Effectiveness of Balance Exercise and Brisk Walking on Alleviating Nonmotor and Motor Symptoms in People With Mild-to-Moderate Parkinson Disease: A Randomized Clinical Trial With 6-Month Follow-up.

OBJECTIVE: To investigate the effects of balance exercise and brisk walking on nonmotor and motor symptoms, balance and gait functions, walking capacity, and balance confidence in Parkinson disease (PD) at posttraining and 6-month follow-up. DESIGN: Two-arm, assessor-blinded randomized controlled trial SETTING: University research laboratory and the community PARTICIPANTS: Ninety-nine eligible individuals with mild-to-moderate PD INTERVENTIONS: Participants were randomized to balance and brisk walking group (B&B, n=49) or active control group (n=50). B&B received ten 90-minute sessions of balance exercises and brisk walking supervised by physical therapists for 6 months (week 1-6: weekly, week 7-26: monthly), whereas control practiced whole-body flexibility and upper limb strength exercise at same dosage (180 min/wk). Both groups performed unsupervised home exercises 2-3 times/wk during intervention and continued at follow-up. MAIN OUTCOME MEASURES: Primary outcomes were Movement Disorder Society Unified Parkinson Disease Rating Scale nonmotor (MDS-UPDRS-I) and motor (MDS-UPRDS-III) scores. Secondary outcomes were mini-Balance Evaluation Systems Test (mini-BEST) score, comfortable gait speed (CGS), 6-minute walk test (6MWT), dual-task timed-Up-and-Go (DTUG) time, and Activities-Specific Balance Confidence Scale score. RESULTS: Eighty-three individuals completed the 6-month intervention with no severe adverse effects. The mean between-group (95% CI) difference for the MDS-UPDRS nonmotor score was 1.50 (0.19-2.81) at 6 months and 1.09 (-0.66 to 2.85) at 12 months. The mean between-group (95% CI) difference for the MDS-UPDRS motor score was 3.75 (0.69-6.80) at 6 months and 4.57 (1.05-8.01) at 12 months. At 6 and 12 months, there were significant between-group improvements of the B&B group in mini-BEST score, CGS, 6MWT, and DTUG time. CONCLUSIONS: This combined balance and brisk walking exercise program alleviates nonmotor and motor symptoms and improves walking capacity, balance, and gait functions posttraining, with positive carryover effects for all except nonmotor outcomes, at 6-month follow-up in mild-to-moderate PD.

Effects of cocoa-rich chocolate on cognitive performance in postmenopausal women. A randomised clinical trial.

OBJECTIVES: The aim of this research was to evaluate the effects of adding 10 g of cocoa-rich chocolate (99%) to the habitual diet on cognitive performance in postmenopausal women. METHODS: Following a randomised controlled parallel clinical trial, a total of 140 postmenopausal women aged 50-64 were recruited. The intervention group (n = 73) consumed daily 10 g of chocolate (99% cocoa) in addition to their usual food intake for 6 months, whereas the control group (n = 67) did not receive any intervention. Attention and executive functions, verbal memory, working memory, phonological fluency, category fluency and clinical variables were assessed at baseline and 6 months. RESULTS: Trail Making Test B execution time showed a decreased of -12.08 s (95% CI: -23.99, -0.18; p = 0.047) in the intervention group compared to the control group, after adjusting for age, educational level, time elapsed from the beginning of menopause and daily energy consumption (Cohen's d = -0.343). Attention, immediate or delayed verbal memory, phonological or category fluency, and working memory remained unchanged. CONCLUSIONS: The consumption of cocoa-rich (99%) chocolate in addition to the habitual diet could be related to a slight improvement in cognitive performance regarding cognitive flexibility and processing speed in postmenopausal women, with no changes in the rest of the cognitive performance variables evaluated.Trial registration: This clinical trial has been registered at clinicaltrials.gov as NCT03492983.

Effectiveness of a multiple health-behaviour-change intervention in increasing adherence to the Mediterranean Diet in adults (EIRA study): a randomized controlled hybrid trial.

BACKGROUND: The present study describes the effectiveness of a complex intervention that addresses multiple lifestyles to promote healthy behaviours in increasing adherence to the Mediterranean diet (MD).  METHODS: Cluster-randomised, hybrid clinical trial controlled with two parallel groups. The study was carried out in 26 primary Spanish healthcare centres. People aged 45-75 years who presented at least two of the following criteria were included: smoker, low adherence to the MD or insufficient level of physical activity. The intervention group (IG) had three different levels of action: individual, group, and community, with the aim of acting on the behaviours related to smoking, diet and physical activity at the same time. The individual intervention included personalised recommendations and agreements on the objectives to attain. Group sessions were adapted to the context of each healthcare centre. The community intervention was focused on the social prescription of resources and activities performed in the environment of the community of each healthcare centre. Control group (CG) received brief advice given in the usual visits to the doctor's office. The primary outcome was the change, after 12 months, in the number of participants in each group with good adherence to the MD pattern. Secondary outcomes included the change in the total score of the MD adherence score (MEDAS) and the change in some cardiovascular risk factors. RESULTS: Three thousand sixty-two participants were included (IG = 1,481, CG = 1,581). Low adherence to the MD was present in 1,384 (93.5%) participants, of whom 1,233 initiated the intervention and conducted at least one individual visit with a healthcare professional. A greater increase (13.7%; 95% CI, 9.9-17.5; p < 0.001) was obtained by IG in the number of participants who reached 9 points or more (good adherence) in the MEDAS at the final visit. Moreover, the effect attributable to the intervention obtained a greater increase (0.50 points; 95% CI, 0.35 to 0.66; p < 0.001) in IG. CONCLUSIONS: A complex intervention modelled and carried out by primary healthcare professionals, within a real clinical healthcare context, achieved a global increase in the adherence to the MD compared to the brief advice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03136211. Retrospectively registered on 02/05/2017 https://clinicaltrials.gov/ct2/show/NCT03136211.

FOLFOXIRI plus Bevacizumab Versus FOLFOX plus Panitumumab for Metastatic Left-Sided RAS/BRAF Wild-Type Colorectal Cancer: Which "Side" Are You On?

This commentary focuses on the results of the study by Pietrantonio et al., which evaluated the clinical conundrum of triplet versus doublet chemotherapy in combination with targeted therapy for metastatic left-sided RAS/BRAF wild-type colorectal cancer and appears in this issue. Both FOLFOXIRI [fluorouracil, leucovorin, oxaliplatin, and irinotecan] plus bevacizumab and FOLFOX [fluorouracil, leucovorin, and oxaliplatin] plus panitumumab have shown impressive activity in this population; however, the two have not been directly compared. The article by Pietrantonio et al. presents a propensity score-adjusted analysis using information from five previous randomized trials and provides best available evidence comparing these regimens. This commentary will discuss their results and how their findings fit in current treatment paradigms.

Cocoa-rich chocolate and body composition in postmenopausal women: a randomised clinical trial.

During menopause, women undergo a series of physiological changes that include a redistribution of fat tissue. This study was designed to investigate the effect of adding 10 g of cocoa-rich chocolate to the habitual diet of postmenopausal women daily on body composition. We conducted a 6-month, two-arm randomised, controlled trial. Postmenopausal women (57·2 (sd 3·6) years, n 132) were recruited in primary care clinics. Participants in the control group (CG) did not receive any intervention. Those of the intervention group (IG) received 10 g daily of 99 % cocoa chocolate in addition to their habitual diet for 6 months. This quantity comprises 247 kJ (59 kcal) and 65·4 mg of polyphenols. The primary outcomes were the between-group differences in body composition variables, measured by impendancemetry at the end of the study. The main effect of the intervention showed a favourable reduction in the IG with respect to the CG in body fat mass (-0·63 kg (95 % CI -1·15, -0·11), P = 0·019; Cohen's d = -0·450) and body fat percentage (-0·79 % (95 % CI -1·31, -0·26), P = 0·004; Cohen's d = -0·539). A non-significant decrease was also observed in BMI (-0·20 kg/m2 (95 % CI -0·44, 0·03), P = 0·092; Cohen's d = -0·345). Both the body fat mass and the body fat percentage showed a decrease in the IG for the three body segments analysed (trunk, arms and legs). Daily addition of 10 g of cocoa-rich chocolate to the habitual diet of postmenopausal women reduces their body fat mass and body fat percentage without modifying their weight.

The emergence of targetable pathways in colorectal cancer.

Colorectal cancer continues to be one of the leading causes of cancer-related morbidity and mortality globally. Despite an overall decreasing incidence of the disease, early-onset colorectal cancer is a growing concern. Fluoropyrimidine-based doublet chemotherapy has remained the backbone of treatment in the metastatic setting during the past 2 decades. The increasing accessibility and decreasing cost of molecular profiling have made it possible to acquire further insight into prognostic and predictive biomarkers that ultimately help physicians to provide precision medicine in the clinic. In this review, we describe a contemporary biomarker-driven approach to first-line and subsequent-line therapies and highlight the important molecular alterations that affect the treatment of advanced colorectal cancer, along with the supporting clinical trial data.

Medical Oncologists' Perspectives on How the Results of the IDEA Collaboration Impact the Adjuvant Treatment of Stage III Colon Cancer.

BACKGROUND: The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy are noninferior to 6 months. Our study objectives were to characterize medical oncologists' perspectives toward the results of the IDEA collaboration and to evaluate how IDEA impacted prescribing patterns of adjuvant FOLFOX and CAPOX in colon cancer. MATERIALS AND METHODS: A list of questions developed by four medical oncologists regarding IDEA results were formulated and distributed online to gastrointestinal medical oncologists globally. Descriptive statistics and chi-square tests were used to summarize information. RESULTS: Of 174 responses, 145 were complete and analyzed. Responses were obtained globally from South America (53%); the U.S. and Canada (28%); Europe, Australia, and New Zealand (12%); and Asia (7%). Most clinicians (98%) were aware of the IDEA study. Prior to IDEA, clinicians preferred FOLFOX over CAPOX (81% vs. 19%). Subsequent to IDEA, 55% of clinicians preferred CAPOX over FOLFOX (odds ratio, 5.0; 95% confidence interval, 3.0-8.5; p < .01 compared with pre-IDEA). Two thirds (68%) of responders tailored duration of adjuvant therapy based on risk stratification. Most oncologists (76%) were more willing to discontinue oxaliplatin early if toxicities develop after the results of IDEA. Half of responders (50%) found that IDEA increased their confidence in decision making for adjuvant treatment; 36% were unchanged, and 15% indicated decreased confidence. Less than half (48%) were comfortable communicating the study results and the concept of a noninferiority trial with patients. CONCLUSION: IDEA appears to have shifted clinician preference from FOLFOX to CAPOX for adjuvant therapy, and most clinicians now use a risk-stratified approach in determining duration of adjuvant therapy. Patient education resources may facilitate better communication of IDEA results to patients. IMPLICATIONS FOR PRACTICE: This global survey illustrates that most gastrointestinal medical oncologists now use a risk-stratified approach for determining the duration of adjuvant chemotherapy for stage III colon cancer. Clinicians are five times more likely to choose CAPOX over FOLFOX after the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration results.

Voluntary Wheel Running Exercise Evoked by Food-Restriction Stress Exacerbates Weight Loss of Adolescent Female Rats But Also Promotes Resilience by Enhancing GABAergic Inhibition of Pyramidal Neurons in the Dorsal Hippocampus.

Adolescence is marked by increased vulnerability to mental disorders and maladaptive behaviors, including anorexia nervosa. Food-restriction (FR) stress evokes foraging, which translates to increased wheel running exercise (EX) for caged rodents, a maladaptive behavior, since it does not improve food access and exacerbates weight loss. While almost all adolescent rodents increase EX following FR, some then become resilient by suppressing EX by the second-fourth FR day, which minimizes weight loss. We asked whether GABAergic plasticity in the hippocampus may underlie this gain in resilience. In vitro slice physiology revealed doubling of pyramidal neurons' GABA response in the dorsal hippocampus of food-restricted animals with wheel access (FR + EX for 4 days), but without increase of mIPSC amplitudes. mIPSC frequency increased by 46%, but electron microscopy revealed no increase in axosomatic GABAergic synapse number onto pyramidal cells and only a modest increase (26%) of GABAergic synapse lengths. These changes suggest increase of vesicular release probability and extrasynaptic GABAA receptors and unsilencing of GABAergic synapses. GABAergic synapse lengths correlated with individual's suppression of wheel running and weight loss. These analyses indicate that EX can have dual roles-exacerbate weight loss but also promote resilience to some by dampening hippocampal excitability.

Peering into the Deep: Characterizing the Internet Search Patterns of Patients with Gynecologic Cancers.

Cancer patients are increasingly using the Internet to learn about their disease, connect with others undergoing similar treatments and obtain support outside of the clinical encounter. The goal of this project was to explore how patients with gynecological cancers (ovarian, cervical, and endometrial) used the Internet as an information resource and how this influenced their treatment decisions and interactions with their health care specialists. From 2013 to 2014, ovarian, endometrial, and cervical cancer patients attending a comprehensive cancer centre were invited to complete a 24-item paper questionnaire detailing their experiences in searching the Internet. Twenty-eight patients completed survey. The largest portion of participants had an ovarian cancer diagnosis (61 %), followed by endometrial (29 %) and cervical cancer (11 %). Results indicate that the majority (85 %) of patients used the Internet as a resource to learn about their gynecological cancers. Most respondents (89 %) used Google as their search engine, and some used multiple search engines. The most frequently searched topics included treatment information (85 %), management of symptoms/treatment toxicity (59 %), and alternative treatments (37 %). Many patients (74 %) felt that the Internet was a useful tool for understanding their diagnosis; however, 33 % reported that the Internet was somewhat hard to understand. Most (78 %) patients reported that Internet information increased their understanding of their diagnosis, and 56 % felt it did not affect their decision-making. This study highlights how gynecological patients are accessing cancer information online and how physicians may support this within the clinical setting.

DNAJC13 mutations in Parkinson disease.

A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case-control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch-German-Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.

Risk and management of venous thromboembolisms in bevacizumab-treated metastatic colorectal cancer patients.

PURPOSE: Bevacizumab may potentiate the risk of venous thromboembolisms (VTEs) in cancer patients, who are already predisposed to pro-thrombotic states. We aimed to characterize the incidence of VTEs in a population-based cohort of metastatic colorectal cancer (mCRC) patients treated with bevacizumab, describe patient and treatment factors associated with VTEs, and examine how VTEs are managed. METHODS: Patients diagnosed with mCRC from 2006 to 2009 and offered bevacizumab were included. Descriptive statistics were used to describe VTE occurrences and management. Univariate and multivariate regression models were constructed to explore associations between clinical factors and VTEs. RESULTS: We identified 541 mCRC patients: 27 never started bevacizumab and 15 were lost to follow-up. Of the 499 evaluable patients, median age was 61, 59.3% were men, 88.1% had ECOG 0/1, and 5.2% reported previous VTEs. Mean number of bevacizumab doses was 13.3 cycles. After receiving bevacizumab, 81 patients developed 93 cases of VTEs, with 9 patients experiencing >1 event. Individuals who experienced VTEs were more likely to have had pre-existing cardiovascular disease (OR 2.259, p = 0.0245), resection of primary cancer (OR 3.262, p = 0.0269), pre-chemotherapy platelet count ≥350,000/µL (OR 2.295, p = 0.0293), and received >12 bevacizumab cycles (OR 2.172, p = 0.0158). Use of bevacizumab varied after occurrence of VTE where it was discontinued in 34.4%, continued in 34.4%, and temporarily held in 1.1%. CONCLUSIONS: VTE risk can be high, especially in patients with specific pre-treatment risk factors as well as in those who received more bevacizumab, suggesting a potential dose-related effect. Management of bevacizumab-related VTEs was variable.

Task- and Context-Specific Balance Training Program Enhances Dynamic Balance and Functional Performance in Parkinsonian Nonfallers: A Randomized Controlled Trial With Six-Month Follow-Up.

OBJECTIVES: To investigate the short- and long-term effects of a task- and context-specific balance training program on dynamic balance and functional performance, and to explore the effects on preventing total and injurious falls in parkinsonian nonfallers. DESIGN: A randomized controlled trial with group allocation single-blinded to the assessor. SETTING: Community centers, malls, and outdoor parks. PARTICIPANTS: Nonfallers with Parkinson disease (PD) (N=70; mean age ± SD, 61.2±8.8y) randomly assigned to either a balance (BAL) group (n=32) or a control (CON) group (n=38). INTERVENTIONS: The BAL group received 4 weeks of indoor and 4 weeks of outdoor balance training (with a 2-h session per week). The CON group received 8 weeks of upper limb training at the same dosage. Both groups were instructed to perform 3 hours of home exercise weekly posttraining. MAIN OUTCOME MEASURES: (1) Dynamic balance performance: Mini-Balance Evaluation Systems Test (Mini-BESTest); (2) Functional performance: functional reach (FR), 5 times sit-to-stand (FTSTS), 1-leg-stance (OLS), Timed Up and Go (TUG), and dual-task TUG tests; (3) Fall-related outcomes: ratios of total nonfallers to fallers and noninjurious fallers to injurious fallers, total and injurious fall rates, times to first falls and injurious falls. RESULTS: Sixty-eight participants completed training. A total of 7 patients (10%) withdrew before the 6-month follow-up, but not because of any adverse effects. At immediate and 6 months posttraining, the BAL group showed significantly greater improvements (from baseline) than the CON group in Mini-BESTest total scores, FR distances, and OLS times, together with greater time reductions in FTSTS, TUG, and dual-task TUG tests (all P<.05). The number of injurious fallers was significantly lower in the BAL group at 6-month follow-up. CONCLUSIONS: This task- and context-specific balance training program improved the dynamic balance and fall-prone functional performance of PD nonfallers for up to 6 months after training. The BAL group showed a reduction in injurious fallers.

Sifting Through It All: Characterizing Melanoma Patients' Utilization of the Internet as an Information Source.

This study describes how melanoma patients used the Internet as a melanoma information source and how it impacted their clinical encounter and treatment decision. From 2010 to 2013, melanoma patients were invited to complete a 23-question paper survey with open- and close-ended questions. Thirty-one of the 62 patients approached completed the survey. The majority (90 %) of respondents used the Internet as a melanoma information source. Most (90 %) had used the search engine Google. The most commonly searched topics were melanoma treatment (96 %), screening (64 %), and prevention (64 %). While most respondents (85 %) found the Internet was a useful melanoma information source, over half (54 %) found melanoma websites at least somewhat difficult to understand. Many (78 %) believed it increased their understanding of their diagnosis, 71 % thought it influenced their treatment decision, and 59 % felt it impacted their specialist consultation. This study informs health care professionals that many melanoma patients search the Internet for information regarding their diagnosis and that it may impact their disease understanding and treatment decisions.

NFKBIA deletion in glioblastomas.

BACKGROUND: Amplification and activating mutations of the epidermal growth factor receptor (EGFR) oncogene are molecular hallmarks of glioblastomas. We hypothesized that deletion of NFKBIA (encoding nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor-α), an inhibitor of the EGFR-signaling pathway, promotes tumorigenesis in glioblastomas that do not have alterations of EGFR. METHODS: We analyzed 790 human glioblastomas for deletions, mutations, or expression of NFKBIA and EGFR. We studied the tumor-suppressor activity of NFKBIA in tumor-cell culture. We compared the molecular results with the outcome of glioblastoma in 570 affected persons. RESULTS: NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. Restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy of cells cultured from tumors with NFKBIA deletion; it also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated with unfavorable outcomes. Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification. These outcomes were poor as compared with the outcomes in patients with tumors that had normal gene dosages of NFKBIA and EGFR. A two-gene model that was based on expression of NFKBIA and O(6)-methylguanine DNA methyltransferase was strongly associated with the clinical course of the disease. CONCLUSIONS: Deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival.

Exploration of Germline Correlates and Risk of Immune-Related Adverse Events in Advanced Cancer Patients Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.

Upfront Versus Delayed Systemic Therapy in Patients With Oligometastatic Cancer Treated With SABR in the Phase 2 SABR-5 Trial.

PURPOSE: The optimal sequencing of local and systemic therapy for oligometastatic cancer has not been established. This study retrospectively compared progression-free survival (PFS), overall survival (OS), and SABR-related toxicity between upfront versus delay of systemic treatment until progression in patients in the SABR-5 trial. METHODS AND MATERIALS: The single-arm phase 2 SABR-5 trial accrued patients with up to 5 oligometastases across SABR-5 between November 2016 and July 2020. Patients received SABR to all lesions. Two cohorts were retrospectively identified: those receiving upfront systemic treatment along with SABR and those for whom systemic treatment was delayed until disease progression. Patients treated for oligoprogression were excluded. Propensity score analysis with overlap weighting balanced baseline characteristics of cohorts. Bootstrap sampling and Cox regression models estimated the association of delayed systemic treatment with PFS, OS, and grade ≥2 toxicity. RESULTS: A total of 319 patients with oligometastases underwent treatment on SABR-5, including 121 (38%) and 198 (62%) who received upfront and delayed systemic treatment, respectively. In the weighted sample, prostate cancer was the most common primary tumor histology (48%) followed by colorectal (18%), breast (13%), and lung (4%). Most patients (93%) were treated for 1 to 2 metastases. The median follow-up time was 34 months (IQR, 24-45). Delayed systemic treatment was associated with shorter PFS (hazard ratio [HR], 1.56; 95% CI, 1.15-2.13; P = .005) but similar OS (HR, 0.90; 95% CI, 0.51-1.59; P = .65) compared with upfront systemic treatment. Risk of grade 2 or higher SABR-related toxicity was reduced with delayed systemic treatment (odds ratio, 0.35; 95% CI, 0.15-0.70; P < .001). CONCLUSIONS: Delayed systemic treatment is associated with shorter PFS without reduction in OS and with reduced SABR-related toxicity and may be a favorable option for select patients seeking to avoid initial systemic treatment. Efforts should continue to accrue patients to histology-specific trials examining a delayed systemic treatment approach.

Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease.

BACKGROUND: Alpha-synuclein plays a central role in the pathophysiology of Parkinson's disease. Three missense mutations in SNCA, the gene encoding alpha-synuclein, as well as genomic multiplications have been identified as causes for autosomal-dominantly inherited Parkinsonism. METHODS: Here, we describe a novel missense mutation in exon 4 of SNCA encoding a H50Q substitution in a patient with dopa-responsive Parkinson's disease with a family history of parkinsonism and dementia. RESULTS: The variant was not observed in public databases or identified in unrelated subjects. CONCLUSIONS: The substitution's evolutionary conservation and protein modeling provide additional support for pathogenicity as the amino acid perturbs the same amphipathic alpha helical structure as the previously described pathogenic mutations.

Immunotherapy: Recent Advances and Its Future as a Neoadjuvant, Adjuvant, and Primary Treatment in Colorectal Cancer.

Immunotherapy in colorectal cancer (CRC) has made great strides within the past decade. Immune checkpoint inhibitors are a class of immunotherapy and have been shown to greatly improve patient outcomes in mismatch repair-deficient (dMMR) CRC. Now, they are part of the standard of care for this subset of CRC. Because of this, there has been a growing interest in the efficacy and timing of immunotherapy for other subsets of CRC, including locally advanced, metastatic, and microsatellite stable (MSS). In this review, we aim to examine the three main classes of immunotherapy for CRC-immune checkpoint inhibitors (ICIs), adoptive cell transfer therapy (ACT), and tumor vaccines-and discuss the most recent advances and future directions for each.

Dedicated esophageal imaging may be unnecessary in marijuana-associated spontaneous pneumomediastinum: Findings from a retrospective cohort study.

Background: Marijuana use has become more common since its legalization, as have reports of marijuana-associated spontaneous pneumomediastinum. Non-spontaneous causes such as esophageal perforation are often ruled out on presentation due to the severe consequences of untreated disease. Here we seek to characterize the presentation of marijuana-associated spontaneous pneumomediastinum and explore whether esophageal imaging is necessary in the setting of an often benign course and rising healthcare costs. Materials and Methods: Retrospective review was performed for all 18-55 year old patients evaluated at a tertiary care hospital between 1/1/2008 and 12/31/2018 for pneumomediastinum. Iatrogenic and traumatic causes were excluded. Patients were divided into marijuana and control groups. Results: 30 patients met criteria, with 13 patients in the marijuana group. The most common presenting symptoms were chest pain/discomfort and shortness of breath. Other symptoms included neck/throat pain, wheezing, and back pain. Emesis was more common in the control group but cough was equally prevalent. Leukocytosis was present in most patients. Four out of eight of computed tomography esophagarams in the control group showed a leak requiring intervention, while only one out of five in the marijuana group showed even a possible subtle extravasation of contrast but this patient ultimately was managed conservatively given the clinical picture. All standard esophagrams were negative. All marijuana patients were managed without intervention. Discussion: Marijuana-associated spontaneous pneumomediastinum appears to have a more benign clinical course compared to non-spontaneous pneumomediastinum. Esophageal imaging did not change management for any marijuana cases. Perhaps such imaging could be deferred if clinical presentation of pneumomediastinum in the setting of marijuana use is not suggestive of esophageal perforation. Further research into this area is certainly worth pursuing.

Analysis of the determinants of sleep quality in a Spanish population: a study protocol for a cross-sectional study.

INTRODUCTION: Sleep problems are a growing public health concern being related, among others, to an increased risk of cardiovascular diseases or worse cognitive functioning. In addition, they can affect aspects related to personal motivation and quality of life. However, very few studies have analysed the possible determinants of sleep quality in the adult population as a whole, establishing patterns based on these determinants.The objectives are to evaluate the determinants of sleep quality in a representative sample of the general adult population between 25 and 65 years old, and to establish patterns of sleep quality based on lifestyles, psychological factors, morbidities, sociodemographic variables, biological markers and other possible determinants. METHODS AND ANALYSIS: Descriptive observational cross-sectional study. The study population will include a representative sample of 500 people between 25 and 65 years old from the cities of Salamanca and Ávila (Spain) selected by random sampling stratified by age groups and sex. A 90-minute visit will be performed, during which sleep quality will be assessed. The variables collected will be: morbidity, lifestyles (physical activity, diet, toxic habits), psychological factors (depression, stress, occupational stress and anxiety), socioeconomic and work-related variables, habitability conditions of the habitual residence and rest area, screen time, relaxation techniques and melatonin as a biological marker related to sleep quality. DISCUSSION: With the results of this work, improved interventions for behaviour modification could be designed, as well as intervention and education programmes or other research aimed at improving sleep quality. ETHICS AND DISSEMINATION: This study has a favourable opinion from the Ethics Committee for Drug Research of the Health Areas of Salamanca and Ávila (CEim Code: PI 2021 07 815). The results of this study will be published in international impact journals of different specialties. TRIAL REGISTRATION NUMBER: NCT05324267.