Faculty Bibliography

BACKGROUND. Melanoma vaccine treatment appears to slow the progression of melanoma in some patients, particularly in patients in whom it stimulates cellular antimelanoma immune responses. The relationship of vaccine-induced antibody responses to clinical outcome is less clear. The purpose of this study was to investigate the clinical relevance of antibody responses to melanoma vaccine immunization. METHODS. Eighty-two evaluable patients with surgically resected American Joint Committee on Cancer Stage III malignant melanoma were immunized to a partially purified, polyvalent, melanoma antigen vaccine. Antimelanoma antibodies were measured by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis before vaccine treatment and 1 week after the fourth immunization. RESULTS. Vaccine treatment induced or augmented antibody responses to melanoma in 32 (39%) of the patients. The antibodies were directed to one or more antigens of 38-43, 75, 110, 150 and/or 210 kDs, which previously have been shown to be expressed preferentially in cultured human melanoma cells. The median disease free survival of patients with a vaccine-induced antibody response to one or more of these antigens was 5.4 years compared with 1.4 years for nonresponders (P = 0.06), and 5-year overall survival was 71% compared with 44%, respectively (P = < 0.01). As determined by Cox multivariate analysis, the difference in overall survival was independent of disease severity or of immunologic competence as evaluated by ability to be sensitized to dinitrochlorobenzene. The difference in survival between antibody responders and nonresponders improved with time. CONCLUSIONS. The antibody response to vaccine treatment is an immune marker of vaccine activity that appears to be predictive of a later reduction in the recurrence of melanoma and is unrelated to the vaccine's ability to induce cellular immune responses. This finding suggests that vaccine treatment may be effective in slowing the progression of melanoma in some patients and that the protective effect is mediated partly by vaccine-induced antimelanoma antibodies

A meta-analysis was performed on the results of randomized placebo-controlled clinical trials of the effect of aspirin on occurrence of stroke or death in people who previously had suffered cerebral ischemia. The data from 8 such trials (a total of 5,287 subjects) shows a beneficial effect overall: the odds ratio is 0.82; 95% confidence interval (CI) 0.72-0.94; p < 0.01. When men are analyzed separately (n = 3,691) the benefit of aspirin is also statistically significant: odds ratio = 0.82; 95% CI = 0.70-0.96; p = 0.01. The analysis for women (n = 1,596) shows a similar odds ratio (0.82), but this result does not reach statistical significance in the smaller female cohort (95% CI = 0.63-1.05; p 0.12). On the basis of these data and in the absence of a valid biological hypothesis for an effect in women different from that in men, we consider justified the recommendation that aspirin be used to reduce the rate of occurrence of stroke or death in women as well as in men who have suffered cerebral ischemia

This study was conducted to examine whether immunization to a melanoma vaccine can induce antibodies that are functionally effective in killing melanoma cells. A group of 79 evaluable patients with surgically resected AJCC stage III melanoma were immunized every 3 weeks to a polyvalent melanoma antigen vaccine (40 mug/immunization). Cytolytic antibodies to melanoma cells, assayed by europium-based complement-dependent cytolysis before vaccine treatment and 1 week following the fourth immunization, were detected in 7 patients (9%) before vaccine treatment but in none of 17 control individuals. Vaccine treatment induced or increased the level of these antibodies in 37 patients (47%; p = 0.0001). Vaccine-induced cytolytic antibodies were predominantly directed to melanoma cells. There was no correlation between the induction of these antibodies and improved clinical outcome. These results indicate that melanoma vaccine treatment can induce antibodies that have the functional ability to kill melanoma cells in vitro but suggest that the induction of such cytolytic antibodies is not associated with a delay in the progression of melanoma

Contralateral ovaries from patients with unilateral ovarian carcinoma were examined and compared to ovaries from age-matched control patients without ovarian carcinoma. The number of inclusion cysts were increased in ovaries from patients with ovarian carcinoma compared to the controls (p < 0.01). In addition, inclusions from cases with ovarian carcinoma showed serous differentiation more frequently than the controls (p < 0.01; odds ratio = 10.0; 95% confidence interval = 1.2-78.1). An age-related increase in the number of inclusion cysts was seen in the study group but not in the control group. These findings support a role of surface inclusion cysts in the genesis of ovarian carcinoma

PURPOSE: To test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer. PATIENTS AND METHODS: Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients). RESULTS: We previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less than .05). Twenty-six patients in the ICRF-187 group received doxorubicin doses of at least 700 mg/m2, and among them, 11 patients received 1,000 mg/m2 or more. Only three patients in the control group received doxorubicin doses of 700 mg/m2; the maximum dose administered to one patient in this group was 950 mg/m2. ICRF-187 cardiac protection was demonstrated by difference in incidence of clinical congestive heart failure (CHF; two patients in the ICRF-187 group v 20 in the control group; P less than .0001) and by differences in resting left ventricular ejection fraction (LVEF) determined by multigated radionuclide (MUGA) scan from baselines and that required patient removal from study (five patients in the ICRF-187 group had a decrease in LVEF to less than 0.45 or a decrease from the baseline LVEF of 0.20 or more v 32 in the control group; P less than .000001). Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05). ICRF-187 cardiac protection was observed in patients with and without prior chest-wall radiation or other risk factors for developing doxorubicin cardiac toxicity. CONCLUSION: By protecting against cumulative doxorubicin-induced cardiac toxicity, ICRF-187 permits significantly greater doses of doxorubicin to be administered to patients with greater safety

To investigate the influence of HLA specificities on the rate of progression and outcome of human immunodeficiency virus (HIV) infection, we performed (a) a case-control study in 1989-1990 of HIV-seropositive individuals stratified by both risk behavior and ethnic background, (b) a longitudinal cohort study of HIV-infected male homosexuals enrolled in 1981-1982, and (c) an analysis of individuals with a diffuse infiltrative CD8 lymphocytosis syndrome. In the case-control study, there was a significantly higher frequency of HLA-B35 among intravenous drug users, but not homosexuals, who developed illnesses meeting the case definition for AIDS compared with asymptomatic HIV-positive controls, regardless of ethnic status. In the longitudinal study, HLA-B35-positive homosexuals had a significantly increased rate of progression to AIDS and decreased survival over a 7-year period compared with those without this specificity. Finally, there was a significantly decreased frequency of HLA-B35 in individuals with the diffuse infiltrative lymphocytosis syndrome, a clinically and genetically distinctive disorder occurring in HIV infection in which a low rate of progression to opportunistic infections was found. The high rate of salivary and lacrimal gland lymphoma in this group suggests that there is dissociation between the presence of HLA-B35 and the development of particular AIDS-defining conditions. We conclude that HLA-B35 is a risk factor for more rapid progression to AIDS, particularly opportunistic infections and Kaposi's sarcoma, operating in groups with high rates of newly acquired HIV infections such as New York City male homosexuals in 1981-1982, and intravenous drug users in 1989-1990.(ABSTRACT TRUNCATED AT 250 WORDS)

Seventy-five patients with advanced epithelial ovarian cancer were treated with a combined modality regimen of systemic, induction chemotherapy followed by intraperitoneal therapy (IPT). All patients underwent initial surgery for staging and/or cytoreduction followed by cisplatin 20 mg/m2 intravenously (IV) for 5 days and cyclophosphamide 600 mg/m2 on day 4 every 3 to 4 weeks for two to four cycles. Patients were then evaluated for IPT and, if eligible, had an intraperitoneal (IP) catheter placed. IPT consisted of cisplatin 60 mg/m2 in 2 L on day 1 and IV cyclophosphamide 600 mg/m2 on day 2 every 3 weeks for three to six cycles. Patients who demonstrated a clinical complete response (CCR) were then referred for second-look laparotomy (SLL). Of 71 patients who completed the induction phase, 53 (75%) were eligible for IPT, and 49 patients entered the therapy phase. Toxicity of the combined modality approach was acceptable and did not differ from our previous experience using the same drugs systemically. Thirty-two of the 49 patients who completed IPT achieved a CCR, which was confirmed by SLL in 20 patients. Twenty recurrences were documented in the 32 CCR patients, 13 occurred in patients after SLL. Projected median survival of all patients is 38 months. Median survival correlated with amount of residual disease following initial surgery (23 months for bulky v 45 months for minimal residual; P less than .001) and with performance status ([PS]; 24 months for PS 2, 3 v greater than 46 months for PS O; P less than .001). Patients who presented with bulky tumors were less likely to reach the consolidation IPT phase. Incorporation of IP cisplatin into the first-line regimen for treatment of ovarian cancer does not appear to have major impact on the survival of all treated patients when compared with our historical control series. Combined IV and IPT cisplatin and cyclophosphamide is feasible with acceptable toxicity. Its impact on response and survival may be limited to only 'good-prognosis' patients