imaging with Contrast-Enhanced Ultrasound (plus Histology), together with Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) or Computerized Tomography of the abdomen, in order to have the HCC lesions diagnosed and staged; [0431] One of the lesions (considered meeting the criteria for percutaneous ablation and intra-tumoral administration of the .sup.90Y-matrix composition) will be treated with radio-ablation using the experimental device; [0432] The proper and effective delivery of a pre-determined dose of the .sup.90Y-matrix composition will be assessed by PET 24-48 hrs. after the ablative procedure; [0433] The degree of necrosis of the treated lesion will be assessed by DW-MRI 21 days after the ablative procedure; [0434] 7-9 days after DW-MRI, the whole tumor mass will be surgically resected; [0435] The resected lesion (pre-treated with radio-ablation) will be sent for histological examination, in accordance with the procedures described in the protocol; and [0436] Follow-up will occur 2 months after surgery.

[0437] Collected data will be summarized by descriptive statistics. Continuous variables will be presented as number of cases, mean, and standard deviation, median with interquartile range, minimum and maximum. Categorical variables will be summarized using counts of subjects and percentages. For the primary endpoint, a confidence interval (CI) for the mean delivered dose and for the standard deviation with a significance level of 5% will be estimated. Secondary endpoints will be summarized by descriptive statistics and 95% confidence intervals. Surgical specimens will be processed by the pathologist for evaluation of surgical margins and will be observed for gross changes due to necrosis. Safety assessments will include recording of all adverse events (AEs) as classified using Common Terminology Criteria for Adverse Events v5.0, as well as of changes in vital signs and laboratory parameters.

[0438] Each subject will be informed about the aims, procedures and possible risks of the study and will be asked to sign the informed consent form. Each screened subject will be identified by a progressive screening number. Subjects will be enrolled only after having signed the informed consent form before any study procedure. All the patients monitored at the investigational center will be checked for adherence to the study inclusion and exclusion criteria.

[0439] The following information will be collected: [0440] Demographic data [0441] Height and weight [0442] Vital signs (e.g. blood pressure (BP); heart rate (HR); respiratory rate (RR)) [0443] ECG [0444] General and physical examination [0445] Medical and surgical history [0446] Alcohol consumption check [0447] Urine analysis, including Bence-Jones protein [0448] Pregnancy urine test for women in fertile age [0449] Concomitant medications/treatments [0450] Tumor evaluation using contrast-enhanced ultrasound plus histology (if applicable) [0451] Imaging of the liver will be made using Magnetic Resonance Imaging (MRI) or Computerized Tomography (CT) [0452] Imaging of the tumor will be performed using a PET scan [0453] The tumor will be staged using the TNM classification and the Barcelona Clinic staging algorithm, in addition to the mRECIST criteria [0454] Quality of life questionnaires (EORTC-QLQ C-30) and HCC18, will be administered to the patients

[0455] Patients will be instructed to contact immediately the research team in case of appearance of any adverse events, which might appear in the timeframe between initial screening and the day of the ablation procedure. On the day of the treatment with the .sup.90Y-matrix composition, each patient will undergo a pre-procedure review that will include: [0456] Vital signs (e.g. BP; HR; RR) [0457] General physical examination [0458] Tumor evaluation [0459] PET imaging (within 24-48 hours after ablation) [0460] Dosimetry assessment [0461] Concomitant medications [0462] Adverse events check [0463] Anesthesia for the injection of the .sup.90Y-matrix composition [0464] Contrast-enhanced ultrasonography [0465] Ablation by using the .sup.90Y-matrix composition

[0466] If all the entry criteria are fulfilled and the patients have signed the Informed Consent form, they will be scheduled for the β-ablation procedure using the .sup.90Y-matrix composition seven days after these screening tests. Each patient will be followed-up for any adverse events or adverse effects from the informed consent signature date, during the whole study duration. A blood sample will be collected for the following determinations: [0467] Complete blood count with differential [0468] Electrophoretic protein pattern [0469] Activated Partial Thromboplastin Time (APTT) [0470] International Normalized Ratio (INR) [0471] Fibrinogen [0472] Blood glucose [0473] Blood urea nitrogen (BUN) [0474] Creatinine [0475] Serum glutamic-oxaloacetic transaminase (AST/SGOT), alanine aminotransferase (ALT/SGPT), total and fractionated bilirubin, gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP). [0476] Serum ions: sodium, calcium, potassium, chloride [0477] Tumor marker (alpha-fetoprotein, AFP)

[0478] Pre-procedure checks will be performed before the performance of the ablative procedure, as follows: [0479] Adherence to inclusion and exclusion criteria [0480] Vital signs (BP; HR; RR) [0481] General and physical examination [0482] Concomitant medications/treatments

[0483] The .sup.90Y-matrix kit will include a radioisotope source and matrix source as described elsewhere herein, e.g. .sup.90Y microspheres from Sirtex Medical (SIRPSHERES®) and BIOGLUE® from Cryolife. In addition, the kit will include a dual-lumen catheter configured to attach to the dual-chamber syringe of the BIOGLUE® to facilitate delivery of the two matrix components separately through the catheter, so that the matrix does not gel or solidify inside the catheter during delivery. The catheter features are described above, along with its introducer needle and its stylet.

[0484] For the procedure, the syringe size, 2 mL or 5 mL, of the BIOGLUE® will be selected based on the size(s) or total volume(s) of the tumor as determined on the pre-procedure work-up. The .sup.90Y-matrix composition is prepared during the pre-procedure set-up as follows: [0485] 1. Open the box containing the vial of microspheres, leaving the vial in the lead container [0486] 2. Place on the bench in a lead or acrylic box if available [0487] 3. Partially remove the aluminum seal from the SIR-SPHERES® vial and clean with an alcohol swab [0488] 4. Insert a 25 G needle into the vial septum to create an opening, making sure the needle is clearly in the contents of the vial [0489] 5. Use a 5 ml syringe screened with a 20-22 G spinal needle at least 70 mm long to pierce the septum of the SIR-SPHERES® microspheres ampoule [0490] 6. Take 2 ml of suspension liquid and dispose of it [0491] 7. Using a dose calibrator, determine activity in the shipping vial and place it in the lead container [0492] 8. Determine the volume to be withdrawn to provide the required radiation dose to the hepatic lesion, depending on the size of the tumor bed.

[0493] For the calculation of the activity, a vial of SIR-SPHERES® was considered containing a concentration dose of 3 GBq/3 ml, after removal of a volume equal to 2 ml of supernatant and it was taken into account that in the dual-lumen catheter, at the end of use in patients, a volume of 158 μL remains. In other variations, however, a different amount of supernatant may be removed or added, or not changed at all. For tumor sizes less than 30 mm diameter, a 2 mL syringe is selected, and assuming that the SIR-SPHERES® and BIOGLUE® are uniformly mixed and the maximum amount of the mixture is dispensed, leaving a nominal 158 μL residual of the mixture in the catheter:

TABLE-US-00027 Subvolumes of .sup.90Y suspension Amount loaded into each Expected .sup.90Y syringe chamber Tumor Syringe suspension Glutar- Combined Injected Residual diameter Activity withdrawn BSA aldehyde Volume Activity Activity (mm) (MBq) (μL) (μL) (μL) (μL) (MBq) (MBq) 0.5 0.48 0.48 0.38 0.10 2.0005 0.44 0.04 10 2.4 2.4 1.9 0.5 2.002 2.2 0.2 15 7.03 7 5.6 1.4 2.007 6.48 0.6 20 15.75 15.8 12.6 3.2 2.016 14.5 1.2 25 29.82 29.8 23.9 6.0 2.030 27.5 2.3

[0494] For tumor sizes from 50 mm radius to 70 mm radius or higher, a 5 mL syringe is selected, and assuming that the SIR-SPHERES® and BIOGLUE® are uniformly mixed and the maximum amount of the mixture is dispensed, leaving a nominal 300 μL residual of the mixture in the syringe:

TABLE-US-00028 Subvolumes of .sup.90Y suspension Amount loaded into each Expected .sup.90Y syringe chamber Tumor Syringe suspension Glutar- Combined Injected Residual radius Activity withdrawn BSA aldehyde Volume Activity Activity (mm) (MBq) (μL) (μL) (μL) (μL) (MBq) (MBq) 25 28.4 28.4 22.7 5.7 5.028 27.5 0.9 30 48.4 48.4 38.7 9.7 5.048 46.9 1.5 35 75.45 75.5 60.4 15.1 5.075 73.1 2.3 40 113.6 11.6 90.8 22.7 5.114 110 3.5 45 159.9 159.9 127.9 32 5.160 155 4.9 50 218.6 218.6 174.9 43.7 5.219 212 6.6 [0495] 9. Insert the syringe back into the vial and move the plunger back and forth to thoroughly mix the SIR-SPHERES® beads. Rapidly withdraw the pre-calculated radiation dose and proceed with the transfer to the BIOGLUE® chambers as described below. [0496] 10. Remove the cap of the double-chamber syringe containing the glue components. [0497] 11. Distribute the microspheres in the double-chamber syringe respecting the 4:1 ratio (80% in the BSA chamber, 20% in the glutaraldehyde chamber). [0498] 12. Put the cap back on the syringe. [0499] 13. Check the patient's dose by re-evaluating the activity in the syringe with the dose calibrator and correct if necessary. [0500] 14. Place the syringe in a radioprotected container suitable for transport in the operating room/radiology suite.

[0501] For the administration of .sup.90Y-matrix composition for percutaneous ablation, the use of the MIPP-Kit by SVAS Biosana system, depicted in FIGS. 1A and 1B, are used as it is specifically designed for optimal use with BIOGLUE® for percutaneous application, with the following sized components: [0502] Introducer needle: 15 G diameter and 150 mm length [0503] Injector catheter: 16 G diameter and 120 mm length

[0504] The procedure would continue as follows: [0505] 15. Percutaneous access should be achieved to facilitate insertion of the needle catheter into the hepatic parenchyma. [0506] 16. Appropriate anesthesia should be used, as per the standard operational approach at the Center. [0507] 17. Place the kit's introducer and stylet in the liver lesion with the aid of an ultrasound scanner or under CT guidance or other imaging modality. [0508] 18. Remove sterile syringe containing the .sup.90Y-matrix composition components from the radio-protected container. [0509] 19. Remove the syringe cap containing the .sup.90Y-matrix composition components. [0510] 20. Holding the syringe firmly with the pin facing up, rotate the cap 90° counterclockwise and remove the cap by swinging it from side to side. Align the dual-lumen catheter of the kit with the syringe using the corresponding notches on each and place the end of the dual-lumen catheter of the kit on the syringe. Take care not to accidentally spill the solution from the syringe during assembly. [0511] 21. Lock the bilateral catheter of the kit in place by pushing the catheter firmly towards the syringe and rotating the catheter collar 90° clockwise. [0512] 22. Keeping the syringe straight, align the large and small reservoirs of the solution syringe over the corresponding syringe plunger heads. Slide the plunger towards the back of the syringe until it meets resistance. The dispensing device is thus assembled. [0513] 23. Remove the stylet of the introducer of the kit. [0514] 24. Insert the catheter into the introducer and lock it through the Luer-lock fitting. [0515] 25. Press the plunger to dispense the mixture. [0516] 26. The plunger should be pressed at a speed in the range of 0.5 and 1.0 mm/s [0517] 27. Wait at least 30 seconds before retracting the introducer while providing a slight rotation to prevent the glue from adhering the introducer with the tissue. [0518] 28. At the end of the procedure, the needle catheter and syringe should be disposed of following the standard operating procedure of the biohazard handling center. [0519] 29. The insertion site must be properly closed and protected by bandaging [0520] 30. It is possible to administer topical antibiotics, if deemed appropriate.

[0521] The preparation and implantation procedure must be considered as a potential radiation hazard for personnel and a serious risk of contamination. Local guidelines on the use of radiation with regard to implantation and post-implant care should be followed.

[0522] The delivery of the .sup.90Y-matrix composition will be evaluated using PET scanning 24-48 hours after the procedure. Dosimetry will be analyzed through mathematical analysis of the data acquired from the PET scan.

[0523] Each patient will also be re-evaluated after 21 days for tumor evaluation, prior to surgical resection, which will include contrast enhanced ultrasound, MRI and/or CT imaging, and a clinical evaluation. Dosimetry will be re-assessed using a PET scan with mathematical analysis of the data. The site of insertion and the liver tissue will be monitored for changes during the time between radio-ablation and excision. Any morbidity and/or complications observed must be recorded on the CRFs. Additional evaluation will include: [0524] Vital signs (e.g. BP; HR; RR) [0525] General physical examination [0526] Complete lab tests (e.g. blood chemistry and hematology parameters) [0527] mRECIST criteria [0528] Concomitant medications [0529] Adverse events check [0530] EORTC-30/HCC18 questionnaires

[0531] Seven to nine days after the re-evaluation, i.e. 28-30 days after the ablation procedure, the patient will return to hospital for the target lesion surgical resection, which will be performed as per standard procedure of the investigation site. The surgery procedure will include: [0532] Vital signs (BP; HR; RR) [0533] General physical examination [0534] Tumor evaluation [0535] Anesthesia for surgery purpose [0536] Surgery [0537] Histological assessment [0538] Concomitant medications [0539] Adverse events check

[0540] From a radioprotection perspective, the surgery is radiologically safe for the surgeon and all the ancillary personnel, because after 20 days, the residual emission after a 2 GBq dose of .sup.90Y injected during the procedure of radio-ablation is reduced to 10 MBq. The effect at 1 meter is approximately 3 mSv/h in vitro, and approximately 1 mSv/h in vivo (in the human body), both below the background environmental radiation level.

[0541] In case surgery becomes contraindicated at the due date, the subject will be withdrawn from the study, but will undergo the same assessments as described for the post-surgery evaluation and followed up for any safety issues.

[0542] The resected liver tissue will be sent to the Pathology Department for assessment. Specimens will be processed by the pathologist for evaluation of surgical margins and will be observed for gross changes due to necrosis. The percentage of tumor mass necrosis will be measured, and the presence of any viable cells in the treated lesion will be assessed histologically. The radial distribution of the .sup.90Y microspheres will also be assessed and measured. Sample orientation will be performed using an appropriate system, such as color inking. Resection margins will be assessed through imaging (when appropriate), grossly, and microscopically. The liver specimen, including the treated liver tissue, will be processed for and evaluated by microscopic examination. After sample orientation, the specimen will be observed for gross changes due to the necrosis, and then tissue within the treated region will be microscopically examined for induced tissue necrosis. The extent of necrosis will be determined using Hematoxylin/Eosin staining technique, which relies on visual examination of the condition of cell membranes and structures in order to assess the viability of cells, and standard immunohistochemistry.

[0543] For the same reasons that the surgery is radiologically safe, the histopathological assessment is also safe for the pathologist and all the ancillary personnel.

[0544] The patient care following surgery will follow the local standard routine and practices, involving (where appropriate) admission to the intensive care unit for 24-48 h after surgery, before being transferred to the hospital regular ward, where patients will undergo the following assessments before discharge: [0545] Vital signs (e.g. BP, HR, RR) [0546] ECG [0547] Physical examination [0548] Blood chemistry (including liver function assessments: AST, ALT, total and fractionated bilirubin, Gamma GT, LDH, alkaline phosphatase) and hematology [0549] Surgical down staging criteria [0550] Concomitant medications/treatments [0551] Tumor evaluation using contrast-enhanced ultrasound [0552] Adverse events and adverse effects check

[0553] After discharge, patients will be followed up for 2 months. The study will be considered concluded for each subject after the 2 months follow-up period; during the follow-up period, information will be collected on any adverse events which might be related with the radio-ablation procedure or the surgical resection and included in the CRFs.

[0554] During the post-discharge follow-up visit, which will occur 28 days after the surgery, 56 days after ablation, the patients will undergo the following study procedures: [0555] Vital signs (e.g. BP, HR; RR) [0556] General physical examination, weight [0557] Complete lab tests (e.g. blood chemistry and hematology parameters) [0558] Tumor evaluation [0559] Imaging evaluation (e.g. PET scan) [0560] Concomitant medications [0561] Adverse events check

[0562] In some further variations of the liver tumor treatment procedures, .sup.90Y matrix composition therapy may be provided without requiring a pre-treatment imaging, e.g. a Technetium-99 scan, to assess for any shunting to the liver or lungs or other off-target locations, including varices and AVMs. In some variations, because pre-treatment imaging to assess shunting is not required, pre-treatment procedures to treat potential shunting are also not required. This may result in reducing the time-to-treatment by one, two, three, four, five, six or seven days or more, because treatment is not delayed by pre-treatment shunt imaging, pre-treatment shunt reduction procedures, and pre-treatment rescanning to assess the effectiveness of the shunt reduction procedures. The shunt procedures that would no longer be required or performed may include arterial embolization, hepatic vein balloon occlusion, and variceal and AVM occlusion procedures. Because dosing adjustments to account for the shunting are no longer required, dosing calculations may also be simplified, e.g. no longer requiring adjustments based on the shunt fraction and/or lung dosing limit. Patients with substantial liver, lung or hepatopulmonary shunt fractions also do not need to be excluded from therapy anymore.

[0563] In order to evaluate the primary endpoint, a confidence interval (CI) for the mean delivered dose with a significance level of 5% will be estimated. In addition, standard deviation of the mean value of delivered dose and its 95% confidence interval will be calculated in order to quantify the dispersion and the dynamic range of the performance of the new technology. Secondary endpoints will be summarized by descriptive statistics and 95% confidence intervals, as appropriate. Quality of life, as measured by the EORTC QLQ C30 and HCC18 questionnaires, will be evaluated at screening visit (V−1) and Visit 1 (V1). Descriptive statistics of single item score at each study visit and change of scores at V1 versus scores at screening visit (V−1) will be provided. Surgical specimens will be processed by the pathologist for evaluation of surgical margins and will be observed for gross changes due to necrosis. Safety assessments will consist of recording and tabulating all adverse events, as well as with an analysis of changes in vital signs and laboratory parameters. Incidence of adverse events, with regards also to the relationship with the .sup.90Y-matrix composition, will be calculated for all patients, along with their severity and the seriousness. The severity assessment for an adverse event or serious adverse event should be completed using the NCI CTCAE Version 5. Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be calculated for each laboratory analyte at baseline and for observed values and changes from baseline at each scheduled time point. A listing of subjects with any laboratory results outside the reference ranges will be provided. Parameters with predefined NCI-CTCAE toxicity grades will be summarized. Descriptive statistics of vital signs values and changes from baseline will be summarized. Descriptive statistics will be provided for safety variables.

[0564] Although the foregoing implementations has, for the purposes of clarity and understanding, been described in some detail by the use of illustration and example, it will be apparent that certain changes and modifications may be practiced, and are intended to fall within the scope of the appended claims. Additionally, it should be understood that the components and characteristics of the devices and materials described herein may be used in any combination, and the methods described herein may comprise all or a portion of the elements described herein. The description of certain elements or characteristics with respect to a specific figure are not intended to be limiting or nor should they be interpreted to suggest that the element cannot be used in combination with any of the other described elements.