Aberrant hormone production from ovarian neoplasms: Strategies for diagnosis and therapy

Syndromes involving peptide or nonsex steroid hormone secretion due to aberrantly located tumors are rare. We report a collected series of 16 patients with ectopic hormone production from ovarian neoplasms, including 3 patients recently encountered at our institution as well as 13 additional cases identified in the recent literature. These tumors included 2 insulin-producing ovarian carcinoids, 1 ACTH-producing pituitary adenoma within a benign ovarian cystic teratoma, 2 cortisol-producing ovarian neoplasms, 8 gastrin-producing ovarian cystadenomata or cystadenocarcinomata, and 3 thyroxine-producing ovarian strumal carcinoids. All patients presented with syndromes of hormone excess. Only 62% of all tumors were localized preoperatively. Following ovarian resection, 87% of patients remained disease-free with a median follow-up period of 1.5 years. In addition to ovariectomy, 8 additional unnecessary ablative procedures were performed in 7 patients. These included distal pancreatectomy, pancreaticoduodenectomy, adrenalectomy, total gastrectomy, selective vagotomy, and subtotal thyroidectomy. Failure to localize the ovarian neoplasm preoperatively was associated with a significantly higher risk of subsequent unnecessary ablative procedures. Because of the potential for the ovary to act as a source of aberrant hormone secretion, we recommend complete preoperative evaluation of the pelvis in female patients presenting with nonlocalizable endocrine tumors.

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Resumen Los síndromes relacionados con la secreción de péptidos o de hormonas esteroideas no sexuales por tumores de ubicación aberrante ocurren infrecuentemente. En este artículo reportamos una serie de 16 pacientes con producción hormonal ectópica por neoplasmas ováricos, la cual incluye 3 pacientes vistos recientemente en nuestra institución y 13 identificados en la literatura médica de los últimos años. El grupo incluye 2 carcinoides ováricos productores de insulina, 1 adenoma pituitario productor de ACTH, 2 neoplasmas ováricos productores de cortisol, 8 cistadenomas o cistadenocarcinomas ováricos productores de gastrina, y 3 carcinoides ováricos estrumales productores de tiroxina. Todas las pacientes se presentaron con síndromes de exceso hormonal. En sólo el 62% de los tumores se pudo establecer la ubicación anatómica en la fase preoperatoria. Después de realizada la resección del ovario, 87% de las pacientes permanecieron libres de enfermedad en el período de seguimiento, que fue de 1.5 años en promedio. Además de la resección ovárica, se practicaron otros 8 procedimientos adicionales innecesarios en 7 pacientes. Estos incluyeron pancreatectomía distal, pancreatoduodenectomía, adrenalectomía, gatrectomía total, vagotomía selectiva, y tiroidectomía subtotal. La falla en la localización preoperatoria del neoplasma ovárico apareció asociada con un riesgo aumentado de ulteriores procedimientos quirúrgicos innecesarios. En vista de la potencialidad del ovario de actuar como fuente de secreción hormonal aberrante, nosotros recomendamos una completa evaluación de la pelvis en las pacientes femeninas en quienes se diagnostiquen tumores endocrinos no localizables.

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Résumé Les syndromes concernant la sécrétion d'hormones peptidique ou stéroïde nonsexuelle due à des tumeurs ectopiques sont rares. Nous rapportons une série de 16 patientes avec une production d'hormone ectopique provenant de néoplasmes ovariens, comprenant 3 patientes récemment soignées dans notre établissement ainsi que 13 cas supplémentaires relevés dans la littérature récente. Ces tumeurs comprennent 2 tumeurs carcinoïdes ovariennes productrices d'insuline, 1 adénome hypophysaire producteur d'ACTH à l'intérieur d'un tératome cystique ovarien bénin, 2 néoplasmes ovariens producteurs de cortisol, 8 cystadénomes ou cystadénocarcinomes ovariens producteurs de gastrine, et 3 carcinoïdes ovariens strumaux producteurs de thyroxine. Toutes les patientes avaient des syndromes d'hyperproduction hormonale. Soixante-deux pour cent seulement des tumeurs avaient été localisées en préopératoire. Après ovariectomie, 87% des patientes étaient apparamment sans récidive avec un suivi médian d'un an et demi. Cependent, outre l'ovariectomie, 8 interventions supplémentaires non nécessaires ont été accomplis chez 7 patientes. Celles-ci comprenaient: pancréatectomie distale, duodénopancréatectomie, surrénalectomie, gastrectomie totale, vagotomie sélective, et thyroïdectomie subtotale. L'impossibilité de localiser le néoplasme ovarien en période préopératoire était associée à un risque notoirement plus grand de faire une résection inutile. Compte tenu de la possibilité pour l'ovaire de se comporter en producteur de sécrétion ectopique d'hormone, nous recommandons un examen complet préopératoire du bassin chez les femmes se présentant avec des tumeurs endocrines non localisables.

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Presented at the International Association of Endocrine Surgeons in Toronto, Ontario, Canada, September, 1989.     

Differential etiology of posttraumatic stress disorder with conduct disorder and major depression in male veterans.

BACKGROUND: Epidemiologic studies reveal that posttraumatic stress disorder (PTSD) is highly comorbid with both conduct disorder and major depression in men. The genetic and environmental etiology of this comorbidity has not been examined. METHODS: Data were analyzed from 6744 middle-aged male-male monozygotic and dizygotic twins from the Vietnam Era Twin Registry. Conduct disorder, major depression, and PTSD were assessed via telephone interview using the Diagnostic Interview Schedule for the DSM-III-R in 1992. Structural equation modeling was used to estimate additive genetic, shared environmental, and individual-specific environmental effects common and specific to conduct disorder, major depression, and PTSD. RESULTS: The association between conduct disorder and PTSD was explained primarily by common shared environmental influences; these explained 10% (95% confidence interval: 6%-17%) of the variance in PTSD. The association between major depression and PTSD was largely explained by common genetic influences; these explained 19% (95% confidence interval: 11%-26%) of the variance in PTSD. CONCLUSIONS: Our findings suggest that different etiologic mechanisms explain the association of conduct disorder and major depression with PTSD in male veterans. If replicated in other populations, results suggest research aimed at identifying specific genetic and environmental factors that influence PTSD may benefit from starting with those that have been more consistently and strongly associated with major depression and conduct disorder.     

Regulation of hepatocyte activator inhibitor-1 expression by androgen and oncogenic transformation in the prostate

Hepatocyte activator inhibitor-1 (HAI-1) is a transmembrane serine protease inhibitor that regulates the conversion of latent to active hepatocyte growth factor (HGF). Studies supporting a role for the HGF pathway in prostate carcinogenesis prompted an analysis of HAI-1 expression in the prostate. Here we analyze the regulation of HAI-1 expression by androgen, oncogenic transformation, and cancer progression. Immunohistochemical analysis revealed that HAI-1 expression was restricted to prostate epithelium, where staining occurred primarily in basal and atrophic luminal epithelial cells. Compared to normal glands, HAI-1 expression was significantly increased in localized prostate cancer and was present in most prostate cancer metastases. HAI-1 protein expression levels were sensitive to androgen in normal epithelium but not in cancer. Although androgen did not increase HAI-1 protein expression levels in LNCaP cells, it decreased HAI-1 surface expression, consistent with previous data from our group (Martin DB, Gifford DR, Wright ME, Keller A, Yi E, Goodlett DR, Aebersold R, Nelson PS: Quantitative proteomic analysis of proteins released by neoplastic prostate epithelium. Cancer Res 2004, 64:347-355). HAI-1 overexpression in cancer was predictive of prostate-specific antigen recurrence (relative risk, 1.24). These results suggest that HAI-1 regulates the HGF Met axis on prostate epithelial cells and influences HGF mediated tumor invasion and metastasis.     

Working conditions and health behavior as causes of educational inequalities in self-rated health: an inverse odds weighting approach

Objective:Using a novel mediation method that presents unbiased results even in the presence of exposure–mediator interactions, this study estimated the extent to which working conditions and health behaviors contribute to educational inequalities in self-rated health in the workforce.Methods:Respondents of the longitudinal Survey of Health, Ageing, and Retirement in Europe (SHARE) in 16 countries were selected, aged 50–64 years, in paid employment at baseline and with information on education and self-rated health (N=15 028). Education, health behaviors [including body mass index (BMI)] and working conditions were measured at baseline and self-rated health at baseline and two-year follow-up. Causal mediation analysis with inverse odds weighting was used to estimate the total effect of education on self-rated health, decomposed into a natural direct effect (NDE) and natural indirect effect (NIE).Results:Lower educated workers were more likely to perceive their health as poor than higher educated workers [relative risk (RR) 1.48, 95% confidence interval (CI) 1.37–1.60]. They were also more likely to have unfavorable working conditions and unhealthy behaviors, except for alcohol consumption. When all working conditions were included, the remaining NDE was RR 1.30 (95% CI 1.15–1.44). When BMI and health behaviors were included, the remaining NDE was RR 1.40 (95% CI 1.27–1.54). Working conditions explained 38% and health behaviors and BMI explained 16% of educational inequalities in health. Including all mediators explained 64% of educational inequalities in self-rated health.Conclusions:Working conditions and health behaviors explain over half of the educational inequalities in self-rated health. To reduce health inequalities, improving working conditions seems to be more important than introducing health promotion programs in the workforce.     

Lack of microsatellite instability in human prostate-cancer

DNA replication errors are especially frequent in repetitive DNA sequences, including microsatellites. Thus, microsatellites are sensitive indicators of the genetic instability observed in many types of human cancers, particularly colorectal cancer. We tested prostate carcinomas for the presence of microsatellite alleles not present in normal tissue from the same individuals. Analysis of 7 microsatellites in each of 30 patients revealed instability at only one microsatellite in one tumor. This level of microsatellite instability, considerably lower than that reported previously, may reflect differences in patient pools. We discuss the implications of the genetic stability of prostate cancers relative to other cancers.