MYCBP2 Is a Guanosine Exchange Factor for Ran Protein and Determines Its Localization in Neurons of Dorsal Root Ganglia.

The small GTPase Ran coordinates retrograde axonal transport in neurons, spindle assembly during mitosis, and the nucleo-cytoplasmic transport of mRNA. Its localization is tightly regulated by the GTPase-activating protein RanGAP1 and the nuclear guanosine exchange factor (GEF) RCC1. We show that loss of the neuronal E3 ubiquitin ligase MYCBP2 caused the up-regulation of Ran and RanGAP1 in dorsal root ganglia (DRG) under basal conditions and during inflammatory hyperalgesia. SUMOylated RanGAP1 physically interacted with MYCBP2 and inhibited its E3 ubiquitin ligase activity. Stimulation of neurons induced a RanGAP1-dependent translocation of MYCBP2 to the nucleus. In the nucleus of DRG neurons MYCBP2 co-localized with Ran and facilitated through its RCC1-like domain the GDP/GTP exchange of Ran. In accordance with the necessity of a GEF to promote GTP-binding and nuclear export of Ran, the nuclear localization of Ran was strongly increased in MYCBP2-deficient DRGs. The finding that other GEFs for Ran besides RCC1 exist gives new insights in the complexity of the regulation of the Ran signaling pathway.

Neighborhood composition and cancer among Hispanics: tumor stage and size at time of diagnosis.

BACKGROUND: We have previously reported that cancer incidence for lung, female breast, and colon and rectum for Hispanics decreases with increasing percentage of Hispanics at the census tract. In contrast, cervical cancer incidence increases with increasing percentage of Hispanics at the census tract. METHODS: In this study, we investigate the hypothesis that Hispanics living in census tracts with high percentages of Hispanics are diagnosed with more advanced cancer, with respect to tumor size and stage of diagnosis. Data from the Surveillance, Epidemiology, and End Results registry and the U.S. Census Bureau were used to estimate the odds of diagnosis at a "late" stage (II, III, IV) versus "early" stage (I) and breast cancer tumor size among Hispanics as a function of census tract percent Hispanic. Hispanic ethnicity in the Surveillance, Epidemiology, and End Results registry was identified by medical record review and Hispanic surname lists. The study also used income of Hispanics living in the census tract and controlled for age at diagnosis and gender. RESULTS: We found that Hispanics living in neighborhoods with higher density of Hispanic populations were more likely to be diagnosed with late-stage breast, cervical, or colorectal cancer, and to have a larger tumor size of breast cancer. CONCLUSIONS: Our findings suggest that the benefits of lower cancer incidence in high tract percent Hispanics are partially offset by poorer access and reduced use of screening in conjunction with lower income, poorer health insurance coverage, and language barriers typical of these communities.

Cardiac morbidity of adjuvant radiotherapy for breast cancer.

PURPOSE: Adjuvant breast irradiation has been associated with an increase in cardiac mortality, because left-sided breast radiation can produce cardiac damage. The purpose of this study was to determine whether modern adjuvant radiotherapy is associated with increased risk of cardiac morbidity. PATIENTS AND METHODS: Data from the Surveillance, Epidemiology, and End Results-Medicare database were used for women who were diagnosed with nonmetastatic breast cancer from 1986 to 1993, had known disease laterality, underwent breast surgery, and received adjuvant radiotherapy. The Cox proportional-hazards model was used to compare patients with left- versus right-sided breast cancer for the end points of hospitalization with the following discharge diagnoses (International Classification of Diseases, 9th Revision codes): ischemic heart disease (410-414, 36.0, and 36.1), valvular heart disease (394-397, 424, 35), congestive heart failure (428, 402.01, 402.11, 402.91, and 425), and conduction abnormalities (426, 427, 37.7-37.8, and 37.94-37.99). RESULTS: Eight thousand three hundred sixty-three patients had left-sided breast cancer, and 7,907 had right-sided breast cancer. Mean follow-up was 9.5 years (range, 0 to 15 years). There were no significant differences in patients with left- versus right-sided cancers for hospitalization for ischemic heart disease (9.9% v 9.7%), valvular heart disease (2.9% v 2.8%), conduction abnormalities (9.7% v 9.6%), or heart failure (9.7% v 9.7%). The adjusted hazard ratio for left- versus right-sided breast cancer was 1.05 (95% CI, 0.94 to 1.16) for ischemic heart disease, 1.07 (95% CI, 0.89 to 1.30) for valvular heart disease, 1.07 (95% CI, 0.96 to 1.19) for conduction abnormalities, and 1.05 (95% CI, 0.95 to 1.17) for heart failure. CONCLUSION: With up to 15 years of follow-up there were no significant differences in cardiac morbidity after radiation for left- versus right-sided breast cancer.

Nuclear factor-κB is involved in oxyhemoglobin-induced endothelin-1 expression in cerebrovascular muscle cells of the rabbit basilar artery.

The present research was designed to investigate whether endothelin-1 (ET-1) secretion can be induced by oxyhemoglobin and whether nuclear factor κB (NF-κB) is involved in the regulation of ET-1 transcription in cerebrovascular muscle cells. Cerebrovascular muscle cells isolated from a rabbit basilar artery were stimulated by oxyhemoglobin (OxyHb) and ET-1 production was increased significantly in the supernatant. Inhibition of NF-κB with pyrrolidine dithiocarbamate and small interfering RNA decreased the expression of ET-1. Nuclear translocation of NF-κB and the degradation of IkB-α was observed with the stimulation of OxyHb. The supernatant obtained from cerebrovascular muscle cells stimulated by OxyHb produced contractions in arterial rings and was blocked by the ET-1 receptor antagonist (BQ-123). The time course of the OxyHb-induced contractions of the basilar artery rings correlated with the time course of the OxyHb-induced ET-1 secretion. The contraction of the basilar artery rings induced by OxyHb was attenuated when the artery rings were preincubated with pyrrolidine dithiocarbamate and SN50 (20 and 10 µM, respectively). These results indicate that cerebrovascular muscle cells may be an important source of ET-1 production after subarachnoid hemorrhage. NF-κB was involved in the expression of ET-1 and the inhibition of the NF-κB pathway may be beneficial for the treatment of cerebral vasospasm.

Effect of depression on diagnosis, treatment, and survival of older women with breast cancer.

OBJECTIVES: To assess the effect of a prior diagnosis of depression on the diagnosis, treatment, and survival of older women with breast cancer. DESIGN: Retrospective analysis of records from Surveillance, Epidemiology and End Results (SEER) and Medicare claims. SETTING: Registries from seven major cities and five states. PARTICIPANTS: A total of 24,696 women aged 67 to 90 diagnosed with breast cancer between 1993 and 1996 and included in the SEER Medicare linked database were studied. MEASUREMENTS: Information on patient demographics, tumor characteristics, treatment received, and survival were obtained from SEER, and the Medicare inpatient and professional charges for the 2 years before diagnosis were searched for a diagnosis of depression. RESULTS: A total of 1,841 of the 24,696 women (7.5%) had been given a diagnosis of depression sometime in the 2 years before the diagnosis of breast cancer. There was no difference in tumor size or stage at diagnosis between depressed and nondepressed women. Women diagnosed with depression were less likely to receive treatment generally considered definitive (59.7% vs 66.2%, P<.0001), and this difference remained after controlling for age, ethnicity, comorbidity, and SEER site. Also, women with a prior diagnosis of depression had a higher risk of death (hazard ratio=1.42; 95% confidence interval= 1.13-1.79) after controlling for other factors that might affect survival. The higher risk of death associated with a prior diagnosis of depression was also seen in analyses restricted to women who received definitive treatment. CONCLUSION: Women with a recent diagnosis of depression are at greater risk for receiving nondefinitive treatment and experience worse survival after a diagnosis of breast cancer, but differences in treatment do not explain the worse survival.

Hospice use by Hispanic and non-Hispanic white cancer decedents.

OBJECTIVE: To investigate rates of hospice use between Hispanic and non-Hispanic white Medicare beneficiaries diagnosed with cancer using data from a large, population-based study. DATA SOURCES: Secondary data from the linked SEER-Medicare database including the SEER areas of Los Angeles, San Francisco, and San Jose-Monterey, California, and the state of New Mexico. All subjects were Hispanic or non-Hispanic whites, aged 67 and older, had a cancer diagnosis of breast, colorectal, lung, or prostate cancer from 1991-1996, and died of cancer from 1991-1998. STUDY DESIGN: This study employed a retrospective cohort design to compare rates of hospice use between Hispanics and non-Hispanic whites across patient characteristics and over time. PRINCIPAL FINDINGS: Rates of hospice use were similar for Hispanics (39.2 percent) and non-Hispanic whites (41.5 percent). In a bivariate logistic regression model, Hispanics were significantly less likely to use hospice than non-Hispanic whites (OR 0.91; 95 percent CI 0.85-0.97). However, after adjusting for age, marital status, sex, educational attainment, income, urban versus rural residence, and type of insurance using multivariate logistic regression analysis, the estimated odds for being a hospice user among Hispanics is similar to the odds of being a hospice user among non-Hispanic whites (OR 1.05; 95 percent CI 0.98-1.13). Stratified analyses revealed significant differences between ethnic groups in the use of hospice by type of insurance and SEER area, indicating interactions between ethnicity and these variables. CONCLUSIONS: Our findings indicate similar rates of hospice use for Hispanics and non-Hispanic whites diagnosed with one of the four leading cancers. Additional studies from other national registries may be necessary to confirm these findings.

The effect of postoperative beam, implant, and combination radiation therapy on GI and bladder toxicities in female Medicare beneficiaries with stage I uterine cancer.

OBJECTIVE: Determine the risk of late gastrointestinal (GI) and bladder toxicities in women treated for Stage I uterine cancer with postoperative beam, implant, or combination radiation. METHODS: The Surveillance, Epidemiology, and End Results (SEER) tumor registry and Medicare claims were used to estimate the risk of developing late GI and bladder toxicities by type of radiation received. Bladder and GI diagnoses were identified 6-60 months after cancer diagnosis. Cox-proportional hazard models were used to estimate risk of any late GI or bladder toxicity due to type of radiation received. RESULTS: A total of 3,024 women with uterine cancer diagnosed from 1992-2005 were identified for analysis with a mean age of 73.9 (Standard Deviation (SD) ± 6.5). Bladder and GI toxicities occurred most frequently in the combination group, and least in the implant group. After controlling for demographic characteristics, tumor grade, diagnosis year, SEER region, comorbidities, prior GI and bladder diagnosis, and chemotherapy, women receiving implant radiation had a 21% absolute decrease in GI toxicities compared to women receiving combination radiation (Hazard Ratio (HR) 0.79, 95% confidence interval (CI) 0.68-0.92). No differences were observed between those receiving beam and combination in GI (HR 1.01 (0.89-1.14)) and bladder (HR 0.95 (0.80-1.11)) toxicities. CONCLUSIONS: Older women receiving combined radiation had the highest rates of GI and bladder toxicities, while women receiving implant radiation alone had the lowest rates. When selecting type of radiation for a patient, these toxicities should be considered. Counseling older women surviving cancer on late toxicities due to radiation must be a priority for physicians caring for them.

Socioeconomic status and chemotherapy use for melanoma in older people.

The study objective was to examine the association, among older persons with cutaneous melanoma, between areal socioeconomic status (SES) and receiving chemotherapy. SEER-Medicare-linked database (1,239 white men and women aged ≥ 66, with invasive melanoma [regional and distant stages]; 1991-1999) was used. SES was measured by census tract poverty level (average of 1990 and 2000 Census data). Covariates were sociodemographics, tumor characteristics, and comorbidity index. Residing in poorer SES areas was associated with a lower likelihood for receiving chemotherapy among patients in the overall sample (adjusted odds ratios = OR 0.97, 95% confidence interval = CI 0.95-0.99), and those with regional stage at diagnosis (OR 0.97, 95% CI 0.94-0.98). These findings reflect socioeconomic disparities in chemotherapy use for melanoma among older white patients in the United States.

Risk of continued institutionalization after hospitalization in older adults.

BACKGROUND: Little is known about the role of hospitalization as a risk factor for placement into long-term care. We therefore sought to estimate the percentage of long-term care nursing home stays precipitated by a hospitalization and factors associated with risk of nursing home placement after hospitalization. METHODS: We studied a retrospective cohort of a 5% sample of Medicare enrollees aged ≥ 66 years. The study included 762,243 patients admitted 1,149,568 times in January-April of 1996-2008, with 3,880,292 nonhospitalized controls. We measured residence in a nursing home 6 months after hospitalization. RESULTS: From 1996 through 2008, 5.55% of hospitalized patients resided in a nursing home 6 months later compared with 0.54% of nonhospitalized control patients. Three quarters of new nursing home placements were precipitated by a hospitalization. Independent risk factors for long-term care placement after hospitalization included advanced age (odds ratio [OR] = 3.56 for age 85-94 vs. 66-74 years), female gender (OR = 1.41), dementia (OR = 6.15), and discharge from the hospital to a skilled nursing facility (SNF; OR = 10.83). Having a primary care physician was associated with reduced odds (OR = 0.75). In the adjusted analyses, risk of institutionalization after hospitalization decreased 4% per year from 1996 to 2008. There were very large geographic variations in rates of long-term care after hospitalization, from < 2% in some hospital referral regions to > 13% in others for patients > 75 years in 2007-2008. CONCLUSIONS: Most placements in nursing homes are preceded by a hospitalization followed by discharge to a SNF. Discharge to a SNF is associated with a high risk of subsequent long-term care.

Outpatient follow-up visit and 30-day emergency department visit and readmission in patients hospitalized for chronic obstructive pulmonary disease.

BACKGROUND: Readmissions in patients with chronic obstructive pulmonary disease (COPD) are common and costly. We examined the effect of early follow-up visit with patient's primary care physician (PCP) or pulmonologist following acute hospitalization on the 30-day risk of an emergency department (ER) visit and readmission. METHODS: We conducted a retrospective cohort study of fee-for-service Medicare beneficiaries with an identifiable PCP who were hospitalized for COPD between 1996 and 2006. Three or more visits to a PCP in the year prior to the hospitalization established a PCP for a patient. We performed a Cox proportional hazard regression with time-dependent covariates to determine the risk of 30-day ER visit and readmission in patients with or without a follow-up visit to their PCP or pulmonologist. RESULTS: Of the 62 746 patients admitted for COPD, 66.9% had a follow-up visit with their PCP or pulmonologist within 30 days of discharge. Factors associated with lower likelihood of outpatient follow-up visit were longer length of hospital stay, prior hospitalization for COPD, older age, black race, lower socioeconomic status, and emergency admission. Those receiving care at nonteaching, for-profit, and smaller-sized hospitals were more likely to have a follow-up visit. In a multivariate, time-dependent analysis, patients who had a follow-up visit had a significantly reduced risk of an ER visit (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.83-0.90) and readmission (HR, 0.91; 95% CI, 0.87-0.96). CONCLUSION: Continuity with patient's PCP or pulmonologist after an acute hospitalization may lower rates of ER visits and readmission in patients with COPD.

Comanagement of hospitalized surgical patients by medicine physicians in the United States.

BACKGROUND: Comanagement of surgical patients by medicine physicians (generalist physicians or internal medicine subspecialists) has been shown to improve efficiency and to reduce adverse outcomes. We examined the extent to which comanagement is used during hospitalizations for common surgical procedures in the United States. METHODS: We conducted a retrospective cohort study of Medicare fee-for-service beneficiaries hospitalized for 1 of 15 inpatient surgical procedures from 1996 to 2006 (n = 694 806). We also calculated the proportion of Medicare beneficiaries comanaged by medicine physicians (generalist physicians or internal medicine subspecialists) during hospitalization. Comanagement was defined by relevant physicians (generalist or internal medicine subspecialist) submitting a claim for evaluation and management services on 70% or more of the days that the patients were hospitalized. RESULTS: Between 1996 and 2006, 35.2% of patients hospitalized for a common surgical procedure were comanaged by a medicine physician: 23.7% by a generalist physician and 14% by an internal medicine subspecialist (2.5% were comanaged by both). The percentage of patients experiencing comanagement was relatively unchanged from 1996 to 2000 and then increased sharply. The increase was entirely attributable to a surge in comanagement by generalist physicians. In a multivariable multilevel analysis, comanagement by generalist physicians increased 11.4% per year from 2001 to 2006. Patients with advanced age, with more comorbidities, or receiving care in nonteaching, midsize (200-499 beds), or for-profit hospitals were more likely to receive comanagement. All of the growth in comanagement was attributed to increased comanagement by hospitalist physicians. CONCLUSIONS: Medical comanagement of Medicare beneficiaries hospitalized for a surgical procedure is increasing because of the increasing role of hospitalists. To meet this growing need for comanagement, training in internal medicine should include medical management of surgical patients.

Risk of subsequent dementia diagnoses does not vary by types of adjuvant chemotherapy in older women with breast cancer.

OBJECTIVE: Little is known about long-term cognitive side effects of adjuvant chemotherapy for breast cancer. We thus examined incidence of dementia diagnoses in older women diagnosed with breast cancer, stratified by types of chemotherapy regimen. METHODS: We identified patients with incident dementia diagnoses through Medicare claims linked to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) tumor registry data. The study population (n = 6,932) consisted of women at least 68 years of age, who were diagnosed with early-stage breast cancer from 1994 through 2002 in one of the SEER areas and received chemotherapy as part of their cancer treatment. Excluded were women with a diagnosis of dementia within the 3 years prior to their cancer diagnosis. RESULTS: Our sample comprised mostly white women. The mean age was 74. Fifty-seven percent were estrogen receptor positive. Over 70% had no comorbidity. The use of taxol and anthracycline-based treatments increased from mid-1990s to early 2000. Increasing age at cancer diagnosis, Black ethnicity, living in a census tract with lower level of education, and increasing number of comorbidities were associated with new claims of dementia diagnoses after chemotherapy. There was no significant association between types of chemotherapy agents and risk of subsequent dementia diagnoses. CONCLUSION: No association was found between types of adjuvant chemotherapy agents for breast cancer and risk of new dementia diagnoses. Our findings suggest that concerns about post-chemotherapy dementia should not be a major factor in determining type of adjuvant chemotherapy regimen to prescribe for older women with breast cancer.

Discharge setting for patients with hip fracture: trends from 2001 to 2005.

OBJECTIVES: To examine recent trends in discharge disposition after hospitalization for hip fracture. DESIGN: Retrospective observational study using data from the 5% random sample of Medicare claims data from 2001 to 2005 that the Centers for Medicare and Medicaid Services makes available for research purposes. SETTING: Inpatient medical rehabilitation pre- and postimplementation of prospective payment (2001-2005). PARTICIPANTS: Forty-four thousand six hundred eighty-four Medicare patients. MEASURES: Postacute discharge setting (home, inpatient rehabilitation, skilled nursing facility, and long-term care nursing home/hospital/hospice). RESULTS: Bivariate analyses showed that discharge from acute care to inpatient rehabilitation increased from 12.2% in 2001 to 23.9% in 2005. The odds of discharge to inpatient medical rehabilitation were 2.26 (95% confidence interval=2.09-2.45) greater in 2005 than in 2001 after adjustment for patient characteristics (age, sex, and race or ethnicity), admitting diagnoses, type of treatment (internal fixation vs arthroplasty), and length of stay. CONCLUSION: The move from fee for service to prospective payment for postacute services for persons with hip fracture was associated with greater use of inpatient medical rehabilitation. Further research is necessary to confirm the trend in discharge setting and determine whether it is related to changes in reimbursement for postacute care.

The role of the surgeon in whether patients with lymph node-positive colon cancer see a medical oncologist.

BACKGROUND: Chemotherapy improves survival for patients with stage III colon cancer, but some older patients with lymph node-positive colon cancer do not see a medical oncologist and, thus, do not receive adjuvant chemotherapy. METHODS: To evaluate the role of the surgeon in determining referrals to medical oncology among patients with stage III colon cancer, the authors conducted a retrospective cohort study of 6158 patients aged >or=66 years who were diagnosed with stage III colon cancer from 1992 through 1999 by using the Surveillance, Epidemiology, and End Results-Medicare linked database. Multilevel analysis was used to simultaneously model variations in patients' seeing a medical oncologist at the patient and surgeon levels. RESULTS: Twenty-one percent of the total variance in seeing a medical oncologist was attributable to the surgeon after adjusting for available patient, tumor, and surgeon characteristics. The individual surgeon characteristics that significantly predicted whether the patient saw a medical oncologist were year since graduation (20 years; hazard ratio [HR], 1.60; 95% confidence interval [95% CI], 1.19-2.16), practicing in a teaching hospital (yes vs. no: HR; 1.30; 95% CI, 1.07-1.58), and volume of patients with colon cancer (<30 patients vs >or=121 patients; HR, 0.66; 95% CI, 0.46-0.94). Surgeon sex, race, board certification, and type of practice were not independent predictors of medical oncology referral. CONCLUSIONS: Surgeons accounted for approximately 20% of the variation in patients seeing a medical oncologist. Interventions at the level of the surgeon may be appropriate to improve the care of patients with colon cancer.

The relationship between depressive symptoms and shoulder mobility among older women: assessment at one year after breast cancer diagnosis.

OBJECTIVE: To examine the association between depressive symptoms and shoulder range of motion at one year after breast cancer diagnosis, controlling for patient characteristics, tumour stage and cancer therapy (surgery, axillary node dissection and radiation). DESIGN: Prospective trial of nurse case management involving 187 older women with complete data, age 60 years and older, newly diagnosed with breast cancer, from 1 November, 1993 to 31 October, 1996 in south-eastern Texas. Depressive symptoms, sociodemographic characteristics and breast cancer treatment were measured at two months and shoulder range of motion at 12 months. The relationship among the variables was evaluated with bivariate chi-square statistics and logistic regression analysis. All logistic models also included a variable indicating whether or not the woman received nurse case management, to control for intervention status. RESULTS: Increasing depressive symptoms at baseline were associated with lower arm mobility at 12 months following breast cancer diagnosis. Each unit increase in depressive symptoms at baseline was associated with an 8% decreased odds of having full range of motion of the shoulder (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.87, 0.97), after controlling for relevant patient and treatment factors. CONCLUSION(S): Older women with depressive symptoms have an elevated risk of not fully recovering shoulder mobility after being treated for breast cancer. Future studies are needed to assess benefits from early intervention with psychological and or physical interventions in the presence of depressive symptoms on shoulder mobility.

A non-parametric method for the comparison of partial areas under ROC curves and its application to large health care data sets.

The receiver operating characteristic (ROC) curve is a statistical tool for evaluating the accuracy of diagnostic tests. Investigators often compare the validity of two tests based on the estimated areas under the respective ROC curves. However, the traditional way of comparing entire areas under two ROC curves is not sensitive when two ROC curves cross each other. Also, there are some cutpoints on the ROC curves that are not considered in practice because their corresponding sensitivities or specificities are unacceptable. For the purpose of comparing the partial area under the curve (AUC) within a specific range of specificity for two correlated ROC curves, a non-parametric method based on Mann-Whitney U-statistics has been developed. The estimation of AUC along with its estimated variance and covariance is simplified by a method of grouping the observations according to their cutpoint values. The method is used to evaluate alternative logistic regression models that predict whether a subject has incident breast cancer based on information in Medicare claims data.