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BackgroundObservational and experimental data support a potential breast cancer chemopreventive effect of green tea.MethodsWe conducted an ancillary study using archived blood/urine from a phase IB randomised, placebo-controlled dose escalation trial of an oral green tea extract, Polyphenon E (Poly E), in breast cancer patients. Using an adaptive trial design, women with stage I-III breast cancer who completed adjuvant treatment were randomised to Poly E 400 mg (n = 16), 600 mg (n = 11) and 800 mg (n = 3) twice daily or matching placebo (n = 10) for 6 months. Blood and urine collection occurred at baseline, and at 2, 4 and 6 months. Biological endpoints included growth factor [serum hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], lipid (serum cholesterol, triglycerides), oxidative damage and inflammatory biomarkers.ResultsFrom July 2007-August 2009, 40 women were enrolled and 34 (26 Poly E, eight placebo) were evaluable for biomarker endpoints. At 2 months, the Poly E group (all dose levels combined) compared to placebo had a significant decrease in mean serum HGF levels (-12.7% versus +6.3%, P = 0.04). This trend persisted at 4 and 6 months but was no longer statistically significant. For the Poly E group, serum VEGF decreased by 11.5% at 2 months (P = 0.02) and 13.9% at 4 months (P = 0.05) but did not differ compared to placebo. At 2 months, there was a trend toward a decrease in serum cholesterol with Poly E (P = 0.08). No significant differences were observed for other biomarkers.ConclusionsOur findings suggest potential mechanistic actions of tea polyphenols in growth factor signalling, angiogenesis and lipid metabolism.

Sex and gender are critical contributors to overall health and disease, and considering both in research informs the development of prevention strategies and treatment interventions for both men and women. The National Institutes of Health (NIH) Office of Research on Women's Health sponsored a preconference workshop on this topic at the 24th Annual Women's Health Congress, which was held in Crystal City, VA, in April 2016. The workshop featured presentations by NIH intramural and extramural scientists who presented data on a variety of topics including polycystic kidney disease, vaccine protection, depression, drug addiction, and cardiovascular disease. In this publication, we discuss the major points of each presentation and demonstrate the importance of considering sex and gender in biomedical research.

In June 2015, the National Institutes of Health (NIH) released a Guide notice (NOT-OD-15-102) that highlighted the expectation of the NIH that the possible role of sex as a biologic variable be factored into research design, analyses, and reporting of vertebrate animal and human studies. Anticipating these guidelines, the NIH Office of Research on Women's Health, in October 2014, convened key stakeholders to discuss methods and techniques for integrating sex as a biologic variable in preclinical research. The workshop focused on practical methods, experimental design, and approaches to statistical analyses in the use of both male and female animals, cells, and tissues in preclinical research. Workshop participants also considered gender as a modifier of biology. This article builds on the workshop and is meant as a guide to preclinical investigators as they consider methods and techniques for inclusion of both sexes in preclinical research and is not intended to prescribe exhaustive/specific approaches for compliance with the new NIH policy.-Miller, L. R., Marks, C., Becker, J. B., Hurn, P. D., Chen, W.-J., Woodruff, T., McCarthy, M. M., Sohrabji, F., Schiebinger, L., Wetherington, C. L., Makris, S., Arnold, A. P., Einstein, G., Miller, V. M., Sandberg, K., Maier, S., Cornelison, T. L., Clayton, J. A. Considering sex as a biological variable in preclinical research., (© FASEB.)

Background: Sex and gender differences play a significant role in the course and outcome of conditions that affect specific organ systems in the human body. Research on differences in the effects of medical intervention has helped scientists develop a number of sex- and gender-specific guidelines on the treatment and management of these conditions. An online series of courses, "The Science of Sex and Gender in Human Health," developed by the National Institutes of Health Office of Research on Women's Health and the U.S. Food and Drug Administration Office of Women's Health, examines sex and gender differences and their implications. Thus far, three online courses have been generated. The first course offers an overview of the scientific and biological basis for sex- and gender-related differences. The second course is focused on disease-specific sex and gender differences in health and behavior and their implications. Finally, the third course covers the influence of sex and gender on disease manifestation, treatment, and outcome., Methods: Data were obtained using website analytics and post-course surveys., Results: To date, over 1000 individuals have completed at least one course. Additionally, 600 users have received continuing education credit for completing a course in the series. Finally, the majority of respondents to the online course survey have indicated that the courses considerably enhanced their professional effectiveness., Conclusions: "The Science of Sex and Gender in Human Health" online courses are freely available sources of information that provide healthcare providers and researchers with the resources to successfully account for sex and gender in their medical practice and research programs.

Although women have reached parity at the training level in the biological sciences and medicine, they are still significantly underrepresented in the professoriate and in mid- and senior-level life science positions. Considerable effort has been devoted by individuals and organizations across science sectors to understanding this disparity and to developing interventions in support of women's career development. The National Institutes of Health (NIH) formed the Office of Research on Women's Health (ORWH) in 1990 with the goals of supporting initiatives to improve women's health and providing opportunities and support for the recruitment, retention, reentry, and sustained advancement of women in biomedical careers. Here, the authors review several accomplishments and flagship activities initiated by the NIH and ORWH in support of women's career development during this time. These include programming to support researchers returning to the workforce after a period away (Research Supplements to Promote Reentry into Biomedical and Behavioral Research Careers), career development awards made through the Building Interdisciplinary Research Careers in Women's Health program, and trans-NIH involvement and activities stemming from the NIH Working Group on Women in Biomedical Careers. These innovative programs have contributed to advancement of women by supporting the professional and personal needs of women in science. The authors discuss the unique opportunities that accompany NIH partnerships with the scientific community, and conclude with a summary of the impact of these programs on women in science.

Women of color face unique health challenges that differ significantly from those of other women and men of color. To bring these issues to light, the National Institutes of Health (NIH) Office of Research on Women's Health sponsored a preconference workshop at the 23rd Annual Women's Health Congress, which was held in Washington, DC, in April 2015. The workshop featured presentations by NIH intramural and extramural scientists who provided insight on the disparities of a wide range of conditions, including cancer, cardiovascular disease, the risk of HIV infection, and disability in an aging population. In this study, we highlight the major points of each presentation and the ensuing discussion.

Background: Breast cancer risk is partially determined by several hormone-related factors. Preclinical and clinical studies suggested that resveratrol may modulate these hormonal factors., Methods: We conducted a pilot study in postmenopausal women with high body mass index (BMI ≥ 25 kg/m2) to determine the clinical effect of resveratrol on systemic sex steroid hormones. Forty subjects initiated the resveratrol intervention (1 gm daily for 12 weeks) with six withdrawn early due to adverse events (AEs). Thirty-four subjects completed the intervention., Results: Resveratrol intervention did not result in significant changes in serum concentrations of estradiol, estrone, and testosterone but led to an average of 10% increase in the concentrations of sex steroid hormone binding globulin (SHBG). Resveratrol intervention resulted in an average of 73% increase in urinary 2-hydroxyestrone (2-OHE1) levels leading to a favorable change in urinary 2-OHE1/16α-OHE1 ratio. One participant had asymptomatic Grade 4 elevation of liver enzymes at the end of study intervention. Two subjects had Grade 3 skin rashes. The remaining adverse events were Grade 1 or 2 events. The most common adverse events were diarrhea and increased total cholesterol, reported in 30% and 27.5% of the subjects, respectively., Conclusion: We conclude that among overweight and obese postmenopausal women, daily 1 gm dose of resveratrol has favorable effects on estrogen metabolism and SHBG. Further placebo-controlled studies are needed to confirm our findings on these hormone-related breast cancer risk factors and the attribution of the adverse effects observed in the study population., Trial Registration: ClinicalTrials.gov: NCT01370889.

Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor-negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade ≥II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400 mg (grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals.

Purpose: Fibrotic sequelae remain the most important dose-limiting toxicity of radiation therapy to soft tissue. Functionally, this is reflected in loss of range of motion and muscle strength and the development of limb edema and pain. Tumor necrosis factor alpha and fibroblast growth factor 2 (FGF2), which are abnormally elevated in irradiated tissues, may mediate radiation fibrovascular injury., Patients and Methods: In an open label drug trial, we studied the effects of pentoxifylline (400 mg orally tid for 8 weeks) on 30 patients who displayed late, radiation-induced fibrosis at 1 to 29 years posttreatment (40 to 84 Gy). The primary outcome measurement was change in physical impairments thought to be secondary to radiation, including active and passive range of motion (AROM and PROM), muscle strength, limb edema, and pain. Plasma levels of cytokines (tumor necrosis factor alpha and FGF2) also were measured. Twenty-seven patients completed baseline and 8-week assessments, and 24 patients completed baseline, 8-week, and 16-week assessments., Results: After 8 weeks of pentoxifylline intervention, 20 of 23 patients with impaired AROM and 19 of 22 with impaired PROM improved; 11 of 19 patients with muscle weakness showed improved motor strength; five of seven patients with edema had decreased limb girth; and nine of 20 patients had decreased pain. Pretreatment FGF2 levels dropped from an average of 44.9 pg/mL to 24.0 pg/mL after 8 weeks of treatment., Conclusion: Patients receiving pentoxifylline demonstrated improved AROM, PROM, and muscle strength and decreased limb edema and pain. Reversal of these delayed radiation effects was associated with a decrease in circulating FGF2.

At the Second International Conference on Cervical Cancer, held April 11-14, 2002, experts in cervical cancer prevention, detection, and treatment reviewed the need for more research in chemoprevention, including prophylactic and therapeutic vaccines, immunomodulators, peptides, and surrogate endpoint biomarkers. Investigators and clinicians noted the need for more rigorous Phase I randomized clinical trials, more attention to the risk factors that can affect study results in this patient population, and validation of optical technologies that will provide valuable quantitative information in real time regarding disease regression and progression. They discussed the role of the human papillomavirus (HPV) in cervical cancer development and the importance of developing strategies to suppress HPV persistence and progression. Results in Phase I randomized clinical trials have been disappointing because few have demonstrated statistically significant regression attributable to the agent tested. Researchers recommended using a transgenic mouse model to test and validate new compounds, initiating vaccine and immunomodulator trials, and developing immunologic surrogate endpoint biomarkers., (Copyright 2003 American Cancer Society.)

Objective: To determine if the incidence of invasive cervical cancer relative to carcinoma in situ decreased in Medicare-eligible women., Methods: A retrospective cohort was amassed from the California Cancer Registry database. The hypothesis was prospectively specified. Mean ratio of invasive (International Federation of Gynecology and Obstetrics Stages I-IV) to in situ cervical carcinoma in 1988-1990 versus 1991-1995 was stratified by age (24 or younger, 25-44, 45-64, 65 or older) and race (all races, whites, blacks, Hispanics, Asian/Pacific Islanders)., Results: The mean ratio of invasive to in situ cervical cancer incidence for women at least 65 years old was lower in 1991-1995 compared with 1988-1990 (P <.001, 95% confidence interval 0.893, 0.954); and had decreased more than observed for women aged 45-64 and 25-44, for all races combined, and for white women. The decreased ratio of invasive to in situ cancer for blacks, Hispanics, and Asian/Pacific Islanders at least 65 years old was no different than the decreased ratio in younger women., Conclusion: In California, in the 5 years after the 1990 change in Medicare funding statutes for cervical cytology screening, the ratio of invasive cervical cancer to in situ disease decreased more in Medicare-eligible patients than in younger women.

More than 11% of the global cancer incidence in females is due to human papillomavirus (HPV) infections, with HPV genotype 16 the most prevalent viral type to infect the cervix. Vaccine strategies currently target HPV 16 genes E6 and E7, constitutively expressed in cervical cancer cells, and L1 and L2, HPV surface antigens. Recent developments in HPV vaccine research are reviewed. Most studies focus on vaccine models showing improved immunogenicity or dual induction of both humeral and cellular systems. Preclinical studies show that (1) L1 /E7 chimeric viral-like proteins induce both neutralizing L1 antibodies and E7-specific T cells; (2) rerouting a cytosolic tumor antigen into the endosomal/lysosomal compartment can improve the therapeutic potency of DNA vaccines; and (3) accelerated E7 protein degradation leads to enhanced antigen presentation in the context of major histocompatability complex class I. Clinical studies show that (1) HPV 16 E7 peptide vaccination can be safely delivered to patients with terminal disease; and (2) HPV-16 capsid proteins harbor at least one HLA-A*201 restricted cytotoxic T lymphocyte (CTL) epitope.

Objective: 1998 Surveillance, Epidemiology, and End Results (SEER) data estimate an 83.1% 5-year survival rate for corpus uteri adenocarcinoma FIGO stage II. The SEER data were evaluated to determine whether primary treatment differences using simple hysterectomy or radical hysterectomy, with or without radiation, altered disease survival., Materials and Methods: SEER incidence data for FIGO II uterine corpus cancer of adenocarcinoma histology from 1988 to 1994 were stratified by hysterectomy type (simple versus radical) and whether radiation was given. Survival rates were calculated using a relative survival method and are expressed as percentages. Statistical analysis was done using a Z test., Results: The 5-year cumulative survival rate for patients with stage II uterine corpus adenocarcinoma who received surgery alone as primary therapy was 84.36% with simple hysterectomy and 92.96% with radical hysterectomy (P<0.05). Survival for patients who received combination radiation and surgery as primary therapy was 82.77% with simple hysterectomy and 88.02% with radical hysterectomy (P<0.05). Pelvic and para-aortic nodes were negative. There was no significant survival difference for radiation versus no radiation in either surgical group., Conclusion: Radical hysterectomy is associated with better survival when compared to simple hysterectomy for FIGO II corpus uteri adenocarcinoma.

To assess the relationship of tubal ligation and risk of ovarian carcinoma, we conducted a case-control, retrospective analysis of 300 ovarian carcinoma cases and 606 nonmalignant disease controls, seen between 1982 and 1988 at Roswell Park Cancer Institute, Buffalo, New York. Women who had a tubal ligation had reduced risk for the development of ovarian cancer. This relative risk was 0.52, with a 95% confidence interval 0.31 to 0.85 (p = 0.0076). Controls were matched by age. Multivariate analysis adjusted for socioeconomic level, marital status, parity, age at first pregnancy, menarche age, menopause age, irregular menses, breast-feeding duration, body habitus, and oral contraceptive use. Suggested explanations for this observation are offered.

Fifty consecutive patients with documented advanced or recurrent endometrial carcinoma from 1978 through 1985 were prospectively treated with melphalan, 5-fluorouracil, medroxyprogesterone acetate (MFP) as first-line chemotherapy. From 1987 through 1993, 50 consecutive patients with documented advanced or recurrent endometrial carcinoma were prospectively treated with cisplatin, Adriamycin, etoposide, megestrol acetate (PAV-M) as first-line chemotherapy. Response rates for MFP versus PAV-M, 2- and 5-year survival, median survival, 2- and 5-year progression-free survival, and median progression-free survival were not statistically different. However, there was a significant improvement favoring PAV-M in 2-year (45 versus 14%), 5-year (30 versus 5%), and median survival (22.3 versus 8.7 months) (P = 0.008) compared to MFP in patients with primary advanced endometrial adenocarcinoma. Moreover, there was a significant improvement in 2- and 5-year and median survival (55 and 15% and 26.7 months) for PAV-M compared to MFP (7 and 0% and 7.3 months) (P = 0.002) for the more aggressive other adenocarcinomas (adenosquamous, clear cell, papillary serous, undifferentiated) compared to the more common endometrioid adenocarcinoma. The current data suggest that cisplatin- and adriamycin-based chemotherapy results in some long-term survival benefit for patients with primary advanced endometrial adenocarcinoma and the more aggressive nonendometrioid adenocarcinoma histologies.

Pancreatic cancer and jejunal cancer are aggressive diseases with grim prognoses. The long term survival of pancreatic carcinoma is still one of the worst of all cancers. Ninety-five percent of the patients die of their disease within 5 years [Wagener et al: Ann Oncol 5(Suppl 3): S87-S90, 1994]. Eighty-five percent of patients with jejunal carcinoma die of their disease within 5 years [Lioe, Biggart: J Clin Pathol 43:533-536, 1990]. To date, there are disappointingly few effective cytotoxic agents in the treatment of these cancers. We present a case of advanced-stage pancreatic carcinoma and a case of advanced stage jejunal carcinoma, each showing marked response to Taxol and platinum chemotherapy.

Renal toxicity is a prominent component of the toxicity profile of platinum-based chemotherapy. Kidney damage, once dose limiting for cisplatin, occurs in some patients who receive carboplatin and may occur with the third-generation platinum analog ormaplatin. Herein, we review what is known about the pathophysiology of therapy-induced renal toxicity for each of these agents and what is known about appropriate maneuvers to circumvent this toxicity. For cisplatin, hydration is always indicated and mannitol may be useful in selected settings. Furosemide is probably not generally useful. For carboplatin, hydration is important for patients with impaired renal function and for patients receiving high doses of drug (> or = 800 mg/m2). For ormplatin, renal toxicity appears not be prominent when hydration is administered in a fashion similar to cisplatin hydration. Detailed suggestions regarding the protection of kidney function when using these compounds are presented.

Background: Cisplatin and carboplatin are essential to management of advanced-stage epithelial ovarian carcinoma. No published data exist regarding carboplatin dose intensity importance in ovarian cancer, nor are there data for the effect of age on the ability to deliver dose-intensive carboplatin., Methods: Retrospective dose intensity analyses were performed for 93 patients with advanced-stage refractory ovarian carcinoma, who received single-agent, high-dose carboplatin chemotherapy (800 mg/m2/35 days of 160 mg/m2/week). These patients had been treated on one of three high-dose carboplatin studies conducted in the Medicine Branch of the National Cancer Institute during the 1980s. Eligibility criteria required age greater than or equal to 18 years, good end organ function, and good performance status., Results: Patients 60 years of age or older comprised 33% of the cohort and patients 70 years of age or older comprised 8% of the cohort. Administered dose intensity of carboplatin did not differ among age groups. Patients of age < or = 39 years received a dose intensity of 136 +/- 28 mg/m2/week, those of age 40-59 years received 129 +/- 33, those of age > or = 60 years received 134 +/- 24, and those of age > or = 70 years received 129 +/- 19. Further, the administered carboplatin dose intensity did not differ among clinical response groups. Dose intensity in complete responders was 138 +/- 18 mg/m2/week; in partial responders, 121 +/- 29; and in nonresponders, 134 +/- 30. The age distribution of responders matched the age distribution of the cohort., Conclusions: These data demonstrate that elderly patients with good end organ function and good performance status tolerate the same level of dose-intensive platinum therapy as younger patients. Age alone should not be a determinant for carboplatin dose modification in the treatment of ovarian carcinoma.

A study was designed to test various high-molecular-weight solutions in the prevention of postoperative intraabdominal adhesions. The bicornuate rat uterus was used as the surgical model, and 80 mature white female rats underwent surgical injury of the right uterine horn. The rats were randomly divided into 5 groups: groups A, B, and C received 5 ml intraperitoneally of chondroitin sulfate, sodium carboxymethylcellulose, and 32% dextran 70, respectively; group D was treated with microsurgical repair; and group E, the control, received no therapy. The animals were killed postoperatively, and the adhesions were scored. Significantly better results in adhesion prevention were demonstrated in the sodium carboxymethylcellulose group vs. the other groups, except in group A where the difference was not significant.