FMRpolyG accumulates in FMR1 premutation granulosa cells.

BACKGROUND: Fragile X premutation (Amplification of CGG number 55-200) is associated with increased risk for fragile X-Associated Premature Ovarian Insufficiency (FXPOI) in females and fragile X-associated tremor/ataxia syndrome (FXTAS) predominantly in males. Recently, it has been shown that CGG repeats trigger repeat associated non-AUG initiated translation (RAN) of a cryptic polyglycine-containing protein, FMRpolyG. This protein accumulates in ubiquitin-positive inclusions in neuronal brain cells of FXTAS patients and may lead to protein-mediated neurodegeneration. FMRpolyG inclusions were also found in ovary stromal cells of a FXPOI patient. The role of FMRpolyG expression has not been thoroughly examined in folliculogenesis related cells. The main goal of this study is to evaluate whether FMRpolyG accumulates in mural granulosa cells of FMR1 premutation carriers. Following FMRpolyG detection, we aim to examine premutation transfected COV434 as a suitable model used to identify RAN translation functions in FXPOI pathogenesis. RESULTS: FMRpolyG and ubiquitin immunostained mural granulosa cells from six FMR1 premutation carriers demonstrated FMRpolyG aggregates. However, co-localization of FMRpolyG and ubiquitin appeared to vary within the FMR1 premutation carriers' group as three exhibited partial ubiquitin and FMRpolyG double staining and three premutation carriers demonstrated FMRpolyG single staining. None of the granulosa cells from the five control women expressed FMRpolyG. Additionally, human ovarian granulosa tumor, COV434, were transfected with two plasmids; both expressing 99CGG repeats but only one enables FMRpolyG expression. Like in granulosa cells from FMR1 premutation carriers, FMRpolyG aggregates were found only in COV434 transfected with expended CGG repeats and the ability to express FMRpolyG. CONCLUSIONS: Corresponding with previous studies in FXTAS, we demonstrated accumulation of FMRpolyG in mural granulosa cells of FMR1 premutation carriers. We also suggest that following further investigation, the premutation transfected COV434 might be an appropriate model for RAN translation studies. Detecting FMRpolyG accumulation in folliculogenesis related cells supports previous observations and imply a possible common protein-mediated toxic mechanism for both FXPOI and FXTAS.

Whole brain radiotherapy after stereotactic radiosurgery or surgical resection among patients with one to three brain metastases and favorable prognoses: a secondary analysis of EORTC 22952-26001.

BACKGROUND: The absence of a survival benefit for whole brain radiotherapy (WBRT) among randomized trials has been attributed to a competing risk of death from extracranial disease. We re-analyzed EORTC 22952 to assess the impact of WBRT on survival for patients with controlled extracranial disease or favorable prognoses. PATIENTS AND METHODS: We utilized Cox regression, landmark analysis, and the Kaplan-Meier method to evaluate the impact of WBRT on survival accounting for (i) extracranial progression as a time-dependent covariate in all patients and (ii) diagnosis-specific graded prognostic assessment (GPA) score in patients with primary non-small-cell lung cancer (NSCLC). RESULTS: A total of 329 patients treated per-protocol were included for analysis with a median follow up of 26 months. One hundred and fifteen (35%) patients had no extracranial progression; 70 (21%) patients had progression <90 days, 65 (20%) between 90 and 180 days, and 79 (24%) patients >180 days from randomization. There was no difference in the model-based risk of death in the WBRT group before [hazard ratio (HR) (95% CI)=0.70 (0.45-1.11), P = 0.133), or after [HR (95% CI)=1.20 (0.89-1.61), P = 0.214] extracranial progression. Among 177 patients with NSCLC, 175 had data available for GPA calculation. There was no significant survival benefit to WBRT among NSCLC patients with favorable GPA scores [HR (95% CI)=1.10 (0.68-1.79)] or unfavorable GPA scores [HR (95% CI)=1.11 (0.71-1.76)]. CONCLUSIONS: Among patients with limited extracranial disease and one to three brain metastases at enrollment, we found no significant survival benefit to WBRT among NSCLC patients with favorable GPA scores or patients with any histology and controlled extracranial disease status. This exploratory analysis of phase III data supports the practice of omitting WBRT for patients with limited brain metastases undergoing SRS and close surveillance. CLINICAL TRIALS NUMBER: NCT00002899.

Medical androgen deprivation therapy and increased non-cancer mortality in non-metastatic prostate cancer patients aged ≥66 years.

PURPOSE: To examine the potential relationship between androgen deprivation therapy and other-cause mortality (OCM) in patients with prostate cancer treated with medical primary-androgen deprivation therapy, prostatectomy, or radiation. METHODS: A total of 137,524 patients with non-metastatic PCa treated between 1995 and 2009 within the Surveillance Epidemiology and End Results Medicare-linked database were included. Cox-regression analysis tested the association of ADT with OCM. A 40-item comorbidity score was used for adjustment. RESULTS: Overall, 9.3% of patients harbored stage III-IV disease, and 57.7% of patients received ADT. The mean duration of ADT exposure was 22.9 months (median: 9.1; IQR: 2.8-31.5). Mean and median follow-up were 66.9, and 60.4 months, respectively. At 10 years, overall-OCM rate was 36.5%; it was 30.6% in patients treated without ADT vs. 40.1% in patients treated with ADT (p < 0.001). In multivariable-analysis, ADT was associated with an increased risk of OCM (Hazard-ratio [HR]: 1.11, 95% Confidence-interval [95% CI]: 1.08-1.13). Patients with no comorbidity (10-year OCM excess risk: 9%) were more subject to harm from ADT than patients with high comorbidity (10-year OCM excess risk: 4.7%). CONCLUSIONS: In patients with PCa, treatment with medical ADT may increase the risk of mortality due to causes other than PCa. Whether this is a simple association or a cause-effect relationship is unknown and warrants further study in prospective studies.

Incidence and determinants of 1-month mortality after cancer-directed surgery.

BACKGROUND: Death within 1 month of surgery is considered treatment related and serves as an important health care quality metric. We sought to identify the incidence of and factors associated with 1-month mortality after cancer-directed surgery. PATIENTS AND METHODS: We used the Surveillance, Epidemiology and End Results Program to study a cohort of 1 110 236 patients diagnosed from 2004 to 2011 with cancers that are among the 10 most common or most fatal who received cancer-directed surgery. Multivariable logistic regression analyses were used to identify factors associated with 1-month mortality after cancer-directed surgery. RESULTS: A total of 53 498 patients (4.8%) died within 1 month of cancer-directed surgery. Patients who were married, insured, or who had a top 50th percentile income or educational status had lower odds of 1-month mortality from cancer-directed surgery {[adjusted odds ratio (AOR) 0.80; 95% confidence interval (CI) 0.79-0.82; P < 0.001], (AOR 0.88; 95% CI 0.82-0.94; P < 0.001), (AOR 0.95; 95% CI 0.93-0.97; P < 0.001), and (AOR 0.98; 95% CI 0.96-0.99; P = 0.043), respectively}. Patients who were non-white minority, male, or older (per year increase), or who had advanced tumor stage 4 disease all had a higher risk of 1-month mortality after cancer-directed surgery, with AORs of 1.13 (95% CI 1.11-1.15), P < 0.001; 1.11 (95% CI 1.08-1.13), P < 0.001; 1.02 (95% 1.02-1.03), P < 0.001; and 1.89 (95% CI 1.82-1.95), P < 0.001 respectively. CONCLUSIONS: Unmarried, uninsured, non-white, male, older, less educated, and poorer patients were all at a significantly higher risk for death within 1 month of cancer-directed surgery. Efforts to reduce 1-month surgical mortality and eliminate sociodemographic disparities in this adverse outcome could significantly improve survival among patients with cancer.

The association between insurance status and prostate cancer outcomes: implications for the Affordable Care Act.

BACKGROUND: The Affordable Care Act (ACA) aims to expand health insurance coverage to over 30 million previously uninsured Americans. To help evaluate the potential impact of the ACA on prostate cancer care, we examined the associations between insurance coverage and prostate cancer outcomes among men <65 years old who are not yet eligible for Medicare. METHODS: The Surveillance, Epidemiology and End Results Program was used to identify 85 203 men aged <65 years diagnosed with prostate cancer from 2007 to 2010. Multivariable logistic regression modeled the association between insurance status and stage at presentation. Among men with high-risk disease, the associations between insurance status and receipt of definitive therapy, prostate cancer-specific mortality (PCSM) and all-cause mortality were determined using multivariable logistic, Fine and Gray competing-risks and Cox regression models, respectively. RESULTS: Uninsured patients were more likely to be non-white and come from regions of rural residence, lower median household income and lower education level (P<0.001 for all cases). Insured men were less likely to present with metastatic disease (adjusted odds ratio (AOR) 0.23; 95% confidence interval (CI) 0.20-0.27; P<0.001). Among men with high-risk disease, insured men were more likely to receive definitive treatment (AOR 2.29; 95% CI 1.81-2.89; P<0.001), and had decreased PCSM (adjusted hazard ratio 0.56; 95% CI 0.31-0.98; P=0.04) and all-cause mortality (adjusted hazard ratio 0.60; 0.39-0.91; P=0.01). CONCLUSIONS: Insured men with prostate cancer are less likely to present with metastatic disease, more likely to be treated if they develop high-risk disease and are more likely to survive their cancer, suggesting that expanding health coverage under the ACA may significantly improve outcomes for men with prostate cancer who are not yet eligible for Medicare.

Health insurance expansion through states in a pluralistic system.

The United States continues to stand almost alone among developed nations in its lack of universal health care coverage. In this essay, we argue that even though the debate over whether the federal government or states should lead the effort to expand health care coverage under the federal system is relevant in strategizing how to cover the uninsured; the more critical issues stem from the challenge of the mixed and fragmented mode of public-private financing of our pluralistic health care system. We base this argument on (1) an in-depth review of Oregon's and Tennessee's five years of experience with broad coverage reform in the context of the United States health care system and on (2) a more abbreviated review of other state experiences in providing health care coverage. We conclude from our review that when the will exists, states can substantially expand coverage. However, as one moves up the income scale, political support and resources are harder to come by. Further, concerns grow about the interface of public and private coverage, with issues of "crowd out" and other distributional questions dominating the discussion of coverage expansion as policy makers focus less on how to cover people than on how to make sure one kind of coverage doesn't preempt another. Concern for crowd out can then lead to policies that keep out some of the very people policy makers may want to cover. In this context the question whether states or the federal government is more likely to succeed in expanding coverage is eclipsed by the more fundamental challenges raised by pluralism. Neither federal nor state government is likely to be fully successful without first identifying ways of better coordinating public and private activities and resources to provide continuous and affordable coverage.

Growing an industry: how managed is TennCare's managed care?

In 1994 Tennessee moved virtually its entire Medicaid population and new eligibles into fully capitated managed care (TennCare). We analyze Tennessee's strategy, given limited existing managed care; and health plans' development of managed care infrastructure. We find signs of progress and developing infrastructure, but these are threatened by concerns over TennCare's financial viability and the state's commitment to TennCare's objectives. State policymakers seeking systems change need to recognize the substantial challenges and be committed to long-term investment.

Disabled Medicare beneficiaries in HMOs.

This study presents new data from a 1996 national survey of Medicare risk enrollees and disenrollees designed to profile access to care in Medicare health maintenance organizations (HMOs). The findings show that expanded benefits and low (or no) premiums are major features attracting disabled Medicare beneficiaries into Medicare HMOs. We found that most disabled persons enrolled in Medicare HMOs do not experience access problems. However, they are more likely than nondisabled Medicare HMO enrollees to experience such problems. We conclude by highlighting the importance of having information to monitor access to care for vulnerable subgroups such as disabled Medicare beneficiaries and to develop incentives to serve them well in Medicare HMOs.

The value and use of the Qualified Medicare Beneficiary Program: early evidence from Tennessee.

The Qualified Medicare Beneficiary (QMB) Program eliminated the out-of-pocket costs of obtaining health care services under the Medicare program for some low-income beneficiaries who were previously ineligible for Medicaid. The program is underused, and little is known about its effects. The article describes the QMB Program and compares program beneficiaries with others whose out-of-pocket payments are covered by Medicaid. Using Medicare claims data covering QMBs in Tennessee, we found that the program financed a relatively high rate of use of Medicare services and saved low-income Medicare beneficiaries hundreds of dollars per month in out-of-pocket costs. Social workers can promote the program and increase the use of its covered services appropriately, thereby by maximizing its potential benefits to low-income people.

Myocardial infarction resulting from caffeine overdose in an anorectic woman.

A 20-year-old bulimic woman ingested 20 g of caffeine in a suicide attempt. After being evaluated and discharged from the emergency department, she was readmitted with ECG changes and ultimately found to have sustained a subendocardial infarction. This case highlights the wide-ranging health consequences of eating disorders and the toxicity of caffeine overdose.