Search

El fruto senescente presentó la mayor concentración de proteína total, sin embargo, esta concentración es baja comparada con otras fuentes vegetales similares. Se realizó electroforesis de la extracción de proteína total y de las albúminas obtenidas por ambos métodos. En los tres estados de madurez y bajo cualquier condición de extracción se presentaron grupos de proteínas (bandas) con perfiles electroforéticos semejantes, lo que sugiere que por cualquier método de extracción se obtuvieron las mismas proteínas. Más adelante, se evaluó la actividad proteolítica de los extractos con la finalidad de conocer si la baja concentración de proteína se debe a una reacción de proteólisis durante el almacenamiento del fruto, sin embargo, se encontró que esta reacción no pudo haber ocurrido bajo las condiciones de refrigeración mantenidas previas al estudio de los frutos. Por último, se aplicaron tratamientos sobre cultivos de 2 líneas celulares de cáncer de mama (MCF7 y MDA-MB-231) y una línea no cancerosa (MCF10A) a diferentes concentraciones de extracto acuoso de fruto rojo para determinar el efecto que éste presenta sobre la muerte celular, utilizando la concentración letal al 50% (CL50). La línea más resistente fue MCF10A (no cancerosa), ya que mostró una mayor CL50 (59.64 µg EAG/mL) mientras que la línea MCF7 fue la más sensible (CL50 = 26.4 µg EAG/mL). Se demostró que el extracto acuoso del fruto de C. loniceroides, que contiene polifenoles, flavonoides, taninos y alcaloides, es capaz de disminuir la viabilidad in vitro de las líneas celulares de cáncer de mama estudiadas, con menor efecto sobre la línea celular no cancerosa, por lo que se recomiendan estudios posteriores para identificar mecanismos de acción y de purificación del extracto que permitan la obtención de una solución estandarizada que pueda usarse en el tratamiento del cáncer de mama humano. El muérdago es una planta parásita que absorbe del hospedero agua y sales a través de haustorios hasta causarle la muerte. No hay un control químico para evitar la propagación de la plaga de muérdago, por lo que solo se podan las ramas o árboles infestados. Sin embargo, se ha demostrado en trabajos previos que la especie Cladocolea (C.) loniceroides, endémica de México, contiene compuestos antioxidantes que pueden presentar efectos benéficos contra el cáncer de mama, posiblemente a través de mecanismos que regulan el estrés oxidativo. El objetivo de este trabajo fue analizar la composición química del fruto de C. loniceroides en diferentes estados de madurez, así como evaluar el efecto que presenta el extracto acuoso de fruto sobre la muerte de cultivos celulares de cáncer de mama. Para lograr esto, se separó el fruto en sus tres estados de madurez en verde, rojo y senescente y se realizaron extractos acuosos para cuantificar los principales compuestos. Con una marcha fitoquímica se detectó la presencia de polifenoles, flavonoides, leucoantocianidinas, hidroxilos fenólicos, alcaloides, aminoácidos y taninos en los tres estados de madurez. Posteriormente, se determinó la concentración de polifenoles totales, misma que es mayor conforme madura el fruto, alcanzando una concentración máxima en el fruto rojo, lo que se refleja también en la mayor concentración de flavonoides observada en el mismo. En el fruto verde se encontró una mayor concentración de taninos que desciende conforme éste madura siendo fruto verde>rojo>senescente. La concentración de alcaloides fue significativamente mayor en el senescente. Se realizó la hidrólisis de taninos de los extractos acuosos en sus tres estados de madurez donde el fruto verde presentó la concentración mayor. Posteriormente se compararon tres métodos distintos de extracción de proteína, donde la fracción proteínica que se aisló en mayor concentración fueron las albúminas.

Characteristic features of chronic pancreatitis (CP) may be absent on standard imaging studies. Quantitative Magnetic Resonance Imaging (MRI) techniques such as T(1) mapping, extracellular volume (ECV) fraction, diffusion-weighted imaging (DWI) with apparent diffusion coefficient map (ADC), MR elastography (MRE), and T(1)-weighted signal intensity ratio (SIR) have shown promise for the diagnosis and grading severity of CP. However, radiologists still use the Cambridge classification which is based on traditional ductal imaging alone. There is an urgent need to develop new diagnostic criteria that incorporate both parenchymal and ductal features of CP seen by MRI/MRCP. Designed to fulfill this clinical need, we present the MINIMAP study, which was funded in September 2018 by the National Institutes of Health. This is a comprehensive quantitative MR imaging study which will be performed at multiple institutions in well-phenotyped CP patient cohorts. We hypothesize that quantitative MRI/MRCP features can serve as valuable non-invasive imaging biomarkers to detect and grade CP. We will evaluate the role of T(1) relaxometry, ECV, T(1)-weighted gradient echo SIR, MRE, arteriovenous enhancement ratio, ADC, pancreas volume/atrophy, pancreatic fat fraction, ductal features, and pancreatic exocrine output following secretin stimulation in the assessment of CP. We will attempt to generate a multi-parametric pancreatic tissue fibrosis (PTF) scoring system. We anticipate that a quantitative scoring system may serve as a biomarker of pancreatic fibrosis; hence this imaging technique can be used in clinical practice as well as clinical trials to evaluate the efficacy of agents which may slow the progression or reverse measures of CP.

There are three liver-specific causality assessment tools currently available to guide clinical diagnosis of Drug-Induced Liver Injury (DILI): Roussel-Uclaf Causality Assessment Method (RUCAM), Digestive-Disease-Week Japan 2004 scale (DDW-J), and Clinical Diagnostic Scale (CDS). The purpose of this review is to assess these tools and discuss how to improve the causality assessment process as a whole.Existing DILI-specific causality assessment tools are surprisingly similar and exhibit only minor differences in point allocation. But difference in threshold for likelihood of being DILI. We reviewed the literature on currently used causality assessment tools, identified areas for future improvement, and herein propose approaches for refinement. Opportunities to improve current models, as well as the assessment process, in general, include in particular provision of more precise clinical detail and to perhaps add new components to scoring systems. For example, the incorporation of drug-specific clinical signature patterns, accounting for a drug's inherent hepatotoxicity potential, and/or incorporation of other drug properties to scoring systems may allow enhancement. Further, more systemic exclusion of competing diagnoses is needed. Finally, causality assessment processes will likely benefit from a data-driven and computer-assisted approach.Current tools used for DILI adjudication are imperfect. Avenues to improve these tools are described.

Background & Aims: Vascular liver diseases (VLDs) are represented mainly by portosinusoidal vascular disease (PSVD), noncirrhotic splanchnic vein thrombosis (SVT), and Budd Chiari syndrome (BCS). It is unknown whether patients with VLDs constitute a high-risk population for complications and greater coronavirus disease 2019 (COVID-19)-related mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our objective was to assess the prevalence and severity of SARS-CoV-2 infection among patients with VLDs, as well as to assess its impact on hepatic decompensation and survival. Methods: This is an observational international study analyzing the prevalence and severity of SARS-CoV-2 infection in VLDs between March 2020 and March 2021, compared with the general population (GP). Patients from Spain (5 centers; n = 493) and France (1 center; n = 475) were included. Results: Nine hundred sixty-eight patients were included: 274 with PSVD, 539 with SVT, and 155 with BCS. Among them, 138 (14%) were infected with SARS-CoV-2: 53 with PSVD, 77 with SVT, and 8 with BCS. The prevalence of SARS-CoV-2 infection in patients with PSVD (19%) and SVT (14%) was significantly higher than in the GP (6.5%; P < .05), whereas it was very similar in patients with BCS (5%). In terms of infection severity, patients with VLDs also presented a higher need of hospital admission (14% vs 7.3%; P < .01), intensive care unit admission (2% vs 0.7%; P < .01), and mortality (4% vs 1.5%; P < .05) than the GP. Previous history of ascites (50% vs 8%; P < .05) and post-COVID-19 hepatic decompensation (50% vs 4%; P < .05) were associated with COVID-19 mortality. Conclusions: Patients with PSVD and SVT could be at higher risk of infection by SARS-CoV-2 and at higher risk of severe COVID-19 disease. © 2021 AGA Institute

Thiacloprid (THI) is a widely used neonicotinoid insecticide where concerns have been raised regarding low absorption by crops, substantial distribution in surrounding areas, and potential adverse effects to terrestrial and aquatic organisms.Prior to this study, there was very limited information addressing the ex vivo (precision-cut liver slices) metabolism of THI by fish species and the metabolic pathways regulating its potential for adverse effects.The in vitro and ex vivo biotransformation pathway of THI is defined by the formation of three primary metabolites (TM1, TM2 and TM3) via separate paths differentiated by reductive decyanation, reductive dechlorination with hydration and dealkylation processes, respectively.Kinetic rates were calculated for the rat microsomal decyanation of THI into TM1 (Km = 299.2 µM and Vmax = 5.3 pmol/min/mg), and for the dealkylation of THI into TM3 (Km = 368.9 µM and Vmax = 3.95 pmol/min/mg).Formation confirmation and identity inference of THI metabolites in absence of standards were achieved by LC-UV and High Resolution-MS strategies.The in vitro and ex vivo metabolic products of THI are conserved both across species (rat and Rainbow trout) and levels of biological organization (microsomes and liver slices), as previously reported for the neonicotinoid insecticides Imidacloprid and Acetamiprid. Thiacloprid (THI) is a widely used neonicotinoid insecticide where concerns have been raised regarding low absorption by crops, substantial distribution in surrounding areas, and potential adverse effects to terrestrial and aquatic organisms. Prior to this study, there was very limited information addressing the ex vivo (precision-cut liver slices) metabolism of THI by fish species and the metabolic pathways regulating its potential for adverse effects. The in vitro and ex vivo biotransformation pathway of THI is defined by the formation of three primary metabolites (TM1, TM2 and TM3) via separate paths differentiated by reductive decyanation, reductive dechlorination with hydration and dealkylation processes, respectively. Kinetic rates were calculated for the rat microsomal decyanation of THI into TM1 (Km = 299.2 µM and Vmax = 5.3 pmol/min/mg), and for the dealkylation of THI into TM3 (Km = 368.9 µM and Vmax = 3.95 pmol/min/mg). Formation confirmation and identity inference of THI metabolites in absence of standards were achieved by LC-UV and High Resolution-MS strategies. The in vitro and ex vivo metabolic products of THI are conserved both across species (rat and Rainbow trout) and levels of biological organization (microsomes and liver slices), as previously reported for the neonicotinoid insecticides Imidacloprid and Acetamiprid.

Ines Aznar-Peralta holds a "Garantia Juvenil" fellowship (contract number 8040), and M. Carmen Garrido-Navas has a postdoctoral fellowship funded by the Ministry of Economy, Competitiveness, Enterprises and Universities (DOC_01682)., The isolation of circulating tumour cells (CTCs) in colorectal cancer (CRC) mostly relies on the expression of epithelial markers such as EpCAM, and phenotypic characterisation is usually performed under fluorescence microscopy with only one or two additional markers. This limits the ability to detect different CTC subpopulations based on multiple markers. The aim of this work was to develop a novel protocol combining two platforms (IsoFluxTM and ImageStream®X) to improve CTC evaluation. Cancer cell lines and peripheral blood from healthy donors were used to evaluate the efficiency of each platform independently and in combination. Peripheral blood was extracted from 16 early CRC patients (before loco-regional surgery) to demonstrate the suitability of the protocol for CTC assessment. Additionally, peripheral blood was extracted from nine patients one month after surgery to validate the utility of our protocol for identifying CTC subpopulation changes over time. Results: Our protocol had a mean recovery efficiency of 69.5% and a limit of detection of at least four cells per millilitre. We developed an analysis method to reduce noise from magnetic beads used for CTC isolation. CTCs were isolated from CRC patients with a median of 37 CTCs (IQ 13.0–85.5) at baseline. CTCs from CRC patients were significantly (p < 0.0001) larger than cytokeratin (CK)-negative cells, and patients were stratified into two groups based on BRAFV600E and PD-L1 expression on CK-positive cells. The changes observed over time included not only the number of CTCs but also their distribution into four different subpopulations defined according to BRAFV600E and PD-L1 positivity. We developed a novel protocol for semi-automatic CTC isolation and phenotypic characterisation by combining two platforms. Assessment of CTCs from early CRC patients using our protocol allowed the identification of two clusters of patients with changing phenotypes over time., "Garantia Juvenil" fellowship 8040, Ministry of Economy, Competitiveness, Enterprises and Universities DOC_01682

Diabetes represents a group of diseases involving persistent hyperglycaemia. Exocrine disorders of the pancreas are increasingly recognised to cause or precede the onset of diabetes, which in this context is referred to as pancreatogenic or type 3c diabetes. Diabetes, as a sequela of acute pancreatitis, is observed across the spectrum of severity in acute pancreatitis and can be associated with other clinical complications. The pathophysiology of acute pancreatitis-related diabetes is poorly understood, and observations suggest that it is probably multifactorial. In this Review, we discuss the epidemiology, pathophysiology, and management considerations of diabetes following acute pancreatitis, and highlight knowledge gaps in this topic.

Simple Summary Most solid tumors share mutations in TP53 that is thus considered one of the main cancer driver genes. Mutations in TP53 occur very early during tumor development, so their identification helps in diagnosing cancer. Furthermore, knowing in advance the TP53 mutation status might help guiding targeted treatments against this gene. However, this analysis is mainly performed in tissue samples, that is, solid biopsies, being an invasive technique. Contrarily, liquid biopsies, consisting of the analysis of blood samples, are non-invasive, can be performed repeatedly, helping in monitoring the patient evolution, and might be useful in early stages when the tumor is not yet detected by other technologies. Here, we review the main studies conducted on two types of liquid biopsies: circulating tumor cells and cell-free DNA. We discuss the main findings regarding TP53 mutation analysis, the clinical utility of this information and some controversies arising from the study of liquid biopsies compared to tissue samples, and we finish by suggesting future directions within this field. Abstract Being minimally invasive and thus allowing repeated measures over time, liquid biopsies are taking over traditional solid biopsies in certain circumstances such as those for unreachable tumors, very early stages or treatment monitoring. However, regarding TP53 mutation status analysis, liquid biopsies have not yet substituted tissue samples, mainly due to the lack of concordance between the two types of biopsies. This needs to be examined in a study-dependent manner, taking into account the particular type of liquid biopsy analyzed, that is, circulating tumor cells (CTCs) or cell-free DNA (cfDNA), its involvement in the tumor biology and evolution and, finally, the technology used to analyze each biopsy type. Here, we review the main studies analyzing TP53 mutations in either CTCs or cfDNA in the three more prevalent solid tumors: breast, colon and lung cancers. We evaluate the correlation for mutation status between liquid biopsies and tumor tissue, suggesting possible sources of discrepancies, as well as evaluating the clinical utility of using liquid biopsies for the analysis of TP53 mutation status and the future actions that need to be undertaken to make liquid biopsy analysis a reality for the evaluation of TP53 mutations.

Background and Aims The accurate measurement of technical skill in ERCP is essential for endoscopic training, quality assurance, and coaching of this procedure. Hypothesizing that technical skill can be measured by analysis of ERCP videos, we aimed to develop and validate a video-based ERCP skill assessment tool. Methods Based on review of procedural videos, the task of ERCP was deconstructed into its basic components by an expert panel that developed an initial version of the Bethesda ERCP Skill Assessment Tool (BESAT). Subsequently, 2 modified Delphi panels and 3 validation exercises were conducted with the goal of iteratively refining the tool. Fully crossed generalizability studies investigated the contributions of assessors, ERCP performance, and technical elements to reliability. Results Twenty-nine technical elements were initially generated from task deconstruction. Ultimately, after iterative refinement, the tool comprised 6 technical elements and 11 subelements. The developmental process achieved consistent improvements in the performance characteristics of the tool with every iteration. For the most recent version of the tool, BESAT-v4, the generalizability coefficient (a reliability index) was .67. Most variance in BESAT scores (43.55%) was attributed to differences in endoscopists’ skill, indicating that the tool can reliably differentiate between endoscopists based on video analysis. Conclusions Video-based assessment of ERCP skill appears to be feasible with a novel instrument that demonstrates favorable validity evidence. Future steps include determining whether the tool can discriminate between endoscopists of varying experience levels and predict important outcomes in clinical practice.

Background The aim of this study was to clarify the pathophysiology of functional dyspepsia (FD), a highly prevalent gastrointestinal syndrome, and its relationship with the better-understood syndrome of gastroparesis. Methods Adult patients with chronic upper gastrointestinal symptoms were followed up prospectively for 48 weeks in multi-center registry studies. Patients were classified as having gastroparesis if gastric emptying was delayed; if not, they were labeled as having FD if they met Rome III criteria. Study analysis was conducted using analysis of covariance and regression models. Results Of 944 patients enrolled during a 12-year period, 720 (76%) were in the gastroparesis group and 224 (24%) in the FD group. Baseline clinical characteristics and severity of upper gastrointestinal symptoms were highly similar. The 48-week clinical outcome was also similar but at this time 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD based on gastric-emptying results at this time point; conversely, 37% of patients with FD were reclassified as having gastroparesis. Change in either direction was not associated with any difference in symptom severity changes. Full-thickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD206+ macrophages in both groups compared with obese controls. Conclusions A year after initial classification, patients with FD and gastroparesis, as seen in tertiary referral centers at least, are not distinguishable based on clinical and pathologic features or based on assessment of gastric emptying. Gastric-emptying results are labile and do not reliably capture the pathophysiology of clinical symptoms in either condition. FD and gastroparesis are unified by characteristic pathologic features and should be considered as part of the same spectrum of truly "organic" gastric neuromuscular disorders. ClinicalTrials.gov Identifier NCT00398801, NCT01696747

OBJECTIVES: Complex food structures can act like barriers towards digestive enzymes and reduce nutrient bioavailability. Nutrients that escape digestion in the upper gut (mainly fibre), becomes available for bacterial fermentation in the distal gut and generates short chain fatty acids (SCFA) which stimulate the release of appetite suppressing hormones Glucagon like peptide 1 (GLP-1) and Peptide YY (PYY). Processing can alter food structures, leading to more digestible products, but reducing nutrients reaching the distal gut, fermentation and appetite suppression. This study aimed to investigate the impact of food structures on the level of carbohydrate reaching the distal ileum and its subsequent effect on SCFA production and appetite hormone release. METHODS: Healthy volunteers (n = 10, 18–65 years) attended three separate 4-day inpatient visits. A nasoenteric tube was inserted into their distal ileum. During each visit, participants had one of three dietary interventions: Low fibre, processed diet (LF); High fibre, unprocessed diet (HF); same as HF but domestically processed (HFP). On day 4, ileal, blood and breath hydrogen (BH) samples were collected at baseline and hourly following food intake for 8 h. Blood samples were analyzed for appetite hormones and SCFAs using radioimmunoassay and GC-MS. Ileal samples were analyzed for metabolic profiling using (1)H-NMR spectroscopy, partial least squares discriminant analysis with Monte-Carlo cross-validation and repeated-measures design. RESULTS: HFP but not HF had higher PYY levels than the LF (P = 0.004). BH and serum total SCFAs were higher in HF and HFP than LF indicating a higher bacterial fermentation (P = 0.021, 0.015 and P = 0.000, 0.003). HFP group had higher total SCFA than HF (P = 0.015). Distinct metabolic differences were identified in ileal samples from groups (e.g., time = 2 h, HF vs HFP R(2)Y: 0.99, Q(2)Y: 0.65). Ileal samples will be analysed for microbial profile (16 s rRNA, Illumina MiSeq), glucose and starch (spectroscopy) and SCFAs (GC-MS). CONCLUSIONS: Current data suggests a potential benefit of domestically processed food structures on appetite suppression as measured by postprandial PYY levels. This may be related to the different metabolic profiles generated in the ileum. Better understanding of this link can aid the design of diets that enhance appetite suppression and reduce food intake. FUNDING SOURCES: BBSRC.

We would like to extend our gratitude to the all the patients and the healthy volunteers who participated in the study, as well as the University of Granada, Biomedicine PhD program. This work was supported by Roche Spain, the PhD grant from the University of Granada (DdMP) (2014) and the PhD grant from the Spanish Government (ARM) (FPU) 2014, REF FPU14/05461., Disseminated disease is present in ≈50% of colorectal cancer patients upon diagnosis, being responsible for most of cancer deaths. Addition of biological drugs, as Bevacizumab, to chemotherapy, has increased progression free survival and overall survival of metastatic colorectal cancer (mCRC) patients. However, these benefits have been only reported in a small proportion of patients. To date, there are not biomarkers that could explain the heterogeneity of this disease and would help in treatment selection. Recent findings demonstrated that microRNAs (miRNAs) play an important role in cancer and they can be encapsulated with high stability into extracellular vesicles (EVs) that are released in biological fluids. EVs can act as cell-to-cell communicators, transferring genetic information, such as miRNAs. In this context, we aimed to investigate serum EV associated miRNAs (EV-miRNAs) as novel non-invasive biomarkers for the diagnosis and prognosis of Bevacizumab-treated mCRC patients. We observed that baseline miRNA-21 and 92a outperformed carcinoembryonic antigen levels in the diagnosis of our 44 mCRC patients, compared to 17 healthy volunteers. In addition, patients who died presented higher levels of miRNA-92a and 222 at 24 weeks. However, in the multivariate Cox analysis, higher levels of miRNA-222 at 24 weeks were associated with lower overall survival. Altogether, these data indicate that EV-miRNAs have a strong potential as liquid biopsy biomarkers for the identification and prognosis of mCRC., Roche Spain, University of Granada (DdMP), Spanish Government REF FPU14/05461

Simple Summary: Most solid tumors share mutations in TP53 that is thus considered one of the main cancer driver genes. Mutations in TP53 occur very early during tumor development, so their identification helps in diagnosing cancer. Furthermore, knowing in advance the TP53 mutation status might help guiding targeted treatments against this gene. However, this analysis is mainly performed in tissue samples, that is, solid biopsies, being an invasive technique. Contrarily, liquid biopsies, consisting of the analysis of blood samples, are non-invasive, can be performed repeatedly, helping in monitoring the patient evolution, and might be useful in early stages when the tumor is not yet detected by other technologies. Here, we review the main studies conducted on two types of liquid biopsies: circulating tumor cells and cell-free DNA.We discuss the main findings regarding TP53 mutation analysis, the clinical utility of this information and some controversies arising from the study of liquid biopsies compared to tissue samples, and we finish by suggesting future directions within this field. Abstract: Being minimally invasive and thus allowing repeated measures over time, liquid biopsies are taking over traditional solid biopsies in certain circumstances such as those for unreachable tumors, very early stages or treatment monitoring. However, regarding TP53 mutation status analysis, liquid biopsies have not yet substituted tissue samples, mainly due to the lack of concordance between the two types of biopsies. This needs to be examined in a study-dependent manner, taking into account the particular type of liquid biopsy analyzed, that is, circulating tumor cells (CTCs) or cell-free DNA (cfDNA), its involvement in the tumor biology and evolution and, finally, the technology used to analyze each biopsy type. Here, we review the main studies analyzing TP53 mutations in either CTCs or cfDNA in the three more prevalent solid tumors: breast, colon and lung cancers. We evaluate the correlation for mutation status between liquid biopsies and tumor tissue, suggesting possible sources of discrepancies, as well as evaluating the clinical utility of using liquid biopsies for the analysis of TP53 mutation status and the future actions that need to be undertaken to make liquid biopsy analysis a reality for the evaluation of TP53 mutations.

The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.

We created the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE (INSPPIRE 2) cohort to study the risk factors, natural history, and outcomes of pediatric acute recurrent pancreatitis and chronic pancreatitis (CP). Patient and physician questionnaires collect information on demographics, clinical history, family and social history, and disease outcomes. Health-related quality of life, depression, and anxiety are measured using validated questionnaires. Information entered on paper questionnaires is transferred into a database managed by Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer's Coordinating and Data Management Center. Biosamples are collected for DNA isolation and analysis of most common pancreatitis-associated genes.Twenty-two sites (18 in the United States, 2 in Canada, and 1 each in Israel and Australia) are participating in the INSPPIRE 2 study. These sites have enrolled 211 subjects into the INSPPIRE 2 database toward our goal to recruit more than 800 patients in 2 years. The INSPPIRE 2 cohort study is an extension of the INSPPIRE cohort study with a larger and more diverse patient population. Our goals have expanded to include evaluating risk factors for CP, its sequelae, and psychosocial factors associated with pediatric acute recurrent pancreatitis and CP.

PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and translational stuDies (PROCEED) is the first prospective, observational cohort study of chronic pancreatitis in the US. The primary goals of PROCEED are to define disease progression, test the predictive capability of candidate biomarkers, and develop a platform to conduct translational and mechanistic studies in chronic pancreatitis. Using objective and consensus-driven criteria, PROCEED will enroll adults at different stages of chronic pancreatitis - controls, Suspected chronic pancreatitis and Definite chronic pancreatitis. In addition to collecting detailed information using structured case report forms and protocol-mandated evaluations at baseline and during follow-up, PROCEED will establish a linked biorepository of blood, urine, saliva, stool, pancreatic fluid and pancreatic tissue. Enrollment for PROCEED began in June 2017. As of July 1, 2018, nine clinical centers of the Consortium to study Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC) are enrolling, and 350 subjects have completed baseline evaluation. In conclusion, PROCEED will provide the most accurate and reliable estimates to date on progression of chronic pancreatitis. The established cohort and biorepository will facilitate numerous analyses, leading to new strategies for diagnosis, methods to monitor disease progression, and treatment of chronic pancreatitis.

The use of circulating tumor cells (CTCs) as indicators of treatment response in metastatic colorectal cancer (mCRC) needs to be clarified. The objective of this study is to compare the Response Evaluation Criteria in Solid Tumors (RECIST) with the Cytologic Criteria Assessing Response (CyCAR), based on the presence and phenotypic characterization of CTCs, as indicators of FOLFOX–bevacizumab treatment response. We observed a decrease of CTCs (42.8 vs. 18.2%) and VEGFR positivity (69.7% vs. 41.7%) after treatment. According to RECIST, 6.45% of the patients did not show any clinical benefit, whereas 93.55% patients showed a favorable response at 12 weeks. According to CyCAR, 29% had a non-favorable response and 71% patients did not. No significant differences were found between the response assessment by RECIST and CyCAR at 12 or 24 weeks. However, in the multivariate analysis, RECIST at 12 weeks and CyCAR at 24 weeks were independent prognostic factors for OS (HR: 0.1, 95% CI 0.02–0.58 and HR: 0.35, 95% CI 0.12–0.99 respectively). CyCAR results were comparable to RECIST in evaluating the response in mCRC and can be used as an alternative when the limitation of RECIST requires additional response analysis techniques., This work was supported by Roche Spain and a Ph.D. grant from the University of Granada.

Background During 2020, a total of 193,318 cases of COVID-19 were reported in Dallas, with daily average case rates exceeding 50 per 100,000 for over 7 weeks. An adaptable survey functionality within a newly implemented COVID-19 surveillance system provided an opportunity to assess case knowledge and attitudes about isolation and contact tracing efforts. Methods COVID-19 illnesses were classified using the 2020 CSTE case definitions. Cases were interviewed and records reviewed for exposures and illness characteristics. Supplemental questionnaires assessing knowledge of public health recommendations were given to a convenience sample of 987 cases during the month of December 2020. Fishers exact and chi-square analyses were performed using SAS 9.4. Results Of the 987 respondents, 99% reported beginning isolation on or before receipt of test results, and 1% were not in isolation at the time of public health interview. Of cases reporting contacts, 92% had advised household members to quarantine prior to interview, and 91% did not want public health to call their household. Of cases reporting non-household close contacts, 75% had advised these contacts to quarantine prior to interview, and 91.3% did not want the health department to call these persons. Cases ≥ 65 years were less likely to have notified their own close contacts (OR: 0.2; 95% CI=0.1-0.8) of their test results, and more likely to prefer the health department to notify their household contacts of their positive result (OR: 4.1; 95% CI=1.3-12.5). Compared with White cases, Hispanic cases were less likely to be aware that their test was positive at the time of interview (OR: 0.3; 95% CI=0.1-0.7). Non-White cases were less likely to be aware of resources for food, rent and utility assistance prior to interview (OR: 0.25; 95% CI=0.1-0.7). All respondents perceived the public health interview to have been of some value to them, most often to answer their questions about retesting (51%) and duration of isolation (48%). Conclusion The aversion of a majority of COVID-19 cases for health department notification of their contacts is a significant deterrent to name-based contact tracing approaches. Acknowledgement of this limitation could better focus existing resources on the delivery of expedited notifications and information to contacts by proxy. Disclosures All Authors: No reported disclosures

Background From March 2020 through May 2021, Dallas County reported a total of 304,056 cases of COVID-19, including 4,073 deaths. During the month of December 2020, a post-holiday surge of cases led to peak daily average case rates of over 50 cases per 100,000. COVID-19 cases and deaths have since declined substantially following the rollout of COVID-19 vaccine delivery. As of June 8, 2021, about 1,831,588 Dallas County residents have received at least one COVID-19 vaccine dose and 910,067 are fully vaccinated. Recent county integration of immunization and case databases enabled identification and analysis of COVID-19 breakthrough infections. Methods A COVID-19 breakthrough infection was defined as a positive test (PCR or antigen) collected from an individual ≥ 14 days after receiving the full series of an FDA-authorized COVID-19 vaccine. Nationally, 10,262 vaccine breakthrough infections had been reported from 46 US states and territories, through April 2021. Vaccine breakthrough cases were reviewed and medical records abstracted to collect demographic information, clinical characteristics, and medical conditions. Data analysis was performed using R, version 4.0.2 (2020). Results Of the 700 vaccine breakthrough cases reported in Dallas County residents as of June 8, 2021, 304 (43%) were male and 396 (57%) female, with an average age of 53 years. The majority of the vaccine breakthrough cases were White (42%); 25% were Hispanic/Latino; and 20% were Black. Almost all breakthrough cases were confirmed with PCR testing, with 451 (64%) cases receiving the Pfizer vaccine. Of breakthrough cases, 49% were symptomatic; 52% (358) had underlying conditions including: tobacco use, obesity, or immunocompromised state; 68 (10%) were hospitalized; and 11 (1.6%) died. Whole genome sequencing was performed on 51 cases, with 14 (27.5%) variants identified, including: eight B.1.1.7, two B.1.429 and one P.1 variants. Conclusion Despite the high levels of vaccine efficacy documented in US vaccine trials, COVID-19 breakthrough infections, though currently uncommon, do occur and are important to investigate. Ongoing close public health surveillance of variants is needed to discern changes in patterns of vaccine efficacy and characteristics of populations at greatest risk of severe disease from COVID-19. Disclosures All Authors: No reported disclosures

Drug-induced liver injury (DILI) is a growing problem. Diagnostic methods to differentiate DILI caused by an adaptive immune response from liver injury of other causes or to identify the responsible drug in patients receiving multiple drugs, herbals and/or dietary supplements (polypharmacy) have not yet been established. The lymphocyte transformation test (LTT) has been proposed as a diagnostic method to determine if a subject with an apparent hypersensitivity reaction has become sensitized to a specific drug. In this test, peripheral blood mononuclear cells (PBMC) collected from a subject are incubated with drug(s) suspected of causing the reaction. Cell proliferation, measured by the incorporation of [3H]-thymidine into new DNA, is considered evidence of a drug-specific immune response. The objectives of the current studies were to: (1) develop and optimize a modified version of the LTT (mLTT) and (2) investigate the feasibility of using the mLTT for diagnosing DILI associated with an adaptive immune response and identifying the responsible drug. PBMC collected from donors with a history of drug hypersensitivity reactions to specific drugs (manifested as skin rash) were used as positive controls for assay optimization. Following optimization, samples collected from 24 subjects enrolled in the U.S. Drug-Induced Liver Injury Network (DILIN) were tested in the mLTT. Using cytokine and granzyme B production as the primary endpoints to demonstrate lymphocyte sensitization to a specific drug, most samples from the DILIN subjects failed to respond. However, robust positive mLTT responses were observed for two of four samples from three DILIN subjects with hepatitis due to isoniazid (INH). We conclude that the mLTT, as performed here on frozen and thawed PBMC, is not a reliable test for diagnosing DILI caused by all drugs, but that it may be useful for confirming the role of the adaptive immune response in DILI ascribed to INH.

Contains fulltext : 215317.pdf (Publisher’s version ) (Closed access) OBJECTIVES: In patients with acute recurrent pancreatitis (ARP), pancreas divisum, and no other etiologic factors, endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy (miES) is often performed to enlarge the minor papillary orifice, based on limited data. The aims of this study are to describe the rationale and methodology of a sham-controlled clinical trial designed to test the hypothesis that miES reduces the risk of acute pancreatitis. METHODS: The SpHincterotomy for Acute Recurrent Pancreatitis (SHARP) trial is a multicenter, international, sham-controlled, randomized trial comparing endoscopic ultrasound + ERCP with miES versus endoscopic ultrasound + sham for the management of ARP. A total of 234 consented patients having 2 or more discrete episodes of acute pancreatitis, pancreas divisum confirmed by magnetic resonance cholangiopancreatography, and no other clear etiology for acute pancreatitis will be randomized. Both cohorts will be followed for a minimum of 6 months and a maximum of 48 months. RESULTS: The trial is powered to detect a 33% risk reduction of acute pancreatitis frequency. CONCLUSIONS: The SHARP trial will determine whether ERCP with miES benefits patients with idiopathic ARP and pancreas divisum. Trial planning has informed the importance of blinded outcome assessors and long-term follow-up.

Cyclic phenones are chemicals of interest to the USEPA and international organizations due to their potential for endocrine disruption to aquatic and terrestrial species. The metabolic conversion of cyclic phenones by liver hepatocytes and the structure of main metabolites yielded have not been assessed in fish species. As part of a larger project, in this study we investigated the structure of metabolites produced in vitro by rainbow trout (rt) liver slices after exposure to the model cyclic phenones benzophenone (DPK), cyclobutyl phenyl ketone (CBP) and cyclohexyl phenyl ketone (CPK). While only one distinct metabolite was detected for DPK and CBP (benzhydrol and CBPOH, respectively), CPK yielded nine positional isomers (M1-M9) as products. In absence of standards, improved inference of CPK metabolites tentative structures was achieved by combining GC-MS with and without derivatization, LC with tandem MS, LC with high resolution time of flight (TOF) MS and LC fractionation data with CPK phase II conjugative metabolism information. Data supported that CPK is metabolized by phase I oxidation of the cyclohexyl ring and not the phenyl group as predicted by metabolism simulators. CPK metabolites M1 and M2 (MW 186), were proposed to be cyclohexenyl-derivatives. Also, M6-M9 were proposed to be hydroxylated metabolites (MW 204), with the potential for undergoing phase II conjugative metabolism to glucuronides and sulfates. Finally, M3, M4 and M5 were proposed as cyclohexanone-derivatives of CPK (MW 202), resulting from the limited redox-interconversion of their hydroxylated pairs M8, M6 and M7, respectively. Assessment of metabolite role in biological responses associated with endocrine disruption will advance the development of methods for species extrapolation and the understanding of differential sensitivity of species to chemical exposure.

Background Restorative proctocolectomy (RPC) is considered the preferred surgical choice for patient with ulcerative colitis (UC) who have failed medical therapy and in some patients with familial adenomatous polyposis (FAP). It has been shown through metabolic profiling of urine that CD patients have higher levels of formate and lower levels of hippurate and 4-cresol sulfate when compared to healthy controls. To date, extensive metabolic profiling in RPC has yet to be studied. This study aimed to determine compounds found in urine that are associated with treatment response in patients that have been treated for pouchitis Methods Patients with pouchitis were recruited from a single centre. Pouchitis was defined using the pouch disease activity index (PDAI) and pouchitis was considered when the score was ³7. Response to antibiotics was defined as either a 2 points reduction in PDAI. Mid-stream morning urine samples were collected. Samples we stored at -80°C until analysis. 1H-NMR profile was recorded using the Bruker® Avance III 600 MHz spectrometer, with a Samplejet 96 well autosampler. The full resolution 1H NMR spectra were imported into the SIMCA-P software package, and multivariate data analyses were carried out. Metabolite assignment was performed by comparing chemical shifts, Jres coupling, and peaks multiplicity with information in databases (such as Human Metabolome DataBase, HMDB). Results There were 21 patients. The median age of the cohort was 50 years (range 28–79). A total of 11 patients were on antibiotics and 10 patients were off antibiotics. Nine were responders. On multivariate modelling there were significant differences found between responders and non-responders (CV-ANOVA p=0.05) (figure 1). Significant spectral differences that corresponded to the multivariate model correlated with Formate (8.84 PPM) Trigonelline (4.45PPM) and Glycine 3.57(PPM) all of which were higher in responders. Conclusions Trigonelline, formate and glycine may help differentiate patients with pouchitis who will respond to treatments versus those that do not. It is currently unclear as to the mechanism as to why these metabolites are reduced in non-responders and further work is required to understand this and validate our findings.

Background Restorative proctocolectomy is a surgical option in patients with ulcerative colitis who become refractory to medical therapy. Short chain fatty acids (SCFA) are organic fatty acids with 1–6 carbons which arise from bacterial metabolism from carbohydrates entering the colon. Various studies have implicated SCFA in both the development of IBD and flares of IBD. Furthermore, it has been shown that SCFA concentrations are significantly lower in faecal samples from patients with pouchitis when compared with healthy controls. Our study aimed to assess longitudinal changes in SCFA that occur in a pouch to determine if they can predict or are associated with the development of pouchitis. To date no study has analysed short chain fatty acids in mucosal biopsy tissue from these patients. Methods Patients who underwent restorative proctocolectomy at a single centre underwent pouchoscopy at the time of restoration of continuity and then every 6 months for a year. Biopsies from the pouch were retrieved from the pouch body. Pouchitis was defined using the pouch disease activity index. The development of pouchitis was assessed at months 6 and 12 months. Biopsies samples were snap frozen at time of biopsy and stored in -80°C. Samples were thawed and weighed. Sterile water and Methyl tertiary-butyl ether with internal standard (IS) were added with a ratio of 20 mg of sample:50µL of H20:250µL of MTBE and IS with a further 4µL of hydrochloric acid added to each sample. 30µL of the polar phase was then placed into silanized Eppendorf tubes. 150µL of derivatiser was added to each sample and the cap of the tube applied immediately. These were then incubated for 45 minutes at 60°C in an oven. 70µL from the silanised vial was placed into vial inserts and analysed in the gas chromatography mass spectrometry machine. (GC-MS). SCFA were measured using an Agilent 7000C Triple Quadrupole GC/MS-MS System according to a previously published method. Simca was used for multivariate analysis and T-tests were used for univariate analysis. Results There were 56 biopsy samples. There were 22 patients (17 males); 16 UC and 6 FAP patients with longitudinal follow up. The median age of the cohort was 40 years (range 20–60 years). Of the UC patients four developed pouchitis within one year. When comparing UC patients at the time of closure of ileostomy, there were there were significant decreases in caproic acid (4674µM vs 12217µM p Conclusion The study has suggested that a decrease in SCFA found in the mucosal tissue at time of closure of ileostomy may predict onset of pouchitis within a year. This study is the first to demonstrate that SCFA can be analysed from biopsies. Future studies need to determine factors that may contribute to tissue SCFA levels which may help develop a potential therapeutic target to optimise and potentially reduce the incidence of pouchitis.

Background Restorative proctocolectomy is a surgical option in patients with ulcerative colitis who become refractory to medical therapy. Various studies have implicated SCFA in both the development of IBD and flares of IBD. Furthermore, it has been shown that SCFA concentrations are significantly lower in faecal samples from patients with pouchitis when compared with healthy controls. Our study aimed to assess longitudinal changes in SCFA that occur in a pouch to determine if they can predict or are associated with the development of pouchitis. To date no study has analysed short chain fatty acids in mucosal biopsy tissue from these patients. Methods Patients who underwent restorative proctocolectomy at a single centre underwent pouchoscopy at the time of restoration of continuity and then every 6 months for a year. Biopsies were retrieved from the pouch body. Pouchitis was defined using the pouch disease activity index. The development of pouchitis was assessed at 6 and 12 months.SCFA were measured using an Agilent 7000C Triple Quadrupole GC/MS-MS System. Simca was used for multivariate analysis and T-tests were used for univariate analysis. Results There were 56 biopsy samples. There were 22 patients (17 males); 16 UC and 6 FAP patients. Median age of the cohort was 40 years (range 20–60 years). Of the UC patients four developed pouchitis within one year. Comparing UC patients at the time of closure of ileostomy, there were significant decreases in caproic acid (4674uM vs 12217uM p Conclusions A decrease in SCFA found in the mucosal tissue at time of closure of ileostomy may predict onset of pouchitis within a year. This study is the first to demonstrate that SCFA can be analysed from biopsies. Future studies need to determine factors that may contribute to tissue SCFA levels which may help reduce the incidence of pouchitis.

Background Bodybuilding supplements can cause a profound cholestatic syndrome. Aim To describe the drug-Induced liver injury network's experience with liver injury due to bodybuilding supplements. Methods Liver injury pattern, severity and outcomes, potential genetic associations, and exposure to anabolic steroids by product analysis were analysed in prospectively enrolled subjects with bodybuilding supplement-induced liver injury with causality scores of probable or higher. Results Forty-four males (mean age 33 years) developed liver injury with a median latency of 73 days. Forty-one per cent presented with hepatocellular pattern of liver injury as defined by the R > 5 ([Fold elevation of ALT] ÷ [Fold elevation of Alk Phos] (mean, range = 6.4, 0.5-31.4, n = 42) despite all presenting with clinical features of cholestatic liver injury (100% with jaundice and 84% with pruritus). Liver biopsy (59% of subjects) demonstrated a mild hepatitis and profound cholestasis in most without bile duct injury, loss or fibrosis. Seventy-one per cent were hospitalised, and none died or required liver transplantation. In some, chemical analysis revealed anabolic steroid controlled substances not listed on the label. No enrichment of genetic variants associated with cholestatic syndromes was found, although mutations in ABCB11 (present in up to 20%) were significantly different than in ethnically matched controls. Conclusions Patients with bodybuilding supplements liver injury uniformly presented with cholestatic injury, which slowly resolved. The ingested products often contained anabolic steroids not identified on the label, and no enrichment in genetic variants was found, indicating a need for additional studies.

1. Cyclic phenones are chemicals of interest to the USEPA and international community due to their potential for endocrine disrupting activity. 2. Prior to this report, there was very limited information addressing metabolism of cyclic phenones by fish species and the potential for Estrogen Receptor (ER) binding and Vitellogenin (Vtg) gene activation by their metabolites. 3. The main objectives of the current research were to characterize rainbow trout (rt) liver slice-mediated in vitro metabolism of model parent cyclic phenones exhibiting disparity between ER binding and ER-mediated Vtg gene induction, and to assess the metabolic competency of fish liver in vitro tests to help determine the chemical form (parent and/or metabolite) associated with the observed biological response. 4. Biochemical strategies and high-throughput analytical methods (GC-MS, HPLC and LC-MS/MS) were applied to investigate the in vitro biotransformation of cyclobutyl phenyl ketone (CBP), benzophenone (DPK), cyclohexyl phenyl ketone (CPK) mostly in the absence of standards for metabolite characterization. 5. It was concluded that estrogenic effects of the studied cyclic phenones are mediated by the parent chemical structure for DPK, but by active metabolites for CPK. A definitive interpretation was not possible for CBP and CBPOH (alcohol), although a contribution of both structures to gene induction is suspected.

1. Cyclic phenones are chemicals of interest to the USEPA due to their potential for endocrine disruption to aquatic and terrestrial species. 2. Prior to this report, there was very limited information addressing metabolism of cyclic phenones by fish species and the potential for estrogen receptor (ER) binding and vitellogenin (Vtg) gene activation by their metabolites. 3. The main objectives of the current research were to characterize rainbow trout (rt) liver slice-mediated in vitro metabolism of model parent cyclic phenones exhibiting disparity between ER binding and ER-mediated Vtg gene induction, and to assess the metabolic competency of fish liver in vitro tests to help determine the chemical form (parent and/or metabolite) associated with the observed biological response. 4. GC-MS, HPLC and LC-MS/MS technologies were applied to investigate the in vitro biotransformation of cyclobutyl phenyl ketone (CBP), benzophenone (DPK), cyclohexyl phenyl ketone (CPK) mostly in the absence of standards for metabolite characterization. 5. It was concluded that estrogenic effects of the studied cyclic phenones are mediated by the parent chemical structure for DPK, but by active metabolites for CPK. A definitive interpretation was not possible for CBP and CBPOH (alcohol), although a contribution of both structures to gene induction is suspected.

e21144 Background: Immune-checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of lung cancer patients. However, its low treatment efficacy is still an issue and the current standard of care tissue PD-L1 presents high variability. Liquid biopsy is a promising tool in the discovery of biomarkers in body fluids. In particular, extracellular vesicles (EVs) can present PD-L1 in their membranes, playing a role in the inhibition of the anti-tumor immune response. Likewise, TGF-β is crucial in the immune response found in the circulation and into EVs. On the other hand, radiomics analysis of conventional imaging provides information about tumor heterogeneity and immune response. Hence, we aimed to evaluate the predictive role of circulating biomarkers in lung cancer patients undergoing ICIs and the additional value of radiomics data. Methods: This is a retrospective analysis of 30 advanced/metastatic non-small lung cancer patients treated with ICIs. Plasma samples were collected at baseline and at 8 weeks during treatment, matching the first response evaluation. Patients with complete, partial response, or stable disease were classified as responders and those with progressive disease as non-responders following RECIST v1.1. EVs were isolated from plasma by ultracentrifugation and PD-L1 expression was revealed by immunoblot. Circulating and EV levels of TGF-β were analyzed by ELISA. Additionally, 400 radiomics features from target and non-target lesions were analyzed to evaluate response in 24 patients according to RECIST v1.1 and irRECIST. Robustness of predictive models was validated by ridge penalty and leave-one-out cross-validation. Results: The analysis of the dynamics of EV PD-L1 during treatment identified increased levels in non-responders in comparison to responders ( p= 0.012), while tissue PD-L1 levels were not associated to the response ( p= 0.585). The predictive model for EV PD-L1 reported a high accuracy with an area under the curve (AUC) = 77%, 91.7% sensitivity, and 61.1% specificity. The combination with radiomics, improved the accuracy and reported an AUC = 83%, 82% sensitivity, and 77% specificity. Additionally, the analysis of the association of the circulating biomarkers with the outcome revealed that increasing dynamics of EV PD-L1 and high baseline EV TGF-β were associated with shorter progression-free survival and overall survival, outperforming the circulating levels of TGF-β. Conclusions: This pilot study demonstrated that EV PD-L1 could serve as better predictive factor than tissue PD-L1 for the stratification of lung cancer patients undergoing ICIs and that it could be complemented with radiomics. Moreover, EV levels of PD-L1 and TGF-β have potential for the stratification and prognosis of patients treated with ICIs and their novel combinations with TGF-β blockade.

Background Providing adjuvant chemotherapy in locally advanced rectal cancer after neoadjuvant chemoradiation is currently a matter of debate. Recommendations from clinical guidelines range from offering no treatment to oxaliplatin-based combinations. We present a risk-adapted approach based on the response to initial chemoradiation as the strongest prognostic factor for disease-free survival (DFS). Patients and Methods One hundred one patients were treated at a single institution with preoperative long-course radiotherapy plus concurrent fluoropyrimidines. Patients with disease downstaged to pT0-2N0 received adjuvant fluoropyrimidines alone, while the remaining received an oxaliplatin-based combination. The primary study end point was 5-year DFS. Results Overall, the disease of 54 patients was downstaged to pT0-2N0 (53.5%), while that of 47 patients was staged as pT3-4 or N+ (46.5%) after surgery. In the intention-to-treat analysis, 5-year DFS for patients in the good-prognosis group (downstaging to pT0-2 N0) and for those with poor prognosis (pT3-4 or N+) were 79.4% and 66.3%, respectively (hazard ratio, 0.489; P = .043). Downstaging and pN+ were independent prognostic factors for DFS. Conclusion A risk-adapted adjuvant therapy strategy based on pathologic stage after neoadjuvant chemoradiation is feasible and achieves high rates of 5-year DFS. Patients with good prognostic factors can be treated with adjuvant fluoropyrimidines alone, thus permitting the avoidance of oxaliplatin-derived toxicities.

It is generally accepted that preadolescents have a limited capacity to develop muscle hypertrophy in response to exercise compared with older populations; however, studies are scarce and conflicting. The main aim of the present study was to assess if playing tennis is associated with the hypertrophy of dominant pectoralis muscles (PM) in professional (PRO) and in prepubescent tennis players (PRE). A secondary aim was to assess if the degree of asymmetry of PM is greater in PRO than PRE. The volume of PM of both sides was determined using magnetic resonance imaging in 8 male PRO (21.9 years), 6 male PRE (11 years, Tanner 1-2) and 12 male non-active controls (6 adults: 23.5 years; and 6 prepubescents: 10.7 years, Tanner 1-2). PRO and PRE had 15 and 30% greater volume, respectively, in the dominant than in the contralateral PM (P