Genomic Landscape of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens for Immunoprevention.

BACKGROUND & AIMS: Lynch syndrome (LS) carriers develop mismatch repair-deficient neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS precancers exists, which is crucial for vaccine development and immune-interception strategies. We report a focused somatic mutation and frameshift-neoAg landscape of microsatellite loci from colorectal polyps without malignant potential (PWOMP), precancers, and early-stage cancers in LS carriers. METHODS: We generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMP, 41 precancers, 8 advanced precancers, and 12 early-stage cancers of 43 LS carriers. A computational pipeline was developed to predict, rank, and prioritize the top 100 detected mutated neoAgs that were validated in vitro using ELISpot and tetramer assays. RESULTS: Mutation calling revealed >10 mut/Mb in 83% of cancers, 63% of advanced precancers, and 20% of precancers. Cancers displayed an average of 616 MHC-I neoAgs/sample, 294 in advanced precancers, and 107 in precancers. No neoAgs were detected in PWOMP. A total of 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were present in 92% of cancers, 50% of advanced precancers, and 29% of precancers. We observed increased levels of naïve CD8+ and memory CD4+ T cells in mismatch repair-deficient cancers and precancers via transcriptomics analysis. CONCLUSIONS: Shared frameshift-neoAgs are generated within unstable microsatellite loci at initial stages of LS carcinogenesis and can induce T-cell responses, generating opportunities for vaccine development, targeting LS precancers and early-stage cancers.

Initiation and Carbene Induced Radical Chain Reactions in CH2F2 Pyrolysis.

High temperature dissociations of organic molecules typically involve a competition between radical and molecular processes. In this work, we use a modeling, experiment, theory (MET) framework to characterize the high temperature thermal dissociation of CH2F2, a flammable hydrofluorocarbon (HFC) that finds widespread use as a refrigerant. Initiation in CH2F2 proceeds via a molecular elimination channel; CH2F2→CHF+HF. Here we show that the subsequent self-reactions of the singlet carbene, CHF, are fast multichannel processes and a facile source of radicals that initiate rapid chain propagation reactions. These have a marked influence on the decomposition kinetics of CH2F2. The inclusion of these reactions brings the simulations into better agreement with the present and literature experiments. Additionally, flame simulations indicate that inclusion of the CHF+CHF multichannel reaction leads to a noticeable enhancement in predictions of laminar flame speeds, a key parameter that is used to determine the flammability of a refrigerant.

Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis.

BACKGROUND: The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown. METHODS: We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease. RESULTS: A total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine-sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine-sulindac as compared with sulindac (P = 0.29) and 0.66 (95% CI, 0.36 to 1.24) for eflornithine-sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.73 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups. CONCLUSIONS: In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.).

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines.

BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.

The Approach to Performance of Quality Upper Endoscopy in Lynch Syndrome (QUELS): An International Expert Statement.

Strong evidence demonstrates the protective benefit of frequent colonoscopy surveillance for colorectal cancer prevention in Lynch Syndrome (LS) and is endorsed by many guidelines. Until recently, the evidence supporting the utility of upper endoscopy [esophagogastroduodenoscopy (EGD)] for upper gastrointestinal (UGI) cancer surveillance was limited. Over the last 3 years, multiple studies have demonstrated that EGD surveillance in LS is associated with the detection of both precancerous lesions and early-stage UGI cancers. On the basis of the emerging favorable evidence derived from EGD surveillance programs, the 2022 National Comprehensive Cancer Network (NCCN) Guidelines for LS recommend UGI surveillance with EGD starting between age 30 and 40 years with repeat EGDs every 2 to 4 years, preferably in conjunction with colonoscopy, in all patients with a germline pathogenic variant (PV) in MLH1, MSH2, EPCAM, and MSH6 and, because of the lack of data, consideration in PMS2. Standardization of the approach to performing EGD surveillance in LS and reporting clinically actionable findings is requisite for both improving quality and understanding the cost efficiency and outcomes of patients undergoing EGD as a surveillance tool. Accordingly, the primary objective of this Quality of Upper Endoscopy in Lynch Syndrome (QUELS) statement is to articulate a framework for standardizing the approach to performing and reporting EGD findings in patients with LS by introducing emerging quality metrics. The recommendations presented herein were developed from available evidence and consensus-based expert opinion and provide a practical approach for clinicians applying EGD surveillance in accordance with the most recent and existing LS guidelines.

Development and evaluation of an online, patient-driven, family outreach intervention to facilitate sharing of genetic risk information in families with Lynch syndrome.

BACKGROUND: Identifying at-risk relatives of individuals with genetic conditions facilitates 'cascade' genetic testing and cancer prevention. Although current standards of care give mutation-positive (index) patients the responsibility of sharing genetic risk information with relatives, the communication is suboptimal, limited largely to close relatives. We developed FamilyCONNECT, a provider-mediated, patient-navigated online tool to facilitate family outreach, and assessed its feasibility, usability and acceptability. METHODS: (1) Development of the FamilyCONNECT prototype; (2) testing using online surveys of: (a) members of Lynch Syndrome (LS) International (LSI); (b) genetics service providers; and (3) hands-on testing with patients with LS. RESULTS: (1) FamilyCONNECT's features include introductory email to elicit participation, informational website/video, identity authentication/account creation, informed consent, sharing of genetic test results, pedigree expansion and process to invite at-risk relatives. (2a) 33% of the 170 LSI participants completed the survey. FamilyCONNECT's features received favourable responses from at least 79% of respondents. Unfavourable responses were for length of the consent document and mistrust of opening emailed links. (2b) Thirty-five genetics professionals responded to the providers' survey. Key perceived barriers to FamilyCONNECT's usage were privacy/confidentiality (83%), a lack of institutional resources (76%), a defined process (66%) and time (69%). (3) Ten patients navigated data collection fields and provided feedback for improvements. CONCLUSION: FamilyCONNECT tool's content and features were well received among patients with LS as well as providers. The tool could be a viable alternative to increase family outreach among patients with LS. Future efforts will focus on refining FamilyCONNECT and assessing its uptake and utilisation by patients with LS.

A validation of models for prediction of pathogenic variants in mismatch repair genes.

PURPOSE: Models used to predict the probability of an individual having a pathogenic homozygous or heterozygous variant in a mismatch repair gene, such as MMRpro, are widely used. Recently, MMRpro was updated with new colorectal cancer penetrance estimates. The purpose of this study was to evaluate the predictive performance of MMRpro and other models for individuals with a family history of colorectal cancer. METHODS: We performed a validation study of 4 models, Leiden, MMRpredict, PREMM5, and MMRpro, using 784 members of clinic-based families from the United States. Predicted probabilities were compared with germline testing results and evaluated for discrimination, calibration, and predictive accuracy. We analyzed several strategies to combine models and improve predictive performance. RESULTS: MMRpro with additional tumor information (MMRpro+) and PREMM5 outperformed the other models in discrimination and predictive accuracy. MMRpro+ was the best calibrated with an observed to expected ratio of 0.98 (95% CI = 0.89-1.08). The combination models showed improvement over PREMM5 and performed similar to MMRpro+. CONCLUSION: MMRpro+ and PREMM5 performed well in predicting the probability of having a pathogenic homozygous or heterozygous variant in a mismatch repair gene. They serve as useful clinical decision tools for identifying individuals who would benefit greatly from screening and prevention strategies.

Combination of Sulindac and Eflornithine Delays the Need for Lower Gastrointestinal Surgery in Patients With Familial Adenomatous Polyposis: Post Hoc Analysis of a Randomized Clinical Trial.

BACKGROUND: Colectomy and proctocolectomy are the initial standard of care for patients with familial adenomatous polyposis. Pharmacotherapy to prevent the progression of polyposis and surgeries in the lower GI tract would be beneficial to patients with this disease. OBJECTIVE: This analysis aimed to evaluate the impact of eflornithine-sulindac combination versus monotherapy in delaying time to disease progression in the lower GI tract of patients with familial adenomatous polyposis. DESIGN: This is a post hoc analysis of a randomized phase 3 trial. SETTING: This study was conducted in 21 hospitals in 7 countries treating patients with familial adenomatous polyposis. PATIENTS: Adults with familial adenomatous polyposis were randomly assigned 1:1:1 into 3 arms. INTERVENTIONS: Patients received either eflornithine (750 mg), sulindac (150 mg), or both once daily for up to 48 months. MAIN OUTCOME MEASURES: Efficacy was evaluated as the time from randomization to predefined primary disease progression end points. RESULTS: A total of 158 patients were included in the study. Disease progression was observed in 2 of 54 (3.7%), 9 of 53 (17.0%), and 10 of 51 (19.6%) patients with at least partial lower GI tract in the combination, sulindac, and eflornithine arms, corresponding to risk reductions of 80% (p = 0.02) and 83% (p = 0.01) between combination and sulindac or eflornithine. When endoscopic excision of adenomas ≥10 mm in size was censored, the need for major surgery was observed in 0 of 54, 7 of 53 (13.2%), and 8 of 51 (15.7%) patients in the combination, sulindac, and eflornithine arms, corresponding to risk reductions approaching 100% between combination and sulindac (p = 0.005) or combination and eflornithine (p = 0.003). LIMITATIONS: This was a post hoc analysis, the sample size was small, and there were fewer than expected events. CONCLUSIONS: Eflornithine-sulindac combination therapy was superior to either drug alone in delaying or preventing the need for lower GI tract surgery in patients with familial adenomatous polyposis. See Video Abstract at http://links.lww.com/DCR/B658. REGISTRATION: ClinicalTrials.gov, NCT01483144; EU Clinical Trials Register, EudraCT 2012-000427-41. LA COMBINACIN DE SULINDAC Y EFLORNITINA RETRASA LA NECESIDAD DE CIRUGA DEL TUBO DIGESTIVO BAJO EN PACIENTES CON PAF ANLISIS POSTHOC DE UN ENSAYO CLNICO ALEATORIZADO: ANTECEDENTES:La colectomía y la proctocolectomía son el estándar inicial de atención para los pacientes con poliposis adenomatosa familiar. La farmacoterapia para prevenir la progresión de la poliposis y las cirugías en el tracto gastrointestinal inferior sería beneficiosa para los pacientes con esta enfermedad.OBJETIVO:Este análisis tuvo como objetivo evaluar el impacto de la combinación de eflornitina-sulindac versus la monoterapia en el retraso del tiempo hasta la progresión de la enfermedad en el tracto gastrointestinal inferior de pacientes con poliposis adenomatosa familiar.DISEÑO:Este es un análisis posthoc de un ensayo de fase 3 aleatorizado.ENTORNO CLINICO:Veintiún hospitales en 7 países que tratan a pacientes con poliposis adenomatosa familiar.PACIENTES:Adultos con poliposis adenomatosa familiar fueron aleatorizados 1: 1: 1 en 3 brazos.INTERVENCIONES:Los pacientes recibieron eflornitina (750 mg), sulindac (150 mg) o ambos una vez al día durante un máximo de 48 meses.PRINCIPALES MEDIDAS DE VALORACION:La eficacia se evaluó como el tiempo desde la aleatorización hasta los criterios de valoración primarios predefinidos de progresión de la enfermedad.RESULTADOS:Los resultados se informan para la población de estudio excluyendo a los pacientes que se habían sometido a ileostomías permanentes (n = 158). Se observó progresión de la enfermedad en 2/54 (3,7%), 9/53 (17,0%) y 10/51 (19,6%) pacientes con al menos tracto gastrointestinal inferior parcial en los brazos de combinación, sulindac y eflornitina, respectivamente, correspondientes al riesgo de reducciones del 80% (p = 0,02) y del 83% (p = 0,01) entre la combinación y el sulindaco o la eflornitina, respectivamente. Cuando se censuró la escisión endoscópica de adenomas ≥10 mm de tamaño, se observó la necesidad de cirugía mayor en 0/54, 7/53 (13,2%) y 8/51 (15,7%) pacientes en la combinación, sulindac y eflornitina, respectivamente, correspondientes a reducciones de riesgo cercanas al 100% entre combinación y sulindac (p = 0,005) o combinación y eflornitina (p = 0,003).LIMITACIONES:Este fue un análisis posthoc, el tamaño de la muestra fue pequeño y hubo menos eventos de los esperados.CONCLUSIONES:La terapia de combinación de eflornitina-sulindac fue superior a cualquier fármaco solo para retrasar o prevenir la necesidad de cirugía del tracto gastrointestinal inferior en pacientes con poliposis adenomatosa familiar. Consulte Video Resumen en http://links.lww.com/DCR/B658.

How much progress have we made?: a 20-year experience regarding esophageal stents for the palliation of malignant dysphagia.

Esophageal stents are widely used for the palliation of malignant esophageal obstruction. Advances in technology have made esophageal stenting technically feasible and widespread for such obstruction, but complications remain frequent. We present outcomes of a large cohort undergoing esophageal stent placement for malignant esophageal obstruction at a tertiary care cancer center. Patients who underwent placement of esophageal stents for malignancy-related esophageal obstruction between 1 January 2001 and 31 July 2020 were identified. Exclusion criteria included stents placed for benign stricture, fistulae, obstruction of proximal esophagus (proximal to 24 cm from incisors), or post-surgical indications. Patient charts were reviewed for demographics, procedure and stent characteristics, complications, and follow-up. A total of 242 patients underwent stent placement (median age: 64 years, 79.8% male). The majority, 204 (84.3%), had esophageal cancer. During the last two decades, there has been an increasing trend in the number of esophageal stents placed. Though plastic stents were previously used, these are no longer utilized. Complications are frequent and include early complications of pain in 68 (28.1%) and migration in 21 (8.7%) and delayed complications of recurrent symptoms of dysphagia in 46 (19.0%) and migration in 26 (10.7%). Over the study period, there has not been a significant improvement in the rate of complications. During follow-up, 92 (38%) patients required other enteral nutrition modalities after esophageal stent placement. No patient, treatment, or stent characteristics were significantly associated with stent complication or outcome. Esophageal stent placement is an increasingly popular method for palliation of malignant dysphagia. However, complications, particularly pain, migration, and recurrent symptoms of dysphagia are common. Almost 40% of patients may also require other methods of enteral access after esophageal stent placement. Given the high complication rates and suboptimal outcomes, removable stents should be considered as first-line in the case of poor palliative response.

Smoking and other patient factors in HPV-mediated oropharynx cancer: A retrospective cohort study.

PURPOSE: To characterize the significance of patient-level influences, including smoking history, on oncologic outcomes in human papillomavirus (HPV)-mediated oropharyngeal cancer (OPC). MATERIALS AND METHODS: A bi-institutional retrospective cohort study of previously untreated, HPV+ OPC patients who underwent curative treatment from 1/1/2008 to 7/1/2018 was performed. The primary outcome was disease-free survival (DFS) and the primary exposure was ≤10 versus >10-pack-year (PY)-smoking history. RESULTS: Among 953 OPC patients identified, 342 individuals with HPV+ OPC were included. The median patient age was 62 years, 33.0% had a > 10-PY-smoking history, 60.2% had AJCC8 stage I disease, and 35.0% underwent primary surgery. The median follow-up was 49 months (interquartile range [IQR] 32-75 months). Four-year DFS-estimates were similar among patients with ≤10-PY-smoking history (78.0%, 95% CI:71.7%-83.1%) compared to >10-PYs (74.8%; 95% CI:65.2%-82.0%; log-rank:p = 0.53). On univariate analysis, >10-PY-smoking history did not correlate with DFS (hazard ratio[HR]:1.15;95% CI:0.74-1.79) and remained nonsignificant when forced into the multivariable model. On adjusted analyses, stage, treatment paradigm, and age predicted DFS. Neither >10-PYs, nor any other definition of tobacco use (e.g., current smoker or > 20-PYs) was predictive of DFS, overall survival, or disease-specific survival. Conversely, age nonsignificantly and significantly predicted adjusted DFS (adjusted HR[aHR]:1.02,95% CI:0.997-1.05, p = 0.08), overall survival (aHR 1.05; 95% CI: 1.02-1.08; p = 0.002) and disease-specific survival (aHR 1.04;95% CI: 0.99-1.09;p = 0.09). CONCLUSION: Other than age, patient-level influences may not be primary drivers of HPV+ OPC outcomes. Although limited by its modest sample size, our study suggests the significance of smoking has been overstated in this disease. These findings and the emerging literature collectively do not support risk-stratification employing the >10-PY threshold. LEVEL OF EVIDENCE: Level 4.

Impact of a resilience and wellbeing program: A longitudinal cohort study of student dietitians.

In response to growing evidence that student healthcare professionals find professional practicum stressful and that it negatively affects their mental health, a six-session psychoeducation Resilience and Wellbeing Program was implemented by a professional counselor in Year 3 of the Bachelor of Nutrition and Dietetics at Griffith University, Australia. The aim of this study was to evaluate student dietitians' perceptions of whether the program improved their ability to cope with practicum stressors. The study used a longitudinal cohort design, with students completing surveys at three time points: before and after the program and after the final practicum. The study was completed with two cohorts of students between 2018 and 2020 (n = 111). Most respondents (95%) found their professional practicum to be stressful or challenging on at least some occasions, mostly due to constantly being assessed (56%), finances (40%), and being away from usual supports (38%). Almost all students rated the program as having some value (99%), with the content about stress and self-care the most highly rated. Qualitative comments revealed the program helped students to manage stress by prioritizing their personal needs. Students used stress management skills during the practicum to achieve balance in their lives, despite pandemic conditions.

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.

OBJECTIVE: Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS. DESIGN: We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs). RESULTS: Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control. CONCLUSIONS: Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. TRIAL REGISTRATION NUMBER: gov Identifier: NCT02052908.

NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021.

Identifying individuals with hereditary syndromes allows for timely cancer surveillance, opportunities for risk reduction, and syndrome-specific management. Establishing criteria for hereditary cancer risk assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provides recommendations for the assessment and management of patients at risk for or diagnosed with high-risk colorectal cancer syndromes. The NCCN Genetic/Familial High-Risk Assessment: Colorectal panel meets annually to evaluate and update their recommendations based on their clinical expertise and new scientific data. These NCCN Guidelines Insights focus on familial adenomatous polyposis (FAP)/attenuated familial adenomatous polyposis (AFAP) syndrome and considerations for management of duodenal neoplasia.

Initiation reactions in the high temperature decomposition of styrene.

The thermal decomposition of styrene was investigated in a combined experimental, theory and modeling study with particular emphasis placed on the initial dissociation reactions. Two sets of shock tube/time-of-flight mass spectrometry (TOF-MS) experiments were performed to identify reaction products and their order of appearance. One set of experiments was conducted with a miniature high repetition rate shock tube at the Advanced Light Source at Lawrence Berkeley National Laboratory using synchrotron vacuum ultraviolet photoionization. The other set of experiments was performed in a diaphragmless shock tube (DFST) using electron impact ionization. The datasets span 1660-2260 K and 0.5-12 atm. The results show a marked transition from aromatic products at low temperatures to polyacetylenes, up to C8H2, at high temperatures. The TOF-MS experiments were complemented by DFST/LS (laser schlieren densitometry) experiments covering 1800-2250 K and 60-240 Torr. These were particularly sensitive to the initial dissociation reactions. These reactions were investigated theoretically and revealed the dissociation of styrene to be a complex multichannel process with strong pressure and temperature dependencies that were evaluated with multi-well master equation simulations. Simulations of the LS data with a mechanism developed in this work are in excellent agreement with the experimental data. From these simulations, rate coefficients for the dissociation of styrene were obtained that are in good agreement with the theoretical predictions. The simulation results also provide fair predictions of the temperature and pressure dependencies of the products observed in the TOF-MS studies. Prior experimental studies of styrene pyrolysis concluded that the main products were benzene and acetylene. In contrast, this study finds that the majority of styrene dissociates to create five styryl radical isomers. Of these, α-styryl accounts for about 50% with the other isomers consuming approximately 20%. It was also found that C-C bond scission to phenyl and vinyl radicals consumes up to 25% of styrene. Finally the dissociation of styrene to benzene and vinylidene accounts for roughly 5% of styrene consumption. Comments are made on the apparent differences between the results of this work and prior literature.

Efficacy of uncovered colonic stents for extrinsic versus intrinsic malignant large bowel obstruction.

BACKGROUND: Previous studies evaluating self-expandable metal stents (SEMS) for management of malignant extrinsic colon obstruction have yielded conflicting results. We evaluated the efficacy of uncovered SEMS for extrinsic colon malignancy (ECM) versus intrinsic colon malignancy (ICM). METHODS: Retrospective review of all patients referred for colonic SEMS at a tertiary cancer center between 2007 and 2018 was performed. Primary outcome measures were technical success, clinical success, intervention rate, and overall survival. RESULTS: 138 patients with ECM and 119 patients with ICM underwent attempted stent placement. The rectum and/or sigmoid colon was the most common stricture site. Technical success was lower in the ECM group [86% vs 96% (p = .009)]. Clinical success was lower in the ECM group both at 7 days [82% vs 95% (p = .004)] and at 90 days [60% vs 86% (p < .001)]. Subsequent intervention was required more frequently [44% vs 35%; p = .23] and earlier [median 9 vs 132 days; p < .001] in the ECM group. Median overall survival in the ECM group was 92 vs 167 days. Among predictive variables analyzed, the ECM group had a higher frequency of peritoneal metastasis (87% vs 32%; p < .001), multifocal strictures with requirement for multiple stents (20% vs 6%; p = .002), sharp angulated strictures (39% vs 25%; p = .04) , and radiation therapy (21% vs 10%; p = .02). CONCLUSIONS: Colonic SEMS for ECM is associated with lower technical and clinical success with earlier intervention rates compared with ICM. Our findings can be used to better inform patients and referring providers as well as guide new stent design to enhance efficacy in this population.

Adaptive Grasping of Moving Objects through Tactile Sensing.

A robot's ability to grasp moving objects depends on the availability of real-time sensor data in both the far-field and near-field of the gripper. This research investigates the potential contribution of tactile sensing to a task of grasping an object in motion. It was hypothesised that combining tactile sensor data with a reactive grasping strategy could improve its robustness to prediction errors, leading to a better, more adaptive performance. Using a two-finger gripper, we evaluated the performance of two algorithms to grasp a ball rolling on a horizontal plane at a range of speeds and gripper contact points. The first approach involved an adaptive grasping strategy initiated by tactile sensors in the fingers. The second strategy initiated the grasp based on a prediction of the position of the object relative to the gripper, and provided a proxy to a vision-based object tracking system. It was found that the integration of tactile sensor feedback resulted in a higher observed grasp robustness, especially when the gripper-ball contact point was displaced from the centre of the gripper. These findings demonstrate the performance gains that can be attained by incorporating near-field sensor data into the grasp strategy and motivate further research on how this strategy might be expanded for use in different manipulator designs and in more complex grasp scenarios.

Decreased number of striatal cholinergic interneurons and motor deficits in dopamine receptor 2-expressing-cell-specific Dyt1 conditional knockout mice.

DYT1 early-onset generalized torsion dystonia is a hereditary movement disorder characterized by abnormal postures and repeated movements. It is caused mainly by a heterozygous trinucleotide deletion in DYT1/TOR1A, coding for torsinA. The mutation may lead to a partial loss of torsinA function. Functional alterations of the basal ganglia circuits have been implicated in this disease. Striatal dopamine receptor 2 (D2R) levels are significantly decreased in DYT1 dystonia patients and in the animal models of DYT1 dystonia. D2R-expressing cells, such as the medium spiny neurons in the indirect pathway, striatal cholinergic interneurons, and dopaminergic neurons in the basal ganglia circuits, contribute to motor performance. However, the function of torsinA in these neurons and its contribution to the motor symptoms is not clear. Here, D2R-expressing-cell-specific Dyt1 conditional knockout (d2KO) mice were generated and in vivo effects of torsinA loss in the corresponding cells were examined. The Dyt1 d2KO mice showed significant reductions of striatal torsinA, acetylcholine metabolic enzymes, Tropomyosin receptor kinase A (TrkA), and cholinergic interneurons. The Dyt1 d2KO mice also showed significant reductions of striatal D2R dimers and tyrosine hydroxylase without significant alteration in striatal monoamine contents or the number of dopaminergic neurons in the substantia nigra. The Dyt1 d2KO male mice showed motor deficits in the accelerated rotarod and beam-walking tests without overt dystonic symptoms. Moreover, the Dyt1 d2KO male mice showed significant correlations between striatal monoamines and locomotion. The results suggest that torsinA in the D2R-expressing cells play a critical role in the development or survival of the striatal cholinergic interneurons, expression of striatal D2R mature form, and motor performance. Medical interventions to compensate for the loss of torsinA function in these neurons may affect the onset and symptoms of this disease.

Management of ampullary adenomas in familial adenomatous polyposis syndrome: 16 years of experience from a tertiary cancer center.

BACKGROUND AND AIMS: The management of ampullary adenomas in familial adenomatous polyposis (FAP) is challenging due to multiple adenomas in the duodenum, history of previous major abdominal surgery, and desmoid lesions. In this study, we aim to define the optimum management for ampullary adenomas, particularly in FAP. METHODS: This is a retrospective study of all patients with pathology-confirmed ampullary adenomas in M.D. Anderson Cancer Center from 2002 to 2018. Relevant data were extracted, including patient demographics, treatments, outcomes, and adverse events. RESULTS: There were 137 patients with ampullary adenomas who underwent 159 procedures; 95 of the 137 patients had FAP and were placed under close observation, 29 underwent endoscopic ampullectomy, 4 underwent surgical ampullectomy, and 31 underwent panreaticoduodenectomy (PD). In the close observation group, 12.6% progressed to advanced adenoma and subsequently underwent resection. There was no ampullary cancer detected in this group. The endoscopic ampullectomy group had a postprocedure adverse event rate of 10.2%. Eleven patients had residual/recurrent disease after endoscopic ampullectomy, 3 of whom needed surgery. Four patients underwent initial surgical ampullectomy and 2 subsequently needed PD. Patients who underwent PD had an adverse event rate of 29%. In this group, there were no cases of residual disease or recurrence. CONCLUSIONS: The management of ampullary adenomas in FAP should be carefully considered for the best outcome. Although these patients can be managed by endoscopic ampullectomy, careful surveillance for recurrence should be followed along with prompt management of the recurrence when detected. Although PD provides a definitive treatment, it is limited by the patient's comorbid conditions and high adverse event rates.

Fundamentals of Radiation Oncology for Neurologic Imaging.

Although the physical and biologic principles of radiation therapy have remained relatively unchanged, a technologic renaissance has led to continuous and ever-changing growth in the field of radiation oncology. As a result, medical devices, techniques, and indications have changed considerably during the past 20-30 years. For example, advances in CT and MRI have revolutionized the treatment planning process for a variety of central nervous system diseases, including primary and metastatic tumors, vascular malformations, and inflammatory diseases. The resultant improved ability to delineate normal from abnormal tissue has enabled radiation oncologists to achieve more precise targeting and helped to mitigate treatment-related complications. Nevertheless, posttreatment complications still occur and can pose a diagnostic challenge for radiologists. These complications can be divided into acute, early-delayed, and late-delayed complications on the basis of the time that they manifest after radiation therapy and include leukoencephalopathy, vascular complications, and secondary neoplasms. The different irradiation technologies and applications of these technologies in the brain, current concepts used in treatment planning, and essential roles of the radiation oncologist in the setting of brain disease are reviewed. In addition, relevant imaging findings that can be used to delineate the extent of disease before treatment, and the expected posttreatment imaging changes are described. Common and uncommon complications related to radiation therapy and the associated imaging manifestations also are discussed. Familiarity with these entities may aid the radiologist in making the diagnosis and help guide appropriate management. ©RSNA, 2020.

An experimental and theoretical study of the high temperature reactions of the four butyl radical isomers.

The high temperature gas phase chemistry of the four butyl radical isomers (n-butyl, sec-butyl, iso-butyl, and tert-butyl) was investigated in a combined experimental and theoretical study. Organic nitrites were used as convenient and clean sources of each of the butyl radical isomers. Rate coefficients for dissociation of each nitrite were obtained experimentally and are at, or close to, the high pressure limit. Low pressure experiments were performed in a diaphragmless shock tube with laser schlieren densitometry at post-shock pressures of 65, 130, and 260 Torr and post-shock temperatures of 700-1000 K. Additional experiments were conducted with iso-butyl radicals at 805 K and 8.7 bar to elucidate changes in mechanism at higher pressures. These experiments were performed in a miniature shock tube with synchrotron-based photoionization mass spectrometry. The mass spectra confirmed that scission of the O-NO bond is the primary channel by which the precursors dissociate, but they also provided evidence of a minor channel (<7.7%) through HNO loss and formation of an aldehyde. These high pressure experiments were also used to determine the disproportionation/recombination ratio for iso-butyl radicals as 0.3. Reanalysis of the lower-temperature literature and the present data yielded rate constants for the disproportionation reaction, iso-butyl + iso-butyl = iso-butene + iso-butane. A chemical kinetics model was developed for the reactions of the butyl isomers that included new paths for highly energized adducts. These adducts are formed by the addition of H, CH3 or C2H5 to the butyl radicals. Accompanying theoretical investigations show that chemically activated pathways are competitive with stabilization of the adduct by collision under the conditions of the laser schlieren experiments. These calculations also show that at 10 bar and T < 1000 K stabilization is the only important reaction, but at higher temperatures, even at 10 bar, chemically activated product channels should also be considered. Branching fractions and rate coefficients are presented for these reactions. This study also highlights the importance of the radical structure for determining branching ratios for disproportionation and recombination of alkyl radicals, and these were facilitated by theoretical calculations of recombination rate coefficients for the four butyl radical isomers. The results reveal previously unknown features of butyl radical chemistry under conditions that are relevant to a wide range of applications and reaction mechanisms are presented that incorporate pressure dependent rate coefficients for the key steps.