Search

eIF2B is a decameric guanine nucleotide exchange factor (GEF) that is essential for protein synthesis and a key effector of the integrated stress response (ISR). Hypomorphic mutations in any of the eIF2B subunits are associated with Vanishing White Matter Disease (VWM), a leukodystrophy characterized by ISR activation and white matter loss. Here, we showed that the VWM-associated N208Y eIF2Bα mutation, which abolishes sugar phosphate binding, led to a drastic reduction in its level in cells and concomitant ISR activation. We found that N208Y homozygous mice are small and die shortly after birth. Remarkably, continuous availability of 2BAct, a small molecule eIF2B activator, in food rescued the lethality and significantly extended their lifespan. 2BAct-maintained N208Y homozygous mice, however, developed motor deficits and loss of myelin with age. As is the case for milder VWM models, ISR induction was restricted to the central nervous system in treated animals. Upon 2BAct withdrawal, adult mutant mice deteriorated quickly, the ISR was induced in all peripheral tissues tested and resulted in high levels of circulating FGF21 and GDF15. This model provides a novel platform to study the impact of ISR activation across tissues with temporal control.

Diagnostic uncertainty is prevalent throughout medicine and significantly impacts patient care, especially when it goes unrecognized. However, we lack a reliable clinical means of identifying uncertainty. This study evaluates the narrative discourse within clinical notes in the Electronic Health Record as a means of identifying diagnostic uncertainty. Recognizing that discourse producers use language ‘semi-automatically’ (Partington et al. 2013), we hypothesized that clinicians include distinct indications of uncertainty in their written assessments, which could be elucidated by linguistic analysis. Using a cohort of patients prospectively identified as having an uncertain diagnosis (UD), we conducted a detailed corpus-assisted discourse analysis. The analysis revealed a set of linguistic indicators constitutive of diagnostic uncertainty including terms of modality, register-specific terms, and linguistically identifiable clinical behaviours. This dictionary of UD indicators was thoroughly tested, and its performance was compared with a matched-control dataset. Based on the findings, we built a machine learning classification algorithm with the ability to predict UD patient cohorts with 87.0% accuracy, effectively demonstrating the feasibility of using clinical discourse to classify patients and directly impact the clinical environment.

Purpose:In metastatic colorectal cancer (mCRC), HER2 (ERBB2) gene amplification is implicated in anti-EGFR therapy resistance. We sought to determine the recommended phase II dose (RP2D) and efficacy of neratinib, a pan-ERBB kinase inhibitor, combined with cetuximab, in patients with progressive disease (PD) on anti-EGFR treatment.Patients and Methods:Twenty-one patients with quadruple-wild-type, refractory mCRC enrolled in this 3+3 phase Ib study. Standard dosage cetuximab was administered with neratinib at 120 mg, 160 mg, 200 mg, and 240 mg/day orally in 28-day cycles. Samples were collected for molecular and pharmacokinetic studies.Results:Sixteen patients were evaluable for dose-limiting toxicity (DLT). 240 mg was determined to be the RP2D wherein a single DLT occurred (1/7 patients). Treatment-related DLTs were not seen at lower doses. Best response was stable disease (SD) in 7 of 16 (44%) patients. HER2 amplification (chromogenic in situ IHC) was detected in 2 of 21 (9.5%) treatment-naïve tumors and 4 of 16 (25%) biopsies upon trial enrollment (post-anti-EGFR treatment and progression). Compared with matched enrollment biopsies, 6 of 8 (75%) blood samples showed concordance for HER2 CNV in circulating cell-free DNA. Five SD patients had HER2 amplification in either treatment-naïve or enrollment biopsies. Examination of gene-expression, total protein, and protein phosphorylation levels showed relative upregulation of ≥2 members of the HER-family receptors or ligands upon enrollment versus matched treatment-naïve samples.Conclusions:The RP2D of neratinib in this combination was 240 mg/day, which was well tolerated with low incidence of G3 AEs. There were no objective responses; SD was seen at all neratinib doses. HER2 amplification, detectable in both tissue and blood, was more frequent post-anti-EGFR therapy.

Supplemental Figure Legends

Figure SF3 Comparisons of the expression of the NRG family of ERBB ligands, at the RNA level, between post-anti-EGFR metastatic biopsies collected upon enrollment into FC-7, and post-neratinib residual tumor tissue samples.

PDF file, 119K.

PDF file, 1583K, Thy1.1-biotin isotype control staining of gut tissues.

PDF file, 1289K, Phyla composition of colonic polyps is not significantly different between healthy and polyp-bearing mice.

PDF file, 3099K, Mastocytosis and eosinophilia representative staining in IL-10-deficiency.

Interleukin (IL)-10 is elevated in cancer and is thought to contribute to immune tolerance and tumor growth. Defying these expectations, the adoptive transfer of IL-10–expressing T cells to mice with polyposis attenuates microbial-induced inflammation and suppresses polyposis. To gain better insights into how IL-10 impacts polyposis, we genetically ablated IL-10 in T cells in APCΔ468 mice and compared the effects of treatment with broad-spectrum antibiotics. We found that T cells and regulatory T cells (Treg) were a major cellular source of IL-10 in both the healthy and polyp-bearing colon. Notably, T cell–specific ablation of IL-10 produced pathologies that were identical to mice with a systemic deficiency in IL-10, in both cases increasing the numbers and growth of colon polyps. Eosinophils were found to densely infiltrate colon polyps, which were enriched similarly for microbiota associated previously with colon cancer. In mice receiving broad-spectrum antibiotics, we observed reductions in microbiota, inflammation, and polyposis. Together, our findings establish that colon polyposis is driven by high densities of microbes that accumulate within polyps and trigger local inflammatory responses. Inflammation, local microbe densities, and polyp growth are suppressed by IL-10 derived specifically from T cells and Tregs. Cancer Res; 73(19); 5905–13. ©2013 AACR.

We applied structural equation modeling to conduct a genome-wide association study (GWAS) of the general factor measured by a Neuroticism questionnaire administered to∼380,000 partic-ipants in the UK Biobank. We categorized significant genetic variants as acting either through the Neuroticism general factor, through other factors measured by the questionnaire, or through paths independent of any factor. Regardless of this categorization, however, significant vari-ants tend to show concordant associations with all items. Bioinformatic analysis showed that the variants associated with the Neuroticism general factor disproportionately lie near or within genes expressed in the brain. Enriched gene sets point to an underlying biological basis as-sociated with brain development, synaptic function, and behaviors in mice indicative of fear and anxiety. Psychologists have long asked whether psychometric common factors are merely a convenient summary of correlated variables or causal entities with a partial biological basis, and our results provide some support for the latter interpretation. Further research is needed to determine the extent to which causes resembling common factors operate alongside other mechanisms to generate the correlational structure of personality.

The vast majority of human pancreatic ductal adenocarcinomas (PDACs) harbor TP53 mutations, underscoring p53’s critical role in PDAC suppression. PDAC can arise when pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), giving rise to premalignant pancreatic intraepithelial neoplasias (PanINs), which finally progress to PDAC. The occurrence of TP53 mutations in late-stage PanINs has led to the idea that p53 acts to suppress malignant transformation of PanINs to PDAC. However, the cellular basis for p53 action during PDAC development has not been explored in detail. Here, we leverage a hyperactive p53 variant—p53 53,54 —which we previously showed is a more robust PDAC suppressor than wild-type p53, to elucidate how p53 acts at the cellular level to dampen PDAC development. Using both inflammation-induced and KRAS G12D -driven PDAC models, we find that p53 53,54 both limits ADM accumulation and suppresses PanIN cell proliferation and does so more effectively than wild-type p53. Moreover, p53 53,54 suppresses KRAS signaling in PanINs and limits effects on the extracellular matrix (ECM) remodeling. While p53 53,54 has highlighted these functions, we find that pancreata in wild-type p53 mice similarly show less ADM, as well as reduced PanIN cell proliferation, KRAS signaling, and ECM remodeling relative to Trp53 -null mice. We find further that p53 enhances chromatin accessibility at sites controlled by acinar cell identity transcription factors. These findings reveal that p53 acts at multiple stages to suppress PDAC, both by limiting metaplastic transformation of acini and by dampening KRAS signaling in PanINs, thus providing key new understanding of p53 function in PDAC.

PURPOSE To develop recommendations involving targeted therapies for patients with advanced gastroesophageal cancer. METHODS The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS Eighteen randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS For human epidermal growth factor receptor 2 (HER2)–negative patients with gastric adenocarcinoma (AC) and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5, first-line therapy with nivolumab and chemotherapy (CT) is recommended. For HER2-negative patients with esophageal or gastroesophageal junction (GEJ) AC and PD-L1 CPS ≥ 5, first-line therapy with nivolumab and CT is recommended. First-line therapy with pembrolizumab and CT is recommended for HER2-negative patients with esophageal or GEJ AC and PD-L1 CPS ≥ 10. For patients with esophageal squamous cell carcinoma and PD-L1 tumor proportion score ≥ 1%, nivolumab plus CT, or nivolumab plus ipilimumab is recommended; for patients with esophageal squamous cell carcinoma and PD-L1 CPS ≥ 10, pembrolizumab plus CT is recommended. For patients with HER2-positive gastric or GEJ previously untreated, unresectable or metastatic AC, trastuzumab plus pembrolizumab is recommended, in combination with CT. For patients with advanced gastroesophageal or GEJ AC whose disease has progressed after first-line therapy, ramucirumab plus paclitaxel is recommended. For HER2-positive patients with gastric or GEJ AC who have progressed after first-line therapy, trastuzumab deruxtecan is recommended. In all cases, participation in a clinical trial is recommended as it is the panel's expectation that targeted treatment options for gastroesophageal cancer will continue to evolve. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

The coronavirus disease 2019 (COVID -19) pandemic caused by the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has affected almost every country in the world, resulting in severe morbidity, mortality and economic hardship, and altering the landscape of healthcare forever. Although primarily a pulmonary illness, it can affect multiple organ systems throughout the body, sometimes with devastating complications and long-term sequelae. As we move into the second year of this pandemic, a better understanding of the pathophysiology of the virus and the varied imaging findings of COVID-19 in the involved organs is crucial to better manage this complex multi-organ disease and to help improve overall survival. This manuscript provides a comprehensive overview of the pathophysiology of the virus along with a detailed and systematic imaging review of the extra-thoracic manifestation of COVID-19 with the exception of unique cardiothoracic features associated with multisystem inflammatory syndrome in children (MIS-C). In Part I, extra-thoracic manifestations of COVID-19 in the abdomen in adults and features of MIS-C will be reviewed. In Part II, manifestations of COVID-19 in the musculoskeletal, central nervous and vascular systems will be reviewed.

Although the correlation between general cognitive ability (g) and performance on speeded cognitive tasks is well-established, there is need for a better understanding of how successive stages of processing contribute to this relationship. Previous research suggests that g is primarily associated with the rapidity of decision-making rather than perceptual processing of stimuli; the implication is that g should statistically interact with a manipulation affecting the difficulty of the decision process, while simultaneously failing to interact with a perceptual manipulation. We applied Sternberg's method of additive factors to test this hypothesis in two reaction time tasks, each of which systematically manipulated the demands on perceptual acuity and decision-making. With a total of 773 participants, we found evidence of an interaction between a short-form measure of g and the decisional-but not perceptual-manipulations. This pattern was found in both number-comparison (Experiment 1) and tone-comparison (Experiment 2) tasks. Additionally, diffusion modeling of the Experiment 1 results revealed that the diffusion rate (v) is associated with g and affected by an informational attribute of the stimulus (numerical magnitude) but not a perceptual attribute (contrast); the nondecision time (Ter) is not associated with g and shows the opposite pattern of selective influence. Taken together, these findings add to the evidence for a theoretical framework partitioning reaction time into several processing stages, of which only the decision-making stage is associated with g. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Where do our political attitudes come from? Early research into the etiology of socially relevant beliefs attributed their origin primarily to the social world in which we develop. The observation that similar beliefs are reflected in our family and immediate social environments suggested that children learn these beliefs through the process of socialization. Genetically sensitive study designs later observed that the sociopolitical beliefs of identical twins are more similar than those of non-identical twins, despite being reared in the same environment, leading to an understanding of the role of genetics in the development of social attitudes. However, it has remained unclear whether and to what extent parents influence the development of these attitudes apart from or in addition to their genetic contribution. In a unique sample of 394 adoptive and biological families with adult offspring (M age = 31.8, SD = 2.7), we demonstrate strong correlations between attitudes of parents with both adoptive and non-adoptive offspring. Biometric modeling reveals a significant contribution of both maternal and paternal phenotypes apart from and in addition to genetic contribution, including evidence for gene-environment correlation. These findings have significant implications for the origin and development of political and social attitudes in a modern political sphere where the etiology of such beliefs may be more important than ever to many.

As the fight against COVID-19 continues, it is critical to discover and accumulate knowledge in scientific literature to combat the pandemic. In this work, we shared the experience in developing an intelligent query system on COVID-19 literature. We conducted a user-centered evaluation with 12 researchers in our institution and identified usability issues in four categories: distinct user needs, functionality errors, suboptimal information display, and implementation errors. Furthermore, we shared two lessons for building such a COVID-19 literature search engine. We will deploy the system and continue refining it through multiple phases of evaluation to aid in redesigning the system to accommodate different user roles as well as enhancing repository features to support collaborative information seeking. The successful implementation of the COVID-IQS can support knowledge discovery and hypothesis generation in our institution and can be shared with other institutions to make a broader impact.

As the fight against COVID-19 continues, it is critical to discover and accumulate knowledge in scientific literature to combat the pandemic. In this work, we shared the experience in developing an intelligent query system on COVID-19 literature. We conducted a user-centered evaluation with 12 researchers in our institution and identified usability issues in four categories: distinct user needs, functionality errors, suboptimal information display, and implementation errors. Furthermore, we shared two lessons for building such a COVID-19 literature search engine. We will deploy the system and continue refining it through multiple phases of evaluation to aid in redesigning the system to accommodate different user roles as well as enhancing repository features to support collaborative information seeking. The successful implementation of the COVID-IQS can support knowledge discovery and hypothesis generation in our institution and can be shared with other institutions to make a broader impact.

Background: We sought to investigate the trajectory of cardiac catheterizations for acute coronary syndrome (ACS) and out-of-hospital cardiac arrest (OHCA) during the pre-isolation (PI), strict-isolation (SI), and relaxed-isolation (RI) periods of the coronavirus disease 2019 (COVID-19) pandemic at three hospitals in Los Angeles, CA, USA. Methods: A retrospective analysis was conducted on adult patients undergoing urgent or emergent cardiac catheterization for suspected ACS or OHCA between January 1, 2020 and June 2, 2020 at three hospitals in Los Angeles, CA, USA. We designated January 1, 2020 to March 17, 2020 as the PI COVID-19 period, March 18, 2020 to May 5, 2020 as the SI COVID-19 period, and May 6, 2020 to June 2, 2020 as the RI COVID-19 period. Results: From PI to SI, there was a significant reduction in mean weekly cases of catheterizations for non-ST elevation myocardial infarction/unstable angina (NSTEMI/UA) (8.29 vs. 12.5, P = 0.019), with all other clinical categories trending downwards. From SI to RI, mean weekly cases of catheterizations for total ACS increased by 17%, NSTEMI/UA increased by 27%, and OHCA increased by 32%, demonstrating a “rebound effect”. Conclusions: Cardiac catheterizations for ACS and NSTEMI/UA exhibited a “rebound effect” once social isolation was relaxed. Cardiol Res. 2021;12(1):47-50 doi: https://doi.org/10.14740/cr1149

Purpose: In metastatic colorectal cancer (mCRC), HER2 (ERBB2) gene amplification is implicated in anti-EGFR therapy resistance. We sought to determine the recommended phase II dose (RP2D) and efficacy of neratinib, a pan-ERBB kinase inhibitor, combined with cetuximab, in patients with progressive disease (PD) on anti-EGFR treatment. Patients and Methods: Twenty-one patients with quadruple-wild-type, refractory mCRC enrolled in this 3+3 phase Ib study. Standard dosage cetuximab was administered with neratinib at 120 mg, 160 mg, 200 mg, and 240 mg/day orally in 28-day cycles. Samples were collected for molecular and pharmacokinetic studies. Results: Sixteen patients were evaluable for dose-limiting toxicity (DLT). 240 mg was determined to be the RP2D wherein a single DLT occurred (1/7 patients). Treatment-related DLTs were not seen at lower doses. Best response was stable disease (SD) in 7 of 16 (44%) patients. HER2 amplification (chromogenic in situ IHC) was detected in 2 of 21 (9.5%) treatment-naïve tumors and 4 of 16 (25%) biopsies upon trial enrollment (post-anti-EGFR treatment and progression). Compared with matched enrollment biopsies, 6 of 8 (75%) blood samples showed concordance for HER2 CNV in circulating cell-free DNA. Five SD patients had HER2 amplification in either treatment-naïve or enrollment biopsies. Examination of gene-expression, total protein, and protein phosphorylation levels showed relative upregulation of ≥2 members of the HER-family receptors or ligands upon enrollment versus matched treatment-naïve samples. Conclusions: The RP2D of neratinib in this combination was 240 mg/day, which was well tolerated with low incidence of G3 AEs. There were no objective responses; SD was seen at all neratinib doses. HER2 amplification, detectable in both tissue and blood, was more frequent post-anti-EGFR therapy.

Background DNA mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is not responsive to pembrolizumab monotherapy. DNA methyltransferase inhibitors can promote antitumor immune responses. This clinical trial investigated whether concurrent treatment with azacitidine enhances the antitumor activity of pembrolizumab in mCRC. Methods We conducted a phase 2 single-arm trial evaluating activity and tolerability of pembrolizumab plus azacitidine in patients with chemotherapy-refractory mCRC (NCT02260440). Patients received pembrolizumab 200 mg IV on day 1 and azacitidine 100 mg SQ on days 1–5, every 3 weeks. A low fixed dose of azacitidine was chosen in order to reduce the possibility of a direct cytotoxic effect of the drug, since the main focus of this study was to investigate its potential immunomodulatory effect. The primary endpoint of this study was overall response rate (ORR) using RECIST v1.1., and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Tumor tissue was collected pre- and on-treatment for correlative studies. Results Thirty chemotherapy-refractory patients received a median of three cycles of therapy. One patient achieved partial response (PR), and one patient had stable disease (SD) as best confirmed response. The ORR was 3%, median PFS was 1.9 months, and median OS was 6.3 months. The combination regimen was well-tolerated, and 96% of treatment-related adverse events (TRAEs) were grade 1/2. This trial was terminated prior to the accrual target of 40 patients due to lack of clinical efficacy. DNA methylation on-treatment as compared to pre-treatment decreased genome wide in 10 of 15 patients with paired biopsies and was significantly lower in gene promoter regions after treatment. These promoter demethylated genes represented a higher proportion of upregulated genes, including several immune gene sets, endogenous retroviral elements, and cancer-testis antigens. CD8+ TIL density trended higher on-treatment compared to pre-treatment. Higher CD8+ TIL density at baseline was associated with greater likelihood of benefit from treatment. On-treatment tumor demethylation correlated with the increases in tumor CD8+ TIL density. Conclusions The combination of pembrolizumab and azacitidine is safe and tolerable with modest clinical activity in the treatment for chemotherapy-refractory mCRC. Correlative studies suggest that tumor DNA demethylation and immunomodulation occurs. An association between tumor DNA demethylation and tumor-immune modulation suggests immune modulation and may result from treatment with azacitidine. Trial registration ClinicalTrials.gov, NCT02260440. Registered 9 October 2014, https://clinicaltrials.gov/ct2/show/NCT02260440.

Background Epacadostat, an oral, selective inhibitor of IDO1, has shown activity when administered with pembrolizumab. We evaluated the addition of chemotherapy to epacadostat and pembrolizumab in patients with advanced or metastatic solid tumors. One proposed mechanism of resistance to PD-1 checkpoint inhibition is through immunosuppression mediated by L-kynurenine. IDO1, indoleamine-2,3-dioxygenase 1 is the rate-limiting enzyme catalyzing the conversion of L-tryptophan to L-kynurenine. If IDO1 is a mechanism of tumor escape from checkpoint inhibition, then addition of an IDO1 inhibitor with a PD-1 checkpoint inhibitor could enable tumor response to immunotherapy. Methods Patients received one of 7 tumor-appropriate chemotherapy regimens. Pembrolizumab 200 mg was infused intravenously every 3 weeks. Epacadostat 100 mg was administered orally twice daily. The primary objectives of phase I were determining safety/tolerability and defining the maximum tolerated or pharmacologically active dose of epacadostat. Phase II of the study was designed to enroll efficacy-expansion cohorts and to assess changes in the tumor and tumor microenvironment via mandatory-biopsy cohorts. Results A total of 70 patients were enrolled. Twelve patients were enrolled in the phase II mandatory-biopsy cohorts. Due to early study closure, efficacy expansion did not enroll. Grades 3 and 4 treatment-emergent adverse events (TEAEs) occurred in 78.6% of patients. Neutropenia and disease progression were the only grades 3 and 4 TEAEs reported in ≥10.0% of patients. One treatment-related death was reported. The ORR was 31.4% across all treatment groups. Conclusion The combination of epacadostat 100 mg bid with pembrolizumab and chemotherapy had an acceptable safety profile. This regimen showed antitumor activity across multiple types of advanced or metastatic solid tumors (ClinicalTrials.gov Identifier: NCT03085914).

PURPOSE: We investigated the combination of tivantinib, a c-MET tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-VEGF-A antibody. METHODS: Patients with advanced solid tumors received bevacizumab (10 mg/kg intravenously every 2 weeks) and escalating doses of tivantinib (120–360 mg orally twice daily). In addition to safety and preliminary efficacy, we evaluated pharmacokinetics of tivantinib and its metabolites, as well as pharmacodynamic biomarkers in peripheral blood and skin. RESULTS: Eleven patients received the combination treatment, which was generally well tolerated. The main dose-limiting toxicity was grade 3 hypertension, which was observed in four patients. Other toxicities included lymphopenia and electrolyte disturbances. No exposure-toxicity relationship was observed for tivantinib or metabolites. No clinical responses were observed. Mean levels of the serum cytokine bFGF increased (p = 0.008) after the bevacizumab-only lead-in and decreased back to baseline (p = 0.047) after addition of tivantinib. Tivantinib reduced levels of both phospho-MET (7/11 patients) and tubulin (4/11 patients) in skin. CONCLUSIONS: The combination of tivantinib and bevacizumab produced toxicities that were largely consistent with the safety profiles of the individual drugs. The study was terminated prior to establishment of the recommended phase II dose (RP2D) due to concerns regarding the mechanism of tivantinib, as well as lack of clinical efficacy seen in this and other studies. Tivantinib reversed the upregulation of bFGF caused by bevacizumab, which has been considered a potential mechanism of resistance to therapies targeting the VEGF pathway. The findings from this study suggest that the mechanism of action of tivantinib in humans may involve inhibition of both c-MET and tubulin expression. TRIAL REGISTRATION: NCT01749384 (First posted 12/13/2012).

OBJECTIVES: Eosinophilic esophagitis (EoE), a chronic food allergic disease, lacks sensitive and specific peripheral biomarkers. We hypothesized that levels of EoE-related biomarkers captured using a 1-hour minimally invasive Esophageal String Test (EST) would correlate with mucosal eosinophil counts and tissue concentrations of these same biomarkers. We aimed to determine whether a 1-hour EST accurately distinguishes active from inactive EoE or a normal esophagus. METHODS: In a prospective, multisite study, children and adults (ages 7–55 years) undergoing a clinically indicated esophagogastroduodenoscopy performed an EST with an esophageal dwell time of 1 hour. Subjects were divided into 3 groups: active EoE, inactive EoE, and normal esophageal mucosa. Eosinophil-associated protein levels were compared between EST effluents and esophageal biopsy extracts. Statistical modeling was performed to select biomarkers that best correlated with and predicted eosinophilic inflammation. RESULTS: One hundred thirty-four subjects (74 children, 60 adults) with active EoE (n = 62), inactive EoE (n = 37), and patient controls with a normal esophagus (n = 35) completed the study. EST-captured eosinophil-associated biomarkers correlated significantly with peak eosinophils/high-power field, endoscopic visual scoring, and the same proteins extracted from mucosal biopsies. Statistical modeling, using combined eotaxin-3 and major basic protein-1 concentrations, led to the development of EoE scores that distinguished subjects with active EoE from inactive EoE or normal esophagi. Eighty-seven percent of children, 95% of parents, and 92% of adults preferred the EST over endoscopy if it provided similar information. DISCUSSION: The 1-hour EST accurately distinguishes active from inactive EoE in children and adults and may facilitate monitoring of disease activity in a safe and minimally invasive fashion.

Similarities between parent and offspring are widespread in psychology; however, shared genetic variants often confound causal inference for offspring outcomes. A polygenic score (PGS) derived from genome-wide association studies (GWAS) can be used to test for the presence of parental influence that controls for genetic variants shared across generations. We use a PGS for educational attainment (EA3; N ≈ 750 thousand) to predict offspring years of education in a sample of 2517 twins and both parents. We find that within families, the dizygotic twin with the higher PGS is more likely to attain higher education (unstandardized β = 0.32; p < 0.001). Additionally, however, we find an effect of parental genotype on offspring outcome that is independent of the offspring’s own genotype; this raises the variance explained in offspring years of education from 9.3 to 11.1% (ΔR(2) = 0.018, p < 0.001). Controlling for parental IQ or socioeconomic status substantially attenuated or eliminated this effect of parental genotype. These findings suggest a role of environmental factors affected by heritable characteristics of the parents in fostering offspring years of education.

Epithelial barrier dysfunction is a significant factor in many allergic diseases, including eosinophilic esophagitis (EoE). Infiltrating leukocytes and tissue adaptations increase metabolic demands and decrease oxygen availability at barrier surfaces. Understanding of how these processes impact barrier is limited, particularly in allergy. Here, we identified a regulatory axis whereby the oxygen-sensing transcription factor HIF-1α orchestrated epithelial barrier integrity, selectively controlling tight junction CLDN1 (claudin-1). Prolonged experimental hypoxia or HIF1A knockdown suppressed HIF-1α–dependent claudin-1 expression and epithelial barrier function, as documented in 3D organotypic epithelial cultures. L2-IL5(OXA) mice with EoE-relevant allergic inflammation displayed localized eosinophil oxygen metabolism, tissue hypoxia, and impaired claudin-1 barrier via repression of HIF-1α/claudin-1 signaling, which was restored by transgenic expression of esophageal epithelial-targeted stabilized HIF-1α. EoE patient biopsy analysis identified a repressed HIF-1α/claudin-1 axis, which was restored via pharmacologic HIF-1α stabilization ex vivo. Collectively, these studies reveal HIF-1α’s critical role in maintaining barrier and highlight the HIF-1α/claudin-1 axis as a potential therapeutic target for EoE.

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the United States. Although immunotherapy has dramatically changed the landscape of treatment for many advanced cancers, the benefit in CRC has thus far been limited to patients with microsatellite instability high (MSI-H):DNA mismatch repair–deficient (dMMR) tumors. Recent studies in the refractory CRC setting have led to US Food and Drug Administration approvals for pembrolizumab as well as nivolumab (with or without ipilimumab) for tumors harboring an MSI-H:dMMR molecular profile. Several randomized controlled trials are underway to move immunotherapy into the frontline for metastatic cancer (with or without chemotherapy) and the adjuvant setting. Awareness of these studies is critical given the relatively low incidence (approximately 3%–5%) of MSI-H:dMMR in advanced or metastatic CRC to support study completion, because the results could be potentially practice changing. The real challenge in this disease is related to demonstrating the benefit of immunotherapy for the vast majority of patients with CRC not harboring MSI-H:dMMR. Given the rapid pace of scientific changes, this article provides a narrative review regarding the current landscape of immunotherapy for CRC. Particular attention is paid to the currently available data that inform today’s clinical practice along with upcoming randomized controlled trials that may soon dramatically change the treatment landscape for CRC.

3569 Background: Most pts with mCRC have microsatellite stable (MSS) disease (95%) which is unresponsive to checkpoint inhibition. Chemotherapy activity is mediated through both cytotoxicity as well as immunological effects including reduced T-regulatory cell activity, enhanced tumor antigen presentation, and induced PD-L1 tumor cell expression. Chemotherapy with checkpoint inhibitors can potentially activate T cells and alter the microenvironment to improve outcomes. Our purpose was to evaluate pembro plus pem in a safety run-in (cohort 1) and the same with dose-escalated oxali (cohort 2). Methods: Eligible pts with MSS mCRC had ECOG PS of 0-1, measurable metastatic disease, adequate organ function, and prior treatment with fluoropyrimidine-, oxali-, and irinotecan-based therapies (plus an anti-EGFR agent, if apropos). Cohort 1 treatment was pem 500 mg/m2 IV plus pembro 200 mg IV every 3 wks. Cohort 2 treatment was the same, plus oxali at an escalating dose of 85-120 mg/m2 utilizing a 3+3 design with expansion of 6 additional pts at the RP2D. Imaging was performed every 3 cycles; response was determined by RECIST 1.1. Primary endpoint (EP) of each cohort: safety and best ORR with cohort 2 also to establish the RP2D. Secondary EPs: Clinical benefit rate (CBR), PFS, OS at 1 year, and exploratory assessments of circulating immunologic profiles and molecular predictors of response. Descriptive statistics were planned as a signal-seeking study. Results: From Jul 2019-Apr 2021, 34 pts enrolled from 4 different centers. In cohort 1 (n=15), one pt was taken off study due to LFT elevation and orchitis attributed to pembro with reduced lymphadenopathy upon withdrawal. There was 1 PR (duration 686 days) and 4 SDs (61, 66, 124, 128 days) among 11 evaluable for response. There were no unexpected nor grade 5 toxicities. In cohort 2 (n=19), 2 pts achieved a PR (127 and 185 days), with SDs in 5 (59, 63, 69, 115, 437), among 13 evaluable for response. At oxali dose of 85 mg/m2, 1/6 pts had DLT (grade 4 neutropenia ≥7 days); another 1/6 pts had DLT at 120 mg/m2 (grade 3 AST/ALT). The RP2D was 120 mg/m2. Common grade 3/4 AEs included: neutropenia (24%), anemia (9%), fatigue (9%), abdominal pain (6%), nausea (6%), and ALT/AST (6%). There was no febrile neutropenia nor any grade 5 events. Combined cohort rates of PR/CBR were 3/24 (12.5%) and 12/24 (50%), respectively. Conclusions: In this study of heavily pretreated pts with MSS mCRC, combining pembro plus pem or pem+oxali was well tolerated. Overall CBR was 50%, with objective responses (PRs) in 3/24 (12.5%) evaluable pts. This compares favorably with KEYNOTE 016, in which pembro in MSS mCRC pts had 0/18 objective responses and CBR=11% (2/18). Further studies testing these agents in earlier lines of treatment with robust correlative analyses is supported. Support: NSABP Foundation; Merck; Lilly. Clinical trial information: NCT03626922.

Biliary tract cancers are rare, aggressive neoplasms. Most patients present with advanced/unresectable or metastatic disease at diagnosis, and no second-line regimen has demonstrated clinical benefit. This was a phase 2 study evaluating the efficacy and safety of regorafenib in patients who had advanced/unresectable or metastatic disease after receiving standard therapy.In this single arm-study, patients with advanced/unresectable or metastatic biliary tract cancer who failed at least 1 line of systemic chemotherapy received regorafenib once daily on a schedule of 21-days on/7-days off in a 28-day cycle. Patients initially received a standard 160 mg dose. After toxicity assessments in the first 3 patients, the dose was reduced to 120 mg for subsequent patients, as preplanned. The primary endpoint was progression-free survival (PFS). Secondary objectives included overall survival (OS), the objective response rate, and the disease control rate.Forty-three patients received at least 1 dose of regorafenib, and 34 patients who received at least 1 cycle of treatment were evaluable for tumor response. The median PFS was 15.6 weeks (90% confidence interval, 12.9-24.7 weeks), and the median OS was 31.8 weeks (90% confidence interval, 13.3-74.3 weeks), with survival rates 40% at 12 months and 32% at 18 months. A partial response was achieved in 5 patients (11%), and 19 had stable disease (44%), for a disease control rate of 56%. The toxicity profile was as expected, with grade 3 and 4 adverse events reported in 40% of patients. The most common toxicities were hypophosphatemia (40%), hyperbilirubinemia (26%), hypertension (23%), and hand-foot skin reaction (7%).The current results suggest promising efficacy of regorafenib in patients with chemotherapy-refractory, advanced/metastatic biliary tract cancer, warranting further studies to confirm its clinical efficacy. There is a clear unmet need for effective therapies in patients who have advanced and metastatic biliary tract cancer.

Metastatic colorectal cancer (mCRC) continues to be associated with a poor prognosis, and there remains a significant unmet need for novel agents and treatment regimens. Major breakthroughs have been made with immune checkpoint blockade therapy in several disease types, including DNA mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) tumors. To date, however, immune checkpoint monotherapy has not shown significant clinical activity in the treatment of patients with mismatch repair proficient (pMMR)/non-MSI-H mCRC. The immune resistance mechanisms in pMMR/non-MSI-H mCRC have not yet been clearly elucidated. Significant efforts are currently focused on identifying effective combination immunotherapy regimens for the treatment of patients with pMMR/non-MSI-H mCRC. The combination of atezolizumab with cobimetinib had shown promising clinical activity in an early-phase clinical trial. Unfortunately, the IMblaze 370 (COTEZO) phase III trial of atezolizumab/cobimetinib combination in patients with mCRC failed to show significant improvement in overall survival in patients treated with the atezolizumab/combimetinib combination in comparison to regorafenib alone. This review summarizes the recent major advances in the clinical development of immunotherapy regimens for patients with pMMR/non-MSI-H mCRC.