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ObjectivesWe examined the association between comorbidity and long-term mortality from breast cancer and other causes among African-American and white women with breast cancer. MethodsA total of 170 African-American and 829 white women aged 40-84. years were followed for up to 28. years with median follow-up of 11.3 years in the Health and Functioning in Women (HFW) study. The impact of the Charlson Comorbidity Score (CCS) in the first few months following breast cancer diagnosis on the risk of mortality from breast cancer and other causes was examined using extended Cox models. ResultsMedian follow-up was significantly shorter for African-American women than their white counterparts (median 8.5 years vs. 12.3 years). Compared to white women, African-American women had significantly fewer years of education, greater body mass index, were more likely to have functional limitations and later stage at breast cancer diagnosis, and fewer had adequate financial resources (all P < 0.05). Proportionately more African-American women died of breast cancer than white women (37.1% vs. 31.4%, P = 0.15). A positive and statistically significant time-varying effect of the Charlson Comorbidity Score (CCS) on other-cause mortality persisted throughout the first 5. years of follow-up (P < 0.001) but not for its remainder. Conclusions Higher CCS was associated with increased risk of other-cause mortality, but not breast cancer specific mortality; the association did not differ among African-American and white women. © 2014 Elsevier Inc.

The prognosis of cervical cancer is linked to lymph node involvement, and this is predicted clinically and pathologically by the stage of the disease, as well as the volume and grade of the tumor. Staging of cervical cancer based on International Federation of Gynecology and Obstetrics (FIGO) staging uses physical examination, cystoscopy, proctoscopy, intravenous urography, and barium enema. It does not include CT or MRI. Evaluation of the parametrium is limited in FIGO staging, and lymph node metastasis, an important prognostic factor, is not included in FIGO staging. The most important role for imaging is to distinguish stages Ia, Ib, and IIa disease treated with surgery from advanced disease treated with radiation therapy with or without chemotherapy. This article reviews the current role of imaging in pretreatment planning of invasive cervical cancer. The ACR Appropriateness Criteria((R)) are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. [ABSTRACT FROM AUTHOR]

Background: Many oncologists consult the Adjuvant! prognostic model to communicate risk with breast cancer patients; however, little is known about how effective that communication is.Methods: The authors analyzed this small data set featuring 20 breast cancer patients' risk estimates, focusing on rankings or gist of the estimates.Results: Overall, there was no gain in the accuracy of patient rankings. The number of patients with more accurate estimates was matched by the number of patients with less accurate estimates after consultation.Conclusions: The current methods used by oncologists to present Adjuvant! risks were not effective in helping patients to get the gist of their risks. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We examined the reach and impact of five decision aids (DAs) routinely distributed to breast cancer patients as part of a shared decision making demonstration project. METHODS: From 2005 to 2008, we surveyed patients' change in knowledge and decisional conflict (DC) before and after their review of DAs. Using bivariate tests, we identified significant predictors of change in knowledge or decisional conflict and entered significant predictors into a multivariate regression model. RESULTS: We distributed 1553 DAs to 1098 patients and received 549 completed surveys. The DAs were associated with increased knowledge and decreased DC. For knowledge, significant predictors of above-average change included: lower baseline knowledge and viewing the surgery decision aid. For decisional conflict, significant predictors of above-average change included: higher decisional conflict; viewing any of the early-stage cancer DAs; and Hispanic ethnicity. CONCLUSIONS: DAs used in routine care were associated with significant knowledge gains and reductions in decisional conflict. Some subsets of patients (those reporting low baseline knowledge, high DC, or Hispanic ethnicity) may benefit more than others. PRACTICE IMPLICATIONS: Breast cancer patients benefit overall from routine distribution of DAs. Our exploratory findings may be useful in generating hypotheses to identify target populations who would most benefit from reviewing DAs. [ABSTRACT FROM AUTHOR]

BACKGROUND: While data are conflicting, studies have appeared in the literature suggesting that mental intentions sent from a distance (eg, intercessory prayer, spiritual healing) can possibly influence clinical outcomes in patients suffering from an array of medical conditions. The purpose of this study was to examine the potential efficacy of distant healing in a population of patients with human immunodeficiency virus (HIV)/aquired immune deficiency syndrome (AIDS). METHODS: One hundred fifty-six patients with a history of AIDS category C and at least one AIDS-defining opportunistic infection were randomized to 1 of 3 study arms: (1) 10 weeks of prayer/distant healing from professional healers, (2) 10 weeks of prayer/distant healing from nurses with no prior training or experience in distant healing, or, (3) no distant healing. RESULTS: No significant treatment effects of distant healing were observed for either professional healers or nurses on any of the primary or secondary outcomes. Despite being blind to group assignment, subjects receiving distant healing (from healers or nurses) were significantly more likely to guess that they had been receiving healing than were subjects randomized to the no-treatment control group. CONCLUSIONS: Distant healing or prayer from a distance does not appear to improve selected clinical outcomes in HIV patients who are on a combination antiretroviral therapy. [ABSTRACT FROM AUTHOR]

Estrogenic overstimulation is carcinogenic to the human breast. Personal care products (PCPs) commonly contain xenoestrogens (XE), such as parabens and phthalates. Here, we identified the adverse effects of persistent exposure to such PCPs directly within human estrogen responsive breast tissue of subjects enrolled in a regimen of reduced XE use (REDUXE). Pre- and post-intervention fine needle aspirates (FNAs) of the breast were collected from healthy volunteers who discontinued the use of paraben and phthalate containing PCPs over a 28 d period. Based on high-dimensional gene expression data of matched FNA pairs of study subjects, we demonstrate a striking reversal of cancer-associated phenotypes, including the PI3K-AKT/mTOR pathway, autophagy, and apoptotic signaling networks within breast cells of REDUXE compliant subjects. These, and other altered phenotypes were detected together with a significant reduction in urinary parabens and phthalate metabolites. Moreover, in vitro treatment of paired FNAs with 17β-estradiol (E2), displayed a 'normalizing' impact of REDUXE on gene expression within known E2-modulated pathways, and on functional endpoints, including estrogen receptor alpha: beta ratio, and S-phase fraction of the cell cycle. In a paradigm shifting approach facilitated by community-based participatory research, REDUXE reveals unfavorable consequences from exposure to XEs from daily-use PCPs. Our findings illustrate the potential for REDUXE to suppress pro-carcinogenic phenotypes at the cellular level towards the goal of breast cancer prevention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Objective: To determine whether a non‑platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma., Methods: Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m 2 plus topotecan 0.75 mg/m 2 days 1-3 (n = 223) vs cisplatin 50 mg/m 2 plus paclitaxel 135 or 175 mg/m 2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS., Results: At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91-1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82-1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86-1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86-1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75-1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones., Conclusions: Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. NCT00803062., Competing Interests: Declaration of Competing Interest Dr. Tewari reports receiving honoraria for lectures, presentations, speakers' bureaus for Merck, Astra Zeneca, Eisai, Seagen, Tesaro and Clovis. He also reports serving on Data Safety Monitoring Board/Advisory Board for Iovance. Dr. Penson reports grants received from Array BioPharma Inc., AstraZeneca, Eisai Inc., Genentech, Inc., Regeneron, Sanofi-Aventis US LLC, Tesaro Inc. and Vascular Biogenics Ltd. Dr. Penson also reports receiving consulting fees from AstraZeneca, Eisai, GSK Inc., ImmunoGen Inc., Merck & Co, Mersana, Novacure, Roche Pharma, Sutro Biopharma, and Vascular Biogenics Ltd. and reports participating on Advisory Boards for AstraZeneca and Roche Pharma. Dr. Oaknin reports grants to her institution from the following: Abbvie Deutschland Gmbh & Co Hg, Ability Pharmaceuticals, Advaxis, Agenus, Aprea Therapeutics AB, AstraZeneca AB, BeiGene USA, Inc., Belgian Gynecological Oncology Group (BGOG), Bristol-Myers Squibb International Corporation (BMSM Clovis Oncology, Corcept Therapeutics, Eisai, F. Hoffmann-La Roche, Grupo Española de Investigación en Cáncer de Ovario (GEICO)), Immunogen, Iovance Biotherapeutics, Lilly, Medimmune, Merck Healthcare, Merck Sharp & Dohme, Millennium Pharmaceuticals, Unipharm Research, Novartis Farmacéutica, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem. Dr. Oaknin also reports receiving consulting fees from: Agenus, AstraZeneca Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, ROCHE FARMA, Sattucklabs, and Sutro Biopharma, Inc., and GEICO. Dr. Oaknin reports personally receiving honoraria for lectures, presentations and Speakers bureaus from ESMO, Edizioni Minerva Medica SpA, Doctaforum Servicios S.L and received support for travel from Roche, AstraZeneca, PharmaMar as well as Clovis. Dr. Oaknin participated on Data Safety Monitoring Board/Advisory Board for Agenus, AstraZeneca Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, GOG, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, ROCHE FARMA, Sattucklabs and Sutro Biopharma. Dr. Leitao reports receiving consulting fees from Medtronic, honoraria for lectures from Intuitive Surgical, Inc. as an Ad-hoc Speaker and participating on an Advisory Board for JnJ/Ethicon. Dr. Monk reports receiving consulting fees from the following: Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, UmmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pleris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, Verastem and Zentalis. He also reports receiving honoraria from: AstraZeneca, Merck, Myriad, Tesaro/GSK, Roche/Genentech, Clovis and Easai. All other authors had no conflicts of interest to disclose with regard to this Study., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin + /anti-CD45 - cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0-18) and, at 36 days posttreatment, was 4 (range, 0-17). The greater the declination in CTCs between time points studied, the lower the risk of death [HR, 0.87; 95% confidence interval (CI), 0.79-0.95)]. Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32-1.03) and PFS (HR, 0.59; 95% CI, 0.36-0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker., (©2020 American Association for Cancer Research.)

Objective: The main aim of this systematic review was to establish the prevalence of pressure ulcers (PU) within published studies from Europe., Method: Using systematic review methodology, quantitative design studies which explored prevalence data and/or the epidemiology of PUs in Europe were considered. The primary outcome was PU prevalence. The search, conducted in April 2019, using Cochrane, Medline, Embase, CINAHL, PubMed, Scopus and Web of Science databases, returned 3065 records, of which 79 met the inclusion criteria. Data were extracted using a pre-designed extraction tool, and validity analysis was undertaken using the Evidence-Based Librarianship (EBL) Critical Appraisal Checklist., Results: We included 79 articles in this review. Across the studies, the median prevalence was 10.8% (standard deviation: 7%; range: 4.6-27.2%). The highest PU prevalence reported was from the Netherlands (27.2%; n=17,494 participants), and the lowest was reported from Finland (4.6%; n=629 participants). Almost 32.4% (n=151,195) of the PUs were category I and the most common site for PUs was the sacrum., Conclusion: The prevalence data is consistently high. These data indicate the continued need for further resource allocation into PU prevention and management.

Background: In recognition of the incidence of traumatic brain injuries (TBIs) in the Iraq and Afghanistan conflicts, the Department of Veterans Affairs (VA) has, since 2007, examined returning U.S. service members for symptoms of TBI, a pre-condition for VA treatment of TBI. This study characterizes "Traumatic Brain Injury screen" service delivery, according to the barrier and facilitator viewpoints of those experiencing the delivery., Methods: The purposeful sample comprised both Veteran patient and VA staff participants in the TBI screen program (n = 64), including patients (n = 14), health care providers (n = 38), and key informants (n = 12). Telephone interviews were conducted per standardized, semi-structured interview scripts; respondent narratives recorded and transcribed verbatim; natural emergence of key themes of discourse fostered through conventional content analysis; themes coded by meaning and meaning units organized by nature of influence on service delivery., Results: A wide variety of structural, administrative, and communications barriers impede TBI screen service delivery, and certain case management and other functions promote delivery., Conclusions: The value of VA TBI screen service delivery is appreciated by its participants, but delivery is perceived as vulnerable to failure; the extent of such failure and short- and long-term effects on patient health and well-being outcomes is incompletely understood and merits investigation. Evaluating VA TBI screen service delivery under alternate modes of delivery, e.g., one-stop visits, expanded hours of delivery, shared appointment sessions, telehealth, and intensified case management is suggested., (Published by Oxford University Press on behalf of Association of Military Surgeons of the United States 2018.)

As a continuous source of hormonal stimulation, environmentally ubiquitous estrogenic chemicals, ie, xenoestrogens (XEs), are a potential risk factor for breast carcinogenesis. Given their wide distribution in the environment and the fact that bisphenol-A (BPA), methylparaben (MP), and perfluorooctanoic acid (PFOA) are uniformly detected in unselected body fluid samples, it must be assumed that humans are simultaneously exposed to these chemicals almost daily. We studied the effects of a ternary mixture of BPA, MP, and PFOA on benign breast epithelial cells at the range of concentrations observed for single chemicals in human samples. Measurements of exposure impact relevant to the breast were based on endpoints associated with "hallmarks" of cancer and "key characteristics" of carcinogens. These included modulation of total estrogen receptor (ER)α, phosphorylated ERα (pERα), total ERβ, S-phase induction, and apoptotic evasion. Data from live cell measurements were fit to a log-linear dose-response model. Concentration-dependent reduction of ERβ and apoptosis evasion was observed concurrently with the induction of ERα, pERα, and S-phase fraction, and an increased rate of cell proliferation. Beyond additive effects predicted by the sum of individual test XEs, mixture treatment demonstrated synergism for the ERβ and apoptosis suppression phenotypes (p > .001). Nonmalignant breast cells were more sensitive than commonly used breast cancer lines to XE treatment in 3 of 5 endpoints. All observations were validated with cells isolated from the normal breast tissue of 14 individuals. At relatively low concentrations, a chemical mixture has striking effects on normal cell function that are missed by evaluation of single components.

Background: On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events., Methods: In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m 2 on day 1 or 2) plus paclitaxel (135 mg/m 2 or 175 mg/m 2 on day 1) or topotecan (0·75 mg/m 2 on days 1-3) plus paclitaxel (175 mg/m 2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062., Findings: Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death., Interpretation: The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer., Funding: National Cancer Institute., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18-85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.5, 2.5, 7.5, or 15 g/dose). Blood, urine and CSF samples, ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) were obtained throughout the trial. Disease progression was compared with matched historical placebo controls from five previous ALS therapeutic trials. Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems. Three patients died during the trial. L-serine was generally well tolerated by the patients and L-serine did not appear to accelerate functional decline of patients as measured by slope of their ALSFRS-R scores. Based on this small study, L-serine appears to be generally safe for patients with ALS.

Background: Imbalance of gamma aminobutyric acid (GABA) and related modulators has been implicated as an important factor in the pathogenesis of amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND). In this context, the role and mechanism of action of gabapentin and baclofen have been extensively investigated, although with conflicting results. This is the first systematic review to assess clinical trials of GABA modulators for the treatment of ALS., Objectives: To examine the efficacy of gabapentin, baclofen, or other GABA modulators in delaying the progression of ALS, and to evaluate adverse effects of these interventions, Search Methods: On 16 August 2016, we searched the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, AMED, and LILACS. In addition, we checked the bibliographies of the trials found in order to identify any other trials, and contacted trial authors to identify relevant unpublished results or additional clinical trials. On 30 August 2016, we searched two clinical trials registries., Selection Criteria: Types of studies: double-blind randomized controlled trials (RCTs) or quasi-RCTsTypes of participants: adults with a diagnosis of probable or definite ALSTypes of interventions: gabapentin, baclofen, or other GABA modulators compared with placebo, no treatment, or each otherPrimary outcome: survival at one year from study enrollmentSecondary outcomes: individual rate of decline of maximum voluntary isometric contraction (MVIC), expressed as arm megascore; rate of decline of per cent predicted forced vital capacity (FVC); rate of decline of ALS Functional Rating Scale (ALSFRS); health-related quality of life; survival evaluated by pooling hazards; and adverse events DATA COLLECTION AND ANALYSIS: At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies., Data Collection and Analysis: At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies., Main Results: We identified two double-blind RCTs of gabapentin treatment in ALS for inclusion in this review. We found no eligible RCTs of baclofen or other GABA modulators. The selected studies were phase II and phase III trials, which lasted six and nine months, respectively. They were highly comparable because both were comparisons of oral gabapentin and placebo, performed by the same investigators. The trials enrolled 355 participants with ALS: 80 in the gabapentin group and 72 in the placebo group in the first (phase II) trial and 101 in the gabapentin group and 102 in the placebo group in the second (phase III) trial. Neither trial was long enough to report survival at one year, which was our primary outcome. We found little or no difference in estimated one-year survival between the treated group and the placebo group (78% versus 77%, P = 0.63 by log-rank test; high-quality evidence). We also found little or no difference in the rate of decline of MVIC expressed as arm megascore, or rate of FVC decline (high-quality evidence). One trial investigated monthly decline in the ALSFRS and quality of life measured using the 12-Item Short Form Survey (SF-12) and found little or no difference between groups (moderate-quality evidence). The trials reported similar adverse events. Complaints that were clearly elevated in those taking gabapentin, based on analyses of the combined data, were light-headedness, drowsiness, and limb swelling (high-quality evidence). Fatigue and falls occurred more frequently with gabapentin than with placebo in one trial, but when we combined the data for fatigue from both trials, there was no clear difference between the groups. We assessed the overall risk of bias in the included trials as low., Authors' Conclusions: According to high-quality evidence, gabapentin is not effective in treating ALS. It does not extend survival, slow the rate of decline of muscle strength, respiratory function and, based on moderate-quality evidence, probably does not improve quality of life or slow monthly decline in the ALSFRS. Other GABA modulators have not been studied in randomized trials.

Objective: To determine the effect of age on completion of and toxicities following treatment of local regionally advanced cervical cancer (LACC) on Gynecologic Oncology Group (GOG) Phase I-III trials., Methods: An ancillary data analysis of GOG protocols 113, 120, 165, 219 data was performed. Wilcoxon, Pearson, and Kruskal-Wallis tests were used for univariate and multivariate analysis. Log rank tests were used to compare survival lengths., Results: One-thousand-three-hundred-nineteen women were included; 60.7% were Caucasian, 15% were age 60-70years and an additional 5% were >70; 87% had squamous histology, 55% had stage IIB disease and 34% had IIIB disease. Performance status declined with age (p=0.006). Histology and tumor stage did not significantly differ. Number of cycles of chemotherapy received, radiation treatment time, nor dose modifications varied with age. Notably, radiation protocol deviations and failure to complete brachytherapy (BT) did increase with age (p=0.022 and p<0.001 respectively). Only all grade lymphatic (p=0.006) and grade≥3 cardiovascular toxicities (p=0.019) were found to vary with age. A 2% increase in the risk of death for every year increase >50 for all-cause mortality (HR 1.02; 95% CI, 1.01-1.04) was found, but no association between age and disease specific mortality was found., Conclusion: This represents a large analysis of patients treated for LACC with chemo/radiation, approximately 20% of whom were >60years of age. Older patients, had higher rates of incomplete brachytherapy which is not explained by collected toxicity data. Age did not adversely impact completion of chemotherapy and radiation or toxicities., (Copyright © 2016. Published by Elsevier Inc.)

Objectives: In women with endometrial carcinoma (EC), tumor recurrences tend to occur in the 2- to 3-year period following surgical staging. Management of disease recurrence in EC poses significant challenges. These patients represent a heterogenous group where histologic subtypes, previous adjuvant management, interval since completion of adjuvant therapy, and size and site(s) of disease recurrence all have important implications on salvage therapies and prognosis. No randomized controlled trials have been published to determine optimal management in this group of patients. An expert panel was convened to reach consensus on the most appropriate management options in this group of patients., Methods: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment., Results: Five clinical variants were developed to address common scenarios in the management of women with recurrent EC. Group members reached consensus on the appropriateness of specific evaluation and treatment approaches with numerical ratings., Conclusions: In combining available medical literature and expert opinions, this manuscript may serve as an aid for other practitioners in the appropriate management of women with recurrent EC.

These consensus guidelines on adjuvant radiotherapy for early-stage endometrial cancer were developed from an expert panel convened by the American College of Radiology. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method; and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. After a review of the published literature, the panel voted on three variants to establish best practices for the utilization of imaging, radiotherapy, and chemotherapy after primary surgery for early-stage endometrial cancer.

Purpose: In the randomized phase III trial, Gynecologic Oncology Group (GOG) protocol 240, the incorporation of bevacizumab with chemotherapy significantly increased overall survival (OS) in women with advanced cervical cancer. A major objective of GOG-240 was to prospectively analyze previously identified pooled clinical prognostic factors known as the Moore criteria., Experimental Design: Potential negative factors included black race, performance status 1, pelvic disease, prior cisplatin, and progression-free interval <365 days. Risk categories included low-risk (0-1 factor), mid-risk (2-3 factors), and high-risk (4-5 factors). Each test of association was conducted at the 5% level of significance. Logistic regression and survival analysis was used to determine whether factors were prognostic or could be used to guide therapy., Results: For the entire population (n = 452), high-risk patients had significantly worse OS (P < 0.0001). The HRs of death for treating with topotecan in low-risk, mid-risk, and high-risk subsets are 1.18 [95% confidence interval (CI), 0.63-2.24], 1.11 (95% CI, 0.82-1.5), and 0.84 (95% CI, 0.50-1.42), respectively. The HRs of death for treating with bevacizumab in low-risk, mid-risk, and high-risk subsets are 0.96 (95% CI, 0.51-1.83; P = 0.9087), 0.673 (95% CI, 0.5-0.91; P = 0.0094), and 0.536 (95% CI, 0.32-0.905; P = 0.0196), respectively., Conclusions: This is the first prospectively validated scoring system in cervical cancer. The Moore criteria have real-world clinical applicability. Toxicity concerns may justify omission of bevacizumab in some low-risk patients where survival benefit is small. The benefit to receiving bevacizumab appears to be greatest in the moderate- and high-risk subgroups (5.8-month increase in median OS). Clin Cancer Res; 21(24); 5480-7. ©2015 AACR., (©2015 American Association for Cancer Research.)

These American College of Radiology consensus guidelines were formed from an expert panel on the appropriate use of adjuvant therapy in vulvar cancer after primary treatment with surgery. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel reviewed the pertinent literature in vulvar cancer and voted on three variants to establish appropriate use of imaging, adjuvant radiation, including dose, fields, and technique, as well as adjuvant chemotherapy. This report will aid clinicians in selecting appropriate patients for adjuvant treatment and will provide guidelines for the optimal delivery of adjuvant radiation therapy and chemotherapy.

Background: Our breast cancer clinic promotes patient use of decision and communication aids (DAs/CAs) through two mechanisms: coaching and prompting. From January through September 2010, we provided services to 462 of 1106 new visitors (42%). Of those 462 visitors, 267 (58%) received coaching. For the remainder (195 or 42%), the best we could do was prompt them to self-administer the DA and CAs., Objective: We wanted to learn whether patients prompted to use DAs/CAs did so., Methods: We surveyed prompted patients after their visits. We asked how much of each DA they reviewed, whether they listed questions, made notes and audio-recorded their consultations. We tallied frequencies and explored associations using logistic regression., Results: Of the 195 prompted patients, 82 responded to surveys (42%). Nearly all (66/73 or 90%) reported reviewing some or all of the booklets and 52/73 (71%) reported viewing some or all of the DVDs. While 63/78 (81%) responded that they wrote a question list, only 14/61 (23%) said they showed it to their doctor. Two-thirds (51/77 or 66%) said someone took notes, but only 16/79 (20%) reported making audio recordings., Discussion: More patients reported following prompts to use DAs than CAs. Few reported showing question lists to physicians or recording their visits. Our exploratory analyses surfaced associations between using CAs and race/ethnicity or education that merit further investigation., Conclusion: Prompting patients assures better use of decision than communication aids. Clinicians may need to take a more active role to ensure patients receive adequate notes and recordings., (© 2013 Blackwell Publishing Ltd.)

Purpose: The Consortium for Spinal Cord Medicine published clinical practice guidelines (CPG) related to upper limb (UL) preservation in people with spinal cord injury (SCI) in 2005. The purpose of this qualitative research was to identify stakeholder agreement with recommendations, performance gaps, and barriers and facilitators to CPG implementation., Design: This 6-month study focused on the perspectives of healthcare providers, veterans, and key informants. The Promoting Action on Research Implementation in Health Services (PARiHS) was used to frame the interview questions, analyze data from focus groups and interviews, and develop conclusions and recommendations., Method: SCI Centers at the Tampa, Seattle, and Hines Veterans' hospitals participated. The purposeful sample for the focus groups included 32 healthcare providers, 21 veterans with SCI, and 3 key informants. Analysis of qualitative data netted the percent of agreement with recommendations, performance gaps, and strategies for CPG implementation., Findings: Content analysis of focus group data revealed that healthcare providers agreed or partially agreed with 20 (57%) of the 35 CSCM CPG on UL preservation of function. Agreement ranged from 100% for assessment to 28% for equipment use. Barriers for implementation related to administrative and system issues., Conclusion: Consideration of gaps, barriers, and facilitators to implementation will assist clinicians to target interventions to preserve UL function., (© 2013 Association of Rehabilitation Nurses.)

Identification of early perturbations induced in cells from non-cancerous breast tissue is critical for understanding possible breast cancer risk from chemical exposure. We have demonstrated previously that exposure to the ubiquitous xenoestrogens, bisphenol A (BPA) and methyl paraben, promotes the hallmarks of cancer in non-malignant human high-risk donor breast epithelial cells (HRBECs) isolated from several donors. Here we show that terephthalic acid (TPA), a major chemical precursor of polyethylene terephthalate (PET) containers used for the storage of food and beverages, increased the ERα: ERβ ratio in multiple HRBEC samples, suggesting an estrogenic effect. Although, like BPA and methyl paraben, TPA also promoted resistance to tamoxifen-induced apoptosis, unlike these chemicals instead of inducing an increased S-phase fraction, TPA treatment arrested cell proliferation. DNA-PK, ATM and members of the MRN complex, known to be involved in DNA damage sensor and effector proteins, were elevated indicating induction of DNA strand breaks. Early DNA damage checkpoint response, mediated through p53/p21, led to G1 arrest in TPA-exposed cells. Removal of TPA from the growth medium resulted in the rapid induction of BCL2, increasing the ratio of anti-: pro-apoptotic proteins, together with overexpression of Cyclin A/CDK2 proteins. Consequently, despite elevated p53(pSer15) and H2AX(pSer139), indicating sustained DNA damage, TPA exposed cells resumed robust growth rates seen prior to TPA exposure. The propensity for the perpetuation of DNA aberrations that activate DNA damage pathways in non-malignant breast cells justifies careful consideration of human exposure to TPA, particularly at vulnerable life stages., (© The Author 2014. Published by Oxford University Press.)

Our objective was to compare the phase II and phase III (EMPOWER) studies of dexpramipexole in ALS and evaluate potential EMPOWER responder subgroups and biomarkers based on significant inter-study population differences. In a post hoc analysis, we compared the baseline population characteristics of both dexpramipexole studies and analyzed EMPOWER efficacy outcomes and laboratory measures in subgroups defined by significant inter-study differences. Results showed that, compared with phase II, the proportion of El Escorial criteria (EEC) definite participants decreased (p = 0.005), riluzole use increased (p = 0.002), and mean symptom duration increased (p = 0.037) significantly in EMPOWER. Baseline creatinine (p < 0.001) and on-study creatinine change (p < 0.001) correlated significantly with ALSFRS-R in EMPOWER. In the EMPOWER subgroup defined by EEC-definite ALS, riluzole use, and < median symptom duration (15.3 months), dexpramipexole-treated participants had reduced ALSFRS-R slope decline (p = 0.015), decreased mortality (p = 0.011), and reduced creatinine loss (p = 0.003). In conclusion, significant differences existed between the phase II and EMPOWER study populations in ALS clinical trials of dexpramipexole. In a post hoc analysis of EMPOWER subgroups defined by these differences, potential clinical benefits of dexpramipexole were identified in the subgroup of riluzole-treated, short-symptom duration, EEC-definite ALS participants. Creatinine loss correlated with disease progression and was reduced in dexpramipexole-treated participants, suggesting it as a candidate biomarker.

The development of nontoxic agents that can selectively enhance the cytotoxicity of chemotherapy is an important aim in oncology. This study evaluates the ability of infrasound exposure to sensitize glioblastoma cells to cisplatin-induced apoptosis. The infrasound was delivered using a device designed to replicate the unique infrasound emissions measured during external Qigong treatments. Human glioblastoma cell lines harboring wild-type p53 (U87) or mutant p53 (U251, SF210, and SF188) were treated in culture with cisplatin, infrasound emissions, or the combination of the 2 agents. Induction of apoptosis was quantified after 24 hours by flow cytometry following annexin V/propidium iodide staining. Infrasound emissions alone, delivered at moderate levels (~10 mPa) with dynamic frequency content (7-13 Hz), did not induce apoptosis, yet combining infrasound with cisplatin augmented the induction of apoptosis by cisplatin in all the 4 cell lines (P < .05). Increased cellular uptake of the fluorophore calcein associated with infrasound exposure was quantified by fluorescence microscopy as well as flow cytometry, demonstrating increased cell membrane permeability. The 4 cell lines differed in the degree to which infrasound exposure increased calcein uptake, and these differences were predictive of the extent to which infrasound enhanced cisplatin-induced apoptosis. When exposed to specific frequencies, membrane permeabilization also appeared to be differentially responsive for each cell line, suggesting the potential for selective targeting of tissue types using isolated infrasonic frequencies. Additionally, the pressure amplitudes used in this study were several orders of magnitude less than those used in similar studies involving ultrasound and shock waves. The results of this study provide support for using infrasound to enhance the chemotherapeutic effects of cisplatin in a clinical setting.

Normal cellular phenotypes that serve an oncogenic function during tumorigenesis are potential candidates for cancer targeting drugs. Within a subset of invasive primary breast carcinoma, we observed relatively abundant expression of Tetherin, a cell surface protein encoded by the Bone Marrow Stromal Cell Antigen (BST2) known to play an inhibitory role in viral release from infected immune cells of the host. Using breast cancer cell lines derived from low and intermediate histopathologic grade invasive primary tumors that maintain growth-suppressive TGFβ signaling, we demonstrate that BST2 is negatively regulated by the TGFβ axis in epithelial cells. Binding of the transcription factor AP2 to the BST2 promoter was attenuated by inhibition of the TGFβ pathway thereby increasing BST2 expression in tumor cells. In contrast, inherent TGFβ resistance characteristic of high grade breast tumors is a key factor underlying compromised BST2 regulation, and consequently its constitutive overexpression relative to non-malignant breast epithelium, and to most low and intermediate grade cancer cells. In both 2-dimensional and 3-dimensional growth conditions, BST2-silenced tumor cells displayed an enhancement in tamoxifen or staurosporine-induced apoptotic cell death together with a reduction in the S-phase fraction compared to BST2 overexpressing counterparts. In a subset of breast cancer patients treated with pro apoptotic hormonal therapy, BST2 expression correlated with a trend for poor clinical outcome, further supporting its role in conferring an anti apoptotic phenotype. Similar to the effects of gene manipulation, declining levels of endogenous BST2 induced by the phytoalexin - resveratrol, restored apoptotic function, and curbed cell proliferation. We provide evidence for a direct approach that diminishes aberrant BST2 expression in cancer cells as an early targeting strategy to assist in surmounting resistance to pro apoptotic therapies.