Metastasis of hepatocellular carcinoma to the right colon manifested by gastrointestinal bleeding.

An 82-year-old black woman with a history of hepatocellular carcinoma presented with gastrointestinal bleeding. Barium enema and fibrocolonoscopy revealed a 4-cm polypoid mass at the level of the ascending colon with evidence of active bleeding. Biopsies of the lesion proved it to be metastatic hepatocellular carcinoma. Exploratory laparotomy revealed no further dissemination of the tumor, and the patient underwent an ileocolectomy. The serosal side of the colonic lesion was free from tumor, and there was no peritoneal implantation, direct extension, or lymph node involvement. This case represents an extremely rare presentation of metastatic hepatocellular carcinoma.

Pharmacologic modulation of experimental postischemic hepatic function.

The present study evaluated and compared the effects of SRI 63-441, a potent platelet activating factor antagonist, superoxide dismutase (SOD), an oxygen free radical scavenger, and ibuprofen, a cyclooxygenase inhibitor on hepatic function after 90 minutes of warm ischemia. After warm ischemia, livers were harvested and underwent 90 minutes of warm, oxygenated, sanguinous perfusion on an isolated liver perfusion apparatus. Pretreatment of donor animals with 20 mg/kg intravenous (I.V.) SRI 63-441 5 minutes before induction of total hepatic ischemia resulted in significantly increased bile production, a significant decrease in transaminase release, and a higher tissue adenosine triphosphate (ATP) content when compared with ischemic nontreated controls. SOD resulted in improved bile production and decreased transaminase liberation only when present in the perfusate at the time of in vitro reperfusion. Ibuprofen did not improve postischemic hepatic function in this model. Electron microscopy revealed patchy hepatocellular vacuolization with an intact sinusoidal endothelium in all ischemic livers. However, the degree of damage was less severe in the livers from those rats pretreated with 20 mg/kg SRI 63-441. This study demonstrates that SRI 63-441 pretreatment significantly reduces hepatic warm ischemic injury, and in the present model, appears superior to two other agents that have been advanced in the treatment of ischemic injury. The use of such agents singly or in combinations have important implications as regards gaining a better understanding of the basic mechanisms in organ ischemia, and moreover, for therapeutic applications in organ ischemia and preservation.

Biopharmaceutical aspects of FK-506.

FK is a potent immunosuppressive agent. FK can be analyzed in biologic fluids by EIA. The oral absorption of FK is rapid but variable in dogs. After intramuscular administration, FK is slowly and continuously absorbed. FK is primarily eliminated by metabolism. Less than 1% of the administered dose is excreted in the bile or the urine. After chronic intramuscular administration FK inhibits drug metabolism. Monitoring of FK levels in plasma is essential for the proper interpretation of efficacy and toxicity studies.

Heterotopic heart transplantation in the rat receiving FK-506 alone or with cyclosporine.

In rats, FK significantly prolonged heterotopic heart graft survival over a wide dose range when given for 2 weeks starting on the day of the operation. Brief courses of FK for one to four days preoperatively, and especially beginning four days postoperatively, allowed long subsequent survival of heart grafts in otherwise untreated recipients. The seeming acceptance of the grafts with postoperative FK treatment was largely but not exclusively donor specific when tested eight days after the last FK dose by second grafts from the same donor v third-party donor grafts. FK in minimally therapeutic doses was synergistic with suboptimal doses of CyA.

Combination therapy for resectable and unresectable adenocarcinoma of the pancreas.

The current report summarizes our experience with 77 patients with cancer of the pancreas treated over 3.5 years. Patients were not assigned to a definite group of therapy, but through the availability of different drugs and different types of treatment several comparable groups have evolved. All patients have received radiofrequency hyperthermia and chemotherapy, but in addition, some have received selective immune stimulation with one of two low-molecular-weight compounds. The data show that radiofrequency hyperthermia permits the use of a lower dose of chemotherapy, with an apparent response to treatment. This response is enhanced significantly by the addition of selective immune stimulation. A further, more rigorously defined study will be undertaken to confirm this data.

Radiofrequency hyperthermia as adjuvant therapy following surgical resection of an experimental malignant neoplasm.

Local recurrence after radical surgery is a major problem with many primary solid cancers. The use of radiofrequency hyperthermia (RFHT) as adjuvant therapy to surgery was explored in the Fischer bladder carcinoma (FBCa)/F344 rat tumor system. After subcutaneous innoculation of 34 rats with 10(6) FBCa cells in suspension, RFHT was administered to 17 animals on days 1, 5, 8, and 12. The development of palpable tumors was delayed but not prevented, and tumor growth was retarded in RFHT-treated animals. In another experiment 40 rats were innoculated by subcutaneous trocar injection with a 1 mm3 piece of FBCa. After tumor excision on day 17, adjuvant therapy (untreated control, mitomycin C, RFHT, or RFHT plus mitomycin C) was started on day 20 (10 rats/treatment). The 20 RFHT-treated rats had only 1 incisional recurrence as compared to 9 recurrences in sham-heated rats (P less than 0.005). The authors conclude that RFHT has considerable value as adjuvant therapy to surgery in these tumors. Additional studies of RFHT as adjuvant treatment after surgical excision of tumors are planned.

Palliation of advanced head and neck cancer with radiofrequency hyperthermia and cytotoxic chemotherapy.

Fourteen patients with recurrent malignant tumours of the head and neck were treated with radiofrequency hyperthermia and chemotherapy after conventional therapy had failed. After 2 to 11 treatment courses and a follow-up of 30 weeks, the neoplasms in three patients had completely regressed and one had a partial response. Of eight patients who died, two had partial responses initially; a third patient died of complications relating to surgical resection of the tumour after a partial response. Three of five patients whose tumours were unresponsive to methotrexate responded when this drug was given with radiofrequency hyperthermia. There were seven minor skin burns in six patients. Further studies of radiofrequency hyperthermia and chemotherapy for palliation of head and neck cancer are planned.

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.

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.

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.

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.

Hyperthermia as a treatment for neoplasia.

The use of hyperthermia to treat malignant neoplasms is currently a "hot" issue. It has been demonstrated that heating tumour cells to 42 degrees C or above leads to their self-destruction by decreased cellular metabolism and aerobic respiration. The selective accumulation of heat in the malignant tissue at 42 degrees to 44 degrees C, compared with the temperature of normal tissue, is probably related to the different blood supply within the tumour. The historical background and the experimental and clinical results of hyperthermia are reviewed. The advantages and disadvantages of the different thermotherapy techniques currently in use are discussed. Hyperthermia is probably more efficient if combined with other antitumour treatment modalities.

Elimination of 51Cr-labelled target cells as a method of in vivo assessment of immune reactions.

This report describes the use of an in vivo 51Cr release assay which is able to monitor various immune reactions in the rat. This assay is able to quantitate the immune response to tumour and also to assess the relative efficacy of different immunostimulants in this tumour model. These data correlate well with survival studies in tumour-bearing rats. This assay can also measure the sensitizing effect of antigens from animals differing at both the major and minor histocompatibility locus using various routes of sensitization and various donor tissues. Allograft survival can also be correlated to in vivo 51Cr release. This method is both reproducible and specific. The in vivo 51Cr release assay is a useful and versatile means of monitoring the development of antitumour responses and the degree of sensitization to histocompatibility antigens in a variety of situations in the rat. It may therefore prove useful as a rapid method for screening new antitumour and immunosuppressive regimens to be used in various studies.

Adjuvant chemoimmunotherapy for gastric carcinoma.

Between July 1974 and August 1978, 78 patients were entered into a study to assess the effect of immune stimulation with bacille Calmette Guérin (BCG) on gastric carcinoma. Patients were selected in random fashion for the two treatment regimens; 41 received BCG and 5-fluorouracil and 37 received 5-fluorouracil alone. Initial results, after a mean follow-up of 72 weeks, are presented. Immunotherapy as used in this study did not affect survival. However, 5-fluorouracil given as an adjuvant to palliative resection did improve survival when compared with a matched control group in which patients received no additional treatment after palliative resection. Although this finding will have to be studied further by multicentre randomized prospective trials, our experience indicates that incurable gastric carcinoma should be managed more aggressively.