PubMed Health⌕ Search

Biomedical subjects

W Sindelar

Publications and source records attributed to W Sindelar.

9 recordsLinked to original sources
PubMed1999

Spontaneous acceptance or rejection of orthotopic liver transplants in outbred and partially inbred miniature swine.

BACKGROUND: Results of clinical liver transplantation have shown that rejection and loss of human liver allografts occurs despite immunosuppression. Because genetic disparity and liver immunogenicity remain a matter of controversy, we reexamined the fate of outbred liver allografts without immunosuppression and used partially inbred miniature swine, in which the genetics of major histocompatibility complex (MHC) antigens have been characterized and can be controlled. METHODS: Orthotopic liver transplantation was performed between pairs of outbred domestic farm pigs and between pairs of inbred miniature swine with genetically defined major histocompatibility (SLA) loci. A passive splenic and vena caval to jugular vein shunt with systemic heparinization prevented hypotension during the anhepatic phase. Immunological responses were monitored by mixed lymphocyte culture (MLC), CML, skin graft rejection, liver biopsies, and serial serum chemistries. RESULTS: Median survival of technically successful liver allografts between pairs of outbred pigs (n=20) was 38 days and between partially inbred swine matched at the SLA locus (n=17) was 79 days. MLC responsiveness did not correlate with the development of rejection. Five of 20 (25%) outbred pigs and 6 of 17 (35%) MHC matched inbred miniature swine survived more than 100 days. In the long-term survivors, donor, but not third party, MHC matched skin graft survival times were prolonged. In contrast, all SLA-mismatched inbred recipients (n=26) died rapidly from massive liver rejection, with a median survival time of 9 days. In these rejecting animals, the marked MLC responsiveness to donor lymphocytes evident pretransplant diminished rapidly after transplantation, but an undiminished PHA responsiveness and a blunted third party MLC response persisted. CONCLUSION: The length of survival and the degree and incidence of rejection were similar in outbred pigs and in SLA-matched inbred miniature pigs, indicating that the outbred animals were, therefore, probably closely related and shared relevant genes. However, survival was significantly shortened and liver allograft rejection was accelerated in SLA-mismatched inbred swine. These results indicate that major histocompatibility differences play an important role in the rejection of liver allografts, as is true for other vascularized grafts in the unimmunosuppressed recipient. The development of liver allograft rejection across non-MHC differences is variable and, when present, appears to be a chronic process.

Animals↗
PubMed1990

Tumor induction following intraoperative radiotherapy: late results of the National Cancer Institute canine trials.

Intraoperative radiotherapy has been employed in human cancer research for over a decade. Since 1979, trials to assess the acute and late toxicity of IORT have been carried out at the National Cancer Institute in an adult dog model in an attempt to establish dose tolerance guidelines for a variety of organs. Of the 170 animals entered on 12 studies with a minimum follow-up of 2 years, 148 dogs received IORT; 22 control animals received only surgery. Animals were sacrificed at designated intervals following IORT, usually at 1, 6, 12, 24, and 60 month intervals. 102 of 148 irradiated dogs were sacrificed less than 24 months; 46 dogs were followed greater than or equal to 24 months after IORT. To date, 34 of the 46 animals have been sacrificed; the 12 remaining animals are to be followed to 5 years. These 12 animals have minimum follow-up of 30 months. In the irradiated group followed for greater than or equal to 24 months, 10 tumors have arisen in 9 animals. One animal developed an incidental spontaneous breast carcinoma outside the IORT port, discovered only at scheduled post-mortem exam. The remaining nine tumors arose within IORT ports. Two tumors were benign neural tumors--a neuroma and a neurofibroma. One animal had a "collision" tumor comprised of grade I chondrosarcoma adjacent to grade III osteosarcoma arising in lumbar vertebrae. Two other grade III osteosarcomas, one grade III fibrosarcoma, and one grade III malignant fibrous histiocytoma arose in retroperitoneal/paravertebral sites. An embryonal rhabdomyosarcoma (sarcoma botryoides) arose within the irradiated urinary bladder of one animal. No sham irradiated controls nor IORT animals sacrificed less than 24 months have developed any spontaneous or radiation-induced tumors. The time range of diagnoses of tumors was 24-58 months (median 40 months). The IORT dose range associated with tumor development was 20-35 Gy (median 30 Gy). The carcinogenesis capability of single fraction, high dose radiation in animals is discussed, as are the implications of these data for continued research and clinical usage of IORT in the treatment of humans.

Animals↗
PubMed1989

Differences in biodistribution of indium-111-and iodine-131-labeled B72.3 monoclonal antibodies in patients with colorectal cancer.

We have compared the biodistributions of [131I]B72.3 and 111In-SCN-Bz-DTPA B72.3 monoclonal antibody (MoAb) in patients with metastatic colon cancers. B72.3 is an IgG1 that recognizes a mucin-like colon cancer associated antigen. Eight patients were infused with 3-5 mCi and 0.36-20 mg of 111In-labeled B72.3 prepared with a bifunctional chelate, isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA). The biodistribution was compared with that of 13 patients previously studied as part of a separate trial, with 1-10 mCi and 0.16-1.35 mg of [131I]B72.3. The Beta T1/2 in serum was 63 +/- 5 hr for 111In-SCN-Bz-DTPA B72.3 and 52 +/- 10 hr for [131I]B72.3. Whole-body retention of the 111In (T1/2 = 11.8 days) was significantly longer than for [131I]B72.3 (T1/2 = 3.3 days), p less than 0.000001. The 131I was excreted primarily through the urine. Urinary excretion of 111In was low and gamma camera images confirmed that some 111In was excreted in the bowel. Tumor localization was seen in one of seven evaluable patients receiving 111In-SCN-Bz-DTPA B72.3. Gamma camera images showed that the liver concentrates 111In but not 131I. We conclude that 111In-SCN-Bz-DTPA B72.3 is metabolized in a different manner from the iodinated B72.3. The high concentration and prolonged retention of 111In by the liver interferes with tumor imaging of metastases.

Antibodies, Monoclonal↗
PubMed1986

Anti-idiotypic antibodies to monoclonal antibody CO17-1A.

Anti-idiotypic antibodies (Ab2) raised during the course of monoclonal antibody (MAb) therapy against anti-colorectal carcinoma (CRC) MAb CO17-1A were characterized in 142 patients with carcinomas of the colon, rectum or pancreas. Ab2 comprised between 21 and 80% of the total human anti-mouse IgG antibodies in various patients, and up to 42 micrograms of Ab2 were isolated per ml serum. In one patient significant levels of Ab2 could be detected for greater than 770 days. Between 20 and 70% of Ab2 in various patients bound to the combining site of MAb CO17-1A and may therefore bear the internal image of the 17-1A tumor antigen. Furthermore, Ab2 isolated from different patients showed considerable cross-reactivities. A beneficial role of the Ab2 responses in the cancer patients who improved clinically following MAb immunotherapy is discussed in light of induction by Ab2 of anti-anti-idiotypic antibodies (Ab3) with tumor-binding activities.

Animals↗
PubMed1985

A randomized, prospective trial of adjuvant chemotherapy in adults with soft tissue sarcomas of the head and neck, breast, and trunk.

Since 1977, 31 patients were entered in a randomized, prospective study testing the efficacy of adjuvant chemotherapy after aggressive local treatment of high-grade sarcomas of the head, neck, breast, and trunk (excluding retroperitoneal sarcomas). All patients had complete resection of gross tumor and underwent postoperative radiotherapy (6000-6300 rads over 7-8 weeks). Seventeen patients received adjuvant chemotherapy consisting of doxorubicin (less than or equal to 550 mg/m2), cyclophosphamide (less than or equal to 5500 mg/m2), and methotrexate (less than or equal to 1000 mg/kg). Three-year actuarial disease-free survival in the chemotherapy arm was 77%, compared to 49% in the no-chemotherapy arm (P = 0.075). Three-year overall actuarial survivals in the two treatment arms, however, were 68% and 58%, respectively (P = 0.38). Considering only patients with tumors of the trunk (22 patients), 3-year actuarial disease-free survival in the chemotherapy arm was 92%, compared to 47% in the no-chemotherapy arm (P = 0.006). Actuarial 3-year overall survival in the chemotherapy arm was 82%, compared to 61% in the no-chemotherapy arm (P = 0.18). An additional 26 patients were treated in an identical fashion, but were not part of the randomized trial because of contraindications to chemotherapy, refusal to enter the randomized trial, or because they were treated before 1977 in a trial in which all patients received chemotherapy. Considering the entire group of 57 patients, follow-up ranged from 10 to 86 months (median, 35 months). Local control was achieved in 46 patients (81%); 3-year actuarial disease-free and overall survivals were 67% and 77%, respectively. A tendency toward improved disease-free survival was apparent among patients treated with chemotherapy (P = 0.018), but there was no statistically significant improvement in overall actuarial survival (P = 0.46). The subgroup of patients with sarcomas of the trunk (39 patients) demonstrated the greatest benefit from chemotherapy, with regard to disease-free survival (P less than or equal to 0.001). The most significant toxicity associated with chemotherapy was doxorubicin-induced cardiomyopathy, which resulted in clinically apparent congestive heart failure in five patients. Thus, the use of chemotherapy when combined with aggressive local measures appears to improve disease-free survival, but additional patients and longer follow-up are necessary to determine if improved overall survival will result.

Actuarial Analysis↗
PubMed1983

Tolerance of canine anastomoses to intraoperative radiation therapy.

Radiation has been given intraoperatively to various abdominal structures in dogs, using a fixed horizontal 11 MeV electron beam at the Armed Forces Radiobiologic Research Institute. Animals were irradiated with single doses of 2000, 3000 and 4500 rad to a field which extended from the bifurcation of the aorta to the rib cage. All animals were irradiated during laparotomy under general anesthesia. Because the clinical use of intraoperative radiotherapy in cancer treatment will occasionally require irradiation of anastomosed large vessels and blind loops of bowel, the tolerance of aortic anastomoses and the suture lines of blind loops of jejunum to irradiation were studied. Responses in these experiments were scored at times up to one year after irradiation. In separate experiments both aortic and intestinal anastomoses were performed on each animal for evaluation of short term response. Response was graded by arteriography, gastrointestinal roentgenography, blind loop bursting pressure, and pathologic findings at autopsy and microscopic evaluation. The dogs with aortic anastomoses showed adequate healing at all doses with no evidence of suture line weakening. On long-term follow-up one animal (2000 rad) had stenosis at the anastomosis and one animal (4500 rad) developed an arteriovenous fistula. Three of the animals that had an intestinal blind loop irradiated subsequently developed intussusception, with the irradiated loop acting as the lead point. One week after irradiation, bursting pressure of an intestinal blind loop was normal at 3000 rad, but markedly decreased at 4500 rad. No late complications were noted after the irradiation of the intestinal anastomosis. Thus, it appears that adequate healing can take place with minimal risk of suture line breakdown even after a high single dose of irradiation (up to 3000 rad) to an anastomotic site. No late complications were observed after irradiation of intestinal anastomoses, but one needs to be cautious with regards to possible late stenosis at the site of an irradiated vascular anastomosis.

Animals↗
PubMed1983

Regulation of membrane function by lipids; implications for tumor development.

Increase in the lipid fluidity of membranes increases the turnover number of each diffusible unit, but in general decreases its accessibility to ligand binding. As a result, many membranal functions reach a maximal activity at a specific lipid fluidity. These effects of membrane fluidity bear direct implications on tumor development with significant clinical potential. Two main avenues, by which lipid manipulation could be applied in cancer treatment are now being studied in experimental animals and cancer patients. In the first, the immunogenicity of tumor cells in syngeneic and autologous systems increase upon increase of the membrane microviscosity which is in line with the findings that membrane antigens become more exposed upon such treatment. Irradiated tumor cells with increased membrane microviscosity (e.g. by incorporation of cholesteryl hemisuccinate, CHS) thus act as strong and specific vaccine against the viable untreated tumor cells of the same kind. The second lipid manipulation relates to restoration of suppressed immune competence. A special mixture of lipids (Active Lipid, AL) designed to efficiently fluidize cell membranes was found to restore various immunological functions of leukocytes from cancer patients. The combination of augmentation of tumor immunogenicity and restoration of immune functions by such lipid manipulations is expected to constitute an innocuous active immunotherapy regimen for cancer treatment.

Animals↗
PubMed1979

Serologic analysis of human tumor antigens. II. Reactivity of sera from eleven osetogenic sarcoma patients against autologous and allogeneic tumor cells.

Sera from eleven patients bearing osteogenic sarcomas were tested for reactivity against autologous and allogeneic normal and tumor cells using a sensitive microcytotoxicity assay. Following absorption with human fetal tissue cultured lines, sera from all 11 patients lost reactivity to autologous and allogeneic normal fibroblasts in culture. However, sera from four patients retained reactivity against both autologous and allogeneic osteogenic sarcoma, sera from five patients retained reactivity to allogeneic but not autologous tumor, and sera from two patients lost all reactivity to tumor. Sera from nine normal individuals did not react with either normal or osteogenic sarcoma cells after fetal cell absorption. Thus it appears that nine of 11 patients bearing osteogenic sarcoma contained antibody to a common tumor-associated antigen. This tumor-associated antigen appears to be expressed on tumor cells and not normal cultured cells, and reactivity to it is present in tumor-bearing but not normal individuals.

Antibodies, Neoplasm↗