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Background: To examine patterns of care and outcomes for patients with stage I esophageal cancer (EC) in the United States., Methods: We identified patients in the National Cancer Data Base diagnosed with stage I EC from 2004 to 2012 and grouped them by primary treatment: esophagectomy (Eso), local excision (LE), concurrent chemoradiation (CRT), or observation (Obs). Multinomial logistic regression was used to predict receipt of treatments. Overall survival (OS) was estimated by Kaplan-Meier methods adjusted for inverse probability of treatment weighting (IPTW) and Cox proportional hazard regressions., Results: Of 5,480 patients, 2,312 (42%) underwent Eso, 1,250 (23%) LE, 758 (14%) CRT, and 1,160 (21%) Obs. LE use increased over time from 17% to 29% while Obs declined from 26% to 19%. Patients least likely to undergo surgery were older, had greater comorbidity, were uninsured, were treated at non-academic centers, and were Black. The rate of surgery for Black patients was half of that for White patients (33% vs. 67%). Postoperative mortality rates were higher after Eso vs. LE at 30 days (2.9% vs. 0.5%; P<0.001) and at 90 days (5.5% vs. 1.4%, P<0.001). Five-year OS was 59% with Eso, 63% LE, 29% CRT, and 31% Obs (P<0.001). On multivariate analysis, outcomes were best after LE [ vs. Eso: hazard ratio (HR) =1.15, 95% CI: 1.01-1.30, P=0.037; CRT: HR =2.41, 95% CI: 2.09-2.78, P<0.001; Obs: HR =3.79, 95% CI: 3.33-4.32, P<0.001)., Conclusions: Disparities are evident in the care of patients with stage I EC throughout the United States. LE was associated with favorable outcomes compared to Eso, CRT, and Obs., Competing Interests: Conflicts of Interest: SH Lin has research funding from Elekta, STCube Pharmaceuticals, Peregrine, Hitachi Chemical Inc., and Roche/Genentech, has served as consultant for AstraZeneca, and received honoraria from US Oncology and ProCure.

Although small cell lung cancer (SCLC) represents less than one-sixth of all lung cancer cases, it is an aggressive disease with a high metastatic potential to various sites including the brain. Most landmark trials assessing individual therapy benefits for SCLC dichotomized patients as having either limited or extensive disease. Over the last decade, however, there has been a clear shift towards categorizing and analyzing survival patterns using a more thorough staging system that accounts for tumor size and the degree of nodal or metastatic disease burden. For the 5% of patients who present with clinical stage I (cT1-2aN0M0) SCLC, extrapolating treatment recommendations from a rather heterogeneous population that constitutes limited disease SCLC remains controversial and has led to numerous investigations of alternative therapies such as stereotactic body radiation therapy (SBRT) for the management of this highly select group of patients. Given the changing landscape of multimodal therapy, this review will summarize relevant data pertaining to and outline optimal treatment algorithms for stage I SCLC, with a particular focus on SBRT as a primary mode of local therapy., Competing Interests: Conflicts of Interest: Grant support: Genentech, Inc., New River Labs, Beyond Spring Pharmaceuticals, Hitachi Chemical Diagnostics. Advisory Board: AstraZeneca, Inc.

Aims: To create a standardized home exercise therapy program that could be implemented by international sites to provide a consistent level of therapeutic intervention for pediatric patients participating in an ongoing Phase-III, randomized, controlled trial of repeat abobotulinumtoxinA injections for pediatric upper limb spasticity (NCT02106351)., Methods: Physical therapists, occupational therapists, and medical doctors worked collaboratively to design an exercise therapy program to be implemented in the home setting. In this article, we describe the development process and the finalized program that is currently being used in the Phase-III trial., Results: The final program is presented as a "toolbox" for therapists, and includes a standardized step-wise process for choosing the most appropriate exercises and functional activities to achieve the agreed treatment goals of each abobotulinumtoxinA injection. The core toolbox includes: a clear protocol for clinicians, information sheets, signature of commitment forms, exercise score charts, and the library of exercises and functional activities that therapists choose from to aid the patient in achieving their treatment goals., Conclusions: Implementation of this home therapy program provides a standardized background of good practice against which to test the efficacy of abobotulinumtoxinA. Preliminary data show that the program is readily accepted by patients and their families.

Radiation therapy plays an integral role in the management of head and neck cancers (HNCs). While most HNC patients have historically been treated with photon-based radiation techniques such as intensity modulated radiation therapy (IMRT), there is a growing awareness of the potential clinical benefits of proton therapy over IMRT in the definitive, postoperative and reirradiation settings given the unique physical properties of protons. Intensity modulated proton therapy (IMPT), also known as "pencil beam proton therapy," is a sophisticated mode of proton therapy that is analogous to IMRT and an active area of investigation in cancer care. Multifield optimization IMPT allows for high quality plans that can target superficially located HNCs as well as large neck volumes while significantly reducing integral doses. Several dosimetric studies have demonstrated the superiority of IMPT over IMRT to improve dose sparing of nearby organs such as the larynx, salivary glands, and esophagus. Evidence of the clinical translation of these dosimetric advantages has been demonstrated with documented toxicity reductions (such as decreased feeding tube dependency) after IMPT for patients with HNCs. While there are relative challenges to IMPT planning that exist today such as particle range uncertainties and high sensitivity to anatomical changes, ongoing investigations in image-guidance techniques and robust optimization methods are promising. A systematic approach towards utilizing IMPT and additional prospective studies are necessary in order to more accurately estimate the clinical benefit of IMPT over IMRT and passive proton therapy on a case-by-case basis for patients with sub-site specific HNCs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To examine the value of early changes in quantitative diffusion-weighted imaging and 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for discriminating complete pathologic response (pCR) to chemoradiation in esophageal cancer., Methods and Materials: Twenty esophageal cancer patients treated with chemoradiation followed by surgery were prospectively enrolled. Patients underwent magnetic resonance imaging and FDG-PET/CT scans at baseline, interim (2 weeks after chemoradiation start), and first follow-up. On the basis of pathologic findings at surgery, patients were categorized into tumor regression groups (TRG1, TRG2, and TRG3+). Distributions of summary statistics in apparent diffusion coefficient (ADC) and FDG-PET at baseline and relative changes at interim and follow-up scans were compared between pCR/TRG1 and non-pCR/TRG2+ groups and across readers. Receiver operating characteristics were evaluated for summary measures to characterize discrimination of pCR from non-pCR., Results: Relative changes in tumor volume ADC (ΔADC) mean and 25th and 10th percentiles from baseline to interim were able to completely discriminate (area under the curve = 1, P < .0011) between pCR and non-pCR (thresholds = 27.7%, 29.2%, and 32.1%, respectively) and were found to have high interreader reliability (95% limits of agreement of 1.001, 0.944, and 0.940, respectively). Relative change in total lesion glycolysis (TLG) from baseline to interim was significantly different among pCR and non-pCR groups (P=.0117) and yielded an area under the curve of 0.947 (95% confidence interval 0.8505-1.043). An optimal threshold of 59% decrease in TLG provided optimal sensitivity (specificity) of 1.000 (0.867). Changes in ADC summary measures were negatively correlated with that of TLG (Spearman, -0.495, P=.027)., Conclusions: Quantitative volume ΔADC and TLG during treatment may serve as early imaging biomarkers for discriminating pathologic response to chemoradiation in esophageal cancer. Validation of these data in larger, prospective, multicenter studies is essential., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In the article by A.C. Moreno, S.K. Sikka, and H.L. Thacker, Genitourinary syndrome of menopause in breast cancer survivors: Treatments are available, Cleve Clin J Med 2018; 85(10):760-766, doi:10.3949/ccjm.85a.17108, Table 2 incorrectly stated that prasterone is contraindicated in women with known or suspected breast cancer. This correction has been made online as follows. "Warning: Estrogen is a metabolite of prasterone; use of exogenous extrogen is contraindicated in women with known or suspected breast cancer; prasterone has not been studied in women with a history of breast cancer."

When treating the genitourinary syndrome of menopause (GSM) in women with breast cancer or at high risk of breast cancer, clinicians must balance the higher cancer risks associated with hormonal treatments against the severity of GSM symptoms, which can be exacerbated by breast cancer treatments. Options for patients who need hormonal therapy include locally applied estrogens, dehydroepiandrosterone (DHEA), and estrogen receptor agonists/antagonists, which vary in their impact on breast cancer risk., (Copyright © 2018 Cleveland Clinic.)

Background: Myotonic Dystrophy is the most common form of muscular dystrophy in adults, affecting an estimated 10 per 100,000 people. It is a multisystemic disorder affecting multiple generations with increasing severity. There are currently no licenced therapies to reverse, slow down or cure its symptoms. In 2009 TREAT-NMD (a global alliance with the mission of improving trial readiness for neuromuscular diseases) and the Marigold Foundation held a workshop of key opinion leaders to agree a minimal dataset for patient registries in myotonic dystrophy. Eight years after this workshop, we surveyed 22 registries collecting information on myotonic dystrophy patients to assess the proliferation and utility the dataset agreed in 2009. These registries represent over 10,000 myotonic dystrophy patients worldwide (Europe, North America, Asia and Oceania)., Results: The registries use a variety of data collection methods (e.g. online patient surveys or clinician led) and have a variety of budgets (from being run by volunteers to annual budgets over €200,000). All registries collect at least some of the originally agreed data items, and a number of additional items have been suggested in particular items on cognitive impact., Conclusions: The community should consider how to maximise this collective resource in future therapeutic programmes.

Purpose: To examine national care patterns in proton radiation therapy (PBT) use for non-small cell lung cancer (NSCLC) and the effect of facility type on survival., Patients and Methods: Using the National Cancer Database, we identified 506 patients with a diagnosis of NSCLC from 2004-2014 who underwent PBT. Patients were categorized as having received treatment at an academic/research facility (ARF) or a form of community cancer program (CCP). Descriptive analysis was performed, and overall survival was analyzed by Kaplan-Meier methods and Cox proportional hazard models., Results: Treatments at ARFs and CCPs were equally distributed with 253 patients at each facility type. A positive trend in PBT use over time was observed with 2.8% of cases being treated in 2008 compared to 21.5% in 2014 ( P  = .001). Definitive doses (≥60 Gy) were more commonly given at ARFs than CCPs (72% versus 45%, respectively; P  < .001). Five-year overall survival was 31% at ARFs and 18% at CCPs ( P  < .001). On multivariate analysis, outcomes were worse with treatments at CCPs (hazard ratio [HR] 1.61; 95% Confidence Interval, 1.14-2.27; P  = .007). On subanalysis of nonsurgical patients treated with ≥60 Gy, facility type became insignificant and dose escalation was associated with improved outcomes (≥70 Gy HR 0.45; 95% CI, 0.25-0.81; P  = .008)., Conclusion: Use of PBT for management of NSCLC is on the rise. Community cancer programs were associated with higher rates of nondefinitive PBT doses and correspondingly worse outcomes. Differences in survival by facility became insignificant when definitive doses were used, warranting further investigation of practice patterns in CCPs at a national level., Competing Interests: Conflicts of Interest: Steven H. Lin, MD, PhD, has received research funding from Elekta, STCube Pharmaceuticals, Peregrine, Hitachi Chemical Inc, and Roche/Genentech; has served as consultant for AstraZeneca; and has received honoraria from US Oncology and ProCure. All other authors have no conflicts of interest to disclose., (© Copyright 2018 International Journal of Particle Therapy.)

Background: Following complete resection of pN2 non-small cell lung cancer (NSCLC), national guidelines recommend either sequential (sCRT) or concurrent chemoradiotherapy (cCRT). This is the largest study to date evaluating survival between both approaches. In sCRT patients, sequencing 'chemotherapy first' versus 'radiotherapy first' was also addressed., Methods: The National Cancer Data Base (NCDB) was queried for patients with primary NSCLC undergoing surgery (without neoadjuvant radiotherapy or chemotherapy), pN2 disease with negative surgical margins, and receiving postoperative CRT. Multivariable logistic regression ascertained factors associated with cCRT administration. Kaplan-Meier analysis evaluated overall survival (OS), and Cox proportional hazards modeling determined variables associated with OS. Propensity matching was performed to address group imbalances and indication biases., Results: Of 1924 total patients, 1115 (58%) received sCRT and 809 (42%) underwent cCRT. Median OS in the sCRT and cCRT cohorts was 53 months versus 37 months (p < 0.001); differences persisted following propensity matching (p = 0.002). In the sCRT population, there was a trend for higher OS in the 'chemotherapy first' group, relative to 'radiotherapy first' (55 vs. 44 months, p = 0.079), but there were no statistically apparent differences following propensity matching (p = 0.302)., Conclusions: For completely resected pN2 NSCLC, delivering adjuvant sCRT was associated with improved survival over cCRT. Toxicity-related factors may help to explain these results but need to be better addressed in further investigations. Differential sequencing of sCRT did not appear to affect survival.

Background: Postoperative chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) can be delivered sequentially (sCRT) or concurrently (cCRT). Without high-volume data, current guidelines recommend either option for patients with negative margins (M-) and cCRT for those with positive margins (M+). In this study, survival was compared between sCRT versus cCRT for M- and M+ disease; survival in patients who underwent sCRT was also assessed with chemotherapy-first versus radiotherapy (RT)-first. Methods: The National Cancer Database was queried for patients with primary NSCLC undergoing surgery followed by CRT. Patients were excluded if they received neoadjuvant chemotherapy or RT. Both M- and M+ (including R1 and R2) subcohorts were evaluated. Multivariable logistic regression ascertained factors associated with cCRT delivery. Kaplan-Meier analysis evaluated overall survival (OS); Cox proportional hazards modeling determined variables associated with OS. Propensity score matching aimed to address group imbalances and indication biases. Results: Of 4,921 total patients, 3,475 (71%) were M-, 1,446 (29%) were M+, 2,271 (46%) received sCRT, and 2,650 (54%) underwent cCRT. Median OS among the sCRT and cCRT groups in patients who were M- was 54.6 versus 39.5 months, respectively ( P <.001); differences persisted following propensity score matching ( P <.001). In the overall M+ cohort, outcomes for sCRT and cCRT were 36.3 versus 30.5 months ( P =.011), but showed equipoise following matching ( P =.745). In the R1 and R2 subsets, no differences in OS were seen between cohorts ( P =.368 and .553, respectively). When evaluating the sCRT population, there were no OS differences between chemotherapy-first and RT-first after matching ( P =.229). Conclusions: Postoperative sCRT was associated with improved survival compared with cCRT in patients with M- disease, with statistical equipoise in those with M+ disease. Differential sequencing of sCRT does not appear to affect survival., (Copyright © 2018 by the National Comprehensive Cancer Network.)

Older patients are at increased risk of toxicities from aggressive oncologic therapy and of nononcologic death. A meta-analysis of non-nasopharyngeal head and neck cancers showed no statistical benefit in adding chemotherapy to radiotherapy (RT) in older patients; another meta-analysis of RT versus chemoradiotherapy (CRT) in NPC found advantages to CRT, but vastly under-represented patients ≥70 years old. This is the largest study to date evaluating outcomes of CRT versus RT alone in this population. The National Cancer Data Base (NCDB) was queried for primary nasopharyngeal cancer cases (2004-2013) in patients ≥70 years old receiving RT alone or CRT. Patients with unknown RT/chemotherapy and T1N0 or M1 disease were excluded. Logistic regression analysis ascertained factors associated with CRT delivery. Kaplan-Meier analysis evaluated overall survival (OS) between both cohorts. Cox proportional hazards modeling determined variables associated with OS. In total, 930 patients were analyzed (n = 713 (77%) CRT, n = 217 (23%) RT). Groups were relatively balanced; CRT was less frequently delivered in patients with advancing age, lower nodal burden, and females (P < 0.05 for all). Median OS in the CRT and RT groups were 35.3 versus 20.0 months, respectively (P = 0.002). On multivariate analysis, independent predictors of OS included age, comorbidities, income and insurance status, tumor grade, and stage (P < 0.05 for all). Notably, receipt of chemotherapy independently predicted for improved OS (P = 0.036). CRT, compared to RT alone, was independently associated with improved survival in NPC patients ≥70 years old. CRT appears to be a promising approach in this population, but treatment-related toxicity risks should continue to be weighed against potential oncologic benefits., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Myotonic Dystrophy type 1 multisystem involvement leads to functional impairment with an increased risk of falling. This multinational study estimates the prevalence of falls and fall-associated fractures. A web-based survey among disease-specific registries (Germany, UK and The Netherlands) was carried out among DM1 ambulant adults with a total of 573 responses retrieved. Results provided a risk ratio estimation of 30%-72% for falls and of 11%-17% for associated fractures. There was no significant difference for falls between male and female, but there was for fall-related fractures with a higher prevalence in women. Balance and leg weakness were the most commonly reported causes for falling. This study is based on a voluntary retrospective survey with naturally inherent limitations; however, the sample size allows for robust comparisons. The estimated risk of falls in this cohort with a mean age of 46 years compares to a previous estimation for a healthy population of over 65 years of age. These results suggest a premature-ageing DM1 phenotype with an increased risk of falling depending on age and disease severity that, so far, might have been underestimated. This may have clinical implications for the development of care guidelines and when testing new interventions in this population., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The goal of regional treatments in breast cancer should be to eradicate any disease within lymph nodes, avoid regional recurrences, minimize the risk of distant metastases, and improve survival. In addition, regional treatments should focus on reducing potential morbidities and optimizing the long-term quality of life of breast cancer survivors. While data from recent surgical and radiation trials have helped clarify many issues regarding regional treatment, there still remains controversy as to the optimal approach for patients with "intermediate risk" disease. Two large radiation oncology studies (MA.20 and EORTC2292-10925) evaluated whether more extensive lymphatic treatment benefited patients with higher-risk lymph node-negative, or lower risk lymph node-positive disease. A meta-analysis of these two studies suggested that the addition of regional nodal irradiation (RNI) to the level III axillary, supraclavicular and upper internal mammary lymph nodes conferred an improvement in disease free survival and distant metastasis free survival as well as a 1-2% overall survival advantage. However, other studies have suggested that many patients with positive sentinel lymph nodes who are treated with breast conservation including breast irradiation may safely avoid the morbidity and costs of further axillary treatment (whether surgical or radiotherapy-based). In general, patients with 1-3 positive lymph nodes or high-risk, node negative stage II breast cancer represent a diverse population who require individualized, rather than group-based, risk assessment when considering RNI. This article will propose a strategic methodology to assess the modern day breast cancer patient's need for RNI in the setting of changing surgical, radiation, and systemic therapies., (Copyright © 2017. Published by Elsevier Ltd.)

Objectives: Stereotactic body radiation therapy (SBRT) has become increasingly utilized over the last decade in the treatment of inoperable stage I non-small cell lung cancer (NSCLC) patients, although no standardized dosing guidelines exist. In this retrospective study, we investigated the dose prescription pattern use in the United States for patients receiving SBRT., Methods: Patients with stage I NSCLC treated with SBRT between 2004 and 2011 were identified within the National Cancer Database (NCDB). Trends in SBRT use and dose prescriptions were analyzed., Results: A total of 5246 patients met criteria as receiving SBRT. The overall mean and median BED10 were 134.5 and 132 Gy, respectively. Of these patients, 94.5% were prescribed a regimen with a BED10≥100 Gy. The most common prescriptions overall were 60 Gy in 3 fractions (24.1%), 48 Gy in 4 fractions (17.8%), 50 Gy in 5 fractions (13.0%), and 54 Gy in 3 fractions (12.8%). Analysis of prescription trends revealed decreased utilization of 54 to 60 Gy in 3 fractions (47.9% in 2006 to 27.9% in 2011, combined) and increased utilization of 50 Gy in 5 fractions (3.1% in 2006 to 20.4% in 2011)., Conclusions: Our findings suggest increasing use of SBRT over the last decade with a majority of patients being treated with regimens employing a BED10≥100 Gy. Since 2006, there has been a decline in the use of 54 to 60 Gy in 3 fractions, with an increase in the use of 50 Gy in 5 fractions. Possible explanations include concern for increased toxicity with higher BED regimens and increasing treatment of centrally located tumors.

Introduction: This study analyzes practice patterns, treatment-related mortality, survival, and predictors thereof in elderly patients with early-stage esophageal cancer (EC)., Methods: The National Cancer Data Base was queried for cT1-2 N0 EC in patients 80 years of age and older. Patients were divided into four treatment groups: observation (Obs), chemoradiotherapy (CRT), local excision (LE), and esophagectomy (Eso). Patient, tumor, and treatment parameters were extracted and compared. Analyses were performed on overall survival (OS) and postoperative 30- and 90-day mortality., Results: A total of 923 patients from 2004 to 2012 were analyzed. Of these, 43% underwent clinical Obs, 22% underwent CRT, 25% underwent LE, and 10% underwent Eso. Patients undergoing Obs were older, had more comorbidities, were treated at nonacademic centers, and lived 25 miles or less from the facility. Patients receiving an operation (Eso or LE) were more often younger, male, white, and in the top income quartile. The postoperative 30-day mortality rates in the LE and Eso groups were 1.3% and 9.6%, respectively (p < 0.001) and increased to 2.6% and 20.2% at 90 days, respectively (p < 0.001). The 5-year OS rate was 7% for Obs, 20% for CRT, 33% for LE, and 45% for Eso (p < 0.001). Multivariate analyses showed improved OS with any local definitive therapy: CRT (hazard ratio [HR] = 0.42, 95% confidence interval [CI]: 0.34-0.52, p < 0.001), LE (HR = 0.3, 95% CI: 0.24-0.38, p < 0.001), and Eso (HR = 0.32, 95% CI: 0.23-0.44, p < 0.001)., Conclusions: There are noteworthy demographic, socioeconomic, and regional disparities influencing management of elderly patients with stage I EC. Despite high rates of Obs, careful consideration of all local therapy options is warranted, given the improved outcomes with treatment., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Cognitive impairment and dementia are associated with a range of cardiovascular conditions, including hypertension, coronary artery disease, and atrial fibrillation. We aimed to describe the association with heart failure, summarizing published data to give estimates of prevalence, incidence, and relative risk of cognitive impairment/dementia in heart failure., Methods: We searched multidisciplinary databases including MEDLINE (OVID), EMBASE (OVID), CINAHL (EBSCO), PsychINFO (EBSCO), Web of Science (Thomson Reuters), and CENTRAL (Cochrane Library) from inception until May 31, 2015. All relevant studies looking at cognitive impairment/dementia in heart failure were included. Studies were selected by 2 independent reviewers using prespecified inclusion/exclusion criteria. Where data allowed, we performed meta-analysis and pooled results using random effects models., Results: From 18,000 titles, 37 studies were eligible (n = 8411 participants). Data from 4 prospective cohorts (n = 2513 participants) suggest greater cognitive decline in heart failure compared with non-heart failure over the longer term. These data were not suitable for meta-analysis. In case control studies describing those with and without heart failure (n = 4 papers, 1414 participants) the odds ratio for cognitive impairment in the heart failure population was 1.67 (95% confidence interval 1.15-2.42). Prevalence of cognitive impairment in heart failure cohorts (n = 26 studies, 4176 participants) was 43% (95% confidence interval 30-55)., Conclusions: This review suggests a substantial proportion of patients with heart failure have concomitant cognitive problems. This has implications for planning treatment and services. These data do not allow us to comment on causation, and further work is needed to describe the underlying pathophysiology., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: The role of regional nodal irradiation (RNI) for patients with breast cancer remains controversial, particularly on the basis of nodal involvement. Using the National Cancer Database, we aimed to validate published data on whether expanding treatment fields from whole-breast irradiation (WBI) to encompass the regional nodes (WBI+RNI) affected overall survival (OS) for patients with node-positive (pN1-3) or high-risk node-negative (pN0) breast cancer treated with breast-conserving surgery and adjuvant chemotherapy., Methods and Materials: Women diagnosed with invasive breast cancer between 2004 and 2012 who met the selection criteria for the National Cancer Institute of Canada MA.20 trial were identified and stratified by receipt of RNI. Propensity score matching was used to compare 1:1 matched pairs of patients. Five-year OS was estimated using the Kaplan-Meier method. We used multivariate logistic regression to predict receipt of WBI+RNI and a multivariable Cox model to examine associations between patients' demographic, tumor, and treatment characteristics and OS using double robust estimation., Results: Of 23,567 patients, 6,920 (29%) received WBI+RNI and 16,647 (71%) WBI. Median follow-up was 56 months. Use of WBI+RNI increased from 25.2% in 2004 to 32.2% in 2012 ( P  < .001). Patients receiving WBI+RNI more often had negative hormone-receptor status, ≥5 cm tumors and >1 involved node, and were not privately insured. For all patients, the 5-year OS rates were 90.8% with WBI+RNI versus 92.6% with WBI ( P < .001). In the matched cohort (n = 10,922), the corresponding 5-year OS rates were 92% and 91.9% ( P = .45), respectively. On multivariate analysis, WBI+RNI did not affect OS in the matched cohort (hazard ratio, 1.02; 95% confidence interval, 0.89-1.17, P = .76), regardless of pathologic nodal status., Conclusions: In this large retrospective analysis, use of WBI+RNI did not affect 5-year OS rates for women with high-risk, early stage breast cancer undergoing breast-conserving surgery and adjuvant chemotherapy, regardless of nodal status, which confirms the findings of the MA.20 trial.

Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy worldwide with complex, multi-systemic, and progressively worsening symptoms. There is currently no treatment for this inherited disorder and research can be challenging due to the rarity and variability of the disease. The UK Myotonic Dystrophy Patient Registry is a patient self-enrolling online database collecting clinical and genetic information. For this cross-sectional "snapshot" analysis, 556 patients with a confirmed diagnosis of DM1 registered between May 2012 and July 2016 were included. An almost even distribution was seen between genders and a broad range of ages was present from 8 months to 78 years, with the largest proportion between 30 and 59 years. The two most frequent symptoms were fatigue and myotonia, reported by 79 and 78% of patients, respectively. The severity of myotonia correlated with the severity of fatigue as well as mobility impairment, and dysphagia occurred mostly in patients also reporting myotonia. Men reported significantly more frequent severe myotonia, whereas severe fatigue was more frequently reported by women. Cardiac abnormalities were diagnosed in 48% of patients and more than one-third of them needed a cardiac implant. Fifteen percent of patients used a non-invasive ventilation and cataracts were removed in 26% of patients, 65% of which before the age of 50 years. The registry's primary aim was to facilitate and accelerate clinical research. However, these data also allow us to formulate questions for hypothesis-driven research that may lead to improvements in care and treatment.

Background: Free-living or habitual physical activity (HPA) refers to someone's performance in his or her free-living environment. Neuromuscular disorders (NMD) manifest through HPA, and the observation of HPA can be used to identify clinical risks and to quantify outcomes in research. This review summarizes and analyses previous studies reporting the assessment of HPA in NMD, and may serve as the basis for evidence-based decision-making when considering assessing HPA in this population., Methods: A systematic review was performed to identify all studies related to HPA in NMD, followed by a critical appraisal of the assessment methodology and a final review of the identified HPA tools., Results: A total of 22 studies were selected, reporting on eight different direct tools (or activity monitors) and ten structured patient-reported outcomes. Overall, HPA patterns in NMD differ from healthy control populations. There was a noticeable lack of validation studies for these tools and outcome measures in NMD. Very little information regarding feasibility and barriers for the application of these tools in this population have been published., Conclusions: The variety and heterogeneity of tools and methods in the published literature makes the comparison across different studies difficult, and methodological guidelines are warranted. We propose a checklist of considerations for the assessment and reporting of HPA in NMD.

Radiation therapy (RT) as part of multidisciplinary oncologic care has been marked by profound advancements over the past decades. As part of multimodality therapy for esophageal cancer (EC), a prime goal of RT is to minimize not only treatment toxicities, but also postoperative complications and hospitalizations. Herein, discussion commences with the historical approaches to treating EC, including seminal trials supporting multimodality therapy. Subsequently, the impact of RT techniques, including three-dimensional conformal RT, intensity-modulated RT, and proton beam therapy, is examined through available data. We further discuss existing data and the potential for further development in the future, with an appraisal of the future outlook of technological advancements of RT for EC., Competing Interests: S.H.L. has research funding from Elekta, STCube Pharmaceuticals, Peregrine Pharmaceuticals, Hitachi Chemical, Inc., and Roche/Genentech, has served as a consultant for AstraZeneca, and received an honorarium from US Oncology and ProCure.

Introduction: We assessed prophylactic use of bisphosphonate (BP) in Duchenne muscular dystrophy (DMD) patients on glucocorticoid (GC) therapy., Methods: Fifty-two DMD patients on daily GC were offered BP (oral risedronate). Patients were reviewed for tolerability, side effects, bone pain, and fracture frequency. Bone mineral density (BMD) was determined by annual dual energy X-ray absorptiometry. BP-treated patients were compared with 15 BP-naïve patients (untreated cohort)., Results: Side effects occurred in 9 patients. Thirty-six patients continued BP therapy for over 12 months (mean, 3.6 years). Five treated patients reported bone pain. Three treated patients suffered a vertebral fracture, significantly less than in the untreated cohort (5/15). Lumbar spine adjusted BMD Z-scores remained unchanged in treated patients and were significantly greater than in the untreated cohort., Conclusions: Prophylactic oral risedronate therapy was tolerated by most DMD patients. It appears to maintain BMD and may reduce fracture rate in DMD patients on GC. Muscle Nerve 54: 79-85, 2016., (© 2015 Wiley Periodicals, Inc.)

Myeloperoxidase (MPO) is an important enzyme in the front-line protection against microorganisms. In peripheral blood, it is accepted that MPO is only produced by myeloid-lineage cells. Thus, MPO presence is unexpected in lymphocytes. We showed recently that B1-lymphocytes from mice have MPO. Here, we showed that subsets of human peripheral B, CD4(+) and CD8(+) T lymphocytes express MPO. The content of MPO in lymphocytes was very low compared to neutrophils/monocytes with a preferential distribution in the nucleus and perinuclear region. Also, we performed a MPO mRNA expression analysis from human blood cells derived from microarray raw data publicly available, showing that MPO is modulated in infectious disease. MPO was increased in CD4(+) T lymphocytes from HIV chronic infection and in CD8(+) T lymphocytes from HCV-positive patients. Our study points out MPO as a multifunctional protein due to its subcellular localization and expression modulation in lymphocytes indicating alternative unknown functions for MPO in lymphocytes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To determine whether there are differences in survival associated with different treatment modalities among patients with lymph node-negative, very large non-small-cell lung cancers (NSCLCs)., Methods: The National Cancer DataBase was used to identify patients diagnosed with NSCLCs >7 cm (T3) without lymph node involvement (N0) or metastatic disease (M0) from 1999 to 2006. Surgical therapy included surgery alone, neoadjuvant chemoradiation therapy or chemotherapy, surgery followed by adjuvant chemoradiation therapy or chemotherapy and surgery followed by postoperative radiation therapy (PORT). The 5-year overall survival (OS) was estimated by the Kaplan-Meier method and comparisons were made using log-rank tests and Cox regression models., Results: Of the 2296 patients identified with cT3N0M0 disease, 45% underwent surgical therapy. The 5-year OS rate was 38%. Across the different treatment regimens, there was a significant difference in 5-year OS. Neither neoadjuvant chemoradiation therapy or chemotherapy nor adjuvant chemoradiation therapy was associated with improved 5-year OS. The use of adjuvant chemotherapy was associated with improved OS relative to surgery alone [hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.54-0.91, P = 0.008]. PORT alone was associated with a detrimental effect on 5-year OS relative to surgery alone [HR 2.04; 95% CI 1.38-3.03, P < 0.001]., Conclusions: Large T3N0 NSCLCs appear to be optimally treated with surgical resection followed by adjuvant chemotherapy., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

A key link between amino acid catabolism and immune regulation in cancer is the augmented tryptophan (Trp) catabolism through the kynurenine pathway (KP), a metabolic route induced by interferon-γ (IFN-γ) and related to poor prognosis in melanomas. Besides its role in cancer, IFN-γ plays a key role in the control of pigmentation homeostasis. Here we measured KP metabolites in human melanoma lines and skin melanocytes and fibroblasts in response to IFN-γ. In general, IFN-γ affected KP in skin cells more than in melanoma cells, supporting IFN-γ roles in skin physiology and that of stromal cells in modulating the tumor microenvironment.

Background: The aim of our study was to investigate the relationship between coronary artery disease (CAD), angina, and clinical outcomes in patients with heart failure and preserved ejection fraction enrolled in the irbesartan in patients with heart failure and preserved systolic function (I-Preserve) trial., Methods and Results: The mean follow-up period for the 4128 patients enrolled in I-Preserve was 49.5 months. Patients were divided into 4 mutually exclusive groups according to history of CAD and angina: patients with no history of CAD or angina (n=2008), patients with no history of CAD but a history of angina (n=649), patients with a history of CAD but no angina (n=468), and patients with a history of CAD and angina (n=1003); patients with no known CAD or angina were the reference group. After adjustment for other prognostic variables using Cox proportional-hazard models, patients with CAD but no angina were found to be at higher risk of all-cause mortality (hazard ratio [HR], 1.58 [1.22-2.04]; P<0.01) and sudden death (HR, 2.12 [1.33-3.39]; P<0.01), compared with patients with no CAD or angina. Patients with CAD and angina were also at higher risk of all-cause mortality (HR, 1.29 [1.05-1.59]; P=0.02) and sudden death (HR, 1.83 [1.24-2.69]; P<0.01) compared with the same reference group and had the highest risk of unstable angina or myocardial infarction (HR, 5.84 [3.43-9.95]; P<0.01)., Conclusions: Patients with heart failure and preserved ejection fraction and CAD are at higher risk of all-cause mortality and sudden death when compared with those without CAD., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238., (© 2015 American Heart Association, Inc.)

Recently, Bacillus subtilis spores were shown to be endowed with strong adjuvant capacity when co-administered with purified antigenic proteins. In the present study we assessed whether spores possess adjuvant properties when combined with DNA vaccines. We showed that B. subtilis spores promoted the activation of dendritic cells in vitro and induced migration of pro-inflammatory cells after parenteral administration to mice. Likewise, co-administration of spores with a DNA vaccine encoding the human papillomavirus type 16 (HPV-16) E7 protein enhanced the activation of antigen-specific CD8(+) T cell responses in vivo. Mice immunized with the DNA vaccine admixed with spores presented a protective immunity increase to previously implanted tumor cells, capable of expressing HPV-16 oncoproteins. Finally, we observed that the adjuvant effect can vary accordingly to the number of co-administered spores which may be ascribed with the ability to induce. Collectively, the present results demonstrate for the first time that B. subtilis spores can also confer adjuvant effects to DNA vaccines., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Study Objective: To show the technique of interval laparoscopic isthmocervical cerclage using cotton cardiac tape., Design: Case report (Canadian Task Force Classification III)., Setting: A private practice hospital in Brasília, Brazil., Patient: A 36-year-old female patient with primary infertility for 2 years caused by previous amputation of the cervix because of intraepithelial neoplasia. There was no other suspected factor for infertility. Before undergoing in vitro fertilization, she was referred for interval cerclage because of anticipated cervical insufficiency during an eventual pregnancy. The patient's clinical history was unremarkable, except for the fact that she had developed secondary dysmenorrhea since the amputation, which prompted her to undergo cervical dilatation on 2 occasions. During the physical examination, we noted the absence of the exocervix, a mobile and normal-sized uterus and adnexa, and no pain. Informed consent was obtained from the patient for this case report. The local institutional review board considered this report exempt from approval., Interventions: The procedure was performed according to the technique described by Pereira et al. We incised the visceral peritoneum in the anterior cul-de-sac and developed the vesicouterine space for complete exposure of the uterine isthmus. Then, we incised the posterior leaf of both broad ligaments superiorly to the uterosacral ligaments and medially to the ureter and uterine vessels. We aimed to identify the bifurcation of the uterine artery and to create a "window" between them and the isthmus to place the cerclage tape. For this purpose, we used a 5-mm 36-cm blunt tip retractor for gastric banding (ref 30623G; Karl Storz, Tuttlingen, Germany) to transfix the broad ligament, anteriorly to posteriorly, under direct vision. We tied 2-0 Vicryl (Ethicon, Sommerville, NJ) sutures to the tips of 0.3 × 80 cm cotton cardiac tape (reference FAB-46; Ethicon) and pulled both edges of the tape through the windows in the broad ligament. The final position of the tape was inferior and medial to the main ascending branch of the uterine artery, right over the isthmus, and without any vessels interposed between them. This is to avoid any possible compression and congestion with uterine progressive enlargement as pregnancy proceeds. We then made 6 square knots in the anterior cul-de-sac and adjusted the tension-free tape firmly enough to give the uterine corpus support during pregnancy evolution. Finally, we closed the visceral peritoneum with a 3-0 PDS running suture (Ethicon)., Measurements and Main Results: The surgery lasted 70 minutes, and bleeding was minimal. The patient was discharged the following day. She is currently undergoing her 18th week of pregnancy resulting from in vitro fertilization treatment, and we wait for her obstetric results., Conclusion: Cotton cardiac tape is feasible for laparoscopic cerclage and can be used as an alternative to the commonly used Mersilene tape (Ethicon). Laparoscopy safely allows tape placement medial to the uterine vessels. Additional cases are necessary to establish the obstetric effectiveness of cotton cardiac tape for laparoscopic cerclage., (Copyright © 2015 AAGL. Published by Elsevier Inc. All rights reserved.)

Although many preclinical studies have implicated β3 integrin receptors (αvβ3 and αIIbβ3) in cancer progression, β3 inhibitors have shown only modest efficacy in patients with advanced solid tumours. The limited efficacy of β3 inhibitors in patients could arise from our incomplete understanding of the precise function of β3 integrin and, consequently, inappropriate clinical application. Data from animal studies are conflicting and indicate heterogeneity with respect to the relative contributions of β3-expressing tumour and stromal cell populations in different cancers. Here we aimed to clarify the function and relative contributions to metastasis of tumour versus stromal β3 integrin in clinically relevant models of spontaneous breast cancer metastasis, with particular emphasis on bone metastasis. We show that stable down-regulation of tumour β3 integrin dramatically impairs spontaneous (but not experimental) metastasis to bone and lung without affecting primary tumour growth in the mammary gland. Unexpectedly, and in contrast to subcutaneous tumours, orthotopic tumour vascularity, growth and spontaneous metastasis were not altered in mice null for β3 integrin. Tumour β3 integrin promoted migration, protease expression and trans-endothelial migration in vitro and increased vascular dissemination in vivo, but was not necessary for bone colonization in experimental metastasis assays. We conclude that tumour, rather than stromal, β3 expression is essential and is required early for efficient spontaneous breast cancer metastasis to bone and soft tissues. Accordingly, differential gene expression analysis in cohorts of breast cancer patients showed a strong association between high β3 expression, early metastasis and shorter disease-free survival in patients with oestrogen receptor-negative tumours. We propose that β3 inhibitors may be more efficacious if used in a neoadjuvant setting, rather than after metastases are established., (Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Aims: To investigate the relationship between angina pectoris and fatal and non-fatal clinical outcomes in heart failure with reduced and preserved ejection fraction (HF-REF and HF-PEF, respectively)., Methods and Results: Of 7599 patients in the CHARM program, 5408 had ischaemic heart disease; 3855 had HF-REF (ejection fraction ≤45%) and 1553 had HF-PEF. These patients were separated into three groups: no history of angina, previous angina, and current angina. Three coronary outcomes were examined: fatal or non-fatal myocardial infarction (MI); MI or hospitalization for unstable angina (UA); and MI, UA or coronary revascularization. The composite heart failure outcome of cardiovascular death or heart failure hospitalization (HFH) was also analysed, along with its components and all-cause mortality. New York Heart Association functional class was worse in both HF-REF and HF-PEF patients with current angina compared with patients without angina (P < 0.001 and P = 0.005 respectively), despite similar clinical examination findings and ejection fraction. Patients with current angina had a higher risk of all three coronary outcomes (adjusted hazard ratios ranging from 1.8-3.1) than those without angina but did not have a higher risk of heart failure outcomes or all-cause mortality., Conclusion: In patients with heart failure current angina is associated with significantly more functional limitation and a higher risk of coronary events, across the spectrum of left ventricular ejection fraction., (© 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.)

One of the most important features of malignant cells is their capacity to invade adjacent tissues and metastasize to distant organs. This process involves the creation, by tumor and stroma cells, of a specific microenvironment, suitable for proliferation, migration and invasion of tumor cells. The ADAM family of proteins has been involved in these processes. This work aimed to investigate the role of the recombinant disintegrin domain of the human ADAM9 (rADAM9D) on the adhesive and mobility properties of DU145 prostate tumor cells. rADAM9D was able to support DU145 cell adhesion, inhibit the migration of DU145 cells, as well as the invasion of this cell line through matrigel in vitro. Overall this work demonstrates that rADAM9D induces specific cellular migratory properties when compared with different constructs having additional domains, specially those of metalloproteinase and cysteine-rich domains. Furthermore, we showed that rADAM9D was able to inhibit cell adhesion, migration and invasion mainly through interacting with α6β1 in DU145 tumor cell line. These results may contribute to the development of new therapeutic strategies for prostate cancer.

Aim: Angina pectoris is common in patients with heart failure and reduced ejection fraction (HF-REF) but its relationship with outcomes has not been well defined. This relationship was investigated further in a retrospective analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)., Methods and Results: Four thousand, eight hundred and seventy-eight patients were divided into three categories: no history of angina and no chest pain at baseline (Group A; n = 1240), past history of angina but no chest pain at baseline (Group B; n = 1353) and both a history of angina and chest pain at baseline (Group C; n = 2285). Outcomes were examined using Kaplan-Meier and Cox regression survival analysis. Compared with Group A, Group C had a higher risk of non-fatal myocardial infarction or unstable angina (HR: 2.36, 1.54-3.61; P < 0.001), this composite plus coronary revascularization (HR: 2.54, 1.76-3.68; P < 0.001), as well as HF hospitalization (HR: 1.35, 1.13-1.63; P = 0.001), over a median follow-up period of 33 months. There was no difference in cardiovascular or all-cause mortality. Group B had a smaller increase in risk of coronary events but not of heart failure hospitalization., Conclusion: Patients with HF-REF and ongoing angina are at an increased risk of acute coronary syndrome and HF hospitalization. Whether these patients would benefit from more aggressive medical therapy or percutaneous revascularization is not known and merits further investigation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Pharmacoinvasive treatment is an acceptable alternative for patients with ST-segment elevation myocardial infarction (STEMI) in developing countries. The present study evaluated the influence of gender on the risks of death and major adverse cardiovascular events (MACE) in this population. Seven municipal emergency rooms and the Emergency Mobile Healthcare Service in São Paulo treated STEMI patients with tenecteplase. The patients were subsequently transferred to a tertiary teaching hospital for early (<24 h) coronary angiography. A total of 469 patients were evaluated [329 men (70.1%)]. Compared to men, women had more advanced age (60.2 ± 12.3 vs. 56.5 ± 11 years; p = 0.002); lower body mass index (BMI; 25.85 ± 5.07 vs. 27.04 ± 4.26 kg/m2; p = 0.009); higher rates of hypertension (70.7 vs. 59.3%, p = 0.02); higher incidence of hypothyroidism (20.0 vs. 5.5%; p < 0.001), chronic renal failure (10.0 vs. 8.8%; p = 0.68), peripheral vascular disease (PVD; 19.3 vs. 4.3%; p = 0.03), and previous history of stroke (6.4 vs. 1.3%; p = 0.13); and higher thrombolysis in myocardial infarction risk scores (40.0 vs. 23.7%; p < 0.001). The overall in-hospital mortality and MACE rates for women versus men were 9.3 versus 4.9% (p = 0.07) and 12.9 versus 7.9% (p = 0.09), respectively. By multivariate analysis, diabetes (OR 4.15; 95% CI 1.86-9.25; p = 0.001), previous stroke (OR 4.81; 95% CI 1.49-15.52; p = 0.009), and hypothyroidism (OR 3.75; 95% CI 1.44-9.81; p = 0.007), were independent predictors of mortality, whereas diabetes (OR 2.05; 95% CI 1.03-4.06; p = 0.04), PVD (OR 2.38; 95% CI 0.88-6.43; p = 0.08), were predictors of MACE. In STEMI patients undergoing pharmacoinvasive strategy, mortality and MACE rates were twice as high in women; however, this was due to a higher prevalence of risk factors and not gender itself.

Tryptophan (TRP) is essential for many physiological processes, and its metabolism changes in some diseases such as infection and cancer. The most studied aspects of TRP metabolism are the kynurenine and serotonin pathways. A minor metabolic route, tryptamine and N,N-dimethyltryptamine (DMT) biosynthesis, has received far less attention, probably because of the very low amounts of these compounds detected only in some tissues, which has led them to be collectively considered as trace amines. In a previous study, we showed a metabolic interrelationship for TRP in melanoma cell lines. Here, we identified DMT and N,N-dimethyl-N-formyl-kynuramine (DMFK) in the supernatant of cultured SK-Mel-147 cells. Furthermore, when we added DMT to the cell culture, we found hydroxy-DMT (OH-DMT) and indole acetic acid (IAA) in the cell supernatant at 24 h. We found that SK-Mel-147 cells expressed mRNA for myeloperoxidase (MPO) and also had peroxidase activity. We further found that DMT oxidation was catalyzed by peroxidases. DMT oxidation by horseradish peroxidase, H2O2 and MPO from PMA-activated neutrophils produced DMFK, N,N-dimethyl-kynuramine (DMK) and OH-DMT. Oxidation of DMT by peroxidases apparently uses the common peroxidase cycle involving the native enzyme, compound I and compound II. In conclusion, this study describes a possible alternative metabolic pathway for DMT involving peroxidases that has not previously been described in humans and identifies DMT and metabolites in a melanoma cell line. The extension of these findings to other cell types and the biological effects of DMT and its metabolites on cell proliferation and function are key questions for future studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Very large, locally advanced non-small cell lung cancers (NSCLC) remain a therapeutic challenge. This retrospective study compares the effect of treatment modalities on survival of patients with large NSCLC with hilar lymph node involvement (T3>7 cmN1)., Methods: The National Cancer Data Base was used to identify adult patients who were diagnosed with T3>7 cmN1 NSCLC from 1999 to 2005 (n=642). Nonsurgical treatments included chemoradiation, chemotherapy, radiation therapy, or no treatment, whereas primary surgical treatments included surgery, chemoradiation or chemotherapy prior to surgery, chemoradiation or chemotherapy after surgery, or postoperative radiotherapy. Five-year overall survival (OS) was estimated by the Kaplan-Meier method and comparisons made using log-rank tests and Cox regression models., Results: A total of 642 patients were evaluated; 425 nonsurgical (66%) and 217 surgical (34%). Primary surgical therapy was associated with improved 5-year OS; 28% versus 8% and 4% for nonsurgical and no treatment, respectively (p<0.001). The 5-year OS were 11%, 5%, 2%, and 4% for chemoradiation, chemotherapy, radiation therapy, and no treatment, respectively (p<0.001). The 5-year OS were 16% for surgery only, 40% and 44% for neoadjuvant chemoradiation or chemotherapy with surgery, respectively, 40% and 38% for adjuvant chemoradiation or chemotherapy with surgery, respectively, and 18% for postoperative radiotherapy (p<0.001). On multivariate analysis, surgery and chemotherapy in most combinations were associated with significantly improved OS compared with chemoradiation only., Conclusions: Surgery with systemic therapy delivered in a neoadjuvant or adjuvant fashion for patients with T3>7 cmN1 NSCLCs is associated with improvements in OS., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to examine the relationship between fatigue and clinical outcomes, using dyspnea as a comparator, in patients with left ventricular ejection fraction (LVEF) ≤35% enrolled in the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study., Background: Although fatigue is a common symptom in heart failure (HF), little is known about its association with prognosis., Methods: At baseline in CORONA, fatigue "during the past few days" was measured using a 5-point exertion scale (0 = none, 1 = heavy exertion, 2 = moderate exertion, 3 = slight exertion, 4 = rest); a 4-point scale was used for dyspnea (1 to 4 as for fatigue). Patients were grouped into 3 categories: a fatigue score 0 to 1 (n = 535), fatigue score 2 (n = 1,632), and fatigue score 3 to 4 (n = 1,663); and a dyspnea score of 1 (n = 292), dyspnea score of 2 (n = 1,695), and dyspnea score of 3 to 4 (n = 1,843). The association between fatigue and dyspnea and the composite outcome of cardiovascular (CV) death or HF hospital stay and each component separately was examined using Kaplan-Meier analysis and Cox proportional-hazard models. We also examined all-cause mortality., Results: In univariate analyses, symptom severity was associated with a higher risk of CV death or HF hospital stay (fatigue: group 3, 49% [n = 810], vs. group 1, 30% [n = 160]; dyspnea: group 3, 50% [n = 918], vs. group 1, 28% [n = 82]) and all-cause mortality (fatigue: group 3, 38% [n = 623], vs. group 1, 24% [n = 130]; dyspnea: group 3, 38% [n = 697], vs. group 1, 23% [n = 66], log-rank p < 0.0001 for all). After adjusting for other prognostic variables, including LVEF, New York Heart Association class, and N-terminal pro-B-type natriuretic peptide level, worse fatigue remained associated with higher risk of HF hospital stay but not mortality (worse dyspnea remained associated with a higher risk of both). An increase in fatigue (or dyspnea) between baseline and 6 months was also associated with worse outcomes., Conclusions: In HF, greater fatigue is associated with worse clinical outcomes. Closer attention should be paid to this symptom in clinical practice, with more done to standardize its measurement and understand its origins, with a view to improving treatment., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Indoleamine 2,3-dioxygenase 1 (IDO1), the rate-limiting enzyme of tryptophan catabolism, has been strongly associated with the progression of malignancy and poor survival in melanoma patients. As a result, IDO1 is a leading target for interventions aimed at restoring melanoma immune surveillance. Here, in a scenario involving the tryptophan catabolism, we report that melatonin biosynthesis is driven by 1-methyl-tryptophan (1-MT), a competitive inhibitor of IDO1, in human fibroblasts, melanocytes and melanoma cells. In addition to melatonin biosynthesis, 1-MT induced the expression of tryptophan hydroxylase, arylalkylamine-N-acetyltransferase and hydroxyindole O-methyltransferase mRNA in fibroblasts and melanocytes. We observed a great variability in the levels of IDO1 mRNA expression and kynurenine release between skin cells and melanoma cell lines in response to interferon-γ, a classical IDO1 inducer. In this setting, melatonin was shown to downregulate kynurenine production. Furthermore, in a condition of low basal activity of IDO1, it was observed that 1-MT, as well melatonin, inhibited the proliferation of human melanoma cells. Taken together, our results suggest that 1-MT may serve as more than just a tool to disrupt tumor immune escape (via the inhibition of IDO1) because it was shown to act directly on the proliferation of human melanoma cells and induce melatonin biosynthesis in the tumor milieu. Moreover, 1-MT-mediated inhibition of IDO occurs in normal skin and melanoma cells, which addresses the possibility that all cells in the skin microenvironment can be targeted by 1-MT. Our findings provide innovative approaches into understanding tumor therapy related to the control of tryptophan metabolism by 1-MT., (© 2013 FEBS.)

Background: Very large non-small cell lung cancers (NSCLC) remain a therapeutic challenge. The objective of this study was to evaluate the effect of surgery in the presence and absence of neoadjuvant radiation (NRT) on survival of patients with T3N0 >7-cm NSCLCs., Materials and Methods: The Surveillance, Epidemiology, and End Results database was used to identify patients undergoing lobectomy or pneumonectomy for T3N0 NSCLC tumors >7 cm from 1999-2008. Patients were categorized into groups based on type of surgery performed and whether NRT was used. Five-year overall (OS) and lung cancer-specific survival (LCSS) were estimated by the Kaplan-Meier method and comparisons made using log-rank tests and Cox regression models., Results: There were 1301 patients evaluated, including 1232 undergoing primary surgical therapy (PST) and 69 receiving NRT. NRT was not associated with improvements in 5-y OS (48% versus 41%, P = 0.062) or LCSS (59% versus 52%, P = 0.116) compared with PST. Lobectomies were associated with better 5-y OS (43% versus 33%; P = 0.006) and LCSS (54% versus 43%, P = 0.005) compared with pneumonectomies. On multivariate analysis, NRT did not produce any significant advantage in OS (P = 0.242) and LCSS (P = 0.208). Pneumonectomies were associated with significantly worse OS (hazard ratio, 1.32; P = 0.007) and LCSS (hazard ratio, 1.38; P = 0.005) when compared with lobectomies., Conclusions: NRT, which most likely was a combination of chemotherapy and radiation, was not associated with improvements in OS or LCSS in patients with T3N0 >7-cm NSCLC compared with PST. When feasible, lobectomy appears more beneficial than pneumonectomy in terms of long-term survival for very large tumors., (Copyright © 2013 Elsevier Inc. All rights reserved.)

ADAM9 (A Disintegrin And Metalloproteinase 9) is a member of the ADAM protein family which contains a disintegrin domain. This protein family plays key roles in many physiological processes, including fertilization, migration, and cell survival. The ADAM proteins have also been implicated in various diseases, including cancer. Specifically, ADAM9 has been suggested to be involved in metastasis. To address this question, we generated ADAM9 knockdown clones of MDA-MB-231 breast tumor cells using silencing RNAs that were tested for cell adhesion, proliferation, migration and invasion assays. In RNAi-mediated ADAM9 silenced MDA-MB-231 cells, the expression of ADAM9 was lower from the third to the sixth day after silencing and inhibited tumor cell invasion in matrigel by approximately 72% when compared to control cells, without affecting cell adhesion, proliferation or migration. In conclusion, the generation of MDA-MB-231 knockdown clones lacking ADAM9 expression inhibited tumor cell invasion in vitro, suggesting that ADAM9 is an important molecule in the processes of invasion and metastasis., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

We examined the effects of hypertonic saline (HS) on inflammatory, metabolic variables, and bacterial translocation (BT) in rats submitted to intestinal obstruction and ischemia (IO). Male Wistar rats were submitted to IO and treated, 2 h thereafter, with lactated Ringer's (LR) (4 mL/kg per 5 min, i.v.) or HS (7.5% NaCl, 4 mL/kg per 5 min, i.v.). Twenty-four hours after IO, rats were also submitted to enterectomy/enteroanastomosis to resection of necrotized small bowel. Leukocyte-endothelial interactions were investigated by intravital microscopy and the expression of P-selectin and intercellular adhesion molecule 1 by immunohistochemistry. Bacterial cultures of mesenteric lymph nodes, liver, spleen, and blood were used to evaluate BT. Levels of chemokines (cytokine-induced neutrophil chemoattractants 1 and 2), insulin, and corticosterone were determined by enzyme-linked immunosorbent assay. Intestinal histology, serum urea and creatinine levels, and hepatic enzymes activities were performed to evaluate local and remote damage. Relative to IO and LR-treated rats, which exhibited increases in the number of rolling (1.5-fold), adhered (3.5-fold) and migrated (9.0-fold) leukocytes, and increased expression of P-selectin (3-fold) and intercellular adhesion molecule 1 (3-fold) on mesenteric microcirculation, treatment with HS followed by enterectomy reduced leukocyte-endothelial interactions and expression of both adhesion molecules to values attained in sham rats. Serum chemokines were normalized after treatment with both solutions followed by enterectomy. Hypertonic saline-treated rats demonstrated a significant reduction in BT to 50% in liver and spleen samples and bacteremia (14%), compared with 82% of BT in liver and spleen samples of IO and LR-treated rats and bacteremia (57%). Local intestinal damage was attenuated, and renal and hepatic function preserved by treatment with HS followed by enterectomy. Survival rate increased to 86% up to 15 days. Data presented suggest that HS solution followed by enterectomy reduces mesenteric microcirculatory dysfunctions and BT, attenuating local and remote damage in a model of strangulated small bowel obstruction.

Culture-independent molecular characterization of infecting Leptospira human blood specimens from a 2008 outbreak of human leptospirosis in central Sri Lanka was carried out. Of 58 quantitative real-time polymerase chain reaction-positive samples analyzed for seven multi-locus sequence typing (MLST) housekeeping genes (mreA, pfkB, pntA, sucA, tpiA, fadD, and glmU), interpretable data was obtained from 12 samples. Mean bacterial load was 2.2 × 10(5) among specimens with complete MLST profiles compared with 1.3 × 10(4) among specimens without complete MLST profiles; all specimens with complete profiles had at least 4.9 × 10(4) Leptospira/mL (t = 5, P < 0.001). Most (11/12) identified sequence types were ST1 (L. interrogans serovar Lai) and ST44 (L. interrogans serovar Geyaweera). MLST can be used to directly identify infecting Leptospira strains in blood samples obtained during acute illness without the need for culture isolation, but it shows important limitations related to bacterial load.

Background: The major cause of death in the city of São Paulo (SP) is cardiac events. At its periphery, in-hospital mortality in acute myocardial infarction is estimated to range between 15% and 20% due to difficulties inherent in large metropoles., Objective: To describe in-hospital mortality in ST-segment elevation acute myocardial infarction (STEMI) of patients admitted via ambulance or peripheral hospitals, which are part of a structured training network (STEMI Network)., Methods: Health care teams of four emergency services (Ermelino Matarazzo, Campo Limpo, Tatuapé and Saboya) of the periphery of the city of São Paulo and advanced ambulances of the Emergency Mobile Health Care Service (abbreviation in Portuguese, SAMU) were trained to use tenecteplase or to refer for primary angioplasty. A central office for electrocardiogram reading was used. After thrombolysis, the patient was sent to a tertiary reference hospital to undergo cardiac catheterization immediately (in case of failed thrombolysis) or in 6 to 24 hours, if the patient was stable. Quantitative and qualitative variables were assessed by use of uni- and multivariate analysis., Results: From January 2010 to June 2011, 205 consecutive patients used the STEMI Network, and the findings were as follows: 87 anterior wall infarctions; 11 left bundle-branch blocks; 14 complete atrioventricular blocks; and 14 resuscitations after initial cardiorespiratory arrest. In-hospital mortality was 6.8% (14 patients), most of which due to cardiogenic shock, one hemorrhagic cerebrovascular accident, and one bleeding., Conclusion: The organization in the public health care system of a network for the treatment of STEMI, involving diagnosis, reperfusion, immediate transfer, and tertiary reference hospital, resulted in immediate improvement of STEMI outcomes.

Background: Quantitative polymerase chain reaction (qPCR), despite cost and logistical challenges, has the potential to provide accurate and timely diagnosis for leptospirosis at the point-of-care in endemic areas. We studied optimal sample types for qPCR, timing of sampling, and clinical manifestations in relation to quantitative leptospiremia., Methods: A new qPCR assay using pathogenic Leptospira-specific 16S ribosomal RNA (rRNA) gene Taqman primers and an optimized temperature stepdown protocol was used to analyze patient blood samples. Serum was compared with whole blood as sample source. Quantitative leptospiremia was compared with clinical manifestations of leptospirosis and outcome., Results: The diagnostic sensitivity of qPCR of whole blood and serum was 18.4% (95% confidence interval [CI]: 9.97%-31.4%) and 51.0% (95% CI: 37.5%-64.4%) respectively. The qPCR on suspected cases confirmed infection in 58 of 381 cases (15.2%). Of these, 6 cases confirmed by nested polymerase chain reaction (PCR) and sequencing were serologically negative using a standard but not regionally optimized microscopic agglutination test panel. The bacterial load in serum/blood ranged from 10(2) to 10(6) Leptospira/mL. Median leptospiral load for uncomplicated, renal failure, myocarditis, and multi-organ failure patients were 8616, 11007, 36100, and 15882 Leptospira/mL respectively. The qPCR window of positivity ranged from day 2 to day 15; sensitivity of qPCR was not affected by the length of the interval between the onset of symptoms and sample collection (P = .328)., Conclusions: Quantitative PCR shows potential as a valid diagnostic test with a wider window of positivity than previously thought. Quantitative leptospiremia in serum/whole blood samples did not directly correlate with clinical manifestations of outcome in this patient population.

This study evaluated the polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) analysis of fliC for typing flagella antigen (H) of Shiga toxin-producing Escherichia coli (STEC) and enteropathogenic E. coli (EPEC) strains isolated from different animals. The molecular typing of the H type was efficient in the determination of 93 (85%) strains. Two nonmotile (H-) E. coli strains showed a PCR-RFLP electrophoretic profile that did not match known H type patterns. The fliC nucleotide sequence of strains B2N and 4a revealed a nucleotide substitution at the restriction site and a nucleotide insertion that generated a stop codon, respectively. The results of this study showed that PCR-RFLP analysis of fliC is faster, less laborious and as efficient for the determination of H type E. coli isolated from animals, compared to serotyping and that it is useful in determining H type in nonmotile strains and strains expressing non-reactive H antigens. Moreover, the fliC sequence of strain B2N suggests that we could have found a new flagellin antigen type., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The innate and adaptive immune responses of dendritic cells (DCs) to enteroinvasive Escherichia coli (EIEC) infection were compared with DC responses to Shigella flexneri infection. EIEC triggered DCs to produce interleukin (IL)-10, IL-12 and tumour necrosis factor (TNF)-α, whereas S. flexneri induced only the production of TNF-α. Unlike S. flexneri, EIEC strongly increased the expression of toll like receptor (TLR)-4 and TLR-5 in DCs and diminished the expression of co-stimulatory molecules that may cooperate to inhibit CD4(+) T-lymphocyte proliferation. The inflammation elicited by EIEC seems to be related to innate immunity both because of the aforementioned results and because only EIEC were able to stimulate DC transmigration across polarised Caco-2 cell monolayers, a mechanism likely to be associated with the secretion of CC chemokine ligands (CCL)20 and TNF-α. Understanding intestinal DC biology is critical to unravelling the infection strategies of EIEC and may aid in the design of treatments for infectious diseases.

Unlabelled: Auditory plasticity refers to the possibility of anatomical and/or functional changes in the system where transmission of auditory information takes place. The auditory system is often required in communication; it is important to learn how the auditory system reacts to stimuli in order to improve performance in individual communication of subjects with impaired hearing., Aim: To review the literature on auditory plasticity and the possibility and ability of plastic responses in the auditory system; also to review the evidence of auditory plasticity., Methodology: A review of the Brazilian and international literature (journals, books, and graduate studies) was carried out. The MEDLINE, SCIELO, BIREME, PUBMED, and LILACS data bases were consulted, as well as 24 papers from the 1990s to the present date; each paper was assessed for relevance to the topic., Conclusion: The findings showed that the auditory system is able to reorganize itself if there is variation, whether by by reducing, increasing, or conditioning of sound stimuli. This is evidence of plasticity in the auditory system.

TLRs (Toll-like receptors) provide a mechanism for host defence immune responses. Activated TLRs lead to the recruitment of adaptor proteins to their cytosolic tails, which in turn promote the activation of IRAKs (interleukin-1 receptor-associated kinases). IRAKs act upon their transcription factor targets to influence the expression of genes involved in the immune response. Tollip (Toll-interacting protein) modulates IRAK function in the TLR signalling pathway. Tollip is multimodular, with a conserved C2 domain of unknown function. We found that the Tollip C2 domain preferentially interacts with phosphoinositides, most notably with PtdIns3P (phosphatidylinositol 3-phosphate) and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate), in a Ca2+-independent manner. However, NMR analysis demonstrates that the Tollip C2 domain binds Ca2+, which may be required to target the membrane interface. NMR and lipid-protein overlay analyses suggest that PtdIns3P and PtdIns(4,5)P2 share interacting residues in the protein. Kinetic studies reveal that the C2 domain reversibly binds PtdIns3P and PtdIns(4,5)P2, with affinity values in the low micromolar range. Mutational analysis identifies key PtdIns3P- and PtdIns(4,5)P2-binding conserved basic residues in the protein. Our findings suggest that basic residues of the C2 domain mediate membrane targeting of Tollip by interaction with phosphoinositides, which contribute to the observed partition of the protein in different subcellular compartments.

Ganoderma lucidum, a traditional Chinese medicine, has been shown to target the Central Nervous System. In this work we analyze whether G. lucidum, collected in Mexico, has a protective effect in the hippocampus of rats treated with kainic acid, a neurotoxin that causes seizures and neuronal loss. The aqueous extract of G. lucidum (10 mg/Kg, i.p.) was administered to rats 30 min before kainic acid injection (5 mg/Kg, i.p.). Animals that had received prior treatment with G. lucidum showed no tonic-clonic seizure activity. Histopathological analysis showed a significant decrease in neuronal loss and cellular alterations in the hippocampal CA3 region. Immunohistochemical analysis shows that when using G. lucidum in rats, there is less immunoreactivity for GFAP as well as TNF-alpha and IL-1beta in the CA3 region when compared with rats treated with kainic acid. Our results demonstrate that G. lucidum protects against kainic acid-induced alterations of hippocampal cells and expression of immunological markers in this model of excitotoxicity.

Enteroinvasive Escherichia coli (EIEC) and Shigella spp cause bacillary dysentery in humans by invading and multiplying within epithelial cells of the colonic mucosa. Although EIEC and Shigella share many genetic and biochemical similarities, the illness caused by Shigella is more severe. Thus, genomic and structure-function molecular studies on the biological interactions of these invasive enterobacteria with eukaryotic cells have focused on Shigella rather than EIEC. Here we comparatively studied the interactions of EIEC and of Shigella flexneri with cultured J774 macrophage-like cells. We evaluated several phenotypes: (i) bacterial escape from macrophages after phagocytosis, (ii) macrophage death induced by EIEC and S. flexneri, (iii) macrophage cytokine expression in response to infection and (iv) expression of plasmidial (pINV) virulence genes. The results showed that S. flexneri caused macrophage killing earlier and more intensely than EIEC. Both pathogens induced significant macrophage production of TNF, IL-1 and IL-10 after 7 h of infection. Transcription levels of the gene invasion plasmid antigen-C were lower in EIEC than in S. flexneri throughout the course of the infection; this could explain the diminished virulence of EIEC compared to S. flexneri.