A Comprehensive Narrative Review of Neuropathic Pain: From Pathophysiology to Surgical Treatment.

Neuropathic pain is a challenging condition. Despite the immense progress made in the pathophysiology and treatment of such conditions, so much work still has to be done. New frontiers previously unexplored are now objects of study with exciting results, mainly regarding neuromodulation and optogenetics. This review explores the already known pathophysiology and the clinical and surgical treatment in the light of evidence-based medicine. Additionally, new concepts and insights are discussed, presenting the hope for the development of new paradigms in the treatment of neuropathic pain.

Temporal Trends of Age-Adjusted Mortality Rates for Rheumatic Heart Disease in Brazil From 2000 to 2021.

Background Rheumatic heart disease (RHD) is a chronic cardiovascular condition stemming from an infectious origin, posing a substantial health burden, particularly in economically disadvantaged regions. It starts with acute rheumatic fever (ARF), a complication following group A Streptococcus infection, leading to heart valve damage and, over time, structural heart abnormalities. RHD contributes to premature deaths, especially in low-middle-income countries. Although the incidence and prevalence have generally reduced globally due to antibiotics and improved healthcare, it remains a significant public health concern in Brazil, echoing its prevalence in many developing nations around the world. RHD stands as a poignant testament to the intersection of socio-economic disparities and healthcare challenges within Brazil's diverse population. In Brazil, despite advancements in healthcare, RHD continues to impact communities, highlighting the urgent need for enhanced prevention strategies, access to quality healthcare services, and heightened awareness to combat this preventable, yet persistent, cardiac condition. Understanding the epidemiological landscape and socio-cultural factors influencing RHD in Brazil is crucial for developing targeted interventions aimed at mitigating its burden on individuals, families, and the healthcare system at large. Thus, our study focuses on analyzing age-related mortality rates linked to ARF and chronic RHD (ARHD) in Brazil from 2000 to 2021, particularly examining gender disparities. Materials and methods This retrospective cohort study employed a descriptive time-series approach, utilizing comprehensive nationwide data from Brazil spanning from 2000 to 2021 to assess trends in diverse age groups, among both sexes, enabling a detailed analysis of temporal patterns. Mortality data, extracted and categorized meticulously, were subjected to Joinpoint statistical analyses enabling comparative assessments, with average annual percent change (AAPC) and annual percent change (APC) serving as key metrics to quantify and interpret trends over the analyzed period. Results The acute RHD (ARHD)-related mortality declined over the analyzed years supported by AAPC, with higher mortality reduction in females. The age-adjusted mortality rate for "males and females" decreased from 78 to 67 deaths/100,000 from 2000 to 2021. Female mortality dropped from 85 to 69/100,000, and male mortality decreased from 73 to 63/100,000 over the same period. For ARHD, male age groups (20-29, 60-69, 70-79, 80+) showed declining mortality, while the 30-59 age group exhibited an upward. Females AAMR for chronic RHD (CRHD) decreased across all age groups, with significant reductions in the 80 years and above age group from 2000-2002 (APC: -11.94*) and steadily from 2002 onwards (APC: -1.33). Conclusions Our study revealed an overall decline in mortality rates for both acute and CRHD across both sexes. Females consistently exhibited higher mortality rates and a more pronounced reduction compared to males in both acute and CRHD. In ARHD, males experience the highest mortality in the 50-59 age group, while females have a peak in the 40-49 age group. The 60-69 age group had the highest mortality in CRHD for both sexes. Conversely, the 20-29 age group displayed the lowest mortality in CRHD, and the 80-89 age group had the lowest mortality in ARHD.

Novel endoscopic scoring system for immune mediated colitis: A Multicenter Retrospective Study of 674 Patients.

BACKGROUND & 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 one point each to calculate an IMC endoscopic score (IMCES). IMCES cutoffs were chosen to maximize specificity for SIT use. This specificity was compared between IMCES, and clinical symptoms 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 Endoscopy Score (MES) of 3 was 74.6% while specificity of clinical symptom grading was much lower at 27.4% and 12.3% respectively. Early endoscopy was associated with timely SIT use (p<0.001, r=0.4084). CONCLUSIONS: This is the largest, multi-center study to devise an endoscopic scoring system to guide IMC management. An IMCES cutoff 4 has a higher specificity for SIT use than clinical symptoms, supporting early endoscopic evaluation for IMC.

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.

Pneumatosis intestinalis in cancer patients who received immune checkpoint inhibitors.

PURPOSE: Immune checkpoint inhibitor (ICI) therapy may give rise to immune-related adverse events (irAEs). Pneumatosis intestinalis (PI), or gas within the bowel wall, has very rarely been observed following ICI therapy, and its clinical significance is unclear. We described the clinical characteristics and outcomes of PI as a possible irAE in cancer patients. METHODS: We retrospectively identified 12 adult cancer patients with radiologic evidence of PI within 1 year after ICI exposure during January 2010-January 2023. Clinical characteristics, treatment, and outcomes were evaluated. RESULTS: The median age of our sample was 64 years. The most common cancer types were thoracic/head & neck and gastrointestinal. Eleven patients (92%) received anti-PD-1/L1 monotherapy, while 1 patient (8%) received a combination of anti-PD-1/L1 and anti-CTLA-4. PI occurred a median of 7 months after the first ICI dose. Half the patients (50%) were asymptomatic on diagnosis, and the most common presenting symptom was abdominal pain (42%). Six patients experienced complications, namely pneumoperitoneum (n = 6, 50%) and microperforation (n = 1, 8%), identified on imaging. Nine patients were treated with antibiotics and 3 patients were monitored conservatively. Nine patients (75%) resumed cancer treatment after PI. CONCLUSION: PI may develop as an irAE. While half of cases were incidental radiologic findings, management with antibiotics as well as hospitalization for observation may still be appropriate. The decision to restart cancer therapy and possibly resume ICI therapy remains to be elucidated. Further large-scale studies may be warranted to clarify the association between PI and ICI therapy.

Immune Checkpoint Inhibitor-Induced (Type 3) Autoimmune Pancreatitis.

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICI) have revolutionized cancer care and work primarily by blocking CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), and/or PD-1 (programmed cell death protein 1), and/or PD-L1 (programmed death-ligand 1), thereby providing highly efficacious anti-tumor activity. However, this unmitigated immune response can also trigger immune related adverse events (irAEs) in multiple organs, with pancreatic irAEs (now referred to as type 3 Autoimmune pancreatitis (AIP) being infrequent. RECENT FINDINGS: Type 3 AIP is a drug-induced, immune mediated progressive inflammatory disease of the pancreas that may have variable clinical presentations viz., an asymptomatic pancreatic enzyme elevation, incidental imaging evidence of pancreatitis, painful pancreatitis, or any combination of these subtypes. Management is largely supportive with intravenous fluid hydration, pain control and holding the inciting medication. Steroids have not been shown to demonstrate a clear benefit in acute management. A rapid development pancreatic atrophy is observed on imaging as early as 1 year post initial injury. Type 3 AIP is a chronic inflammatory disease of the pancreas that though predominantly asymptomatic and mild in severity can lead to rapid organ volume loss regardless of type of clinical presentation and despite steroid therapy.

Colon Adenoma After Diagnosis of Immune Checkpoint Inhibitor-mediated Colitis.

Purpose: While the occurrence of colitis during immune checkpoint inhibitor (ICI) treatment is recognized as a sign of robust immune activation and correlates with better oncological outcomes, the long-term impact of ICI-mediated colitis on the colonic mucosa has not been studied. We thus aim to describe the colonoscopy and histology findings in patients at a follow-up time of ≥ 6 months post initial colitis event. Methods: This retrospective analysis included adult cancer patients diagnosed with ICI colitis at a tertiary cancer center between October 2013 and June 2020. The study group included patients diagnosed with immune mediated colitis who had also undergone a follow up colonoscopy or flex sigmoidoscopy. The control group was patients exposed to ICI without immune mediated colitis. We reported patients' colitis clinical course, treatment, outcomes, and endoscopic and histologic features at diagnosis and at follow-up time of ≥ 6 months. Results: Total 39 patients met the study criteria, with 82% being male, and 35.8% having melanoma. Most patients received a combination of CTLA-4 and PD-1/L1 inhibitors (82%). On initial endoscopic evaluation, inflammation without ulceration was reported in 76.9% of patients and active inflammation on histologic examination in 79.3% of patients. Most patients (79.4%) received corticosteroids, and 56.4% received add-on selective immunosuppressive therapy. Four patients received fecal microbiota transplantation. On follow-up, new incidence of colonic polyps was reported in 51.2% of patients, including adenomas in 33.3% among the colitis patients with median follow up duration of 12 months. The incidence of adenoma polyps 12 months after the colitis event was significantly higher compared to the control group without colitis based on the time-to-event analysis (p=0.041). Conclusion: At a median follow up of 12 months after their initial colitis diagnosis, 51.2% of the patients had new incidence of colonic polyps, including a third with adenoma, at a significantly higher incidence than the control group without colitis. Studies with larger sample sizes are needed to further define the long-term impact of colitis and its treatments on colon health and to refine recommendations for surveillance of colonic adenomas and colorectal cancer.

The Safety of Immunosuppressants Used in the Treatment of Immune-Related Adverse Events due to Immune Checkpoint Inhibitors: a Systematic Review.

Purpose: Immune checkpoint inhibitor (ICI) use can lead to immune-related adverse events (irAEs) that require treatment with immunosuppressive medications in moderate to severe cases. Oncology society guidelines recommend systemic steroids and immunosuppressants such as infliximab and vedolizumab for the treatment of refractory cases. Limited information is available about the safety profile and potential adverse effects of these immunosuppressants. We have investigated the safety profile of multiple immunosuppressants which are used in the treatment of ICI-related irAEs. Methods: We performed a systematic review of studies reporting irAEs, from ICI use, and their medical management with immunosuppressants in adult cancer patients. We searched MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov from inception through September 1, 2022, using the following keywords or their equivalents: ICI, immunosuppressant, and irAE. We extracted observational studies and clinical trials that matched our criteria. A random effects model was used to estimate the overall incidence of infections associated with the treatment of irAEs. Results: Among the 11 studies included in this review (1036 total patients), melanoma (548 patients, 52.9%) was the most common primary cancer, followed by lung cancer (139 patients, 13.4%) and genitourinary cancers (131 patients, 12.6%). PD-1/PD-L1 monotherapy (460 patients, 44.4%) was used most, followed by a combination of PD-1/PD-L1 and CTLA-4 therapy (350 patients, 33.8%) and CTLA-4 monotherapy (226 patients, 22%). A total of 1024 (98.8%) patients had their irAEs treated with systemic steroids with majority having colitis and hepatobiliary irAEs; 335 patients (32.3%) were also treated with infliximab (mainly for colitis). Our review found 22.3% of patients treated for irAEs developed infectious adverse events (95% CI: 15.6%-29.1%, p<0.001). Among the 3 studies reporting the types of infections (41 total patients), bacterial (80.5%), followed by fungal (36.6%), infections were most common. Conclusions: Adverse events from irAE treatment occurred in about one-third of patients that received either steroids or a combination of steroids and other immunosuppressants. Clinicians should be aware of these immunosuppressant-related adverse effects, which can negatively impact cancer treatment and patient outcomes, when treating irAEs and consider shortening treatment duration or using alternative strategies when possible to mitigate these complications, future prospective studies should further investigate the safety of immunosuppressants in treating irAEs.

Role of C-Reactive Protein in Predicting the Severity and Response of Immune-Mediated Diarrhea and Colitis in Patients with Cancer.

Background: Immune-mediated diarrhea and colitis (IMDC) frequently develop after treatment with immune checkpoint inhibitors. C-reactive protein (CRP) is a serum inflammatory biomarker used to stratify and monitor disease severity in many inflammatory conditions. However, CRP level is not specific and is widely influenced by various factors non-specific to bowel inflammation. We aimed to study the utility of CRP as a predictor of disease severity and therapy response in IMDC. Methods: We performed a retrospective analysis of patients diagnosed with IMDC who had CRP measured at IMDC onset and after treatment with selective immunosuppressive therapy (SIT: infliximab and vedolizumab), between 01/2016 and 02/2022 at MD Anderson Cancer Center. Patient demographics, clinical characteristics, and IMDC data were collected and analyzed. Results: Our sample of 128 patients had a median age of 67 years; most were white (89.8%); and male (65.6%). Prior to development of IMDC, 15 (11.7%) were initially treated with anti-CTLA-4, 42 (32.8%) with anti-PD-1 or PD-L1, and 71 (55.5%) with a combination of both. We found higher CRP level was associated with higher CTCAE grade of clinical symptoms such as diarrhea (p=0.015), colitis (p=0.013), and endoscopic findings (p=0.016). While CRP levels decreased after IMDC treatment, there was no significant association between CRP levels with clinical remission, endoscopic remission or histologic remission. There also was no significant correlation between CRP level and recurrence of IMDC, or with fecal calprotectin levels. Conclusion: CRP level may be useful to assess initial severity of IMDC, including grade of diarrhea and colitis and degree of endoscopic inflammation. However, CRP is not a robust surrogate biomarker for assessing treatment response or disease recurrence. Despite the reduction of CRP levels observed following IMDC treatment, this finding might be nonspecific and potentially confounded by concurrent clinical factors, such as underlying malignancy, other inflammatory processes, and systemic anti-cancer therapy. Further studies of the role of CRP are warranted in patients with cancer and IMDC.

Microbiome alteration via fecal microbiota transplantation is effective for refractory immune checkpoint inhibitor-induced colitis.

Immune checkpoint inhibitors (ICIs) target advanced malignancies with high efficacy but also predispose patients to immune-related adverse events like immune-mediated colitis (IMC). Given the association between gut bacteria with response to ICI therapy and subsequent IMC, fecal microbiota transplantation (FMT) represents a feasible way to manipulate microbial composition in patients, with a potential benefit for IMC. Here, we present a large case series of 12 patients with refractory IMC who underwent FMT from healthy donors as salvage therapy. All 12 patients had grade 3 or 4 ICI-related diarrhea or colitis that failed to respond to standard first-line (corticosteroids) and second-line immunosuppression (infliximab or vedolizumab). Ten patients (83%) achieved symptom improvement after FMT, and three patients (25%) required repeat FMT, two of whom had no subsequent response. At the end of the study, 92% achieved IMC clinical remission. 16S rRNA sequencing of patient stool samples revealed that compositional differences between FMT donors and patients with IMC before FMT were associated with a complete response after FMT. Comparison of pre- and post-FMT stool samples in patients with complete responses showed significant increases in alpha diversity and increases in the abundances of Collinsella and Bifidobacterium, which were depleted in FMT responders before FMT. Histologically evaluable complete response patients also had decreases in select immune cells , including CD8+ T cells, in the colon after FMT when compared with non-complete response patients (n = 4). This study validates FMT as an effective treatment strategy for IMC and gives insights into the microbial signatures that may play a critical role in FMT response.

Clinical Features and Management of Acute and Chronic Radiation-Induced Colitis and Proctopathy.

BACKGROUND: RICAP is a recognized adverse effect of radiation therapy (RT) that can adversely affect cancer patients' quality of life. Data on the clinical characteristics and outcomes of RICAP are scarce. We aimed to analyze the clinical and endoscopic characteristics of acute or chronic radiation-induced colitis and proctopathy (ARICAP and CRICAP) based on symptom onset after RT (≤ or >45 days, respectively). METHODS: This is a retrospective observational study of a single tertiary cancer center, from January 2010 and December 2018, of cancer patients with endoscopically confirmed ARICAP and CRICAP. We conducted univariate and multivariate logistic regression analyses to associate clinical variables with endoscopic and medical outcomes. RESULTS: One hundred and twelve patients were included (84% Caucasian; 55% female; median age of 59 years); 46% had ARICAP with non-bloody diarrhea as the predominant symptom, whereas 55% had CRICAP with mostly bloody diarrhea. Neovascularization was the most frequent finding on endoscopy, followed by bleeding. ARICAP patients more often received medical management (p < 0.001), whereas CRICAP patients with bleeding more often received argon plasma coagulation (APC) (p = 0.002). Female sex and undergoing less-intense RT treatments were more associated with medical treatment; bleeding clinically and during the endoscopy was more associated with APC treatment. However, APC treatment did not significantly reduce bleeding recurrence or RICAP symptoms. CONCLUSION: Patients with ARICAP and CRICAP experience different symptoms. Medical management should be considered before endoscopic therapy. APC may be useful in patients with endoscopically apparent bleeding.

Concurrent immune checkpoint inhibition and selective immunosuppressive therapy in patients with immune-related enterocolitis.

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<0.001). The total number of ICI doses administered after irEC resolution and ICI resumption was similar in both groups (four to five doses). Recurrence of severe colitis or diarrhea after ICI resumption was seen in 34.4% of controls compared with 20.8% of patients receiving concurrent SIT. Concurrent SIT was associated with reduced risk of severe irEC recurrence after ICI resumption in a multivariate logistic regression model (OR 0.34; 95% CI 0.13 to 0.92; p=0.034). There was no difference in survival outcomes between patients in the control group and patients concurrently treated with SIT. CONCLUSION: After resolution of irEC symptoms, reinitiation of ICI with concurrent SIT is safe, reduces severe irEC recurrence, and has no negative impact on survival outcomes.

Obesity Measured via Body Mass Index May Be Associated with Increased Incidence but Not Worse Outcomes of Immune-Mediated Diarrhea and Colitis.

Obesity defined by high body mass index (BMI) has traditionally been associated with gastrointestinal inflammatory processes but has recently been correlated with better survival in patients receiving immune checkpoint inhibitors (ICI). We sought to investigate the association between BMI and immune-mediated diarrhea and colitis (IMDC) outcomes and whether BMI reflects body fat content on abdominal imaging. This retrospective, single-center study included cancer patients with ICI exposure who developed IMDC and had BMI and abdominal computed tomography (CT) obtained within 30 days before initiating ICI from April 2011 to December 2019. BMI was categorized as <25, ≥25 but <30, and ≥30. Visceral fat area (VFA), subcutaneous fat area (SFA), total fat area (TFA: VFA+SFA), and visceral to subcutaneous fat (V/S) ratio were obtained from CT at the umbilical level. Our sample comprised 202 patients; 127 patients (62.9%) received CTLA-4 monotherapy or a combination, and 75 (37.1%) received PD-1/PD-L1 monotherapy. Higher BMIs ≥ 30 were associated with a higher incidence of IMDC than BMIs ≤ 25 (11.4% vs. 7.9%, respectively; p = 0.029). Higher grades of colitis (grade 3-4) correlated with lower BMI (p = 0.03). BMI level was not associated with other IMDC characteristics or did not influence overall survival (p = 0.83). BMI is strongly correlated with VFA, SFA, and TFA (p < 0.0001). Higher BMI at ICI initiation was linked to a higher incidence of IMDC but did not appear to affect outcomes. BMI strongly correlated with body fat parameters measured by abdominal imaging, suggesting its reliability as an obesity index.

Sclerosing mesenteritis following immune checkpoint inhibitor therapy.

PURPOSE: Sclerosing mesenteritis (SM), a fibroinflammatory process of the mesentery, can rarely occur after immune checkpoint inhibitor (ICI) therapy; however, its clinical significance and optimal management are unclear. We aimed to assess the characteristics and disease course of patients who developed SM following ICI therapy at a single tertiary cancer center. METHODS: We retrospectively identified 12 eligible adult cancer patients between 05/2011 and 05/2022. Patients' clinical data were evaluated and summarized. RESULTS: The median patient age was 71.5 years. The most common cancer types were gastrointestinal, hematologic, and skin. Eight patients (67%) received anti-PD-1/L1 monotherapy, 2 (17%) received anti-CTLA-4 monotherapy, and 2 (17%) received combination therapy. SM occurred after a median duration of 8.6 months from the first ICI dose. Most patients (75%) were asymptomatic on diagnosis. Three patients (25%) reported abdominal pain, nausea, and fever and received inpatient care and corticosteroid treatment with symptom resolution. No patients experienced SM recurrence after the completion of corticosteroids. Seven patients (58%) experienced resolution of SM on imaging. Seven patients (58%) resumed ICI therapy after the diagnosis of SM. CONCLUSIONS: SM represents an immune-related adverse event that may occur after initiation of ICI therapy. The clinical significance and optimal management of SM following ICI therapy remains uncertain. While most cases were asymptomatic and did not require active management or ICI termination, medical intervention was needed in select symptomatic cases. Further large-scale studies are needed to clarify the association of SM with ICI therapy.

Impact of Selective Immunosuppressive Therapy on Subsequent Immune-Related Adverse Events After Immune Checkpoint Inhibitor-Induced Colitis Treatment.

OBJECTIVES: Immune checkpoint inhibitors (ICI) can cause immune-related adverse events (irAEs) such as colitis. irAEs can be managed by selective immunosuppressive therapy (SIT) agents such as infliximab and vedolizumab. We aimed to elucidate the incidence of subsequent new irAEs after exposure to SIT by describing patients' clinical course. METHODS: We conducted a retrospective chart review of adult patients at a tertiary cancer center diagnosed with ICI-mediated colitis (IMC) treated with SIT from February 2013 through October 2021. Patients' clinical courses, treatments, and outcomes of new irAEs after SIT were collected and analyzed. RESULTS: The study included 156 patients. Most were male (67.3%), 44.8% had melanoma, and 43.5% received anti-PD1/L1 ICIs. For IMC treatment, 51.9% received infliximab and 37.8% received vedolizumab. Twenty-six patients (16.6%) resumed ICI treatment after their colitis event. Twenty-five patients (16%) developed a new irAE after receiving SIT. The most common new irAE involved skin (44%), and most (60%) were treated with steroids. Higher diarrhea grade and ≥2 doses of SIT were associated with lower incidence of post-SIT irAEs ( P =0.038, P =0.050). However, the type of SIT or individual dosage of infliximab did not affect the occurrence of subsequent irAEs. CONCLUSIONS: New irAEs usually occur more than 6 months after SIT completion for initial colitis event. Severe diarrhea grade and higher number of SIT infusions appeared to have protective effect to lower the occurrence of new irAEs. Otherwise, the type of SIT or individual dosage of infliximab did not affect the occurrence of subsequent irAEs.

IL12/23 Blockade for Refractory Immune-Mediated Colitis: 2-Center Experience.

INTRODUCTION: Immune checkpoint inhibitor-mediated colitis (IMC) is commonly managed with steroids and biologics. We evaluated the efficacy of ustekinumab (UST) in treating IMC refractory to steroids plus infliximab and/or vedolizumab. RESULTS: Nineteen patients were treated with UST for IMC refractory to steroids plus infliximab (57.9%) and/or vedolizumab (94.7%). Most of them had grade ≥3 diarrhea (84.2%), and colitis with ulceration was present in 42.1%. Thirteen patients (68.4%) attained clinical remission with UST, and mean fecal calprotectin levels dropped significantly after treatment (629 ± 101.5 mcg/mg to 92.0 ± 21.7 mcg/mg, P = 0.0004). DISCUSSION: UST is a promising therapy for the treatment of refractory IMC.

Effects of immunosuppressive treatment on patient outcomes after immune checkpoint inhibitor-related gastrointestinal toxicity.

PURPOSE: Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of certain cancers but cause immune-related adverse events (irAEs). Gastrointestinal irAEs may necessitate extended periods of steroid use and the initiation of selective immunosuppressive therapy (SIT) which could theoretically counteract the effect of ICIs. In this study, we aim to explore the impact of immunosuppression use and duration on cancer progression and progression-free survival (PFS). METHODS: This is a single-center retrospective review exploring cancer outcomes in patients taking ICIs who developed gastrointestinal irAEs within 1 year of ICI initiation. Cancer outcome and progression free survival (PFS) were measured and compared by using IBM SPSS Statistics 26. RESULTS: Of the 116 patients included in this study, 69 received immunosuppression to treat irAEs. The occurrence of colitis and use of immunosuppression for colitis were associated with less cancer progression by later assessment (p < 0.05). Shorter durations of steroids with or without SIT for colitis were associated with less cancer progression within the study window than no immunosuppression (p < 0.05). Immunosuppression has no effect on PFS (p < 0.05). CONCLUSION: Our study reported shorter duration of steroid treatment for colitis may be associated with less cancer progression. Though the use of immunosuppression was not found to impact PFS, this may be confounded by the presence of colitis, which is known to improve cancer outcomes and could mask any negative impact of immunosuppression on survival. It may be preferable to limit long-term immunosuppression in the treatment of immune-mediated colitis to minimize potential complications. Prospective studies are needed to clarify this relationship, and treatments that abrogate the need for immunosuppression in these patients such as fecal microbiota transplantation.

Immune-related adverse events after immune checkpoint inhibitor exposure in adult cancer patients with pre-existing autoimmune diseases.

PURPOSE: Immune checkpoint inhibitor (ICI) therapy can predispose patients to immune-related adverse events (irAEs) and autoimmune disease (AD) flare-ups, but the characteristics of irAEs among patients with pre-existing ADs are largely unknown. We conducted this study to determine the clinical courses, irAEs, AD flares, treatment, and outcomes of patients with AD on ICIs. METHODS: This was a retrospective study of adult cancer patients at a large cancer center who were diagnosed with ADs before undergoing ICI therapy. Patients' clinical courses, complications, treatments, and outcomes related to both ADs flares and irAEs were collected and analyzed. RESULTS: The study included 197 patients. Most (55.4%) were women. Melanoma comprised the highest proportion (28.4%) of malignancies, and most (83.8%) patients received PD-1/PD-L1 inhibitors. Fifty (25.3%) patients developed a new irAE after starting ICI therapy, while 29 (14.7%) patients had an AD flare-up. Patients with inflammatory bowel disease had the highest incidence of AD flare-ups (31.7%), while patients with Hashimoto hypothyroidism had the highest incidence of new irAEs (39.2%). Patients with inflammatory bowel disease had more severe adverse events. In our cohort, patients with a new diagnosis of irAE were treated with immunosuppressive therapy. AD flares were managed similarly. With regard to irAE manifestations, the most common presentations were colitis (24 [12.1%] patients), hepatic transaminase elevations (8 [4%] patients), and pneumonitis (7 [3.5%] patients). CONCLUSION: Our findings suggest that patients with gastrointestinal and rheumatologic ADs had a higher incidence of AD flare-ups, while patients with Hashimoto hypothyroidism and neurologic ADs had a higher incidence of new irAEs. Patients with prior ADs experiencing flare-ups or new irAEs after ICI therapy tend to require aggressive immunosuppressive treatment. Thorough evaluation of baseline disease status, appropriate medical management before ICI therapy, and early recognition of inflammatory exacerbation may help ensure long-term success in treating and improving outcomes in these patients.

Characteristics and Outcomes of Cancer Patients With Venous Thromboembolic Events After Treatment With Immune Checkpoint Inhibitors.

OBJECTIVE: This study aimed to describe the clinical characteristics and outcomes of patients with venous thromboembolism (VTE) after Immune checkpoint inhibitors (ICI), focusing on patients with gastrointestinal (GI) immune-related adverse events (irAE). METHODS: In this retrospective, single-center study, we report the clinical outcomes of adult cancer patients who developed a VTE within 2 years of ICI initiation. Patients were excluded if alternate causes of VTE were present apart from malignancy and cancer therapy. The cohort was classified into those with GI-irAE, non-GI-irAE, and no irAE. A control group with ICI exposure without irAE and VTE was selected for comparative analysis. RESULTS: Of all ICI-treated patients, 1891 (17.2%) were diagnosed with VTE. In all, 501 (4.6%) had no etiology for VTE aside from malignancy and cancer therapy. Of these, 137 patients were included and classified as: 44 GI-irAE, 42 non-GI-irAE, and 51 no irAE. Chemotherapy within 6 months of ICI therapy was associated with increased VTE risk. There was no difference in the clinical course between those exposed to chemotherapy versus ICI therapy alone, time from ICI initiation to VTE, and VTE type, recurrence, or related hospitalization. While there was no difference in VTE-related mortality, the GI-irAE group was associated with lower all-cause mortality and superior overall survival. CONCLUSION: Combined ICI and chemotherapy use increased VTE risk. There is a similar disease course of VTE after ICI exposure, regardless of other irAEs. Co-existing GI-irAE with VTE is associated with superior overall survival. Prospective studies are needed to evaluate the relationship between ICI therapy and VTE and irAE impact on VTE outcomes.

Characteristics, treatment, and outcome of patients with bowel perforation after immune checkpoint inhibitor exposure.

PURPOSE: Exposure to immune checkpoint inhibitors (ICIs) can predispose to immune-related adverse events (irAEs) involving the gastrointestinal tract. The association between ICIs and bowel perforation has not been well studied. We aimed to describe the clinical course, complications, treatment, and outcomes of patients experiencing bowel perforation during or after ICI treatment. METHODS: This retrospective, single-center study included adult cancer patients with bowel perforation that occurred between the first dose of ICI treatment and up to 1 year thereafter between 1/1/2010 and 4/30/2021. Patients' clinical course, imaging, treatment, and outcomes related to bowel perforation were collected and analyzed. RESULTS: Of the 13,991 patients who received ICIs during the study period, 90 (0.6%) met the inclusion criteria. A majority were male (54.4%), the most common cancer type was melanoma (23.3%), and most patients had received PD-1/L1 inhibitor treatment (58.8%). Onset of perforation occurred after a median of four ICI treatment cycles. The most common symptom was abdominal pain (95.5%). The colon was the most common location for the perforation (37.7%). Evidence of diverticulitis, enterocolitis, or appendicitis was seen in 32 (35.6%) patients, and 6 (6.6%) patients had luminal cancer involvement at the time of perforation. The overall hospitalization rate related to perforation was 95.5%, with mortality of 15.5% during the same admission. Antibiotics were given in 95% of our sample; 37.8% of patients also required surgical/interventional radiology intervention. Forty-six patients (51.1%) had perforation-related complications (e.g., sepsis, fistula, abscess), which were associated with a higher mortality rate (30%). CONCLUSION: Our findings suggest a low incidence of bowel perforation after ICI treatment (0.6%), with 40% of patients having coexisting bowel inflammation as a potential contributing factor. Patients with bowel perforation had an aggressive disease course and high rates of hospitalization, complications, and mortality. Early recognition and prompt intervention is critical to improve patient outcomes. Future studies are warranted to further investigate the cause, predictive markers, and optimal treatment for this patient population.