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ACE2 expression; COVID-19; Cancer Expresión ACE2; COVID-19; Cáncer Expressió ACE2; COVID-19; Càncer Background: SARS-CoV-2 (COVID-19) elicits a T-cell antigen-mediated immune response of variable efficacy. To understand this variability, we explored transcriptomic expression of angiotensin-converting enzyme 2 (ACE2, the SARS-CoV-2 receptor) and of immunoregulatory genes in normal lung tissues from patients with non-small cell lung cancer (NSCLC). Methods: This study used the transcriptomic and the clinical data for NSCLC patients generated during the CHEMORES study [n = 123 primary resected (early-stage) NSCLC] and the WINTHER clinical trial (n = 32 metastatic NSCLC). Results: We identified patient subgroups with high and low ACE2 expression (p = 1.55 × 10−19) in normal lung tissue, presumed to be at higher and lower risk, respectively, of developing severe COVID-19 should they become infected. ACE2 transcript expression in normal lung tissues (but not in tumor tissue) of patients with NSCLC was higher in individuals with more advanced disease. High-ACE2 expressors had significantly higher levels of CD8+ cytotoxic T lymphocytes and natural killer cells but with presumably impaired function by high Thymocyte Selection-Associated High Mobility Group Box Protein TOX (TOX) expression. In addition, immune checkpoint-related molecules – PD-L1, CTLA-4, PD-1, and TIGIT – are more highly expressed in normal (but not tumor) lung tissues; these molecules might dampen immune response to either viruses or cancer. Importantly, however, high inducible T-cell co-stimulator (ICOS), which can amplify immune and cytokine reactivity, significantly correlated with high ACE2 expression in univariable analysis of normal lung (but not lung tumor tissue). Conclusions: We report a normal lung immune-tolerant state that may explain a potential comorbidity risk between two diseases – NSCLC and susceptibility to COVID-19 pneumonia. Further, a NSCLC patient subgroup has normal lung tissue expressing high ACE2 and high ICOS transcripts, the latter potentially promoting a hyperimmune response, and possibly leading to severe COVID-19 pulmonary compromise. FundingThe authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The research leading to these results on the CHEMORES study data, an initiative from the Chemotherapy resistance consortium, has received funding from the European Union Sixth Framework (FP6) Integrated Project. The research on the WINTHER trial data leading to these results has received funding from the European Union Seventh Framework Program (FP7) (WINTHER: FP7/2007-2013 under grant agreement n°306125). WINTHER, an initiative from the WIN Consortium, was funded in part by ARC Foundation for cancer research (France), Pfizer Oncology, Lilly France SAS, and Novartis Pharmaceuticals Corporation. Funded in part by The FERO/J.P. Morgan Private Bank Clinical Oncology Research Grant, National Cancer Institute grant P30 P30-CA023100 (RK), Israeli Science Foundation grant 1188/16 (ER), Instituto Salud Carlos III – Programa Rio Hortega Contract grant CM15/00255 (EF) and Canadian Institutes for Health Research (grant MOP-142281, GB) and the Canadian Cancer Society (grant 703811, GB).

Abdominal pain is a cardinal sign of functional bowel disorders (FBD), in favor of irritable bowel syndrome (IBS). However, the determinants of abdominal pain severity (APS) are unknown. The present study aimed to search the relationships between APS and demographic, psychological, and clinical parameters in tertiary care FBD outpatients. In this retrospective study, we included 2043 new outpatients with FBD or functional abdominal pain. They fulfilled the Rome III questionnaire, psychological evaluation, and four 10-points Likert scale for the perceived severity of constipation, diarrhea, bloating, and abdominal pain. Linear regression was performed for each phenotype to model the severity of abdominal pain with demographic, psychological parameters, and symptoms severity. APS was positively associated with bloating severity in all phenotypes, but APS was also associated with other variables according to gender and phenotype. APS was negatively associated with age and positively with depression, constipation severity, and diarrhea severity in female patients. In male patients, APS was associated with state anxiety, constipation severity, and diarrhea severity. APS severity was associated with bloating severity and transit severity in IBS patients, while in non-IBS patients, APS was only associated with bloating severity. Perceived abdominal pain severity is always associated with perceived bloating severity in FBD and FAP patients.

BACKGROUND/OBJECTIVES Suicidal ideation (SI), a symptom of depression, is known to be associated with irritable bowel syndrome (IBS) but is not known to be associated with other functional gastrointestinal disorders (FGIDs). However, the source of this association is discussed. It could be related to a possible abnormal biochemical pathway implicating neurotransmitters common to both disorders like serotonin or pain and an ill-being associated with a chronic disorder of unknown etiology. The present study aims to search for the FGIDs associated with suicidal ideation. DESIGN Observational study. METHODS A total of 1469 patients with FGIDs (71% of women) were included in the present study. They filled the Rome III questionnaire, Beck depression inventory, and state and trait anxiety questionnaires. Data were analyzed using analysis of variance with Bonferroni correction and logistic regression analysis. RESULTS Suicidal ideation was reported by 15% of patients, associated with increased scales of depression (P

Background/aims Self-reported lactose intolerance (LI) is frequent in patients with functional bowel disorders (FBD) that could be interpreted as irritable bowel syndrome (IBS). The present study aims to characterize the responses of patients with FBD, without small intestinal bacterial overgrowth (SIBO), and LI, in terms of lactose malabsorption (LM) and lactose sensitivity (LS) according to psychological and clinical features. Methods One hundred and fifty-eight consecutive FBD outpatients with LI, and no SIBO, were classified according to the Rome III questionnaire and filled Beck Depression Inventory, and State and Trait Anxiety questionnaires. They underwent a lactose tolerance test in which glycemia during 60 minutes and digestive symptoms for 3 hours were recorded. Results Abnormal lactose tolerance tests were found in 110 patients (70%), 44 (28%) with LM, 96 (61%) with LS, and 30 (19%) having both LM and LS. LM patients had a higher frequency of functional diarrhea (P = 0.040) and a lower frequency of dysphagia (P = 0.031). LS patients had a higher depression score (P = 0.007), higher frequency of globus (P = 0.042), irritable bowel syndrome (IBS) (P = 0.027) and mixed IBS (P = 0.049), and lower frequency of abdominal pain (P = 0.040). LS was significantly associated with a higher depression score (P = 0.002), and a higher frequency of globus (P = 0.046). Conclusions Thirty percent of LI patients have normal lactose absorption and normal LS. In the other 70% of patients, LI could be associated with LM and/or LS.

Although idiopathic fecal incontinence (FI) patients have some psychological characteristics, the personality of FI patients was not described. The present study aims to describe the clinical and personality characteristics of FI patients. This retrospective observational study included 996 outpatients, 72 with fecal incontinence. They filled out the Rome III diagnostic questionnaire, the personality inventory MMPI-2, the questionnaires for urological and sexual disorders, and Likert scales for bowel disorders perceived symptom severity. The main outcome measures were the presence in FI patients of functional gastrointestinal disorders, the self-reported symptom severity, and the personality profile. Patients were mainly females (72%). FI patients were characterized by higher age (P = 0.015), and by a higher prevalence of functional diarrhea (P = 0.001), urological (P = 0.001), and sexual disorders (P = 0.005). These patients also report higher diarrhea severity (P < 0.001) and lower abdominal pain severity (P = 0.009). The personality of FI patients is distinguished by a higher score for psychopathic deviate (P = 0.006), social responsibility (P = 0.003), Mac Andrew revised scale (P = 0.005), and antisocial practice (P = 0.007), and a lower score for type A behavior (P = 0.005). FI patients are characterized not only by older age, and a high prevalence of diarrhea but also by a specific personality profile characterized by an unfavorable comparison with others.

Background/aims The aim of our study is to evaluate the association between meals and perceived gastrointestinal symptoms in real life in a French cohort of irritable bowel syndrome (IBS) patients. Methods This prospective cross-sectional observational study included patients from the French association (association des patients souffrant du syndrome de l'intestin irritable [APSSII]) of IBS. Data were collected on demographics, IBS subtype, dietary food, and meal-induced gastrointestinal symptoms from patient filled self-questionnaires or questionnaires. Results Eighty-four patients with IBS were included; 82.3% female with a mean age of 46.9 ± 15.7 years. Each transit pattern subtype represented one-third of the population. Forty-five percent of patients had severe IBS according to IBS-Severity Scoring System; mean IBS Quality of Life score was 53.9 ± 18.3. Patients believed that food could trigger or exacerbate gastrointestinal symptoms in 73.3% and 93.4%, respectively. Eighty-nine percent had already tried diets, mostly lactose free diet and low fermentable, oligosaccharides, disaccharides, monosaccharides, and polyols diet in 61.3% and 53.6% of cases. Thirty-nine percent of meals induced gastrointestinal symptoms. Meal-induced gastrointestinal symptoms were associated with severity and subtype but not with quality of life. Conclusions This study has confirmed the important link between gastrointestinal symptoms and food. Gastrointestinal symptoms induced by meals are frequent and associated with severity and IBS-diarrhea subtype. Our study also underlines patients' interest in food and diet. More knowledge is needed on food that triggers IBS symptoms but also on diet conditions in order to improve this condition.

Summary Background While all resources have been mobilized to fight COVID-19, this study aimed to analyze the consequences of lockdown and pandemic stress in participants with and without Irritable Bowel Syndrome (IBS). Methodology An online survey was proposed to people with or without IBS during the exponential phase of the pandemic in France. The questionnaire included questions about socio-demographic data, conditions of confinement , activities carried out, IBS characteristics, measurement of stress level, consequences on sleep, fatigue, anxiety and depression, and quality of life (both perceived non-specific and specific for IBS). Results/Discussion From March 31 to April 15, 2020, 304 participants, 232 with IBS and 72 without were included in the survey (mean age: 46.8 ± 16.8 years, female gender: 75.3%). Age, level of education, financial resources, living space per person and activities performed during confinement were identical in both groups. Stress linked to fear of COVID-19, lockdown and financial worries was at the same level in both groups, but the psychological consequences and deterioration of quality of life (QOL) were both higher in IBS participants. In a univariate analysis , teleworking, solitary confinement, and low household resources had a variable impact on the scores of depression, anxiety, fatigue and non-specific perceived QOL, but in a multivariate analysis , the only factor explaining a deterioration of non-specific QOL was the fact of suffering from IBS. Conclusion/Perspectives Stress linked to the COVID-19 pandemic and confinement is high and equivalent in both IBS and non-IBS participants, with higher psychological and QOL consequences in IBS patients who have altered coping capacities.

Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. The WINTHER trial ( NCT01856296 ) navigated patients to therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The clinical management committee (investigators from five countries) recommended therapies, prioritizing genomic matches; physicians determined the therapy given. Matching scores were calculated post-hoc for each patient, according to drugs received: for DNA, the number of alterations matched divided by the total alteration number; for RNA, expression-matched drug ranks. Overall, 303 patients consented; 107 (35%; 69 in arm A and 38 in arm B) were evaluable for therapy. The median number of previous therapies was three. The most common diagnoses were colon, head and neck, and lung cancers. Among the 107 patients, the rate of stable disease ≥6 months and partial or complete response was 26.2% (arm A: 23.2%; arm B: 31.6% (P = 0.37)). The patient proportion with WINTHER versus previous therapy progression-free survival ratio of >1.5 was 22.4%, which did not meet the pre-specified primary end point. Fewer previous therapies, better performance status and higher matching score correlated with longer progression-free survival (all P

Background: The prognosis of patients with non-small cell lung cancer (NSCLC) is traditionally determined by anatomic staging using the Tumor, Node, Metastasis (TNM) staging system. TNM staging neglects the biological features of the tumor that may be important in determining patient outcome and guiding therapeutic interventions. Identifying NSCLC patients at increased risk of recurrence after curative-intent surgery remains an important unmet need as adjuvant therapies are available that may reduce the risk of recurrence and improve patient survival. Methods: Digital Display Precision Predictor (DDPP), based on differential RNA expression in tumor versus normal tissue, was used to interrogate gene sets to determine their association with disease-free survival (DFS) in patients with non-small cell lung cancer (NSCLC) who underwent curative-intent surgery. Findings: Low versus high DDPP score was significantly associated with shorter DFS (highest recurrence risk): HR=1.88, 95% CI [1.2-2.9] (p=0.006) in all patients (n=120) and in patients with TNM stages 1-2 (p= 0.00051) (n=83). For patients with stages 1-2 and low DDPP (n=29), adjuvant chemotherapy was associated with improved DFS (p= 0.0041). High co-overexpression of CTLA-4, PD-L1 and ICOS in normal lung (28 of 120 patients), hypothesized to reflect the host immune status, was also significantly associated with decreased DFS (p= 0.0013) suggesting an immune tolerance to tumor neoantigens in some patients. Patients with DDPP low and immunotolerant normal tissue had the shortest DFS (p=2.12E-11). Interpretation: We identified stage 1-2 NSCLC patients with high risk of recurrence who benefitted from adjuvant chemotherapy. Furthermore, identified a subset of NSCLC patients who may have poor post-surgery outcome related to an immunotolerant normal tissue profile that might be amenable to modulation by specific checkpoint blockade immunotherapies. Funding: European Union Frame Pprogram 6-funded project (Chemores FP6 Health, Grant 37 665). Declaration of Interest: Dr. Vladimir Lazar, Catherine Bresson, are full time employees of Worldwide Innovative Network (WIN) Association - WIN Consortium. Worldwide Innovative Network (WIN) Association - WIN Consortium is the owner of the patent family entitled Digital Display. The inventors are Dr. Vladimir Lazar, and Shai Magidi. Dr. Jean-Francois Martini, is a full-time employee and stockholder of Pfizer Inc. Dr. Susan Galbraith is a full-time employee and stockholder of AstraZeneca. Dr. Benjamin Solomon received honorarium for Advisory Board from AstraZeneca and Bayer. Shai Magidi receives consultancy from Worldwide Innovative Network (WIN) Association. Dr. Amir Onn receives consulting fees from Roche Israel, MSD Israel, Boehringer Ingelheim 552 and AstraZeneca. Dr. Enriqueta Felip receives advisory board and/or speaker’s bureau fee from Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffman-LaRoche, Glaxi Smith Kline, Janssen, Medical Trends, Medscape, Merck Sharp & Dohme, Merck Serono, Peptomyc, Peervoice, Pfizer, Puma, Regeneron, Sanofi, Springer, Syneos Health, Takeda, Touch Medical; on the board of Grifols, Independent member. Receives research funding from Fundacion Merck Salud, Grant for Oncology Innovation (GOI) EMD Serono. Dr. Josep Tabernero declares scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics. Dr. Gerald Batist collaborates in formal clinical trial contracts, IITs and in joint grants funded by Canadian and Quebec governments with Roche, Merck, Novartis, Astra-Zeneca, Bayer, Esperas, Aurka, Caprion, MRM. Pr. Angel Porgador declares scientific consultancy role for PiNK Biopharma. Dr. Razelle Kurzrock has received research funding from Genentech, Merck Serono, Pfizer, Boehringer Ingelheim, TopAlliance, Takeda, Incyte, Debiopharm, Medimmune, Sequenom, Foundation Medicine, Konica Minolta, Grifols, Omniseq, and Guardant, as well as consultant and/or speaker fees and/or advisory board for X-Biotech, Neomed, Pfizer, Actuate Therapeutics, Roche, Turning Point Therapeutics, TD2/Volastra, Bicara Therapeutics, Inc., and Biological Dynamics, has an equity interest in IDbyDNA and CureMatch Inc, serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch. Dr. Richard L. Schilsky’s institution (ASCO) receives research grants in support of a clinical trial that he directs from the following companies: AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Genentech, Lilly, Merck, Pfizer. Dr. Schilsky reports being a consultant to Cellworks, Clarify Precision Medicine, Bryologx, EQRx and Scandion Oncology. The remaining authors declare no competing interests. Ethical Approval: The bio-banking study was approved by the IMM’s Ethics Committee.

The expanding targeted therapy landscape requires combinatorial biomarkers for patient stratification and treatment selection. This requires simultaneous exploration of multiple genes of relevant networks to account for the complexity of mechanisms that govern drug sensitivity and predict clinical outcomes. We present the algorithm, Digital Display Precision Predictor (DDPP), aiming to identify transcriptomic predictors of treatment outcome. For example, 17 and 13 key genes were derived from the literature by their association with MTOR and angiogenesis pathways, respectively, and their expression in tumor versus normal tissues was associated with the progression-free survival (PFS) of patients treated with everolimus or axitinib (respectively) using DDPP. A specific eight-gene set best correlated with PFS in six patients treated with everolimus: AKT2, TSC1, FKB-12, TSC2, RPTOR, RHEB, PIK3CA, and PIK3CB (r = 0.99, p = 5.67E−05). A two-gene set best correlated with PFS in five patients treated with axitinib: KIT and KITLG (r = 0.99, p = 4.68E−04). Leave-one-out experiments demonstrated significant concordance between observed and DDPP-predicted PFS (r = 0.9, p = 0.015) for patients treated with everolimus. Notwithstanding the small cohort and pending further prospective validation, the prototype of DDPP offers the potential to transform patients’ treatment selection with a tumor- and treatment-agnostic predictor of outcomes (duration of PFS).

Background and study aims Endoscopic retrograde cholangiopancreatography (ERCP) in patients with a preexisting duodenal stent is particularly challenging and has a low success rate. Endoscopic ultrasound (EUS)-guided biliary drainage (EUS-BD) has been increasingly used as an alternative to percutaneous transhepatic biliary drainage after failed ERCP. EUS-guided choledochoduodenostomy (EUS-CD) and EUS-guided hepaticogastrostomy (EUS-HGS) have been reported to have similar efficacity. Recently, a novel dedicated fully-covered lumen-apposing metal stent (LAMS) has been developed for EUS-CD (Hot AXIOS; Boston Scientific, Massachusetts, United States). It seems that this new device decreases the morbidity of EUS-CD. We present a case in which EUS-CD with LAMS through an uncovered metal duodenal stent was used successfully.

The originality of this retrospective study relies on the evaluation of the effectiveness of the endoscopic internal drainage (EID) according to the type of fistula. METHODS: The type of fistula was classified initially according to a CT scan with oral opacification: fistula without a communicating abscess (type I), fistula with a communicating abscess (type II), and fistula with an abscessed sub- and sus-diaphragmatic communicating collection (type III). Treatment algorithm consisted of the insertion of a nasojejunal feeding tube (NJFT) for type I fistulas and the placement of a NJFT with EID with or without surgical drainage for types II and III. RESULTS: Forty-nine patients were included. The clinical success rate with fistula healing was 100% in group I, 96% in group II, and 12% for group III (p = 0.001). Mean time for diagnosis of the fistula was significantly higher in type III (p = 0.04). The mean estimated size of the defect was higher in type II, 11.2 mm and III, 10 mm versus type I, 2.8 mm (p = 0.001). The average number of scheduled endoscopic sessions were 2, 2.7, and 5.2 for types I, II, and III, respectively (p = 0.001). The number of unscheduled reinterventions was also significantly higher in type III (p = 0.03). The NJFT was left in place for a significantly longer duration in type III (136 days) compared to types I (3, 13) and II (49) p = 0.001. CONCLUSION: This study shows that proper characterization of the type of fistula before the endoscopic treatment of post-sleeve fistulas improves the efficacy of the endoscopic treatment.

9581 Background: The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) algorithm in order to predict treatment response by comparing tumor and normal tissue biopsies on both genomic and transcriptomic platforms. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC (no EGFR or ALK alterations; no ROS1 alterations if tested; PD-L1 unrestricted; ≤2 prior therapy lines) were treated with avelumab, axitinib, and palbociclib (3+3 dose escalation design). Tumor and normal endobronchial mucosal biopsies were obtained on all patients for retrospective SIMS algorithm validation. Results: Fifteen patients were treated: 6 at dose level 1 (DL1); 6, dose level 2 (DL2); 3, dose level 3 (DL3). Three dose-limiting toxicities (DLTs) at least possibly drug-related occurred: 1 DLT at DL2 (Grade 3 (G3) infusion reaction); 2 patients with DLTs at DL3 (1 with G3 hand/foot syndrome and G3 fatigue and 1 with G5 respiratory failure). Among 14 evaluable patients, the partial response (PR) rate was 28.6% (4/14 patients including 2/6 patients at DL1; two PRs in patients who failed prior pembrolizumab; two PRs in patients with PD-L1 < 1%). The maximum tolerated dose was avelumab 10 mg/kg IV q2weeks, axitinib 5 mg PO BID continuous, palbociclib 75 mg PO daily on days 8-28 of a 28 day cycle (DL2). DL2 was above the recommended phase II dose (RP2D), since 5/6 patients treated at DL2 required later treatment delays and/or dose reductions, mostly due to neutropenia. To further evaluate DL1, 3 patients were added to this cohort (total of 6). Since no DLTs were seen at DL1, and 5 of 6 patients did not require dose reduction, DL1 (avelumab 10 mg/kg IV q2weeks, axitinib 3 mg PO BID continuous, palbociclib 75 mg PO daily on days 8-28 of a 28 day cycle) is the RP2D. Conclusions: The RP2D was determined to be dose level 1. This triplet showed antitumor activity in patients with NSCLC, including those progressing on prior pembrolizumab. SIMS algorithm correlates of response are being assessed. Clinical trial information: NCT03386929 .

At the end of the XVIIIth century, travel literature was supposed to provide information about the places visited by the author/narrator. Consequently, description is an essential feature of those books. When travel writers came to places which had no equivalent in their home country, they had nothing to refer their readers to to give them an idea of what they were talking about. That is the problem Arthur Young had to face during his stay in the Pyrenees in 1787. Objective description was practically impossible. The only way to convey an idea of what high mountains are like is through emotion but Young is obviously reluctant to let his feelings show. At the time, outbursts of feeling were considered as improper in that type of literature

Background: NSCLC is the leading cause of cancer death. Recently, much progress has been made to identify and target specific oncogenic drivers such as EGFR mutations and ALK translocations. Unfortunately, the majority of NSCLCs do not have a single driver, but instead harbor complex systems of molecular alterations. The advent of immunooncology has opened newer avenues for treating these patients, but still, many tumors are resistant. Therefore, selection of precise therapies targeting the appropriate pathways in these tumors is an important area of research. In previously published work, the Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) algorithm to match patients to a targeted drug triplet. The SIMS algorithm is based on the hypothesis that the use of both genomic as well as transcriptomic data is important in selecting an ideal tri-therapy regimen. Since the transcriptome varies widely between different types of normal tissue, the relative level of transcription of any given gene in a tumor must be normalized against the expected level of transcription of that gene in the analogous normal tissue. The SPRING trial is the first trial assessing a rational, SIMS-based tri-therapy regimen in advanced NSCLC. The drugs utilized for SPRING–avelumab (anti-PDL1), axitinib (VEGFR inhibitor) and palbociclib (CDK4/6 inhibitor)–were chosen because the SIMS genomic/transcriptomic analysis demonstrated that ~10% of NSCLCs have a combination of these targets. Methods: Patients with locally advanced or metastatic NSCLC without EGFR or ALK alterations are being enrolled and treated with avelumab, palbociclib, and axitinib after informed consent. During phase I, any prior treatment is allowed. SPRING will assess the safety of the tri-therapy combination and determine the recommended phase II dose (RP2D) (3+3 dose escalation). Once the RP2D is found, the study will proceed directly to the phase II portion, which will permit only previously untreated patients in the metastatic setting. A biopsy of both tumor and normal tissue (by endobronchial mucosal biopsy) is obtained on all patients, both of which are analysed in a central genomics and transcriptomics platform. The SIMS algorithm is being validated retrospectively by determining the degree of genomic and transcriptomic matching and correlating with outcome. Results: The phase I study is open in USA, Israel, Spain and Luxembourg and has enrolled 12 patients to date and has progressed to cohort 3. The phase II portion is expected to open later in 2019. This research is supported by the EMD Serono/Pfizer alliance and ARC Foundation for cancer research. Citation Format: Benjamin Solomon, Enriqueta Felip, Jair Bar, Guy Berchem, Lyudmila Bazhenova, Pierre Saintigny, Nicolas Girard, Raed Sulaiman, Catherine Bresson, Fanny Wunder, J Jack Lee, Jacques Raynaud, Eitan Rubin, Brandon Young, Vladimir Lazar, Amir Onn, Brian Leyland Jones, Razelle Kurzrock. Survival Prolongation by Rationale INnovative Genomics (SPRING): An international WIN Consortium Phase I/II proof-of-concept study to explore the safety and efficacy of a tri-therapy approach using avelumab, palbociclib and axitinib in advanced/metastatic non-small cell lung cancer (NSCLC) with integrated genomic and transcriptomic correlates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT223.

SummaryBackground Gastrointestinal angiodysplasias (GIADs) may be the cause of recurrent bleeding, despite endoscopic treatment. Aim To evaluate the effect of long-acting somatostatin analogues on blood transfusion requirements, in patients with refractory bleeding due to GIADs. Methods Consecutive patients with recurrent bleeding from GIADs were enrolled. They received somatostatin analogue treatment for at least 6 months. The efficacy was evaluated in terms of blood transfusions, frequency of bleeding episodes and haemoglobin level during 6 months of treatment (Period During) compared to a 6-months' period before treatment (Period Before). Results Fifteen patients were enrolled from 2007 to 2010. The median duration of somatostatin analogue treatment was 12 months (range: 6–36). The number of transfusions significantly decreased in Period During compared with Period Before [median number: 2 (0–14) vs. 10 (6–24); P

Colonic response to food (CRF) is abnormal in irritable bowel syndrome (IBS) patients.The aim of this study was to compare CRF in patients who complain of abnormal defecation pattern according to the presence or absence of abdominal pain.One hundred forty-nine patients and 50 controls were studied: 96 IBS patients (46 IBS-C, 13 IBS-D, 15 IBS-M, and 22 IBS-U not included), 43 patients with functional constipation (group C) and ten with functional diarrhea (group D). Clinical evaluation and visual analog scales about four items (constipation, diarrhea, abdominal bloating and abdominal pain) were filled by all subjects. Colonic transit time (CTT) was measured in fasting conditions and after eating a standard 1,000-cal test meal. CRF was quantified by calculating the variation in number of markers between the two films.The frequency of meal-related symptoms did not vary among the different groups of patients but was significantly higher than in controls. Compared to IBS-C patients, constipated patients of the group C had longer total and segmental colonic transit time, and compared to IBS-D patients, diarrheic patients of the group D had shorter oro-anal and segmental colonic transit time except in the recto-sigmoid area. CRF was different in patients and controls, and differed between IBS and non IBS patients with similar transit abnormalities. Stool output was greater in patients of the group D than in patients of the IBS-D group.The different subgroups of IBS patients have different CRF patterns, distinct from subjects with constipation and diarrhea, but without abdominal pain.

Background: Gastrointestinal angiodysplasias (GIADs) could be responsible for recurrent bleeding and severe anemia. Somatostatin analogs could reduce transfusion requirements in these patients but no randomized controlled study is available. The main objective of the ANGIOPAS phase II double-blinded randomized, noncomparative study was to assess the effectiveness of pasireotide-LAR in reducing transfusion requirements in patients with refractory GIADs bleeding. Methods: A total of 22 patients with transfusion requirements ⩾6 units of packed red blood cells (pRBCs) during the 6 months prior to inclusion were randomized to receive pasireotide-LAR 60 mg ( n = 10) or placebo ( n = 12) every 28 days for 6 months. Patients were then followed for an additional 6 months after stopping treatment. Results: The pasireotide-LAR and placebo groups were equivalent for age, sex, comorbidities and transfusion requirement during the reference period (median 13 and 9.5 pRBCs). A 50 and 83% success rate (success defined as a decrease of at least 30% of transfused pRBCs) was observed in the pasireotide-LAR arm in the Intent to Treat (ITT) and per protocol (PP) analysis respectively. The need for transfusion during the intervention period was 3 pRBC units in the pasireotide-LAR group (range 0–26) and 11.5 pRBC units in the placebo group (range 0–23). Overall, three cases with glycemic control impairment were observed in the pasireotide-LAR group including one de novo diabetes. Conclusion: This double-blinded noncomparative randomized phase II study suggests, for the first time, the effectiveness of pasireotide-LAR 60 mg every 28 days to decrease the transfusion requirement in patients with recurrent bleeding due to GIADs.

Free-form geometries in architecture pose new challenges to designers and engineers. Form, structure and fabrication processes are closely linked, which makes the realization of complex architectural free-form structures even harder. Free-form transparent design today is mainly based on triangularly facetted forms or quadrilateral meshes supported by a structure composed of rectilinear bars, with strong shape restrictions. After a brief review of the history, we report on some very recent progress in this area. Beginning with a presentation of improved methods for triangle mesh design, we also discuss experiences in coupling triangular glass panels with continuous curved structures, seeking an optimised structural behaviour and simplified connections. Furthermore, we present how the results of research on planar quadrilateral (PQ) meshes lead the way to optimized beam layouts and the breakdown of free-form shapes using planar quadrilateral panels. PQ meshes are rooted in discrete differential geometry, an active area of mathematical research. Using recent projects as examples, we discuss how transparent free-form envelopes with a smooth visual appearance are achievable if the structure is designed to adhere to the limits of current glazing technology and the surfaces are reasonably simple (e.g. rotational, overall developable, or of a small scale). In section 6 we show how the latter restriction can be relaxed: the theoretical and computational methodology for PQ meshes can easily be extended to create nearly smooth approximations of free-form surfaces by single-curved panels. This has a strong impact on glass panelling design, since it avoids expensive double-curvature glass and exploits cold-bending technology. We elaborate on how this discretisation technique goes hand in hand with the technology for construction of the structure, glazing system and structural joints. Our approach has been tested in three case studies, each one validating a particular aspect of the design process.

Measuring colonic transit time with radiopaque markers is simple, inexpensive, and very useful in constipated patients. Yet, the algorithm used to identify colonic segments is subjective, rather than founded on prior experimentation. The aim of the present study is to describe a rational way to determine the colonic partition in the measurement of colonic transit time. Colonic transit time was measured in seven segments: ascending colon, hepatic flexure, right and left transverse colon, splenic flexure, descending colon, and rectosigmoid in 852 patients with functional bowel and anorectal disorders. An unsupervised algorithm for modeling Gaussian mixtures served to estimate the number of subgroups from this oversegmented colonic transit time. After that, we performed a k-means clustering that separated the observations into homogenous groups of patients according to their oversegmented colonic transit time. The Gaussian mixture followed by the k-means clustering defined 4 populations of patients: “normal and fast transit” (n = 548) and three groups of patients with delayed colonic transit time “right delay” (n = 82) in which transit is delayed in the right part of the colon, “left delay” (n = 87) with transit delayed in the left part of colon and “outlet constipation” (n = 135) for patients with transit delayed in the terminal intestine. Only 3.7 % of patients were “erroneously” classified in the 4 groups recognized by clustering. This unsupervised analysis of segmental colonic transit time shows that the classical division of the colon and the rectum into three segments is sufficient to characterize delayed segmental colonic transit time.

Resume L’histiocytose langerhansienne est une maladie de l’enfant et de l’adulte jeune caracterisee par une proliferation clonale histiocytaire, positive en immunohistochimie pour le CD1a, touchant un ou plusieurs organes. Les formes de l’adulte sont rares. Nous rapportons un cas d’histiocytose langerhansienne multisystemique de l’adulte associant une cholangite sclerosante compliquee d’une degradation rapide de la fonction hepatocytaire, d’evolution rapidement mortelle et d’une atrophie cerebelleuse progressive. L’histiocytose langerhansienne est une cause tres rare de cholangite sclerosante de l’adulte.

Resume Introduction La fistule pancreatique est une complication qui survient dans 3 a 15 % des cas au cours de l’evolution d’une pancreatite aigue ou chronique, le plus souvent alcoolique. Une bisalbuminemie se caracterise par un dedoublement de la bande de l’albumine sur un trace d’electrophorese des protides. La presence d’une bisalbuminemie est tres inconstante et n’a ete que rarement rapportee. Observation Il s’agit d’un homme de 42 ans, buveur excessif, chez lequel est survenue une ascite pancreatique en rapport avec une fistule pancreatico-peritoneale associee a une bisalbuminemie transitoire. Le traitement a ete medical avec une bonne efficacite a court terme. Discussion L’ascite etait secondaire a une fistule pancreaticoperitoneale. Elle peut etre constitutionnelle ou acquise et transitoire, secondaire a un traitement prolonge par β-lactamines chez un insuffisant renal ou a une fistule pancreatique.

Variable immunodeficiency is frequently associated with subtotal villous atrophy, unchanged by gluten free diet. We report two cases of common variable immunodeficiency associated with chronic symptoms of malabsorption due to total villous atrophy. Symptoms of malabsorption disappeared and histological abnormalities improved after a gluten free diet. The association between celiac disease and common variable immunodeficiency should not be considered as fortuitous. Clinicians should be aware of this association and of the low sensitivity of serologic testing in this setting.

Quatre formes de sarcome de kaposi (SK) sont actuellement identifiees (classique, endemique, post-transplantation et epidemique, c’est-a-dire liee au VIH). La forme dite post-transplantation est rare et liee a une immunodepression iatrogene (traitement immunosuppresseur). Nous presentons le cas clinique d’un patient de 73 ans, traite depuis 1999 par corticoides et Azathioprine (100 mg/J) pour une fibrose pulmonaire idiopathique et qui a presente au cours de l’evolution une reactivation virale B et un sarcome de Kaposi digestif. L’arret du traitement immunosuppresseur associe a un traitement local par electrocoagulation au plasma argon des lesions de SK a permis l’evolution rapide vers la guerison.

Resume Nous rapportons l’observation d’une malade de 36 ans presentant un hemangiome geant du foie revele par une hepatomegalie febrile et une perte de poids. Cette malade presentait un syndrome inflammatoire sans hyperleucytose, une anemie et une cholestase anicterique moderee. La concentration plasmatique de l’interleukine-6 etait tres elevee alors que celle de l’interleukine-1 etait peu elevee et celle du Tumor necrosis factor normale. Quarante milligrammes par jour de prednisone ont permis une disparition des symptomes en 48 heures et une normalisation des anomalies biologiques en 6 semaines. La corticotherapie a ete poursuivie 8 semaines au total. Un suivi clinique de 36 mois et par imagerie de 24 mois a permis de verifier l’absence de recidive des symptomes et d’evolution de l’hemangiome.

Le syndrome hemolytique et uremique (SHU) est considere comme une complication rare des chimiotherapies par gemcitabine [1]. Vingt-neuf cas cliniquement documentes ont ete rapportes dans la litterature [1-8]. La precocite du diagnostic et la rapidite de la mise en oeuvre du traitement conditionnent en partie le pronostic [6]. Plusieurs observations de la litterature suggerant l'existence de forme d'installation progressive, avec un tableau biologique evocateur (apparition ou majoration progressive d'une anemie, augmentation moderee de la creatininemie) dans les semaines precedant la phase d'expression clinique du SHU [2-6], nous avons mis en place au cours de l'annee 2000 un depistage clinique et biologique (NFS-plaquettes, dosage de la creatininemie avant chaque injection de gemcitabine) du SHU dans un centre chez tous les malades traites par gemcitabine. Lorsqu'il existait des signes cliniques evocateurs (hypertension arterielle (HTA), oedeme) et/ou une anemie, une alteration de la fonction renale (creatininemie superieure a la normale, appartition d'une proteinurie et/ou d'une hematurie a la bandelette), un bilan biologique complet (compte des reticulocytes, recherche de schizocytes, bilan d'hemostase, dosage des LDH, de l'haptoglobine, de la proteinurie des 24 H, recherche d'une hematurie) etait systematiquement realise. Lorsque le diagnostic de SHU etait retenu, un bilan etiologique (coprocultures avec recherche de l'Escherichia coli serotype O157 : H7, serologies shigelles, salmonelles, echovirus, coxsackies, virus Epstein-Barr, VIH, recherche d'anticorps anti-nucleaires, anti-phospholipides et de cryoglobuline) etait realise. L'ensemble des dossiers a ete analyse afin d'identifier les cas de SHU secondaire a la gemcitabine. Nous rapportons et commentons brievement les resultats de cette etude.

Background Abdominal pain is common in patients with functional bowel disorders (FBDs). The aim of this study was to characterize the predominant sites of abdominal pain associated with FBD subtypes, as defined by the Rome III criteria. Methods A total of 584 consecutive patients attending FBD consultations in a tertiary center participated in the study. Stool form, abdominal pain location (nine abdominal segments), and pain intensity (10-point Likert scale) during the previous week were recorded. Logistic regression analysis was used to characterize the association of abdominal pain sites with specific FBD subtypes. Key Results FBDs were associated with predominant pain sites. Irritable bowel syndrome (IBS) with constipation was associated with pain in the left flank and patients were less likely to report pain in the right hypochondrium. Patients with functional constipation reported pain in the right hypochondrium and were less likely to report pain in the left flank and left iliac site. IBS with alternating constipation and diarrhea was associated with pain in the right flank, and unsubtyped IBS with pain in the hypogastrium Patients with functional abdominal pain syndrome reported the lower right flank as predominant pain site. Patients with unspecified FBDs were least likely to report pain in the hypogastrium. Patients with functional diarrhea, IBS with diarrhea, or functional bloating did not report specific pain sites. Conclusions & Inferences The results from this study provide the basis for developing new criteria allowing for the identification of homogeneous groups of patients with non-diarrheic FBDs based on characteristic sites of pain.

Drug induced pancreatitis are rare but potentially serious. Thus, drug withdrawal is warranted.A 79-year-old woman who was treated with antituberculosis therapy for 5 weeks was admitted to our unit for pancreatitis. Usual etiologies of pancreatitis were eliminated. Because of vomiting, antituberculosis therapy was withdrawn and symptoms disappeared. Eight days later, the same treatment was reintroduced and the patient presented recurrent pancreatitis; thus, treatment was withheld again followed by disappearance of clinical and biological abnormalities. Two days later, a treatment without isoniazid was reintroduced and no recurrence of symptoms was observed.We have experienced a case of isoniazid induced pancreatitis. This is a rare cause of pancreatitis but potentially fatal thus recognition of drug induced pancreatitis and definitive withdrawal of the drug is required.

Summary Background & aims Pancreatic exocrine insufficiency (PEI) impairs fat absorption, but few data are available on protein absorption. We investigated this question in patients with chronic pancreatitis, both in the absence and presence of enzyme therapy, using a stable isotope sensitive method. Methods Eleven patients with sustained PEI and regular enzyme substitution were investigated at hospital, after a washout period without enzyme substitution, and later after reintroduction of substitution. The digestibility and postprandial metabolism of dietary protein were characterized after the ingestion of a semi-synthetic single meal containing 20 g 15 N-labeled casein. Results At baseline, 20 ± 8% of dietary nitrogen was transferred to the metabolic pools vs. 24.5 ± 7% under enzyme treatment ( P = 0.04). After treatment, the transfer of dietary nitrogen tended to increase in plasma amino acids, and increased significantly in plasma proteins and the deamination pool. In contrast, the fecal excretion of dietary nitrogen did not demonstrate any treatment effect. In patients not receiving insulin for diabetes, the treatment stimulated insulin secretion. Conclusions Protein malabsorption was mostly undetectable using standard fecal tests. The study of the postprandial fate of dietary protein revealed a moderate increase of its transfer to metabolic pools after enzyme substitution.

Introduction: L'obesite est un probleme medical dont l'importance est croissante. La pose d'un ballon intragastrique est une des modalites therapeutiques proposees pour la prise en charge des patients resistant a une prise en charge dietetique adaptee. Le ballon entraine une distension gastrique permanente qui pourrait modifier le comportement alimentaire. Cependant, peu d'etudes prospectives se sont interessees a l'effet du ballon intra-gastrique a eau de type Allergan sur la composition corporelle et l'effet de ce ballon sur la prise alimentaire n'a jamais ete etudie sur le long terme. Le but de cette etude est de preciser l'efficacite du ballon intra-gastrique sur la perte de poids et la composition corporelle ainsi que sur l'evolution des sensations de satiete chez des sujets obeses beneficiant de ce procede. Patients et Methodes: La pose d'un ballon intra-gastrique a ete realisee chez 36 sujets obeses âges de 18 a 60 ans (IMC >35 ou >30 avec co-morbidite) ne presentant pas de contre-indications medicales a ce procede. Les ballons de modele Allergan sont retires 6 mois apres leur pose. Le poids des sujets ainsi que leur consommation energetique sur 24h ont ete mesures avant la pose du ballon intra-gastrique ainsi qu'a 3, 6 et 12 mois. La composition corporelle des volontaires a ete mesuree par Dual Energy X-ray Absorptiometry avant la pose du ballon gastrique, a son retrait et 6 mois apres le retrait. L'activite physique a ete mesuree par actimetrie brassard SenseWear Pro2 Bodymedia sur 3 jours avant la pose du ballon intra-gastrique ainsi qu'a 3, 6 et 12 mois. Resultats: Un recul de 6 mois apres la pose du ballon est actuellement disponible pour 16 patients. La perte de poids est de 4.7±3.4kg (p