Memory-like differentiation enhances NK cell responses against colorectal cancer.

Metastatic (m) colorectal cancer (CRC) is an incurable disease with a poor prognosis and thus remains an unmet clinical need. Immune checkpoint blockade (ICB)-based immunotherapy is effective for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC patients, but it does not benefit the majority of mCRC patients. NK cells are innate lymphoid cells with potent effector responses against a variety of tumor cells but are frequently dysfunctional in cancer patients. Memory-like (ML) NK cells differentiated after IL-12/IL-15/IL-18 activation overcome many challenges to effective NK cell anti-tumor responses, exhibiting enhanced recognition, function, and in vivo persistence. We hypothesized that ML differentiation enhances the NK cell responses to CRC. Compared to conventional (c) NK cells, ML NK cells displayed increased IFN-γ production against both CRC cell lines and primary patient-derived CRC spheroids. ML NK cells also exhibited improved killing of CRC target cells in vitro in short-term and sustained cytotoxicity assays, as well as in vivo in NSG mice. Mechanistically, enhanced ML NK cell responses were dependent on the activating receptor NKG2D as its blockade significantly decreased ML NK cell functions. Compared to cNK cells, ML NK cells exhibited greater antibody-dependent cytotoxicity when targeted against CRC by cetuximab. ML NK cells from healthy donors and mCRC patients exhibited increased anti-CRC responses. Collectively, our findings demonstrate that ML NK cells exhibit enhanced responses against CRC targets, warranting further investigation in clinical trials for mCRC patients, including those who have failed ICB.

Performance of ASCVD Risk Prediction Models in Individuals With Inflammatory Bowel Disease: A UK Biobank Study.

This study suggests that the current atherosclerotic cardiovascular disease risk prediction models used in clinical practice performed better in the non­inflammatory bowel disease (IBD) cohort compared with IBD, highlighting the need for a more specific risk prediction model tailored to the IBD population.

NAFLD Is Associated With Quiescent Rather Than Active Crohn's Disease.

BACKGROUND AND AIMS: Crohn's disease (CD) confers an increased risk of nonalcoholic fatty liver disease (NAFLD), but the pathogenesis remains poorly understood. We determined if active intestinal inflammation increases the risk of NAFLD in patients with CD. METHODS: Two cohorts (2017/2018 and 2020) with CD and no known liver disease were enrolled consecutively during staging magnetic resonance enterography. We quantified proton density fat fraction, MaRIA (Magnetic Resonance Index of Activity), and visceral adipose tissue. NAFLD was diagnosed when proton density fat fraction ≥5.5%. Synchronous endoscopy was graded by the Simple Endoscopic Score for CD and Rutgeerts score, while clinical activity was graded by the Harvey-Bradshaw index. Cytokine profiling was performed for the 2020 cohort. Transient elastography and liver biopsy were requested by standard of care. RESULTS: NAFLD was diagnosed in 40% (n = 144 of 363), with higher prevalence during radiographically quiescent disease (odds ratio, 1.7; P = .01), independent of body mass index/visceral adipose tissue (adjusted odds ratio, 7.8; P = .03). These findings were corroborated by endoscopic disease activity, but not by aggregate clinical symptoms. Circulating interleukin-8 was independent of body mass index to predict NAFLD, but traditional proinflammatory cytokines were not. NAFLD subjects had similar liver stiffness estimates regardless of CD activity. Definitive or borderline steatohepatitis was present in most patients that underwent liver biopsy. CONCLUSIONS: Quiescent CD is associated with risk of NAFLD. These findings suggest potentially distinct pathogenic mechanisms of NAFLD in patients with CD compared with the prevailing leaky gut hypothesis proposed for individuals without inflammatory bowel disease. Future validation and mechanistic studies are needed to dissect these distinct disease modifying factors.

Crohn's disease patients had an independently increased risk for nonalcoholic fatty liver disease when the disease was quiescent, measured by magnetic resonance/endoscopy, and was unrelated to symptom severity. Nonalcoholic fatty liver disease was associated with the pleiotropic cytokine interleukin (IL)-8/CXCL8 but not with traditional proinflammatory cytokines (eg, tumor necrosis factor α, IL-1, IL-6).

Nonalcoholic Fatty Liver Disease Is a Risk Factor for Thiopurine Hepatotoxicity in Crohn's Disease.

Background: Patients with Crohn's disease (CD) are predisposed to nonalcoholic fatty liver disease (NAFLD). CD management often includes thiopurines which can promote hepatotoxicity. We aimed to identify the role of NAFLD on the risk of developing liver injury from thiopurines in CD. Methods: In this prospective cohort analysis, CD patients at a single center were recruited 6/2017-5/2018. Patients with alternative liver diseases were excluded. The primary outcome was time to elevation of liver enzymes. Patients underwent MRI with assessment of proton density fat fraction (PDFF) on enrollment, where NAFLD was defined as PDFF >5.5%. Statistical analysis was performed using a Cox-proportional hazards model. Results: Of the 311 CD patients studied, 116 (37%) were treated with thiopurines, 54 (47%) of which were found to have NAFLD. At follow-up, there were 44 total cases of elevated liver enzymes in those treated with thiopurines. Multivariable analysis demonstrated that NAFLD was a predictor of elevated liver enzymes in patients with CD treated with thiopurines (HR 3.0, 95% CI 1.2-7.3, P = .018) independent of age, body mass index, hypertension, and type 2 diabetes. Steatosis severity by PDFF positively correlated with peak alanine aminotransferase (ALT) at follow-up. Kaplan-Meier analysis demonstrated poorer complication-free survival (log-rank 13.1, P < .001). Conclusions: NAFLD at baseline is a risk factor for thiopurine-induced hepatotoxicity in patients with CD. The degree of liver fat positively correlated with the degree of ALT elevation. These data suggest that evaluation for hepatic steatosis be considered in patients with liver enzyme elevations with thiopurine therapy.

Healthcare Disparities Among Homeless Patients Hospitalized With Gastrointestinal Bleeding: A Propensity-Matched, State-Level Analysis.

GOALS: Examine outcomes among homeless patients admitted with gastrointestinal (GI) bleeding, including all-cause mortality and endoscopic intervention rates. BACKGROUND: Hospitalizations among homeless individuals have increased steadily since at least 2007 but little is known about GI outcomes in these patients. STUDY: The 2010-2014 Healthcare Utilization Project (HCUP) State Inpatient Databases from New York and Florida were used to identify adults admitted with a primary diagnosis of acute upper or lower GI bleed. Homeless patients were 1:3 matched with nonhomeless patients using a propensity-score greedy-matched algorithm. The primary outcome (all-cause in-hospital mortality) and secondary outcomes (30-day readmission rates, endoscopy utilization, length of stay, and total hospitalization costs) were compared. RESULTS: We matched 4074 homeless patients with 12,222 nonhomeless patients. Most hospitalizations for homeless individuals were concentrated in 113 (26.4%) of 428 hospitals. Homeless adults were more likely to be younger, male, African American or Hispanic, and on Medicaid. They experienced significantly higher odds of all-cause inpatient mortality compared with nonhomeless patients admitted with GI bleeding (OR 1.37, 95% CI 1.11-1.69). Endoscopy utilization rates were also lower for both upper (OR 0.62, 95% CI 0.55-0.71) and lower (OR 0.76, 95% CI 0.68-0.85) GI bleeding, though upper endoscopy rates within the first 24 hours were comparable (OR 1.11, 95% CI 1.00-1.23). Total hospitalization costs were lower ($9,715 vs. $12,173, P <0.001) while 30-day all-cause readmission rates were significantly higher in the homeless group (14.9% vs. 18.4%, P <0.001). CONCLUSIONS: Homeless patients hospitalized for GI bleeding face disparities, including higher mortality rates and lower endoscopy utilization.

Inflammatory Bowel Disease Is Associated With an Increased Risk of Incident Acute Arterial Events: Analysis of the United Kingdom Biobank.

BACKGROUND & AIMS: Population-based studies have suggested an increased risk of acute arterial events (AAEs) in patients with inflammatory bowel disease (IBD). We aimed to assess the risk of incident AAEs and premature AAEs, adjusted for diet, physical activity, and inflammation biomarkers, in participants with IBD in the UK Biobank (UKB) METHODS: UKB participants with IBD and without prevalent AAEs at enrollment were matched to random non-IBD controls. A Cox regression model, adjusting for baseline cardiovascular and IBD risk factors, diet, physical activity, and high-sensitivity C-reactive protein, estimated adjusted hazard ratios (aHRs) for association between IBD and AAEs or premature AAEs (age, <55 years for men and <65 years for women). Predictors of AAEs within the IBD cohort were identified in a Cox model adjusting for disease severity (IBD-related hospitalizations or surgeries). RESULTS: Among 455,950 UKB participants, 5094 with IBD were matched to 20,376 non-IBD controls. After a median follow-up period of 12.4 years, participants with IBD had a higher incident rate of AAE (924.1 vs 730.9 per 100,000 person years; P < .001), risk of all AAEs (aHR, 1.19; 95% CI, 1.08-1.31; P < .001), and premature AAEs (aHR, 1.38; 95% CI, 1.11-1.72; P = .001). High-sensitivity C-reactive protein levels (highest quartile: aHR, 1.53; 95% CI, 1.15-2.03) and disease severity (aHR, 5.40; 95% CI, 4.03-7.22) were independent predictors of AAE in IBD. CONCLUSIONS: In a prospective cohort, there was an increased risk of incident AAEs and premature AAEs in IBD participants. Beyond traditional AAE risk factors, quantifiable indices of IBD disease activity and severity were independent predictors of AAEs.

Systematic Review With Meta-analysis: Safety and Effectiveness of Combining Biologics and Small Molecules in Inflammatory Bowel Disease.

Background: Combining biologics and small molecules could potentially overcome the plateau of drug efficacy in inflammatory bowel disease (IBD). We conducted a systematic review and meta-analysis to assess the safety and effectiveness of dual biologic therapy (DBT), or small molecule combined with a biologic therapy (SBT) in IBD patients. Methods: We searched MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, and Clinical trials.gov until November 3, 2020, including studies with 2 or more IBD patients on DBT or SBT. Main outcome was safety assessed as pooled rates of adverse events (AEs) and serious AEs (SAEs) for each combination. Effectiveness was reported as pooled rates of clinical, endoscopic, and/or radiographic response and remission. The certainty of evidence was rated according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Results: Of the 3688 publications identified, 13 studies (1 clinical trial, 12 observational studies) involving 266 patients on 7 different combinations were included. Median number of prior biologics ranged from 0 to 4, and median duration of follow-up was 16-68 weeks. Most common DBT and SBT were vedolizumab (VDZ) with anti-tumor necrosis factor (aTNF, n = 56) or tofacitinib (Tofa, n = 57), respectively. Pooled rates of SAE for these were 9.6% (95% confidence interval [CI], 1.5-21.4) for VDZ-aTNF and 1.0% (95% CI, 0.0-7.6) for Tofa-VDZ. The overall certainty of evidence was very low due to the observational nature of the studies, and very serious imprecision and inconsistency. Conclusions: DBT or SBT appears to be generally safe and may be effective in IBD patients, but the evidence is very uncertain.

The Impact of Night-time Emergency Department Presentation on Upper Gastrointestinal Hemorrhage Outcomes.

GOALS: The aim was to investigate the impact of night-time emergency department (ED) presentation on outcomes of patients admitted for acute upper gastrointestinal hemorrhage (UGIH). BACKGROUND: The relationship between time of ED presentation and outcomes of gastrointestinal hemorrhage is unclear. STUDY: Using the 2016 and 2017 Florida State Inpatient Databases which provide times of ED arrival, we identified and categorized adults hospitalized for UGIH to daytime (07:00 to 18:59 h) and night-time (19:00 to 06:59 h) based on the time of ED presentation. We matched both groups with propensity scores, and assessed their clinical outcomes including all-cause in-hospital mortality, in-hospital endoscopy utilization, length of stay (LOS), total hospitalization costs, and 30-day all-cause readmission rates. RESULTS: Of the identified 38,114 patients with UGIH, 89.4% (n=34,068) had acute nonvariceal hemorrhage (ANVH), while 10.6% (n=4046) had acute variceal hemorrhage (AVH). Compared with daytime patients, ANVH patients admitted at night-time had higher odds of in-hospital mortality (odds ratio: 1.32; 95% confidence interval: 1.06-1.60), lower odds of in-patient endoscopy (odds ratio: 0.83; 95% confidence interval: 0.77-0.90), higher total hospital costs ($9911 vs. $9545, P <0.016), but similar LOS and readmission rates. Night-time AVH patients had a shorter LOS (5.4 vs. 5.8 d, P =0.045) but similar mortality rates, endoscopic utilization, total hospitalization costs, and readmission rates as daytime patients. CONCLUSIONS: Patients arriving in the ED at night-time with ANVH had worse outcomes (mortality, hospitalization costs, and endoscopy utilization) compared with daytime patients. However, those with AVH had comparable outcomes irrespective of ED arrival time.

STEMI associated with SARS-CoV-2 infection and the use of ECMO as a potential therapeutic approach in addition to the PCI.

A 55-year-old male presented to the emergency department with the complaints of chest pain that started 4 h before presentation. Pain was located over the anterior chest, 5 out of 10 intensity, with radiation to the left arm. Chest x-ray on admission showed severe diffuse bilateral pulmonary infiltrates concerning for COVID-19 pneumonia. Electrocardiogram showed inferior and lateral ST-segment elevation compatible with acute inferolateral myocardial infarction. Successful percutaneous coronary intervention (PCI) of the proximal and mid-right coronary artery using the balloon angioplasty and drug-eluting stent was performed. Post-PCI stenosis was 0% with a thrombolysis in myocardial infarction (TIMI) flow of 3. Five-day course of azithromycin and hydroxychloroquine was completed with no improvement overall. Patient received two doses of 400 mg of tocilizumab intravenously on hospital days 5 (HD#5) and #6. The patient was proned, on FiO2 100%, PEEP 15 cm H2O, on epoprostenol sodium and paralytics and eventually received venovenous ECMO, which improved outcome.

Predictors, rates, and trends of opioid use disorder among patients hospitalized with chronic pancreatitis.

BACKGROUND: Patients with chronic pancreatitis (CP) suffer from pain and receive increased opioid prescriptions with a high risk of opioid use disorder (OUD). We studied the predictors, trends and outcomes of OUD among patients hospitalized with CP. METHODS: Records with CP (with/without OUD) were extracted from the Nationwide Inpatient Sample (NIS) 2012-2014, and the association of OUD with the burden of CP was calculated. We then charted the trends of OUD and its interaction with concomitant CP from NIS 2007-2014 (SAS 9.4). RESULTS: In the period 2012-2014, 4349 (4.99%) of the 87,068 CP patients had concomitant OUD, with higher risk among patients who were young, females, white vs. Hispanics, and individuals with chronic back pain, arthritis, non-opioid substance use, mental health disorders, and those hospitalized in urban centers. OUD was associated with a longer hospital stay (6.9 vs. 6.5 days, P=0.0015) but no significant difference in charges ($47,151 vs. $49,017, P=0.0598) or mortality (1.64% vs. 0.74%, P=0.0506). From 2007-2014, the average yearly rate of OUD was 174 cases per 10,000 hospitalizations (174/10,000), almost 3 times higher among CP vs. non-CP (479/10,000 vs. 173/10,000, P<0.001), and it increased from 2007 to 2014 (135/10,000 to 216/10,000, P<0.001). The yearly increase was 2.7 times higher among patients with CP vs. non-CP (29.9/10,000 vs. 11.3/10,000 hospitalizations/year, P<0.001). CONCLUSIONS: CP is associated with higher rates and trends of OUD. Patients with CP at high risk of OUD may benefit from alternate analgesic regimens or surveillance for OUD when they are prescribed opioids.

Real-World Effectiveness and Safety of Tofacitinib in Crohn's Disease and IBD-U: A Multicenter Study From the TROPIC Consortium.

The safety and efficacy of tofacitinib in Crohn's disease (CD) has been studied in 2 phase II trials in patients with moderate-to-severe CD with no new safety signals observed, but no significant difference from placebo in the primary efficacy endpoint of clinical response.1-3 However, post hoc analyses and smaller studies have observed clinical and biologic response to tofacitinib in patients with CD.2,4,5 There is a paucity of real-world effectiveness and safety data for tofacitinib in non-Food and Drug Administration label usage in patients with CD and patients with inflammatory bowel disease-unclassified (IBD-U).

Safety of Tofacitinib in a Real-World Cohort of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Adverse events (AEs) including reactivation of herpes zoster (HZ) and venous thromboembolism (VTE) have been reported from clinical trials of tofacitinib in ulcerative colitis (UC). We investigated the incidence rates of AEs in a real-world study of UC patients given tofacitinib. METHODS: We collected data from 260 patients with UC in the Tofacitinib Real-world Outcomes in Patients with ulceratIve colitis and Crohn's disease consortium study, performed at 6 medical centers in the United States. Patients were followed up for a median of 6 months (interquartile range, 2.7-11.5 mo). AEs were captured using a standardized data collection instrument before study initiation and at weeks 8, 16, 26, 39, and 52. Serious AEs were defined as life-threatening or resulting in a hospitalization, disability, or discontinuation of therapy. Logistic regression was performed to examine risk factors for AEs. RESULTS: AEs occurred in 41 patients (15.7%); most were infections (N = 13; 5.0%). The incidence rate of any AE was 27.2 (95% CI, 24.4-30.7 per 100 patient-years of follow-up evaluation). Fifteen were serious AEs (36.6% of AEs), and tofacitinib was discontinued for 12 patients (4.6% of cohort). The incidence rates of serious AEs was 10.0 (95% CI, 8.9-11.2 per 100 patient-years of follow-up evaluation). Five patients developed HZ infection and 2 developed VTE (all receiving 10 mg tofacitinib, twice per day). CONCLUSIONS: Real-world safety signals for tofacitinib are similar to those for clinical trials, with AEs reported from almost 16% of patients. HZ infection and VTE occurred in patients receiving 10 mg tofacitinib twice per day. These results support dose de-escalation after induction therapy, to reduce the risk of AEs.

Gender and Racial Differences in Hospitalizations for Primary Biliary Cholangitis in the USA.

BACKGROUND/AIM: The prevalence, characteristics, burden and trends of primary biliary cholangitis (PBC) hospitalizations in the USA remain unclear. METHOD: We identified primary PBC hospitalizations from the National Inpatient Sample (NIS) 2007 through 2014 using ICD-9-CM codes. We calculated the rates and trends of hospitalization for PBC per 100,000 US population among each gender (males and females) and racial categories (Whites, Blacks, Hispanics and other racial minorities), and measured the predictors of hospitalization, and of mortality, charges and length of stay (LOS) among PBC hospitalizations. RESULT: There were 8460 (weighted: 41,191) PBC hospitalizations between 2007 and 2014. The mean national PBC hospitalization rate was 2.2 cases per 100,000 population (2.2/100,000), increasing from 1.7/100,000 (2007) to 2.5/100,000 (2014). From 2007 to 2014, the in-hospital mortality and LOS were unchanged while the charges increased from $65,993 to $73,093 ($225 million to $447 million overall expenses). Compared to Whites, the PBC hospitalization rate was 12% higher among Hispanics (RR: 1.12 [1.09-1.16]), 53% lower in Blacks (RR: 0.47 [0.45-0.49]) and 5% lower among other racial minorities (0.95 [0.91-0.99]). The rate was higher among females (RR:4.02 [3.93-4.12]) compared to males. On multivariate analysis, Blacks and other racial minorities, respectively, had higher odds of mortality (AOR: 1.47 [1.03-2.10] and 1.33 [0.96-1.84]), while other racial minorities had longer LOS (7.0 vs. 5.6 days) and higher hospital charges ($48,984 vs. $41,495) when compared to Whites. CONCLUSION: The hospitalization rate and burden of PBC in the USA have increased disproportionately among females and Hispanics with higher mortality in Blacks.

Tumor Interferon Signaling Is Regulated by a lncRNA INCR1 Transcribed from the PD-L1 Locus.

Tumor interferon (IFN) signaling promotes PD-L1 expression to suppress T cell-mediated immunosurveillance. We identify the IFN-stimulated non-coding RNA 1 (INCR1) as a long noncoding RNA (lncRNA) transcribed from the PD-L1 locus and show that INCR1 controls IFNγ signaling in multiple tumor types. Silencing INCR1 decreases the expression of PD-L1, JAK2, and several other IFNγ-stimulated genes. INCR1 knockdown sensitizes tumor cells to cytotoxic T cell-mediated killing, improving CAR T cell therapy. We discover that PD-L1 and JAK2 transcripts are negatively regulated by binding to HNRNPH1, a nuclear ribonucleoprotein. The primary transcript of INCR1 binds HNRNPH1 to block its inhibitory effects on the neighboring genes PD-L1 and JAK2, enabling their expression. These findings introduce a mechanism of tumor IFNγ signaling regulation mediated by the lncRNA INCR1 and suggest a therapeutic target for cancer immunotherapy.

Glioblastoma infiltration of both tumor- and virus-antigen specific cytotoxic T cells correlates with experimental virotherapy responses.

The mode of action for oncolytic viruses (OVs) in cancer treatment is thought to depend on a direct initial cytotoxic effect against infected tumor cells and subsequent activation of immune cell responses directed against the neoplasm. To study both of these effects in a mouse model of glioblastoma (GBM), we employed murine GBM cells engineered to constitutively express the type I Herpes Simplex Virus (HSV1) HSV-1 receptor, nectin-1, to allow for more efficient infection and replication by oncolytic HSV (oHSV). These cells were further engineered with a surrogate tumor antigen to facilitate assays of T cell activity. We utilized MRI-based volumetrics to measure GBM responses after injection with the oHSV and bioluminescent imaging (BLI) to determine oHSV replicative kinetics in the injected tumor mass. We found increased infiltration of both surrogate tumor antigen- and oHSV antigen-specific CD8+ T cells within 7 days after oHSV injection. There was no increase in tumor infiltrating CD8+ T cells expressing "exhaustion" markers, yet oHSV infection led to a reduction in PD-1+ CD8+ T cells in injected GBMs and an increase in IFNγ+ CD8+ T cells. There was a significant direct correlation between oHSV-mediated reduction in GBM volume and increased infiltration of both viral and tumor antigen-specific CD8+ T cells, as well as oHSV intratumoral gene activity. These findings imply that CD8+ T cell cytotoxicity against both tumor and viral antigens as well as intratumoral oHSV gene expression are important in oHSV-mediated GBM therapy.

Predictors, burden and impact of cardiac arrhythmias among patients hospitalized with end-stage liver disease.

BACKGROUND: Cirrhotic cardiomyopathy, hyperammonemia, and hepatorenal syndrome predispose to cardiac arrhythmias in End-stage liver disease (ESLD). OBJECTIVES: Among ESLD hospitalizations, we evaluate the distribution and predictors of arrhythmias and their impact on hospitalization outcomes. METHODS: We selected ESLD records from the Nationwide Inpatient Sample (2007-2014), identified concomitant arrhythmias (tachyarrhythmias and bradyarrhythmias), and their demographic and comorbid characteristics, and estimated the effect of arrhythmia on outcomes (SAS 9.4). RESULTS: Of 57,119 ESLD hospitalizations, 6,615 had arrhythmias with higher odds with increasing age, males, jaundice, hepatorenal syndrome, alcohol use, and cardiopulmonary disorders. The most common arrhythmias were atrial fibrillation, cardiac arrest/asystole, and ventricular tachycardia. After propensity-matching (arrhythmia: no-arrhythmia, 6,609:6,609), arrhythmias were associated with 200% higher mortality, 1.7-days longer stay, $32,880 higher cost, and higher rates of shock, respiratory and kidney failures. CONCLUSIONS: Due to worse outcomes with arrhythmias, there is a need for better screening and follow-up of ESLD patients for dysrhythmias.