Mevalonate availability affects human and rat resistance vessel function.

Previous data in rat conductance vessels indicated that cellular mevalonate contributes to vascular tone and systemic blood pressure control. Using exogenous mevalonate (M) or lovastatin, a 3-hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitor (L), we characterized the role of mevalonate availability in resistance artery function, both in experimental animals and humans. Rat mesenteric artery resistance vessels (MARV, n = 9) were incubated for 48 h with either L, M, L + M, or vehicle (V) and tested for reactivity to NE, serotonin, acetylcholine, atrial natriuretic peptide, and sodium nitroprusside (SNP). Lovastatin increased sensitivity to NE (P < 0.03) and serotonin (P < 0.003), and significantly impaired the response to all three vasodilators. These effects were reversed by co-incubation with mevalonate. Mevalonate alone had no effect. In separate experiments, intravascular free Ca2+ concentration (ivfCa2+) was determined in fura-2AM loaded MARV. Basal ivfCa2+ was increased after a 48-h exposure to L (52.7 +/- 4.6 nM, L, vs. 29.7 +/- 2.4 nM, V, n = 12, P < 0.003), as were ivfCa2+ levels following stimulation with low (100 nM) NE concentrations. Similar ivfCa2+ concentrations were achieved during maximum contraction with NE (10 mM) in both groups. Human resistance arteries of human adipose tissue were also studied. Lovastatin increased the sensitivity to NE (ED50 = 372 +/- 56 nM, V, and 99 +/- 33 nM, L, P < 0.001) and significantly decreased the relaxation to acetylcholine and SNP of human vessels. We conclude that mevalonate availability directly contribute to resistance vessel function and vascular signal transduction systems in both experimental animals and humans. The study calls for the identification of non-sterol, mevalonate-derived vasoactive metabolites, and suggests that disorders of the mevalonate pathway can alter vascular tone and cause hypertension.

Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study.

Disseminated soft-tissue sarcomas are a group of uncommon malignancies generally treated in a uniform manner. This study questioned the impact of schedule on response rate and toxicity in patients with metastatic soft-tissue sarcoma treated with the two-drug combination doxorubicin and dacarbazine. Patients were randomly assigned to receive either bolus therapy with doxorubicin at a dose of 60 mg/m2 and dacarbazine at a dose of 750 mg/m2 intravenously on day 1 (118 patients) or infusional therapy with doxorubicin at 60 mg/m2 and dacarbazine at 750 mg/m2 delivered by continuous intravenous infusion for 96 hours on days 1-4 (122 patients). Chemotherapy was to be repeated every 3 weeks. A unique feature of this cooperative group protocol was a provision for surgical resection of residual disease in patients with a partial response or with stable disease following chemotherapy. Similar overall response rates (17% in both treatment arms) and complete response rates (5% in both treatment arms) were observed. For patients receiving bolus therapy, the median response duration was 19.6 months for those in complete remission and 6.6 months for those in partial remission. For patients receiving infusional therapy, the median response duration was 12.6 months for those in complete remission and 9.3 months for those in partial remission. Examination of dose intensity received when combining treatment arms revealed a weak doxorubicin dose-response relationship. There was no difference in median survival times between the two treatment arms (bolus therapy, 10.6 months; infusional therapy, 10.5 months; logrank P = .97). Analysis of toxic effects favored infusional therapy. Significant reductions in cardiac toxicity (all events, P = .04; clinical events, P = .01) and nausea and emesis (P = .04) were seen in infusional therapy. Of 47 patients eligible for cytoreductive surgery following chemotherapy, 12 received surgery, and of those 12, eight were rendered disease free. The use of a 96-hour continuous intravenous infusion of doxorubicin-dacarbazine was comparable therapeutically with bolus dosing of these two agents and was better tolerated by the patients.

Tamoxifen and oophorectomy in the treatment of recurrent breast cancer: a Southwest Oncology Group Study.

The relatively short survival following chemotherapy in patients with metastatic carcinoma of the breast and the introduction of antiestrogens has led to renewed interest in the hormonal therapy of breast cancer. Pritchard et al. (Cancer Treat. Rep., 64: 787-796, 1980) have recently stated that response to the antiestrogen tamoxifen (TAM) strongly predicts a subsequent response to oophorectomy in premenopausal patients. The Southwest Oncology Group administered TAM to pre- and postmenopausal women with first recurrence of breast cancer. Following response and subsequent relapse, or after no response, patients underwent an oophorectomy while continuing on TAM. None of 14 premenopausal patients who responded to TAM had a response to oophorectomy plus TAM, while 5 of 22 had a remission with oophorectomy plus TAM after initially failing with TAM alone. The reverse was seen in postmenopausal women; 4 of 18 responders to TAM subsequently responded to oophorectomy plus TAM, but none of 18 TAM failures responded to oophorectomy plus TAM. These results suggest that in the premenopausal women the TAM dose may be insufficient to block all estrogen action and that oophorectomy, by removing the major source of estrogen, can result in a more effective antiestrogen action of TAM leading to a response. No explanation is readily available for the results in postmenopausal patients.

Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a Southwest Oncology Group study.

PURPOSE: A national cooperative group trial was conducted in patients with early-stage cutaneous malignant melanoma to determine if oral vitamin A can increase disease-free survival or survival. PATIENTS AND METHODS: Two hundred forty-eight patients with completely resected melanoma of Breslow's thickness greater than 0.75 mm and clinically negative lymph nodes were randomized to oral vitamin A (100,000 IU/d) for 18 months or to observation. Patients were stratified by Breslow's thickness of primary lesion (0.76 to 1.50 mm, 1.51 to 3.00 mm, or > 3.00 mm), sex, and type of therapy (excision, excision plus node dissection, excision plus perfusion, or excision plus both). The median duration of follow-up observation of living patients is greater than 8 years. The relative risk (RR) in disease-free survival and overall survival in the treatment compared with the observation group was calculated using Cox proportional hazards models. RESULTS: Overall, there was no difference in disease-free survival or overall survival between the two groups. Examination of treatment by stratification interactions and subset analysis did not show any treatment-effect differences based on sex or type of therapy. There was also no difference between groups in disease-free survival based on Breslow's thickness of the primary lesion. Overall, 12% of patients who received vitamin A experienced grade 3 or 4 toxicities. CONCLUSION: Based on the lack of overall survival benefit, further evaluation of vitamin A as adjuvant therapy for melanoma does not appear warranted.

Effect of alternating combination chemotherapy on survival of ambulatory patients with metastatic large-cell and adenocarcinoma of the lung. A Southwest Oncology Group Study.

Using a randomized prospective trial design, chemotherapy with 5-fluorouracil, vincristine, and mitomycin C (FOMi) was compared with cyclophosphamide, doxorubicin, and cisplatin (CAP) and with FOMi alternating with CAP (FOMi/CAP) in 452 eligible patients with metastatic large-cell undifferentiated and adenocarcinoma of the lung. Objective responses were obtained in 26%, 17%, and 22% of patients treated with FOMi, CAP, and FOMi/CAP, respectively. The median survival was similar for FOMi, CAP, and FOMi/CAP therapies (20, 24, and 23 weeks, respectively), but the overall survival (log rank test), 1-year survival, and remission duration were longer for FOMi/CAP-treated patients. Survival was significantly longer for fully ambulatory FOMi/CAP-treated patients compared with either FOMi (P = .01) or CAP (P = .04). Younger patients treated with full doses of therapy responded more often than older patients receiving reduced drug doses (26% and 11%, respectively; P = .003). A prognostic factor regression analysis of all eligible patients indicates that sex, performance status, stage, and treatment assigned were important independent variables determining survival (P less than .05). Toxicity was comparable in each treatment group.

Phase II study of carmustine, dacarbazine, cisplatin, and tamoxifen in advanced melanoma: a Southwest Oncology Group study.

PURPOSE: The combination of carmustine (BCNU), dacarbazine (DTIC), cisplatin (DDP), and tamoxifen (Tam) has been reported in small series to provide a response rate of 50%, but with significant myelosuppression and risk of thromboembolic complications. We performed this phase II study to assess the antitumor activity and important toxicities of this combination in the cooperative group setting. PATIENTS AND METHODS: Seventy-nine eligible patients were treated with BCNU 150 mg/m2/d, every 6 weeks, DTIC 220 mg/m2/d on days 1 to 3 every 3 weeks, DDP 25 mg/m2/d on days 1 to 3 every 3 weeks, and Tam 20 mg orally daily throughout treatment. Treatment cycles were repeated every 6 weeks in responding or stable patients for a maximum duration of 1 year. RESULTS: Twelve objective responses were achieved (response rate 15%, 95% confidence interval 8%-25%). Five responses were complete (CR) and seven were partial (PR). The median response duration was 8+ (range, 4-19+) months, (16+ [4-19+] for CR and 8+ [4-11] for PR), and the median survival of the entire group was 9 months. The toxicities were predominantly neutropenia and thrombocytopenia. Four patients developed thromboembolic events. Two patients died while on protocol therapy, one with complications of neutropenia, and the other with disease progression. CONCLUSION: The activity of this regimen is in the range reported for single agents or DTIC plus DDP, and the addition of BCNU and Tam appears to increase toxicity. We do not recommend this combination for routine treatment of advanced melanoma or as the control arm in randomized studies of combination therapy.

Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small-cell lung cancer.

PURPOSE: A phase II study was conducted by the Southwest Oncology Group (SWOG) to assess the efficacy and toxicity of concurrent carboplatin, etoposide, and thoracic radiation (XRT) in a defined population of poor-risk patients with stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage III NSCLC were eligible if they were excluded from cisplatin-based protocols because of poor pulmonary or renal function, history of congestive heart failure, hearing loss, peripheral neuropathy, or weight loss. Carboplatin 200 mg/m2 daily intravenously days 1, 3, 29, and 31 and etoposide 50 mg/m2 daily intravenously days 1 through 4 and 29 through 32 were administered. Beginning day 1, XRT was delivered at 1.8 to 2.0 Gy daily to a total dose of 61 Gy. RESULTS: Within a period of 1 year, 63 patients were registered and 60 were eligible. Patient characteristics were age 47 to 79 years, performance status 0 to 1 (82%) and 2 (18%), and stages IIIA (60%) and IIIB (40%) NSCLC. The most common grades 3 and 4 toxicities included leukopenia (50%), thrombocytopenia (23%), and esophagitis (15%). There were no treatment-related deaths. The overall confirmed response rate was 29%, and median overall survival was 13 months (95% confidence interval, 11 to 14 months). The 2-year survival rate was 21%. CONCLUSION: This chemoradiotherapy regimen is well tolerated in poor-risk patients and yields a median survival similar to that of good-risk patients who received cisplatin-based chemoradiotherapy. This chemoradiotherapy regimen will be compared with XRT alone in poor-risk patients with stage III NSCLC in a randomized phase III trial.

Phase I-II pilot of whole abdominal radiation and concomitant 5-FU as an adjuvant in colon cancer: a Southwest Oncology Group Study.

Thirty-eight patients with Stage B2, C1 or C2 colon cancer (Astler-Coller Modification of Dukes) received 3000 rads whole abdominal radiation and concomitant intermittent bolus 5-FU as part of a phase I-II adjuvant trial. Patients whose tumor penetrated the serosa (B2 or C2) in addition received a 1600 rad boost to the tumor bed. 5-FU was administered only during radiation. It was given at a dose of 300 mg/m2 days 1-5 and 28-32 in 21 patients (Group A) and day 1-3 and 28-31 in 17 patients (Group B). Median follow-up time for Group A is 44 months. Group A patients have a disease-free survival of 66% and overall survival of 73% at 44 months. The 16 C2 patients in Group A have a disease-free survival of 54% and overall survival of 65% at 44 months. There was a 26% incidence of moderate to severe acute toxicity in Group A but no long term bowel, liver, or hematologic toxicity. One patient developed acute myelogenous leukemia 2 years after treatment. Group B patients had only a 6% incidence of moderate to severe toxicity, but had a disease-free survival of 60% and overall survival of 100% at median follow-up of 23 months. Group B Stage C2 patients had a disease-free survival of 53% and overall survival of 100% at this same follow-up period. Disease-free and overall survival in Group A Stage C2 patients is superior to that in several published trials. Given the manageable toxicity, adjuvant whole abdominal radiation with concomitant 5-FU and tumor bed boost should be tested in a randomized fashion for possible therapeutic benefits.

Phase II trial of biochemotherapy with interferon alpha, dacarbazine, cisplatin and tamoxifen in metastatic melanoma: a Southwest Oncology Group trial.

The therapeutic benefit of adding interferon alpha (IFNalpha) to established single-agent and combination chemotherapy regimens for the treatment of metastatic melanoma has not been proven. We designed the present study to estimate the response rate of IFNalpha, dacarbazine, cisplatin and tamoxifen in patients who had not been treated with systemic therapy for advanced disease. Using a schedule similar to that which had previously been shown to favor IFNalpha plus dacarbazine over dacarbazine alone, we treated patients with an "induction" regimen of IFNalpha, 15 mU m(-2) day(-1) intravenously 5 days/week for 3 weeks. Following induction, schedules of IFNalpha, 5 mU m(-2) day(-1) subcutaneously three times a week, and tamoxifen, 10 mg orally twice a day, were begun. Dacarbazine, 250 mg m(-2) day(-1) and cisplatin 33 mg m(-2) day(-1) for 3 consecutive days were repeated every 4 weeks, and subcutaneous IFNalpha and oral tamoxifen were continued until the discontinuation of chemotherapy. We treated 25 patients (18 men and 7 women, median age 52 years) and observed only 1 objective response (response rate 4%, 95% confidence interval 0.1%-20%). The toxicities of the regimen consisted of moderate myelosuppression and constitutional side-effects. On the basis of the low antitumor activity of this regimen, we do not recommend it for further study or for use as standard therapy of metastatic melanoma.

High dehydroepiandrosterone-sulfate predicts breast cancer progression during new aromatase inhibitor therapy and stimulates breast cancer cell growth in tissue culture: a renewed role for adrenalectomy.

BACKGROUND: Stage IV hormone-sensitive breast cancer is often treated with aromatase inhibitors (anastrozole, letrozole, exemestane), which block the conversion of dehydroepiandrosterone (DHEA) to estrone and estradiol. This is intended to obviate the need for steroid replacement and antiquate adrenalectomy. METHODS: Patients who underwent oophorectomy and were being treated with new aromatase inhibitor therapy received serial measurements of serum estrone, estradiol, and DHEA-sulfate (DHEA-S). Steroid values during responsive and progressive phases of disease were compared. In vitro, human breast cancer cell lines T-47D (estrogen-receptor and progesterone-receptor positive) and HCC 1937 (estrogen-receptor and progesterone-receptor negative) were treated with DHEA-S. Proliferation rates were measured by colorimetric assay. RESULTS: Disease in 12 of the 19 patients progressed. DHEA-S was less than 89 microg/dL in patients during the responsive phase and more than or equal to 89 microg/dL during disease progression, with 1 exception (P < .0005). Estrone and estradiol remained suppressed. After disease progression, the condition of 9 patients stabilized with aminoglutethimide therapy (n = 8) or adrenalectomy (n = 1), and their DHEA-S levels were reduced to less than 89 microg/dL. In vitro, elevated DHEA-S induced cell proliferation in T-47D cells. CONCLUSIONS: DHEA-S levels more than or equal to 89 microg/dL predicted disease progression in states of low estrogen. Tissue culture results supported the role of DHEA-S as an estrogenic agent. Oophorectomies with either aminoglutethimide therapy or adrenalectomy were effective remedies for breast cancer progression due to high DHEA-S.

Analysis of the risk reduction of prophylactic partial mastectomy in Sprague-Dawley rats with 7,12-dimethylbenzanthracene-induced breast cancer.

The effectiveness of prophylactic mastectomy in preventing breast cancer was studied in female albino Sprague-Dawley rats. Group A served as untreated controls. Groups B, C, and D underwent 50%, 75%, and total mastectomies 2 weeks after the administration of 7,12-dimethylbenzanthracene (DMBA). Group E was initially subjected to total mastectomy. Two weeks after surgery, group E received 5 mg of DMBA intravenously. Group F underwent sham procedures. All animals were sacrificed at age 8 months. The mean number of tumors per animal developing in groups A through E was 5.00, 5.17, 4.67, 5.46, and 5.20, respectively. There was 0.21 tumor per animal in group F. The mean time to tumor development in groups A through E was 11.33, 10.05, 9.88, 19.25, and 19.38 weeks, respectively. All results were subjected to an analysis of variance. There was no statistically significant difference in the number of DMBA-induced tumors in groups A through E. Groups D and E had a significant prolonged time to tumor development. The overall risk of the development of breast tumors was not significantly reduced by prophylactic mastectomy. Residual breast tissue after prophylactic mastectomy is at increased risk for the development of breast tumors. The risk of developing breast tumors in this model is not reduced in proportion to the amount of breast tissue removed. (This study suggests that subcutaneous mastectomy in high-risk individuals may not have appropriate prophylaxis against the development of carcinoma of the breast.)

Treatment of nonendocrine gastrointestinal disorders with octreotide acetate.

Somatostatin and its longer-acting analog, octreotide acetate, can be used effectively for the treatment of nonendocrine gastrointestinal disorders. Octreotide has been shown to decrease pancreatic fistula output by suppressing exocrine pancreatic function. We believe that octreotide acetate may be useful to prophylaxis against the development of pancreatic fistulas following pancreatic resection and may reduce the enzymatic and volume output of established pancreatic fistulas. We also have shown that administration of octreotide acetate 2 hours before a high carbohydrate test meal reduces gut peptide levels, which increase following meal ingestion in patients with the dumping syndrome. Reduction of circulating peptides in these patients may slow gut motility and improve glucose regulation, thus, providing relief of postvagotomy dumping symptoms.

Results of treatment of inferior vena cava syndrome with expandable metallic stents.

BACKGROUND: Patients with hepatic metastases often develop obstruction of the intrahepatic inferior vena cava (IVC), known as IVC syndrome. This obstruction is debilitating due to the development of ascites and anasarca. OBJECTIVES: To update our experience in the diagnosis and treatment of IVC syndrome and to evaluate the efficacy of expandable stents in the treatment of IVC syndrome. DESIGN: Retrospective review. SETTING: University hospital. PATIENTS: Twenty-eight patients with hepatic metastases diagnosed as having IVC syndrome. INTERVENTION: Patients underwent transfemoral placement of Gianturco-Rosch self-expandable Z metallic stents in the intrahepatic IVC. One patient was treated with a Wallstent. Stents were 15 to 25 mm in diameter and 60 to 140 mm in length. Pressure gradients across the IVC were measured before and after stent placement in all patients. MAIN OUTCOME MEASURES: Change in pressure gradient, relief of ascites and anasarca, loss of weight, patency of the primary stent, and survival after stent placement. RESULTS: Pressure gradients were reduced in all patients, which was followed by rapid reduction of ascites and anasarca with a median weight loss of 5.85 kg. Survival after stent placement varied from 1 to 99 days, with a mean of 34 days. Stent patency remained until death in all patients. CONCLUSION: The debilitation of IVC syndrome due to ascites and anasarca can be considerably palliated by placement of transfemoral percutaneous stents.

The mechanism of hormone-sensitive breast cancer progression on antiestrogen therapy. Implications for treatment and protocol planning.

Fifteen patients whose tumors progressed while they received tamoxifen citrate therapy were studied by serial determinations of serum levels of estrone (E1), estradiol (E2), and dehydroepiandrosterone (DHEA) obtained during progression after withdrawal from tamoxifen therapy and total endocrine ablation or suppression. Discontinuation of tamoxifen therapy resulted in reductions of DHEA, E1, and E2 levels by 44%, 49%, and 42%, respectively. Ablation or suppression reduced sex steroids to minimal levels and produced responses in all patients. Elevations of DHEA, E1, and E2 could be provoked by readministering tamoxifen to hypophysectomized and oophorectomized, but not adrenalectomized, patients, indicating that the adrenal gland is the source of these sex steroids. We conclude that tamoxifen stimulates adrenal production of DHEA, which is aromatized to E1 and E2. Buildup of E1 and E2 overwhelms the competitive binding of tamoxifen to the estrogen receptor, resulting in tumor progression.

Long-term results with primary retroperitoneal tumors.

Primary retroperitoneal tumors represent a variety of lesions, with different treatments and prognoses. Of 182 patients in our study, retroperitoneal tumor was recognized preoperatively in only 39% of them. Sarcomas were most common (43% of patients), followed by lymphomas (23%), benign tumors (11%), undifferentiated malignant tumors (11%), carcinomas (8%), and germ cell tumors (4%). In 81 patients since 1960, the resection rate was 50%. Operative determinants of resectability were pathologic category and grade and extent of tumor. Resection included segments of the gastrointestinal tract (30% of the patients), kidney (25%), and pancreas, bladder, spleen, aorta, and vena cava (for each, 5% or less of the patients). The operative mortality was 6%. Tumor caused late death in 95% of the patients. Pathologic findings were a significant determinant of survival in the 81 patients. For sarcomas, 69% of the patients underwent resection, and the 1- and 5-year actuarial survival rates were 80% and 43%, respectively. Sixty percent of these patients underwent multiple operations. For lymphomas, most patients were treated with radiotherapy and chemotherapy; the 1- and 5-year survival rates were 67% and 35%, respectively. Benign tumors, almost all resected, yielded a 5-year survival rate of 100%. Undifferentiated tumors and carcinomas, most treated with radiotherapy and chemotherapy, had a 1-year survival rate of less than 33%. Other determinants of survival were age, weight loss, grade of tumor, and extent of tumor. Patients who underwent palliative resection had the same survival rate as patients who underwent biopsy alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Nonanatomic hepatic resection for secondary hepatic tumors with special reference to hemostatic technique.

The techniques for resection of hepatic tumors have traditionally been based on lobar anatomy. The morbidity and mortality associated with hepatic resection have been most closely correlated with intraoperative blood loss. The results of 37 hepatic resections for secondary neoplasms were retrospectively reviewed. This group included 18 patients who underwent anatomic resections and 19 patients who underwent nonanatomic resections. The nonanatomic group experienced significantly less blood loss, shorter operating times, shorter hospital stays, and no significant difference in long-term survival. A positive relationship between blood loss and postoperative complications is demonstrated for the combined groups. These results support the use of nonanatomic resection whenever feasible for secondary hepatic tumors. We describe the technique for nonanatomic hepatic resection for metastatic lesions, with special emphasis on hemostatic techniques.

Changes in serum sex steroid levels during megestrol acetate therapy.

We hypothesized that megestrol acetate (MA) may work on breast carcinoma by inducing changes in serum sex steroid levels. We prospectively measured levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone (DHEA), estrone (E1), and estradiol (E2) in 18 postmenopausal women before and during megestrol acetate therapy. MA significantly suppressed serum FSH, LH, DHEA and E1 levels. However, this was accompanied by a marked increase in serum E2 levels as measured by radioimmunoassay performed on whole serum. MA did not cross-react with the anti-E2 antibodies used in the assay. Elevated E2 levels also occurred in oophorectomized and/or adrenalectomized patients indicating the ovary and adrenal are not the source of the elevated E2 levels. We conclude that MA may be metabolized to oestrogenic compounds that crossreact with antibodies to E2, explaining the elevated E2 levels observed. The effects of these oestrogenic metabolites on breast carcinoma are unknown.

Results of cisplatin hyperthermic isolation perfusion for stage IIIA and IIIAB extremity melanoma.

Between 1983 and 1992, 21 patients with extremity stage IIIA or IIIAB melanoma underwent hyperthermic isolation limb perfusion (HILP) with cisplatin in dosages varying from 26 to 237 mg/m2 as part of a pharmacokinetics and maximum-tolerated dose study. Extremity temperatures were up to 40 degrees C and the pH was controlled near 7.4. There were no major complications in this series of patients. Overall survival was 55% at 2 years and 47% at 5 years. Local control rates excluding regional nodal control was 79% at 2 years and 53% at 5 years. Local control, including regional nodal control, was 61% at 2 years and 36% at 5 years, indicating that cisplatin is not as effective at nodal control as it is at control of dermal or subcutaneous metastases. Three patients who failed cisplatin HILP have responded to re-perfusion with melphalan and actinomycin D. Two of the three patients had complete responses. It is concluded that cisplatin is an active agent against melanoma when employed by HILP. The drug is well tolerated at the doses and temperature employed, but it is not superior to HILP with melphalan.

Phase I-II trial of hyperthermic isolated limb perfusion with cisplatin in the treatment of high risk malignant melanoma of the extremities.

Between 1983 and 1990, 59 patients with malignant melanoma were retrospectively reviewed to assess the safety, efficacy and the maximal tolerated dose of cisplatin used in hyperthermic isolated limb perfusion. The median follow-up was 29 months (range 3-54 months). The local recurrence rate was 12% in Stage I, 33% in Stage II and 30% in Stage III patients. The maximal tolerated dose of cisplatin in hyperthermic isolated limb perfusion was 3.2 mg/kg for forequarter perfusions and 6 mg/kg for hindquarter perfusions based on lean body weight. At these dosages, there is an 8% major complication rate and only one patient experienced long-term sequelae. Hyperthermic isolated limb perfusion using cisplatin in the dosages of 3-6 mg/kg lean body weight is associated with low morbidity and appears to have efficacy comparable to L-phenylalanine mustard for the control of locally recurrent malignant melanoma.

Human umbilical cord vein allograft arteriovenous fistula for chemotherapy access.

Seven patients who received chronic chemotherapy and required vascular access underwent construction of an arteriovenous fistula of the leg using gluteraldehyde-tanned human umbilical cord vein allografts. No wound or graft complications have occurred and patient tolerance of the operative procedure and subsequent use of the fisulas for chemotherapy has been excellent. Our preliminary results suggest that the use of umbilical vein allograft arteriovenous fistulas is quite satisfactory for long-term chemotherapy access.