James J. Schlesselman

Factors Related to Inflammation of the Ovarian Epithelium and Risk of Ovarian Cancer

Previous epidemiologic observations consistently suggest that suppression of ovulation, tubal ligation, and hysterectomy reduce the risk of ovarian cancer and that perineal talc use increases the risk. We examined these and other risk factors in the context of a new hypothesis: that inflammation may play a role in ovarian cancer risk. Ovulation entails ovarian epithelial inflammation; talc, endometriosis, cysts, and hyperthyroidism may be associated with inflammatory responses of the ovarian epithelium; gynecologic surgery may preclude irritants from reaching the ovaries via ascension from the lower genital tract. We evaluated these risk factors in a population-based case-control study. Cases 20-69 years of age with a recent diagnosis of epithelial ovarian cancer (767) were compared with community controls (1,367). We found that a number of reproductive and contraceptive factors that suppress ovulation, including gravidity, breast feeding, and oral contraception, reduced the risk of ovarian cancer. Environmental factors and medical conditions that increased risk included talc use, endometriosis, ovarian cysts, and hyperthyroidism. Gynecologic surgery including hysterectomy and tubal ligation were protective. Tubal ligation afforded a risk reduction even 20 or more years after the surgery. The spectrum of associations provides support for the hypothesis that inflammation may mediate ovarian cancer risk.

A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors.

PurposeThis phase I trial was initiated to evaluate the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of the glycolytic inhibitor, 2-deoxy-d-glucose (2DG) in combination with docetaxel, in patients with advanced solid tumors.MethodsA modified accelerated titration design was used. 2DG was administered orally once daily for 7xa0days every other week starting at a dose of 2xa0mg/kg and docetaxel was administered intravenously at 30xa0mg/m2 for 3 of every 4xa0weeks beginning on day 1 of week 2. Following the completion of dose escalation, cohorts of patients were then treated with 2DG for 21xa0days or every day of each 4-week cycle for up to 12 cycles.ResultsThirty-four patients were enrolled: 21 on every other week, 6 on a 21 of 28-day cycle and 7 on the continuous 2DG dosing schedule. There were no dose-limiting toxicities which met the MTD criteria. The most common adverse events were fatigue, sweating, dizziness and nausea mimicking the hypoglycemic symptoms expected from 2DG administration. Therefore, 63xa0mg/kg was selected as the clinically tolerable dose. The most significant adverse effects noted at 63–88xa0mg/kg doses were reversible hyperglycemia (100xa0%), gastrointestinal bleeding (6xa0%) and reversible grade 3 QTc prolongation (22xa0%). Eleven patients (32xa0%) had stable disease, 1 patient (3xa0%) partial response and 22 patients (66xa0%) progressive disease as their best response. There was no PK interaction between 2DG and docetaxel.ConclusionThe recommended dose of 2DG in combination with weekly docetaxel is 63xa0mg/kg/day with tolerable adverse effects.

Hormonal contraception and risk of cardiovascular disease: An international perspective

The most frequent major adverse effect of hormonal contraception is an increased risk of cardiovascular disease. The effect on the risk of venous thromboembolism (VTE), ischemic and hemorrhagic stroke, and myocardial infarction (MI) differs and is strongly influenced by smoking and the presence of other cardiovascular risks factors, such as hypertension and diabetes mellitus. The incidence of each disease rises with age and there are differences in risk among hormonal contraceptive preparations. This article provides a framework within which to assess the balance of risks among types of hormonal contraceptives according to individual circumstances. Data on cardiovascular disease mortality rates in women of reproductive age in different countries of the world were compiled from nationally reported statistics and supplemented where possible with reported disease incidence rates. Risks associated with current use of hormonal contraception were compiled from the most recent publications on the cardiovascular effects of steroid hormone contraception. These were combined to estimate the total cardiovascular incidence and mortality according to baseline cardiovascular risk and individual characteristics. Mortality rates for cardiovascular diseases are very low in women of reproductive age. Myocardial infarction mortality rates rise from < 0.4 per 100,000 woman-years at age 15-24 years to the range 2 to 7 per 100,000 woman-years at age 35-44 years. Stroke mortality rates similarly rise steeply with age and are between 3 and 5 times higher than those for MI. VTE mortality rates rise less steeply with age and are approximately one-tenth the MI mortality rates at age 35-44 years. The adverse effect of oral contraceptives (OC) on the risk of VTE is the most important contributor to the total number of cardiovascular cases attributable to OC use. The increased risk of stroke and MI dominate the patterns of mortality in OC users and smokers. The additional risks attributable to smoking are greater than the additional risks attributable to OC use. The risk attributable to OC use in women < 35 years of age is small, even if they smoke, but there are substantially increased risks in older women who both smoke and use OC. The additional mortality attributable to OC use can be reduced by screening users, as this results in lower relative risks of ischemic stroke and MI. Differences between OC types in the relative risk of VTE contribute little to the total cardiovascular mortality associated with OC use, even though the total number of cardiovascular events is increased. A potential reduction in the risk of MI with desogestrel and gestodene compared with levonorgestrel-containing OC would have little difference on overall mortality rates in women in their 20s and 30s, but may result in a net reduction in OC-attributable mortality in women aged 40-44 years who smoke. An overall quantification of the risks for different types of oral contraceptive users is necessary for an informed choice of contraceptive method, and any assessment of the balance of cardiovascular risks is complex. The model provides a tool to assess, at the level of the individual, the risks associated with use of different OC according to personal circumstances. It is important to consider the users age and smoking status when determining OC attributable risks.

Risk of Positive Margins and Biochemical Recurrence in Relation to Nerve-Sparing Radical Prostatectomy

PURPOSEnTo assess the effect of nerve-sparing (NS) radical retropubic prostatectomy (RRP) on surgical margins and biochemical recurrence.nnnPATIENTS AND METHODSnLocation and incidence of positive surgical margins, recurrence, and time to recurrence were assessed in a consecutive series of 734 men who underwent RRP for localized prostate cancer from 1992 through February 2000. NS procedures were used in 33% (n = 240) of 734 patients studied.nnnRESULTSnSurgical margins were positive for 24% (n = 58) and 31% (n = 152) of NS and non-NS patients, respectively (P =.06). No significant difference between the groups was found in location of positive margins (P =.92). Prostate-specific antigen level greater than 10 ng/mL, extraprostatic extension, tumor volume more than 20%, capsular penetration, Gleason score > or = 7, positive margins, and seminal vesicle invasion were associated with significantly increased risk of recurrence. However, NS patients were not at increased risk of recurrence compared with non-NS patients (hazard ratio, 0.96; 95% confidence interval, 0.53 to 1.72). The cumulative risk of recurrence within 3 and 5 years of surgery in NS patients was 9.7% and 14.4%, respectively, as compared with 17.1% and 21.1% for non-NS patients.nnnCONCLUSIONnIn patients with localized prostate cancer, neither margin status nor biochemical-free survival within 5 years of surgery were altered by the nerve preservation technique. Given our experience, we recommend preservation of neurovascular bundles in these patients whenever the procedure is technically feasible.

Allogeneic Vaccination With a B7.1 HLA-A Gene-Modified Adenocarcinoma Cell Line in Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSEnTo determine the safety, immunogenicity, and clinical response to an allogeneic tumor vaccine for non-small-cell lung cancer, we conducted a phase I trial in patients with advanced metastatic disease.nnnPATIENTS AND METHODSnWe treated 19 patients with a vaccine based on an adenocarcinoma line (AD100) transfected with B7.1 (CD80) and HLA A1 or A2. Patients were vaccinated intradermally with 5 x 10(7) cells once every 2 weeks. Three vaccinations represented one course of treatment. If patients had complete response, partial response, or stable disease, they continued with the vaccinations for up to three courses (nine vaccinations). Immune response was assessed by a change between pre-study and postvaccination enzyme-linked immunospot frequency of purified CD8 T-cells secreting interferon-gamma in response to in vitro challenge with AD100.nnnRESULTSnFour patients experienced serious adverse events that were unrelated to vaccine. Another four patients experienced only minimal skin erythema. All but one patient had a measurable CD8 response after three immunizations. The immune response of six surviving, clinically responding patients shows that CD8 titers continue to be elevated up to 150 weeks, even after cessation of vaccination. Overall, one patient had a partial response, and five had stable disease. Median survival for all patients is 18 months (90% CI, 7 to 23 months), with corresponding estimates of 1-year, 2-year, and 3-year survival of 52%, 30%, and 30%, respectively. HLA matching of vaccine, age, sex, race, and pathology did not bear a significant relation to response.nnnCONCLUSIONnMinimal toxicity and good survival in this small population suggest clinical benefit from vaccination.

Optimal Allocation for the Comparison of Proportions

Optimal allocation strategies for the comparison of proportions, p1 and p2, in two groups are discussed. Allocations which (i) maximize the precision in the estimation of the difference p1-p2, (ii) maximize the precision in the estimation of the ratio p1/p2, (iii) maximize the power to detect a group difference, and (iv) minimize the total cost of a study are compared. The recommended allocation varies markedly with the desired objective. Furthermore, there is a wide range of allocation schemes which are effectively optimal with regard to each criterion considered. A study of congenital malformations occurring in pregnancies of diabetic women is used to illustrate how these considerations apply to the planning of a study.

Induction of CD8 T-cell-Ifn- γ response and positive clinical outcome after immunization with gene-modified allogeneic tumor cells in advanced non-small-cell lung carcinoma

Large tumor burdens in advanced non-small-cell lung carcinoma (NSCLC) are thought to be immunosuppressive. To determine whether CD8-mediated immune responses could be elicited in stage IIIB/IV NSCLC patients, 14 subjects were immunized several times with allogeneic NSCLC cells transfected with CD80 (B7.1) and HLA-A1 or A2. Patients enrolled were matched or unmatched at the HLA A1 or A2 locus and their immune response compared. Immunization significantly increased the frequencies of interferon-γ secreting CD8 T cells in all but one patient in response to ex vivo challenge with NSCLC cells. The CD8 response of matched and unmatched patients was not statistically different. NSCLC reactive CD8 cells did not react to K562. Clinically, five of 14 patients responded to immunization with stable disease or partial tumor regression. The study demonstrates that CD8 Ifn-γ responses against nonimmunogenic or immunosuppressive tumors can be evoked by cellular vaccines even at advanced stages of disease. The positive clinical outcome suggests that nonimmunogenic tumors may be highly susceptible to immune effector cells generated by immunization.

Oral Contraceptive Use in Women With a Family History of Breast Cancer

&NA; To evaluate the effect of oral contraceptive use on the risk of breast cancer from 20‐54 years of age in women with a family history of the disease, we analyzed data from the Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. For 2 years, beginning December 1980, the study enrolled from eight geographical areas in the United States 4730 women with breast cancer and 4646 controls who were breast cancer‐free. For women with a first‐degree family history of breast cancer, 554 cases and 280 controls, there was no evidence that use of oral contraceptives, even long‐term, contributed to their risk of the disease. Neither total duration of use nor duration of use before first term pregnancy bore any relationship with breast cancer risk. Analyses designed to reveal a potential latent effect also showed no evidence of an adverse effect. For women with a second‐degree family history of breast cancer, 777 cases and 595 controls, some isolated elevations in risk were observed for selected subgroups of oral contraceptive users. Detailed analyses of oral contraceptive formulation, the characteristics of the women involved, and the patterns of risk observed by latent period and duration of use suggest that these results, most within the limits of chance variation, are not likely to be a consequence of oral contraception. (Obstet Gynecol 73:977, 1989)

Perimenopausal use of reproductive hormones: Effects on breast and endometrial cancer

The effect of reproductive hormone use in the form of oral contraception or HRT on endometrial cancer incidence is not caused by simply bias: the epidemiologic studies are consistent; the effect of ERT is large; the biologic rationale cited is a plausible mechanism; and the response to progestin in oral contraception or combined HRT tends to confirm the biologic mechanism. In contrast, it remains unclear whether changes in breast cancer incidence following use of oral contraception and HRT are caused by hormone exposure or to other factors: the results of epidemiologic studies are not entirely consistent, and the smaller relative effect on risk of breast cancer is susceptible to bias and other sources of error. Although the exact nature of the association between repro ductive hormone use and breast cancer incidence is not yet clear, breast cancer is a common neoplasm in older women. Prescribers and users should take this into account in weighing benefits to ensure that unnecessary risks are avoided.

Family History of Cancer, Oral Contraceptive Use, and Ovarian Cancer Risk

The use of oral contraceptives has been shown to reduce the risk of ovarian cancer in women with a BRCA1 or BRCA2 genetic mutation. This study was conducted to determine if oral contraceptives give the same protection to women with a family history of ovarian cancer but whose genetic predisposition to ovarian cancer is unknown. The study population was drawn from the hospital records of 39 hospitals in three northeastern states. Seven hundred sixty-seven women aged 20 to 69 years, who were treated for ovarian cancer at these hospitals from May 1994 to July 1998 were interviewed in detail for family history and personal information. A group of control subjects, 1367 women aged 65 to 69 years at risk for ovarian cancer but without disease, was recruited from Health Care Financing Administration lists and similarly interviewed. Women who had multiple relatives with ovarian cancer, a relative with early onset of ovarian cancer, or a mother or a sister with ovarian cancer were described as having a positive family history. Among the study subjects, serous cell tumors were the most common (47%), followed by endometrioid (18%), mucinous (15%), clear cell (8%), undifferentiated (7%), and mixed/others (5%). The tumors were invasive in 80% of the women and borderline in 20%.