Sheba Medical Center

BACKGROUND: The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. METHODS: In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. RESULTS: The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). CONCLUSIONS: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).

BACKGROUND: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients. METHODS: Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions. RESULTS: The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. CONCLUSIONS: Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572 [ClinicalTrials.gov].).

PURPOSE: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer. PATIENTS AND METHODS: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review. RESULTS: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events. CONCLUSION: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23. AT is characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. The disease is genetically heterogeneous, with four complementation groups that have been suspected to represent different genes. ATM, which has a transcript of 12 kilobases, was found to be mutated in AT patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. A partial ATM complementary DNA clone of 5.9 kilobases encoded a putative protein that is similar to several yeast and mammalian phosphatidylinositol-3' kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. The discovery of ATM should enhance understanding of AT and related syndromes and may allow the identification of AT heterozygotes, who are at increased risk of cancer.

BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. METHODS: In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. RESULTS: At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. CONCLUSIONS: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).

BACKGROUND: mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies. METHODS: -mutated cancer. Secondary end points included overall response and safety. RESULTS: -mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. CONCLUSIONS: -mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.).

BACKGROUND: Although significant associations of childhood adversities with adult mental disorders are widely documented, most studies focus on single childhood adversities predicting single disorders. AIMS: To examine joint associations of 12 childhood adversities with first onset of 20 DSM-IV disorders in World Mental Health (WMH) Surveys in 21 countries. METHOD: Nationally or regionally representative surveys of 51 945 adults assessed childhood adversities and lifetime DSM-IV disorders with the WHO Composite International Diagnostic Interview (CIDI). RESULTS: Childhood adversities were highly prevalent and interrelated. Childhood adversities associated with maladaptive family functioning (e.g. parental mental illness, child abuse, neglect) were the strongest predictors of disorders. Co-occurring childhood adversities associated with maladaptive family functioning had significant subadditive predictive associations and little specificity across disorders. Childhood adversities account for 29.8% of all disorders across countries. CONCLUSIONS: Childhood adversities have strong associations with all classes of disorders at all life-course stages in all groups of WMH countries. Long-term associations imply the existence of as-yet undetermined mediators.

Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients' smoking status, and the response to immunotherapy.

STUDY QUESTION: What is the optimal management of women with endometriosis based on the best available evidence in the literature? SUMMARY ANSWER: Using the structured methodology of the Manual for ESHRE Guideline Development, 83 recommendations were formulated that answered the 22 key questions on optimal management of women with endometriosis. WHAT IS KNOWN ALREADY: The European Society of Human Reproduction and Embryology (ESHRE) guideline for the diagnosis and treatment of endometriosis (2005) has been a reference point for best clinical care in endometriosis for years, but this guideline was in need of updating. STUDY DESIGN, SIZE, DURATION: This guideline was produced by a group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to January 2012 and consensus within the guideline group on all recommendations. To ensure input from women with endometriosis, a patient representative was part of the guideline development group. In addition, patient and additional clinical input was collected during the scoping and review phase of the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS: NA. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 83 recommendations on diagnosis of endometriosis and on the treatment of endometriosis-associated pain and infertility, on the management of women in whom the disease is found incidentally (without pain or infertility), on prevention of recurrence of disease and/or painful symptoms, on treatment of menopausal symptoms in patients with a history of endometriosis and on the possible association of endometriosis and malignancy. LIMITATIONS, REASONS FOR CAUTION: We identified several areas in care of women with endometriosis for which robust evidence is lacking. These areas were addressed by formulating good practice points (GPP), based on the expert opinion of the guideline group members. WIDER IMPLICATIONS OF THE FINDINGS: Since 32 out of the 83 recommendations for the management of women with endometriosis could not be based on high level evidence and therefore were GPP, the guideline group formulated research recommendations to guide future research with the aim of increasing the body of evidence. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. All guideline group members disclosed any relevant conflicts of interest (see Conflicts of interest). TRIAL REGISTRATION NUMBER: NA.

OBJECTIVE: To analyze the clinical and immunologic manifestations of antiphospholipid syndrome (APS) in a large cohort of patients and to define patterns of disease expression. METHODS: The clinical and serologic features of APS (Sapporo preliminary criteria) in 1,000 patients from 13 European countries were analyzed using a computerized database. RESULTS: The cohort consisted of 820 female patients (82.0%) and 180 male patients (18.0%) with a mean +/- SD age of 42 +/- 14 years at study entry. "Primary" APS was present in 53.1% of the patients; APS was associated with systemic lupus erythematosus (SLE) in 36.2%, with lupus-like syndrome in 5.0%, and with other diseases in 5.9%. A variety of thrombotic manifestations affecting the majority of organs were recorded. A catastrophic APS occurred in 0.8% of the patients. Patients with APS associated with SLE had more episodes of arthritis and livedo reticularis, and more frequently exhibited thrombocytopenia and leukopenia. Female patients had a higher frequency of arthritis, livedo reticularis, and migraine. Male patients had a higher frequency of myocardial infarction, epilepsy, and arterial thrombosis in the lower legs and feet. In 28 patients (2.8%), disease onset occurred before age 15; these patients had more episodes of chorea and jugular vein thrombosis than the remaining patients. In 127 patients (12.7%), disease onset occurred after age 50; most of these patients were men. These patients had a higher frequency of stroke and angina pectoris, but a lower frequency of livedo reticularis, than the remaining patients. CONCLUSION: APS may affect any organ of the body and display a broad spectrum of manifestations. An association with SLE, the patient's sex, and the patient's age at disease onset can modify the disease expression and define specific subsets of APS.

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Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

BACKGROUND: The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). METHODS: . RESULTS: for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively. CONCLUSIONS: Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).

BACKGROUND: Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines. RESULTS: Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75). CONCLUSIONS: Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).

This is the third European Crohn’s and Colitis Organisation [ECCO] consensus guideline that addresses ulcerative colitis [UC]. It has been drafted by 28 ECCO members from 14 European countries. It is derived from and updates the previous ECCO consensus advice on UC.1–3 All the authors recognise and are grateful to previous ECCO members who contributed to creating the previous consensus guidelines1–6 on which some of the text is based. Attention is also drawn to other ECCO consensus guidelines which have contributed to this endeavour, on extra-intestinal manifestations [EIMs],7 malignancy,8 imaging,9 small bowel endoscopy,10 opportunistic infections [OIs],11 surgery,12 endoscopy,13 pathology,14 anaemia,15 reproduction and pregnancy,16 and paediatric UC.17 The guideline has been condensed into two papers, the first detailing definitions, classification, diagnosis, imaging, pathology, and management of special situations [EIMs, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders of UC]; and the second describing current therapeutic management [treatment of active disease and maintenance of medically induced remission]. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu]. Briefly, an open call for participants was made, with participants selected by the Guidelines’ Committee of ECCO [known as GuiCom] on the basis of their publication record and a personal statement. Working parties were established to review the consensus statements published in 2012,1–3 after which a recommendation was issued on whether they required revision based upon advances in the published literature. There was agreement that extensive review of histopathology, endoscopy, OI, anaemia, EIMs, surgery, and pregnancy was not required, as these subjects are reviewed in other recent ECCO guidelines7,11–16; rather, abbreviated text and selected statements from these guidelines specific to UC are provided. Paediatric UC is dealt with in a separate ECCO initiative17 which is currently being updated. Provisional ECCO statements and supporting text were written following a comprehensive literature review, then refined following two voting rounds which included national representative participation by ECCO’s 35 member countries. The level of evidence was graded according to the Oxford Centre for Evidence-Based Medicine [www.cebm.net]. The ECCO statements were finalised by the authors at a meeting in Barcelona in October 2015 and represent consensus with agreement of at least 80% of participants. Consensus statements are intended to be read in context with their qualifying comments and not in isolation. The supporting text was then finalised under the direction of each working group leader [FM, FC, AD, PG, FR], including an updated literature search to October 2016 of the most relevant [eight] journals, before being integrated by a consensus leader [MH]. This consensus guideline is pictorially represented within the freely available ECCO e-Guide [http://www.e-guide.ecco-ibd.eu/]. UC is a lifelong disease arising from an interaction between genetic and environmental factors, observed predominantly in developed countries. Its precise aetiology is unknown, and therefore curative medical therapy is not yet available. Within Europe there is an east-west and north-south gradient, but the incidence appears to have increased in southern and eastern countries during recent years.18–20 Patients may live with a considerable symptom burden and high risk of disability21 despite medical treatment.22 Clinicians must advise and treat patients on the basis of currently available information. Despite robust evidence from rigorously conducted randomised trials, the strict and somewhat necessarily restrictive inclusion and exclusion criteria in trial design may limit translation of such evidence to ‘real-world’ patients. Ulcerative colitis [UC] is a chronic inflammatory condition that causes continuous mucosal inflammation of the colon, usually without granulomas on biopsy. It affects the rectum and to a variable extent the colon in a continuous fashion, and is characterised by a relapsing and remitting course.23 Inflammatory bowel disease unclassified [IBDU] is the term best suited for a minority of cases in which a definitive distinction between UC, Crohn’s disease, or other causes of colitis cannot be made after taking into account the history, endoscopic appearance, histopathology of multiple mucosal biopsies, and appropriate radiology.23,24 Indeterminate colitis is a term reserved for pathologists to describe a colectomy specimen with overlapping features of UC and Crohn’s disease.24,25 Detailed information on definitions can be found in Supplementary material, available as Supplementary data at ECCO-JCC online.1,23,24,26–39 Distribution of UC [adapted from Silverberg et al.23]. Disease activity in UC [adapted from Truelove & Witts32]. Montréal classification of disease activity in UC [adapted from Silverberg et and et Disease extent whether therapy and and of It is by the extent at as and extensive colitis of inflammation the management and the of for a therapy in the of or is usually the for and therapy with is appropriate for extensive of colitis the risk of of or cancer and the and the of Patients with extensive colitis have the risk of with have a risk similar to the Patients with colitis an their risk that of patients with extensive colitis as disease patients with and extensive colitis are to have patients with not such It be that the extent at may the extent of disease as with and are to the extent of information and risk for of or colitis may in of patients with Disease and of of disease have not been imaging, and endoscopic including histopathology, on management is as and at of a inflammatory of disease It be to the of active colitis by and before which may causes of that active disease such as mucosal Crohn’s disease, or bowel and patients with active disease including to Patients with an appropriate also have to a from of patients are in at during a a of a relapsing after of Disease activity in the first after to an increased of of active a an was between the to first and the of a the the was patients a for the maintenance of in patients with at patients from to at and from to at in the of described the in patients in the first following of UC between and the most recent the of patients an during the first after was a or within the first but and an activity at least during the first is also UC, a chronic inflammatory was in and were in of patients with an inflammatory after of with who without such an were in with and mucosal The of bowel inflammation is also a risk for in patients with extensive Detailed information on the of can be found in Supplementary material, available as Supplementary data at ECCO-JCC and and are of have been with of The is not as in UC as is in Crohn’s disease for the of disease in colitis have been established for and patients a to following for colitis with to a is for and have been but has been to be to The most are and other such as and have also at has for and of disease a with endoscopic and to can be as a for in patients with inflammatory bowel disease of was with an increased risk of It must be that of these is specific for UC, they represent active with disease there is of The consensus group that the best to define is a of with and mucosal at classification of ulcerative colitis according to at is of as disease has a according to the of is as the for and of patients with UC to have disease and and with All current available for UC have an in with The risk of in patients with UC the of is an in patients with UC, as the risk for The of genetic or is not for the classification of ulcerative colitis Detailed information on can be found in Supplementary material, available as Supplementary data at ECCO-JCC of ulcerative colitis are upon extent and of disease and and and are bowel and colitis UC in and the may be made at small in incidence has been in some after the of UC appears to The inflammation in the rectum and in a and to a variable extent of the colon, or mucosal The extent of inflammation may or but after disease the of inflammation to the extent of previous in the of The that UC continuous inflammation been by of a in and of patients with active UC the of mucosal disease, and may according to disease in for extensive UC from most cases of Patients with active disease also of and patients with usually with and may in UC, or the of Crohn’s The of UC is usually are for or before medical advice is with a in with including and EIMs, in or and may the in of cases and can in of of ulcerative colitis or Crohn’s disease the risk for ulcerative colitis for before and the risk and of UC may to ulcerative colitis of patients with UC have an increased risk of the The risk of UC is in but is also in and of UC as as in of patients with Crohn’s disease in a and the of but may not the of the have a risk of the disease, which is extensive and to with who have or but the data are and during or are to a risk of UC in The of is to that of but not to the of is after the of UC, the on the of disease is and is to may the evidence from and a trial that with is medical the of and and extra-intestinal with and of inflammatory bowel disease or and previous be The of UC is in the context of or of colitis be and be and and for and and may be may be in patients with or disease on on the extent and of of patients with or activity is usually from on Patients with a may and bowel for of ulcerative colitis not It is established by imaging, and endoscopic including be with review after an may be The of UC is characterised by of and of continuous in of the as a by The that of patients a in The of of is usually during the first and may be characterised as continuous UC without or the recent the of patients with UC in from at the of to after of It is to the diagnosis, and of disease, as these and disease It is to the to to a diagnosis, but mucosal active UC as the of of the may to Crohn’s disease or be during the first and and The be including be and be diagnosis, have a inflammatory and and a for is an of of chronic inflammation may be in or The may as a of the chronic inflammatory or chronic active disease, and which the of an UC, and with the of with patients with an is with an and have been as to the for colectomy in after a of extensive colitis an increased risk of is specific to UC from or other causes of be to and for may be according to the medical history, for the of for or other or with are required at and may be required to disease is in patients with colitis This for and is a and has been with and ECCO guidelines with disease be in the of or of can in UC, not in patients with may not disease can or It be in patients who The for relevant in patients with colitis has not been but most of in the inclusion with on histopathology not necessarily but multiple are usually including information on can be reviewed in the ECCO Consensus on and in a recent The most are and are in to of patients with UC and in of patients with Crohn’s the current of these their for the of UC and for therapeutic is not such as and have been as of inflammation in appears to be the most the of in patients for in the of disease with endoscopic and in the of and to with the to between of a in the of UC a to inflammation and to be a to a of patients by and has been described in with a or inflammation in the rectum is to to inflammation in the is to as a and may be observed in patients with the of and or a in of the small bowel in to an is The of patients with inflammation to be similar to with of the as a is in to of patients with inflammation has been with a and a risk of after pouch a recent a similar in patients with an of inflammation with with a in of disease and of or inflammation from the into is and is observed in to of patients with extensive may in patients without which the that that from a of into the Patients with to be to a of which may an increased risk of colon in not to be with pouch of the small bowel be in cases of to UC from Crohn’s bowel by or or endoscopy, as reviewed in the ECCO consensus on in Crohn’s and small bowel in is not is the of an to Crohn’s disease in to an is for endoscopic disease activity in ulcerative colitis are available. The of a endoscopic is to of ulcerative colitis patients and to a for inflammatory bowel disease to is for patients criteria for to which may to increased and The classification of UC was by Truelove and in This classification is to be the for of in of to and the of patients with colitis have inflammatory or and with a for and of be to and to the extent of disease and for features that to The extent of disease with the of in a of the extent of disease was in and in The of mucosal by or two of small bowel is with a to the of colitis and may be required is as a on with high in which histopathology be with a within before is in patients with colitis is not in in patients on criteria for colitis with mucosal on the of these and of which can be by is of is appropriate at for or ulcerative colitis or colectomy Despite the of disease in risk of and of the of after has been a mucosal after of was with a risk of in of the patients with mucosal with of without of patients who endoscopic as a of inflammation at and on during of in to of patients that to endoscopic in patients with UC, who were the disease and endoscopic after and and then at the third were to patients with or between and in the of and colectomy were of mucosal was the with and a disease patients with UC with and in that with endoscopic as with to after patients in The most endoscopic of ulcerative colitis is with of inflammation and ulcerative colitis is by mucosal and at the and in a and The between and is usually and may within in in the endoscopic of disease activity is and have been to the of endoscopic and are within the for UC, which is for trial The Ulcerative Colitis of the and the of and each with or of This is the first endoscopic of in The is the of in the of the colon at the of the a of to the of a a was made to the of the a to a of that the of the from to for ulcerative for The endoscopic features of inflammation are and at least of the active colitis is characterised by a of to the of the and with a and mucosal to colitis is characterised by and in et to Crohn’s disease, in UC are in The of is a disease, mucosal can in of and The of in UC has therefore been the of information on colon can be found in Supplementary material, available as Supplementary data at ECCO-JCC Detailed information on can be found in Supplementary material, available as Supplementary data at ECCO-JCC in ulcerative multiple endoscopic be to by be are not or the is not UC, a an increased risk for and the be by a second is the most in the of and then management in a is to a the mucosal to the and extra-intestinal is for diagnosis, of disease and of and The following and updates of the ECCO guideline on UC is a chronic inflammatory to the of features have been and they can be into mucosal and information on on the can be found in Supplementary material, available as Supplementary data at ECCO-JCC a of ulcerative a of two from at least the colon the and the be be by including endoscopic of disease and 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IMPORTANCE: Health care-associated infections (HAIs) account for a large proportion of the harms caused by health care and are associated with high costs. Better evaluation of the costs of these infections could help providers and payers to justify investing in prevention. OBJECTIVE: To estimate costs associated with the most significant and targetable HAIs. DATA SOURCES: For estimation of attributable costs, we conducted a systematic review of the literature using PubMed for the years 1986 through April 2013. For HAI incidence estimates, we used the National Healthcare Safety Network of the Centers for Disease Control and Prevention (CDC). STUDY SELECTION: Studies performed outside the United States were excluded. Inclusion criteria included a robust method of comparison using a matched control group or an appropriate regression strategy, generalizable populations typical of inpatient wards and critical care units, methodologic consistency with CDC definitions, and soundness of handling economic outcomes. DATA EXTRACTION AND SYNTHESIS: Three review cycles were completed, with the final iteration carried out from July 2011 to April 2013. Selected publications underwent a secondary review by the research team. MAIN OUTCOMES AND MEASURES: Costs, inflated to 2012 US dollars. RESULTS: Using Monte Carlo simulation, we generated point estimates and 95% CIs for attributable costs and length of hospital stay. On a per-case basis, central line-associated bloodstream infections were found to be the most costly HAIs at $45,814 (95% CI, $30,919-$65,245), followed by ventilator-associated pneumonia at $40,144 (95% CI, $36,286-$44,220), surgical site infections at $20,785 (95% CI, $18,902-$22,667), Clostridium difficile infection at $11,285 (95% CI, $9118-$13,574), and catheter-associated urinary tract infections at $896 (95% CI, $603-$1189). The total annual costs for the 5 major infections were $9.8 billion (95% CI, $8.3-$11.5 billion), with surgical site infections contributing the most to overall costs (33.7% of the total), followed by ventilator-associated pneumonia (31.6%), central line-associated bloodstream infections (18.9%), C difficile infections (15.4%), and catheter-associated urinary tract infections (<1%). CONCLUSIONS AND RELEVANCE: While quality improvement initiatives have decreased HAI incidence and costs, much more remains to be done. As hospitals realize savings from prevention of these complications under payment reforms, they may be more likely to invest in such strategies.

This new diagnostic consensus guideline is a joint project of the European Crohn’s and Colitis Organisation [ECCO] and the European Society of Gastrointestinal and Abdominal Radiology [ESGAR] that now merges the former ECCO-ESGAR Imaging Guideline and the former ECCO Endoscopy Guideline, also including laboratory parameters. It has been drafted by 30 ECCO and ESGAR members from 17 European countries. All the authors recognize th e work of and are grateful to previous ECCO and ESGAR members who contributed tocreating the earlier consensus guidelines on imaging and endoscopy. The former guidelines have been condensed into this new diagnostic consensus guideline which consists of two papers: the first detailing assessment at initial diagnosis, to monitor treat ment and for the detection of complications; the second dealing with the available scoring systems and general considerations regarding the different diagnostic tools. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu]. Briefly, an open call for participants was made, with ECCO participants selected by the Guidelines’ Committee of ECCO [known as GuiCom] on the basis of their publication record and a personal statement and ESGAR participants nominated by ESGAR. The following working parties were established: diagnostics at initial diagnosis, diagnostics for monitoring treatment in patients with known IBD, diagnostics for the detect ion of complications, scores for IBD, and general principles and technical aspects. Provisional guideline statements and supporting text were written following a comprehensive literature review, then refined following two voting rounds. The first voting round introduced a more comprehensive voting procedure, in which each Guidelines participants voted on all statements by explicitly reviewing those statements together with their respective supporting text and references. The second voting round included optional national representative participation of ECCO’s 36 member countries and ESGAR’s 28 member countries. The level of evidence was graded according to the Oxford Centre for Evidence-Based Medicine [www.cebm.net]. The ECCO statements were finalized by the authors at a face-to-face meeting in Barcelona in October 2017 and represent consensus with agreement of at least 80% of the present participants. Consensus statements are intended to be read in context with their qualifying comments and not in isolation. The supporting text was then finalised under the direction of each working group leader [SV, TK, GF, VA, EC], before being integrated by the consensus leaders [CM, JS, AS].

Importance: Therapeutic options are needed for patients with advanced gastric cancer whose disease has progressed after 2 or more lines of therapy. Objective: To evaluate the safety and efficacy of pembrolizumab in a cohort of patients with previously treated gastric or gastroesophageal junction cancer. Design, Setting, and Participants: In the phase 2, global, open-label, single-arm, multicohort KEYNOTE-059 study, 259 patients in 16 countries were enrolled in a cohort between March 2, 2015, and May 26, 2016. Median (range) follow-up was 5.8 (0.5-21.6) months. Intervention: Patients received pembrolizumab, 200 mg, intravenously every 3 weeks until disease progression, investigator or patient decision to withdraw, or unacceptable toxic effects. Main Outcomes and Measures: Primary end points were objective response rate and safety. Objective response rate was assessed by central radiologic review per Response Evaluation Criteria in Solid Tumors, version 1.1, in all patients and those with programmed cell death 1 ligand 1 (PD-L1)-positive tumors. Expression of PD-L1 was assessed by immunohistochemistry. Secondary end points included response duration. Results: Of 259 patients enrolled, most were male (198 [76.4%]) and white (200 [77.2%]); median (range) age was 62 (24-89) years. Objective response rate was 11.6% (95% CI, 8.0%-16.1%; 30 of 259 patients), with complete response in 2.3% (95% CI, 0.9%-5.0%; 6 of 259 patients). Median (range) response duration was 8.4 (1.6+ to 17.3+) months (+ indicates that patients had no progressive disease at their last assessment). Objective response rate and median (range) response duration were 15.5% (95% CI, 10.1%-22.4%; 23 of 148 patients) and 16.3 (1.6+ to 17.3+) months and 6.4% (95% CI, 2.6%-12.8%; 7 of 109 patients) and 6.9 (2.4 to 7.0+) months in patients with PD-L1-positive and PD-L1-negative tumors, respectively. Forty-six patients (17.8%) experienced 1 or more grade 3 to 5 treatment-related adverse events. Two patients (0.8%) discontinued because of treatment-related adverse events, and 2 deaths were considered related to treatment. Conclusions and Relevance: Pembrolizumab monotherapy demonstrated promising activity and manageable safety in patients with advanced gastric or gastroesophageal junction cancer who had previously received at least 2 lines of treatment. Durable responses were observed in patients with PD-L1-positive and PD-L1-negative tumors. Further study of pembrolizumab for this group of patients is warranted. Trial Registration: clinicaltrials.gov Identifier: NCT02335411.

BACKGROUND: Despite high vaccine coverage and effectiveness, the incidence of symptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been increasing in Israel. Whether the increasing incidence of infection is due to waning immunity after the receipt of two doses of the BNT162b2 vaccine is unclear. METHODS: We conducted a 6-month longitudinal prospective study involving vaccinated health care workers who were tested monthly for the presence of anti-spike IgG and neutralizing antibodies. Linear mixed models were used to assess the dynamics of antibody levels and to determine predictors of antibody levels at 6 months. RESULTS: The study included 4868 participants, with 3808 being included in the linear mixed-model analyses. The level of IgG antibodies decreased at a consistent rate, whereas the neutralizing antibody level decreased rapidly for the first 3 months with a relatively slow decrease thereafter. Although IgG antibody levels were highly correlated with neutralizing antibody titers (Spearman's rank correlation between 0.68 and 0.75), the regression relationship between the IgG and neutralizing antibody levels depended on the time since receipt of the second vaccine dose. Six months after receipt of the second dose, neutralizing antibody titers were substantially lower among men than among women (ratio of means, 0.64; 95% confidence interval [CI], 0.55 to 0.75), lower among persons 65 years of age or older than among those 18 to less than 45 years of age (ratio of means, 0.58; 95% CI, 0.48 to 0.70), and lower among participants with immunosuppression than among those without immunosuppression (ratio of means, 0.30; 95% CI, 0.20 to 0.46). CONCLUSIONS: Six months after receipt of the second dose of the BNT162b2 vaccine, humoral response was substantially decreased, especially among men, among persons 65 years of age or older, and among persons with immunosuppression.

expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.