Review article: Contemporary management of gastrointestinal, pancreatic and hepatic toxicities of immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective oncologic agents which frequently cause immune-related adverse events (irAEs) which can impact multiple organ systems. Onco-Gastroenterology is a novel and emerging subspecialty within gastroenterology focused on cancer treatment-related complications. Gastroenterologists must be prepared to identify and manage diverse immune-mediated toxicities including enterocolitis, hepatitis, pancreatitis and other ICI-induced toxicities. AIM: To provide a narrative review of the epidemiology, diagnostic evaluation and management of checkpoint inhibitor-induced gastrointestinal and hepatic toxicities. METHODS: We searched Cochrane and PubMed databases for articles published through August 2023. RESULTS: Gastrointestinal and hepatic irAEs include most commonly enterocolitis and hepatitis, but also pancreatitis, oesophagitis, gastritis, motility disorders (gastroparesis) and other rarer toxicities. Guidelines from the National Comprehensive Cancer Network, American Society of Clinical Oncology and European Society for Medical Oncology, in combination with emerging cohort and clinical trial data, offer strategies for management of ICI toxicities. Evaluation of irAEs severity by formal classification and clinical stability, and a thorough workup for alternative etiologies which may clinically mimic irAEs underlie initial management. Treatments include corticosteroids, biologics and other immunosuppressive agents plus supportive care; decisions on dosing, timing and choice of steroid adjuncts and potential for subsequent checkpoint inhibitor dosing are nuanced and toxicity-specific. CONCLUSIONS: Expanding clinical trial and cohort data have clarified the epidemiology and clinical characteristics of gastrointestinal, pancreatic and hepatic toxicities of ICIs. Guidelines, though valuable, remain based principally on retrospective cohort data. Quality prospective, controlled studies may refine algorithms for treatment and potential immunotherapy rechallenge.

Imaging gastrointestinal damage due to acute mercury poisoning using a mitochondria-targeted dual near-infrared fluorescent probe.

Mercury (Hg) is one of the most widespread pollutants that pose serious threats to public health and the environment. People are inevitably exposed to Hg via different routes, such as respiration, dermal contact, drinking or diet. Hg poisoning could cause gingivitis, inflammation, vomiting and diarrhea, respiratory distress or even death. Especially during the developmental stage, there is considerable harm to the brain development of young children, causing serious symptoms such as intellectual disability and motor impairments, and delayed neural development. Therefore, it's of great significance to develop a specific, quick, practical and labor-saving assay for monitoring Hg2+. Herein, a mitochondria-targeted dual (excitation 700 nm and emission 728 nm) near-infrared (NIR) fluorescent probe JZ-1 was synthesized to detect Hg2+, which is a turn-on fluorescent probe designed based on the rhodamine fluorophore thiolactone, with advantages of swift response, great selectivity, and robust anti-interference capability. Cell fluorescence imaging results showed that JZ-1 could selectively target mitochondria in HeLa cells and monitor exogenous Hg2+. More importantly, JZ-1 has been successfully used to monitor gastrointestinal damage of acute mercury poisoning in a drug-induced mouse model, which provided a great method for sensing Hg species in living subjects, as well as for prenatal diagnosis.

Polystyrene exposure induces lamb gastrointestinal injury, digestive disorders and inflammation, decreasing daily gain, and meat quality.

Microplastics (MPs), recognized as an emerging environmental menace, have been extensively investigated in both marine and terrestrial fauna. This study is comprehensive to investigate how polystyrene (PS) affects ruminant animals. The experimental design comprised 24 individually housed lambs, divided into a CON group (diet without PS) and three PS-exposed (25 µm, 50 µm, 100 µm) groups, each with six lambs, the exposure of PS was 100 mg/day, and the duration of exposure was 60 days. The study yielded noteworthy results: (ⅰ) PS leads to a decrease in average daily gain along with an increase in feed conversion rate. (ⅱ) PS decreases rumen ammonia nitrogen. The rumen microbiota diversity remains consistent. However, the relative abundance of Bacteroidetes and Actinobacteria increased in the PS-exposed groups, while the relative abundance of Coriobacteriales_incertae_Sedis and Prevotellaceae_YAB2003_group decreased. (ⅲ) PS leads to decrease in hemoglobin, thrombocytocrit, and albumin levels in lamb blood, thus triggering oxidative stress accumulation, along with swelling of the kidneys and liver. (ⅳ) PS inflicts severe damage to jejunum, consequently impacting digestion and absorption. (ⅴ) PS reduces meat quality and the nutritional value. In conclusion, PS-exposure inhibited lambs' digestive function, adversely affects blood and organs' health status, reducing average daily gain and negatively influencing meat quality. PS particles of 50-100 µm bring worse damage to lambs. This research aims to fill the knowledge void concerning MPs' influences on ruminant animals, with a specific focus on the meat quality of fattening lambs.

Tolerance and Safety of an Anti-Regurgitation Formula Containing Locust Bean Gum, Pre-, and Postbiotics: A Multi-Country Multi-Center Prospective Randomized Controlled Study in Infants with Regurgitation.

This multi-center prospective randomized controlled trial was a tolerance and safety study investigating the thickener locust bean gum (LBG) in infants with regurgitation, to support the re-evaluation of the safety of LBG in infant formula. The primary objective was to demonstrate that after an 8-week intervention, stool consistency was not inferior (i.e., was not looser or more watery) in infants fed an anti-regurgitation (AR) formula containing LBG vs. the stool consistency of infants fed with an unthickened control formula. A total of 103 full-term infants with regurgitation were randomized to the test or control formula. The test formula contained LBG (0.4 g/100 mL), short-chain galacto-oligosaccharides, and long-chain fructo-oligosaccharides (scGOS/lcFOS; 9:1; 0.4 g/100 mL) and postbiotics and the control formula contained scGOS/lcFOS (0.8 g/100 mL), the same amount of postbiotics, and did not contain LBG. The average stool consistency score at the 8th intervention week was the primary outcome parameter. Secondary outcome parameters were stool consistency at other timepoints, stool frequency, Infant Gastrointestinal Symptom Questionnaire (IGSQ) score, growth, (serious) adverse events ([S]AEs), regurgitation severity, and infant well-being. Overall, the infants were 36.9 ± 12.9 [mean ± SD] days old, 62.7% girls in the test, and 50.0% girls in the control group. The primary analysis showed that the test group did not have looser or more watery stools than the control group. IGSQ sum scores decreased comparably in both groups. The frequency of regurgitation was significantly lower in the test group compared to the control group (mixed model repeated measurement, p ≤ 0.028) and parent-reported well-being scores were favorable. Adequate growth was observed in both groups. Both products were well-tolerated and safe and the AR formula with LBG was efficacious in reducing regurgitation frequency. This study provides further evidence for the dietary management of regurgitation by LBG-containing formulae in infants who are not exclusively breastfed, and the reassurance it can bring to parents.

Managing Gastrointestinal Symptoms Resulting from Treatment with Trofinetide for Rett Syndrome: Caregiver and Nurse Perspectives.

Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder mainly affecting female individuals. Trofinetide was recently approved as the first treatment for RTT, largely on the basis of results from the phase 3 LAVENDER trial, in which trofinetide showed improvements in core symptoms of RTT compared with placebo. However, gastrointestinal (GI) symptoms such as diarrhea and vomiting were commonly reported side effects, and taste was also a reported issue. The objective of this article is to describe the perspectives of five caregivers of girls in trofinetide clinical trials as well as those of three nurse trial coordinators, with a focus on management of GI symptoms of trofinetide treatment.Audio Abstract available for this article. Audio Abstract: Jane Lane provides an overview and discusses key findings of the article titled "Managing Gastrointestinal Symptoms Resulting from Treatment with Trofinetide for Rett Syndrome: Caregiver and Nurse Perspectives." (MP4 83274 KB).

Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU.

The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2% to 40%, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.

Sevelamer-Induced Gastrointestinal Disease in 12 Patients with End-Stage Renal Disease: A Case Series.

INTRODUCTION: Isolated case reports and case series have linked the use of sevelamer to severe gastrointestinal (GI) inflammation and perforation among patients with end-stage renal disease. METHODS: In this study, we identified 12 cases of biopsy-proven sevelamer-induced gastrointestinal disease from a large urban community hospital over the course of 5 years. We described baseline characteristics, sites and types of injury, histological findings, timing and dosing of sevelamer initiation compared with symptom onset, and in a smaller subset, endoscopic resolution post drug cessation. We also reviewed preexisting conditions to identify trends in populations at risk. RESULTS: Several of the patients reviewed had preexisting conditions of decreased motility and/or impaired mucosal integrity. The presentation of disease was broad and included both upper-GI and lower-GI pathologies and in varying severity. DISCUSSION: There is a broad phenotypic range of sevelamer-induced gastrointestinal disease. As this becomes a more frequently recognized pathology, clinicians should be aware of how it may present and which populations may be more susceptible.

Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU.

The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2 % to 40 %, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.

Prediction of gastrointestinal symptoms trajectories using omega-3 and inflammatory biomarkers in early-stage breast cancer patients receiving chemotherapy.

PURPOSE: Gastrointestinal (GI) symptoms are common among breast cancer patients undergoing chemotherapy, negatively impacting treatment outcomes and quality of life. Evidence points to inflammatory processes as the underlying cause of chemotherapy-associated GI symptoms. Relatedly, omega-3 (n-3) has been linked to anti-inflammatory processes. The primary objective of this study was to examine the associations between baseline n-3, baseline inflammatory markers and GI symptom progression in early-stage breast cancer patients receiving chemotherapy. METHODS: In this secondary analysis of a prospective cohort study, we analyzed baseline levels of inflammatory biomarkers (measured using a Luminex bead-immunoassay) and plasma levels of DHA, EPA, and FFA (measured using enzyme-linked immunosorbent assay). GI symptoms were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire in Cancer Patients (EORTC QLQ-C30) symptom scale scores at baseline (T1) and at least 6 weeks after, during chemotherapy (T2). Inferential statistics were used to analyze associations between the variables of interest. RESULTS: The analysis included 31 female breast cancer patients (mean age ± SD = 50.5 ± 8.8; 89.6% receiving anthracycline-based chemotherapy). Higher levels of docosahexaenoic acid (DHA) and interleukin-8 (IL-8) predicted increases in appetite loss. Similarly, higher IL-8 predicted worsened nausea and vomiting. CONCLUSION: Baseline IL-8 and DHA predicted GI symptom progression in early-stage breast cancer patients undergoing chemotherapy. Future studies are required to evaluate how therapeutic intervention targeting these biomarkers may mitigate gastrointestinal symptoms in cancer patients.

Magnitude and Determinants of Long-term Use of Proton Pump Inhibitors Among Portuguese Older Adults in Primary Health Care.

PURPOSE: Proton Pump Inhibitors (PPIs) have been associated with several adverse effects of particular concern in older populations. Their use for a period longer than 8 weeks is not recommended for older adults. Strategies to discontinue PPIs have been offered; however, their use remains high. This study aims to characterize PPI use in Portuguese older people and to identify the factors associated with potentially inappropriate use. METHODS: A cross-sectional study was conducted on 1200 randomly selected older adults (≥65 years of age), users of primary health care facilities in the Regional Health Administration (Administração Regional de Saúde of Centro [ARSC]) of Portugal between April 2021 and August 2022. Data concerning their characteristics and PPI use were provided by the Shared Services of the Health Ministry (Serviços Partilhados do Ministério da Saúde) and collected retrospectively. Associations between independent variables and PPI use were investigated by logistic regression analysis. FINDINGS: Of the older adults, 37.92% were receiving PPIs and 78.68% of them were taking them for a longer period than recommended; 49.79% were taking PPIs without having any digestive system-related disease. Multivariate analysis showed that the prolonged use of PPIs was not associated with any specific pattern, although inappropriate PPI use is high among Portuguese older adults. IMPLICATIONS: Long-term PPI use in older adults is widespread and does not fit any particular patient profile; therefore, cross-cutting educational interventions should be designed independently of the patient's pathologic condition or treatment.

Regular use of low-dose of opioids after gastrointestinal surgery may lead to postoperative gastrointestinal tract dysfunction in children: a Chinese national regional health center experience sharing.

BACKGROUND: The need for pain management is increasing in pediatrics, but the side effects of overuse or abuse of analgesics can be harmful to children's health and even life-threatening in severe cases. METHODS: Patients who underwent resection of Meckel's diverticulum at the Children's Hospital of Chongqing Medical University from July 1, 2019, to July 1, 2022, were included in this study. Opioids were administered through patient-controlled analgesia (PCA). Based on the preoperative choices made by the legal guardians, patients were stratified into two groups: PCA Group (PCAG) and Non-PCA Group (NPCAG). Data pertaining to the clinical characteristics and prognoses of these patients were subsequently collected and analyzed to assess the impact of opioid administration. RESULTS: In the study, a total of 126 patients were enrolled, with 72 allocated to the Patient-Controlled Analgesia Group (PCAG) and 54 to the Non-Patient-Controlled Analgesia Group (NPCAG). When compared to the NPCAG, the PCAG exhibited a longer duration of postoperative fasting (median 72 vs. 62 h, p = 0.044) and increased utilization of laxatives (12[16.7%] vs. 2[3.7%], p = 0.022). However, the PCAG also experienced higher incidences of intestinal stasis and abnormal intestinal dilation (13[18.1%] vs. 3[5.6%], p = 0.037). No statistically significant differences were observed in pain assessments at the conclusion of the surgical procedure (0 vs. 1[1.9%], p = 0.429) or within the first 24 h postoperatively (16[22.2%] vs. 18[33.3%], p = 0.164). Additionally, NPCAG patients did not necessitate increased administration of rescue analgesics (2[2.8%] vs. 4[7.4%], p = 0.432). CONCLUSIONS: The administration of opioids did not demonstrably ameliorate postoperative pain but was associated with a heightened incidence of postoperative gastrointestinal tract dysfunction. The retrospective nature of the current research should be considered and should be clarified further.

Immune-related adverse events with severe pain and ureteral expansion as the main manifestations: a case report of tislelizumab-induced ureteritis/cystitis and review of the literature.

Immune checkpoint inhibitor (ICI) is an up-to-date therapy for cancer with a promising efficacy, but it may cause unique immune-related adverse events (irAEs). Although irAEs could affect any organ, irAEs-induced whole urinary tract expansion was rarely reported. Herein, we reported a 27-year-old male patient with thymic carcinoma who received the treatment of tislelizumab, paclitaxel albumin and carboplatin. He was hospitalized for severe bellyache and lumbago after 6 courses of treatment. Antibiotic and antispasmodic treatment did not relieve his symptoms. The imaging examinations reported whole urinary tract expansion and cystitis. Therefore, we proposed that the patient's pain was caused by tislelizumab-induced ureteritis/cystitis. After the discontinuation of tislelizumab and the administration of methylprednisolone, his symptoms were markedly alleviated. Herein, we reported a rare case of ICI-induced ureteritis/cystitis in the treatment of thymic cancer and reviewed other cases of immunotherapy-related cystitis and tislelizumab-related adverse events, which will provide a reference for the diagnosis and treatment of ICI-related irAEs.

Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss.

This database study examines the association between glucagon-like peptide 1 agonists (eg, semaglutide, liraglutide) used for weight loss and reports of gastrointestinal adverse events.

Relevance of early management by proton-pump inhibitor in acute upper gastro-intestinal tract disorder: A scoping review.

BACKGROUND: Proton-pump inhibitors (PPI) are frequently used in the emergency and general practice settings in several clinical presentations linked to acute upper gastro-intestinal tract disorders as abdominal or chest pain without recommendations. OBJECTIVE: The aim of this scoping review was to assess pain reduction, diagnostic performance, and safety in the first 24 h-management in primary care or emergency medicine. METHODS: Search was realized by 2 independent reviewers in PubMed, Embase, and Web of Science following PRISMA-ScR guidelines. Only original articles or systematic reviews in English were included. Studies about chronic and/or bleeding conditions, therapeutic cocktails and studies without pain evaluation were excluded. Two methodologies were used for bias estimation. RESULTS: From 4442 titles, 79 full-text articles were assessed, and 9 were included. There is no strong evidence supporting the use of PPI as a first line analgesic or diagnostic test in acute syndromes linked to acute upper gastro-intestinal tract disorder. A small effect in pain reduction was retrieved in patients with low pain scores. A poor additional value in patients with gastric reflux, and a low specificity compared to other diagnostic tests were observed. A short-term PPI administration appears to be safe with low risk of serious allergic reactions, and poor adverse effects (moderate evidence). CONCLUSION: Although PPIs may contribute to the multimodal analgesia in acute settings, with few and/or minor side effects, no recommendation can be drawn for their use as a primary analgesic. Data regarding the relevance of the PPI test are much less clear, no data regarding care pathways are available.

Comparison of gastrointestinal adverse events between fast release tablets and regular acetylsalicylic acid (aspirin) galenics after short-term use: a meta-analysis of randomized clinical trials.

This study aimed at determining whether there is a difference in the safety profile between fast release (FR) aspirin tablets and regular galenic formulations of aspirin. This study was based on a clinical study database pool (Bayer HealthCare) including 84 clinical studies and 16,095 human subjects. The meta-analysis included 72 studies applying a single dose of aspirin of at most 1000 mg and was, therefore, based on individual data from 9288 subjects. Of these, 6029 subjects took aspirin and 3259 subjects took placebo. Endpoints were adverse events (AEs) of any kind and, especially of gastrointestinal (GI) nature. Event incidence and odds ratios (OR) based on Mantel-Haenszel risk estimates were calcuated. Subjects on aspirin FR had a significantly decreased OR of 0.65 [0.48, 0.90] [95% confidence interval] for all AEs and of 0.39 [0.20, 0.79] for drug-related all AEs versus placebo. The risk of all GI AEs tended to be reduced for subjects on aspirin FR (0.65 [0.41; 1.03]), but not for drug-related GI AEs. Subject on aspirin mono and aspirin mono (plain only, w/o FR) showed an increased risk of drug-related all AEs compared to placebo (1.34 [1.11; 1.62] and 1.43 [1.13; 1.80]). However, subjects on aspirin FR and those on regular aspirin had almost the same risk of all determined AEs. In conclusion, aspirin FR tablets showed a comparable GI tolerability to regular galenic formulations of aspirin after short-term treatment. Major GI complication did not occur after intake of any galenic formulation of aspirin.

[Clinical characteristics and related factors analysis of adrenal crisis occurred in children with primary nephrotic syndrome].

Objective: To investigate the clinical characteristics and related factors of corticosteroid induced adrenal crisis (AC) in children with primary nephrotic syndrome (NS). Methods: Case control study. The case group included 7 children aged 1 to 18 years with NS combined with AC hospitalized in Peking University First Hospital from January 2016 to May 2021 (AC group). According to the ratio of case group: control group 1: 4, 28 children aged 1 to 18 years who were diagnosed with NS without AC during the same period were matched as controls (non-AC group). Clinical data were collected. The clinical characteristics of AC were described. The clinical parameters were compared between the 2 groups by t test, Mann-Whitney U test or Fisher's test. Receiver operating characteristic (ROC) curve was used to analyze the cutoff values of clinical parameters for prediction of AC. Results: The AC group included 4 boys and 3 girls aged 6.9 (4.6, 10.8) years. The non-AC group included 20 boys and 8 girls aged 5.2 (3.3, 8.4) years. All AC events occurred during the relapse of NS with infection. Seven children had gastrointestinal symptoms such as nausea, vomiting and abdominal pain. Six children had poor mental state or impaired consciousness. No significant differences in NS course, corticosteroid treatment course, corticosteroid type, steroid dosage, steroid medication interval, the proportion of gastroenteritis and fever existed between the two groups (all P>0.05). Compared with the non-AC group, the duration from the onset of the relapse of NS until hospitalization in the AC group was significantly shorter (0.2 (0.1, 0.6) vs. 1.0 (0.4, 5.0) month,U=25.50, P=0.005). The 24 h urinary total protein (UTP) level was significantly higher in the AC group (193 (135, 429) vs. 81 (17, 200) mg/kg, U=27.00,P=0.036) than the non-AC group. The serum albumin level in the AC group was significantly lower((13.1±2.1) vs. (24.5±8.7) g/L,t=-6.22,P<0.001) than the non-AC group. There were significantly higher total white blood cell counts ((26±9)×109 vs. (11±5)×109/L,t=4.26,P=0.004), percentage of neutrophils (0.71±0.08 vs. 0.60±0.19,t=2.56,P=0.017) and the proportion of children with C reactive protein level≥8 mg/L (3/7 vs. 0,P=0.005) in the AC group than in the non-AC group. ROC curve analysis showed that the cutoff value of 24 h UTP was 122 mg/(kg·d) with a sensitivity of 100.0% and specificity of 70.4%. The cutoff value of serum albumin was 17.0 g/L with a sensitivity of 100.0% and specificity of 82.1%. Conclusions: Gastrointestinal symptoms and poor mental state were prominent manifestations of AC in children with NS. High 24 h UTP level, low serum albumin level, high peripheral white blood cell counts, high neutrophils percentage, and high C-reactive protein level during the early stage of NS relapse may be related to the occurrence of AC in children with NS.

Capecitabine-induced Gastrointestinal Injury Shows a Graft-Versus-Host Disease (GVHD)-like Pattern.

Capecitabine is a commonly used oral chemotherapeutic agent. Gastrointestinal (GI) side effects are clinically well-known, however, the histopathologic changes have not been comprehensively studied. This study describes the largest case series (8 patients) characterizing the histopathology of capecitabine-induced GI injury. All patients were adults (median age: 64.5 y, range: 61 to 76 y) and there was gender parity. Patients were receiving treatment for malignancies of the colorectum (n=5), breast (n=1), pancreas (n=1), and appendix (n=1). All had GI symptoms, including 7 with diarrhea and abdominal pain and 1 with melena. Five of 8 (63%) showed graft-versus-host disease (GVHD)-like histologic changes in small intestinal and/or colonic biopsies characterized by crypt disarray and dropout, crypt atrophy, dilated crypts lined by attenuated epithelium, and increased crypt apoptosis. Neuroendocrine cell aggregates were present in 4 of 5 cases. Four of 5 showed patchy prominence in lamina propria eosinophils. One patient receiving concomitant radiation therapy had a small intestinal biopsy showing regenerative changes. Two patients had histologically unremarkable biopsies. On follow-up, capecitabine was discontinued or dose-reduced in all patients. Three of 5 patients with a GVHD-like pattern had clinical improvement, whereas 2 died shortly after biopsy. One with regenerative changes also had radiation dose reduction and improved clinically. Two with unremarkable biopsies improved symptomatically. In summary, capecitabine-related GI injury shows a GVHD-like pattern. Knowledge of this is important to confirm the diagnosis as patients typically improve with dose reduction or discontinuation of the drug.