Feminization as a result of both peripheral conversion of androgens and direct estrogen production from an adrenocortical carcinoma.

A 45-year-old man presented with gynecomastia, hypertension and a large left adrenal mass. Further evaluation revealed elevated serum concentrations of estrogen, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, deoxycorticosterone, and aldosterone and increased 24-hour urinary 17-ketosteroid and free cortisol excretion. Removal of a 10 kg adrenocortical carcinoma led to normalization of the hormone concentrations and partial resolution of the gynecomastia. There was no clinical evidence of metastases. Incubation of tumor slices demonstrated that the tumor had an active aromatase and sulfotransferase. We estimated that about half the serum estrone arose from peripheral conversion of androstenedione. Feminizing adrenocortical carcinomas are rare and this case is unusual given the lack of clinical metastases and the probable dual source of estrogen from tumor as well as from the peripheral conversion of tumor-derived androgens.

Alternated versus syncopated CHOP-PVB: two studies for the treatment of non-Hodgkin's lymphoma by the Southwest Oncology Group.

Based on a preliminary trial that suggested that CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), and PVB (cisplatinum, vinblastine, bleomycin), are at least partially non-cross-resistant, the Southwest Oncology Group treated patients with unfavorable histology, non-Hodgkin's lymphoma with CHOP and PVB. In the first study, 76 eligible patients were given three courses of CHOP, with complete or partial responders receiving three courses of PVB followed by three further courses of CHOP. Nonresponders after the initial three cycles of CHOP, received six courses of PVB. In the second study, 154 eligible patients were treated with alternating cycles of the two drug regimens. The overall objective antitumor response (CR + PR) was 77% for the first study and 58% for the second. The complete remission rates were 48% and 38%, respectively. The overall survival for both studies is similar. These results are interpreted in terms of the Goldie-Coldman hypothesis.

Melanoma and soft tissue sarcoma in seven patients.

Seven patients with both melanoma and sarcoma were seen at the Dana Farber Cancer Institute (Boston, MA) over a 4-year period. Three had additional malignant neoplasms; one of these patients also had the hereditary cutaneous malignant melanoma, dysplastic nevus syndrome. These observations suggest the possibility of a biologic relationship between melanoma and sarcoma, the nature of which remains unknown.

Cisplatin, VP-16-213 and MGBG (methylglyoxal bis guanylhydrazone) combination chemotherapy in refractory lymphoma, a phase II study.

In an effort to improve the treatment of patients with refractory or recurrent lymphoma, we developed a protocol using cis-platinum combined with two other agents of known efficacy in these disorders but with differing side effects: VP-16 and MGBG. Twenty-six eligible patients were treated with this regimen. There were 15 men and 11 women with a median age of 54 years (22-73), and performance status of 1 (0-3). Their diagnoses were Hodgkin's disease 5 and non-Hodgkin's lymphoma [NHL] 21 which included 11 with diffuse histocytic lymphoma [DHL]. The median number of chemotherapy regimens was 2 (1-5); 12 also received radiotherapy. Twenty patients are evaluable for response: 15 NHL and 5 Hodgkin's disease. Three patients, all of whom had DHL entered complete remission (20%) with a median time to treatment failure of 7 1/2 months. Six NHL (40%) and one Hodgkin's disease (20%) patients entered a partial remission. There were three early deaths: one due to progressive disease, one to acute respiratory failure, and one with disease status undocumented. Toxicity included leukopenia, thrombocytopenia, anorexia, nausea, vomiting, stomatitis, alopecia, renal failure, profound peripheral neuropathy, and hypersensitivity vasculitis. Treatment was stopped because of the latter two. These agents are non-crossresistant with doxorubicin-containing regimens. The drugs are possibly synergistic and modestly active with moderate to severe toxicity.

Treatment of advanced ovarian cancer with sequential combination chemotherapy.

Fifty previously untreated patients with advanced or recurrent ovarian cancer (FIGO Stages III and IV) were treated with alternating combination chemotherapy. This consisted of high-dose doxorubicin (70 mg/m2) and cisplatin (100 mg/m2) alternated with CHF (cyclophosphamide, hexamethylmelamine, and 5-fluorouracil). Toxicity (myelosuppression, nephropathy, and neuropathy) was infrequent and mild. Clinical response rates were high (94% response, 62% complete clinical response), but the majority of patients had residual intraabdominal disease at second-look surgery (75%). Thirteen patients (26%) are alive after 4 years of observation (minimum follow-up). Survival was adversely influenced in patients who were older than 70, had Stage IV disease, residual tumor bulk greater than 2 cm, and who failed to achieve complete clinical remission. The median duration of survival (28 months) and percentage of long-term survivors appear similar to that in other platinum-based chemotherapy studies. Although the role of alternating combination chemotherapy in epithelial ovarian cancer remains undefined, it is likely that an alternate approach will be necessary to markedly improve survival rates for patients with this disease.

Endocarditis as a complication of indwelling right atrial catheters in leukemic patients.

Three patients with acute leukemia who had chronic indwelling right atrial catheters developed endocarditis. In all cases, the infection was cured with antibiotics only after removal of the infected catheter. Although infective endocarditis has been rarely noted in leukemic patients, the use of chronic indwelling catheters may lead to an increased incidence of this infection in these patients.

Efficacy of ketoconazole v nystatin in prevention of fungal infections in neutropenic patients.

A prospective randomized study was undertaken in neutropenic patients to evaluate the efficacy of prophylactic ketoconazole v nystatin in reducing yeast infections. Eighteen patients received 500,000 units of nystatin suspension four times daily, and 18 patients received 200 mg of ketoconazole daily. The nystatin group experienced nine local yeast infections (four thrush, three esophagitis, and two vaginitis); three patients receiving ketoconazole had thrush. No cases of disseminated candidiasis occurred in either group. Ketoconazole was better tolerated than nystatin and neither drug caused toxic effects. In addition to being nontoxic and better tolerated, ketoconazole appeared to be slightly more effective than nystatin in reducing locally severe yeast infections.

Intensive sequential chemotherapy with bleomycin, Oncovin, mitomycin C, and methotrexate followed by adriamycin, cisplatin, and cyclosphosphamide in squamous cell cancer of the head and neck.

Twenty-six patients with advanced squamous cell cancer of the head and neck were treated with bleomycin, Oncovin, mitomycin C, and methotrexate (BOMM) for ten weeks. Partial and nonresponders then received adriamycin, cisplatin, and cyclophosphamide (APC) in a planned sequential program. The response rate to BOMM was 65% (19% complete remission, CR). The overall response rate to APC was 20%. Only three of eight nonresponders to BOMM could receive APC and non responded. Six of seven partial responders received APC and only one responded. One complete responder to BOMM received APC at relapse and attained a partial response. The major side effects of BOMM were mucositis and myelosuppression. Patients receiving methotrexate 60-72 hours following the bleomycin infusion had less myelosuppression than patients who were treated 36-42 hours after bleomycin. The toxicities with APC included nausea, vomiting, and myelosuppression. Including a prior series, a total of 45 patients have been treated with BOMM with a 71% response rate (69% in previously irradiated patients). Twenty-eight percent of previously treated patients achieved complete remission, and two of these patients are disease free at 31 and 37 months. Methotrexate dose-rate alteration to low dose twice weekly followed by a single dose of oral leucovorin did not improve the complete or partial response rate when compared to weekly methotrexate administration. The complete remission rate and response duration were also not improved by the planned sequential use of this cisplatin-containing regimen.

Combination chemotherapy of refractory lymphoma with cis-dichlorodiamineplatinum, vinblastine, and bleomycin.

Therapy of advanced lymphomas after failure of chemotherapy with cytoxan and adriamycin containing combinations remains poor. We have treated 17 patients with refractory lymphomas of various histologies with an intensive regimen of cisplatin, vinblastine and bleomycin. These were three complete clinical responses (6, 10+, 8 months, respectively) and five partial responses (2.5, 3, 4, 7, 18 months, respectively) for a total of 8/17 responders. Four of the eight responders had bone or bone marrow involvement. In addition, three patients had dramatic shrinkage of measureable lesions, but the duration (less than 1 month) was too short to allow classification as a response. Toxicity included severe myelosuppression requiring that patients be hospitalized to the majority of cases, mild to moderate rise in serum creatinine levels in 41% of patients and one case of fatal pulmonary fibrosis. This regimen may be useful in patients with refractory or relapsing lymphoma; alternatively, it may be useful as part of an initial treatment protocol utilizing non-cross-resistant regimens for the management of patients with poor prognosis lymphomas.

Splenectomy for agnogenic myeloid metaplasia.

Only a fraction of the patients with myeloid metaplasia have indications for splenectomy develop. Palliation for symptomatic splenomegaly is highly successful. Significant relief from hypersplenism, anemia or thrombocytopenia was achieved, however, in less than half of the patients. Since patients with severe thrombocytopenia are at continuing risk of spontaneous hemorrhage and of bleeding after minor trauma, splenectomy appears to be justified in these patients, provided that studies of peripheral blood and bone marrow have excluded those with leukemic conversion. The benefit obtained from splenectomy in patients with chronic anemia requiring frequent transfusions in less certain, particularly in men and in patients converting to myeloid metaplasia from polycythemia vera. In some instances, the continuation of transfusions may result in less morbidity and better palliation than operation. Although the course of this myeloproliferative disorder from first symptoms to death frequently extends for more than a decade, the manifestations which may provide an indication for splenectomy usually occur late in the course of the disease. The element as well as the morbidity of the operation makes a thorough evaluation of each patients essential before splenectomy is considered.

Clostridium difficile colitis associated with cancer chemotherapy.

Administration of cancer chemotherapeutic agents to humans and animals is frequently complicated by diarrhea and enterocolitis. Clostridium difficile and its toxin were found in the stools of two patients with colitis after chemotherapy for malignant neoplasms. Diarrhea in both patients resolved with oral vancomycin hydrochloride therapy. Clostridium difficile was also isolated from several fomites within the room of one of these patients and also from the hands of his nurses. Based on these two recent experiences, we believe patients with cancer and diarrhea or signs suggestive of colitis should be studied for toxigenic C difficile and appropriate isolation techniques employed.

Meningeal leukemia complicating chronic lymphocytic leukemia.

Two patients with classic chronic lymphocytic leukemia had meningeal leukemia as a complication of their disease. Intrathecal chemotherapy was successful in eradicating signs and symptoms of meningeal involvement. One of these patients is alive without evidence of central nervous system leukemia 30 months after diagnosis of meningeal leukemia, and 5 1/2 years after the diagnosis of chronic lymphocytic leukemia. Although uncommon, meningeal involvement in chronic lymphocytic leukemia may occur at various times in the course of the disease, it responds to conventional therapy.

Surgical management of pericardial tamponade as a presenting manifestation of acute leukemia.

Two patients with acute leukemia presented with symptomatic acute pericarditis and rapidly developed cardiac tamponade. Conservative management was not possible in either patient due to mechanical problems with fluid removal. Thoracotomy with pericardial decompression resulted in permanent relief of symptoms in both cases. Management of cardiac tamponade in acute leukemia by surgical decompression even in severely immunocompromised hosts is a feasible alternative and should be considered when more conservative measures fail or are not possible.

Bleomycin, vincristine, and mitomycin C with or without methotrexate in the treatment of squamous cell carcinoma.

Forty-two patients with metastatic squamous cell carcinoma were treated with bleomycin, vincristine, and mitomycin C with or without methotrexate (BOM +/- M). The overall response rate of 64% (complete response [CR] rate, 19%) included 19 responses among 26 patients (seven CRs) with head and neck cancer, three responses among eight patients with cervical cancer, and three responses among five patients (one CR) with lung cancer. Six of 12 patients (two CRs) responded to BOM and 21 of 30 patients (six CRs) responded to BOMM. The median duration of response was 16 weeks. Toxic effects included nausea or vomiting in 33% of the patients, fever of > 101 degrees C in 26%, stomatitis in 29% and pulmonary toxicity in 19%. Four of eight cases of pulmonary toxicity were fatal and the incidence was related to the amount of both bleomycin and mitomycin C administered. The occurrence of pulmonary toxicity could not be predicted by serial determination of pulmonary function or blood gases. A wbc count nadir of < 2500/mm3 occurred in 15 of 42 patients. There were two episodes of sepsis with one death. A platelet count nadir of > 75,000/mm3 occurred in eight of 42 patients with no episodes of hemorrhage. BOMM produces a high objective response rate in patients with squamous cell cancer. However, the duration of remission is brief, and use of the regimen carries an increased risk of fatal pulmonary toxicity.

The chronic leukemias.

Chronic granulocytic leukemia, chronic lymphocytic leukemia and its variants, and hairy cell leukemia are characterized by prominent organ infiltration and marrow replacement, with a course consisting of years. Although treatment is effective in ameliorating symptoms, little has been gained in terms of increased survival.