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We investigate a new approach to compute the gradients of artificial neural networks (ANNs), based on the so-called push-out likelihood ratio method. Unlike the widely used backpropagation (BP) method that requires continuity of the loss function and the activation function, our approach bypasses this requirement by injecting artificial noises into the signals passed along the neurons. We show how this approach has a similar computational complexity as BP, and moreover is more advantageous in terms of removing the backward recursion and eliciting transparent formulas. We also formalize the connection between BP, a pivotal technique for training ANNs, and infinitesimal perturbation analysis, a classic path-wise derivative estimation approach, so that both our new proposed methods and BP can be better understood in the context of stochastic gradient estimation. Our approach allows efficient training for ANNs with more flexibility on the loss and activation functions, and shows empirical improvements on the robustness of ANNs under adversarial attacks and corruptions of natural noises. Summary of Contribution: Stochastic gradient estimation has been studied actively in simulation for decades and becomes more important in the era of machine learning and artificial intelligence. The stochastic gradient descent is a standard technique for training the artificial neural networks (ANNs), a pivotal problem in deep learning. The most popular stochastic gradient estimation technique is the backpropagation method. We find that the backpropagation method lies in the family of infinitesimal perturbation analysis, a path-wise gradient estimation technique in simulation. Moreover, we develop a new likelihood ratio-based method, another popular family of gradient estimation technique in simulation, for training more general ANNs, and demonstrate that the new training method can improve the robustness of the ANN.

The Edmonton Symptom Assessment Scale (ESAS) is a validated tool used in patients with varied cancer diagnoses to measure patient symptoms. The present manuscript will review the literature assessing the ability of the ESAS to predict patient-related outcomes in breast cancer patients. A literature search was conducted of Cochrane Central Register of Controlled Trials databases, Ovid MEDLINE, and Embase for English articles that investigated the use of predictive modelling with the ESAS in the breast cancer population. Study type, publication year, sample size, patient demographics, predicted outcomes, and strongest predictive factors/symptoms were summarized for each study. A total of nine articles were included in this review. Five articles used the ESAS in predictive models to determine patient time to death. ESAS was also used to predict emergency department visits, determine symptoms associated with decreased quality of life, and generate a Health Utility Score. Lack of appetite was the most common ESAS symptom, as it was reported in five studies to be associated with decreased survival. In four of the nine articles, an additional survey investigating physical functioning was used in combination with ESAS to strengthen the predictive models. Included studies support the use of ESAS in predictive models, particularly for predicting survival. Using the ESAS as a predictive tool allows for more accurate time to death predictions, potentially improving symptom management and preventing overtreatment of palliative patients near the end of life.

Radiation dermatitis is a common adverse effect of radiotherapy (RT) in breast cancer patients. Although radiation dermatitis is reported by either the clinician or the patient, previous studies have shown disagreement between clinician-reported outcomes (CROs) and patient-reported outcomes (PROs). This review evaluated the extent of discordance between CROs and PROs for radiation dermatitis. Studies reporting both clinician and patient-reported outcomes for external beam RT were eligible. Nine studies met the inclusion criteria for the systematic review, while 8 of these studies were eligible for inclusion in a meta-analysis of acute and late skin toxicities. We found an overall agreement between CROs and PROs of acute skin colour change, fibrosis and/or retraction, and moist desquamation (p > 0.005). Reporting of late breast pain, breast edema, skin colour change, telangiectasia, fibrosis and/or retraction and induration/fibrosis alone (p > 0.005) were also in agreement between clinicians and patients. Our meta-analysis revealed a greater reporting of acute breast pain by patients (RR = 0.89, 95% CI 0.87–0.92, p, Highlights • Patient- and clinician-reported outcomes generally demonstrated high levels of agreement. • Patients reported more acute breast pain and late breast shrinkage than clinicians. • Clinicians reported more acute breast edema than patients. • The measurement tools and time points at which radiotherapy side effects were assessed varied considerably across studies. • Standardized reporting of radiotherapy side effects by clinicians and patients could impact future symptom management.

Purpose: Several studies have used objective radiologic data to assess the effect of palliative radiotherapy on tumor burden. The purpose of this literature review was to survey the various metrics that have been used to quantify bone tumor response to palliative radiotherapy by radiographical means and to determine whether any of these metrics were associated with clinical palliative outcomes. Methods: In accordance with PRISMA extension for Scoping Reviews guidelines, a literature search Ovid Medline and OldMedline from 1946 to February 6, 2019, Embase Classic/Embase from 1947 to 2019 week 5, and Cochrane Central Register of Controlled Trials February 2019 to extract articles related to quantified radiologic evaluation of bone metastases following palliative radiotherapy. Imaging modality, quantification metric, and association between imaging modality and clinical response were recorded. Results: Fourteen articles selected for full-text review utilized computed tomography (10 studies), fluorodeoxyglucose-positron emission tomography (3 studies), magnetic resonance imaging (1 study), diffusion-weighted magnetic resonance imaging (3 studies), and X-ray (1 study) imaging modalities. Variables assessed included tumor volume regression, bone density, metabolic activity, and signal intensity. Studies differed both in the type of imaging modality used and metric derived to quantify the radiologic findings. Fifty percent of the included studies aimed to identify a relationship between a quantified radiologic metric and clinical palliative response. Of these studies, 86% reported a correlation. Conclusion: Quantified radiologic metrics can provide an objective measure of response to palliative radiotherapy and may be useful in predicting clinical palliative response. More studies are needed to validate these metrics and develop a standardized protocol for radiologic evaluation that can be implemented into a clinical workflow.

IntroductionMeasurement-based care (MBC) represents the approach of regularly using symptom rating scales to guide patient care decisions in mental healthcare. MBC is an effective, feasible and acceptable approach to enhance clinical outcomes in various disciplines, including medicine, psychology, social work and psychotherapy. Yet, it is infrequently used by clinicians, potentially due to limited education for care providers. The objective of this scoping review is to survey the characteristics of MBC educational programmes for undergraduate, graduate and postgraduate clinical trainees in mental healthcare.Methods and analysisUsing database-tailored search strategies, we plan on searching Medline, PsycINFO, Embase, CINAHL and Cochrane Central for relevant studies. Thereafter, we will analyse the selected studies to extract information on the delivery of educational programmes, the clinical and educational outcomes of these programmes, and the potential enablers and barriers to MBC education. In this paper, we articulate the protocol for this scoping review.Ethics and disseminationThis scoping review does not require research ethics approval. The findings from this scoping review will be incorporated into the creation of a novel MBC curriculum and handbook. Results will be disseminated at appropriate national or international conferences, as well as in a peer-reviewed journal publication.

Despite having an excellent prognosis, patients with ductal carcinoma in situ (DCIS) report significant anxiety and depression following diagnosis. This study evaluated psychological morbidity using the Edmonton Symptom Assessment Scale (ESAS) in patients with DCIS compared with women with early-stage invasive breast cancer (EIBC) receiving radiotherapy (RT). We identified patients diagnosed with DCIS or EIBC (stage I or II breast cancer) from 2011 to 2017 who had at least one ESAS completed pre- and post-RT. Data on systemic treatment, radiation, patient demographics, and disease stage were extracted from existing databases. Psychological morbidity was evaluated through measurement of depression, anxiety, and overall wellbeing within the ESAS. The Wilcoxon rank-sum test or chi-square test was performed for continuous or categorical variables. This study included 137 women with DCIS and 963 women with EIBC. ESAS was completed on average 28 days before RT (baseline) and 142 days after RT. Baseline ESAS scores showed significantly higher rates of depression among women with EIBC compared with those with DCIS (p = 0.006). Patients with EIBC also reported higher levels of anxiety and lower overall wellbeing than patients with DCIS, but this difference was not statistically significant. Post-RT ESAS scores showed significantly higher anxiety in patients with EIBC compared with DCIS (p = 0.049). Post-RT measures of anxiety and overall wellbeing were higher in patients with EIBC but differences were not statistically significant. Women with DCIS experience relatively less psychological morbidity than women with EIBC, pre- and post-RT.

OBJECTIVE Seasonal effects on patients diagnosed with depression/anxiety-related psychological disorders have varying impacts on symptom severity. Seasonal changes in psychological distress may be due to decreased daylight exposure during the fall/winter seasons. Patients receiving radiation therapy (RT) for early-stage invasive breast cancer (EIBC) are at high risk for developing depressive symptoms. Of interest is whether seasonal factors influence the psychological symptoms of patients being treated for EIBC. METHODS Patients treated with RT for EIBC between January 2011 and June 2017 were identified. Patients who completed at least one Edmonton Symptom Assessment Scale (ESAS-r) pre-RT and post-RT were included in our analysis. Patients receiving RT during the autumn and winter (November-March) were compared with patients receiving RT during the spring and summer (April-August). Psychological distress was evaluated based on patient-reported depression, anxiety, and overall wellbeing on the ESAS-r. Data on systemic treatment and radiation were extracted from existing databases. RESULTS Eight-four patients treated with RT in spring/summer and 102 patients treated with RT in autumn/winter were included. Patients receiving RT during spring/summer had better wellness score prior to RT, compared with those receiving RT during winter/autumn (P = .03). However, patients receiving RT in the spring/summer had worse symptom trajectories across three domains of depression, anxiety, and wellbeing (P = .03, P = .008, and P < .0001, respectively). CONCLUSIONS Seasonality influenced the symptoms reported by patients with EIBC receiving RT. Future studies are needed to understand when during treatment patients are at highest risk for psychological distress and how seasonality may influence high-risk periods.

Background: During recovery from stroke, the contralesional motor cortex (M1) may undergo maladaptive changes that contribute to impaired interhemispheric inhibition (IHI). Transcranial direct current stimulation (tDCS) with the cathode over contralesional M1 may inhibit this maladaptive plasticity, normalize IHI, and enhance motor recovery.Objective: The objective of this systematic review and meta-analysis was to evaluate available evidence to determine whether cathodal tDCS on contralesional M1 enhances motor re-learning or recovery post-stroke more than sham tDCS.Methods: We searched OVID Medline, Embase, and the Cochrane Central Register of Controlled Trials for participants with stroke (>1 week post-onset) with motor impairment and who received cathodal or sham tDCS to contralesional M1 for one or more sessions. The outcomes included a change in any clinically validated assessment of physical function, activity, or participation, or a change in a movement performance variable (e.g., time, accuracy). A meta-analysis was performed by pooling five randomized controlled trials (RCTs) and comparing the change in Fugl–Meyer upper extremity scores between cathodal and sham tDCS groups.Results: Eleven studies met the inclusion criteria. Qualitatively, four out of five cross-over design studies and three out of six RCTs reported a significant effect of cathodal vs. sham tDCS. In the quantitative synthesis, cathodal tDCS (n = 65) did not significantly reduce motor impairment compared to sham tDCS (n = 67; standardized mean difference = 0.33, z = 1.79, p = 0.07) with a little observed heterogeneity (I2 = 5%).Conclusions: The effects of cathodal tDCS to contralesional M1 on motor recovery are small and consistent. There may be sub-populations that may respond to this approach; however, further research with larger cohorts is required.

IntroductionColchicine may inhibit inflammasome signaling and reduce proinflammatory cytokines, a purported mechanism of COVID-19 pneumonia. The aim of this systematic review and meta-analysis is to report on the state of the current literature on the use of colchicine in COVID-19 and to investigate the reported clinical outcomes in COVID-19 patients by colchicine usage.MethodsThe literature was searched from January 2019 through January 28, 2021. References were screened to identify studies that reported the effect of colchicine usage on COVID-19 outcomes including mortality, intensive care unit (ICU) admissions, or mechanical ventilation. Studies were meta-analyzed for mortality by the subgroup of trial design (RCT vs observational) and ICU status. Studies reporting an risk ratio (RR), odds ratio (OR) and hazard ratio (HR) were analyzed separately.ResultsEight studies, reporting on 16,248 patients, were included in this review. The Recovery trial reported equivalent mortality between colchicine and non-colchicine users. Across the other studies, patients who received colchicine had a lower risk of mortality - HR of 0.25 (95% CI: 0.09, 0.66) and OR of 0.22 (95% CI: 0.09, 0.57). There was no statistical difference in risk of ICU admissions between patients with COVID-19 who received colchicine and those who did not – OR of 0.26 (95% CI: 0.06, 1.09).ConclusionColchicine may reduce the risk of mortality in individuals with COVID-19. Further prospective investigation may further determine the efficacy of colchicine as treatment in COVID-19 patients in various care settings of the disease, including post-hospitalization and long-term care.

We consider a context-dependent ranking and selection problem. The best design is not universal but depends on the contexts. Under a Bayesian framework, we develop a dynamic sampling scheme for context-dependent optimization (DSCO) to efficiently learn and select the best designs in all contexts. The proposed sampling scheme is proved to be consistent. Numerical experiments show that the proposed sampling scheme significantly improves the efficiency in context-dependent ranking and selection., Comment: The article was published without the co-Author's notice, and it is withdrawn due to his objection

Introduction The aim of this study is to rigorously review the efficacy and safety of olanzapine in defined hematology oncology settings including (1) the setting of highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) settings (2) at 5 mg and 10 mg doses, and (3) for response rates for use in the acute, delayed, and overall settings post-MEC and HEC. Methods Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched through April 23, 2020. The primary efficacy endpoints were the rate of complete response, in the acute (0–24 h post-chemotherapy), delayed (24–120 h post-chemotherapy), and overall (0–120 h post-chemotherapy) phases. The secondary efficacy endpoints were the rates of no nausea and no emesis, for each phase. Safety endpoints were the rate of no serious adverse events (i.e., no grade 3 or 4 toxicities), as assessed by Common Terminology Criteria for Adverse Events (CTCAE) criteria. The Mantel-Haenszel, random-effects analysis model was used to compute risk ratios and accompanying 95% confidence intervals for each endpoint. For endpoints that statistically favored one arm, absolute risk differences were computed to assess whether there is a 10% or greater difference, used as the threshold for clinical significance by MASCC/ESMO. Fragility indices were also calculated for each statistically significant endpoint, to quantitatively assess the robustness of the summary estimate. A cumulative meta-analysis was conducted for each efficacy meta-analysis with more than 5 studies, also using the Mantel-Haenszel random-effects analysis model. Results Three studies reported on olanzapine for the rescue of breakthrough chemotherapy-induced nausea and vomiting (CINV); 22 studies reported on olanzapine in the prophylactic setting. For studies reporting on HEC patients, olanzapine-containing regimens were statistically and clinically superior in seven of nine efficacy endpoints in the prophylaxis setting. When olanzapine is administered at a 10-mg dose, it is statistically and clinically superior to control patients in eight of nine endpoints among adults. Olanzapine may be effective in the MEC setting and when administered at 5-mg doses, but the paucity of data leads to notable uncertainty. Conclusion Further RCTs are needed in the setting of MEC patients and administration of olanzapine at a lower 5-mg dose, which may be given to reduce the sedative effect of olanzapine at 10 mg. Supplementary Information The online version contains supplementary material available at 10.1007/s00520-020-05935-7.

This review aimed to assess the quality and efficacy of tools currently used in breast cancer patients to score radiation dermatitis (RD), a common debilitating side effect of radiotherapy (RT). A search was conducted through Ovid Medline, Embase, and Cochrane Central Register of Controlled Trials databases on 14 February 2020. English articles that evaluated an instrument’s use in assessing RD among breast cancer patients receiving external beam RT were included. Studies that reported on the reliability, validity, or concordance of items between assessment tools were included in accordance with the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) criteria. Twelve studies were included in this review, with a total of 13 skin toxicity assessment tools discussed. Tools that assessed clinician-reported outcomes (CROs) mostly reported moderate correlation with biophysical parameter (BP) measurements and low correlation with patient-reported outcomes (PROs). Traditionally used CRO scoring tools demonstrated moderate inter-rater reliability between clinicians, likely due to the subjective nature of items on the grading scales. Most commonly used tools were found to be either insufficient or indeterminate in their measurement properties. Current standardized tools that measure CROs are subject to clinician interpretation and fail to represent the patient experience. Tools designed to assess PROs are promising in their assessments of the impact of RT on patient quality of life; however, most PRO tools are generic to all skin conditions and require further validation for use in breast cancer. Among tools that measure CROs, PROs, and BPs, there is insufficient evidence on their measurement properties to establish a “gold standard” for the assessment of RD in breast cancer patients.

Background The influence of cigarette smoking on cancer risk has been well-studied. Similarly, exposure to ionizing radiation from radiotherapy (RT) can produce detrimental effects on an individual's health. In patients administered RT, there has been an observed relationship in other primary carcinomas. The purpose of this systematic review was to summarize the influence of cigarette smoking on outcomes post adjuvant RT in breast cancer patients. Methods OVID Medline, Cochrane and Embase were searched and 1893 articles were identified. A total of 71 articles were included in the review. Study type, published year and sample size, age, systemic therapies, RT techniques and treatment side effects were collected if available. Results The review found 198 different outcomes which fell into 7 categories and similar outcomes were recorded. 40% of skin reaction outcomes, 50% of cardiovascular outcomes, 71% of reconstruction outcomes, 29% of pulmonary function outcomes, 33% of mortality outcomes and 42% of secondary recurrence outcomes reported significant differences between smokers and non-smokers. None of the articles reported non-smokers to have a higher risk than smokers. Conclusion Cigarette smoking can pose a higher risk of post-treatment complications that can influence an individual's quality of life, survival rate and/or recurrence risk. This review further assessed the impact of smoking on various patient outcomes and side-effects in the adjuvant breast RT setting. The information provided in this review suggest that smoking cessation programs would help educate patients to understand their risks of being a current or former smoker when undergoing RT.

To answer the increasing need for detecting and validating protein biomarkers in clinical specimens, proteomic techniques are required that support the fast, reproducible and quantitative analysis of large clinical sample cohorts. Targeted mass spectrometry techniques, specifically SRM, PRM and the massively parallel SWATH/DIA technique have emerged as a powerful method for biomarker research. For optimal performance, they require prior knowledge about the fragment ion spectra of targeted peptides. In this report, we describe a mass spectrometric (MS) pipeline and spectral resource to support data-independent acquisition (DIA) and parallel reaction monitoring (PRM) based biomarker studies. To build the spectral resource we integrated common open-source MS computational tools to assemble an open source computational workflow based on Docker. It was then applied to generate a comprehensive DIA pan-human library (DPHL) from 1,096 data dependent acquisition (DDA) MS raw files, and it comprises 242,476 unique peptide sequences from 14,782 protein groups and 10,943 SwissProt-annotated proteins expressed in 16 types of cancer samples. In particular, tissue specimens from patients with prostate cancer, cervical cancer, colorectal cancer, hepatocellular carcinoma, gastric cancer, lung adenocarcinoma, squamous cell lung carcinoma, diseased thyroid, glioblastoma multiforme, sarcoma and diffuse large B-cell lymphoma (DLBCL), as well as plasma samples from a range of hematologic malignancies were collected from multiple clinics in China, the Netherlands and Singapore and included in the resource. This extensive spectral resource was then applied to a prostate cancer cohort of 17 patients, consisting of 8 patients with prostate cancer (PCa) and 9 with benign prostate hyperplasia (BPH), respectively. Data analysis of DIA data from these samples identified differential expressions of FASN, TPP1 and SPON2 in prostate tumors. Thereafter, PRM validation was applied to a larger PCa cohort of 57 patients and the differential expressions of FASN, TPP1 and SPON2 in prostate tumors were validated. As a second application, the DPHL spectral resource was applied to a patient cohort consisting of samples from 19 DLBCL patients and 18 healthy individuals. Differential expressions of CRP, CD44 and SAA1 between DLBCL cases and healthy controls were detected by DIA-MS and confirmed by PRM. These data demonstrate that the DPHL supported that DIA-PRM MS pipeline enables robust protein biomarker discoveries.

Introduction: Clinician predicted survival (CPS) is a crucial part of palliative care but is often found to be inaccurate with most clinicians providing overestimates of survival, potential...

Chemotherapy-induced nausea and vomiting (CINV) continues to be a common side effect of systemic anticancer therapy, decreasing quality of life and increasing resource utilization. The aim of this meta-analysis was to investigate the comparative efficacy and safety of palonosetron relative to other 5-HT3RAs. A literature search was carried out in Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Full-text references were then screened and included in this meta-analysis if they were an RCT and had adequate data regarding one of the five primary endpoints—complete response (CR), complete control (CC), no emesis, no nausea, or no rescue medications. A total of 24 RCTs were included in this review. Palonosetron was statistically superior to other 5-HT3RAs for 10 of the 19 assessed endpoints. Only one endpoint—emesis in the overall phase—had noticeable more favorable data for palonosetron to the point that it approached the 10% risk difference (RD) threshold as specified by the MASCC/ESMO antiemetic panel; another two endpoints (CR in the overall phase and nausea in the delayed phase) approached the 10% threshold. Palonosetron seems to be more efficacious and safe than other 5-HT3RAs—statistically superior in 10 of 19 endpoints. It is, however, only clinically significant in one endpoint and approached clinically significant difference in another two endpoints. Within the limits of this meta-analysis, our results indicate that palonosetron may not be as superior in efficacy and safety as reported in a previous meta-analysis, and supports the recent MASCC/ESMO, ASCO, and NCCN guidelines in not generally indicating palonosetron as the 5-HT3RA of choice.

Despite the prevalence of radiation dermatitis in breast cancer patients, current practice guidelines for its treatment are limited. We aimed to discuss the quality of evidence for the barrier-forming Mepitel Film for prophylaxis of radiation dermatitis, and argue for further investigation into evidence-based management of skin toxicities. Two studies assessing Mepitel Film were critically evaluated. Both reported that Mepitel Film decreased radiation dermatitis; moreover, patient-reported outcomes significantly favoured Mepitel Film. However, there has not been global adoption of barrier-forming films such as Mepitel, in part due to the absence of multi-centred randomised trials and the heterogeneity of study designs.

Introduction: Epstein-Barr virus (EBV) is a globally prevalent herpesvirus with an estimated 90-95% seropositivity rate worldwide. It is most known for causing infectious mononucleosis characterized by the classic triad of fever, pharyngitis, and lymphadenopathy. Hepatitis is a common manifestation seen in 90% of cases;however, isolated acute hepatitis in the absence of infectious mononucleosis is a rare clinical presentation. Case Description/Methods: An 18-year-old female with no medical history presented with fevers, fatigue, myalgia, and headache ongoing for one week. She had been evaluated previously with recommendations for supportive care for an unspecified viral illness. Workup at the time had been negative for urine hCG, COVID-19, heterophile antibody, Lyme disease, and bacteremia. However, symptoms worsened with the development of nausea, vomiting, and darkening of her urine. Prior to this, patient had been in her normal state of health without sick contacts, travel history, animal exposures, risky sexual practices, or substance use. Exam revealed cervical lymphadenopathy and hepatosplenomegaly. Labs showed normal leukocyte count 8.4 thou/cmm with differential significant for reactive lymphocytosis 19% and bandemia 8%. Liver function tests were abnormal with elevated total bilirubin 3.8 mg/dL, AST 366 U/L, ALT 460 U/L, ALP 562 U/L. Synthetic function was intact. Hepatic ultrasound was unrevealing. Extensive infectious workup revealed acute EBV infection with serologies showing positive VCA IgM Ab 74.3 U/mL, negative VCA IgG Ab 11.9 U/mL, negative EA Ab < 5 U/mL, negative EBNA Ab < 3 U/mL. Patient was managed supportively with improved symptoms. She was instructed to avoid physical contact sports for one month upon discharge. Discussion: Clinically significant EBV induced hepatitis is a rare entity seen in < 5% of cases. Nevertheless, it is important to consider EBV as a causative pathogen of acute hepatitis. Heterophile antibody or Monospot test is the diagnostic test of choice with a sensitivity of 85% and a specificity of 100%;however, false negatives can occur especially early in the disease course. EBV serology has an improved sensitivity of 97% with a comparable specificity of 94%. As such, follow-up serology is necessary especially if clinical suspicion is high. While no specific EBV targeted therapies exist, it is important to identify it given the potential complications, including splenic rupture, airway obstruction, malignancies, lymphoproliferative disorders, among others.

To investigate the natural history of taxane-associated acute pain syndrome (TAPS) in a docetaxel patient cohort and to examine the long-term manifestation of TAPS. For three consecutive treatment cycles, taxane-naive breast cancer patients completed diaries on days 1–7, 14, and 21 and telephone questionnaires 1, 3, 6, 9, and 12 months following treatment. Questionnaires to assess pain and interference were adapted from the Brief Pain Inventory. To examine the experience of arthralgia and myalgia as one syndrome, information on patient experiences with arthralgia or myalgia was elicited separately in order to determine how closely experiences of each toxicity correlated with each other. A ≥2 point increase from baseline was defined as an arthralgia or myalgia “pain flare,” and only those with “flare” were included in calculations of incidence. A total of 278 patients were accrued. Thirty-eight patients were omitted due to missing information, and 24 patients were omitted due to metastatic disease, for a total of 216 patients overall and 188 in the docetaxel cohort. A total of 74.5% of docetaxel patients experienced joint pain flare, and 78.2% experienced muscle pain flare at some point in the overall course of three treatment cycles. Joint and muscle pain peaked on days 4–5 for each cycle, and median pain severity for both joint and muscle pain was 4/10 during the 21-day period. Median onset of joint pain flare was 3 days for cycle 1 and 4 days for cycles 2 and 3, with an average median duration of 4 days. Median onset of muscle pain flare was 4 days for all three cycles, with a median duration of 4 days for cycles 1 and 2, and 5 days for cycle 3. Both joint and muscle pain persisted 1 year after treatment in approximately half of responding patients. This study documents the significant incidence of TAPS in patients treated with docetaxel chemotherapy and shows a long-term persistence of the syndrome.

Background and purpose Impending or pathological fractures due to bone metastases may require surgical fixation. Postoperative radiation is often recommended to reduce local progression and prevent prosthesis displacement, hence reducing the need for second surgery. The objectives of this study were to investigate the need for second surgery, and to report on rates of re-irradiation, tumor progression and prosthesis displacement following postoperative radiation. Materials and methods Data were collected from 65 patients who received postoperative radiation to 74 sites in the extremities in a palliative radiation clinic between January 2009 and January 2017. Descriptive statistical analyses were performed. Results Only 2 patients required a second surgery (2.7%) at 9 and 10months after postoperative radiation. Increase in pain requiring re-irradiation was reported in 7 patients (9.5%), at a median time of 9.3months after the delivery of radiation. Of the 47 patients who had radiological imaging available post-radiation, local progression of bone metastases was seen in 8 patients (17.0%) and displacement of the prosthesis in 1 patient (2.1%). Conclusion Rates of prosthesis displacement and progression of bone metastases at site of surgery were low after postoperative radiation. There were few incidences of second surgery and re-irradiation observed in the cohort. These findings provide support for the benefit of postoperative radiation.

Clinical trials in radiation therapy-induced nausea and vomiting (RINV) appear to have varied methodologies, endpoints, and outcome measures. This complicates trial comparisons, weakens practice guideline recommendations, and contributes to variability in supportive care patterns of practice. We systematically reviewed RINV trials to describe and compare their pertinent design features. Ovid versions of the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, EMBASE, and MEDLINE to January/February 2017 were searched for adult phase III trials of RINV management strategies. Key abstracted data included trial interventions and eligibility criteria, standard radiation therapy (RT) metrics, symptom assessment procedures, symptom definitions and grading systems, pre-specified and reported endpoints, and other outcome measures. From 1166 references identified in the initial database search, we selected 34 trials for analysis that collectively randomized 4529 patients (median 61, range 11–1492). Twenty-eight trials (82%) were published prior to the year 2000. Twenty-seven trials (79%) involved multiple fraction RT and 7 (21%) single fraction RT. Twenty-four trials (71%) evaluated prophylactic interventions, 9 (26%) rescue interventions, and 1 trial did not specify. Thirty-three trials (97%) evaluated pharmacologic interventions. Twenty trials (59%) had patient report symptoms, 5 (15%) healthcare professionals or researchers, and 10 (29%) did not specify. Nausea was not defined in any trial but was reported as a stand-alone symptom in 26 trials (76%) and was graded in 20 (59%), with categorical qualitative scales being the most common method. Vomiting was defined in 3 trials (9%), was reported as a stand-alone symptom in 17 (47%), and was graded in 7 (21%), with continuous numerical scales being the most common method. Retching was defined in 3 trials, was not reported as a stand-alone symptom in any trial, and was graded in 1 (3%). Twenty-one trials (62%) created compound symptom measures that combined individual symptoms. Fifteen trials (44%) reported “emetic episode/event” measures but only 9 defined them. Seventeen trials (50%) reported complicated endpoints (e.g., “response,” “control,” “success”) that combined multiple symptom or compound symptom measures, but 7 did not define them comprehensively. Ten trials (29%) defined a primary endpoint a priori. Methodologies, endpoints, and outcome measures varied considerably among 34 randomized trials in RINV.

Background: Radiation therapy is effective for painful uncomplicated bone metastases, with multiple fraction radiation therapy (MFRT) administered frequently. The optimal dose for MFRT to yield maximum pain relief remains unclear. The aim of this systematic review was to determine pain response across MFRT doses. Methods: A literature search was conducted in Ovid MEDLINE(R) , Embase Classic & Embase and Cochrane Central Register of Controlled Trials . Pain response rates and the side effects for MFRT doses were extracted. Results: From the 3719 articles identified from the search, 17 were included for quantitative synthesis. 22.5Gy/5 had the highest overall response (OR) rate, 30Gy/15 had better complete response (CR) rate and 20Gy/2 had better partial response (PR) rate. Only 4 of the 17 included studies directly compared MFRT doses with each other – one reported marginally-better OR for 24Gy/6 over 20Gy/2; another found 20Gy/10 to be slightly more efficacious than 30Gy/15 and 22.5Gy/5 for OR. Two randomized trials compared 20Gy/5 and 30Gy/10 – one favored 20Gy/5 while the other concluded 30Gy/10 to be the better option. The overall rate of GI toxicities, nausea, and vomiting did not differ greatly between MFRT doses. Conclusion: No major difference exists between the schedules and toxic events studied in these trials. This is consistent with the wealth of randomized data which show no dose response for pain relief after radiotherapy for metastatic bone pain.

Weight loss in cancer patients is a worrisome constitutional change predicting disease progression and shortened survival time. A logical approach to counter some of the weight loss is to provide nutritional support, administered through enteral nutrition (EN) or parenteral nutrition (PN). The aim of this paper was to update the original systematic review and meta-analysis previously published by Chow et al., while also assessing publication quality and effect of randomized controlled trials (RCTs) on the meta-conclusion over time. A literature search was carried out; screening was conducted for RCTs published in January 2015 up until December 2018. The primary endpoints were the percentage of patients achieving no infection and no nutrition support complications. Secondary endpoints included proportion of patients achieving no major complications and no mortality. Review Manager (RevMan 5.3) by Cochrane IMS and Comprehensive Meta-Analysis (version 3) by Biostat were used for meta-analyses of endpoints and assessment of publication quality. An additional seven studies were identified since our prior publication, leading to 43 papers included in our review. The results echo those previously published; EN and PN are equivalent in all endpoints except for infection. Subgroup analyses of studies only containing adults indicate identical risks across all endpoints. Cumulative meta-analysis suggests that meta-conclusions have remained the same since the beginning of publication time for all endpoints except for the endpoint of infection, which changed from not favoring to favoring EN after studies published in 1997. There was low risk of bias, as determined by assessment tool and visual inspection of funnel plots. The results support the current European Society of Clinical Nutrition and Metabolism guidelines recommending enteral over parenteral nutrition, when oral nutrition is inadequate, in adult patients. Further studies comparing EN and PN for these critical endpoints appear unnecessary, given the lack of change in meta-conclusion and low publication bias over the past decades.

Purpose Symptoms experienced by breast cancer patients often cluster together in groups known as “symptom clusters”. The aim was to determine the symptom clusters in women with non-metastatic breast cancer treated by radiation therapy (RT). Methods Edmonton Symptom Assessment Scale (ESAS) scores were taken from breast cancer patients receiving RT before, at completion of RT, and after RT. Exploratory factor analysis (EFA), principal component analysis (PCA), and hierarchical cluster analysis (HCA) were used to identify symptom clusters among the nine ESAS items at all three time points. Results This study included 1224 patients. The PCA and EFA identified the same two symptom clusters before the start of RT: 1) pain, tiredness, nausea, drowsiness, appetite, and dyspnea; 2) depression, anxiety, and wellbeing. The HCA further split the symptoms into three clusters. Wellbeing, depression, and anxiety consistently clustered together. Among the ESAS scores collected at the end of and after RT, each statistical method identified different symptom clusters. For the symptom clusters experienced at the end of RT, the following symptoms were always in the same cluster: wellbeing, depression, and anxiety; nausea and appetite; drowsiness and dyspnea. Following RT, depression and anxiety consistently clustered together, with nausea and appetite in a second cluster. Conclusion Among the symptom clusters derived before, at the end of RT, and after RT, the following symptoms consistently presented together: depression and anxiety, nausea and appetite, pain and tiredness, and drowsiness, dyspnea, and tiredness. Understanding symptom clusters in this population can improve management of symptoms.

INTRODUCTION: There has been a long-standing debate regarding the efficacy of single fraction radiotherapy (SFRT) compared to multiple fraction radiotherapy (MFRT); many systematic reviews and meta-analyses have been conducted to resolve the debate and suggested SFRT is equally as effective as MFRT. Given the adequate amalgamated sample size that exists, it is difficult to appreciate the need for further RCTs. The aim of this paper was to conduct a cumulative meta-analysis to determine whether further trials will be of value to the meta-conclusion. This paper also assessed publication quality.METHODS: A total of 29 studies were used in our meta-analysis. Comprehensive Meta-Analysis (Version 3) by Biostat was used to conduct a cumulative meta-analysis. The Cochrane Risk of Bias assessment tool was employed to assess study quality of the included RCTs. Funnel plots were generated using Review Manager (RevMan 5.3) by Cochrane IMS, to visually assess for publication bias.RESULTS: All but one endpoint, overall response rates in assessable patients, maintained the same meta-conclusion over publication time; published studies did not change the amalgamated scientific conclusion of existing literature. Additional studies have simply confirmed pre-existing conclusions and refined the point estimate of the efficacy estimate. The majority of included studies have low risk of bias.CONCLUSION: In conclusion, the meta-conclusion has remained consistent over time - SFRT is equally as efficacious as MFRT. Recent studies have had little impact on the overall conclusion, and given the vast amount of resources to execute a randomized trial, future resources should not be used to repeat these studies, and can be better allocated to test other hypotheses.

Introduction The aim is to conduct an updated systematic review comparing palonosetron to other 5-HT3RAs for the prophylaxis of CINV, assess for publication biases, and determine whether further RCTs are required, that could potentially lead to a different meta-conclusion. Methods Random-effects analysis model was used to generate odds ratio (OR), risk differences (RD) and accompanying 95% confidence intervals (CI). Funnel plots to assess for biases and cumulative meta-analyses to assess effect size over time were generated. Results 4145 patients were randomized to palonosetron and 4911 received other 5-HT3RAs. In the majority of efficacy endpoints, the meta-conclusion has not changed over time - recent clinical trials simply narrow CIs the meta-conclusion. Safety profile boasts a stable conclusion over time. No publication biases exist. Conclusion Considering the vast amount of resources needed to conduct RCTs, resources should be dedicated to other prophylactic treatments/settings which have not been as well explored.

Background Breast cancer patients often experience multiple symptoms that negatively affect quality of life (QOL). Patient-reported scores on symptom screening tools are used by health care professionals to manage QOL. We aimed to examine which symptoms from the Edmonton Symptom Assessment Scale (ESAS) were most predictive of overall well-being (QOL) in breast cancer patients over the course of radiotherapy (RT). Patients and Methods ESAS results completed before, at the end of, and after RT were obtained from all nonmetastatic breast cancer patients. Univariate and multivariable (backward stepwise selection) linear regression analyses were applied to select the most significant ESAS symptoms or treatment variables related to overall QOL at all 3 time points. Results A total of 1224 patients were included in the study. Before RT, multivariable analysis identified 5 symptoms that were significantly associated with overall QOL: pain, tiredness, anxiety, depression, and loss of appetite. At the end of RT, pain, tiredness, and anxiety were the most significant predictors of QOL. After RT, 6 symptoms were found to have the strongest correlation with QOL: pain, tiredness, anxiety, depression, loss of appetite, and drowsiness. At each time point, patients with higher scores for the identified significant symptoms were likely to have a worse overall QOL. Conclusion Of the ESAS symptoms identified as significant predictors of QOL, pain, tiredness, and anxiety correlated with overall well-being at all time points. Special attention should be paid to manage symptoms that are most predictive of overall QOL in order to ensure optimal symptom management in breast cancer patients receiving RT.

Purpose Arthralgia and myalgia following taxane chemotherapy has been documented in the literature. However, these two toxicities associated with taxane treatment have not been closely examined in the literature, and data remain inconsistent in terms of the reported incidences of these toxicities. The purpose of this literature review was to provide a more comprehensive understanding of the incidence of taxane-induced arthralgia and myalgia, as well as to document the risk factors and preventative and therapeutic treatments that have been investigated. Methods A literature search was conducted in Ovid Medline, OldMedline, Embase, Embase Classic, and Cochrane Central Register of Controlled Trials using relevant subject headings and keywords such as: “arthralgia,” “myalgia,” “muscle pain,” “joint pain,” “taxane,” “chemotherapy,” “docetaxel,” “paclitaxel.” Results The reported incidences of arthralgia and myalgia were variable. Taxane chemotherapy was found to be associated with greater incidences of arthralgia and myalgia than non-taxane forms of chemotherapy. Moreover, docetaxel and nab-paclitaxel seem to be associated with lower incidences of arthralgia and myalgia than paclitaxel. Finally, the literature on prevention and therapeutic treatment of taxane-induced arthralgia and myalgia is scarce. Conclusion More studies should be done in order to more conclusively identify optimal therapeutic and preventative treatments as well as different risk factors. We recommend that a prospective study be done in order to better understand the true incidence of arthralgia and myalgia in patients being treated with the paclitaxel, docetaxel, and nab-paclitaxel.

Background: Studies have reported that performance status (PS) is a good prognostic indicator in patients with advanced cancer. However, different health care professionals (HCPs) could grade PS differently. The purpose of this review is to investigate the PS scores evaluated by different HCPs as reported in the literature. Methods: A literature search was conducted in Ovid MEDLINE and OLDMEDLINE from 1946 to Present (July 5, 2015), Embase Classic and Embase from 1947 to 2015 Week 26, and Cochrane Central Register of Controlled Trials up to May 2015. Information of interest was whether there was a difference of PS assessment between HCPs. Other statistical information provided to assess the agreement in ratings, such as Cohen’s kappa coefficient, Krippendorff’s alpha coefficient, Spearman Rank Coefficient, and Kendall’s correlation, was noted. Results: Of the fifteen articles, eleven compared PS assessments between HCPs of different disciplines, one between the attending and resident physician, two between similarly-specialized physicians, and one between two unspecified-specialty physicians. Three studies reported a lack of agreement (kappa =0.19–0.26; Krippendorff’s alpha =0.61–0.63), four reported moderate inter-rater reliability (kappa =0.31–0.72), two reported mixed reliability, and six reported strong reliability (kappa =0.91–0.92; Spearman rank correlation =0.6–1.0; Kendall’s correlation =0.75–0.82). Four studies reported that Karnofsky performance status (KPS) had better inter-rater reliability than both the Eastern Cooperative Oncology Group Performance Status (ECOG PS) and the palliative performance scale (PPS). Conclusions: The existing literature cites both good and bad inter-rater reliability of PS scores. It is difficult to conclude which HCPs’ PS assessments are more accurate.

Olanzapine is a potent antipsychotic medication that inhibits a wide variety of receptors. It has been used in trials for the prophylaxis and rescue of chemotherapy-induced nausea and vomiting (CINV). This study systematically investigates the efficacy of olanzapine in relation to other antiemetics in the prophylaxis and rescue of CINV. A literature search of Ovid MEDLINE, EMBASE, and CENTRAL was conducted to identify randomized controlled trials (RCTs) comparing olanzapine to other standard antiemetics for either prevention or rescue. The primary endpoints were the percentage of patients achieving no emesis or no nausea, in the acute, delayed, and overall phases. Ten RCTs in the preventative setting and three RCTs in the breakthrough setting were identified. Subgroup analysis demonstrated a similar degree of benefit from a 5- and 10-mg dose of olanzapine for the no emesis endpoint in the overall phase. In the prophylaxis setting, olanzapine was statistically superior in five of six endpoints and clinically superior in four of six endpoints. In the breakthrough setting, olanzapine was statistically and clinically superior in the only endpoint analyzed: no emesis. Olanzapine is more efficacious than other standard antiemetics for the rescue of CINV and its inclusion improves control in the prevention setting. Given the possible reduction in side effects, the use of a 5-mg dose of olanzapine should be considered. Future RCTs should compare the 5-mg versus the 10-mg dosages further and report on the efficacy and percentage of patients developing side effects. Further analyses should be done without the influence of corticosteroids.

Background The aim of this review is to describe the challenges and barriers to conducting research in long-term care facilities. Methods A literature search was conducted in Ovid MEDLINE, Embase, Cochrane Central, PsycINFO and CINAHL. Keywords used included “long term care”, “nursing home”, “research”, “trial”, “challenge” and “barrier”, etc. Resulting references were screened in order to identify relevant studies that reported on challenges derived from first-hand experience of empirical research studies. Challenges were summarized and synthesized. Results Of 1723 references, 39 articles were selected for inclusion. To facilitate understanding we proposed a classification framework of 8 main themes to categorize the research challenges presented in the 39 studies, relating to the characteristics of facility/owner/administrator, resident, staff caregiver, family caregiver, investigator, ethical or legal concerns, methodology, and budgetary considerations. Conclusions Conducting research in long-term care facilities is full of challenges which can be categorized into 8 main themes. Investigators should be aware of all these challenges and specifically address them when planning their studies. Stakeholders should be involved from an early stage and flexibility should be built into both the methodology and research budget. Electronic supplementary material The online version of this article (10.1186/s12877-018-0934-9) contains supplementary material, which is available to authorized users.