The impact of cancer-related diarrhea on changes in cancer therapy.

PURPOSE: The impact of cancer-related diarrhea (CRD) on changes in cancer therapy remains poorly characterized despite its prevalence. METHODS: We performed a longitudinal observational study using IQVIA PharMetrics Plus claims data. Patients included adults with CRD identified by diagnosis codes or pharmacy claims and compared their outcomes to matched (1:1) patients without CRD. Treatment parameters (discontinuation, persistence, augmentation, dose titration, adherence) were evaluated and stratified for the first cancer therapy (chemotherapy vs. targeted therapy vs. both). A multivariate Cox proportional hazards model was used to estimate the difference in risk of each treatment parameter between cohorts, adjusting for cancer type, therapy, and comorbidities. RESULTS: We identified 104,135 matched pairs of patients with solid (n = 94,411) or hematologic cancers (n = 9,724) receiving chemotherapy (n = 47,220), targeted therapy (n = 2,427), or both (n = 5,313). Patients with CRD discontinued therapy more frequently than those without CRD (chemotherapy [81.5% vs. 62.3%], targeted therapy [69.2% vs. 64.3%], both [96.0% vs. 85.5%], p < 0.0001). The overall proportion of discontinuation was higher (82.4% vs. 64.6%, p < 0.0001), including a higher risk of discontinuation (HR = 1.40, p < 0.001) for patients with CRD. The mean time to discontinuation (59.6 ± 54.1 vs. 68.3 ± 76.6 days), switch (72.0 ± 48.6 vs. 96.9 ± 84.0 days), persistence (95.1 ± 98.1 vs. 154.3 ± 142.7 days), and adherence (25.5% ± 37.2 vs. 47.9 ± 41%) were all lower (p < 0.0001) among patients with CRD. CONCLUSION: Patients who develop CRD undergo significant and clinically impactful index treatment discontinuation, treatment switching, and have lower adherence and persistence of anticancer therapy compared to patients without CRD. Strategies to control CRD to optimize cancer therapy are urgently needed.

Toxicity in the era of immune checkpoint inhibitor therapy.

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.

Immune Checkpoint Inhibitor-Induced Pancreatic Injury: Clinical and Radiological Profile and Response to Steroids.

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.

The Effect of Immune Checkpoint Inhibitor Therapy on Pre-Existing Gastroparesis and New Onset of Symptoms of Delayed Gastric Emptying.

Immune checkpoint inhibitors (ICIs) can cause myenteric plexopathy, which could result in delayed gastric emptying (GE) and possibly gastroparesis. We assessed the clinical outcomes of patients who had pre-existing gastroparesis or who developed symptoms of delayed GE following ICI therapy. We retrospectively identified adults with ICD-9 and ICD-10 codes for gastroparesis who received ICI therapy between 1 January 2020 and 31 December 2022 at a tertiary cancer center. Of 76 eligible patients, 37 had pre-existing gastroparesis; 39 (0.2% of the more than 18,000 screened) developed symptoms of delayed GE after ICI therapy, of which 27 (69%) patients had an alternative etiology for delayed GE. Four patients (11%) with pre-existing gastroparesis had a flare-up after ICI, and the median time to flare-up was 10.2 months (IQR, 0.7-28.6 months); for patients with new onset of suspected delayed GE after ICI, the median time to symptom onset was 12.8 months (IQR, 4.4-35.5 months). The clinical symptom duration of patients without an alternative etiology (74.5 days (IQR, 21.5-690 days)) and those with an alternative etiology (290 days (IQR, 147-387 days)) did not differ significantly (p = 1.00). Delayed GE after ICI therapy is a rare presentation but has a late onset and a prolonged symptom duration.

2', 3', 5'-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine alleviates diet-induced hyperlipidemia by modulating intestinal gene expression profiles and metabolic pathway.

There is a growing body of evidence suggesting that the composition of intestinal flora plays a significant role in regulating lipid metabolism. 2', 3', 5'-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine (IMMH007) is a new candidate compound for regulating blood cholesterol and other lipids. In this study, we conducted metagenomic and metabolomic analyses on samples from high-fat diet-fed (HFD) hamsters treated with IMMH007. Our findings revealed that IMM-H007 reversed the imbalance of gut microbiota caused by a high-fat diet. Additionally, it activated adiponectin receptor and pantothenate and CoA biosynthesis pathway-related genes, which are known to regulate lipid and glucose metabolism. Furthermore, IMM-H007 promotes cholesterol metabolism by reducing the abundance of genes and species associated with 7α-dehydroxylation and bile salt hydrolase (BSH). Metabolomics and pharmacological studies have shown that IMM-H007 effectively improved glucose and lipid metabolism disorders caused by HFD, reduced the aggregation of secondary bile acids (SBAs), significantly increased the content of hyodeoxycholic acid (HDCA), and also activated the expression of VDR in the small intestine. As a result, there was a reduction in the leakage of diamine oxidase (DAO) into the bloodstream in hamsters, accompanied by an upregulation of ZO-1 expression in the small intestine. The results suggested that IMM-H007 regulated glucose and lipid metabolism, promoted cholesterol metabolism through activating the expression of VDR, inhibiting inflammatory and improving the permeability of the intestinal barrier. Thus, our study provides new understanding of how IMM-H007 interacts with intestinal function, microbiota, and relevant targets, shedding light on its mechanism of action.

Emodin suppresses mast cell migration via modulating the JAK2/STAT3/JMJD3/CXCR3 signaling to prevent cystitis.

AIMS: This study aimed to determine the preventive effects of emodin on cyclophosphamide (CYP)-induced cystitis and to explore the molecular mechanism. METHODS: In vivo, mice were modeled by CYP. Before a half hour of CYP treatment, Jumonji domain-containing protein-3 (JMJD3) inhibitors (GSK-J4) and emodin were used to treat CYP model mice. Bladder samples were stained for hematoxylin-eosin and toluidine blue. Next, JMJD3 was quantified by immunofluorescence staining, RT-PCR, and Western blot. CXCR3 was quantified by Western blot and ELISA. In vitro, before stimulated by lipopolysaccharide (LPS), human bladder smooth muscle cells (hBSMCs) were transfected with pcDNA3.1-JMJD3 plasmids, shRNA-JMJD3 plasmids or pretreated with emodin. Collected cells to detect JMJD3 and CXCR3 ligands again; collected supernatant of culture for Transwell assay. Finally, as the JAK2 inhibitor, AG490 was used to pretreat LPS-induced hBSMCs. Western blot was performed to quantify proteins. RESULTS: Emodin inhibited mast cell migration and suppressed the expression of JMJD3, CXCR3, and CXCR3 ligands, not only in vivo but also in vitro. The pharmacological effects of emodin were similar to GSK-J4 or JMJD3 inhibition. In addition, emodin significantly downregulated the phosphorylation of JAK2 and STAT3, and inhibited JMJD3/CXCR3 axis transduction like AG490. CONCLUSION: Emodin has a preventive effect on cystitis by inhibiting mast cell migration through inhibition of the JAK2/STAT3/JMJD3/CXCR3 signaling pathway.

Gastrointestinal toxicities of proteasome inhibitor therapy.

PURPOSE: Proteasome inhibitors (PIs), which cause cell death via tumor suppressor and pro-apoptotic proteins, are integral to treatment of many hematologic malignancies but are limited by their gastrointestinal adverse effects. Evidence regarding these PI-related adverse effects is scant. In this study, we evaluated gastrointestinal adverse events caused by PIs and compared gastrointestinal toxicities between bortezomib, carfilzomib, and ixazomib. METHODS: We conducted a retrospective study of cancer patients treated with PIs at a tertiary care cancer center to investigate the clinical characteristics of PI-related gastrointestinal adverse events. RESULTS: Our sample comprised 973 patients with PI exposure and stool studies ordered between January 2017 and December 2022. Of these, 193 patients (20%) had PI-related gastrointestinal toxicity based on clinical symptoms and stool study results. The most common symptom was diarrhea, present in 169 (88% of those with gastrointestinal toxicity). Twenty-two (11%) required hospitalization, and 71 (37%) developed recurrence of symptoms. Compared to bortezomib or carfilzomib, ixazomib had a longer interval from PI initiation to the onset of gastrointestinal symptoms (313 days vs 58 days vs 89 days, p = 0.002) and a significantly lower percentage of diarrhea-predominant presentation of gastrointestinal toxicity (71% vs 96% vs 91%, p = 0.048). CONCLUSION: While PI-related gastrointestinal toxicities have various presentations and courses based on different regimens, the vast majority of patients presented with milder disease behavior. Despite a considerably high rate of hospitalization and recurrence after treatment necessitating optimization of clinical management, our cohort demonstrates favorable outcomes without long-term consequences.

Safety and efficacy outcomes of early cessation of anti-PD1 therapy in patients 80 years or older: A retrospective cohort study.

Older patients have similar immune checkpoint inhibitor efficacy and rates of adverse events as younger patients, but appear to have decreased tolerability, particularly in the oldest patient cohort (>80 years), often leading to early cessation of therapy. We aimed to determine whether early discontinuation impacts efficacy of anti-PD-1 therapy in patients ≥80 years old. In this retrospective, multicenter, international cohort study, we examined 773 patients with 4 tumor types who were at least 80 years old and treated with anti-PD-1 therapy. We determined response rate, overall survival (OS), and progression-free survival (PFS) in patients who discontinued therapy early (<12 months) for reasons other than progression or death. We used descriptive statistics for demographics, response, and toxicity rates. Survival statistics were described using Kaplan Meier curves. Median (range) age at anti-PD-1 initiation was 83.0 (75.8-97.0) years. The cancer types included were melanoma (n = 286), non-small cell lung cancer (NSCLC) (n = 345), urothelial cell carcinoma (UCC) (n = 108), and renal cell carcinoma (RCC) (n = 34). Of these, 102 met the primary endpoint of <12 months to discontinuation for reasons other than death or progression. Median PFS and OS, respectively, for these patients were 34.4 months and 46.6 months for melanoma, 15.8 months and 23.4 months for NSCLC, and 10.4 months and 15.8 months for UCC. This study suggests geriatric patients who have demonstrated therapeutic benefit and discontinued anti-PD-1 therapy at less than 12 months of duration for reasons other than progression may have durable clinical benefit without additional therapy.

Outcomes of Budesonide as a Treatment Option for Immune Checkpoint Inhibitor-Related Colitis in Patients with Cancer.

BACKGROUND: Current treatment guidelines for moderate to severe colitis (IMC) secondary to immune checkpoint inhibitors (ICI) recommend systemic corticosteroids as the primary therapy in conjunction with biologics, namely infliximab and/or vedolizumab. We aimed to explore the efficacy and safety of oral budesonide in the treatment of IMC. METHODS: We performed a retrospective analysis at MD Anderson Cancer Center of adult cancer patients with a confirmed (based on clinical, radiographic and laboratory assessment) diagnosis of IMC between 1 January 2015 and 31 November 2022, treated with budesonide. Data collection included demographics, oncologic history, IMC-related information and outcomes up to 6 months after the last dose of ICI. RESULTS: Our sample (n = 69) comprised primarily of Caucasian (76.8%) females (55.1%). The majority of patients received combination therapy with anti-PD-1/L1 and anti-CTLA-4 (49.3%), and the most common malignancy treated was melanoma (37.6%). The median grade of diarrhea was 3 and of colitis was 2. Of the 50 patients who underwent endoscopic evaluation, a majority had non-ulcerative inflammation (64%) and active colitis on histology (78%). Budesonide was used as primary treatment at onset of IMC in 56.5% patients, as well as a bridging therapy from systemic corticosteroids in 33.3%. Less than half of the patients (44.9%) required additional therapies such as biologics or fecal microbiota transplant. Additionally, 75.3% of patients achieved full remission of IMC and 24.6% had a recurrence of IMC. ICI was resumed in 31.9% of patients and 17.4% received other forms of cancer therapies. CONCLUSIONS: Budesonide may be an effective strategy to treat and prevent the recurrence of IMC. The remission rates observed in our analysis with budesonide alone are comparable to systemic corticosteroids. Patients that require an extended duration of steroid exposure and those with moderate to severe colitis may benefit from budesonide given its lower risk of infection and complications. Furthermore, we observe that budesonide may serve as a successful bridge from systemic corticosteroids with subsequent biologic treatment. Larger prospective studies are necessary to determine the role of budesonide as well as its safety profile.

Bilateral matching decision-making for rural homesteads withdrawal patterns and types of peasant households' welfare needs: Evidence from China in the context of land spatial planning regulation.

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.

Peroxyacetyl nitrate can be used as a comprehensive indicator of air pollution complex.

With the acceleration of air cleaning activities in China, air pollution has entered a new stage characterized by seasonal interplay and predominance of fine particulate matter (PM2.5) and ozone (O3) pollutants. However, the differing peak seasons of these two pollution preclude the use of a unified indicator for air pollution complex. Given that peroxyacetyl nitrate (PAN) originates from secondary formation and persists under low-temperature conditions for extended periods, it is vital to determine whether its concentration can be used as an indicator to represent air pollution, not only in summer but also in winter. Here, PAN observational data from 2018 to 2022 for Beijing were analyzed. The results showed that during photochemical pollution events in summer, secondary formation of PAN was intense and highly correlated with O3 (R = 0.8), while during PM2.5 pollution events in winter, when the lifetime of PAN is extended due to the low temperature, the PAN concentration was highly consistent with the PM2.5 concentration (R = 0.9). As a result, the PAN concentration essentially exhibited consistency with both the seasonal trends in the exceedance of air pollution (R = 0.6) and the air quality index (R = 0.8). When the daily average concentration exceeds 0.5 and 0.9 ppb, the PAN concentration can be used as a complementary indicator of the occurrence of primary and secondary standard pollution, respectively. This study demonstrated the unique role of PAN as an indicator of air pollution complex, highlighting the comprehensive ability for air quality characterization and reducing the burden of atmospheric environment management.

Practice Changes in Checkpoint Inhibitor-Induced Immune-Related Adverse Event Management at a Tertiary Care Center.

Understanding of immune-related adverse events (irAEs) has evolved rapidly, and management guidelines are continually updated. We explored temporal changes in checkpoint inhibitor-induced irAE management at a tertiary cancer care center to identify areas for improvement. We conducted a single-center retrospective study of patients who developed a gastrointestinal, pulmonary, renal, or cardiac irAE between July and 1 October in 2019 or 2021. We collected patient demographic and clinical information up to 1 year after toxicity. Endoscopic evaluation and specialty follow-up after discharge for patients with gastrointestinal irAEs declined between the 2019 and 2021 periods. Symptom duration and steroid taper attempts also declined. For pulmonary irAEs, rates of specialty consultation, hospital admission and readmission, and mortality improved in 2021 compared with 2019. Follow-up rates after hospital discharge were consistently low (<50%) in both periods. For cardiac irAEs, consultation with a cardiologist was frequent and prompt in both periods. Outpatient treatment and earlier specialty consultation improved outcomes with gastrointestinal irAEs. Our study exploring irAE practice changes over time identified areas to improve management; specifically, timely specialty consultation was associated with better outcomes for gastrointestinal irAEs. These findings can help improve the quality of management algorithms at our institution and may inform policies in other institutions.

A risk model based on 10 ferroptosis regulators and markers established by LASSO-regularized linear Cox regression has a good prognostic value for ovarian cancer patients.

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.

Development of a Strategic Initiative at MD Anderson Cancer Center to Improve Outcomes in Immune-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for many cancer types. The clinical use of ICIs is increasing rapidly, including in combinations associated with increased risk of toxicities, termed "immune-related adverse events" (irAEs). Therefore, MD Anderson Cancer Center (MDACC) in Houston, Texas has proactively responded by developing a priority endeavor known as the Immuno-Oncology Toxicity (IOTOX) initiative. This strategic initiative aims to facilitate the seamless integration of key domains: (1) standardized clinical practice and innovative decision toolsets; (2) patient and provider education; and (3) a comprehensive clinical and translational research platform. The ultimate goal of this initiative is to develop and disseminate clinical best practices and biologic insights into irAEs to improve outcomes of patients with irAEs at MDACC and in the wider oncology community.

Novel endoscopic scoring system for immune mediated colitis: a multicenter retrospective study of 674 patients.

BACKGROUND AND AIMS: No endoscopic scoring system has been established for immune-mediated colitis (IMC). This study aimed to establish such a system for IMC and explore its utility in guiding future selective immunosuppressive therapy (SIT) use compared to clinical symptoms. METHODS: This retrospective, international, 14-center study included 674 patients who developed IMC after immunotherapy and underwent endoscopic evaluation. Ten endoscopic features were selected by group consensus and assigned 1 point each to calculate an IMC endoscopic score (IMCES). IMCES cutoffs were chosen to maximize specificity for SIT use. This specificity was compared between IMCESs, and clinical symptoms were graded according to a standardized instrument. RESULTS: A total of 309 (45.8%) patients received SIT. IMCES specificity for SIT use was 82.8% with a cutoff of 4. The inclusion of ulceration as a mandatory criterion resulted in higher specificity (85.0% for a cutoff of 4). In comparison, the specificity of a Mayo endoscopic subscore of 3 was 74.6%, and the specificity of clinical symptom grading was much lower at 27.4% and 12.3%, respectively. Early endoscopy was associated with timely SIT use (P < .001; r = 0.4084). CONCLUSIONS: This is the largest multicenter study to devise an endoscopic scoring system to guide IMC management. An IMCES cutoff of 4 has a higher specificity for SIT use than clinical symptoms, supporting early endoscopic evaluation for IMC.

Management of infliximab refractory immune checkpoint inhibitor gastrointestinal toxicity: a multicenter case series.

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.

Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma.

BACKGROUND: A well-recognized class effect of immune checkpoint inhibitors (ICI) is immune-related adverse events (IrAEs) ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI. Deaths are reported in < 5% of patients treated with ICI. There are, however, no reliable markers to predict the onset and severity of IrAEs. We tested the association between neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) at baseline with development of clinically significant IrAEs (grade ≥ 2) in hepatocellular carcinoma (HCC) patients treated with ICI. AIM: To test the association between NLR and PLR at baseline with development of clinically significant IrAEs (grade ≥ 2) in HCC patients treated with ICI. METHODS: Data was extracted from an international database from a consortium of 11 tertiary-care referral centers. NLR = absolute neutrophil count/absolute lymphocyte count (ALC) and PLR = platelet count/ALC. Cutoff of 5 was used for NLR and 300 for PLR based on literature. We also tested the association between antibiotic and steroid exposure to IrAEs. RESULTS: Data was collected from 361 patients treated between 2016-2020 across the United States (67%), Asia (14%) and Europe (19%). Most patients received Nivolumab (n = 255, 71%). One hundred sixty-seven (46%) patients developed at least one IrAE, highest grade 1 in 80 (48%), grade ≥ 2 in 87 (52%) patients. In a univariable regression model PLR > 300 was significantly associated with a lower incidence of grade ≥ 2 IrAEs (OR = 0.40; P = 0.044). Similarly, a trend was observed between NLR > 5 and lower incidence of grade ≥ 2 IrAEs (OR = 0.58; P = 0.097). Multivariate analyses confirmed PLR > 300 as an independent predictive marker of grade ≥ 2 IrAEs (OR = 0.26; P = 0.011), in addition to treatment with programmed cell death ligand 1 (PD-1)/cytotoxic T lymphocyte-associated protein-4 (OR = 2.57; P = 0.037) and PD-1/tyrosine kinase inhibitor (OR = 3.39; P = 0.01) combinations. Antibiotic use was not associated with IrAE incidence (OR = 1.02; P = 0.954). Patients treated with steroids had a > 2-fold higher incidence of grade ≥ 2 IrAEs (OR = 2.74; P < 0.001), although 74% were prescribed steroids for the treatment of IrAEs. CONCLUSION: Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs, lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI. This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.

Assessment of the Purity of IMM-H014 and Its Related Substances for the Treatment of Metabolic-Associated Fatty Liver Disease Using Quantitative Nuclear Magnetic Resonance Spectroscopy.

An accurate, rapid, and selective quantitative nuclear magnetic resonance method was developed and validated to assess the purity of IMM-H014, a novel drug for the treatment of metabolic-associated fatty liver disease (MAFLD), and four related substances (impurities I, II, III, and IV). In this study, we obtained spectra of IMM--H014 and related substances in deuterated chloroform using dimethyl terephthalate (DMT) as the internal standard reference. Quantification was performed using the 1H resonance signals at δ 8.13 ppm for DMT and δ 6.5-7.5 ppm for IMM-H014 and its related substances. Several key experimental parameters were investigated and optimized, such as pulse angle and relaxation delay. Methodology validation was conducted based on the International Council for Harmonization guidelines and verified with satisfactory specificity, precision, linearity, accuracy, robustness, and stability. In addition, the calibration results of the samples were consistent with those obtained from the mass balance method. Thus, this research provides a reliable and practical protocol for purity analysis of IMM-H014 and its critical impurities and contributes to subsequent clinical quality control research.