Rochelle Scheib

Increasing Mortality Due to End-Stage Liver Disease in Patients with Human Immunodeficiency Virus Infection

Highly active antiretroviral therapy has decreased human immunodeficiency virus (HIV)-associated mortality; other comorbidities, such as chronic liver disease, are assuming greater importance. We retrospectively examined the causes of death of HIV-seropositive patients at our institution in 1991, 1996, and 1998-1999. In 1998-1999, 11 (50%) of 22 deaths were due to end-stage liver disease, compared with 3 (11.5%) of 26 in 1991 and 5 (13.9%) of 36 in 1996 (P=.003). In 1998-1999, 55% of patients had nondetectable plasma HIV RNA levels and/or CD4 cell counts of >200 cells/mm(3) within the year before death. Most of the patients that were tested had detectable antibodies to hepatitis C virus (75% of patients who died in 1991, 57.7% who died in 1996, and 93.8% who died in 1998-1999; P=NS). In 1998-1999, 7 patients (31.8%) discontinued antiretroviral therapy because of hepatotoxicity, compared with 0 in 1991 and 2 (5.6%) in 1996. End-stage liver disease is now the leading cause of death in our hospitalized HIV-seropositive population.

Docetaxel Administered on a Weekly Basis for Metastatic Breast Cancer

PURPOSE To evaluate the safety and efficacy of weekly docetaxel in women with metastatic breast cancer. PATIENTS AND METHODS Twenty-nine women were enrolled onto a study of weekly docetaxel given at 40 mg/m(2)/wk. Each cycle consisted of 6 weeks of therapy followed by a 2-week treatment break, repeated until disease progression or removal from study for toxicity or patient preference. Fifty-two percent of patients had been previously treated with adjuvant chemotherapy; 21% had received prior chemotherapy for metastatic breast cancer, and 31% had previously received anthracyclines. All patients were assessable for toxicity; two patients were not assessable for response but are included in an intent-to-treat analysis. RESULTS Patients received a median of 18 infusions, with a median cumulative docetaxel dose of 720 mg/m(2). There were no complete responses. Twelve patients had partial responses (overall response rate, 41%; 95% confidence interval, 24% to 61%), all occurring within the first two cycles. Similar response rates were observed among subgroups of patients previously treated either with any prior chemotherapy or with anthracyclines. An additional 17% of patients had stable disease for at least 6 months. The regimen was generally well tolerated. There was no grade 4 toxicity. Only 28% of patients had any grade 3 toxicity, most commonly neutropenia and fatigue. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and eye tearing/conjunctivitis became more common with repetitive dosing, although these side effects rarely exceeded grade 2. Dose reductions were made for eight of 29 patients, most often because of fatigue (n = 5). CONCLUSION Weekly docetaxel is active in treating patients with metastatic breast cancer, with a side effect profile that differs from every-3-weeks therapy.

Urinary Metalloproteinases: Noninvasive Biomarkers for Breast Cancer Risk Assessment

Matrix metalloproteinases (MMP) and a disintegrin and metalloprotease 12 (ADAM 12) can be detected in the urine of breast cancer patients and provide independent prediction of disease status. To evaluate the potential of urinary metalloproteinases as biomarkers to predict breast cancer risk status, urine samples from women with known risk marker lesions, atypical hyperplasia and lobular carcinoma in situ (LCIS), were analyzed. Urine samples were obtained from 148 women: 44 women with atypical hyperplasia, 24 women with LCIS, and 80 healthy controls. MMP analysis was done using gelatin zymography and ADAM 12 analysis was done via immunoblotting with monospecific antibodies and subsequent densitometric measurement. Positive urinary MMP-9 levels indicated a 5-fold risk of atypical hyperplasia and >13-fold risk of LCIS compared with normal controls. Urinary ADAM 12 levels were significantly elevated in women with atypical hyperplasia and LCIS from normal controls, with receiver operating characteristic curve analysis showing an area under the curve of 0.914 and 0.950, respectively. To assess clinical applicability, a predictive index was developed using ADAM 12 in conjunction with Gail risk scores for women with atypia. Scores above 2.8 on this ADAM 12-Gail risk prediction index score are predictive of atypical hyperplasia (sensitivity, 0.976; specificity, 0.977). Our data suggest that the noninvasive detection and analysis of urinary ADAM 12 and MMP-9 provide important clinical information for use as biomarkers in the identification of women at increased risk of developing breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1034–12)

Atypical Hodgkin's Disease and the Acquired Immunodeficiency Syndrome

Excerpt To the editor: The increased incidence of Kaposis sarcoma and non-Hodgkins lymphoma in patients with the acquired immunodeficiency syndrome has been well documented (1, 2). A recent repor...

In vitro effects of thymosin and lithium on lymphoproliferative responses of normal donors and HIV seropositive male homosexuals with AIDS-related complex

The in vitro effects of thymosin fraction 5 (TF5) and lithium chloride (LiCl) on the ability of peripheral blood mononuclear cells (PBMC) obtained from 37 normal male donors and 33 male patients with AIDS-related complex (ARC) to respond to alloantigenic stimulation (mixed leukocyte reaction, MLR) and to produce interleukin 2 (IL-2) in response to mitogens were studied. TF5 significantly increased MLR responses in normal donors (P less than 0.01) and in a group of 33 ARC patients with depressed cellular immunity (P less than 0.05). Similar effects were observed when LiCl was added to the MLR assays in both the normal and the ARC patient groups. Furthermore, TF5 and LiCl exhibited additive immunoenhancing properties. In 10 normal donors TF5 enhanced phytohemaggutinin (PHA)-induced IL-2 production as well as IL-2 production in response to pokeweed mitogen (PWM) (P less than 0.02). TF5-mediated enhancement of IL-2 production by PBMC obtained from ARC patients was observed in response to both mitogens, i.e., PHA and PWM. Additionally, LiCl increased PHA-induced IL-2 production in both normal subjects and ARC patients. LiCl and TF5 together had an additive effect in the enhancement of IL-2 production in both groups of subjects. Our data extend previous observations regarding the immunoregulatory activities of TF5 and LiCl and provide evidence that PBMC obtained from ARC patients have the potential to respond in vitro to these agents. The significance of these findings is discussed.

Abstract LB-431: Randomized trial of oral melatonin supplementation in breast cancer survivors

Background: Night shift work has been classified by the International Agency for Research and Cancer and the World Health Organization as a probable carcinogen, presumably due to its effect on the melatonin pathway. Extensive laboratory and some human data also support that melatonin may influence breast cancer risk, although the mechanism is not clear. Both pharmacologic and physiologic doses of melatonin inhibit the growth of malignant cells of the breast in vitro and in animal models. Study Design: 95 postmenopausal women with a prior history of Stage 0-III breast cancer who had completed active cancer treatment (including hormonal therapy) were recruited to a double-blind randomized trial of 4 months of 3 mg melatonin daily compared to placebo. Endpoints included changes in breast cancer biomarkers, sleep, hot flashes, and mood. Results: 5 subjects on melatonin and 4 on placebo withdrew from the study or did not complete the 4 month assessment leaving 86 women (43 on placebo and 43 on melatonin) with evaluable data. Melatonin was well-tolerated without any grade 3/4 toxicity. At baseline, there was no statistical difference between the two arms for any of the endpoints or standard demographic characteristics. Mean age was 59 years (range 38-71) with mean 8 years since diagnosis. At 4 months, there were no statistically significant differences between the two groups for the biomarker endpoints (estradiol, IGF-1, IGFBP-3, or IGF-1/IGFBP-3 ratios), depressive symptoms, or hot flashes. However, subjects taking melatonin had significantly improved sleep quality, sleep duration, and total sleep scores compared with subjects taking placebo. Conclusions: Among postmenopausal women with a prior history of breast cancer, a 4 month course of 3 mg melatonin daily did not influence IGF-1, IGFBP-3 or estradiol levels. Effects of longer courses of melatonin and among premenopausal women are unknown. However, melatonin was effective in improving sleep quality among breast cancer survivors without any significant adverse effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-431.

A randomized trial of two different genetic counseling interventions for BRCA1/2 genetic testing

1002 Background: We compared a randomly assigned standard genetic counseling (GC) intervention by genetic counselors versus an enhanced informed consent (EC) [modeled on routine chemotherapy informed consent] administered by oncology nurses for women enrolled into a BRCA1/2 testing program for several outcomes: satisfaction, risk perception, genetics knowledge, psychological state and health behaviors. METHODS A cohort of 236 of 310 high-risk women enrolled in a BRCA1/2 randomized control trial of semi-structured counseling interventions completed all questionnaires at enrollment, test result disclosure, 4 months and 1-year post disclosure. Women were asked about their satisfaction with the testing program at results disclosure only using the Shiloh scale; breast cancer risk perception, knowledge of cancer genetics and the Impact of Events scale at all time points. For the repeated measures, comparison was made for differences in trends over time and between the intervention arms. Exploring separately for cancer status and genetic test result, multivariate analysis of variance (MANOVA) for repeated measures was used to assess the statistical significance of the within subjects change over time and the main effects of the intervention/gene test result. Regarding satisfaction with the testing program, the Fishers exact test was used to assess differences between intervention. RESULTS The overall cohort, cancer survivors, and women receiving a negative or variant BRCA1/2 result were significantly more satisfied with the GC intervention than with the EC intervention on several sub-scales. No differences were found between intervention on breast cancer risk perception or psychological state, where mutation status was significant. Contrary to expectation, knowledge of cancer genetics was not superior in the GC arm. CONCLUSIONS Genetic counseling by genetic counselors does not prepare women better for the results of BRCA1/2 genetic testing, though women generally prefer it to a more informed consent approach to testing administered by oncology nurses within a structured program. Additional data on health behaviors will be presented. No significant financial relationships to disclose.