Sleeve Gastrectomy is Associated with Longitudinal Improvements in Lung Function and Patient-Reported Respiratory Outcomes.

PURPOSE: Obesity exerts negative effects on pulmonary function through proven mechanical and biochemical pathways. Multiple studies have suggested that bariatric surgery can improve lung function. However, the timing of these effects on lung function and its association with patient reported outcomes is not known. MATERIALS AND METHODS: A prospective cohort study of patients undergoing laparoscopic sleeve gastrectomy (LSG) at a tertiary care hospital was undertaken. Spirometry tests, laboratory tests, and self-reported questionnaires on asthma symptoms and asthma control (ACQ and ACT) were administered. All data were recorded pre-operatively (T0) and every 3 months post-operatively for 1 year (T3, T6, T9, T12) and were compared using a mixed-models approach for repeated measures. RESULTS: For the 23 participants, mean age was 44.2 ± 12.3 years, mean BMI was 45.2 ± 7.2 kg/m2, 18(78%) were female, 9(39%) self-reported as non-white and 6(26%) reported to have asthma. Following LSG, % total body weight loss was significant at all follow-up points (P < 0.0001). Rapid improvement in forced expiratory volume (FEV)% predicted and forced vital capacity (FVC)% predicted was seen at T3. Although the overall ACQ and ACT score remained within normal range throughout the study, shortness of breath declined significantly at 3 months post-op (P < 0.05) and wheezing resolved for all patients by twelve months. Patients also reported reduced frequency of sleep interruption and inability to exercise by the end of the study (P < 0.05). CONCLUSION: Improvements in objective lung function assessments and patient-reported respiratory outcomes begin as early as 3 months and continue until 12 months after sleeve gastrectomy.

Osteosarcoma Explorer: A Data Commons With Clinical, Genomic, Protein, and Tissue Imaging Data for Osteosarcoma Research.

PURPOSE: Osteosarcoma research advancement requires enhanced data integration across different modalities and sources. Current osteosarcoma research, encompassing clinical, genomic, protein, and tissue imaging data, is hindered by the siloed landscape of data generation and storage. MATERIALS AND METHODS: Clinical, molecular profiling, and tissue imaging data for 573 patients with pediatric osteosarcoma were collected from four public and institutional sources. A common data model incorporating standardized terminology was created to facilitate the transformation, integration, and load of source data into a relational database. On the basis of this database, a data commons accompanied by a user-friendly web portal was developed, enabling various data exploration and analytics functions. RESULTS: The Osteosarcoma Explorer (OSE) was released to the public in 2021. Leveraging a comprehensive and harmonized data set on the backend, the OSE offers a wide range of functions, including Cohort Discovery, Patient Dashboard, Image Visualization, and Online Analysis. Since its initial release, the OSE has experienced an increasing utilization by the osteosarcoma research community and provided solid, continuous user support. To our knowledge, the OSE is the largest (N = 573) and most comprehensive research data commons for pediatric osteosarcoma, a rare disease. This project demonstrates an effective framework for data integration and data commons development that can be readily applied to other projects sharing similar goals. CONCLUSION: The OSE offers an online exploration and analysis platform for integrated clinical, molecular profiling, and tissue imaging data of osteosarcoma. Its underlying data model, database, and web framework support continuous expansion onto new data modalities and sources.

Clinical practice guideline recommendation summaries for pediatric oncology health care professionals: A qualitative study.

OBJECTIVE: To develop a summary format of clinical practice guideline (CPG) recommendations to improve understandability among health care professionals. METHODS: We developed a summary format based on current research and used the "Think Aloud" technique in one-on-one cognitive interviews to iteratively improve it. Interviews of health care professionals from Children's Oncology Group-member, National Cancer Institute Community Oncology Research Program sites were conducted. After every five interviews (a round), responses were reviewed, and changes made to the format until it was well understood and no new, substantive suggestions for revision were raised. We took a directed (deductive) approach to content analysis of the interview notes to identify concerns related to recommendation summary usability, understandability, validity, applicability and visual appeal. RESULTS: During seven rounds of interviews with 33 health care professionals, we identified important factors that influenced understandability. Participants found understanding weak recommendations more challenging than strong recommendations. Understanding was improved when the term 'conditional' recommendation was used instead of 'weak' recommendation. Participants found a Rationale section to be very helpful but desired more information when a recommendation entailed a practice change. In the final format, the recommendation strength is clearly indicated in the title, highlighted, and defined within a text box. The rationale for the recommendation is in a column on the left, with supporting evidence on the right. In a bulleted list, the Rationale section describes the benefits and harms and additional factors, such as implementation, that were considered by the CPG developers. Each bullet under the supporting evidence section indicates the level of evidence with an explanation and the supporting studies with hyperlinks when applicable. CONCLUSIONS: A summary format to present strong and conditional recommendations was created through an iterative interview process. The format is straightforward, making it easy for organizations and CPG developers to use it to communicate recommendations clearly to intended users.

Validation of healthcare professional proxy-reported children's International Mucositis Evaluation Scale.

OBJECTIVE: The objective was to describe the reliability and validity of the healthcare professional proxy-report version of the Children's International Mucositis Evaluation Scale (ChIMES). METHODS: We included pediatric patients who were between 4 and 21 years of age and scheduled to undergo hematopoietic cell transplantation. Mucositis was evaluated by trained healthcare professionals who scored ChIMES, the World Health Organization oral toxicity scale, mouth, and throat pain visual analogue scale, National Cancer Institute-Common Terminology Criteria and the Oral Mucositis Daily Questionnaire. Measures were completed daily and evaluated on days 7-17 post-stem cell infusion for this analysis. Psychometric properties examined were internal consistency, test-retest reliability (days 13 and 14), and convergent construct validity. RESULTS: There were 192 participants included. Cronbach's alpha was 0.90 for ChIMES Total Score and 0.93 for ChIMES Percentage Score. Test-retest reliability were as follows: intraclass correlation coefficient (ICC) 0.82 (95% confidence interval (CI) 0.77-0.85) for ChIMES Total Score and ICC 0.82 (95% CI 0.77-0.86) for ChIMES Percentage Score. In terms of construct validation, all correlations between measures met or exceeded those hypothesized (all p < 0.05). CONCLUSIONS: The healthcare professional proxy-report version of ChIMES is reliable and valid for children and adolescents undergoing hematopoietic cell transplantation.

Predicting Molecular Subtype and Survival of Rhabdomyosarcoma Patients Using Deep Learning of H&E Images: A Report from the Children's Oncology Group.

PURPOSE: Rhabdomyosarcoma (RMS) is an aggressive soft-tissue sarcoma, which primarily occurs in children and young adults. We previously reported specific genomic alterations in RMS, which strongly correlated with survival; however, predicting these mutations or high-risk disease at diagnosis remains a significant challenge. In this study, we utilized convolutional neural networks (CNN) to learn histologic features associated with driver mutations and outcome using hematoxylin and eosin (H&E) images of RMS. EXPERIMENTAL DESIGN: Digital whole slide H&E images were collected from clinically annotated diagnostic tumor samples from 321 patients with RMS enrolled in Children's Oncology Group (COG) trials (1998-2017). Patches were extracted and fed into deep learning CNNs to learn features associated with mutations and relative event-free survival risk. The performance of the trained models was evaluated against independent test sample data (n = 136) or holdout test data. RESULTS: The trained CNN could accurately classify alveolar RMS, a high-risk subtype associated with PAX3/7-FOXO1 fusion genes, with an ROC of 0.85 on an independent test dataset. CNN models trained on mutationally-annotated samples identified tumors with RAS pathway with a ROC of 0.67, and high-risk mutations in MYOD1 or TP53 with a ROC of 0.97 and 0.63, respectively. Remarkably, CNN models were superior in predicting event-free and overall survival compared with current molecular-clinical risk stratification. CONCLUSIONS: This study demonstrates that high-risk features, including those associated with certain mutations, can be readily identified at diagnosis using deep learning. CNNs are a powerful tool for diagnostic and prognostic prediction of rhabdomyosarcoma, which will be tested in prospective COG clinical trials.

A Community-Based Pancreatic Cancer Screening Study in High-Risk Individuals: Preliminary Efficacy and Safety Results.

INTRODUCTION: Pancreatic cancer (PC) screening recommendations have been based on studies performed solely at high-volume academic centers. To make PC screening more widely available, community-based efforts are essential. We implemented a prospective PC screening study in the community of Fairfield County, CT, and report our early safety and efficacy results. METHODS: Eligible individuals were enrolled into an investigator-initiated study and underwent a baseline and 3 annual magnetic resonance imagings/magnetic resonance cholangiopancreatographies (MRIs/MRCPs) with gadolinium, biannual blood donations for biobanking, and assessments for anxiety and depression. All MRIs were presented at a multidisciplinary board to determine whether further investigation was warranted. RESULTS: Seventy-five individuals have been enrolled and 201 MRIs performed over a 2.6-year average length of follow-up. Abnormal pancreatic findings (predominantly small cysts) were detected in 58.7% of the participants. Among these, 6.7% underwent endoscopic ultrasound, with 1 case complicated by postprocedural pancreatitis. One surgical resection was performed on a 4.7-cm intraductal papillary mucinous neoplasm with a focus on low-grade pancreatic intraepithelial neoplasia. One incidental finding of fibrosing mediastinitis was detected. Anxiety and depression scores decreased over the course of this study from 21.4% to 5.4% and 10.7% to 3.6%, respectively. DISCUSSION: This preliminary report supports the feasibility of performing MRI/magnetic resonance cholangiopancreatographies-based PC screening as part of a clinical trial in a community setting. A longer follow-up is needed to better assess safety and efficacy. To the best of our knowledge, this is the first report from a community-based PC screening effort ( clinicaltrials.gov ID: NCT03250078).

Early Changes in Immune Cell Count, Metabolism, and Function Following Sleeve Gastrectomy: A Prospective Human Study.

OBJECTIVE: To characterize longitudinal changes in blood biomarkers, leukocyte composition, and gene expression following laparoscopic sleeve gastrectomy (LSG). BACKGROUND: LSG is an effective treatment for obesity, leading to sustainable weight loss and improvements in obesity-related comorbidities and inflammatory profiles. However, the effects of LSG on immune function and metabolism remain uncertain. METHODS: Prospective data were collected from 23 enrolled human subjects from a single institution. Parameters of weight, comorbidities, and trends in blood biomarkers and leukocyte subsets were observed from preoperative baseline to 1 year postsurgery in 3-month follow-up intervals. RNA sequencing was performed on pairs of whole blood samples from the first 6 subjects of the study (baseline and 3 months postsurgery) to identify genome-wide gene expression changes associated with undergoing LSG. RESULTS: LSG led to a significant decrease in mean total body weight loss (18.1%) at 3 months and among diabetic subjects a reduction in hemoglobin A1c. Improvements in clinical inflammatory and hormonal biomarkers were demonstrated as early as 3 months after LSG. A reduction in neutrophil-lymphocyte ratio was observed, driven by a reduction in absolute neutrophil counts. Gene set enrichment analyses of differential whole blood gene expression demonstrated that after 3 months LSG induced transcriptomic changes not only in inflammatory cytokine pathways but also in several key metabolic pathways related to energy metabolism. CONCLUSIONS: LSG induces significant changes in the composition and metabolism of immune cells as early as 3 months postoperatively. Further evaluation is required of bariatric surgery's effects on immunometabolism and the consequences for host defense and metabolic disease.

The longitudinal associations of physical activity, time spent outdoors in nature and symptoms of depression and anxiety during COVID-19 quarantine and social distancing in the United States.

Stressors associated with COVID-19 pandemic stay-at-home orders are associated with increased depression and anxiety and decreased physical activity. Given that physical activity and time spent outdoors in nature are associated with improved mental health, we examined the longitudinal association of these variables during the pandemic. Over 20,000 adults who participated in the U.S. Kaiser Permanente Research Bank, did not report COVID-19 symptoms, and responded to an online baseline and 3 follow-up surveys over approximately 3 months formed the cohort. Physical activity was assessed from a modified survey, time spent outdoors was assessed from one question, and anxiety and depression scores were assessed from validated instruments. Almost 60% were women, 82.8% were non-Hispanic white, and more than 93% of respondents were over the age of 50. Less in-person contact with friends and visiting crowded places was highly prevalent (>80%) initially and decreased somewhat (>70%). Participants in the lowest physical activity category (no physical activity) had the highest depression and anxiety scores compared to each successive physical activity category (p < 0.001). Spending less time outdoors was associated with higher depression and anxiety scores. This effect was greater for participants in the younger age categories compared with older age categories. The effect of less time spent outdoors on anxiety (p = 0.012) and depression (p < 0.001) scores was smaller for males than females. Results suggest that physical activity and time outdoors is associated with better mental health. People should be encouraged to continue physical activity participation during public health emergencies.

Daily transient coating of the intestine leads to weight loss and improved glucose tolerance.

INTRODUCTION: Roux-en-Y gastric bypass surgery (RYGB) has been shown to be the gold standard treatment for obesity associated type-2-diabetes (T2D), however many T2D patients do not qualify or are reluctant to proceed with surgery due to its potential risks and permanent changes to GI anatomy. We have previously described a novel oral formulation, LuCI, that provides a transient coating of the proximal bowel and mimics the effects of RYGB. Herein, we aim to investigate the outcome of chronic LuCI administration on weight and glucose homeostasis. METHODS: Sprague-Dawley rats on a high fat diet achieving diet-induced obesity (DIO) received 5 weeks of daily LuCI or normal saline as control (n = 8/group). Daily weights and glucose tolerance were monitored throughout the experiment. At 5 weeks, systemic blood was sampled through a surgically placed jugular vein catheter, before and during an intestinal glucose bolus, to investigate changes in key hormones involved in glucose metabolism. To elucidate the effects of LuCI on nutrient absorption, fecal output and food intake were measured simultaneously with the analysis of homogenized stool samples performed using bomb calorimetry. RESULTS: At 5 weeks, LuCI animals weighted 8.3% less and had lower fasting glucose levels than Controls (77.6 ±â€¯3.8 mg/dl vs. 99.1 ±â€¯2.7 mg/dl, P < 0.001). LuCI-treated animals had lower baseline insulin and HOMA-IR. Post-prandially, LuCI group had increased GLP-1 and GIP secretion following a glucose challenge. Serum lipid analysis revealed lowered LDL levels highlighting the potential to not only improve glucose control but also modify cardiovascular risk. We then investigated whether LuCI's effect on proximal bowel exclusion may play a role in energy balance. Bomb calorimetry analysis suggested that LuCI reduced calorie absorption with no difference in caloric consumption. CONCLUSION: We demonstrated that LuCI recapitulates the physical and hormonal changes seen after RYGB and can ameliorate weight gain and improve insulin sensitivity in a DIO rat model. Since LuCI's effect is transient and without systemic absorption, LuCI has the potential to be a novel therapy for overweight or obese T2D patients.

Facilitators and barriers to clinical practice guideline-consistent supportive care at pediatric oncology institutions: a Children's Oncology Group study.

BACKGROUND: Clinical practice guideline (CPG)-consistent care improves patient outcomes, but CPG implementation is poor. Little is known about CPG implementation in pediatric oncology. This study aimed to understand supportive care CPG implementation facilitators and barriers at pediatric oncology National Cancer Institute (NCI) Community Oncology Research Program (NCORP) institutions. METHODS: Healthcare professionals at 26 pediatric, Children's Oncology Group-member, NCORP institutions were invited to participate in face-to-face focus groups. Serial focus groups were held until saturation of ideas was reached. Supportive care CPG implementation facilitators and barriers were solicited using nominal group technique (NGT), and implementation of specific supportive care CPG recommendations was discussed. Notes from each focus group were analyzed using a directed content analysis. The top five themes arising from an analysis of NGT items were identified, first from each focus group and then across all focus groups. RESULTS: Saturation of ideas was reached after seven focus groups involving 35 participants from 18 institutions. The top five facilitators of CPG implementation identified across all focus groups were organizational factors including charging teams with CPG implementation, individual factors including willingness to standardize care, user needs and values including mentorship, system factors including implementation structure, and implementation strategies including a basis in science. The top five barriers of CPG implementation identified were organizational factors including tolerance for inconsistencies, individual factors including lack of trust, system factors including administrative hurdles, user needs and values including lack of inclusivity, and professional including knowledge gaps. CONCLUSIONS: Healthcare professionals at pediatric NCORP institutions believe that organizational factors are the most important determinants of supportive care CPG implementation. They believe that CPG-consistent supportive care is most likely to be delivered in organizations that prioritize evidence-based care, provide structure and resources to implement CPGs, and eliminate implementation barriers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02847130. Date of registration: July 28, 2016.

Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium.

PURPOSE: Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond PAX-FOXO1 fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome. PATIENTS AND METHODS: Tumor samples collected from patients enrolled on Children's Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed. RESULTS: DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In FOXO1 fusion-negative cases, mutation of any RAS pathway member was found in > 50% of cases, and 21% had no putative driver mutation identified. BCOR (15%), NF1 (15%), and TP53 (13%) mutations were found at a higher incidence than previously reported and TP53 mutations were associated with worse outcomes in both fusion-negative and FOXO1 fusion-positive cases. Interestingly, mutations in RAS isoforms predominated in infants < 1 year (64% of cases). Mutation of MYOD1 was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database (ClinOmics), containing all genomic variants, and clinical annotation including survival data. CONCLUSION: This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.

Restored TDCA and valine levels imitate the effects of bariatric surgery.

Background: Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities. Methods: Metabolic profiling was performed on diet-induced obese (DIO) mice, lean mice, and DIO mice that underwent sleeve gastrectomies (SGx). In addition, mice were subjected to intraperitoneal (i.p.) injections with taurodeoxycholic acid (TDCA) and valine. Indirect calorimetry was performed to assess food intake and energy expenditure. Expression of appetite-regulating hormones was assessed through quantification of isolated RNA from dissected hypothalamus tissue. Subsequently, i.p. injections with a melanin-concentrating hormone (MCH) antagonist and intrathecal administration of MCH were performed and weight loss was monitored. Results: Mass spectrometric metabolomic profiling revealed significantly reduced systemic levels of TDCA and L-valine in DIO mice. TDCA and L-valine levels were restored after SGx in both human and mice to levels comparable with lean controls. Systemic treatment with TDCA and valine induced a profound weight loss analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the MCH. Conclusions: In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders. Funding: This work has been supported in part by a grant from NIH (UO-1 A1 132898 to S.G.T., DP and MA). M.Q. was supported by the IFB Integrated Research and Treatment Centre Adiposity Diseases (Leipzig, Germany) and the German Research Foundation (QU 420/1-1). J.I. was supported by the Biomedical Education Program (BMEP) of the German Academic Exchange Service (DAAD). T.H. (HE 7457/1-1) and F.K. (KR 4362/1-1) were supported by the German Research Foundation (DFG). H.R.C.B. was supported the Swiss Society of Cardiac Surgery. Y.N. was supported by the Chinese Scholarship Council (201606370196) and Central South University. H.U., T.M. and R.M. were supported by the Osaka Medical Foundation. C.S.F. was supported by the German Research Foundation (DFG, SFB738, B3).

Musculoskeletal impairments in children receiving intensive therapy for acute leukemia or undergoing hematopoietic stem cell transplant: A report from the Children's Oncology Group.

BACKGROUND: Children receiving intensive chemotherapy for leukemia or undergoing hematopoietic stem cell transplant (HSCT) for solid tumors or leukemia are at risk for musculoskeletal (MSK) impairment from their underlying disease and from treatment. Data are limited on the incidence and nature of these disorders during intensive therapy. This study's objective was to provide a cross-sectional description of MSK impairments in this population. PROCEDURE: Children with acute myeloid leukemia (AML), relapsed acute lymphoblastic leukemia (rALL), or undergoing HSCT were systematically assessed for MSK impairments as part of Children's Oncology Group study ACCL0934. Assessments occurred at study entry, at 2 months, and at 12 months and included evaluation for signs or symptoms of MSK impairment and the type, site, and diagnosis. RESULTS: Six hundred three patients were included. MSK signs or symptoms were present in 48 (8.0%) children at study entry, 64 (13.5%) children at 2 months, and 40 (11.6%) children at 12 months. Arthralgia and/or gait abnormalities were the most common impairments; the knee was the most common site. Arthritis and tendonitis were both rare. Vincristine neuropathy, MSK impacts from central nervous system pathology, and bone or joint pain from underlying cancer were the most common diagnoses. Multivariate analysis demonstrated that having rALL (odds ratio [OR] 2.00, 95% CI 1.07-3.76, p = .03) or obesity (OR 2.10, 95% CI 1.12-3.95, p = .02) were risk factors for MSK impairment at study entry. CONCLUSIONS: MSK impairments are common in this intensively treated patient population, especially in those with rALL and those who are obese.

Glycemic Control as an Early Prognostic Marker in Advanced Pancreatic Cancer.

PURPOSE: Impaired glucose metabolism is present in most patients with pancreatic ductal adenocarcinoma (PDAC). Whereas previous studies have focused on pre-treatment glycemic indices and prognosis in those with concomitant diabetes, the effects of glycemic control during chemotherapy treatment on prognosis, in patients with and without diabetes, have not been well characterized. We examined the relationship between early glycemic control and overall survival (OS) in a cohort of patients with advanced PDAC treated in a community setting. PATIENTS AND METHODS: Seventy-three patients with advanced PDAC (38% with diabetes) receiving chemotherapy while participating in a biobanking clinical trial were included. Clinical characteristics and laboratory results during 1 year were obtained from the electronic medical record. Kaplan-Meier estimate, log-rank test and hazard ratios were computed to assess the effect of glycemic control on OS. The Cox proportional hazards regression model was applied to ascertain the significance of glycemic control with other survival variables. RESULTS: One thousand four hundred eighteen random blood glucose (RBG) values were analyzed. In accord with previous findings, a 50% decline in the serum tumor marker CA 19-9 at any time was predictive of survival (P=0.0002). In univariate analysis, an elevated pre-treatment average RBG, 3-month average RBG (RBG-3) and the FOLFIRINOX regimen were associated with longer survival. Based on ROC analysis (AUC=0.82), an RBG-3 of 120 mg/dl was determined to be the optimal cutoff to predict 12-month survival. In multivariate analysis that included age, stage, BMI, performance status, presence of diabetes, and chemotherapy regimen, only RBG-3 maintained significance: an RBG-3 ≤120 mg/dl predicted for improved OS compared to >120 mg/dl (19 vs. 9 months; HR=0.37, P=0.002). In contrast, an early decline in CA 19-9 could not predict OS. CONCLUSION: Lower glucose levels during the first 3 months of treatment for advanced PDAC predict for improved OS in patients both with and without diabetes. These results suggest that RBG-3 may be a novel prognostic biomarker worthy of confirmation in a larger patient cohort and that studies exploring a possible cause and effect of this novel survival-linked relationship are warranted.

Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group.

BACKGROUND: Several cancer-susceptibility syndromes are reported to underlie pediatric rhabdomyosarcoma (RMS); however, to our knowledge there have been no systematic efforts to characterize the heterogeneous genetic etiologies of this often-fatal malignancy. METHODS: We performed exome-sequencing on germline DNA from 615 patients with newly diagnosed RMS consented through the Children's Oncology Group. We compared the prevalence of cancer predisposition variants in 63 autosomal-dominant cancer predisposition genes in these patients with population controls (n = 9963). All statistical tests were 2-sided. RESULTS: We identified germline cancer predisposition variants in 45 RMS patients (7.3%; all FOXO1 fusion negative) across 15 autosomal dominant genes, which was statistically significantly enriched compared with controls (1.4%, P = 1.3 × 10-22). Specifically, 73.3% of the predisposition variants were found in predisposition syndrome genes previously associated with pediatric RMS risk, such as Li-Fraumeni syndrome (TP53) and neurofibromatosis type I (NF1). Notably, 5 patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) associated with Costello syndrome. Also, genetic etiology differed with histology, as germline variants were more frequent in embryonal vs alveolar RMS patients (10.0% vs 3.0%, P = .02). Although patients with a cancer predisposition variant tended to be younger at diagnosis (P = 9.9 × 10-4), 40.0% of germline variants were identified in those older than 3 years of age, which is in contrast to current genetic testing recommendations based on early age at diagnosis. CONCLUSIONS: These findings demonstrate that genetic risk of RMS results from germline predisposition variants associated with a wide spectrum of cancer susceptibility syndromes. Germline genetic testing for children with RMS should be informed by RMS subtypes and not be limited to only young patients.

Early changes in immune cell metabolism and function are a hallmark of sleeve gastrectomy: a prospective human study.

OBJECTIVE: To characterize longitudinal changes in blood biomarkers, leukocyte composition, and gene expression following laparoscopic sleeve gastrectomy (LSG). BACKGROUND: LSG is an effective treatment for obesity, leading to sustainable weight loss and improvements in obesity-related co-morbidities and inflammatory profiles. However, the effects of LSG on immune function and metabolism remain uncertain. METHODS: Prospective data was collected from 23 enrolled human subjects from a single institution. Parameters of weight, co-morbidities, and trends in blood biomarkers and leukocyte subsets were observed from pre-operative baseline to one year in three-month follow-up intervals. RNA-sequencing was performed on pairs of whole blood samples from the first six subjects of the study (baseline and three months post-surgery) to identify genome-wide gene expression changes associated with undergoing LSG. RESULTS: LSG led to a significant decrease in mean total body weight loss (18.1%) at three months and among diabetic subjects a reduction in HbA1c. Improvements in clinical inflammatory and hormonal biomarkers were demonstrated as early as three months after LSG. A reduction in neutrophil-lymphocyte ratio was observed, driven by a reduction in absolute neutrophil counts. Gene set enrichment analyses of differential whole blood gene expression demonstrated that after three months, LSG induced transcriptomic changes not only in inflammatory cytokine pathways but also in several key metabolic pathways related to energy metabolism. CONCLUSIONS: LSG induces significant changes in the composition and metabolism of immune cells as early as three months post-operatively. Further evaluation is required of bariatric surgery's effects on immunometabolism and consequences for host defense and metabolic disease.

ATM-Mutated Pancreatic Cancer: Clinical and Molecular Response to Gemcitabine/Nab-Paclitaxel After Genome-Based Therapy Resistance.

Metastatic pancreatic cancer (PC) is an aggressive malignancy, with most patients deriving benefit only from first-line chemotherapy. Increasingly, the recommended treatment for those with a germline mutation in a gene involved in homologous recombination repair is with a platinum drug followed by a poly (ADP-ribose) polymerase (poly adenosine phosphate-ribose polymerase [PARP]) inhibitor. Yet, this is based largely on studies of BRCA1/2 or PALB2 mutated PC. We present the case of a 44-year-old woman with ATM-mutated PC who achieved stable disease as the best response to first-line fluorouracil, leucovorin, irinotecan, and oxaliplatin, followed by progression on a PARP inhibitor. In the setting of jaundice, painful hepatomegaly, and a declining performance status, she experienced rapid disease regression with the nonplatinum regimen, gemcitabine plus nab-paclitaxel. Both physical stigmata and abnormal laboratory values resolved, imaging studies showed a reduction in metastases and her performance status returned to normal. Measurement of circulating tumor DNA for KRAS G12R by digital droplet polymerase chain reaction confirmed a deep molecular response. This case highlights that first-line treatment with a platinum-containing regimen followed by PARP inhibition may not be the best choice for individuals with ATM-mutated pancreatic cancer. Additional predictors of treatment response are needed in this setting.

Short-Term Outcomes of Inflammatory Bowel Disease after Roux-en-Y Gastric Bypass vs Sleeve Gastrectomy.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the most effective therapies for obesity and may have beneficial effects on the immune system. Therefore, we compared RYGB vs SG outcomes in patients with inflammatory bowel disease (IBD). STUDY DESIGN: In this retrospective cohort study, we identified 54 patients with either Crohn's disease (CD; n = 31) or ulcerative colitis (UC; n = 23), diagnosed before bariatric surgery, between 2000 and 2017. Nineteen patients underwent RYGB and 35 patients underwent SG. RESULTS: Patients presenting for RYGB and SG were of similar age (46.2 ± 9.5 years vs 47.2 ± 12.3 years), preoperative BMI (48.5 ± 7.7 kg/m2 vs 44.9 ± 7.3 kg/m2) and IBD status, as measured by medications. Both operations led to significant weight loss at 1 year. After RYGB and SG, there were no significant differences in the proportion of patients with UC who had improved (27% vs 8%), unchanged (64% vs 92%), or worse (9% vs 0%) IBD medication requirements, respectively. Similar analysis in the patients with CD showed no significant differences in the proportion who had improved (37.5% vs 44%), or unchanged (25% vs 52%) IBD-medication requirements after RYGB and SG, respectively. However, there was a significant difference in the proportion of patients who had worsened CD after RYGB compared with SG (37.5% vs 4%; p = 0.016). There was a greater rate of surgical complications after RYGB compared to SG (26% vs. 3%; p = 0.02). CONCLUSIONS: A sizable proportion of patients experienced improvements in IBD post-bariatric surgery. However, in CD patients, RYGB was associated with a significantly greater number of patients with increased IBD-medication requirements. Sleeve gastrectomy led to less weight loss, but had a lower rate of severe complications compared with RYGB. In patients with IBD, and particularly CD, SG may be the safer surgery.

The role of colonoscopy and CT colonography in patients presenting with symptoms of constipation.

OBJECTIVE: There is controversy whether constipation as a primary presenting complaint is an indication for diagnostic colonoscopy. CT colonography (CTC) is a less invasive and more acceptable alternative. We compared the completion and sensitivity of colonoscopy with CTC in patients who presented with the primary symptom of constipation. METHODS: A retrospective study was conducted which examined the first 100 colonoscopies and 100 CTCs carried out for the primary symptom of constipation from June 2012 to December 2013. The primary outcome measure was failure rate of the investigations. Secondary outcomes included reasons for failure and comparison of cost effectiveness between the two modalities. RESULTS: A total of 200 patients were included in this study. Of these, the first consecutive 100 colonoscopies and 100 CTCs were included. One colonic cancer was detected in each of the CTC and the colonoscopy arm, respectively. 37 (37%) attempted colonoscopies were incomplete examinations. The most common reasons were discomfort (51.4%) and poor bowel preparation (27%). There was no failure of CTC. For 100 patients, CTC as a primary investigation was a more cost-effective investigation (p ≤ 0.01) costing £55,016 as compared with colonoscopy costing £73,666. CONCLUSION: There is an unacceptably high failure rate of colonoscopy in patients who presented with the primary symptom of constipation. Hence, we propose that CTC may be an acceptable first-line investigation with a further colonoscopy/flexible sigmoidoscopy if lesions are detected. Advances in knowledge: First study to examine the use of CTC in patients with constipation.

A rare presentation of complication arising from Meckel's diverticulum in the form of diverticulotransverse colonic fistula in an adult.

Meckel's diverticulum is a common congenital malformation of the gastrointestinal tract, reported to be present in 2-4% of the population. Although most patients with Meckel's diverticulum remain asymptomatic throughout life, reports of acute inflammation, perforation, haemorrhage, intussusception, intestinal obstruction, vesicodiverticular fistulae and primary tumours are described. We present a rare diagnosis of diverticulotransverse colonic fistula and its management.