Developmentally arrested structures preceding cerebellar tumors in von Hippel-Lindau disease.

There is increasing evidence that suggests that knockout of tumor-suppressor gene function causes developmental arrest and protraction of cellular differentiation. In the peripheral nervous system of patients with the tumor-suppressor gene disorder, von Hippel-Lindau disease, we have demonstrated developmentally arrested structural elements composed of hemangioblast progenitor cells. Some developmentally arrested structural elements progress to a frank tumor, hemangioblastoma. However, in von Hippel-Lindau disease, hemangioblastomas are frequently observed in the cerebellum, suggesting an origin in the central nervous system. We performed a structural and topographic analysis of cerebellar tissues obtained from von Hippel-Lindau disease patients to identify and characterize developmentally arrested structural elements in the central nervous system. We examined the entire cerebella of five tumor-free von Hippel-Lindau disease patients and of three non-von Hippel-Lindau disease controls. In all, 9 cerebellar developmentally arrested structural elements were detected and topographically mapped in 385 blocks of von Hippel-Lindau disease cerebella. No developmentally arrested structural elements were seen in 214 blocks from control cerebella. Developmentally arrested structural elements are composed of poorly differentiated cells that express hypoxia-inducible factor (HIF)2α, but not HIF1α or brachyury, and preferentially involve the molecular layer of the dorsum cerebelli. For the first time, we identify and characterize developmentally arrested structural elements in the central nervous system of von Hippel-Lindau patients. We provide evidence that developmentally arrested structural elements in the cerebellum are composed of developmentally arrested hemangioblast progenitor cells in the molecular layer of the dorsum cerebelli.

A study of pregnancy rates in "cleared" male factor couples.

BACKGROUND: Among couples with male factor infertility, the natural pregnancy rates associated with classic male factor treatments are well described. In couples with unexplained infertility, the proportion due to occult male factor is unclear. We hypothesized that many men diagnosed with unexplained infertility are actually fertile. We describe the 1-year natural pregnancy rates among couples in whom the male partner has been "cleared" of infertility on urologic evaluation. METHODS: Consecutive infertile couples were recruited from a single practice (PJT) over a 3-year period. A thorough male factor evaluation was performed, including a history, physical examination and 2 semen analyses. Based on this assessment, male partners in whom bulk semen parameters were normal were "cleared" from further evaluation. Lifestyle modifications were allowed, but no medical or surgical treatments were offered. The presence or absence of a female factor evaluation was not required for study inclusion. Subjects were followed for 12 months or until a pregnancy was achieved. Subjects were contacted via telesurvery 1-year later and pregnancy status ascertained. Simple descriptive statistics were used to evaluate the significance of observations. RESULTS: Fifty-four men were enrolled in the study. The mean duration of infertility was 1.5 years (range, 0.4 to 4.0 years) and the mean male and female partner ages were 38.6 and 35.1 years, respectively. On evaluation, 40% of men were noted to have significant fertility risks that included a clinical varicocele, exposures, and androgen altering medications. Among n=31 couples with known pregnancy outcomes, 20/31 (65%) conceived naturally at a mean of 9 months after evaluation (range, 3-30 mos). Another 1/31 (3%) couples conceived with intrauterine insemination (IUI) and 4/31 (13%) conceived with IVF-ICSI. CONCLUSIONS: A significant proportion of men diagnosed with unexplained infertility have lifestyle risk factors on urologic evaluation. Care in the form of counseling at-risk patients regarding lifestyle issues, in the absence of formal treatment, may have value in improving the fertility potential in this population. Indeed, natural conception rates among men identified with unexplained infertility are substantial and suggest that many of these men are truly fertile.

Assessing trends in urinary diversion after radical cystectomy for bladder cancer in the United States.

OBJECTIVES: We assessed recent trends in both urinary diversion after radical cystectomy for bladder cancer in the United States and patient- and hospital-related characteristics. We also identified variables associated with undergoing continent diversion. MATERIALS AND METHODS: We queried the National Cancer Database and identified 27,170 patients who underwent radical cystectomy with urinary diversion from 2004 to 2013. Patient demographics, socioeconomic variables, and hospital-related factors were compared between incontinent and continent diversion and trended over time. Multivariable logistic regression was used to identify variables associated with undergoing continent diversion. RESULTS: Overall, 23,224 (85.5%) and 3,946 (14.5%) patients underwent incontinent and continent diversion, respectively. Continent diversion declined from 17.2% in 2004 to 2006 to 12.1% in 2010 to 2013 (P < 0.01). When analyzing high-volume facilities, those performing ≥75% minimally invasive radical cystectomy had fewer continent diversions (10.2%) compared to centers with higher rate of open approach (19.7%), P < 0.01. Higher income, facility located in the West, academic programs, high-volume facilities, and patients traveling >60 miles for care were significantly associated with undergoing continent diversion. Rate of continent diversion has declined in most patient- and hospital-related subgroups. Compared to 2004 to 2006, patients in 2010 to 2013 were more likely to be older, have more comorbidities, and be operated on at a high-volume academic facility. CONCLUSION: The rate of continent diversion has declined to 12.1% in the United States. Hospital volume and type, patient income, distance traveled for care, and geography are significantly associated with undergoing continent diversion. Even among high-volume and academic centers, the rate of continent diversion is declining.