Psychological distress and health behaviours in people living with and beyond cancer: a cross-sectional study.

This study aimed to examine whether psychological distress was cross-sectionally associated with meeting World Cancer Research Fund (WCRF) recommendations in people living with and beyond cancer. Participants were adults living with and beyond breast, prostate and colorectal cancer, participating in the baseline wave of the Advancing Survivorship after Cancer Outcomes Trial (ASCOT). Anxiety/depression was assessed using the EQ-5D-5L and dichotomised into any/no problems. WCRF recommendations were assessed via pedometers, 24-h dietary recalls, self-reported alcohol intake (AUDIT-C), and self-reported smoking status. Participants were categorised as meeting WCRF recommendations using the following cut-offs: average daily steps (≥ 10,000/day), average weekly aerobic steps (≥ 15,000/day), fruit and vegetables (≥ 400 g/day), fibre (≥ 30 g/day), red meat (< 500 g/week), processed meat (0 g/day), high calorie food (fat ≤ 33% of total daily energy intake and free sugar ≤ 5% of total daily energy intake), alcohol (≤ 14 units/week) and smoking (non-smoking). A composite health behaviour risk index (CHBRI) was calculated by summing the number of WCRF recommendations met (range: 0-9). Among 1348 participants (mean age = 64 years (SD = 11.4)), 41.5% reported anxiety/depression problems. The mean CHBRI score was 4.4 (SD = 1.4). Anxiety/depression problems were associated with lower odds of meeting WCRF recommendations for average daily steps (odds ratio (OR) = 0.73; 95% CI 0.55, 0.97), but not for any other health behaviour. Psychological distress is associated with lower adherence to WCRF recommendations for physical activity in people living with and beyond cancer. Physical activity may be a mechanism linking psychological distress and poorer outcomes among people living with and beyond cancer, and this should be explored in longitudinal studies.

Tumor Regression Following Engineered Polyomavirus-Specific T Cell Therapy in Immune Checkpoint Inhibitor-Refractory Merkel Cell Carcinoma.

Although immune check-point inhibitors (CPIs) revolutionized treatment of Merkel cell carcinoma (MCC), patients with CPI-refractory MCC lack effective therapy. More than 80% of MCC express T-antigens encoded by Merkel cell polyomavirus, which is an ideal target for T-cell receptor (TCR)-based immunotherapy. However, MCC often repress HLA expression, requiring additional strategies to reverse the downregulation for allowing T cells to recognize their targets. We identified TCRMCC1 that recognizes a T-antigen epitope restricted to human leukocyte antigen (HLA)-A*02:01. Seven CPI-refractory metastatic MCC patients received CD4 and CD8 T cells transduced with TCRMCC1 (TTCR-MCC1) preceded either by lymphodepleting chemotherapy or an HLA-upregulating regimen (single-fraction radiation therapy (SFRT) or systemic interferon gamma (IFNγ)) with concurrent avelumab. Two patients who received preceding SFRT and IFNγ respectively experienced tumor regression. One experienced regression of 13/14 subcutaneous lesions with 1 'escape' lesion and the other had delayed tumor regression in all lesions after initial progression. Although TTCR-MCC1 cells with an activated phenotype infiltrated tumors including the 'escape' lesion, all progressing lesions transcriptionally lacked HLA expression. While SFRT/IFNγ did not immediately upregulate tumor HLA expression, a secondary endogenous antigen-specific T cell infiltrate was detected in one of the regressing tumors and associated with HLA upregulation, indicating in situ immune responses have the potential to reverse HLA downregulation. Indeed, supplying a strong co-stimulatory signal via a CD200R-CD28 switch receptor allows TTCR-MCC1 cells to control HLA-downregulated MCC cells in a xenograft mouse model, upregulating HLA expression. Our results demonstrate the potential of TCR gene therapy for metastatic MCC and propose a next strategy for overcoming epigenetic downregulation of HLA in MCC.

Depressive Symptoms, Socioeconomic Position, and Mortality in Older People Living With and Beyond Cancer.

OBJECTIVE: Evidence shows that higher depressive symptoms are associated with mortality among people living with and beyond cancer (LWBC). However, prior studies have not accounted for a wider range of potential confounders, and no study has explored whether socioeconomic position (SEP) moderates the association. This study aimed to examine the association between depressive symptoms and mortality among people LWBC, and moderation by SEP. METHODS: Participants from the English Longitudinal Study of Aging, diagnosed with cancer and with a measure of depressive symptoms within 4 years after their diagnosis, were included. Elevated depressive symptoms were indicated by a score of ≥3 on the eight-item Center for Epidemiologic Studies Depression Scale. Cox regression models examined associations with all-cause mortality. Competing risk regression examined associations with cancer mortality. RESULTS: In 1352 people LWBC (mean age = 69.6 years), elevated depressive symptoms were associated with a 93% increased risk of all-cause mortality (95% confidence interval = 1.52-2.45) within the first 4 years of follow-up and a 48% increased risk within a 4- to 8-year follow-up (95% confidence interval = 1.02-2.13) after multivariable adjustment. Elevated depressive symptoms were associated with a 38% increased risk of cancer mortality, but not after excluding people who died within 1 year after baseline assessments. There were no interactions between depressive symptoms and SEP. CONCLUSIONS: Elevated depressive symptoms are associated with a greater risk of all-cause mortality among people LWBC within an 8-year follow-up period. Associations between depressive symptoms and cancer mortality might be due to reverse causality.

Associations of self-reported and device-assessed physical activity with fatigue, quality of life, and sleep quality in adults living with and beyond cancer.

BACKGROUND: Greater physical activity is associated with improved outcomes in people living with and beyond cancer. However, most studies in exercise oncology use self-reported measures of physical activity. Few have explored agreement between self-reported and device-based measures of physical activity in people living with and beyond cancer. This study aimed to describe physical activity in adults affected by cancer across self-reported and device-assessed activity, to explore levels of agreement between these measures in terms of their utility for categorizing participants as meeting/not meeting physical activity guidelines, and to explore whether meeting guidelines is associated with fatigue, quality of life, and sleep quality. METHODS: A total of 1348 adults living with and beyond cancer from the Advancing Survivorship Cancer Outcomes Trial completed a survey assessing fatigue, quality of life, sleep quality, and physical activity. The Godin-Shephard Leisure-Time Physical Activity Questionnaire was used to calculate a Leisure Score Index (LSI) and an estimate of moderate-to-vigorous physical activity (MVPA). Average daily steps and weekly aerobic steps were derived from pedometers worn by participants. RESULTS: The percentage of individuals meeting physical activity guidelines was 44.3% using LSI, 49.5% using MVPA, 10.8% using average daily steps, and 28.5% using weekly aerobic steps. Agreement (Cohen's κ) between self-reported and pedometer measures ranged from 0.13 (LSI vs. average daily steps) to 0.60 (LSI vs. MVPA). After adjusting for sociodemographic and health-related covariates, meeting activity guidelines using all measures was associated with not experiencing severe fatigue (odds ratios (ORs): 1.43-1.97). Meeting guidelines using MVPA was associated with no quality-of-life issues (OR = 1.53). Meeting guidelines using both self-reported measures were associated with good sleep quality (ORs: 1.33-1.40). CONCLUSION: Less than half of all adults affected by cancer are meeting physical activity guidelines, regardless of measure. Meeting guidelines is associated with lower fatigue across all measures. Associations with quality of life and sleep differ depending on measure. Future research should consider the impact of physical activity measure on findings, and where possible, use multiple measures.

Fatigue, quality of life and associations with adherence to the World Cancer Research Fund guidelines for health behaviours in 5835 adults living with and beyond breast, prostate and colorectal cancer in England: A cross-sectional study.

BACKGROUND: Many individuals living with and beyond cancer (LWBC) have ongoing quality of life (QoL) issues, including fatigue. The World Cancer Research Fund (WCRF) provides health behaviour recommendations for people LWBC, and there is some evidence linking adherence to these with improved QoL. METHODS: Adults LWBC (specifically breast, colorectal or prostate cancer) completed a survey covering health behaviours (diet, physical activity, alcohol consumption and smoking), fatigue (FACIT-Fatigue Scale, version 4) and a broad measure of QoL (EQ-5D-5L descriptive scale). Participants were categorised as meeting/not meeting WCRF recommendations, using the following cut-offs classified as meeting the guidelines: ≥150 min physical activity/week, fruit and vegetables (≥5 portions/day), fibre (≥30 g fibre per day), free sugar (<5% of total calories from free sugar), fat (<33% total energy), red meat (<500 g/week), processed meat (none), alcohol consumption (<14 units/week) and not a current smoker. Logistic regression analyses explored associations between WCRF adherence and fatigue and QoL issues, controlling for demographic and clinical variables. RESULTS: Among 5835 individuals LWBC (mean age: 67 years, 56% female, 90% white, breast 48%, prostate 32% and colorectal 21%), 22% had severe fatigue and 72% had 1+ issue/s on the EQ-5D-5L. Adhering to physical activity recommendations (odds ratio [OR] = 0.88, confidence interval [CI] = 0.77-0.99), meeting various dietary recommendations (fruit and vegetables OR = 0.79; CI = 0.68-0.91, free sugar OR = 0.85; CI = 0.76-0.96, fat OR = 0.71; CI = 0.62-0.82, red meat OR = 0.65; CI = 0.50-0.85) and not smoking (OR = 0.53, CI = 0.41-0.67) were associated with decreased odds of experiencing severe fatigue. Adhering to physical activity guidelines (OR = 0.71, CI = 0.62-0.82) was also associated with decreased odds of having 1+ QoL issue/s. CONCLUSIONS: Adherence to various WCRF recommendations, particularly the recommendation for physical activity, was associated with less fatigue and better QoL in a large UK cohort of people living with and beyond breast, colorectal or prostate cancer. Multi-component interventions designed to support people LWBC to improve health behaviours, in line with the levels recommended by the WCRF, may also improve QoL.

Pericardial Fat, Socioeconomic Status, and Biological Responses to Acute Mental Stress.

OBJECTIVE: Central adiposity is associated with impaired biological responses to mental stress, and socioeconomic status (SES) might moderate this relationship. However, evidence for associations between pericardial fat, a fat depot implicated in the pathogenesis of cardiovascular disease (CVD), with cardiovascular and inflammatory responses to mental stress is lacking, and moderation by SES is unknown. METHODS: The sample was 473 healthy men and women (mean age = 62.8 years) from the Whitehall II study. Cardiovascular and inflammatory responses to laboratory-induced mental stress, consisting of a 5-minute Stroop task and 5-minute mirror tracing task, were assessed. Pericardial fat volume was measured using electron bean computed tomography and adjusted for body surface area. SES was defined by grade of employment within the British civil service (higher/intermediate/lower). RESULTS: Pericardial fat was associated with lower heart rate variability, raised heart rate, plasma interleukin-6, fibrinogen, and C-reactive protein at baseline. Furthermore, greater pericardial fat was associated with lower systolic blood pressure reactivity to mental stress, independent of sociodemographics, smoking status, waist-to-hip ratio, and baseline systolic blood pressure. There were no interactions between pericardial fat and SES for any outcome. CONCLUSIONS: Greater pericardial fat was associated with numerous cardiovascular and inflammatory factors implicated in CVD. It was also related to reduced systolic blood pressure reactivity to acute mental stress, independent of central adiposity and baseline systolic blood pressure. This association did not vary by SES. Reduced systolic blood pressure reactivity to mental stress might contribute to the association between greater pericardial fat and CVD.

The role of partner support for health behaviours in people living with and beyond cancer: A qualitative study.

OBJECTIVE: This study aimed to qualitatively explore how partner support for health behaviours is perceived, received, and utilised in people living with and beyond cancer (LWBC). METHODS: Semi-structured audio interviews were conducted with 24 participants, 15 men and nine women, living with and beyond breast, prostate, and colorectal cancer. Inductive and deductive Thematic Analysis was used to analyse the data. RESULTS: Three key themes with six subthemes were identified relating to partner support for health behaviours: (1) Interdependence (Reciprocity, Overt Control, Influence & Motivation) (2) Concordance (Shared Attitudes & Health Beliefs, Shared Health Behaviour) and (3) Communal Coping (Communal Orientation towards Health and Decision Making, Co-operative Action in Health Behaviour). CONCLUSIONS: Partner support plays a unique and significant role in the health behaviours of people LWBC. Partners play a collaborative role in managing health and facilitating health behaviours, while the high level of concordance in couples may represent a potential barrier to change via the reinforcement of maladaptive health beliefs and behaviours. IMPLICATIONS FOR CANCER SURVIVORS: Overall, findings demonstrate that partners should be considered and included where possible when designing future behaviour change interventions for people LWBC.

Exploring the perceived impact of social support on the health behaviours of people living with and beyond cancer during the COVID-19 pandemic: a qualitative study.

PURPOSE: Social support facilitated healthy behaviours in people living with and beyond cancer (LWBC) before the COVID-19 pandemic. Little is known about how social support impacted their health behaviours during the pandemic when social restrictions were imposed. The aim of this study was to qualitatively explore how social support was perceived to impact the health behaviours of people LWBC during the COVID-19 pandemic. METHODS: Semi-structured interviews were conducted via telephone with 24 adults living with and beyond breast, prostate and colorectal cancer. Inductive and deductive framework analysis was used to analyse the data. RESULTS: Five themes developed. These were (1) Companionship and accountability as motivators for physical activity, (2) Social influences on alcohol consumption, (3) Instrumental support in food practices, (4) Informational support as important for behaviour change and (5) Validation of health behaviours from immediate social networks. CONCLUSION: This study described how companionship, social influence, instrumental support, informational support and validation were perceived to impact the health behaviours of people LWBC during the COVID-19 pandemic. Interventions for people LWBC could recommend co-participation in exercise with friends and family; promote the formation of collaborative implementation intentions with family to reduce alcohol consumption; and encourage supportive communication between partners about health behaviours. These interventions would be useful during pandemics and at other times. Government policies to help support clinically extremely vulnerable groups of people LWBC during pandemics should focus on providing access to healthier foods.

SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance.

Protein arginine methyltransferase 5 (PRMT5) overexpression in hematologic and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell-cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here, we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with in vitro and in vivo characterization of clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the cofactor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of non-small cell lung cancer (NSCLC) cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity to PF-06939999 in NSCLC cells associates with cancer pathways including MYC, cell cycle and spliceosome, and with mutations in splicing factors such as RBM10. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 in the treatment of splicing dysregulated NSCLC.

Small cell neuroendocrine carcinoma presenting as inguinal hernia: A case report.

INTRODUCTION: One of the most common surgical procedures performed annually is inguinal hernia repair. Inguinal hernias are traditionally known to be caused by a weakening in the abdominal wall and precipitated by increased intraabdominal pressure. Recently, intra-abdominal cancer producing the increased intraabdominal pressure, along with metastasis directly into the inguinal canal, have been identified in more studies as causes of inguinal hernias. PRESENTATION OF CASE: This case focuses on a unique presentation of small-cell neuroendocrine carcinoma presenting as an inguinal hernia. DISCUSSION: This patient's rapid demise and advanced metastatic disease upon presentation is alarming, but his advanced disease process presenting as a routine inguinal hernia is noteworthy. Upon literature analysis, the number of advanced disease processes - most notably cancer - presenting as hernias is significant. CONCLUSION: This case emphasis the importance of perioperative screening, and presents the question, should hernias indicate further workup in the appropriate, at-risk patient populations.

Patterns and timing of perioperative blood transfusion and association with outcomes after radical cystectomy.

BACKGROUND: Perioperative blood transfusion (PBT) has been associated with worse outcomes across tumor types, including bladder cancer. We report our institutional experience with PBT utilization in the setting of radical cystectomy (RC) for patients with bladder cancer, exploring whether timing of PBT receipt influences perioperative and oncologic outcomes. METHODS: Consecutive patients with bladder cancer treated with RC were identified. PBT was defined as red blood cell transfusion during RC or the postoperative admission. Clinicopathologic and peri and/or postoperative parameters were extracted and compared between patients who did and did not receive PBT using Mann Whitney U Test, chi-square, and log-rank test. Overall (OS) and recurrence-free survival (RFS) were estimated with the Kaplan Meier method. Univariate/multivariate logistic and Cox proportional hazards regression were used to identify variables associated with postoperative and oncologic outcomes, respectively. RESULTS: The cohort consisted of 747 patients (77% men; median age 67 years). Median follow-up was 61.5 months (95% CI 55.8-67.2) At least one postoperative complication (90-day morbidity) occurred in 394 (53%) patients. Median OS and RFS were 91.8 months (95% CI: 76.0-107.6) and 66.0 months (95% CI: 48.3-83.7), respectively. On multivariate analysis, intraoperative, but not postoperative, BT was independently associated with shorter OS (HR: 1.74, 95% CI: 1.32-2.29) and RFS (HR: 1.55, 95%CI: 1.20-2.01), after adjusting for relevant clinicopathologic variables. PBT (intra- or post- operative) was significantly associated with prolonged postoperative hospitalization ≥10 days. CONCLUSIONS: Intraoperative BT was associated with inferior OS and RFS, and PBT overall was associated with prolonged hospitalization following RC. Further studies are needed to validate this finding and explore potential causes for this observation.

A New Prognostic Model in Patients with Advanced Urothelial Carcinoma Treated with First-line Immune Checkpoint Inhibitors.

BACKGROUND: While immune checkpoint inhibitors (ICIs) are approved in the first-line (1L) setting for cisplatin-unfit patients with programmed death-ligand 1 (PD-L1)-high tumors or for platinum (cisplatin/carboplatin)-unfit patients, response rates remain modest and outcomes vary with no clinically useful biomarkers (except for PD-L1). OBJECTIVE: We aimed to develop a prognostic model for overall survival (OS) in patients receiving 1L ICIs for advanced urothelial cancer (aUC) in a multicenter cohort study. DESIGN, SETTING, AND PARTICIPANTS: Patients treated with 1L ICIs for aUC across 24 institutions and five countries (in the USA and Europe) outside clinical trials were included in this study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used a stepwise, hypothesis-driven approach using clinician-selected covariates to develop a new risk score for patients receiving ICIs in the 1L setting. Demographics, clinicopathologic data, treatment patterns, and OS were collected uniformly. Univariate Cox regression was performed on 18 covariates hypothesized to be associated with OS based on published data. Variables were retained for multivariate analysis (MVA) if they correlated with OS (p < 0.2) and were included in the final model if p < 0.05 on MVA. Retained covariates were assigned points based on the beta coefficient to create a risk score. Stratified median OS and C-statistic were calculated. RESULTS AND LIMITATIONS: Among 984 patients, 357 with a mean age of 71 yr were included in the analysis, 27% were female, 68% had pure UC, and 13% had upper tract UC. Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases were significant prognostic factors on MVA and were included in the risk score. C index for new 1L risk score was 0.68 (95% confidence interval 0.65-0.71). Limitations include retrospective nature and lack of external validation. CONCLUSIONS: We developed a new 1L ICI risk score for OS based on data from patients with aUC treated with ICIs in the USA and Europe outside of clinical trials. The score components highlight readily available factors related to tumor biology and treatment response. External validation is being pursued. PATIENT SUMMARY: With multiple new treatments under development and approved for advanced urothelial carcinoma, it can be difficult to identify the best treatment sequence for each patient. The risk score may help inform treatment discussions and estimate outcomes in patients treated with first-line immune checkpoint inhibitors, while it can also impact clinical trial design and endpoints. TAKE HOME MESSAGE: A new risk score was developed for advanced urothelial carcinoma treated with first-line immune checkpoint inhibitors. The score assigned Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases each one point, with a higher score being associated with worse overall survival.

Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes.

BACKGROUND AND OBJECTIVES: Historically, autosomal recessive 5q-linked spinal muscular atrophy (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age <2 years without end-stage weakness. However, gene transfer with onasemnogene abeparvovec-xioi has been only studied in children age ≤8 months. METHODS: In this article, we report key safety and early outcome data from the first 21 children (age 1-23 months) treated in the state of Ohio. RESULTS: In children ≤6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with γ glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and γ glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% (n = 2) experienced stabilization and 89% (n = 17) experienced improvement in motor function. CONCLUSIONS: In this population, with thorough screening and careful post-gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy.

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial.

Importance: Micro-dystrophin gene transfer shows promise for treating patients with Duchenne muscular dystrophy (DMD) using recombinant adeno-associated virus serotype rh74 (rAAVrh74) and codon-optimized human micro-dystrophin driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7). Objective: To identify the 1-year safety and tolerability of intravenous rAAVrh74.MHCK7.micro-dystrophin in patients with DMD. Design, Setting, and Participants: This open-label, phase 1/2a nonrandomized controlled trial was conducted at the Nationwide Children's Hospital in Columbus, Ohio. It began on November 2, 2017, with a planned duration of follow-up of 3 years, ending in March 2021. The first 4 patients who met eligibility criteria were enrolled, consisting of ambulatory male children with DMD without preexisting AAVrh74 antibodies and a stable corticosteroid dose (≥12 weeks). Interventions: A single dose of 2.0 × 1014 vg/kg rAAVrh74.MHCK7.micro-dystrophin was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion). Main Outcomes and Measures: Safety was the primary outcome. Secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. Functional outcomes measured by North Star Ambulatory Assessment (NSAA) and serum creatine kinase were exploratory outcomes. Results: Four patients were included (mean [SD] age at enrollment, 4.8 [1.0] years). All adverse events (n = 53) were considered mild (33 [62%]) or moderate (20 [38%]), and no serious adverse events occurred. Eighteen adverse events were considered treatment related, the most common of which was vomiting (9 of 18 events [50%]). Three patients had transiently elevated γ-glutamyltransferase, which resolved with corticosteroids. At 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, with a mean of 81.2% of muscle fibers expressing micro-dystrophin with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment. All patients had confirmed vector transduction and showed functional improvement of NSAA scores and reduced creatine kinase levels (posttreatment vs baseline) that were maintained for 1 year. Conclusions and Relevance: This trial showed rAAVrh74.MHCK7.micro-dystrophin to be well tolerated and have minimal adverse events; the safe delivery of micro-dystrophin transgene; the robust expression and correct localization of micro-dystrophin protein; and improvements in creatine kinase levels and NSAA scores. These findings suggest that rAAVrh74.MHCK7.micro-dystrophin can provide functional improvement that is greater than that observed under standard of care. Trial Registration: ClinicalTrials.gov Identifier: NCT03375164.

Histological Subtypes and Response to PD-1/PD-L1 Blockade in Advanced Urothelial Cancer: A Retrospective Study.

PURPOSE: Urinary tract cancer can be pure urothelial carcinoma, pure nonurothelial carcinoma or variant urothelial carcinoma (defined here as mixed urothelial carcinoma). Little is known regarding outcomes for patients with variant urothelial carcinoma receiving immune checkpoint inhibitors. We hypothesized that variant urothelial carcinoma does not compromise immune checkpoint inhibitor efficacy in patients with advanced urothelial carcinoma. MATERIALS AND METHODS: We performed a retrospective cohort study across 18 institutions. Demographic, clinicopathological, treatment and outcomes data were collected for patients with advanced urothelial carcinoma who received immune checkpoint inhibitors. Patients were divided into pure vs variant urothelial carcinoma subgroups, with variant urothelial carcinoma further divided by type of variant (ie squamous, neuroendocrine etc). We compared overall response rate using univariate and multivariate logistic regression and progression-free survival and overall survival using Kaplan-Meier and univariate and multivariate Cox proportional hazards. RESULTS: Overall 519 patients were identified, with 395, 406 and 403 included in overall response rate, overall survival and progression-free survival analyses, respectively. Overall response rate to immune checkpoint inhibitors between patients with pure vs variant urothelial carcinoma was comparable (28% vs 29%, p=0.90) without significant differences for individual subtypes vs pure urothelial carcinoma. Median overall survival for patients with pure urothelial carcinoma was 11.0 months vs 10.1 months for variant urothelial carcinoma (p=0.60), but only 4.6 months for patients with neuroendocrine features (9 patients, HR 2.75, 95% CI 1.40-5.40 vs pure urothelial carcinoma, p=0.003). Median progression-free survival was 4.1 months for pure vs 5.2 months for variant urothelial carcinoma (p=0.43) and 3.7 months for neuroendocrine features (HR 1.87, 95% CI 0.92-3.79 vs pure urothelial carcinoma, p=0.09). CONCLUSIONS: Overall response rate to immune checkpoint inhibitors was comparable across histological types. However, overall survival was worse for patients with tumors containing neuroendocrine features. Variant urothelial carcinoma should not exclude patients from receiving immune checkpoint inhibitors.

Differences in Parent and Child Report on the Screen for Child Anxiety-Related Emotional Disorders (SCARED): Implications for Investigations of Social Anxiety in Adolescents.

Social anxiety typically emerges by adolescence and is one of the most common anxiety disorders. Many clinicians and researchers utilize the Screen for Child Anxiety Related Disorders (SCARED) to quantify anxiety symptoms, including social anxiety, throughout childhood and adolescence. The SCARED can be administered to both children and their parents, though reports from each informant tend to only moderately correlate. Here, we investigated parent-child concordance on the SCARED in a sample of adolescents (N = 360, Mage = 13.2) using a multi-trait multi-method (MTMM) model. Next, in a selected sample of the adolescents, we explored relations among child report, parent report, and latent social anxiety scores with two laboratory tasks known to elicit signs of social anxiety in the presence of unfamiliar peers: a speech task and a "Get to Know You" task. Findings reveal differences in variance of the SCARED accounted for by parent and child report. Parent report of social anxiety is a better predictor of anxiety signs elicited by a structured speech task, whereas child report of social anxiety is a better predictor of anxiety signs during the naturalistic conversation with unfamiliar peers. Moreover, while latent social anxiety scores predict both observed anxiety measures, parent report more closely resembles latent scores in relation to the speech task, whereas child report functions more similarly to latent scores in relation to the peer conversation. Thus, while latent scores relate to either observed anxiety measure, parent and child report on the SCARED each provide valuable information that differentially relate to naturalistic social anxiety-related behaviors.

Intratumoral Delivery of Plasmid IL12 Via Electroporation Leads to Regression of Injected and Noninjected Tumors in Merkel Cell Carcinoma.

PURPOSE: IL12 promotes adaptive type I immunity and has demonstrated antitumor efficacy, but systemic administration leads to severe adverse events (AE), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer. PATIENTS AND METHODS: Fifteen patients with MCC with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (cohort A, N = 3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (cohort B, N = 12) received up to four cycles total, administered at least 6 weeks apart. Serial tumor and blood samples were collected. RESULTS: All patients successfully completed at least one cycle with transient, mild (grades 1 and 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL12 protein was observed along with local inflammation and increased tumor-specific CD8+ T-cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in cohort B, with 2 patients experiencing durable clinical benefit (16 and 55+ months, respectively). Two cohort A patients (1 with pathologic complete remission) were recurrence-free at 44+ and 75+ months, respectively. CONCLUSIONS: I.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer.

Gene Delivery for Limb-Girdle Muscular Dystrophy Type 2D by Isolated Limb Infusion.

In a previous limb-girdle muscular dystrophy type 2D (LGMD2D) clinical trial, robust alpha-sarcoglycan gene expression was confirmed following intramuscular gene (SGCA) transfer. This paved the way for first-in-human isolated limb infusion (ILI) gene transfer trial to the lower limbs. Delivery of scAAVrh74.tMCK.hSGCA via an intravascular route through the femoral artery predicted improved ambulation. This method was initially chosen to avoid safety concerns required for large systemic vascular delivery viral loads. ILI methods were adopted from the extensive chemotherapy experience for treatment of malignancies confined to the extremities. Six LGMD2D subjects were enrolled in a dose-ascending open-label clinical trial. Safety of the procedure was initially assessed in the single limb of a non-ambulant affected adult at a dose of 1 × 1012 vg/kg. Subsequently, ambulatory children (aged 8-13 years) were enrolled and dosed bilaterally with either 1 × 1012 vg/kg/limb or 3 × 1012 vg/kg/limb. The six-minute walk test (6MWT) served as the primary clinical outcome; secondary outcomes included muscle strength (maximum voluntary isometric force testing) and SGCA expression at 6 months. All ambulatory participants except one had pre- and post-treatment muscle biopsies. All four subjects biopsied had confirmed SGCA gene delivery by immunofluorescence, Western blot analysis (14-25% of normal), and vector genome copies (5.4 × 103-7.7 × 104 vg/µg). Muscle strength in the knee extensors (assessed by force generation in kilograms) showed improvement in two subjects that correlated with an increase in fiber diameter post gene delivery. Six-minute walk times decreased or remained the same. Vascular delivery of AAVrh74.tMCK.hSGCA was effective at producing SGCA protein at low doses that correlated with vector copies and local functional improvement restricted to targeted muscles. Future trials will focus on systemic administration to enable targeting of proximal muscles to maximize clinical benefit.

Intratumoral G100, a TLR4 Agonist, Induces Antitumor Immune Responses and Tumor Regression in Patients with Merkel Cell Carcinoma.

PURPOSE: G100 is a toll-like receptor 4 (TLR4) agonist that triggers innate and adaptive antitumor immune responses in preclinical models. This pilot study assessed the safety, efficacy, and immunologic activity of intratumoral (IT) administration of G100 in patients with Merkel cell carcinoma (MCC). PATIENTS AND METHODS: Patients with locoregional MCC (n = 3; cohort A) received neoadjuvant IT G100 (2 weekly doses at 5 µg/dose) followed by surgery and radiotherapy; patients with metastatic MCC (n = 7; cohort B) received 3 doses in a 6-week cycle and could receive additional cycles with/without radiotherapy. RESULTS: IT G100 was safe and feasible in both neoadjuvant and metastatic settings. Treatment-related adverse events were mostly grade 1 or 2 injection-site reactions. IT G100 led to increased inflammation in the injected tumors with infiltration of CD8+ and CD4+ T cells and activation of immune-related genes. These proinflammatory changes were associated with local tumor regression and appeared to promote systemic immunity. All 3 cohort A patients successfully completed therapy; 2 patients remain recurrence free at 44+ and 41+ months, including 1 with a pathologic complete response after G100 alone. In cohort B, 2 patients achieved sustained partial responses, both lasting 33+ months after 2 cycles of therapy. CONCLUSIONS: In this first-in-human study, IT G100 induced antitumor immune responses, demonstrated acceptable safety, and showed encouraging clinical activity.See related commentary by Marquez-Rodas et al., p. 1127.

Merkel cell polyomavirus-specific immune responses in patients with Merkel cell carcinoma receiving anti-PD-1 therapy.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer that frequently responds to anti-PD-1 therapy. MCC is associated with sun exposure and, in 80% of cases, Merkel cell polyomavirus (MCPyV). MCPyV-specific T and B cell responses provide a unique opportunity to study cancer-specific immunity throughout PD-1 blockade therapy. METHODS: Immune responses were assessed in patients (n = 26) with advanced MCC receiving pembrolizumab. Peripheral blood mononuclear cells (PBMC) were collected at baseline and throughout treatment. MCPyV-oncoprotein antibodies were quantified and T cells were assessed for MCPyV-specificity via tetramer staining and/or cytokine secretion. Pre-treatment tumor biopsies were analyzed for T cell receptor clonality. RESULTS: MCPyV oncoprotein antibodies were detectable in 15 of 17 (88%) of virus-positive MCC (VP-MCC) patients. Antibodies decreased in 10 of 11 (91%) patients with responding tumors. Virus-specific T cells decreased over time in patients who had a complete response, and increased in patients who had persistent disease. Tumors that were MCPyV(+) had a strikingly more clonal (less diverse) intratumoral TCR repertoire than virus-negative tumors (p = 0.0001). CONCLUSIONS: Cancer-specific T and B cell responses generally track with disease burden during PD-1 blockade, in proportion to presence of antigen. Intratumoral TCR clonality was significantly greater in VP-MCC than VN-MCC tumors, suggesting expansion of a limited number of dominant clones in response to fewer immunogenic MCPyV antigens. In contrast, VN-MCC tumors had lower clonality, suggesting a diverse T cell response to numerous neoantigens. These findings reveal differences in tumor-specific immunity for VP-MCC and VN-MCC, both of which often respond to anti-PD-1 therapy.