Pamela Stratton

National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report.

The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.

Mutations in the Fumarate Hydratase Gene Cause Hereditary Leiomyomatosis and Renal Cell Cancer in Families in North America

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in the fumarate hydratase (FH) gene in European families supports it as the susceptibility gene for HLRCC, its role in families in North America has not been studied. We screened for germline mutations in FH in 35 families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (89%). Twenty different mutations in FH were identified, of which 18 were novel. Of these 20 mutations, 2 were insertions, 5 were small deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals (47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine leiomyomas. Eighty-nine percent (41/46) of women with cutaneous and uterine leiomyomas had a total hysterectomy, 44% at age < or =30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from four families had papillary type II renal cell carcinoma, and another individual from one of these families had collecting duct carcinoma of the kidney. The present study shows that mutations in FH are associated with HLRCC in North America. HLRCC is associated with clinically significant uterine fibroids and aggressive renal tumors. The present study also expands the histologic spectrum of renal tumors and FH mutations associated with HLRCC.

Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications

BACKGROUND Many clinicians and patients believe that endometriosis-associated pain is due to the lesions. Yet causality remains an enigma, because pain symptoms attributed to endometriosis occur in women without endometriosis and because pain symptoms and severity correlate poorly with lesion characteristics. Most research and reviews focus on the lesions, not the pain. This review starts with the recognition that the experience of pain is determined by the central nervous system (CNS) and focuses on the pain symptoms. METHODS Comprehensive searches of Pubmed, Medline and Embase were conducted for current basic and clinical research on chronic pelvic pain and endometriosis. The information was mutually interpreted by a basic scientist and a clinical researcher, both in the field of endometriosis. The goal was to develop new ways to conceptualize how endometriosis contributes to pain symptoms in the context of current treatments and the reproductive tract. RESULTS Endometriotic lesions can develop their own nerve supply, thereby creating a direct and two-way interaction between lesions and the CNS. This engagement provides a mechanism by which the dynamic and hormonally responsive nervous system is brought directly into play to produce a variety of individual differences in pain that can, in some women, become independent of the disease itself. CONCLUSIONS Major advances in improving understanding and alleviating pain in endometriosis will likely occur if the focus changes from lesions to pain. In turn, how endometriosis affects the CNS would be best examined in the context of mechanisms underlying other chronic pain conditions.

Return of Chronic Pelvic Pain From Endometriosis After Raloxifene Treatment: A Randomized Controlled Trial

OBJECTIVE: To evaluate whether 6 months of raloxifene was effective in treatment of chronic pelvic pain in women with endometriosis. METHODS: Women with chronic pelvic pain and no endometriosis treatment for 6 months underwent laparoscopy for excision of all lesions. Those with biopsy-proven endometriosis were randomly allocated to raloxifene (180 mg) or placebo daily. A second laparoscopy was performed at 2 years, or earlier, if pain returned. Return of pain was defined as 2 months of pain equal to or more severe than that at study entry. Menstrual cycles and adverse events were recorded. The log rank test was used to compare the time to return of pain by drug group. Analyses were done as intent-to-treat. RESULTS: A total of 127 of 158 women underwent surgery. Of these, 93 had biopsy-confirmed endometriosis and were randomly assigned to study treatment. Menstrual cycle length, pelvic pain severity, quality of life, bone mineral density, and adverse events did not differ between treatment groups. The Data Safety Monitoring Committee terminated the study early when the raloxifene group experienced pain (P=.03) and had second surgery (P=.016) significantly sooner than the placebo group. Interestingly, biopsy-proven endometriosis was not associated with return of pain (P=.6). CONCLUSION: Raloxifene significantly shortened the time to return of chronic pelvic pain. Because recurrence of endometriosis lesions did not correlate with return of pain, other factors are implicated in pelvic pain. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.cliicaltrials.gov, NCT00001848 LEVEL OF EVIDENCE: I

Reduced expression of biomarkers associated with the implantation window in women with endometriosis

OBJECTIVE To evaluate the expression of biomarkers of implantation, glycodelin A (GdA), osteopontin (OPN), lysophosphatidic acid receptor 3 (LPA3), and HOXA10, in eutopic endometrium of women with and without endometriosis. DESIGN Prospective observational study. SETTING Clinical research center. PATIENT(S) Twenty-four women with endometriosis and 23 healthy volunteers of similar age. INTERVENTION(S) Secretory phase endometrial biopsy. MAIN OUTCOME MEASURE(S) Expression of immunohistochemical staining intensity and localization of GdA, OPN, LPA3, and HOXA10 in eutopic endometrium. RESULT(S) Endometrial GdA expression was significantly reduced in patients after cycle day 22. The endometrium from women with endometriosis also showed decreased expression of OPN in the late secretory phase and LPA3 and HOXA10 expression in the midsecretory and late secretory phases. CONCLUSION(S) The decreased expression of these four biomarkers of implantation may indicate impaired endometrial receptivity in patients with endometriosis, providing one explanation for the subfertility observed even in women with few pelvic implants. Because many of these markers are P dependent, these findings suggest the possibility of reduced endometrial P action in this population.

Diagnostic experience among 4,334 women reporting surgically diagnosed endometriosis

OBJECTIVE To determine whether first physician seen and symptoms beginning in adolescence have an impact on the diagnostic experience of endometriosis. DESIGN Cross-sectional study of self-reported survey data. SETTING Academic research. PATIENT(S) Four thousand three hundred thirty-four Endometriosis Association Survey respondents reporting surgical diagnosis of endometriosis. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Specialty of first physician seen, timing of onset of symptoms, time to seeking medical care and to diagnosis, number of physicians seen, and satisfaction with care. RESULT(S) Almost all respondents reported pelvic pain. Fifty percent first saw a gynecologist and 45% saw a generalist for symptoms related to endometriosis. Two thirds reported symptoms beginning during adolescence; they waited longer to seek medical care than adults did. Those seeing a generalist first took longest to get diagnosed; those seeing a gynecologist first saw fewer physicians. Sometime before diagnosis, 63% were told nothing was wrong with them. CONCLUSION(S) Women and girls who reported seeing a gynecologist first for symptoms related to endometriosis were more likely to have a shorter time to diagnosis, to see fewer physicians, and to report a better experience overall with their physicians. The majority reported symptoms beginning during adolescence, also reporting a longer time and worse experience while obtaining a diagnosis.

Obstetric and newborn outcomes in a cohort of HIV-infected pregnant women: a report of the women and infants transmission study.

OBJECTIVE To determine obstetric and neonatal outcomes in a cohort of HIV-infected pregnant women and to assess whether HIV-related immunosuppression increases the risk of adverse outcomes of pregnancy. METHODS Between 1989 and 1994, interview, physical examination, laboratory, and medical record data were prospectively collected from HIV-infected pregnant women and on their newborns. Factors associated with adverse pregnancy outcome and HIV disease status were correlated with pregnancy outcome using logistic regression analysis. RESULTS 634 women delivered after 24 weeks of gestation. Preterm birth, low birth weight, and small-for-gestational-age neonates occurred in 20.5%, 18.9%, and 24.0% of pregnancies, respectively. Factors associated with low birth weight were CD4 percentage <14%, history of adverse pregnancy outcome, pediatric HIV infection, bleeding during pregnancy, and Trichomonas infection. Preterm birth was associated with CD4 percentage <14%, a history of adverse pregnancy outcome, and bleeding during pregnancy. Being small for gestational age was associated with maternal hard drug use during pregnancy, Trichomonas infection, history of adverse pregnancy outcome, and hypertension. CONCLUSIONS Adverse pregnancy outcomes are common for HIV-infected women and are associated with low maternal CD4 percentage and pediatric HIV infection. Preterm birth, low birth weight, and small-for-gestational-age ranking, however, are also associated with previously recognized sociodemographic and obstetric factors that are not unique to HIV infection.

Development of the selective progesterone receptor modulator CDB-2914 for clinical indications

CDB-2914 (17 alpha-acetoxy-11 beta-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione) is a 19-norprogesterone derivative that acts as an antagonist in progesterone-responsive tissues. It binds to progesterone receptors A and B with high affinity. After oral dosing in humans, CDB-2914 serum levels peak at 60-90 min. CDB-2914 binds to serum proteins and is cleared slowly. Doses of 1, 10 and 50 mg exhibit proportional increases in peak serum levels, but serum levels from higher doses, 100 and 200 mg, are not dose-dependent, suggesting saturation of carrier sites. The biological effects of CDB-2914 vary according to time of the menstrual cycle that the drug is given. In the mid-follicular phase, CDB-2914 (50 mg) inhibits follicular development and delays ovulation and menses. At 100 mg, in some cases the original follicle ceases development and a new follicle is recruited. Endometrial maturation is delayed at all doses tested (10, 50, 100 mg). Given at mid-luteal phase, there was a dose-dependent effect on menses, with higher doses (100-200 mg) resulting in earlier menses. On average, CDB-2914 tends to lengthen the menstrual cycle by approximately 1-2 days although the amount of delay varies with timing in the menstrual cycle and dose.

Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914

OBJECTIVE To test potential contraceptive mechanisms of the selective P receptor modulator CDB-2914 in the early luteal phase. DESIGN Prospective randomized clinical trial. SETTING Clinical research center. PATIENT(S) Fifty-six women with regular cycles. INTERVENTION(S) Women received a single dose of CDB-2914 (10, 50, or 100 mg) or placebo given after ovulation and within 2 days of the LH surge. Four to 6 days later, a transvaginal ultrasound scan measured endometrial thickness, and an endometrial biopsy specimen was obtained. MAIN OUTCOME MEASURE(S) The endometrium was evaluated by thickness and by immunohistochemical analysis for P-dependent markers; safety laboratory tests were performed, and E(2) and P levels were obtained. RESULT(S) CDB-2914 caused a significant dose-dependent decrease in endometrial thickness, an increase in glandular P receptors, and a decrease in peripheral node addressins. Estradiol and P levels and menstrual cycle timing were not altered. No adverse effects were observed. CONCLUSION(S) The alteration in endometrial thickness and P-dependent markers of implantation in the absence of changes in hormone levels and cycle length suggests that CDB-2914 may have contraceptive properties.

Pain scoring in endometriosis: entry criteria and outcome measures for clinical trials. Report from the Art and Science of Endometriosis meeting

Standardized entry criteria and outcome measures for clinical trials in endometriosis-related pain would facilitate the comparison of trial results and the production of systematic reviews, improving evidence-based practice in this area. This report summarizes the recommendations from an international meeting for these criteria.