phosphorus-radioisotopes and Pancreatic-Neoplasms

This study evaluated clinical outcomes of combined chemotherapy and endoscopic ultrasound (EUS)-guided intratumoral radioactive phosphorus-32 (. Consecutive patients with newly diagnosed LAPC were recruited over 20 months. Baseline computed tomography and. 12 patients with LAPC (median age 69 years [interquartile range 61.5-73.3]; 8 male) completed treatment. Technical success was 100 % with no procedural complications. At 12 weeks, median reduction in tumor volume was 8.2 cm. EUS-guided

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Pancreatic Neoplasms; Phosphorus Radioisotopes; Pilot Projects; Ultrasonography, Interventional

This prospective randomized trial was undertaken to determine the added efficacy of (32)P in treating locally advanced unresectable pancreatic cancer. Thirty patients with biopsy proven locally advanced unresectable adenocarcinoma of the pancreas were assessable after receiving 5-fluorouracil and radiation therapy with or without (32)P, followed by gemcitabine. Intratumoral (32)P dose was determined by tumor size and volume and was administered at months 0, 1, 2, 6, 7, and 8. Tumor cross-sectional area and liquefaction were determined at intervals by computed tomography scan. Tumor liquefaction occurred in 78% of patients receiving (32)P and in 8% of patients not receiving (32)P, although tumor cross-sectional area did not decrease. Serious adverse events occurred more often per patient for patients receiving (32)P (4.2 +/- 3.1 vs. 1.8 +/- 1.9; p = 0.03) leading to more hospitalizations. Death was because of disease progression (23 patients), gastrointenstinal hemorrhage (4 patients), and stroke (1 patient). One patient not receiving (32)P and one receiving (32)P are alive at 28 and 13 months, respectively. (32)P did not prolong survival (7.4 +/- 5.5 months with (32)P vs. 11.5 +/- 8.0 months without (32)P, p = 0.16). (32)P promoted tumor liquefaction, but did not decrease tumor size. Intratumoral (32)P was associated with more serious adverse events and did not improve survival for locally advanced unresectable pancreatic cancer.

Topics: Adenocarcinoma; Aged; Female; Fluorouracil; Humans; Male; Middle Aged; Pancreatic Neoplasms; Phosphorus Radioisotopes; Prospective Studies; Treatment Outcome

This is a preliminary report of five patients diagnosed with locally advanced nonresectable pancreatic cancer who achieved improved quality of life, delay of local progression, and reduction of biomarker CA 19-9 after infusion of colloidal phosphorus 32 (32P) and administration of combined chemoradiotherapy. A phase II trial using intratumoral colloidal 32P delivery for nonresectable pancreatic cancer without metastases is in progress. Patients initially were given infusions of decadron followed by macroaggregated albumin and 30 mCi colloidal 32P to the interstitial space of the tumor by two infusions 1 week apart. Through this method, doses ranging from 750,000 to 1,800,000 cGy were delivered. After administration of colloidal 32P, external radiation to a dose of 6000 cGy minimum tumor dose, including regional lymph nodes, was given concomitantly with four intravenous infusions of 500 mg bolus 5-fluorouracil on alternating days within the first 2 weeks after initiation of external radiation. All five of these patients demonstrated cessation of local tumor growth or regression of disease on serial computed tomography scans for a minimum of 10 months from completion of therapy. Three of these patients have survived without local disease progression over 24 months from initiation of therapy, with one patient approaching 36 months. CA 19-9 values for all patients declined within weeks after completion of therapy. This new method of isotope delivery has resulted in reduction of tumor volume, normalization of the biomarker CA 19-9, and improved performance status in those patients who have localized nonresectable disease without dissemination.

Topics: Aged; Antimetabolites, Antineoplastic; Brachytherapy; CA-19-9 Antigen; Combined Modality Therapy; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intralesional; Male; Middle Aged; Pancreatic Neoplasms; Phosphorus Radioisotopes; Radiopharmaceuticals; Radiotherapy Dosage; Remission Induction

The purpose of this study was to validate a previously reported body contour measurement using Compton backscatter sources with bremsstrahlung SPECT imaging.. Bremsstrahlung SPECT imaging was performed with 32P using a dual-headed camera system fitted with medium-energy, parallel-hole collimators. Two sources of 99mTc were placed directly on each collimator. Energy windows of 100 keV +/- 25% were used to image the 32P and also to record the Compton scatter from the 99mTc sources. Eleven patients enrolled in clinical Phase I therapeutic protocols were injected with 32P-chromic phosphate and SPECT images were acquired and reconstructed in the transaxial plane. The 32P distribution and the patient body contour were both visualized in these slices. The anteroposterior and lateral patient dimensions were measured by generating count profiles parallel to the anteroposterior and lateral body contour, respectively, at the midline in a transaxial slice. The distance in centimeters between the two centroids of each profile is representative of the anteroposterior and lateral dimensions and was determined for each patient. These anteroposterior and lateral dimensions were compared to the same distance measurements made in these patients by CT in an anatomically comparable transaxial slice. A cylindrical SPECT phantom was also studied to further validate the contour measurements.. The mean percent difference in the patient dimension measurements between SPECT and CT was -0.8% with a range of -8.5% to 9.9%. The percent difference between the known and SPECT measured dimensions in the cylindrical phantom was 0.5%.. The two external Compton scatter source method is accurate for determining the body contour.

Topics: Chromium Compounds; Head and Neck Neoplasms; Humans; Image Processing, Computer-Assisted; Liver Neoplasms; Lung Neoplasms; Pancreatic Neoplasms; Phantoms, Imaging; Phosphates; Phosphorus Radioisotopes; Scattering, Radiation; Technetium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

In the past, we have clinically evaluated radiolabelled antibodies in Hodgkin's disease and hepatocellular cancer. Increased tumour pressure, reduced vascularity and poor diffusion has limited significant radiolabelled antibody tumour dose deposition. Using intratumoural infusion of macroaggregated albumin to blockade exiting vasculature followed by colloidal chromic 32Phosphorous, we have been able to achieve 75% to 100% tumour dose deposition by interstitial tumour infusion under computerised tomographic guidance. Phase I studies in a variety of solid tumours indicate extremely high doses may be achieved without toxicity (i.e. non-resectable pancreas 900,000 cGy to 1.7 million cGy) with tumour control and remission. This is a review of those studies and how the technique was applied.

Topics: Astrocytoma; Brachytherapy; Brain Neoplasms; Carcinoma, Hepatocellular; Carcinoma, Small Cell; Chemoembolization, Therapeutic; Chromium; Colloids; Dexamethasone; Head and Neck Neoplasms; Hodgkin Disease; Humans; Injections, Intralesional; Liver Neoplasms; Lung Neoplasms; Pancreatic Neoplasms; Phosphorus Radioisotopes; Radiography, Interventional; Radioimmunotherapy; Radiotherapy Dosage; Remission Induction; Serum Albumin; Tomography, X-Ray Computed

To develop a Monte Carlo model for patient-specific dosimetry of. Spherical tumor geometries and a pancreatic phantom were modeled, as well as different 3-dimensional non-uniform clinical pancreatic geometries based on patient-specific ultrasound images. The dosimetry simulations modeled the dose distribution due to the energy spectrum of emitted beta particles.. The average dose for small (3-cm diameter) and large (6-cm diameter) spherical tumors was 111 Gy (for 7.6 MBq administered activity) and 128 Gy (for 58 MBq), respectively. For the clinical 3-dimensional geometries, on the basis of patient data, the mean doses delivered to the tumor were calculated to be in the range 102 to 113 Gy, with negligible dose to the pancreas for the smallest tumor volumes. The calculated dose distributions are highly non-uniform. For the largest tumor studied, the pancreas received approximately 6% of the tumor dose (5.7 Gy). Importantly, we found that because the smallest tumor studied exhibited the most dynamic changes in volume in response to the treatment, the dose to tumor and pancreas is significantly underestimated if a static tumor volume is assumed.. These results demonstrate the dosimetry of

Topics: Beta Particles; Humans; Monte Carlo Method; Pancreas; Pancreatic Neoplasms; Phosphorus Radioisotopes; Precision Medicine; Radiotherapy Dosage; Spheroids, Cellular; Tumor Burden; Tumor Cells, Cultured; Ultrasonography

Our laboratory has developed a novel delivery platform using an attenuated non-toxic and non-pathogenic bacterium Listeria monocytogenes that infects tumor cells and selectively survives and multiplies in metastases and primary tumors with help of myeloid-derived suppressor cells (MDSC) and immune suppression in the tumor microenvironment (TME). 32P was efficiently incorporated into the Listeria bacteria by starvation of the bacteria in saline, and then cultured in phosphorus-free medium complemented with 32P as a nutrient. Listeria-32P kills tumor cells through both 32P-induced ionizing radiation and Listeria-induced reactive oxygen species (ROS). The levels of 32P and Listeria were studied in various normal and tumor tissues, at sequential time points after injection of mice with pancreatic cancer (syngeneic model Panc-02). We found that 32P and Listeria predominantly accumulated in tumors and metastases, with their highest accumulation 4 hrs (32P) and 3 days (Listeria) after injection. Listeria also penetrated the transgenic KPC (conditionally express endogenous Kras-G12D and p53-R172H mutant alleles) pancreatic tumors and metastases. This is remarkable since KPC tumors, like human tumors, exhibit a stromal barrier, which prevents most drugs from penetrating the pancreatic tumors. Therapeutic treatment with Listeria -32P resulted in a strong reduction of the growth of pancreatic cancer at early and late stages in Panc-02 and KPC mice. These results highlight the power of Listeria as new delivery platform of anticancer agents to the TME. Not only were therapeutic levels of radioactive Listeria reached in tumors and metastases but the selective delivery also led to minimal side effects.

Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Drug Delivery Systems; Listeria monocytogenes; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Pancreatic Neoplasms; Phosphorus Radioisotopes

Abstract Background: Radiotherapy is an important treatment for the patients with advanced pancreatic cancer. Emerging studies determined apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) might associate with the resistance of human pancreatic cancer cells to radiotherapy.. To investigate whether downregulation of APE1/Ref-1 expression by ribonucleic acid interference would increase the sensitivity of chromic-P32 phosphate to pancreatic cancer cells.. The plasmids containing APE-specific and unspecific short hairpin were transfected into Patu-8898 cells. Stable cell clones were selected by G418. The mRNA expression of APE1/Ref-1 was detected by semiquantitative reverse transcription-polymerase chain reaction and the protein expression of APE1/Ref-1 was detected by Western blot analysis; cell proliferation was studied by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and colony formation assay; apoptosis was detected by flow cytometry.. After 24 hours irradiation, APE1/Ref-1 mRNA and protein expression were upregulated, in a concentration-dependent manner. Suppression of APE1/Ref-1 by siRNA increased the pancreatic cancer cells hypersensitive to (32)P-CP. In the combination of (32)P-CP and siRNA group, MTT assay showed that the cell inhibition increased to (74.33%±9.02%), the surviving fraction in the colony formation assay was only 25.00%, and the apoptosis rate was up to (16.77%±0.98%).. Knockdown APE1/Ref-1 gene expression may significantly sensitize the Patu-8988 cells to radiotherapy, which may be a useful target for modifying radiation resistance of pancreatic cancer cells to irradiation.

Topics: Apoptosis; Blotting, Western; Cell Proliferation; Chromium Compounds; Colony-Forming Units Assay; DNA-(Apurinic or Apyrimidinic Site) Lyase; Flow Cytometry; Humans; In Vitro Techniques; Pancreatic Neoplasms; Phosphates; Phosphorus Radioisotopes; Radiation Tolerance; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Tumor Cells, Cultured

The aim of this study was to observe the biological distribution and anticancer effect of (32)P-chromic phosphate colloid (Cr(32)PO(4), (32)P-CP) after intratumoral injection to Pc-3 human pancreatic carcinoma-bearing nude mice.. Eighty-four (84) BALB/c nude mice with transplanted tumor were allocated to 11 groups. Groups 1-5 (n = 6) were intratumorally injected with 14.8 MBq of (32)P-CP and sacrificed at 2, 24, 48, 72, and 168 hours, respectively. Groups 6-11 (n = 9) received injections of 3.7, 7.4, 14.8, 18.5, 29.6, and 0 MBq of (32)P-CP, respectively, and the tumor volume on body surface was measured daily. The animals (n = 6) were sacrificed at 14 days after administration. The dynamic distribution of radioactivity in body (percentage of injected dose per g), morphological changes, the tumor-inhibiting rate (TIR), proliferating index (PI), proliferating cell nuclear antigen (PCNA) tumor microvascular density (MVD), continuous counting of white blood cells (WBCs) and platelets (PLTs) in venous blood, body weight, and toxic reactions were observed.. The injected (32)P-CP mainly accumulated in the tumor mass and was retained for a long time. The TIR of each dosage group in order was 21.68%, 39.73%, 50.43%, 71.18%, and 74.09% (F = 159.74; p < 0.001), PI was 70.85, 67.90, 46.70, 20.66, 10.75, and 90.11 (F = 509.54; p < 0.001), and MVD count was 39.19, 28.33, 17.45, 8.89, 8.10, and 64.80 (F = 643.26; p < 0.001), respectively. The data for WBC, PLT, and body weight observed for 28 days in the treatment groups did not indicate significant differences compared with those of the control group.. Interstitial injection of (32)P-CP seems to be a safe and effective interventional nuclide therapy for pancreatic carcinoma-bearing nude mice.

Topics: Animals; Chromium Compounds; Humans; Injections, Intralesional; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Phosphates; Phosphorus Radioisotopes; Tissue Distribution; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

32P BioSilicon is a new, implantable, radiological medical device that comprises particles of highly pure silicon encapsulating 32phosphorus (32P) for the treatment of unresectable solid tumors. Prior to administration, the device particles are suspended in a formulant which provides an even suspension of the intended dose for implantation. The primary objective of this animal trial study was to investigate the effects of intratumoral injection of 32)P BioSilicon on human hepatocellular (HepG2) and pancreatic carcinoma (2119) xenografts implanted in nude mice (BALB/c). A secondary objective was the histopathologic examination of the tumor foci and surrounding tissue during the study.. Cultured human carcinoma cells (HepG2 and 2119) were injected s.c. into the gluteal region of nude mice. When the implanted tumors were approximately 1 cm in diameter, 32P BioSilicon (0.5, 1.0, and 2.0 MBq) or formulant was injected into the tumors. Implanted tumor size was measured once a week for 10 weeks. At study termination, the tumor and surrounding normal tissue were collected and fixed in 10% formalin and processed for histopathologic analysis.. 32P BioSilicon produced a reduction in HepG2 tumor volume when compared with formulant control, and complete response was observed among tumors in the 1.0 and 2.0 MBq treatment groups after week 8. There was also significant reduction in 2119 tumor volume in all treated groups, with the complete response rate of 67% in the 2.0 MBq group.. 32P BioSilicon suppressed the growth of both human hepatocellular and pancreatic carcinoma xenografts implanted in nude mice and complete responses were also observed in tumors at higher radiation doses.

Topics: Animals; Brachytherapy; Carcinoma, Hepatocellular; Cell Line, Tumor; Dose-Response Relationship, Radiation; Humans; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Phosphorus Radioisotopes; Silicon; Treatment Outcome; Xenograft Model Antitumor Assays

Topics: Aged; Brachytherapy; Fatal Outcome; Female; Humans; Pancreatic Fistula; Pancreatic Neoplasms; Phosphorus Radioisotopes; Stomach Neoplasms; Vascular Fistula

Topics: Animals; Carrier Proteins; Cell Differentiation; Female; Gene Expression Regulation, Neoplastic; Oocytes; Pancreatic Neoplasms; Phosphorus Radioisotopes; RNA, Messenger; Sodium-Phosphate Cotransporter Proteins; Symporters; Tumor Cells, Cultured; Xenopus

To find the mechanisms of the ongoing clinical trials in intralesional colloidal chromic 32P (32P-CP) brachytherapy, the cellular uptake of 32P-CP, changes in tumor interstitial fluid pressure (TIFP), and tumor blood flow (TBF) using two (AsPC-1, Ls174T) human tumors were measured.. After exposure to 32p-CP using exponential and plateau-phase cells, cells were trypsinized at various time intervals, then measured for the levels of radioactivity using a y-counter. Also measured were TIFP using the WIN technique and TBF with laser Doppler flowmetry.. The plateau growth-phase of both tumors showed the maximal uptake of 32P-CP at approximately 100 min. TBF decreased within 10 min after an intratumoral (i.t.) injection of 32P-CP, and reached 75% of control value by 1 h.. If 32P-CP was introduced i.t., it maintained highly efficient tumor targeting, mainly due to two physiological mechanisms: the high adherence of 32P-CP to the infused regions and the reduction in TBF by this therapeutic colloid.

Topics: Adenocarcinoma; Animals; Brachytherapy; Colloids; Colonic Neoplasms; Female; Humans; Injections, Intralesional; Laser-Doppler Flowmetry; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Phosphorus Radioisotopes; Radiotherapy

To overcome the physiological barrier in solid tumors (i.e., tumor hypertension), a large volume of material is required via an intratumoral injection. Alternatively, a method of reduction in tumor hypertension is also feasible. In this study, we focused on the physiological response after an intratumoral infusion of various therapeutic agents. Tumor interstitial fluid pressure (TIFP) was intermittently monitored for up to 7 days after treatment using AsPC-1 human pancreatic tumors in nude mice. Macroaggregated albumin (MAA), colloidal chromic 32P (32P-CP), albumin, dexamethasone, 5-fluoro-2'deoxyuridine, dextrose, saline, and trypan blue increased TIFP within approximately 5 min, and TIFP returned to the original level within 1 h, except in the case of MAA and 32P-CP. We also found that the maximal uptake for AsPC-1 tumors in both the exponential and plateau growth phases occurred at approximately 100 min postincubation; the maximum value in the exponential growth phase was approximately 2 times less than that of plateau growth phase (P < 0.01). Therefore, this study supports intralesional 32P-CP brachytherapy for nonresectional pancreatic cancer patients. This may offer a promising treatment modality for delivering high doses of tumor-selective radiation, mainly due to two physiological mechanisms: (a) the high adherence of 32P-CP to the infused regions; and (b) reduction in either tumor blood flow or TIFP by this therapeutic colloid.

Topics: Animals; Brachytherapy; Colloids; Extracellular Space; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Phosphorus Radioisotopes; Pressure; Transplantation, Heterologous

Infusional brachytherapy for treatment of neoplasms, with colloidal 32P has been used to treat various tumors in the pancreas, liver, brain, lung, and head and neck. In performing such treatments, anatomical verification of the location of the administered 32P from the image obtained by Bremsstrahlung SPECT alone is not possible due to the lack of internal landmarks, since the radionuclide is distributed only in the tumor and does not usually accumulate in the normal organs. The purpose of this study was to provide a practical three-dimensional approach for image fusion between Bremsstrahlung SPECT and CT.. The tumors in four cancer patients were injected directly with 32P under CT guidance. A Bremsstrahlung SPECT study using 99mTc backscatter sources to obtain the body contour was then performed. SPECT images were used to generate the skin contours using a threshold detection method. A three-dimensional surface was generated from these contours using a tiling program and fused with a corresponding CT surface generated from a CT scan in the same patient through an iterative surface-fitting algorithm. The three-dimensional surface of the region of high-activity, corresponding to the infused tumor, was then generated using the Bremsstrahlung SPECT data by mapping the iso-count surfaces through a computer program. The three-dimensional image of the organ then was fused with the registered CT-SPECT datasets.. The accuracy of fit measured as the mean distance between the SPECT and CT surfaces was in the range of 3-4 mm.. The anatomical co-registration of Bremsstrahlung SPECT with CT images using the outer surface-fitting algorithm is a reliable tool. This correlation permits direct anatomic confirmation of the region of the 32P activity distribution with the anatomic site selected for injection.

Topics: Algorithms; Brachytherapy; Humans; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Pancreatic Neoplasms; Phosphorus Radioisotopes; Radiotherapy Planning, Computer-Assisted; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

Analogues of somatostatin (SS) and luteinizing hormone-releasing hormone (LH-RH) activate tyrosine phosphatases in MIA PaCa-2 human pancreatic cancer cell line membranes and inhibit growth. We compared the substrates phosphorylated by epidermal growth factor (EGF) to those dephosphorylated by the SS analogue RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2) and [D-Trp6]LH-RH in cancer cell lines such as MIA PaCa-2 (human pancreatic cancer), HCPC (hamster cheek pouch carcinoma), A-549 (human lung cancer), HT-29 (human colon cancer), and R3230AC (breast cancer). EGF phosphorylated proteins of 170, 65, and 60 kDa and analogues of SS and LH-RH promoted the dephosphorylation of these proteins in MIA PaCa-2 and HCPC cell lines. The EGF receptor is 170 kDa. pp60src (60 kDa) is known to be a substrate for EGF receptor. The LH-RH receptor is also 60 kDa. The effects of RC-160 and [D-Trp6]LH-RH were quantitatively different. Examinations of HT-29, A-549, and R3230AC cancer cell lines revealed no phosphorylation by EGF or dephosphorylation by RC-160 and [D-Trp6]LH-RH. In addition to the 170-, 65-, and 60-kDa proteins, 35-kDa proteins were also phosphorylated in some cancer cell lines. This work demonstrates that analogues of SS and LH-RH can reverse the effects of EGF biochemically as well as functionally.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Autoradiography; Breast Neoplasms; Cell Line; Colonic Neoplasms; Epidermal Growth Factor; Gonadotropin-Releasing Hormone; Humans; Kinetics; Lung Neoplasms; Membrane Proteins; Molecular Sequence Data; Pancreatic Neoplasms; Phosphorus Radioisotopes; Phosphorylation; Protein Kinases; Protein-Tyrosine Kinases; Somatostatin; Triptorelin Pamoate; Tyrosine

Topics: Abdomen; Female; Humans; Injections, Intraperitoneal; Neoplasm Seeding; Ovarian Neoplasms; Pancreatic Neoplasms; Peritoneal Cavity; Phosphorus Radioisotopes; Radionuclide Imaging