Citations

Bilateral oophorectomy at the time of hysterectomy for benign disease is commonly practiced in order to prevent the subsequent development of ovarian cancer or other ovarian pathology that might require additional surgery. At present, bilateral oophorectomy is performed in 78% of women aged between 45 and 64 years having a hysterectomy, and a total of approximately 300,000 prophylactic oophorectomies are performed in the USA every year. Estrogen deficiency resulting from pre- and post-menopausal oophorectomies has been associated with higher risks of coronary heart disease, stroke, hip fracture, Parkinsonism, dementia, cognitive impairment, depression and anxiety in many studies. While ovarian cancer accounts for 14,800 deaths per year in the USA, coronary heart disease accounts for 350,000 deaths per year. In addition, 100,000 cases of dementia may be attributable annually to prior bilateral oophorectomy. At present, observational studies suggest that bilateral oophorectomy may do more harm than good. In women who are not at high risk of developing ovarian or breast cancer, removing the ovaries at the time of hysterectomy should be approached with caution.

Abstract Edmonston vaccine strains of measles virus (MV) have shown significant antitumor activity in preclinical models of ovarian cancer. We engineered MV to express the marker peptide carcinoembryonic antigen (MV-CEA virus) to also permit real-time monitoring of viral gene expression in tumors in the clinical setting. Patients with Taxol and platinum-refractory recurrent ovarian cancer and normal CEA levels were eligible for this phase I trial. Twenty-one patients were treated with MV-CEA i.p. every 4 weeks for up to 6 cycles at seven different dose levels (103–109 TCID50). We observed no dose-limiting toxicity, treatment-induced immunosuppression, development of anti-CEA antibodies, increase in anti-MV antibody titers, or virus shedding in urine or saliva. Dose-dependent CEA elevation in peritoneal fluid and serum was observed. Immunohistochemical analysis of patient tumor specimens revealed overexpression of measles receptor CD46 in 13 of 15 patients. Best objective response was dose-dependent disease stabilization in 14 of 21 patients with a median duration of 92.5 days (range, 54–277 days). Five patients had significant decreases in CA-125 levels. Median survival of patients on study was 12.15 months (range, 1.3–38.4 months), comparing favorably to an expected median survival of 6 months in this patient population. Our findings indicate that i.p. administration of MV-CEA is well tolerated and results in dose-dependent biological activity in a cohort of heavily pretreated recurrent ovarian cancer patients. Cancer Res; 70(3); 875–82

Abstract Background Controversy exists regarding the aggressiveness of initial therapy in childhood papillary thyroid cancer (PTC). Few studies with long‐term outcome exist and second primary malignancies have rarely been analyzed. Methods We studied 215 PTC patients younger than 21 years old managed during 1940 through 2008. The patients were aged 3–20 year old (median age = 16 years); the median follow‐up was 29 years. Recurrence and mortality details were taken from a computerized database. Results Median primary tumor size was 2.2 cm. Six percent had distant metastases at presentation, 5% had incomplete tumor resection, 86% had nodes removed at initial surgery, and 78% had nodal metastases. After complete surgical resection, PTC recurred in 32% by 40 years. At 20 years, the recurrence rates at local, regional, and distant sites were 7, 21, and 5%, respectively. During 1940–1969, local and regional recurrence rates after unilateral lobectomy (UL) were significantly ( P < 0.001) higher than after bilateral lobar resection (BLR). During 1950–2008 radioiodine remnant ablation (RRA) was administered within 18 months to 32%; it did not diminish the 25‐year regional recurrence rate of 16% seen after BLR alone ( P = 0.86). Only two fatal events from PTC occurred at 28 and 30 years, for a cause‐specific mortality at 40 years of only 2%. All‐causes mortality rates did not exceed expectation through 20 years, but from 30 through 50 years, the number of deaths was significantly ( P < 0.001) higher than predicted. Fifteen of 22 deaths (68%) resulted from nonthyroid malignancy. Conclusion Survival from childhood PTC should be expected, but later death from nonthyroid malignancy is disconcerting. Seventy‐three percent of those who died from nonthyroid malignancy had received postoperative therapeutic irradiation.

Cigarette smoking and/or nicotine administration have been shown to transiently ameliorate several psychophysiological deficits in patients with schizophrenia such as indicators of deficient sensory gating and attention, but acute effects of smoking on positive and negative symptoms in schizophrenia have not been evaluated in experimental paradigms. The current study assessed whether smoking of cigarettes, after 6–12 h abstinence, transiently alters the expression of negative and/or positive symptoms in patients with schizophrenia who have a history of regular smoking. In a double–blind, placebo controlled study patients with schizophrenia participated in two sessions in which they smoked either cigarettes moderately high in nicotine content or denicotinized cigarettes. They were interviewed pre–and postsmoking to obtain ratings of PANSS and SANS scales, and had blood pressure and pulse serially recorded before and after smoking. Pulse rate and blood pressure were slightly higher after smoking in the high nicotine cigarette session. Negative symptom scores on both scales were significantly lower after cigarette smoking compared to same–day predrug baseline, but there were no differences in active versus denicotinized cigarette drug effects. These results suggest that acute smoking of cigarettes reduces negative symptoms in patients with schizophrenia in this experimental paradigm. Future work needs to identify the mechanism responsible for this behavioral effect.

Background— Genetic testing for long-QT syndrome (LQTS) has diagnostic, prognostic, and therapeutic implications. Hundreds of causative mutations in 12 known LQTS-susceptibility genes have been identified. Genetic testing that includes the 3 most commonly mutated genes is available clinically. Distinguishing pathogenic mutations from innocuous rare variants is critical to the interpretation of test results. We sought to quantify the value of mutation type and gene/protein region in determining the probability of pathogenicity for mutations. Methods and Results— Type, frequency, and location of mutations across KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) were compared between 388 unrelated “definite” (clinical diagnostic score ≥4 and/or QTc ≥480 ms) cases of LQTS and >1300 healthy controls for each gene. From these data, estimated predictive values (percent of mutations found in definite cases that would cause LQTS) were determined according to mutation type and location. Mutations were 10 times more common in cases than controls (0.58 per case versus 0.06 per control). Missense mutations were the most common, accounting for 78%, 67%, and 89% of mutations in KCNQ1 , KCNH2 , and SCN5A in cases and >95% in controls. Nonmissense mutations have an estimated predictive value >99% regardless of location. In contrast, location appears to be critical for characterizing missense mutations. Relative frequency of missense mutations between cases and controls ranged from ≈1:1 in the SCN5A interdomain linker to infinity in the pore, transmembrane, and linker in KCNH2. These correspond to estimated predictive values ranging from 0% in the interdomain linker of SCN5A to 100% in the transmembrane/linker/pore regions of KCNH2. The estimated predictive value is also high in the linker, pore, transmembrane, and C terminus of KCNQ1 and the transmembrane/linker of SCN5A. Conclusions— Distinguishing pathogenic mutations from rare variants is of critical importance in the interpretation of genetic testing in LQTS. Mutation type, mutation location, and ethnic-specific background rates are critical factors in predicting the pathogenicity of novel mutations. Novel mutations in low-estimated predictive value regions such as the interdomain linker of SCN5A should be viewed as variants of uncertain significance and prompt further investigation to clarify the likelihood of disease causation. However, mutations in regions such as the transmembrane, linker, and pore of KCNQ1 and KCNH2 may be defined confidently as high-probability LQTS-causing mutations. These findings will have implications for other genetic disorders involving mutational analysis.

Niemann-Pick disease type C is a rare, genetic disease associated with impaired intracellular lipid trafficking and progressive neurological symptoms. Miglustat slowed disease progression in a 12-month randomized trial in juveniles and adults with Niemann-Pick disease type C, and in a parallel, noncontrolled study in affected children. Here, the authors report the open-label extension to the pediatric study. Patients aged 4 to 12 years received open-label miglustat (dose adjusted for body surface area) for an initial 12 months, during a further 12-month extension, and a long-term, continued extension phase. Efficacy assessments included horizontal saccadic eye movement, swallowing, and ambulation. Ten children completed 24 months’ treatment. Horizontal saccadic eye movement, ambulation, and swallowing were stabilized at 24 months. Analysis of key parameters of disease progression showed disease stability in 8 of 10 patients (80%). Miglustat stabilized neurological disease progression in pediatric patients with Niemann-Pick disease type C, with comparable safety and tolerability to that observed in adults and juveniles.

Abstract Background: The next-generation, high-sensitivity cardiac troponin assays can measure quantifiable concentrations of cTn in a majority of individuals, but there are few studies assessing these assays for risk stratification. The present study was undertaken to determine if a research hs-cTnI assay can be useful for predicting death/myocardial infarction (MI), both short- and long-term, in an emergency department acute coronary syndrome (ACS) population. Methods: In a cohort of 383 subjects, originally recruited in 1996, presenting to the emergency department with symptoms suggestive of ACS, the heparin plasma obtained at initial presentation was thawed and measured in 2007 with a research hs-cTnI assay. AccuTnI (Beckman Coulter) measurements were made on these same samples in 2003. The population was divided into 4 groups by hs-cTnI: &lt;5.00, 5.00–9.99, 10.00–40.00, and &gt;40.00 ng/L. Kaplan–Meier, Cox proportional hazards, ROC curves, and logistic regression analyses were used to identify which hs-cTnI concentrations were predictive of death/MI within 10 years after presentation. Results: There were significant differences between the hs-cTnI groups for the probability of death/MI up to 10 years after presentation (P &lt; 0.05). At 6 months, patients with hs-cTnI ≥10.00 ng/L were at higher risk for death/MI (hazard ratio &gt;3.7; P &lt; 0.05) compared with those having hs-cTnI &lt;5.00 ng/L. ROC curve analysis for death/MI at 30 days with the hs-cTnI assay had an area under the curve of 0.74 (95% CI 0.65–0.82), with logistic models yielding an optimal assay threshold of 12.68 ng/L. Conclusions: This research hs-cTnI assay appears useful for risk stratification for death/MI in an ACS population.

The purpose of this study was to assess tendon metabolism and suture pull-out strength after simple tendon suture in a tissue culture model. One hundred and twelve flexor digitorum profundus tendons from 28 dogs were cultured for 7, 14, or 21 days with or without a static tensile load. In both groups increased levels of matrix metalloproteinase (MMP) mRNA was noted. Suture pull-out strength did not decrease during tissue culture. While the presence of a static load had no effect on the pull-out strength, it did affect MMP mRNA expression. This tissue culture model could be useful in studying the effect of factors on the tendon-suture interface.

Pregnancy-associated plasma protein A (PAPPA) is a metalloproteinase that controls the tissue availability of insulin-like growth factor (IGF). Homozygous deletion of PAPPA in mice leads to lifespan extension. Since immune function is an important determinant of individual fitness, we examined the natural immune ecology of PAPPA −/− mice and their wild-type littermates reared under specific pathogen-free condition with aging. Whereas wild-type mice exhibit classic age-dependent thymic atrophy, 18-month-old PAPPA −/− mice maintain discrete thymic cortex and medulla densely populated by CD4 + CD8 + thymocytes that are capable of differentiating into single-positive CD4 and CD8 T cells. Old PAPPA −/− mice have high levels of T cell receptor excision circles, and have bone marrows enriched for subsets of thymus-seeding progenitors. PAPPA −/− mice have an overall larger pool of naive T cells, and also exhibit an age-dependent accumulation of CD44 + CD43 + memory T cells similar to wild-type mice. However, CD43 + T cell subsets of old PAPPA −/− mice have significantly lower prevalence of 1B11 and S7, glycosylation isoforms known to inhibit T cell activation with normal aging. In bioassays of cell activation, splenic T cells of old PAPPA −/− mice have high levels of activation antigens and cytokine production, and also elicit Ig production by autologous B cells at levels equivalent to young wild-type mice. These data suggest an IGF-immune axis of healthy longevity. Controlling the availability of IGF in the thymus by targeted manipulation of PAPPA could be a way to maintain immune homeostasis during postnatal development and aging.