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Biomedical subjects

R E Falk

Publications and source records attributed to R E Falk.

At least 73 records · Page 4Linked to original sources
PubMed1984

Peripheral nerve allograft: an immunological assessment of pretreatment methods.

An in vivo immunological assay was used to determine quantitatively the nerve allograft response in a rat model. The nerve allograft was then pretreated with a number of pretreatment methods that have been used clinically and experimentally. Using the same immunological assay to determine quantitatively the nerve allograft response, we found that lyophilization and high doses of irradiation could modify the nerve allograft in such a way as to make it less immunogenetic to the host animal. The other methods of pretreatment did not alter the antigenicity of the allograft.

Animals↗
PubMed1983

The effect of liver cytosol on hepatic regeneration and tumor growth.

This report further evaluates the concept that the interaction of factors that originate within the liver can contribute, regulate or even initiate the actual development of hepatic regeneration after liver cell necrosis or partial hepatectomy. The effect of liver cytosol (100,000 g supernatant), both from intact adult rat liver (NLC) and from adult rat liver remnants that had been regenerating for 24 hours after 70% partial hepatectomy (PH) in posthepatectomy liver regeneration in the rat was studied. The specificity of the growth-controlling properties in liver cytosol was determined using tumor cells. The intraperitoneal administration of NLC after PH resulted in approximately 70-80% inhibition of the peak 3H-DNA specific activity seen in controls at 18 and 24 hours post-PH, with a significant increase in DNA synthesis at 31-40 hours post-PH. The intraperitoneal administration of RLC after PH, augmented the hepatic regenerative response normally produced. Autoradiographic determination of hepatic nuclear labeling confirmed the inhibitory and stimulatory properties of NLC and RLC respectively. Syngeneic NLC or RLC at six and 24 days after subcutaneous tumor inoculation resulted in significant inhibition of tumor growth for both a methylcholanthrene-induced bladder carcinoma (FBCa) and an HTC-hepatoma. The retardation of FBCa growth could be enhanced by administering NLC or RLC every three or seven days. Syngeneic and xenogeneic liver cytosol resulted in dose-dependent inhibition of P815 mastocytoma cell proliferation in vitro. It is apparent from these studies that both stimulatory and inhibitory factors can be extracted from liver tissue that not only influence liver cell regeneration, but also affect tumor growth. Further isolation and characterization of these factors may lead to an understanding of more fundamental problems such as the control of normal and malignant cell growth.

Animals↗
PubMed1983

Nonspecific and selective stimulation of the immune system in the treatment of carcinoma in humans.

The experience of the Toronto General Hospital in the use of nonspecific stimulation of the immune system with bacille Calmette-Guérin (BCG) for the treatment of cancer of the gastrointestinal tract, malignant melanoma and breast cancer is described. The results are presented in terms of survival curves. The use of BCG administered intraperitoneally in a randomized study of patients with gastric, pancreatic and colorectal cancer proved of no benefit. On the other hand, when BCG was given orally in a randomized study of patients with resectable cancer of the colon and in nonrandomized consecutive studies of patients with malignant melanoma and stage IV carcinoma of the breast survival was increased. In a group of patients with advanced gastrointestinal cancer selective stimulation of the immune system with NED 137 produced a significant increase in survival when compared with the survival of historical controls (the patients given BCG intraperitoneally along with 5-fluorouracil for gastrointestinal cancer). The results of these studies suggest the need for a more rational approach in manipulating the immune response that would combine chemotherapy with selective stimulation of the immune system.

Aged↗
PubMed1983

Hyperthermochemotherapeutic in vivo isolated perfusion of the rat liver.

This report describes a system of in vivo isolated perfusion of the rat liver. The effects of perfusion with 5-fluorouracil (5-FU) (0.125-1.5 g/kg) on survival, liver function, and hepatic regeneration are studied. A dose of 0.125-0.25 g/kg of 5-FU produced acceptable toxicity with 0% and 25% mortality rate, but induced liver dysfunction indicated by abnormal biochemical values and severe inhibition of hepatic regeneration. Doses of 0.5 g/kg, 1.0 g/kg, and 1.5 g/kg produced a mortality of 60%, 100%, and 100%, respectively. Regional hyperthermia (37-43 degrees C) achieved by perfusion of the liver with heated saline produced an adverse effect on survival, liver function and hepatic regeneration, which are both temperature- and perfusion time-dependent. Hyperthermochemotherapy using in vivo isolated hepatic perfusion might be acceptable for the treatment of unresectable liver cancer, but should not be utilized as an adjuvant therapy prior to hepatic resection without the use of hepatic growth factors which could reverse the inhibitory effect of hepatic perfusion.

Alanine Transaminase↗
PubMed1983

Menningococcal antigens (MA): a novel immune stimulant in experimental neoplasia.

An extract of the meningococcus antigens (MA) prepared from N. meningitidis was tested for an anti-tumor effect in rat and murine metastasizing tumor models. Effectiveness of MA in each model varied with dose and was manifested as significantly improved survival of the treated animals. Growth of the primary Fischer bladder carcinoma (FBCa) and metastases to lungs and lymph nodes were significantly inhibited in F344 rats treated weekly with 1 mg MA. Administration of MA at 100 micrograms per animal significantly prolonged survival of P815 mastocytoma-inoculated DBA/2 mice. Survival of C-26 colon adenocarcinoma-bearing Balb/c mice was significantly improved in animals that received weekly injections of 20 micrograms MA, without significant effect on the development of local tumor. The meningococcal antigens demonstrate strong mitogenic activity in B-cell-enriched murine spleen cultures. Thus the immunostimulatory activity of MA in experimental malignancy could involve, directly or indirectly, activation of B lymphocytes.

Adjuvants, Immunologic↗
PubMed1983

Protection of thermochemotherapeutic-induced lethal acute hepatic necrosis in the rat by 16,16-dimethyl prostaglandin E2.

These studies further evaluate the hepatocytoprotective properties of 16,16-dimethyl prostaglandin E2 (dmPGE2) by assessing its effect on survival, liver function, and hepatic regeneration in a model of in vivo isolated perfusion of the rat liver with high concentrations of cytotoxic drugs and regional hyperthermia. Isolated perfusion with 1.0 g/kg of 5-FU or hyperthermia of 41 degrees C X 10 min resulted in 90-100% mortality in control rats, with extensive, patchy necrosis and infarction on histologic examination, and markedly elevated levels of SGOT and SGPT at 24 hr after perfusion. Pretreatment with dmPGE2 (10 micrograms/kg sc) at 30 min before, and at 6 and 24 hr after hepatic perfusion significantly improved survival to 80% (P less than 0.01) following 5-FU perfusion and to 40% (P less than 0.05) following hyperthermic perfusion. Animals were followed for at least 21 days after perfusion and demonstrated normal liver histology, dmPGE2-treated rats demonstrated significantly lower SGOT and SGPT levels at 24 hr after perfusion. dmPGE2 (2 micrograms/kg sc) given as above improved the length of time of survival but eventual mortality was not significantly improved. Oral administration (50 micrograms/kg po at 30 min before, 6 and 24 hr after perfusion) and posttreatment (10 micrograms/kg sc at 1, 6, and 24 hr after perfusion) had no significant effect on survival. Hepatic regenerative capacity following partial hepatectomy was severely suppressed following isolated hyperthermochemotherapeutic hepatic perfusion. Pretreatment with dmPGE2 (10 micrograms/kg sc) restored the DNA synthetic response in perfused rats to that seen in normal control rats after partial hepatectomy (P less than 0.05 and P less than 0.01). The results from these studies further confirm the role of dmPGE2 as a hepatocytoprotective agent and suggest potential clinical application in situations where there has been deliberate, therapeutic insult to the liver.

16,16-Dimethylprostaglandin E2↗
PubMed1983

Comparison of in-vivo thermochemotherapy of isolated rat liver through portal vein and hepatic artery.

A model for the in-vivo perfusion of the isolated rat liver with either cytotoxic agents or hyperthermic saline, administered through either the hepatic artery or the portal vein, is described. Rats were able to survive following perfusion with a dose of up to 0.25 g/kg of 5-fluorouracil and 2.0 to 2.5 mg/kg of mitomycin-C by both routes. Regional hyperthermic perfusion of the liver produced temperature and time-dependent hepatotoxic effects. A marked elevation of serum glutamic oxaloacetic and glutamic pyruvic transaminase levels was noted 24 hours after perfusion, but was reversible. Aminopyrine N-demethylase activity in both normal intact and regenerating rat liver was not affected; however, the activity in normal intact liver was markedly suppressed with hyperthermic perfusion at 43 degrees C only. Incorporation of tritiated thymidine into hepatic deoxyribonucleic acid 24 hours after partial hepatectomy was severely inhibited by prior hepatic perfusion with either cytotoxic drugs or hyperthermic saline. This in-vivo isolated perfusion technique could be used to assess the effect of thermochemotherapy on tumour growth in the liver.

Aminopyrine N-Demethylase↗
PubMed1983

Reversal of lethal, chemotherapeutically induced acute hepatic necrosis in rats by regenerating liver cytosol.

In this report we further evaluate the role of regenerating liver cytosol (RLC) as a stimulator of hepatic regeneration by assessing its effect on survival, liver function, and hepatic regeneration in a model of in vivo isolated perfusion of the rat liver with high concentrations of cytotoxic drugs and regional hyperthermia. Isolated perfusion with 500 mg/kg of 5-fluorouracil (5-FU) and 2.5 mg/kg of mitomycin-C (Mit-C) resulted in 70% (n = 20) and 71% (n = 14) mortality, respectively, from 2 to 7 days after perfusion, with extensive, patchy necrosis and infarction seen on histologic examination and markedly elevated levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) at 6 and 24 hours after perfusion. The intraperitoneal administration of RLC (80 mg total protein/rat) at the time of hepatic perfusion resulted in 70% (5-FU, n = 20, P less than 0.05) and 80% (Mit-C, n = 20, P less than 0.01) survival at 21 days post perfusion. RLC-treated rats demonstrated significantly lower SGOT and SGPT levels at 6 and 24 hours after perfusion and normal liver histologic appearance by 14 days after perfusion in surviving rats. Hepatic regenerative capacity following partial hepatectomy was severely inhibited (P less than 0.001) following isolated hepatic perfusion with sublethal doses of 5-FU (125 mg/kg, 250 mg/kg), Mit-C (1.5 mg/kg) and hyperthermia (41 degrees C and 43 degrees C X 5 minutes). The administration of RLC at the time of partial hepatectomy restored the DNA synthetic response in perfused rats to that seen in normal control rats after partial hepatectomy (P less than 0.05). These results demonstrate that the liver is the source of a factor (s) (RLC) that significantly improves survival after lethal chemotherapeutic injury to the liver by stimulating endogenous hepatic regeneration. A potential clinical application for a stimulator of hepatic regeneration in situations of deliberate, therapeutic insult to the liver is suggested.

Acute Disease↗
PubMed1983

Genetic linkage studies with cleft lip and palate: report of two family studies.

Genetic linkage studies are reported on two families with cleft lip +/- cleft palate. For the first family (LP01) the etiology of the clefting is unknown, and the linkage analyses were done assuming both autosomal dominant and autosomal recessive inheritance. Close linkage is rejected with the Duffy blood group under the dominant model and with four loci (Duffy, Kidd, and ABO blood groups and haptoglobin) under the recessive model. The second family (LP02) is a Mexican-American family segregating the van der Woude syndrome with lip pits. The linkage analyses for this autosomal dominant trait excluded close linkage with seven genetic markers, including three on chromosome one. The maximum lod scores were 0.6 with BF (chromosome 6) and 0.4 with the P blood group, which is not yet mapped.

Cleft Lip↗
PubMed1983

Effect of radiofrequency hyperthermia and chemotherapy on primary and secondary hepatic malignancies when used with metronidazole.

Hyperthermia is selectively toxic to neoplastic tissue. Since August 1981, 357 patients with incurable tumors in various body areas have been treated with chemotherapy and radiofrequency hyperthermia (RFHT) with adjuvant metronidazole at this center. Of this group, the cases of 102 patients with hepatic tumors are reported here. Patients received one to ten treatment courses, each course consisting of two to five daily RFHT sessions. Systemic temperature rose 0.6 +/- 0.3 degrees C during treatment, and tumor core temperature (measured by percutaneous transhepatic thermistor) reached 39.5 +/- 1.2 degrees C in 38 monitored patients. Results have been encouraging; in particular, among 15 patients with newly diagnosed colorectal metastases limited to the liver (and as yet untreated for their secondary disease), there has been objective partial tumor regression in 66.7%. Side effects have been few. Skin burns and subcutaneous fat necrosis were seen in 3.9% and 13.7% of patients, respectively. Tumor temperature is difficult to measure reliably and does not correlate with machine power or tumor response. A phase III trial is currently underway to determine the efficacy of RFHT and chemotherapy for patients with hepatic metastases from colorectal adenocarcinoma.

Adult↗
PubMed1983

The effect of radiofrequency hyperthermia and chemotherapy upon human neoplasms when used with adjuvant metronidazole.

It appears that metronidazole causes an increase in tumor core temperature above that achieved with RFHT alone, by an as yet undetermined mechanism. Furthermore, radiofrequency hyperthermia, in combination with chemotherapy, can produce objective evidence of tumor repression in 30 to 50 per cent of the patients with metastatic cancer. These results justify proceeding to a randomized prospective trial of RFHT and chemotherapy in specific human neoplasms. Such a study is currently being undertaken at this center.

Adult↗
PubMed1983

Role of resection in the management of metastases to the liver.

The results of 22 hepatic resections for metastatic disease are reviewed. There were no operative deaths and survival was encouraging. Life-table analysis of all 22 patients predicted a 5-year survival of 56.4%, and if 16 patients who had primary colorectal tumours are considered separately, the expected 42-month survival was 42.2%. Patients with a single metastasis generally lived longer, and there was no difference in survival between hepatic metastases resected synchronously or metachronously. The authors recommend an aggressive approach to the treatment of hepatic metastases.

Actuarial Analysis↗
PubMed1982

Modulation of the immune response to teratocarcinoma in mice sensitized by sperm antigens.

Mouse primitive teratocarcinoma cells share a common surface antigen with morulae, preimplantation embryo cells and murine and human spermatozoa. 129/Sv mice were immunized with either spermatozoa and subsequently inoculated with various doses of teratocarcinoma 6050. A significant inhibition or acceleration of tumor growth was observed when compared with controls immunized with compatible fibroblasts. These effects were sex-dependent, both the incidence and tumor growth being suppressed in sperm-immunized males. The opposite effects were observed in sperm-presensitized females. Immune sera obtained from both male and female 129/Sv mice exhibited a high binding activity to human spermatozoa when tested in a cellular radioimmunoassay. Thus, immunization with sperm antigens provides immunotherapeutic and/or enhancing effects in male and female 129/Sv mice, respectively.

Animals↗
PubMed1982

Mechanisms of altered in vitro antibody response in the rat by a small synthetic polymer.

NED 137, a low molecular weight synthetic polymer, enhances the rat humoral immune response to cellular antigens in vivo. The effect of NED 137 on the in vitro antibody response to sheep erythrocytes was studied in normal and macrophage-depleted rat spleen cultures. The polymer stimulated the IgM antibody response of normal splenocytes, and its immunopotentiating activity was increased in macrophage-depleted spleen cell preparations. NED 137 enhanced both the primary and the secondary plaque-forming cell (PFC) response of rat splenocytes in a dose- and time-dependent manner. This stimulatory effect of the polymer was dependent on the presence of antigen and demonstrated antigen specificity. The PFC and mitogenic responses of both normal and macrophage-depleted rat splenocytes were dramatically inhibited in cultures prepared from animals pretreated with NED 137 before culture initiation. The antigen dependency, specificity and potentiation of a secondary response suggest that NED 137 acts through the triggering of the lymphoid system but not as a "conventional" B-cell polyclonal activator.

Adjuvants, Immunologic↗
PubMed1982

Thymic hormone-induced accelerated development of antibody responsiveness to sheep red blood cells in the newborn mouse.

The influence of thymic preparations on the kinetics of the development of PFC response to sheep erythrocytes was tested in mice 0 to 4 weeks old. Soluble thymic factor (STF) or thymic epithelial culture supernatant (TES) was prepared from the thymuses of C57B1/6 mice. STF was injected to gravid mice on day 13 or on day 18 of gestation. A marked acceleration in the appearance of PFC to SRBC was noted only in the offspring from those mothers having received STF on day 18. The ability to generate anti-SRBC response in vitro by splenocytes from 1- to 4-week-old mice was significantly improved in the presence of TES. The accelerated appearance of the response to a T-dependent antigen is attributed to increase in the ratio of T helper/T suppressor cells resulting from differentiation and/or clonal expansion under the influence of STF crossing of the placental barrier in the materno-fetal direction.

Animals↗
PubMed1982

Sensitization to low dose 5-fluorouracil. Subsequent enhancement of its systemic antitumor effect in the rat.

This report describes a novel method of immunochemotherapy; the active immunization to the drug 5-fluorouracil (5-FU) with enhanced antitumor activity resulting from its subsequent systemic administration. Two metastasizing carcinomas in the Fischer strain (F344) rat have been used: a chemically induced bladder carcinoma (FBCa) and a spontaneous mammary adenocarcinoma (MACa). Both tumors grow rapidly and result in 100% mortality within 10 wk of implantation. Neither tumor is sensitive to systemic 5-FU alone. Intradermal sensitization to 5-FU before FBCa tumor implantation, followed by 5-FU administered systemically, resulted in significant tumor regression and improvement in survival with eradication of all tumor and cure in 20% of animals. A similar antitumor effect was observed with the MACa. A comparable drug effect was observed when methotrexate sensitization was given before FBCa implantation followed by systemic MTX. Specificity to the sensitizing drug was demonstrated by the lack of effect of sensitization with either 5-FU or MTX unless followed by systemic therapy with the requisite sensitizing agent. Sensitization to 5-FU has also been assessed after FBCa implantation followed by resection of the local tumor. Resection was performed after distant tumor metastases had occurred, and was followed by systemic 5-FU therapy. Whereas tumor resection alone failed to cure any animal, sensitization to 5-FU increased cure rate fourfold over animals receiving systemic 5-FU alone. Antibody to 5-FU in the sera of sensitized animals has been suggested by an immunoenzymatic staining technique and its specificity confirmed in a radioimmunoassay. It is postulated that a combination of the systemic agent and the antibody elicited to it by sensitization produces the significant antitumor effect observed. The antitumor effect observed with this new approach to immunochemotherapy warrants further experimental and clinical study.

Animals↗