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Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25-CD127+Foxp3-effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1+CD4+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1+ CD4+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1+TIM-3+ CD4+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1-CD4+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1-CD4+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial.

BackgroundHereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome most often caused by pathogenic variants in CDH1. The International Gastric Cancer Linkage Consortium (IGCLC) recently updated its criteria for genetic testing. The purpose of this study was to estimate the sensitivity of IGCLC’s 2020 criteria for identifying carriers of CDH1 pathogenic variants and to formulate a new set of criteria that is simpler and more sensitive.MethodsMedical histories of 112 CDH1 mutation carriers, identified predominantly by multigene panel testing, and their 649 family members were reviewed. The percentage of subjects fulfilling the IGCLC 2015 and 2020 criteria was calculated, once without making any assumptions about unavailable pathology, and once assuming gastric cancer to be diffuse when pathology was unavailable. For comparison, we calculated the percentage of subjects who fulfilled our proposed criteria.ResultsWhen making no assumptions about missing pathology, a small (19%) and equal percentage of CDH1 mutation carriers fulfilled the IGCLC 2015 and 2020 criteria. When assuming unspecified gastric cancer to be diffuse, 45 out of 112 (40%) subjects met the 2015 criteria and 53 out of 112 (47%) met the 2020 criteria. Eighty-seven per cent (97/112) fulfilled our proposed criteria.ConclusionIn consecutive cases, mostly unselected for clinical criteria of HDGC, the IGCLC 2020 criteria are, at best, marginally more sensitive than previous iterations, but they are also more cumbersome. Unavailable cancer pathology reports are a real-world obstacle to their proper application. Our proposed Yale criteria both address this issue and offer significantly greater sensitivity than the IGCLC 2020 criteria.

While the gluten-free diet (GFD) is the only known effective therapy for celiac disease, in recent years it has become increasingly popular in the USA and worldwide, with many believing it to be more “healthful” and others claiming that it has beneficial effects for health conditions, many extraintestinal, other than celiac disease. This review examines the evidence for use of the GFD in patients without celiac disease who self-report intestinal and/or extraintestinal symptoms (non-celiac gluten sensitivity), as well as for enhancement of athletic performance and treatment of autism, rheumatoid arthritis, and psychiatric disorders. Overall, the evidence for use of GFDs in conditions other than celiac disease is poor. Though non-celiac gluten sensitivity may ultimately emerge as a biomarker-defined condition, a large proportion of patients with apparent non-celiac gluten sensitivity have, after careful investigation, an alternative diagnosis. In light of this, and coupled with the potential physical and psychological harms associated with the avoidance of gluten, initiating a GFD should not be encouraged for people who have these other conditions or are seeking physical/athletic enhancement.

BackgroundDiffuse gastric and lobular breast cancer (LBC) syndrome is an autosomal-dominant syndrome characterised by early-onset diffuse gastric cancer and LBC most often caused by germline pathogenic variants (PVs) in CDH1. We previously showed the International Gastric Cancer Linkage Consortium (IGCLC) criteria for genetic testing to have poor sensitivity for CDH1 PV and proposed our own simpler and more sensitive Yale criteria. The European Reference Network on Genetic Tumour Risk Syndromes subsequently proposed expanding the IGCLC criteria and showed its LBC-expanded criteria to be more sensitive than the IGCLC criteria in a European cohort of CDH1 PV carriers.MethodsWe aggregated demographic and clinical data of all CDH1 PV carriers identified at three US commercial laboratories. These data were used to calculate the sensitivity of the IGCLC, LBC-expanded and National Comprehensive Cancer Network (NCCN)/Yale criteria.ResultsData on 708 probands and their 4318 family members were included in the analysis. In this cohort, the sensitivities for detecting CDH1 PVs were 23.6% for IGCLC criteria, 35.7% for LBC-expanded criteria and 82.2% for NCCN/Yale criteria.ConclusionIn a large cohort of CDH1 PV carriers to date, the IGCLC and LBC-expanded criteria called for genetic testing in a minority of CDH1 PV carriers while the Yale criteria detected the large majority. Along with their superior sensitivity, the NCCN/Yale criteria address critical practical challenges in cancer genetics by not depending heavily on pathology information from family members which is often lacking and by incorporating recommendations from other cancer genetics guidelines.

Adherence to a gluten-free (GF) diet is the mainstay of therapy for celiac disease. Until now, those wishing to avoid gluten in restaurants had to rely on menu labels, word of mouth, intuition, and restaurant workers' advice, with a relative dearth of supporting data. We used crowd-sourced data from users of a portable gluten detection device to estimate rates of, and identify risk factors for, gluten contamination of supposed GF restaurant foods. We analyzed data from a portable gluten detection device (Nima), collected across the United States during an 18-month period by users who opted to share the results of their point-of-care tests. Data were sorted by region, time of day, median household income in the restaurant's vicinity, restaurant genre, and food items. We used the χ test for bivariate analysis and multiple logistic regression for multivariate analysis to identify predictors of gluten detection in restaurant food. There were 5,624 tests, performed by 804 users, in the examined period. Gluten was detected in 32% of GF labeled foods. Rates of gluten detection differed by meal, with 27.2% at breakfast and 34.0% at dinner (P = 0.0008). GF labeled pizza and pasta were most likely to test positive for gluten, with gluten detected in 53.2% of pizza and 50.8% of pasta samples. On multivariate analysis, GF labeled food was less likely to test positive for gluten in the West than in the Northeast United States (odds ratio 0.80; 95% confidence interval 0.67-0.95). This study of crowd-sourced data suggests that a substantial fraction of GF labeled restaurant foods contain detectable gluten. Although the highly sensitive Nima device may detect gluten at levels <20 parts per million (ppm), leading to gluten exposure of unknown clinical significance, our findings raise a potential concern. In addition, our findings of higher rates of gluten detection in pizza and pasta provide practical data when providing dining strategies for patients with celiac disease.

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4.sup.+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1.sup.+ CD4.sup.+ CD25.sup.- CD127.sup.+ Foxp3.sup.- effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1.sup.+ CD4.sup.+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFN[gamma]. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1.sup.+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1.sup.+ CD4.sup.+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1.sup.+ TIM-3.sup.+ CD4.sup.+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4.sup.+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1.sup.- CD4.sup.+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1.sup.- CD4.sup.+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial.

Introduction: Adherence to a gluten-free (GF) diet is the mainstay of therapy for celiac disease (CD). Potential gluten exposure when eating in restaurants can be a hazard and source of anxiety for CD patients. Advice about avoiding cross-contaminated GF restaurant food has relied on clinical expertise with a relative dearth of data. The advent of portable gluten detection devices allows for crowd-sourced evaluation of restaurant food for GF safety. We aimed to identify factors associated with presence of gluten in restaurant food. Methods: We analyzed data from a portable gluten detection device (Nima), collected across the USA during an 18-month period by users (n = 804) who opted to share results of their point-of-care tests. Each test included a date/time, food item, restaurant name and address, presence/absence of GF label and presence/absence of gluten. Data was sorted by region, time of day, median household income in the restaurant's vicinity (extrapolated from zip code and 2016 American Community Survey), restaurant genre, and food item. We used chi-square test for bivariate analysis and multiple logistic regression for multivariate analysis to identify predictors of the presence of gluten in restaurant food. Results: There were 5624 tests in the examined period, 3327 (59%) during dinner hours, 2576 (46%) in Western states, and 3449 (63%) in the highest income quartile of zip codes. 4732 (84%) of tested foods were labeled GF; 32% of GF labeled foods contained gluten. Presence of gluten in GF labeled foods differed by meal, with 27.2% at breakfast and 34.0% at dinner detecting gluten (p = 0.001). On multivariate analysis adjusting for region, income, and time of day, GF labeled food was less likely to contain gluten in the West than in the Northeast (OR 0.80, 95% CI 0.67 to 0.95, p = 0.01). Compared to other foods, GF labeled pizza and pasta were most likely to be contaminated, with 53.2% of pizza (OR 2.5, 95% CI 2.0 to 3.2, p = < 0.0001) and 50.8% of pasta (OR 2.1, 95% CI 1.5 to 3.1, p = < 0.0001) detecting gluten. Conclusion: One-third of restaurant foods labeled GF contained at least 20 ppm of gluten. Higher rates of gluten contamination during dinner may reflect cumulative contamination of GF ingredients/equipment over the course of the day. Lower rates in the West may relate to greater interest in GF diets in that region. Our findings of higher rates of cross-contamination in pizza and pasta provide practical data when providing dining strategies for patients with CD.

We report and analyze eight cases in which patients were referred from gastroenterology (GI) to otolaryngology following esophagogastroduodenoscopy (EGD). We aim to provide specific examples of head and neck pathology encountered by gastroenterologists during upper endoscopy. A series of eight cases between 2016 and 2019 were analyzed by chart review. In each case, otolaryngology consultation was requested after an abnormality was noticed by a gastroenterologist during EGD. Subsequent laryngoscopy or bronchoscopy was performed in all cases allowing for image comparison. Select images comparing EGD to laryngoscopy findings are included as well as a literature review concerning the nature of communication between the two specialties. Eight adult patients were referred to otolaryngology for abnormalities noted by a gastroenterologist during EGD at the following anatomic sites: soft palate (n=1), base of tongue (n=2), glottis (n=3), and interarytenoid mucosa (n=1). Additionally, a potential airway foreign body was noted on EGD which was ultimately determined to represent normal subglottic anatomy by bronchoscopy. Some 5/8 (63%) cases were considered true pathology while 3/8 (37%) represented normal anatomy or anatomic variants upon subsequent otolaryngologic evaluation. There is minimal literature regarding the nature of referrals from GI to otolaryngology following EGD. Our findings suggest that EGD offers a unique opportunity for early detection of otolaryngologic pathology. However, certain inter-specialty anatomic knowledge gaps were noted which contributed to occasional unnecessary referrals, procedures, and associated patient anxiety. We hope that the results of this study can inform future research aimed at improving communication and collaboration between the two specialties.

To identify co-inhibitory immune pathways important in the brain, we hypothesized that comparison of T cells in lesions from patients with MS with tumor infiltrating T cells (TILs) from patients with GBM may reveal novel targets for immunotherapy. Focusing on PD-1 and TIGIT, we found that TIGIT and its ligand CD155 were highly expressed on GBM TILs but were near-absent in MS lesions, while lymphocytic expression of PD-1/PDL-1 was comparable. TIGIT was also upregulated in peripheral lymphocytes in GBM, suggesting recirculation of TILs. These data raise the possibility that anti-TIGIT therapy may be beneficial for patients with glioblastoma.