Neil Dubin

Protective Effect of the Bispiperazinedione ICRF-187 against Doxorubicin-Induced Cardiac Toxicity in Women with Advanced Breast Cancer

Studies in animals suggest that the bispiperazinedione ICRF-187 can prevent the development of dose-related doxorubicin-induced cardiac toxicity. In a randomized trial in 92 women with advanced breast cancer, we compared treatment with fluorouracil, doxorubicin, and cyclophosphamide (FDC), given every 21 days, with the same regimen preceded by administration of ICRF-187 (FDC + ICRF-187). Patients were withdrawn from the study when cardiac toxicity developed or the cancer progressed. The mean cumulative dose of doxorubicin tolerated by patients withdrawn from study was 397.2 mg per square meter of body-surface area in the FDC group and 466.3 mg in the FDC + ICRF-187 group (no significant difference). Eleven patients on the FDC + ICRF-187 arm received cumulative doxorubicin doses above 600 mg per square meter, whereas one receiving FDC was able to remain in the study beyond this dose. Antitumor response rates were similar (FDC vs. FDC + ICRF-187, 3 vs. 4 complete responses; 17 vs. 17 partial responses; and 9.3 vs. 10.3 months to disease progression). Although myelosuppression was slightly greater in the FDC + ICRF-187 group, the incidence of fever, infections, alopecia, nausea and vomiting, or death due to toxicity did not differ between the groups. Cardiac toxicity was evaluated by clinical examination, determination of the left ventricular ejection fraction by multigated nuclear scans, and endomyocardial biopsy. In comparisons of the FDC group with the FDC + ICRF-187 group, clinical congestive heart failure was observed in 11 as compared with 2 patients; the mean decrease in the left ventricular ejection fraction was 7 vs. 1 percent when the cumulative dose of doxorubicin was 250 to 399 mg per square meter (P = 0.02), 16 vs. 1 percent at 400 to 499 mg (P = 0.001), and 16 vs. 3 percent at 500 to 599 mg (P = 0.003); and the Billingham biopsy score was 2 or more in 5 of 13 patients undergoing biopsy vs. none of 13 (P = 0.03). We conclude that ICRF-187 offers significant protection against cardiac toxicity caused by doxorubicin, without affecting the antitumor effect of doxorubicin or the incidence of noncardiac toxic reactions.

RISK FACTORS FOR KAPOSI'S SARCOMA IN HOMOSEXUAL MEN

An investigation of 20 homosexual men with histologically confirmed Kaposis sarcoma and 40 controls revealed significant associations between Kaposis sarcoma and use of a number of drugs (amyl nitrite, ethyl chloride, cocaine, phencyclidine, methaqualone, and amphetamine), history of mononucleosis, and sexual activity in the year before onset of the disease. Patients with Kaposis sarcoma also reported substantially higher rates of sexually transmitted infections than did controls. Multivariate analysis indicated independent significant associations for amyl nitrite and sexual activity and showed use of phencyclidine, methaqualone, and ethyl chloride to be non-significant. Evaluated at the median exposure for patients, the analysis yielded risk-ratio estimates of 12.3 for amyl nitrite (95% confidence limits 4.2, 35.8) and 2.0 for sexual activity (95% confidence limits 1.3, 3.1).

Epidemiology of Malignant Melanoma: Pigmentary Traits, Ultraviolet Radiation, and the Identification of High-Risk Populations

We report on a case-control study begun in 1979 to identify factors responsible for the observed high incidence of malignant melanoma among Caucasians. Interview data were collected on a comprehensive set of risk factors, including pigmentary characteristics, ultraviolet light exposure, family history, reproductive factors, drug use, ethnicity, smoking and dietary history, and chemical exposures. Quantification of risk factors was emphasized, whereas previous case-control studies had relied on qualitative assessments of exposure. A profile of high-risk individuals was to be developed for the purpose of identifying a subpopulation at whom future monitoring for malignant melanoma could be directed. In this report we present results for a subset of the available risk factor data, including pigmentary traits, sun exposure, and family history variables. Because of current interest in the relationship between fluorescent light exposure and melanoma risk (Beral et al. 1982; Maxwell and Elwood 1983; Pasternack et al. 1983) we include these data as well. The remaining risk factors will be analyzed in detail in subsequent reports.

Heterosexual transmission of HIV in a cohort of couples in New York City

Objective:Since heterosexual transmission of HIV in the United States is occurring at an increasing rate, especially among black and Hispanic couples and those in which one member has a history of intravenous drug use, we sought to study the heterosexual transmission of HIV in couples. Design:Multiple logistic regression analysis of risks for HIV infection in female partners. Methods:We enrolled 158 non-intravenous drug user (IVDU) steady heterosexual partners of HIV-infected individuals (indexes) in this study. Of these, 93% were women, 54% were Hispanic whites, 23% were black and 65.6% were partners of IVDU. Results:In a multiple logistic regression analysis of risks for HIV infection in female partners, the strongest predictors of transmission were AIDS or AIDS-related complex (ARC) in the index [adjusted odds ratios (OR), 16.81; P< 0.001 and 12.53; P = 0.003, respectively], a history of anal intercourse (adjusted OR, 10.81; P< 0.001) and bleeding as a result of intercourse (adjusted OR, 4.90; P< 0.05). Female-to-male transmission was detected in seven out of 11 couples at risk. Ethnicity, number of episodes of vaginal intercourse, number of other sexual partners and history of sexually transmitted infections were not significantly associated with transmission to women. Conclusion:Our study demonstrates that health of the index, anal intercourse and bleeding as a result of intercourse are the major determinants of sexual transmission of HIV to women in couples.

Secondary ovarian carcinoma: a clinical and pathological evaluation

SummaryA retrospective clinical and pathological analysis was performed of 96 patients with secondary ovarian carcinoma diagnosed between January 1972 and June 1985 at New York University Medical Center. Secondary tumors accounted for 17.4% (96/553) of ovarian malignancies. The most common sites of origin were breast (32 cases), unilateral ovary (with contralateral metastases) (20), endometrium (14), colon (12), stomach (6), cervix (2), ileum (2), and I each for 8 additional sites. The patients ranged in age from 19 to 87 years, averaging 54.8 years, and 55 patients were postmenopausal. Ninety percent of the patients had extraovarian metastases at the time of abdominal surgery. The ovarian metastases tended to be bilateral for breast, colon and stomach, and unilateral for endometrial and ovarian primary sites. The metastases tended to be solid except for colon. The overall survival rate was 24.1% at 5 years and 7.1% at 10 years. Comparison of median survival times for the various major primary sites showed a significant overall difference (p = 0.04) and was as follows: gastric primary 0.79 years, breast 1.9 years, ovary 2.0 years, colon 3.0 years, and endometrium 3.4 years. Postmenopausal patients with unilateral ovarian carcinoma and contralateral metastases had a significantly (p = 0.04) longer median survival time (4.2 years) than analogous premenopausal patients (1.3 years). For breast and endometrium, menopausal status was not significantly associated with survival differences. These findings should prove useful in the differential diagnosis of ovarian tumors and in the medical management of these patients.

Prognosis of patients with pathologic stage II cutaneous malignant melanoma.

The prognostic relevance of the extent of nodal metastases, lesion thickness, level of invasion, site of lesion, satellitosis, age, sex, and year of diagnosis and treatment were assessed in 213 consecutive patients with pathologic Stage II malignant melanoma (157 with clinical Stage I disease and 56 with clinical Stage II disease). Of these factors, only three were significant: 1) clinical status of the lymph nodes (p less than 0.0001); 2) thickness of the primary lesion in the ranges of less than 2.0 mm, 2.0 to 4.9 mm, and 5.0 mm or greater (p = 0.002); and 3) level of invasion (p = 0.0002). The extent of nodal metastases in those patients with clinical Stage I disease was not significant. The difference in survival between patients with clinically negative/histologically positive nodes (clinical Stage I) and clinically positive/histologically positive nodes (clinical Stage II) was apparent throughout the follow-up period. The 5- and 10-year survival rates for the clinical Stage I patients were 44% and 28%, respectively, and for the clinical Stage II patients 21% and 12%, respectively (p less than 0.0001). A 5-year cumulative survival rate of 65% was achieved for clinical Stage I patients having primary lesions of less than 2.0 mm in thickness, while it was 19% for patients having primary lesions of 5.0 mm or more in thickness. For pathologic Stage II malignant melanoma patients, prognosis is most dependent on the clinical status of the lymph nodes, not on the number of lymph nodes with micrometastases.

HIV risk-related sexual behaviors among heterosexuals in New York City: associations with race, sex, and intravenous drug use.

ObjectiveTo investigate the relationship between heterosexual behaviors associated with HIV infection and ethnicity, sex, and intravenous drug use. MethodsSubjects were recruited from Bellevue Hospital Center, New York City between 1986 and 1989, and interviewed about sexual behaviors and intravenous drug use. Analyses were based on 1561 black, white, or Hispanic individuals who reported having sexual contact with a member of the opposite sex. ResultsTwenty-seven per cent of the study population were black, 43% Hispanic, and 31% white. Blacks were more likely than whites or Hispanics to have initiated sexual intercourse at an early age, and to have had a sexually transmitted disease. Sex with a female drug user was more common among white men, and contact with a prostitute more frequent among Hispanic men. Among the women, Hispanics had fewer sexual risk factors overall than whites or blacks. Use of barrier contraceptives was uniformly low across all ethnic groups. Intravenous drug use was significantly associated with sexual risk-taking. Women were more likely than men to have an intravenous drug-using (IVDU) sexual partner. ConclusionsThe large prevalence of high-risk sexual practices observed in this study emphasizes the continuing need to target AIDS prevention programs at those at highest risk of heterosexually transmitted HIV: racial minorities, IVDU, and their sexual partners.

The prognostic significance of nuclear DNA content in malignant epithelial tumors of the ovary

Recent studies have indicated that the nuclear DNA content of certain malignant neoplasms can be used as an adjunct in predicting their biologic behavior. The DNA content of 99 ovarian carcinomas was determined by flow cytometric analysis of nuclei obtained from paraffin‐embedded tissue. Of the 99 tumors, 51 were diploid and 48 showed one or more aneuploid peaks. The 5‐year survival for patients with diploid tumors (50%) was significantly higher than for patients with aneuploid tumors (22%) (P <0.01). Other factors which significantly affected survival were clinical stage (P <0.001), tumor pattern grade (P <0.01), DNA index (P <0.01), the presence of ascites (P < 0.001), peritoneal carcinomatosis (P <0.0001), and residual tumor at second‐look laparotomy (P <0.05). Diameter of the primary ovarian tumor, diameter of the largest peritoneal implant before debulking, and the percent S‐phase had no significant correlation with survival. Of 16 patients with aneuploid tumors who underwent second‐look laparotomy, nine (56%) had residual tumor, compared to six of 22 of patients with diploid tumors (27%). Of seven patients with aneuploid tumors and a negative second‐look laparotomy, four (57%) died from recurrent tumor. By comparison, of 16 patients with diploid tumors and a negative second‐look laparotomy, only four (25%) died from recurrent tumor. The determination of DNA ploidy in ovarian carcinomas may be used as an adjunct in predicting tumor behavior, response to chemotherapy, and late recurrence of disease.

Endometrioid and clear cell carcinoma of the ovary: factors affecting survival

Eighty-five patients, 52 with endometrioid carcinoma (EC), nine with mixed endometrioid and clear cell carcinoma (MC), and 24 with clear cell carcinoma (CC), were studied to determine if prognosis was affected by (a) mixed tumor histology, (b) grade of the endometrioid component in ECs, and MCs, (c) presence of benign or malignant squamous differentiation in ECs, (d) solid versus tubular histology in CCs, (e) endometriosis in the same ovary as the tumor or elsewhere in the pelvis, (f) tumor stage, (g) patient age, or (h) presence of a coexisting carcinoma of the endometrium. The 5 year survivals for the ECs, MCs, and CCs were 52%, 22%, and 69%, respectively, for all stages. The 5 year survivals for Stage I ECs and CCs were 82% and 93%, respectively. None of these differences were statistically significant. Higher stages of disease for all three tumor types and higher grades of the endometrioid component of the ECs and the MCs were associated with significantly decreased survival. Patients with CCs had a significantly increased incidence of pelvic endometriosis (67%) versus patients with ECs (17%) or MCs (22%) (p less than 0.001). Survival was not significantly affected by benign or malignant squamous differentiation in ECs, tubular differentiation in CCs, patient age, the presence of endometriosis, or a coexisting carcinoma of the endometrium.

Prognostic factors for malignant mixed müllerian tumors of the uterus.

This study examined factors affecting the survival of 28 consecutive patients with malignant mixed Mullerian tumors diagnosed at New York University Medical Center from 1971 through 1985. The cumulative 5-year survival for all patients was 38%. Patients with pedunculated tumors (18/25) had a significantly improved 5-year survival of 53% compared with patients having a tumor with a broad-based attachment (7/25), all of whom died within 1 year (p less than 0.01). Eleven patients whose tumors demonstrated vascular invasion had a worse prognosis compared with 14 patients without demonstrable vascular invasion (18% versus 53% 5-year survival; p less than 0.05). Interestingly, patients with pedunculated tumors persisted in having an improved survival even after correcting for vascular invasion, compared with patients having broad-based tumor attachment. Small tumor size (less than or equal to 7 cm) also proved to be a significant and independent prognostic indicator for improved survival. Advanced stage, heterologous sarcomatous elements, and deep myometrial invasion (greater than one-third invasion) tended to be associated with decreased survival, but not with statistical significance. Patient age and grade of the carcinoma element did not appear to affect survival.