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Abstract We report 14 cases of immune effector cell (IEC)-associated enterocolitis following chimeric antigen receptor T-cell (CAR-T) therapy in multiple myeloma, with a 1.2% incidence overall (0.2% for idecabtagene vicleucel and 2.2% for ciltacabtagene autoleucel). Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 92.5 days (range: 22–210 days) after CAR-T therapy and a median of 85 days after cytokine release syndrome resolution. Gut biopsies uniformly demonstrated inflammation, including intra-epithelial lymphocytosis and villous blunting. In one case where CAR-specific immunofluorescence stains were available, CAR T-cell presence was confirmed within the lamina propria. Systemic corticosteroids were initiated in 10 patients (71%) a median of 25.5 days following symptom onset, with symptom improvement in 40%. Subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. Five patients (36%) have died from bowel perforation or treatment-emergent sepsis. In conclusion, IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy typically beginning 1–3 months after infusion. Thorough diagnostic workup is essential, including evaluation for potential T-cell malignancies. The early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.

Gastrointestinal immune-related adverse events (GI irAEs) are common manifestations of immune checkpoint inhibitor (ICI) toxicity. We present a comprehensive systematic review of the incidence, management, and clinical course of irAEs across the entire GI system, including the luminal GI tract, liver, and pancreas. MEDLINE, Embase, Web of Science Core Collection, and Cochrane Library were used to conduct this review. All studies pertaining to GI irAEs were included. Both abstracts and full manuscripts were eligible if they included human subjects and were written in the English language. Articles not available in English, animal studies, or research not specific to GI toxicity of immunotherapy were excluded. We excluded certain article types depending on whether stronger evidence was available in the literature for a specific toxicity, for example, if prospective studies were available on a topic, retrospective studies and case reports were excluded. We extracted a final 166 articles for our review and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for data reporting. Risk of bias tools were not used to evaluate the extracted studies given the narrative nature of this manuscript, but each study was critically appraised by the manuscript writer. We detail the incidence, presentation, evaluation, management, and outcomes of the various GI toxicities that may arise with ICI therapy. Specifically, we discuss the characteristics of upper GI toxicity (esophagitis and gastroenteritis), lower GI toxicity (colitis), hepatobiliary inflammation, pancreatitis, and rarer forms of GI toxicity. We hope this review serves as a useful and accessible clinical tool that helps physicians familiarize themselves with the nuances of gastrointestinal/hepatic/pancreatic ICI toxicity diagnosis and management.

Immune checkpoint inhibitors (ICIs) reinvigorate anti-tumor immune responses by disrupting co-inhibitory immune checkpoint molecules such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4). Although ICIs have had unprecedented success and have become the standard of care for many cancers, they are often accompanied by off-target inflammation that can occur in any organ system. These immune related adverse events (irAEs) often require steroid use and/or cessation of ICI therapy, which can both lead to cancer progression. Although irAEs are common, the detailed molecular and immune mechanisms underlying their development are still elusive. To further our understanding of irAEs and develop effective treatment options, there is pressing need for preclinical models recapitulating the clinical settings. In this review, we describe current preclinical models and immune implications of ICI-induced skin toxicities, colitis, neurological and endocrine toxicities, pneumonitis, arthritis, and myocarditis along with their management.

Abstract Ovarian cancer is the deadliest gynecologic cancer due to its high rate of recurrence and limited early diagnosis. For certain patients, particularly those with recurring disorders, standard treatment alone is insufficient in the majority of cases. Ferroptosis, an iron- and ROS (reactive oxygen species)-reliant cell death, plays a vital role in the occurrence of ovarian cancer. Herein, subjects from TCGA-OV were calculated for immune scores using the ESTIMATE algorithm and assigned into high- (N = 185) or low-immune (N = 193) score groups; 259 ferroptosis regulators and markers were analyzed for expression, and 64 were significantly differentially expressed between two groups. These 64 differentially expressed genes were applied for LASSO-regularized linear Cox regression for establishing ferroptosis regulators and a markers-based risk model, and a 10-gene signature was established. The ROC curve indicated that the risk score-based curve showed satisfactory predictive efficiency. Univariate and multivariate Cox risk regression analyses showed that age and risk score were risk factors for ovarian cancer patients’ overall survival; patients in the high-risk score group obtained lower immune scores. The Nomogram analysis indicated that the model has a good prognostic performance. GO functional enrichment annotation confirmed again the involvement of these 10 genes in ferroptosis and immune activities. TIMER online analysis showed that risk factors and immune cells were significantly correlated. In conclusion, the risk model based on 10 ferroptosis regulators and markers has a good prognostic value for ovarian cancer patients.

Background and Aims: Immune checkpoint inhibitor therapy causes numerous immune-related adverse events, including autoimmune pancreatic injury (AIPI), which results in rapid organ atrophy. We profiled the clinico-radiological features, short-term natural history, and response to steroids of AIPI. Methods: We retrospectively reviewed medical records of 229/11,165 (2.1%) adult patients with AIPI. One hundred and ten out of 229 (48%) had abdominal computerized tomography (CT) scan at lipase elevation; data of 110 without pancreatic metastases were analyzed. We analyzed serial CT-based pancreas volumetry data in 48 patients with AIPI (32 with normal CT and 16 with pancreatitis on CT at lipase elevation). We examined impact of steroids on pain and disease course. Results: In AIPI (n = 229), median lipase elevation was 4x upper limit of normal (range: 3–40x). The injury was more often asymptomatic than painful (143/229 (62%) vs 86/229 (38%), P < .000). Majority (83/110 (75%) had normal CT, often in painless vs painful disease: 51/57 (90%) vs 32/53 (60%), P < .001) 25% had interstitial pancreatitis. On serial pancreas volumetry, marked volume (cc) loss occurred 1 year after vs 3 months before lipase elevation in both normal CT (median 81.6 vs 61.3, P = .00) and pancreatitis on CT groups (91.8 vs 60.5, P = .00), ≥20% volume loss occurred in 47% vs 73%, respectively (P = .08). Steroids, when used did not mitigate pain, biochemical relapse, pancreas volume loss or 1-year diabetes incidence (7.2%). Conclusion: Autoimmune pancreatic injury (AIPI) is uniquely characterized by painless lipase elevation, normal pancreas on CT and rapid pancreatic volume loss on follow-up. Steroids do not appear to have a role in management.

In order to solve the issue of idle rural homesteads and enhance the welfare of peasant households, the Chinese government has implemented various rural homestead withdrawal patterns. In the context of land spatial planning regulation, based on the field survey data from 210 peasant households in Xuzhou City and Ganzhou City, this study constructs a bilateral matching model between rural homestead withdrawal patterns and types of welfare needs of peasant households. This study uses a Discrete Particle Swarm Optimization algorithm improved on the 0–1 knapsack strategy to solve the matching model, aiming to find the optimal homestead withdrawal patterns that match the types of peasant households. The results show that: (1) The matching of rural homestead withdrawal patterns and types of peasant households conforms to the principle of comparative advantage. (2) In the case of “one-to-one matching” between peasant households and homestead withdrawal patterns, matching the “economic-material-oriented” peasant households with the withdrawal pattern of “monetary compensation”, matching the “social-service-oriented” peasant households with withdrawal pattern of “indicator replacement”, and matching the “welfare-assistance-oriented” peasant households with the withdrawal pattern of “asset replacement”. (3) The bilateral overall preference of the combined rural homestead withdrawal patterns is higher than that of the single rural homestead withdrawal pattern, and satisfaction has increased by at least 8 %. The authors argue that the government should design and implement diversified withdrawal patterns based on a full understanding of the welfare needs of peasant households.

Identifying the dominant factors influencing ecosystem health and their optimal thresholds is essential for the management and restoration of ecosystems. Most of the works, however, have less detected the importance level of individual factors, especially their changes over time and scale, and rarely determined their threshold effects on ecosystem health (EH), which seriously hinders the formulation of targeted policies for sustainable ecosystem management. To address these research gaps, we present an innovative visualization approach to reveal importance changes in natural and anthropogenic variables and their nonlinear coupling process with EH in the China’s Yellow River Basin (YRB) in the last two decades. Results show that (i) Although the EH in the YRB has improved slightly in the past 20 years, it is still not optimistic and shows distinct spatial heterogeneity. (ii) The impact of human activities on the ecosystem health of the YRB has increased and increasingly plays a decisive role, while that of the natural aspect has decreased recently. Specifically, environmental factors (slope, NDVI, and annual temperature) are the dominant factors affecting the upstream EH. Midstream EH is significantly affected by the synergistic effect of natural and anthropogenic factors, but the importance of the proportion of built-up land is intensified (ranked from 8th to 4th). Anthropogenic factors exert the greatest influence on downstream EH variation, especially for population density whose importance order rising from 7th to 2nd. (iii) By illustrating the nonlinear response curves of EH at multi-scale, the tipping point caused ecosystem deterioration in the YRB is explored and the optimal thresholds of leading factors oriented towards the most effective ecosystem conservation goal are obtained. These results help precisely identify the current health status of YRB's ecosystem, as well as providing a valuable reference for moderate restoration standards and sustainable ecosystem management.

Abstract Soluble salt and freeze–thaw are two significant weathering factors that contribute to the deterioration of rock-hewn heritages. Previous research has predominantly focused on the separate influences of salt weathering and freeze–thaw. However, in a realistic scenario, these two processes can occur simultaneously in nature, leading to a more complex decay process for such heritage. The aim of this study was to assess the combined impact of salt weathering and freeze–thaw on the severity of deterioration in rock-hewn heritage through evaluation of the variation of stone samples’ appearance and physical–mechanical properties, such as deterioration patterns, pore structure, surface hardness and splitting tensile strength. A laboratory ageing test was conducted using materials and climatic conditions representative of the West Lake Cultural Landscape of Hangzhou (WLCL), a UNESCO World Heritage Site located in Southeast China. Five different types of stones were collected from the WLCL area and its vicinity and subjected to 25 ageing cycles, each consisting of three phases: salt impregnation, freezing-thaw, and evaporation. The mixture of $${{Na}_{2}SO}_{4}{-MgSO}_{4}$$ Na 2 S O 4 - M g S O 4 was used as the contaminant substance. Results show that stones with moderate porosity (~ 5%) and a higher proportion of micropores, like flint, were susceptible to the combined effects of salt weathering and freeze–thaw, exhibiting significant surface deformation and strength decline. The porous tuff was primarily impacted by the development of a hard and thick crust on its surface, along with noticeable pore fill. The compact carbonate rock exhibited limited dimensional expansion with no discernible signs of deterioration patterns. Most rock specimens, except tuff, experienced a shift in their pore size distribution towards larger magnitudes, resulting in an increased average pore radius. This suggests that the inherent properties of rock-hewn heritages play a significant role in determining their vulnerability to various weathering agents. Consequently, these properties should serve as the foundation for developing future preventive conservation measures. Graphical Abstract

Background Immune checkpoint inhibitor (ICI) gastrointestinal toxicity (gastritis, enteritis, colitis) is a major cause of morbidity and treatment-related death. Guidelines agree steroid-refractory cases warrant infliximab, however best management of infliximab-refractory ICI gastrointestinal toxicity (IRIGItox) is unknown.Methods We conducted an international multicenter retrospective case series. IRIGItox was defined as failure of symptom resolution ≤grade 1 (Common Terminology Criteria for Adverse Events V.5.0) following ≥2 infliximab doses or failure of symptom resolution ≤grade 2 after one dose. Data were extracted regarding demographics, steroid use, response to treatment, and survival outcomes. Toxicity was graded at symptom onset and time of infliximab failure. Efficacy of infliximab refractory therapy was assessed by symptom resolution, time to resolution and steroid wean duration. Survival outcomes were examined based on immunosuppressive therapy received.Results 78 patients were identified: median age 60 years; 56% men; majority melanoma (N=70, 90%); 60 (77%) received anti-cytotoxic T-lymphocyte-associated protein 4 alone or in combination with anti-programmed cell death protein-1 and most had colitis (N=74, 95%). 106 post-infliximab treatments were given: 31 calcineurin inhibitors (CNIs); 27 antimetabolites (mycophenolate, azathioprine); 16 non-systemic immunomodulatory agents (eg, mesalazine or budesonide); 15 vedolizumab; 5 other biologics (anti-interleukin-12/23, 16, Janus kinase inhibitors) and 7 interventional procedures (including colectomy); 5 did not receive post-infliximab therapy. Symptom resolution was achieved in most (N=23/31, 74%) patients treated with CNIs; 12/27 (44%) with antimetabolites; 7/16 (44%) with non-systemic immunomodulation, 8/15 (53%) with vedolizumab and 5/7 (71%) with interventional procedures. No non-vedolizumab biologics resulted in toxicity resolution. CNIs had the shortest time to symptom resolution (12 days) and steroid wean (43 days); however, were associated with poorer event-free survival (6.3 months) and overall survival (26.8 months) than other agents. Conversely, vedolizumab had the longest time to toxicity resolution and steroid wean, 66 and 124 days, but most favorable survival data: EFS 24.5 months; median OS not reached. Six death occurred (three due to IRIGItox or management of toxicity; three with persisting IRIGItox and progressive disease).Conclusions IRIGItox causes major morbidity and mortality. Management is heterogeneous. CNIs appear most likely to result in toxicity resolution in the shortest time period, however, are associated with poorer oncological outcomes in contrast to vedolizumab.

BackgroundCombining immune checkpoint therapy (ICT) and vascular endothelial growth factor inhibitors (VEGFi) may result in increased treatment-related and immune-related adverse events (TRAEs and irAEs) compared to ICT alone. This metanalysis was conducted to identify prospective phase II or III clinical studies that evaluated the toxicity profile of ICT + VEGFi compared to ICT alone.MethodsA systematic search was performed across all cancer types and major databases until August 10, 2022, and screening was done by two independent investigators. Inclusion criteria included phase 2 or 3 studies with at least one arm of patients treated with combination therapy and one arm treated with monotherapy. Adverse event data were pooled using a restricted maximum likelihood fixed effects model, and heterogeneity using Cochran’s Q (chi-square) test.Results7 out of 9366 studies met the inclusion criteria, and 808 and 927 patients were treated with ICT monotherapy and a combination of ICT with VEGFi, respectively. Only one study reported irAEs, so the analysis was restricted to TRAEs. The total number of TRAEs was significantly higher in the ICT + VEGFi group (RR:1.49; 95% CI 1.37 -1.62; p=1.5×10-21), and more frequent treatment withdrawals were attributed to TRAEs (RR:3.10; 95% CI 1.12-8.59; p=0.029). The highest TRAE effect size increases noted for rash (RR 6.50; 95% CI 3.76 – 11.25; p=2.1×10-11), hypertension (RR:6.07; 95% CI 3.69–10.00; p=1.3×10-12), hypothyroidism (RR:5.02; 95% CI 3.08 – 8.19; p=8.9×10-11), and diarrhea (RR:4.94; 95% CI 3.21–7.62; p=3.8×10-13). Other significantly more frequent TRAEs included nausea, anemia, anorexia, and proteinuria.ConclusionCombination therapy with ICT and VEGFi carries a higher risk of certain TRAEs, such as rash, hypertension, hypothyroidism, diarrhea, nausea, anorexia, and proteinuria, compared to ICT monotherapy. More granular details on the cause of AEs, particularly irAEs, should be provided in future trials of such regimens.

Abstract. Background:. Ovarian cancer is one of the most widespread malignant diseases of the female reproductive system worldwide. The plurality of ovarian cancer is diagnosed with metastasis in the abdominal cavity. Epithelial-mesenchymal transition (EMT) exerts a vital role in tumor cell metastasis. However, it remains unclear whether long non-coding RNA (lncRNA) are implicated in EMT and influence ovarian cancer cell invasion and metastasis. This study was designed to investigate the impacts of lncRNA AC005224.4 on ovarian cancer. Methods:. LncRNA AC005224.4, miR-140-3p, and snail family transcriptional repressor 2 (SNAI2) expression levels in ovarian cancer and normal ovarian tissues were determined using real-time quantitative polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK-8) and Transwell (migration and invasion) assays were conducted to measure SKOV3 and CAOV-3 cell proliferation and metastasis. E-cadherin, N-cadherin, Snail, and Vimentin contents were detected using Western blot. Nude mouse xenograft assay was utilized to validate AC005224.4 effects in vivo. Dual-luciferase reporter gene assay confirmed the targeted relationship between miR-140-3p and AC005224.4 or SNAI2. Results:. AC005224.4 and SNAI2 upregulation and miR-140-3p downregulation were observed in ovarian cancer tissues and cells. Silencing of AC005224.4 observably moderated SKOV3 and CAOV-3 cell proliferation, migration, invasion, and EMT process in vitro and impaired the tumorigenesis in vivo. miR-140-3p was a target of AC005224.4 and its reduced expression level was mediated by AC005224.4. miR-140-3p mimics decreased the proliferation, migration, and invasion of ovarian cancer cells. SNAI2 was identified as a novel target of miR-140-3p and its expression level was promoted by either AC005224.4 overexpression or miR-140-3p knockdown. Overexpression of SNAI2 also facilitated ovarian cancer cell viability and metastasis. Conclusion:. AC005224.4 was confirmed as an oncogene via sponging miR-140-3p and promoted SNAI2 expression, contributing to better understanding of ovarian cancer pathogenesis and shedding light on exploiting the novel lncRNA-directed therapy against ovarian cancer.

Abstract Background To examine the association between elevated serum uric acid (SUA) levels and the rapid decline in kidney function by conducting a retrospective cohort study on a physically healthy population in Urumqi, China. Methods A cohort study of 2,802 physically healthy people with a normal estimated glomerular filtration rate (eGFR) was investigated from 2018 to 2021. The examination procedure included using questionnaires, taking physical measurements, and blood sampling. The rapid decline in kidney function was defined as eGFR > 5 mL·min–1 ·(1.73 m2 )–1 year. The relationship between elevated SUA levels and the rapid decline in kidney function was assessed. Results When performing the three-year retrospective analysis, 688 (28.55%) cases experienced a rapid decline in kidney function, and 52 (1.9%) cases developed chronic kidney disease (CKD). They were divided into the stable group and the rapidly declining kidney function group according to eGFR > 15 mL·min–1·(1.73 m2 )–1. The comparison revealed a greater increase in uric acid in the rapidly declining kidney function group [0.30 (-0.29, 0.82) mg/dL vs. − 0.07(-0.54, 0.37) mg/dL, Z = − 8.822, P

Introduction: Acute myocardial infarction (AMI) accounts for the majority of deaths caused by coronary artery disease (CAD). Early warning of AMI, especially for patients with stable coronary artery disease (sCAD), is urgently needed. Our previous study showed that alterations in the gut microbiota were correlated with CAD severity. Objectives: Herein, we tried to discover accurate and convenient biomarkers for AMI by combination of gut microbiota and fecal/blood/urinary metabolomics. Methods: We recruited 190 volunteers including 93 sCAD patients, 49 AMI patients, and 48 subjects with normal coronary artery (NCA), and measured their blood biochemical parameters, 16S rRNA-based gut microbiota and NMR-based fecal/blood/urinary metabolites. We further selected 20 subjects from each group and analyzed their gut microbiota by whole-metagenome shotgun sequencing. Results: Multi-omic analyses revealed that AMI patients exhibited specific changes in gut microbiota and serum/urinary/fecal metabolites as compared to subjects with sCAD or NCA. Fourteen bacterial genera and 30 metabolites (11 in feces, 10 in blood, 9 in urine) were closely related to AMI phenotypes and could accurately distinguish AMI patients from sCAD patients. Some species belonging to Alistipes, Streptococcus, Ruminococcus, Lactobacillus and Faecalibacterium were effective to distinguish AMI from sCAD and their predictive ability was confirmed in an independent cohort of CAD patients. We further selected nine indicators including 4 bacterial genera, 3 fecal and 2 urinary metabolites as a noninvasive biomarker set which can distinguish AMI from sCAD with an AUC of 0.932. Conclusion: Combination of gut microbiota and fecal/urinary metabolites provided a set of potential useful and noninvasive predictive biomarker for AMI from sCAD.

The roles of preexisting auto-reactive antibodies in immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy are not well defined. Here, we analyzed plasma samples longitudinally collected at predefined time points and at the time of irAEs from 58 patients with immunotherapy naïve metastatic non-small cell lung cancer treated on clinical protocol with ipilimumab and nivolumab. We used a proteomic microarray system capable of assaying antibody reactivity for IgG and IgM fractions against 120 antigens for systemically evaluating the correlations between auto-reactive antibodies and certain organ-specific irAEs. We found that distinct patterns of auto-reactive antibodies at baseline were associated with the subsequent development of organ-specific irAEs. Notably, ACHRG IgM was associated with pneumonitis, anti-cytokeratin 19 IgM with dermatitis, and anti-thyroglobulin IgG with hepatitis. These antibodies merit further investigation as potential biomarkers for identifying high-risk populations for irAEs and/or monitoring irAEs during immunotherapy treatment.Trial registrationClinicalTrials.gov identifier: NCT03391869.

We describe the unique case of a 73-year-old man who developed diffuse metastatic melanoma throughout the GI tract following potent immunosuppressive treatment for his immune-mediated colitis. Diagnosis of his metastatic GI luminal disease was confirmed with colonoscopy and EGD biopsies. Immunosuppressive therapy including corticosteroids and vedolizumab is the mainstay treatment for immune-mediated colitis and has generally been thought to have a safe toxicity profile. This unique case of diffuse luminal metastasis of melanoma after intensive immunosuppressant treatment raised the concern of their long-term safety on the cancer outcome and the need for safer alternatives.

Abstract The availability of immune checkpoint inhibitors (ICIs) for the management of advanced hepatocellular cancer (HCC) has changed the treatment paradigm. There are emerging questions regarding the efficacy of subsequent anticancer therapies. The primary aim of this retrospective, multicenter study was to examine the types of anticancer treatment received after ICIs and to assess the impact on post‐ICI survival. We established an international consortium of 11 tertiary‐care referral centers located in the USA (n = 249), Europe (n = 74), and Asia (n = 97), and described patterns of care following ICI therapy. The impact of subsequent therapy on overall survival (OS) was estimated using the Kaplan–Meier method and presented with a 95% confidence interval (CI). A total of 420 patients were treated with ICIs for advanced HCC after one line of systemic therapy (n = 371, 88.8%): 31 (8.8%) had died, 152 (36.2%) received best supportive care (BSC) following ICIs, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKIs, n = 132, 80.9%), in particular sorafenib (n = 49, 30.0%), were the most common post‐ICI therapy followed by external beam radiotherapy (n = 28, 17.2%), further immunotherapy (n = 21, 12.9%), locoregional therapy (n = 23, 14.1%), chemotherapy (n = 9, 5.5%), and surgery (n = 6, 3.6%). Receipt of post‐ICI therapy was associated with longer median OS compared with those who had received BSC (12.1 vs. 3.3 months; hazard ratio [HR]: 0.4 (95% CI: 2.7–5.0). No difference in OS was noted in those patients who received TKI before ICIs compared with those who received ICIs followed by TKI. Conclusion: Post‐ICI therapy is associated with OS in excess of 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICIs.

Purpose Immune checkpoint inhibitor (ICI) therapy is often suspended because of immune-related enterocolitis (irEC). We examined the effect of resumption of ICIs with or without concurrent selective immunosuppressive therapy (SIT) on rates of symptom recurrence and survival outcomes.Methods This retrospective, multicenter study examined patients who were treated with ICI and developed irEC requiring SIT (infliximab or vedolizumab) for initial symptom control or to facilitate steroid tapering between May 2015 and June 2020. After symptom resolution, patients were restarted either on ICI alone or on concurrent ICI and SIT at the discretion of the treating physicians. The associations between irEC recurrence and treatment group were assessed via univariate analyses and multivariate logistic regression. Cox proportional hazards model was used for survival analysis.Results Of the 138 included patients who required SIT for initial irEC symptom control, 61 (44.2%) patients resumed ICI without concurrent SIT (control group) and 77 (55.8%) patients resumed ICI therapy with concurrent SIT: 33 with infliximab and 44 with vedolizumab. After symptom resolution, patients in the control group were more commonly restarted on a different ICI regimen (65.6%) compared with those receiving SIT (31.2%) (p

Public participation in river basin ecological compensation is one of the effective means to adjust the multi stakeholder relationship and promote low-carbon development. This paper takes the upper Yellow River basin section as the research area, adds ecological compensation policy variables to the Theory of Planned Behavior (TPB). An integrated theoretical framework is established from the two levels of personal psychological cognition and policy environment, which can comprehensively consider multiple factors that affect individual behavior. This paper uses the Structural Equation Modeling (SEM) to empirically analyze the impact of psychological factors and river basin ecological compensation policy on the public's willingness and behavior to participate in river basin ecological compensation. The results showed that the three psychological cognitive factors of behavior attitude, subjective norm and perceived behavior control had a significant impact on the public's willingness to participate in ecological compensation. The ecological compensation policy also has a significant impact on the willingness and behavior of the public to participate in ecological compensation. The impact coefficient of ecological compensation policy on the participation willingness is 0.085, and the impact coefficient on the participation behavior is 0.551. The existing ecological compensation policies in carbon neutral contexts have a stronger effect on the public participation behavior, but a weaker impact on the public's willingness to participate. The existing policies in carbon neutral contexts play a small role in mobilizing the public's enthusiasm from the psychological cognitive level, but the willingness to participate has a significant direct impact on the participation behavior. The research conclusions of this paper can help to broaden the theoretical framework of public participation and provide new ideas and methods for improving the ecological compensation mechanism of the river basin.

Encorafenib, a BRAF kinase inhibitor, in combination with binimetinib, a selective MEK inhibitor have known gastrointestinal adverse events; however, adverse colitis events have not been well studied. We report a case series of 4 patients with melanoma who developed inflammatory colitis after BRAF and MEK inhibition with encorafenib and binimetinib, respectively. In the setting of immune checkpoint inhibitor use, BRAF and MEK inhibitors can cause significant inflammatory colitis with endoscopic patterns of predominant right colon ulcerations. It can lead to significant morbidity and frequent interruption of cancer treatment. Early recognition and prompt intervention are critical to improving patient outcomes.

Background and Rationale: Immune checkpoint inhibitor (ICI) therapy is an expanding therapeutic option for hepatocellular carcinoma (HCC). Antibiotics (ATB) taken prior to or early during ICI therapy can impact immunotherapy efficacy across indications; however, the effect of ATB is undefined in HCC. Methods: In a large international cohort of 450 ICI recipients from Europe, North America, and Asia, we categorized patients according to timing of ATB focusing on exposure within −30 to +30 days from ICI (early immunotherapy period [EIOP]). EIOP was evaluated in association with overall survival (OS), progression-free survival (PFS), and best radiologic response using RECIST 1.1 criteria. Results: Our study comprised mostly cirrhotic (329, 73.3%) males (355, 79.1%) with a Child-Turcotte Pugh class of A (332, 73.9%), receiving ICI after 1 therapy line (251, 55.9%) for HCC of Barcelona clinic liver cancer stage C (325, 72.4%). EIOP (n = 170, 37.9%) was independent of baseline clinicopathologic features of HCC and correlated with longer PFS (6.1 vs. 3.7 months, log-rank p = 0.0135). EIOP+ patients had similar OS, overall response, and disease control rates (DCRs) compared to EIOP. The effect of EIOP persisted in landmark time analyses and in multivariable models, confirming the independent predictive role of EIOP in influencing PFS following adjustment for covariates reflective of tumor burden, liver function, and ICI regimen administered. In patients receiving programmed cell death-1 receptor/ligand inhibitors monotherapy, EIOP was also associated with higher DCRs (61.4% vs. 50.9%, p = 0.0494). Conclusions: Unlike other oncological indications, ATB in the 30 days before or after ICI initiation is associated with improved benefit from immunotherapy, independent of disease and treatment-related features. Evaluation of the immune microbiologic determinants of response to ICI in HCC warrants further investigation.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a disastrous condition, which can be caused by a wide range of diseases, such as pneumonia, sepsis, traumas, and the most recent, COVID-19. Even though we have gained an improved understanding of acute lung injury/acute respiratory distress syndrome pathogenesis and treatment mechanism, there is still no effective treatment for acute lung injury/acute respiratory distress syndrome, which is partly responsible for the unacceptable mortality rate. In the pathogenesis of acute lung injury, the inflammatory storm is the main pathological feature. More and more evidences show that immune cells and cytokines secreted by immune cells play an irreplaceable role in the pathogenesis of acute lung injury. Therefore, here we mainly reviewed the role of various immune cells in acute lung injury from the perspective of immunotherapy, and elaborated the crosstalk of immune cells and cytokines, aiming to provide novel ideas and targets for the treatment of acute lung injury.

Summary: Owing to the impact of the western development of China, there have been signs of air pollution over the Qinghai-Tibet Plateau in recent years. However, monitoring data on atmospheric volatile organic compounds (VOCs) are lacking in plateau areas. Here, VOCs concentrations in urban and background areas in North China and the Qinghai-Tibet Plateau were observed from 2012 to 2014 and 2020 to 2022, respectively. Compared to 2012–2014, the concentration of VOCs increased to 2.5 times in urban areas on the Qinghai-Tibet Plateau, which was equivalent to that in North China. Oil, gas, and solvent evaporation caused by a low atmospheric pressure is the primary factor for the increase in VOCs in plateau areas, and weak VOCs degradation is the secondary factor. Hence, we put forward the VOCs control strategies in plateau areas and point out the defects in the current research.

A new method for determining the burning rate of a solid propellant, called the Impulse Method, is proposed in this paper. It is based on the proportional relationship between the impulse generated and the mass of the burned propellant. The pressure–time and thrust–time curves are obtained from a tubular propellant grain burning in the chamber, whose inner surface serves as the initial burning surface. Consequently, the mass of the propellant that was burned off at different pressures can be determined, and the burning rates at different pressures are derived according to the geometric parameters of the propellant grain. The Impulse Method was applied to test the burning rate of two types of propellants twice. The results show that the burning rates were consistent for the same propellant at corresponding pressures, demonstrating the feasibility and reliability of the Impulse Method. The burning rate of a GAP-based composite propellant at 20 MPa measured using the Standard Motor Method was 22.6 mm/s, and that measured using the Impulse Method was 22.2 mm/s and 22.7 mm/s, respectively. These findings indicate that the two methods have comparable accuracy. However, the Impulse Method has the advantage of obtaining the burning rate of the solid propellant at any pressure through a single test. In addition, the nozzle erosion only affected the pressure and not the burning rate. Finally, the rationality of the approach for determining the actual specific impulse was proven by comparing the results with those from another testing method.

It is acknowledged that chronic inflammation is associated with a rise in extracellular proton concentrations. The acid-sensing ion channel 1a (ASIC1a) belongs to the extracellular H+-activated cation channel family. Recently, many studies have been conducted on ASIC1a and inflammatory immune diseases. Here, in this review, we will focus on the role of ASIC1a in several inflammatory immune diseases so as to provide new perspectives for clinical treatment.

The quality of Panax Linn products available in the market is threatened by adulteration with different Panax species, such as Panax quinquefolium (PQ), Panax ginseng (PG), and Panax notoginseng (PN). In this paper, we established a 2D band-selective heteronuclear single quantum coherence (bs-HSQC) NMR method to discriminate species and detect adulteration of Panax Linn. The method involves selective excitation of the anomeric carbon resonance region of saponins and non-uniform sampling (NUS) to obtain high-resolution spectra in less than 10 min. The combined strategy overcomes the signal overlap limitation in 1H NMR and the long acquisition time in traditional HSQC. The present results showed that twelve well-separated resonance peaks can be assigned in the bs-HSQC spectra, which are of high resolution, good repeatability, and precision. Notably, the identification accuracy of species was found to be 100% for all tests conducted in the present study. Furthermore, in combination with multivariate statistical methods, the proposed method can effectively determine the composition proportion of adulterants (from 10% to 90%). Based on the PLS-DA models, the identification accuracy was greater than 80% when composition proportion of adulterants was 10%. Thus, the proposed method may provide a fast, practical, and effective analysis technique for food quality control or authenticity identification.

Rfn (formaldehyde/nitrogen dioxide) is a common indicator based on satellite observations used to classify ozone formation sensitivity. However, it may underestimate anthropogenic volatile organic compounds (VOCs) in heavily polluted cities when only formaldehyde (HCHO) is used in Rfn to measure VOCs, since it is mainly derived from natural sources worldwide. In this study, we used multiaxis differential optical absorption spectroscopy to acquire tropospheric observations of nitrogen dioxide (NO2), HCHO and glyoxal (CHOCHO) in Beijing from 1 April 2019 to 31 March 2020. Combined with VOCs detected simultaneously by gas chromatography—mass spectrometry and proton transfer reaction–time-of-flight/mass spectrometry near the ground, we evaluated the representativeness of HCHO column densities on total VOCs (TVOC) in equivalent propylene concentrations, which is called reactivity. The results showed that there were significant seasonal differences in the response of HCHO to TVOC reactivity, with fitting slopes of 2.3 (spring), 2.6 (summer), 2.9 (autumn) and 1.0 (winter) in the four seasons, respectively. Since CHOCHO can be used to partly characterize the contribution of anthropogenic VOC emissions and demonstrated a better response to TVOC reactivity in winter, with fitting slopes of 0.2 (spring), 0.2 (summer), 0.2 (autumn) and 0.5 (winter) in the four seasons, respectively, we introduced CHOCHO to construct a new indicator (HCHO + 6 × CHOCHO). The fitting slopes of the four seasons were more similar, being 3.2 (spring), 3.6 (summer), 4.0 (autumn) and 4.0 (winter). The ratio of the new indicator to NO2, Rmn ((HCHO + 6 × CHOCHO)/NO2), was used to reclassify the ozone formation sensitivity of urban areas in North China, revealing that it is a transition regime before 1300 LST (LST = UST + 8) and an NOx-limited regime afterwards. Rmn improved the sensitivity from the VOC-limited regime to the NOx-limited regime, enhancing the sensitivity of NOx and providing new robust support for ozone pollution prevention and control.

The vertical distribution of carbon dioxide (CO2) is important for the calibration and validation of transport models and remote sensing measurements. Due to the large mass and volume of traditional instruments as well as supporting systems, in-situ measurements of the CO2 vertical profile within the boundary layer are rare. This study used a miniaturized CO2 monitoring instrument based on a low-cost non-dispersive infrared (NDIR) sensor to measure the CO2 vertical profile and meteorological parameters of the lower troposphere (0–1000 m) in southwestern Shijiazhuang, Hebei Province, China. The sensors were onboard a tethered balloon with two processes: the ascending process and the descending process. The results showed that the overall trend of CO2 concentration decreased with height. Weather conditions and CO2 emission sources caused fluctuations in CO2 concentrations. The CO2 concentration varied from morning to afternoon due mainly to the faster spread of air mass during daytime, with strong convections and the accumulation of emissions at night. The low-cost sensor produced results consistent with the traditional gas chromatography method. The Weather Research and Forecasting model could not capture the CO2 profiles well due mainly to the bad performances in boundary layer height and the potential outdated fossil fuel emissions around the experimental site. This experiment is the first successful attempt to observe the CO2 vertical distribution in the lower troposphere by using low-cost NDIR sensors. The results help us to understand the vertical structure of CO2 in the boundary layer, and provide data for calibrating and validating transport models.

Identifying spatiotemporal heterogeneity and impact mechanism of ecosystem service value (ESV) is critical for enhancing ecosystem management and regional sustainability. However, the existing findings have failed to investigate the synergetic effect of multiple drivers on ESV, nor have considered the threshold effects under different conditions, which is important to understand the complex and frequently interacting ecosystem. In this study, we applied the improved ESV calculation method, Pearson correlation analysis and conditional inference tree model to depict the dynamic changes of ESV, to explore separate and synergetic effects of various factors, and further to identify key thresholds under combined effects in urban agglomerations along the upper and middle Yellow River area (UMYRA). The results showed that: (1) The total ESV of the study area increased by 5936.63 million CNY over the study period. With the exception of the urban agglomeration along the Yellow River in Ningxia (YRNX), four types of sub-services in Hulunbeier-Baotou-Erdos-Yulin urban agglomeration (HBEY) and Taiyuan urban agglomeration (TY) showed a rising trend. Spatially, the greater growth of ESV mainly concentrated in the northern desert belt, whereas the major grain production areas and urban areas presented different degrees of degradation. (2) Climate factors and land use intensity are the main factors affecting the total ESV, followed by economic density and terrain condition, while landscape metrics exert a relatively small impact on ESV. But the influences of these factors on single ESV show distinct internal differences. (3) Synergetic effects of multi-factors showed that: ①When the evapotranspiration and precipitation are at a certain threshold (1277 mm＜PET＜1317 mm and PRE＞417.55 mm), rising temperature can effectively promote the growth of ESV. The same effect is also observed on steep slopes under matched hydrothermal conditions; ②When economic development is at a high level, intensifying human activities within a certain range (0.11＜HAI＜0.29 and 184.32＜LUI＜210.6) could greatly promote the ESV, but the opposite effect was also true when the thresholds were breached; ③Fragmented landscapes with low diversity (SHDI＜0.86) can promote ESV improvement, but high diversity fragmented landscapes (PD＞0.14 or SHDI＞0.85) would lead to ESV decline. Our research sheds light on the key thresholds under synergetic effect of multiple factors on ESV from a novel perspective, which provide a specific and practical guidance for achieving sustainable management.

Chinese government has proposed a national contribution plan that involves achieving the peak CO2 emissions by 2030 and carbon neutrality by 2060. To explore the pathway of achieving carbon neutrality, we tried to use resources taxes and land reclamation deposits as compulsory ecological compensation (CEC). In order to test if CEC can affect CO2 emissions, energy intensity was selected as the intermediate variable. We found that the CO2 emissions trend in China is consistent with environmental Kuznets curve hypothesis and proved that CEC displayed a spillover effect on energy intensity. Likely, energy intensity presented a spillover effect on CO2 emissions. Therefore, CEC will spatially affect CO2 emissions. The generalized spatial two-stage least-squares estimate model was used to identify the impact mechanism of coal production on energy intensity with CEC as the instrumental variable. The results indicated that reducing coal production in neighboring regions may cause the mitigation of local CO2 emissions. Finally, regression analyses carried out by region suggested regional cooperation should be carried out in the process of carbon mitigation.

In the context of international carbon neutrality, energy prices are affected by several nonlinear and nonstationary factors, making it challenging for traditional forecasting models to predict energy prices effectively. The existing literature mainly uses linear models or a combination of multiple models to forecast energy prices. For the nonlinear relationship between variables and the mining of historical data information, the prediction strategy and accuracy of the existing literature need to be improved. Thus, this paper improves the prediction accuracy of energy prices by developing a “decomposition-reconstruction-integration” thinking strategy that affords medium- and short-term energy price prediction based on carbon constraint, eigenvalue transformation and deep learning neural networks. Considering 2011–2020 as the research period, the prices for traditional energy resources and polysilicon in clean photovoltaic energy raw materials are selected as representatives. Based on energy price decomposition using the Singular Spectrum Analysis (SSA) method, and combining it with Learning Vector Quantization (LVQ) cluster technology, the decomposed quantities are aggregated into price sequences with different characteristics. Additionally, the carbon intensity is considered the leading market’s overall constraint, which is input with the processed price data into a Long Short-Term Memory network (LSTM) model for training. Thus, the SSA-LSTM combined forecasting model is developed to predict the energy price under carbon neutrality. Four indices are employed to evaluate the prediction accuracy: Root Mean Squared Error (RMSE), Mean Absolute Error (MAE), Mean Absolute Percentage Error (MAPE) and R-squared. The results highlight the following observations. (1) Using a sequence decomposition clustering strategy significantly improves the model’s prediction accuracy. This strategy enhances predicting the overall trend of the price series and the changes in different periods. For coal price, the RMSE value decreased from 0.135 to 0.098, the MAE value decreased from 0.087 to 0.054, the MAPE value decreased from 0.072 to 0.064, and the R-squared value increased from 0.643 to 0.725. Regarding the polysilicon price, the RMSE value decreased from 0.121 to 0.096, the MAE value decreased from 0.068 to 0.064, the MAPE value decreased from 0.069 to 0.048, and the R-squared value increased from 0.718 to 0.764. (2) The prediction effect is better in the case of carbon constraint. Considering “carbon emission intensity” as the overall constraint of the leading market, it can effectively explore the typical characteristics of energy price information. Four evaluation indicators show that the accuracy of the model prediction can be improved by more than 3%. (3) When the proposed SSA-LSTM model is used to predict both prices, the results show that the evaluation index of the prediction error remained at about 1%, while the model’s accuracy was high. This also proves that the proposed model can predict traditional energy prices and new energy sources such as solar energy.

Described herein is the first application of perfluorinated solvent in the stereoselective formation of O-/S-glycosidic linkages that occurs via a Ferrier rearrangement of acetylated glycals. In this system, the weak interactions between perfluoro-n-hexane and substrates could augment the reactivity and stereocontrol. The initiation of transformation requires only an extremely low loading of resin-H+ and the mild conditions enable the accommodation of a broad spectrum of glycal donors and acceptors. The ‘green’ feature of this chemistry is demonstrated by low toxicity and easy recovery of the medium, as well as operational simplicity in product isolation.

Abstract Background The gut microbiome impacts the efficacy of immune checkpoint inhibitor (ICI) therapy and the development of ICI-mediated diarrhea and/or colitis (IMDC). Antibiotic therapy,especially that with anaerobic activity, has profound effects on the gut microbiome. Therefore, we sought to assess the effect of antibiotics on the development of IMDC. Methods Patients who received ICI therapy from January 2016 to January 2018 were examined retrospectively. A Cox regression model was used to assess factors associated with overall survival. Results A total of 826 patients were included. Of these patients, 51.6% received inhibitors of programmed cell death protein-1 or its ligand, 32.0% received inhibitors of cytotoxic T-lymphocyte-associated antigen-4, and 16.5% received a combination of the two. IMDC occurred in 52.5% of the patients after a median of 8 weeks. Overall, 569 patients (68.9%) received antibiotic therapy. Antibiotic use at any time was associated with reduced IMDC occurrence and recurrence rates but also with frequent hospitalization and intensive care unit admission for IMDC as well as increased IMDC severity. Compared with patients who received antibiotic therapy only before ICI therapy initiation, those receiving it after ICI had a higher IMDC rate and more often needed immunosuppressive therapy and hospitalization for IMDC. Antibiotics with anaerobic activity were included in 51% of the antibiotic therapy regimens and were associated with increased immunosuppressant use, hospitalization, intensive care unit admission for IMDC, and severe IMDC grades. Forty-one patients received empiric prophylactic antibiotic therapy at IMDC onset. These patients more often needed immunosuppressive therapy, intravenous steroids, and infliximab/vedolizumab; had more frequent and longer hospitalization for IMDC and higher IMDC grades; and more frequently had IMDC recurrence than did patients who did not receive antibiotic therapy at the time of IMDC symptom onset. Conclusions Whereas antibiotic therapy appeared to be protective against IMDC onset, use of antibiotics, especially those with anaerobic activity, after ICI therapy was associated with increased risk of severe IMDC.

Immune checkpoint inhibitors (ICIs) have emerged as a novel therapeutic class for various malignancies. Their immune upregulation promotes significant anti-tumor effect, but simultaneously, can also result in treatment-limiting immune-related adverse events (irAEs). The data on upper gastrointestinal (GI) tract irAEs are sparse. We herein describe a case of steroid-dependent upper GI toxicity with nivolumab (an anti-programmed death [PD] protein-1) that achieved clinical and histological remission with vedolizumab treatment (a GI tract targeted anti-integrin antibody). A 65-year-old male patient with progressive lung cancer was treated with nivolumab and following 16 cycles, developed severe nausea, vomiting, and epigastric abdominal cramps requiring five hospitalizations. His initial esophagogastroduodenoscopy (EGD) showed active inflammation in both the stomach and duodenum. Nivolumab was discontinued, but despite treatment with multiple steroid courses, his symptoms always recurred during prednisone taper. Clinical remission was ultimately achieved with vedolizumab. His last EGD after five infusions of vedolizumab demonstrated resolution of inflammation. His lung cancer has since relapsed and the treatment plan was to resume nivolumab concurrently with vedolizumab. In conclusion, ICIs, such as nivolumab, have emerged as therapy for various malignancies. Their use can be associated with various irAEs including the upper GI adverse events which is uncommon. This case scenario showed that vedolizumab can provide a steroid-sparing therapeutic effect to achieve remission of upper GI irAEs even in cases where multiple steroid courses have failed.

Abstract Background Current treatment guidelines for immune-mediated colitis (IMC) recommend 4 to 6 weeks of steroids as first-line therapy, followed by selective immunosuppressive therapy (SIT) (infliximab or vedolizumab) in patients who do not respond to steroids. We assessed the effect of early SIT introduction and number of SIT infusions on clinical outcomes. Methods We performed a retrospective review of patients with IMC who received SIT at The University of Texas MD Anderson Cancer Center between January and December 2018. Logistic regression analyses were used to assess associations between clinical outcomes and features of IMC. Results Of the 1459 patients who received immune checkpoint inhibitors, 179 developed IMC of any grade; 84 of these 179 patients received SIT. Of the 84 patients who received SIT, 79% were males, and the mean age was 60 years (standard deviation, 14). Compared with patients who received SIT > 10 days after IMC onset, patients who received early SIT (≤10 days) required fewer hospitalizations (P = 0.03), experienced steroid taper failure less frequently (P = 0.03), had fewer steroid tapering attempts (P

Abstract Background Immune checkpoint inhibitor (ICI)-induced pancreatic injury (ICIPI) is not well documented in the literature. We aimed to describe the clinical characteristics and outcomes of patients who developed ICIPI. Methods We reviewed the medical records of consecutive patients who had a confirmed diagnosis of ICIPI (Common Terminology Criteria for Adverse Events grade ≥ 3 lipase elevation with or without clinical symptoms) from April 2011 through April 2018. Results Among the 2,279 patients received ICI and had lipase values checked thereafter, 82 (4%) developed ICIPI. Overall, 65% of patients received inhibitors of programmed death protein-1 or its ligand. Compared with asymptomatic presentation, patients who had clinical symptoms of pancreatitis (n = 32) had higher levels of lipase (P = 0.032), more frequent imaging evidence of pancreatitis (P = 0.055), and more frequent hospitalization (P

Abstract Background Immune checkpoint inhibitors (ICPIs), used to treat different advanced malignancies, are associated with a wide range of immune-related adverse reactions (irAEs) that deserve close monitoring of patients. Gastrointestinal reactions and hepatotoxicity may occur, which warrant careful evaluation to confirm the etiology and attribution to ICPIs as these events could affect future management. Case presentation We describe a case of a patient with prostate adenocarcinoma, treated with dual ICPIs comprised of ipilimumab and nivolumab, who developed elevated liver enzymes in the context of infliximab therapy prescribed to treat gastrointestinal irAE from his ICPIs. The patient’s grade 3 colitis became steroid-refractory, requiring a one-time infusion of infliximab, a biologic agent used commonly in inflammatory bowel disease, as a rescue therapy, to which he responded. The patient subsequently developed liver injury. This presented a diagnostic dilemma involving differential diagnoses of hepatotoxicity due to ICPI or infliximab exposure. A careful review of the clinical history, evaluation of the chronology of events, and exclusion of other causes of acute hepatitis were employed to make the final diagnosis of this event as infliximab-associated hepatotoxicity. Conclusion ICPIs such as CTLA-4 and PD-1 inhibitors have the potential to cause both gastrointestinal reactions and hepatotoxicity. An additional confounding factor in our patient’s case was the exposure to infliximab used to manage an established irAE that developed after the last exposure to ICPIs. The clinical history and data supported infliximab-associated hepatotoxicity, rather than an irAE. With the increasing application of ICPIs for different cancers, in conjunction with potential risks for irAE, the liver profile should be closely monitored during treatment with ICPI as well as with anti-TNF-α agents in this patient population.

Background Immune-mediated diarrhea and colitis (IMDC) is currently diagnosed and monitored by evaluating clinical symptoms. Deep remission is determined by endoscopic and histologic evaluation of the disease process. However, repeating these invasive procedures frequently can become cumbersome. We sought to assess the role of fecal calprotectin (FC) concentration as a non-invasive biomarker of endoscopic or histologic remission.Methods We performed a retrospective study of patients with IMDC who were tested for FC at IMDC onset and after IMDC treatment between June 2016 and March 2020. Patient demographics, clinical variables, and FC data were collected and analyzed to determine the optimal cut-off FC concentration to predict endoscopic and histologic remission.Results Our sample comprised 77 patients with a median age of 62 years; 66% were male and 94% were Caucasian. Sixty-five patients (84%) achieved clinical remission, 46 (60%) achieved endoscopic remission, and 24 (31%) achieved histologic remission after IMDC treatment. FC concentrations decreased from the time of IMDC onset to the end of treatment (p

Background Nivolumab is Food and Drug Administration approved in sorafenib-experienced, advanced hepatocellular carcinoma (HCC). Post-registration data of treatment in a real-world setting is lacking.Patients and methods We performed an international, multicenter observational study to confirm safety and efficacy of nivolumab in 233 patients treated outside clinical trials from eight centers in North America, Europe and Asia.Results Patients received nivolumab for Barcelona Clinic Liver Cancer stage C (n=191, 92.0%) and Child-Pugh (CP) A (n=158, 67.8%) or B (n=75, 32.2%) HCC as first (n=85, 36.5%) or second to fourth systemic therapy line (n=148, 63.5%). Objective response rate (ORR) was 22.4% and disease control rate was 52.1%. Median overall survival (OS) was 12.2 months (95% CI 8.4 to 16.0) and median progression-free survival was 10.1 months (95% CI 6.1 to 14.2). Treatment-related adverse events of grade >2 occurred in 26 patients (11.2%). Efficacy and safety were similar across CP classes and therapy line. OS was shorter in CP-B than A (7.3 months vs 16.3 months, p

The impact of corticosteroid therapy (CT) on efficacy of immune checkpoint inhibitors (ICI) is undefined in hepatocellular carcinoma (HCC). We evaluated whether CT administered at baseline (bCT) or concurrently with ICI (cCT) influences overall (OS), progression-free survival (PFS) and overall response rates (ORR) in 341 patients collected across 3 continents. Of 304 eligible patients, 78 (26%) received >10 mg prednisone equivalent daily either as bCT (n=14, 5%) or cCT (n=64, 21%). Indications for CT included procedure/prophylaxis (n=37, 47%), management of immune-related adverse event (n=27, 35%), cancer-related symptoms (n=8, 10%) or comorbidities (n=6, 8%). Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in univariable and multivariable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (p

Patients with cancer who developed severe, grade 3 or 4 immune-related adverse events (irAEs) during therapy with immune checkpoint inhibitors are at risk for developing severe toxicities again on rechallenge with checkpoint inhibitors. Consequently, medical oncologists and multidisciplinary teams are hesitant to retreat in this scenario, despite the fact that a number of patients may derive clinical benefit from this approach. Balancing such clinical benefit and treatment-related toxicities for each patient is becoming increasingly challenging as more and more patients with cancer are being treated with checkpoint inhibitors. In this manuscript, we provide an extensive overview of the relevant literature on retreatment after toxicity, and suggest prophylactic approaches to minimize the risk of severe irAE following rechallenge with immune checkpoint blockade, since treatment may be lifesaving in a number of occasions.

Background and study aims Endoscopic mucosal resection (EMR) is increasingly used for the treatment of large colonic polyps (≥ 20 mm). A drawback of EMR is local adenoma recurrence. Therefore, we studied the impact of argon plasma coagulation (APC) of the EMR edge on local adenoma recurrence. Patients and methods This was a retrospective study of patients with laterally spreading tumors (LST) ≥ 20 mm, who underwent EMR from January 2009 to August 2018 and follow-up endoscopic assessment. A cap-fitted endoscope was used to assess completeness of resection by systematically inspecting the EMR defect for any macroscopic disease. This was followed by forced APC of the resection edge followed by clip closure of the defect. Surveillance colonoscopy was performed at 6 months after resection to detect recurrence. Results Two hundred forty-six patients met the inclusion criteria. Most were female (53 %) and white (80 %), with a Median age of 64 years. Median polyp size was 35 mm (interquartile range, 30–45 mm). Most polyps were located in the right colon (77 %) and were removed by piecemeal EMR (70 %). Eleven patients (5 %) had residual tumor at the resection site. Conclusions We observed low adenoma recurrence after argon plasma coagulation of the EMR edge with a cap fitted colonoscope in patients with LST ≥ 20 mm of the colon, which requires further validation in a randomized controlled study.

Abstract Background Immune-mediated diarrhea and colitis (IMDC) can limit immune checkpoint inhibitors (ICIs) treatment, which is efficacious for advanced malignancies. Steroids and infliximab are commonly used to treat it. These agents induce systemic immunosuppression, with its associated morbidity. We assessed clinical outcomes of vedolizumab as an alternative treatment for IMDC. Methods We analyzed a retrospective case series of adults who had IMDC refractory to steroids and/or infliximab and received vedolizumab from 12/2016 through 04/2018. Results Twenty-eight patients were included. The median time from ICI therapy to IMDC onset was 10 weeks. Fifteen patients (54%) had grade 2 and 13 (46%) had grade 3 or 4 IMDC. Mucosal ulceration was present in 8 patients (29%), and nonulcerative inflammation was present in 13 (46%). All patients had features of active histologic inflammation; 14 (50%) had features of chronicity, and 10 (36%) had features of microscopic colitis concurrently. The mean duration of steroid therapy was 96 days (standard deviation 74 days). Nine patients received infliximab in addition to steroids and their IMDC was refractory to it. Among these, the duration of steroid use was 131 days compared with 85 days in patients who did not receive infliximab. Likewise, patients who failed infliximab before vedolizumab had a clinical success rate of 67% compared to 95% for patients that did not receive infliximab. The median number of vedolizumab infusions was 3 (interquartile range 1–4). The mean duration of follow-up was 15 months. Twenty-four patients (86%) achieved and sustained clinical remission. Repeat endoscopic evaluation was performed in 17 patients. Endoscopic remission was attained in 7 (54%) of the 13 patients who had abnormal endoscopic findings initially; 5/17 patients (29%) reached histologic remission as well. Conclusions Vedolizumab can be appropriate for the treatment of steroid-refractory IMDC, with favorable outcomes and a good safety profile.

Abstract Background Immune-related enterocolitis (irEC) is the most common serious complication from checkpoint inhibitors (CPIs). The current front-line treatment for irEC, high-dose corticosteroids (CS), have significant side effects and prolonged therapy may reduce CPI-anti-tumor activity. Early addition of TNF-α inhibitors such as infliximab (IFX) may expedite symptom resolution and shorten CS duration. Thus, we conducted the first retrospective study, to our knowledge, evaluating symptom resolution in patients with irEC treated with and without IFX. Methods Data were collected from the medical records of patients diagnosed with irEC. The primary endpoint was time to symptom resolution for irEC for cases managed with IFX plus CS (IFX group) versus CS alone (CS group). Duration of CS, overall survival (OS), and time to treatment failure (TTF) were secondary endpoints. Results Among 75 patients with irEC, 52% received CS alone, and 48% received IFX. Despite higher grade colitis in the IFX group (grade 3/4: 86% vs. 34%; p

Abstract Background Immune checkpoint inhibitors (ICPI) are efficacious treatments for advanced malignancies but can result in immune mediated diarrhea and colitis (IDC). Currently, the guidelines for the treatment of IDC depend only on clinical symptoms. Endoscopic and histologic features of such adverse events are not well studied in a manner that can help to gauge treatment plans. We aimed to characterize endoscopic and histologic features of IDC and to assess their association with clinical outcomes. Methods Our study included patients who had undergone endoscopy for IDC (1/2010 to 3/2018). Patients with GI infection at time of onset were excluded. High-risk endoscopic features were ulcers deeper than 2 mm, larger than 1 cm, and extensive colonic involvement. Univariate and multivariate logistic regression were performed to assess the association of endoscopic and histological features with clinical outcomes. Results A total of 182 patients was included; most were white (92%), males (65%) with a mean age of 60 years. Median time from ICPI initiation to IDC was 7 weeks. Fifty-three percent had grade 3–4 diarrhea, and 32% grade 3–4 colitis. Forty-nine patients had mucosal ulcerations, 66 non-ulcerative inflammation and 67 normal endoscopy. Calprotectin was higher in patients with ulceration (P = 0.04). The sensitivity of lactoferrin to detect histologic and endoscopic inflammation was 90% and 70% respectively. Patients who underwent endoscopy earlier than 7 days after IDC onset had shorter duration of IDC symptoms and duration of steroid treatment than those who underwent endoscopy after 7 days of IDC onset (P = 0.026 and P = 0.053, respectively). Patients who underwent endoscopy > 30 days of symptom onset required longer duration of steroids (P = 0.02), had more recurrent symptoms (P < 0.01) and received later infliximab/vedolizumab add-on therapy than did those who underwent endoscopy ≤30 days (P = 0.03). High-risk features were associated with more frequent (P = 0.03) and longer duration (P = 0.02) hospitalization and infliximab/vedolizumab requirement (P < 0.01). Patients with active histological inflammation had more recurrence (P < 0.01) and repeat endoscopy (P < 0.01). Repeat endoscopy was required in 47 patients. A multivariate logistic regression revealed that longer ICPI treatment was associated with more frequent hospitalizations (OR 1.00; 95%CI 1.00–1.01; P < 0.01) and high-risk endoscopic features were associated with the requirement of infliximab/vedolizumab (OR 3.89; 95%CI 1.68–9.01; P < 0.01). Conclusion High risk endoscopic features and active histologic inflammation represent important markers of disease severity with clinical implications and should be used in a timely manner to devise IDC-focused treatment algorithms.

Background: Immune checkpoint inhibitors (ICPIs) are gaining more popularity as a treatment for advanced cancers. However, immune-related adverse events (irAEs) limit their use. We aimed to assess the impact of irAEs and their treatment on clinical and survival outcomes. Materials and Methods: We retrospectively reviewed records of the patients who received ICPIs between 2011 and 2017. Descriptive analyses were employed to compare different groups. Kaplan–Meier curves and log-rank tests were used to estimate and compare overall survival durations. Results: Of 427 identified patients, 202 (47.3%) had one or more irAEs. Overall, the patients who developed irAEs had better overall survival than did patients with no-irAEs, regardless of immunosuppressant treatment (P < 0.01). Patients with mild irAEs who did not require immunosuppressive treatment had longer overall survival duration than did patients without irAEs (P < 0.01). Patients with three or more irAEs had longer median overall survival compared to patients with two or less irAEs (P = 0.01). Infliximab was associated with shorter duration of steroid use as compared to steroid treatment only (2 months [standard deviation (SD), 8] vs. 4 months [SD, 4]). Steroid treatment for >30 days was associated with higher rate of infections compared to shorter duration (P = 0.03). Conclusion: IrAEs are associated with favorable overall survival, regardless of immunosuppression treatment requirement. IrAEs involving multiple organs appeared to be beneficial for overall survival. Early infliximab use shortens the duration of steroid treatment and therefore balances better cancer outcomes with decreased risk of infection.

Abstract Background Immune checkpoint inhibitors (ICPIs) are gaining increasing popularity as an efficacious treatment for advanced malignancies. ICPI treatment can be complicated by diarrhea and colitis. Systemic steroids are the first line treatment. Infliximab is reserved for severe refractory cases. We aimed to assess the impact of ICPI-induced diarrhea and colitis and their immunosuppressive treatment on patients’ outcomes. Methods This retrospective analysis was conducted in 327 cancer patients who received ICPIs between 2011 and 2017. Patients with ICPI-induced toxicities in other organs were excluded. We collected data about patient demographics, clinical variables, and overall survival. We used descriptive analysis to compare different groups based on the occurrence and the treatment of diarrhea and colitis. Kaplan-Meier and log-rank test were used to estimate and compare overall survival durations between groups. Results Diarrhea was recorded in 117 (36%) patients; 79 (24%) of them required immunosuppressive treatment of either systemic corticosteroid without infliximab (n = 44) or with infliximab (n = 35). Caucasian ethnicity, melanoma, stage 3 cancer, and ipilimumab were predictors of colitis that requires immunosuppression. Patients who required immunosuppressants had better overall survival than those who did not require treatment for colitis or diarrhea (P 30 days) had numerically higher infection rate than those who received steroid for shorter duration (40.4 vs. 25.8%, P = 0.160). Likewise, long duration of steroid without infliximab was associated with increased risk of infection compared to short duration of steroid with infliximab (42.9% vs. 14.3%, P = 0.089). Conclusions Patients with ICPI-induced diarrhea or colitis have improved survival outcomes. Diarrhea is an independent predictor of an improved survival regardless of treatment requirement. Immunosuppressive treatment for diarrhea did not significantly affect overall survival, however, infection rates were numerically higher among patients who received steroids for a long duration. Therefore, early non-steroid immunosuppressive therapy may ensure a more favorable overall outcome.

Pollutant gases, such as CO, NO2, O3, and SO2 affect human health, and low-cost sensors are an important complement to regulatory-grade instruments in pollutant monitoring. Previous studies focused on one or several species, while comprehensive assessments of multiple sensors remain limited. We conducted a 12-month field evaluation of four Alphasense sensors in Beijing and used single linear regression (SLR), multiple linear regression (MLR), random forest regressor (RFR), and neural network (long short-term memory (LSTM)) methods to calibrate and validate the measurements with nearby reference measurements from national monitoring stations. For performances, CO > O3 > NO2 > SO2 for the coefficient of determination (R2) and root mean square error (RMSE). The MLR did not increase the R2 after considering the temperature and relative humidity influences compared with the SLR (with R2 remaining at approximately 0.6 for O3 and 0.4 for NO2). However, the RFR and LSTM models significantly increased the O3, NO2, and SO2 performances, with the R2 increasing from 0.3–0.5 to >0.7 for O3 and NO2, and the RMSE decreasing from 20.4 to 13.2 ppb for NO2. For the SLR, there were relatively larger biases, while the LSTMs maintained a close mean relative bias of approximately zero (e.g., 3 and NO2), indicating that these sensors combined with the LSTMs are suitable for hot spot detection. We highlight that the performance of LSTM is better than that of random forest and linear methods. This study assessed four electrochemical air quality sensors and different calibration models, and the methodology and results can benefit assessments of other low-cost sensors.

Numerous particulate matter (PM) sensors with great development potential have emerged. However, whether the current sensors can be used for reliable long-term field monitoring is unclear. This study describes the research and application prospects of low-cost miniaturized sensors in PM2.5 monitoring. We evaluated five Plantower PMSA003 sensors deployed in Beijing, China, over 7 months (October 2019 to June 2020). The sensors tracked PM2.5 concentrations, which were compared to the measurements at the national control monitoring station of the Ministry of Ecology and Environment (MEE) at the same location. The correlations of the data from the PMSA003 sensors and MEE reference monitors (R2 = 0.83~0.90) and among the five sensors (R2 = 0.91~0.98) indicated a high accuracy and intersensor correlation. However, the sensors tended to underestimate high PM2.5 concentrations. The relative bias reached −24.82% when the PM2.5 concentration was >250 µg/m3. Conversely, overestimation and high errors were observed during periods of high relative humidity (RH > 60%). The relative bias reached 14.71% at RH > 75%. The PMSA003 sensors performed poorly during sand and dust storms, especially for the ambient PM10 concentration measurements. Overall, this study identified good correlations between PMSA003 sensors and reference monitors. Extreme field environments impact the data quality of low-cost sensors, and future corrections remain necessary.