Development and Evaluation of a Machine Learning Model for the Early Identification of Patients at Risk for Sepsis.

STUDY OBJECTIVE: The Third International Consensus Definitions (Sepsis-3) Task Force recommended the use of the quick Sequential [Sepsis-related] Organ Failure Assessment (qSOFA) score to screen patients for sepsis outside of the ICU. However, subsequent studies raise concerns about the sensitivity of qSOFA as a screening tool. We aim to use machine learning to develop a new sepsis screening tool, the Risk of Sepsis (RoS) score, and compare it with a slate of benchmark sepsis-screening tools, including the Systemic Inflammatory Response Syndrome, Sequential Organ Failure Assessment (SOFA), qSOFA, Modified Early Warning Score, and National Early Warning Score. METHODS: We used retrospective electronic health record data from adult patients who presented to 49 urban community hospital emergency departments during a 22-month period (N=2,759,529). We used the Rhee clinical surveillance criteria as our standard definition of sepsis and as the primary target for developing our model. The data were randomly split into training and test cohorts to derive and then evaluate the model. A feature selection process was carried out in 3 stages: first, we reviewed existing models for sepsis screening; second, we consulted with local subject matter experts; and third, we used a supervised machine learning called gradient boosting. Key metrics of performance included alert rate, area under the receiver operating characteristic curve, sensitivity, specificity, and precision. Performance was assessed at 1, 3, 6, 12, and 24 hours after an index time. RESULTS: The RoS score was the most discriminant screening tool at all time thresholds (area under the receiver operating characteristic curve 0.93 to 0.97). Compared with the next most discriminant benchmark (Sequential Organ Failure Assessment), RoS was significantly more sensitive (67.7% versus 49.2% at 1 hour and 84.6% versus 80.4% at 24 hours) and precise (27.6% versus 12.2% at 1 hour and 28.8% versus 11.4% at 24 hours). The sensitivity of qSOFA was relatively low (3.7% at 1 hour and 23.5% at 24 hours). CONCLUSION: In this retrospective study, RoS was more timely and discriminant than benchmark screening tools, including those recommend by the Sepsis-3 Task Force. Further study is needed to validate the RoS score at independent sites.

Patient Reported Comparative Effectiveness of Contemporary Intensity Modulated Radiation Therapy Versus External Beam Radiation Therapy of the Mid 1990s for Localized Prostate Cancer.

INTRODUCTION: Little is known about differences in patient reported outcomes between contemporary external beam radiation therapy for localized prostate cancer that delivers higher doses of conformal radiation and older techniques. We examined sexual, urinary and bowel function between men undergoing contemporary intensity modulated radiation therapy vs those undergoing external beam radiation therapy in the mid 1990s. METHODS: Subjects were selected from 2 large population based prospective cohort studies. Main outcomes were between-group differences in adjusted mean scores at 6 and 12 months. Secondary analyses examined odds ratios comparing groups reporting a clinically significant decline in function. RESULTS: The cohort consisted of 943 men, 467 diagnosed in 2011 to 2012 and 476 diagnosed in 1994 to 1995. Men undergoing contemporary intensity modulated radiation therapy reported better bowel function at 6 months (mean difference 4.3 points, 95% CI 1.6-7.0) but not at 12 months. Patients receiving contemporary intensity modulated radiation therapy reported statistically worse but probably not clinically meaningful different urinary function at 12 months (2.7, 0.5 to 4.8 points), and no difference at 6 months. No differences in sexual function at 6 or 12 months were found. Secondary analyses demonstrated lower odds of reporting clinically meaningful declines in bowel function at 6 and 12 months and sexual function at 12 months for contemporary intensity modulated radiation therapy. However, patients receiving intensity modulated radiation therapy had higher odds of reporting clinically meaningful declines in urinary continence at 12 months. CONCLUSIONS: Despite the delivery of higher doses of radiation, men treated with contemporary intensity modulated radiation therapy reported fewer gastrointestinal and possibly fewer sexual side effects than those treated with external beam radiation therapy in the mid 1990s. However, delivery of dose escalated intensity modulated radiation therapy may cause more urinary side effects.

Variation in the Diagnostic Evaluation among Persons with Hematuria: Influence of Gender, Race and Risk Factors for Bladder Cancer.

PURPOSE: We sought to determine whether race, gender and number of bladder cancer risk factors are significant predictors of hematuria evaluation. MATERIALS AND METHODS: We used self-reported data from SCCS (Southern Community Cohort Study) linked to Medicare claims data. Evaluation of subjects diagnosed with incident hematuria was considered complete if imaging and cystoscopy were performed within 180 days of diagnosis. Exposures of interest were race, gender and risk factors for bladder cancer. RESULTS: Of the 1,412 patients evaluation was complete in 261 (18%). On our adjusted analyses African American patients were less likely than Caucasian patients to undergo any aspect of evaluation, including urology referral (OR 0.72, 95% CI 0.56-0.93), cystoscopy (OR 0.67, 95% CI 0.50-0.89) and imaging (OR 0.75, 95% CI 0.59-0.95). Women were less likely than men to be referred to a urologist (OR 0.59, 95% CI 0.46-0.76). Also, although all patients with 2 or 3 risk factors had 31% higher odds of urology referral (OR 1.31, 95% CI 1.02-1.69), adjusted analyses indicated that this effect was only apparent among men. CONCLUSIONS: Only 18% of patients with an incident hematuria diagnosis underwent complete hematuria evaluation. Gender had a substantial effect on referral to urology when controlling for socioeconomic factors but otherwise it had an unclear role on the quality of evaluation. African American patients had markedly lower rates of thorough evaluation than Caucasian patients. Number of risk factors predicted referral to urology among men but it was otherwise a poor predictor of evaluation. There is opportunity for improvement by increasing the completion of hematuria evaluations, particularly in patients at high risk and those who are vulnerable.

Association Between Radiation Therapy, Surgery, or Observation for Localized Prostate Cancer and Patient-Reported Outcomes After 3 Years.

Importance: Understanding the adverse effects of contemporary approaches to localized prostate cancer treatment could inform shared decision making. Objective: To compare functional outcomes and adverse effects associated with radical prostatectomy, external beam radiation therapy (EBRT), and active surveillance. Design, Setting, and Participants: Prospective, population-based, cohort study involving 2550 men (≤80 years) diagnosed in 2011-2012 with clinical stage cT1-2, localized prostate cancer, with prostate-specific antigen levels less than 50 ng/mL, and enrolled within 6 months of diagnosis. Exposures: Treatment with radical prostatectomy, EBRT, or active surveillance was ascertained within 1 year of diagnosis. Main Outcomes and Measures: Patient-reported function on the 26-item Expanded Prostate Cancer Index Composite (EPIC) 36 months after enrollment. Higher domain scores (range, 0-100) indicate better function. Minimum clinically important difference was defined as 10 to 12 points for sexual function, 6 for urinary incontinence, 5 for urinary irritative symptoms, 5 for bowel function, and 4 for hormonal function. Results: The cohort included 2550 men (mean age, 63.8 years; 74% white, 55% had intermediate- or high-risk disease), of whom 1523 (59.7%) underwent radical prostatectomy, 598 (23.5%) EBRT, and 429 (16.8%) active surveillance. Men in the EBRT group were older (mean age, 68.1 years vs 61.5 years, P < .001) and had worse baseline sexual function (mean score, 52.3 vs 65.2, P < .001) than men in the radical prostatectomy group. At 3 years, the adjusted mean sexual domain score for radical prostatectomy decreased more than for EBRT (mean difference, -11.9 points; 95% CI, -15.1 to -8.7). The decline in sexual domain scores between EBRT and active surveillance was not clinically significant (-4.3 points; 95% CI, -9.2 to 0.7). Radical prostatectomy was associated with worse urinary incontinence than EBRT (-18.0 points; 95% CI, -20.5 to -15.4) and active surveillance (-12.7 points; 95% CI, -16.0 to -9.3) but was associated with better urinary irritative symptoms than active surveillance (5.2 points; 95% CI, 3.2 to 7.2). No clinically significant differences for bowel or hormone function were noted beyond 12 months. No differences in health-related quality of life or disease-specific survival (3 deaths) were noted (99.7%-100%). Conclusions and Relevance: In this cohort of men with localized prostate cancer, radical prostatectomy was associated with a greater decrease in sexual function and urinary incontinence than either EBRT or active surveillance after 3 years and was associated with fewer urinary irritative symptoms than active surveillance; however, no meaningful differences existed in either bowel or hormonal function beyond 12 months or in in other domains of health-related quality-of-life measures. These findings may facilitate counseling regarding the comparative harms of contemporary treatments for prostate cancer.

The Influence of Psychosocial Constructs on the Adherence to Active Surveillance for Localized Prostate Cancer in a Prospective, Population-based Cohort.

OBJECTIVE: To evaluate the influence of psychosocial factors such as prostate cancer (PCa) anxiety, social support, participation in medical decision-making (PDM), and educational level on patient decisions to discontinue PCa active surveillance (AS) in the absence of disease progression. METHODS: The Comparative Effectiveness Analysis of Surgery and Radiation study is a prospective, population-based cohort study of men with localized PCa diagnosed in 2011-2012. PCa anxiety, social support, PDM, educational level, and patient reasons for discontinuing AS were assessed through patient surveys. A Cox proportional hazards model examined the relationship between psychosocial variables and time to discontinuation of AS. RESULTS: Of 531 patients on AS, 165 (30.9%) underwent treatment after median follow-up of 37 months. Whereas 69% of patients cited only medical reasons for discontinuing AS, 31% cited at least 1 personal reason, and 8% cited personal reasons only. Patients with some college education discontinued AS significantly earlier (hazard ratio: 2.0, 95% confidence interval: 1.2, 3.2) than patients with less education. PCa anxiety, social support, and PDM were not associated with seeking treatment. CONCLUSION: We found that 31% of men who choose AS for PCa discontinue AS within 3 years. Eight percent of men who sought treatment did so in the absence of disease progression. Education, but not psychosocial factors, seems to influence definitive treatment-seeking. Future research is needed to understand how factors unrelated to disease severity influence treatment decisions among patients on AS to identify opportunities to improve adherence to AS.

Racial Variation in Patient-Reported Outcomes Following Treatment for Localized Prostate Cancer: Results from the CEASAR Study.

BACKGROUND: Relatively little is known about the relationship between race/ethnicity and patient-reported outcomes after contemporary treatments for localized prostate cancer. OBJECTIVE: To test the hypothesis that treatment-related changes in urinary, bowel, sexual, and hormonal function vary by race/ethnicity. DESIGN, SETTING, AND PARTICIPANTS: The Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) study is a prospective, population-based, observational study that enrolled 3708 men diagnosed with localized prostate cancer in 2011-2012. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient-reported disease-specific function was measured using the 26-item Expanded Prostate Index Composite (EPIC) at baseline and 6 and 12 mo after enrollment. Mean treatment differences in function were compared by race using risk-adjusted generalized estimating equations. RESULTS AND LIMITATIONS: While all race/ethnic groups reported considerable declines in scores for urinary incontinence after radical prostatectomy (RP) when compared to active surveillance, African-American men reported a greater difference than white men did (adjusted difference-in-differences 8.4 points, 95% confidence interval 2.0-14.8; p=0.01). No difference in bother scores was noted and the overall proportion of explained variation attributable to race/ethnicity was relatively small in comparison to primary treatment and baseline function. No clinically significant racial variation was noted for the sexual, bowel, irritative voiding, or hormone domains. Limitations include the lack of well-established thresholds for clinical significance using the EPIC instrument. CONCLUSION: While these data demonstrate that incontinence at 1 yr after RP may be worse for African-American compared to white men, the difference appears to be modest overall. Treatment selection and baseline function explain a much greater proportion of the variation in function after treatment. PATIENT SUMMARY: We observed that the effect of treatment for prostate cancer on patient-reported function did not vary dramatically by race/ethnicity. Compared to white men, African-American men experienced a somewhat more pronounced decline in urinary continence after radical prostatectomy, but the corresponding changes in bother scores were not significantly different between the two groups.

The Comparative Harms of Open and Robotic Prostatectomy in Population Based Samples.

PURPOSE: Robotic assisted radical prostatectomy has largely replaced open radical prostatectomy for the surgical management of prostate cancer despite conflicting evidence of superiority with respect to disease control or functional sequelae. Using population cohort data, in this study we examined sexual and urinary function in men undergoing open radical prostatectomy vs those undergoing robotic assisted radical prostatectomy. MATERIALS AND METHODS: Subjects surgically treated for prostate cancer were selected from 2 large population based prospective cohort studies, the Prostate Cancer Outcomes Study (enrolled 1994 to 1995) and the Comparative Effectiveness Analysis of Surgery and Radiation (enrolled 2011 to 2012). Subjects completed baseline, 6-month and 12-month standardized patient reported outcome measures. Main outcomes were between-group differences in functional outcome scores at 6 and 12 months using linear regression, and adjusting for baseline function, sociodemographic and clinical characteristics. Sensitivity analyses were used to evaluate outcomes between patients undergoing open radical prostatectomy and robotic assisted radical prostatectomy within and across CEASAR and PCOS. RESULTS: The combined cohort consisted of 2,438 men, 1,505 of whom underwent open radical prostatectomy and 933 of whom underwent robotic assisted radical prostatectomy. Men treated with robotic assisted radical prostatectomy reported better urinary function at 6 months (mean difference 3.77 points, 95% CI 1.09-6.44) but not at 12 months (1.19, -1.32-3.71). Subjects treated with robotic assisted radical prostatectomy also reported superior sexual function at 6 months (8.31, 6.02-10.56) and at 12 months (7.64, 5.25-10.03). Sensitivity analyses largely supported the sexual function findings with inconsistent support for urinary function results. CONCLUSIONS: This population based study reveals that men undergoing robotic assisted radical prostatectomy likely experience less decline in early urinary continence and sexual function than those undergoing open radical prostatectomy. The clinical meaning of these differences is uncertain and longer followup will be required to establish whether these benefits are durable.

Analysis of Risk of Recurrence by Subtype in ≤ 1-cm Breast Tumors.

INTRODUCTION: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with higher recurrence rates than other breast cancer subtypes. Increasing numbers of women are being diagnosed with early-stage breast cancer because of improvements in screening mammography. TNBC is known to be highly sensitive to chemotherapy; however, the benefit of adjuvant chemotherapy among women with ≤ 1-cm, lymph node-negative TNBC is unknown. MATERIALS AND METHODS: We evaluated the recurrence rates and recurrence-free survival of 437 women diagnosed with stage T1a-T1bN0 breast cancer from 1997 to 2009 at 2 institutions, with a median follow-up time of 6.2 years. Furthermore, we examined the treatment regimens of these women and evaluated the association of adjuvant chemotherapy with recurrence-free survival. RESULTS: Chemotherapy was administered more often to younger women and to women with high-grade, human epidermal growth factor receptor 2-positive or TNBC. Recurrence-free survival did not differ significantly between TNBC and estrogen receptor-positive breast cancer (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.10-1.04; P = .058). After appropriate adjustments, no significant differences were detected in recurrence-free survival between the women who had received chemotherapy and those who had not among the women with TNBC (P = .132) or within any of the breast cancer subtypes (HR, 0.6; 95% CI, 0.2-1.9; P = .392). CONCLUSION: Prospective trials of this subcentimeter node-negative breast cancer population are warranted to guide adjuvant chemotherapy decisions.

Validity and reliability of the Patient-Reported Arthralgia Inventory: validation of a newly-developed survey instrument to measure arthralgia.

BACKGROUND: There is a need for a survey instrument to measure arthralgia (joint pain) that has been psychometrically validated in the context of existing reference instruments. We developed the 16-item Patient-Reported Arthralgia Inventory (PRAI) to measure arthralgia severity in 16 joints, in the context of a longitudinal cohort study to assess aromatase inhibitor-associated arthralgia in breast cancer survivors and arthralgia in postmenopausal women without breast cancer. We sought to evaluate the reliability and validity of the PRAI instrument in these populations, as well as to examine the relationship of patient-reported morning stiffness and arthralgia. METHODS: We administered the PRAI on paper in 294 women (94 initiating aromatase inhibitor therapy and 200 postmenopausal women without breast cancer) at weeks 0, 2, 4, 6, 8, 12, 16, and 52, as well as once in 36 women who had taken but were no longer taking aromatase inhibitor therapy. RESULTS: Cronbach's alpha was 0.9 for internal consistency of the PRAI. Intraclass correlation coefficients of test-retest reliability were in the range of 0.87-0.96 over repeated PRAI administrations; arthralgia severity was higher in the non-cancer group at baseline than at subsequent assessments. Women with joint comorbidities tended to have higher PRAI scores than those without (estimated difference in mean scores: -0.3, 95% confidence interval [CI] -0.5, -0.2; P<0.001). The PRAI was highly correlated with the Functional Assessment of Cancer Therapy-Endocrine Subscale item "I have pain in my joints" (reference instrument; Spearman r range: 0.76-0.82). Greater arthralgia severity on the PRAI was also related to decreased physical function (r=-0.47, 95% CI -0.55, -0.37; P<0.001), higher pain interference (r=0.65, 95% CI 0.57-0.72; P<0.001), less active performance status (estimated difference in location (-0.6, 95% CI -0.9, -0.4; P<0.001), and increased morning stiffness duration (r=0.62, 95% CI 0.54-0.69; P<0.0001). CONCLUSION: We conclude that the psychometric properties of the PRAI are satisfactory for measuring arthralgia severity.

Knowledge of diagnosis, treatment history, and risk of late effects among childhood cancer survivors and parents: The impact of a survivorship clinic.

BACKGROUND: Childhood cancer survivors are at risk for treatment-related adverse health outcomes, known as late effects. Through matched and longitudinal cohorts, we assessed the impact of survivorship care on patient and parent knowledge of treatment history and associated health risks. PROCEDURE: Childhood cancer survivors were recruited from a single-institution survivorship clinic and matched with survivors receiving routine follow-up care (controls) on diagnosis, age, and time off therapy. One hundred seventy-four participants completed telephone interviews assessing knowledge of diagnosis, treatment history, and risk of late effects. Additionally, 48 new survivorship patients were followed longitudinally with serial interviews for 18 months. RESULTS: In the case-control study, survivorship participants were more likely than controls to correctly report their diagnosis (98% vs. 90%, P = 0.039) and indicate a previous discussion of risk of late effects (99% vs. 62%, P<0.0001). Compared to controls, survivorship participants were 13% more sensitive reporting chemotherapeutics (95%CI 2.8-23.7%, P = 0.013) and 12% more sensitive reporting late effect risk (95%CI 7.3-16.6%, P<0.0001). In the longitudinal cohort, participants were 7% more sensitive reporting chemotherapeutics (95%CI 5.4-10.8%, P < 0.001) and 9% more sensitive reporting late effect risk (95%CI 5.6-23.8%, P<0.001) at 3 months compared to baseline. In regression analysis, baseline knowledge correlated with subsequent interview performance, and time since survivorship visit correlated with decreased knowledge of late effects, but not diagnosis or treatment history. CONCLUSIONS: Survivorship care was associated with increased knowledge of diagnosis, treatment history, and risk of late effects in both cohorts. Knowledge of late effects decreases with time, suggesting the need for additional educational strategies.

Gender, race, and variation in the evaluation of microscopic hematuria among Medicare beneficiaries.

BACKGROUND: Female gender and black race are associated with delayed diagnosis and inferior survival in patients with bladder cancer. OBJECTIVE: We aimed to determine the association between gender, race, and evaluation of microscopic hematuria (an early sign of bladder cancer). DESIGN AND PARTICIPANTS: This was a cohort study using a 5 % random sample of fee-for-service Medicare beneficiaries diagnosed with incident hematuria (International Classification of Diseases, Ninth Revision [ICD-9] code 599.7x) between January 2009 and June 2010 in a primary care setting. Beneficiaries with pre-existing explanatory diagnoses or genitourinary procedures were excluded. MAIN MEASURES: The main endpoint was completeness of the hematuria evaluation in the 180 days after diagnosis. Evaluations were categorized as complete, incomplete, or absent based on receipt of relevant diagnostic procedures and imaging studies. KEY RESULTS: In all, 9,211 beneficiaries met the study criteria. Hematuria evaluations were complete in 14 %, incomplete in 21 %, and absent in 65 % of subjects. Compared to males, females were less likely to have a procedure (26 vs. 12 %), imaging (41 vs. 30 %), and a complete evaluation (22 vs. 10 %) (p < 0.001 for each comparison). Receipt of a complete evaluation did not differ by race. Controlling for baseline characteristics, a complete evaluation was less likely in white women (OR, 0.40 [95 % CI, 0.35-0.46]) and black women (OR, 0.46 [95 % CI, 0.29-0.70]) compared to white men; no difference was found between black and white men. CONCLUSIONS: Women are less likely than men to undergo a complete and timely hematuria evaluation, a finding likely relevant to women's more advanced stage at bladder cancer diagnosis. System-level process improvement between providers of urologic and primary care in the evaluation of hematuria may benefit women harboring malignancy.

The utility of Bayesian predictive probabilities for interim monitoring of clinical trials.

BACKGROUND: Bayesian predictive probabilities can be used for interim monitoring of clinical trials to estimate the probability of observing a statistically significant treatment effect if the trial were to continue to its predefined maximum sample size. PURPOSE: We explore settings in which Bayesian predictive probabilities are advantageous for interim monitoring compared to Bayesian posterior probabilities, p-values, conditional power, or group sequential methods. RESULTS: For interim analyses that address prediction hypotheses, such as futility monitoring and efficacy monitoring with lagged outcomes, only predictive probabilities properly account for the amount of data remaining to be observed in a clinical trial and have the flexibility to incorporate additional information via auxiliary variables. LIMITATIONS: Computational burdens limit the feasibility of predictive probabilities in many clinical trial settings. The specification of prior distributions brings additional challenges for regulatory approval. CONCLUSIONS: The use of Bayesian predictive probabilities enables the choice of logical interim stopping rules that closely align with the clinical decision-making process.

Should mesenteric tumor deposits be included in staging of well-differentiated small intestine neuroendocrine tumors?

Well-differentiated small intestine neuroendocrine tumors can give rise to mesenteric tumor deposits, which are not included in the current American Joint Committee on Cancer staging system for small intestine neuroendocrine tumors, and their impact on patient prognosis is unknown. Seventy-two small intestine neuroendocrine tumors resections were identified in our files with slides, reports, and follow-up data available. Cases were assessed for T-category and for the presence of mesenteric tumor deposits, lymph node metastases, lymphovascular invasion, and liver metastases. Mesenteric tumor deposits were defined as discrete mesenteric tumor nodules ≥1 mm with an irregular growth profile. Similar lesions clearly resulting from extranodal extension or direct contiguous spread by the primary lesion were excluded. Forty-three of the 72 cases had mesenteric tumor deposits (60%). The deposits were significantly associated with lymphovascular invasion (P=0.001), pT3 or pT4 disease (P=0.001), nodal metastases (P=0.040), and liver metastases (P<0.001) at the time of surgery. In addition, four of six cases with tumor deposits and no nodal disease had liver disease. Tumor deposits were associated with an increased incidence of disease progression and death due to the disease (P=0.001). Finally, the presence of tumor deposits at the time of surgery was associated with an increase in hazard of progression or death due to disease (hazard ratio: 4.0; 95% confidence interval: 1.3, 12.5; P=0.016). Mesenteric tumor deposits are present in the majority of cases of small intestine neuroendocrine tumors and are indicators of poor prognosis for this disease. Therefore, they may have a place in staging of small intestine neuroendocrine tumors, perhaps as analogous to lymph node disease.

Racial variation in the quality of surgical care for bladder cancer.

BACKGROUND: Differences in quality of care may contribute to racial variation in outcomes of bladder cancer (BCa). Quality indicators in patients undergoing surgery for BCa include the use of high-volume surgeons and high-volume hospitals, and, when clinically indicated, receipt of pelvic lymphadenectomy, receipt of continent urinary diversion, and undergoing radical cystectomy instead of partial cystectomy. The authors compared these quality indicators as well as adverse perioperative outcomes in black patients and white patients with BCa. METHODS: The Healthcare Cost and Utilization Project State Inpatient Databases for New York, Florida, and Maryland (1996-2009) were used, because they consistently included race, surgeon, and hospital identifiers. Quality indicators were compared across racial groups using regression models adjusting for age, sex, Elixhauser comorbidity sum, insurance, state, and year of surgery, accounting for clustering within hospital. RESULTS: Black patients were treated more often by lower volume surgeons and hospitals, they had significantly lower receipt of pelvic lymphadenectomy and continent diversion, and they experienced higher rates of adverse outcomes compared with white patients. These associations remained significant for black patients who received treatment from surgeons and at hospitals in the top volume decile. CONCLUSIONS: Black patients with BCa had lower use of experienced providers and institutions for BCa surgery. In addition, the quality of care for black patients was lower than that for whites even if they received treatment in a high-volume setting. This gap in quality of care requires further investigation.

The Impact of Gender on Use of Pelvic Lymphadenectomy at the Time of Radical Cystectomy.

INTRODUCTION: Although women are less likely to be diagnosed with bladder cancer than men, they experience a disproportionally high rate of cancer specific mortality. Underuse of evidence-based processes of care may contribute to this mortality difference. We explored variation in the use of pelvic lymphadenectomy at the time of radical cystectomy between men and women, and determined if this was impacted by surgeon or hospital volume. METHODS: We identified all patients with bladder cancer who underwent radical cystectomy from 1996 to 2009 in the New York, Maryland and Florida State Inpatient Databases. The effect of gender on the use of pelvic lymphadenectomy was analyzed using multivariate logistic regression models. RESULTS: Approximately 25% of our cohort was female. Compared to men, women were less likely to be treated with pelvic lymphadenectomy (54% vs 60%, p <0.001), and tended to be treated by lower volume surgeons and at lower volume hospitals. Women had 21% lower odds (95% CI 5-35) of undergoing pelvic lymphadenectomy compared to men when adjusting for patient characteristics, even when treated by high volume surgeons and at high volume hospitals. CONCLUSIONS: At radical cystectomy women were less likely to undergo pelvic lymphadenectomy even when treated by high volume providers. Since pelvic lymphadenectomy is an evidence-based process of care that is associated with improved survival in patients with bladder cancer, lower use of pelvic lymphadenectomy may contribute to the lower bladder cancer survival rate observed in women. Our findings identify an opportunity to improve quality of care in women with bladder cancer.

Prevalence of 25-hydroxyvitamin D deficiency in child and adolescent patients undergoing hematopoietic cell transplantation compared to a healthy population.

BACKGROUND: Pediatric patients undergoing allogeneic hematopoietic cell transplant (HCT) are at risk for low bone mineral density, which may due, in part, to low 25-hydroxyvitamin D levels. PROCEDURE: We compared the serum 25-hydroxyvitamin D status of 22 pediatric HCT patients with 100 healthy pediatric controls. We determined the prevalence of and risk factors for 25-hydroxyvitamin D insufficiency and deficiency. RESULTS: Serum 25-hydroxyvitamin D levels were lower in the pediatric HCT patients at time of transplant than healthy pediatric controls (median 19.5 ng/ml vs. 31.0 ng/ml, P < 0.001). Of HCT patients, 27% were 25-hydroxyvitamin D deficient (<15 ng/dl) and 68% insufficient (15-29 ng/dl), compared with 4% and 40%, respectively, of healthy pediatric controls (P < 0.001). In multivariable analysis, treatment with HCT, decreased ambient ultraviolet light exposure, non-Caucasian race, and older age were associated with decreased serum 25-hydroxyvitamin D levels. No association was found between 25-hydroxyvitamin D levels and gender, body mass index, dietary vitamin D intake, or patient-reported vitamin D supplementation. Few patients in either group reported sunscreen use, vitamin D supplementation, or recommended dietary vitamin D intake. CONCLUSIONS: At time of transplant, pediatric HCT patients frequently have 25-hydroxyvitamin D insufficiency/deficiency, and this occurs more commonly than in the healthy pediatric population. HCT patients rarely follow recommended guidelines to take supplemental vitamin D, consume the Recommended Daily Allowance for vitamin D, or regularly use sunscreen. Further studies are needed to determine whether vitamin D insufficiency/deficiency persists long term in HCT patients and requires dietary and behavioral interventions.

Time course of arthralgia among women initiating aromatase inhibitor therapy and a postmenopausal comparison group in a prospective cohort.

BACKGROUND: More than 80,000 postmenopausal breast cancer patients in the United States each year are estimated to begin a 5-year course of aromatase inhibitors (AIs) to prevent recurrence. AI-related arthralgia (joint pain and/or stiffness) may contribute to nonadherence, but longitudinal data are needed on arthralgia risk factors, trajectories, and background in postmenopause. This study sought to describe 1-year arthralgia trajectories and baseline covariates among patients with AI and a postmenopausal comparison group. METHODS: Patients initiating AIs (n = 91) were surveyed at the time of AI initiation and at 6 repeated assessments over 1 year. A comparison group of postmenopausal women without breast cancer (n = 177) completed concomitantly timed surveys. Numeric rating scales (0-10) were used to measure pain in 8 joint pair groups (bilateral fingers, wrists, elbows, shoulders, hips, knees, ankles, and toes). Poisson regression models were used to analyze arthralgia trajectories and risk factors. RESULTS: By week 6, the AI-initiating group had more severe arthralgia than did the comparison group (ratio of means = 1.8, 95% confidence interval = 1.24-2.7, P = .002), adjusting for baseline characteristics. Arthralgia then worsened further over 1 year in the AI group. Menopausal symptom severity and existing joint-related comorbidity at baseline among women initiating AI were associated with more severe arthralgia over time. CONCLUSIONS: Patients initiating AI should be told about the timing of arthralgia over the first year of therapy, and advised that it does not appear to resolve over the course of a year. Menopausal symptoms and joint-related comorbidity at AI initiation can help identify patients at risk for developing AI-related arthralgia.

Impact of evidence-based standardized assessment on the disability clinical interview for diagnosis of service-connected PTSD: a cluster-randomized trial.

Posttraumatic stress disorder (PTSD) is one of the fastest growing compensated medical conditions. The present study compared usual disability examiner practices for PTSD with a standardized assessment that incorporates evidence-based assessments. The design was a multicenter, cluster randomized, parallel-group study involving 33 clinical examiners and 384 veterans at 6 Veterans Affairs medical centers. The standardized group incorporated the Clinician Administered PTSD Scale and the World Health Organization Disability Assessment Schedule-II into their assessment interview. The main outcome measures were completeness and accuracy of PTSD diagnosis and completeness of functional assessment. The standardized assessments were 85% complete for diagnosis compared to 30% for nonstandardized assessments (p < .001), and, for functional impairment, 76% versus 3% (p < .001). The findings demonstrate that the quality of PTSD disability examination would be improved by using evidence-based assessment.

Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial.

BACKGROUND: Severe TBI, defined as a Glasgow Coma Scale ≤ 8, increases intracranial pressure and activates the sympathetic nervous system. Sympathetic hyperactivity after TBI manifests as catecholamine excess, hypertension, abnormal heart rate variability, and agitation, and is associated with poor neuropsychological outcome. Propranolol and clonidine are centrally acting drugs that may decrease sympathetic outflow, brain edema, and agitation. However, there is no prospective randomized evidence available demonstrating the feasibility, outcome benefits, and safety for adrenergic blockade after TBI. METHODS/DESIGN: The DASH after TBI study is an actively accruing, single-center, randomized, double-blinded, placebo-controlled, two-arm trial, where one group receives centrally acting sympatholytic drugs, propranolol (1 mg intravenously every 6 h for 7 days) and clonidine (0.1 mg per tube every 12 h for 7 days), and the other group, double placebo, within 48 h of severe TBI. The study uses a weighted adaptive minimization randomization with categories of age and Marshall head CT classification. Feasibility will be assessed by ability to provide a neuroradiology read for randomization, by treatment contamination, and by treatment compliance. The primary endpoint is reduction in plasma norepinephrine level as measured on day 8. Secondary endpoints include comprehensive plasma and urine catecholamine levels, heart rate variability, arrhythmia occurrence, infections, agitation measures using the Richmond Agitation-Sedation Scale and Agitated Behavior scale, medication use (anti-hypertensive, sedative, analgesic, and antipsychotic), coma-free days, ventilator-free days, length of stay, and mortality. Neuropsychological outcomes will be measured at hospital discharge and at 3 and 12 months. The domains tested will include global executive function, memory, processing speed, visual-spatial, and behavior. Other assessments include the Extended Glasgow Outcome Scale and Quality of Life after Brain Injury scale. Safety parameters evaluated will include cardiac complications. DISCUSSION: The DASH After TBI Study is the first randomized, double-blinded, placebo-controlled trial powered to determine feasibility and investigate safety and outcomes associated with adrenergic blockade in patients with severe TBI. If the study results in positive trends, this could provide pilot evidence for a larger multicenter randomized clinical trial. If there is no effect of therapy, this trial would still provide a robust prospective description of sympathetic hyperactivity after TBI. TRIAL REGISTRATION: ClinicalTrials.gov NCT01322048.

Anti-transforming growth factor ß antibody treatment rescues bone loss and prevents breast cancer metastasis to bone.

Breast cancer often metastasizes to bone causing osteolytic bone resorption which releases active TGFß. Because TGFß favors progression of breast cancer metastasis to bone, we hypothesized that treatment using anti-TGFß antibody may reduce tumor burden and rescue tumor-associated bone loss in metastatic breast cancer. In this study we have tested the efficacy of an anti-TGFß antibody 1D11 preventing breast cancer bone metastasis. We have used two preclinical breast cancer bone metastasis models, in which either human breast cancer cells or murine mammary tumor cells were injected in host mice via left cardiac ventricle. Using several in vivo, in vitro and ex vivo assays, we have demonstrated that anti-TGFß antibody treatment have significantly reduced tumor burden in the bone along with a statistically significant threefold reduction in osteolytic lesion number and tenfold reduction in osteolytic lesion area. A decrease in osteoclast numbers (p = 0.027) in vivo and osteoclastogenesis ex vivo were also observed. Most importantly, in tumor-bearing mice, anti-TGFß treatment resulted in a twofold increase in bone volume (p<0.01). In addition, treatment with anti-TGFß antibody increased the mineral-to-collagen ratio in vivo, a reflection of improved tissue level properties. Moreover, anti-TGFß antibody directly increased mineralized matrix formation in calverial osteoblast (p = 0.005), suggesting a direct beneficial role of anti-TGFß antibody treatment on osteoblasts. Data presented here demonstrate that anti-TGFß treatment may offer a novel therapeutic option for tumor-induced bone disease and has the dual potential for simultaneously decreasing tumor burden and rescue bone loss in breast cancer to bone metastases. This approach of intervention has the potential to reduce skeletal related events (SREs) in breast cancer survivors.