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.

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.

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.

Characteristics, treatment, and outcome of diverticulitis after immune checkpoint inhibitor treatment in patients with malignancies.

PURPOSE: Immune checkpoint inhibitors (ICIs) are efficacious for treating various malignancies. In addition to immune-related adverse events (irAEs), growing evidence suggests that ICIs might also be associated with diverticulitis. We aim to assess the clinical presentations and management of colonic diverticulitis among cancer patients after ICI treatment. METHODS: A retrospective study was conducted on ICI-treated adult cancer patients between 01/2010 and 06/2020. Patients were grouped based on when diverticulitis developed relative to ICI treatment, either before (controls) or after (cases). Patient clinical characters, treatment, and outcomes were compared between both groups. RESULTS: 77 eligible patients were included: 63 patients developed diverticulitis after ICI exposure (46 had initial episode after ICI exposure, 17 had a history of diverticulitis prior then recurred after ICI exposure), and 14 had diverticulitis before ICI exposure. Diverticulitis occurred after a median of 129 days after ICI initiation. Clinical characteristics overlapped with traditional diverticulitis. 93% of patients had symptom resolution after treatment, while 23.8% experienced complications. These patients exhibited higher rates of hospitalization (87% vs 48%, P = 0.015) and surgery/interventional radiology procedures (27% vs 0, P = 0.002), and worse overall survival (P = 0.022). History of diverticulitis was not associated with a more severe disease course. Immunosuppressants (e.g., corticosteroids) were rarely required unless for concurrent ICI-mediated colitis. CONCLUSION: Colonic diverticulitis can occur after ICI therapy at very low incidence (0.5%). Its clinical presentation, evaluation, and management are similar to traditional diverticulitis, but associated with higher complication rates requiring surgical intervention and has lower overall survival.

Characteristics and outcomes of cancer patients with pre-existing microscopic colitis after exposure to PD-1 and PD-L1 inhibitors.

PURPOSE: Immune checkpoint inhibitors (ICIs) are frequently associated with adverse events, often affecting the gastrointestinal tract. We conducted this study to determine the characteristics and outcomes of cancer patients with pre-existing microscopic colitis (MC) who underwent ICI treatment. METHODS: In this retrospective study, we identified 10 patients with pre-existing MC who received ICIs at our center 01/2010-06/2020. Clinical characteristics and disease outcomes were recorded. RESULTS: Of 124 screened patients with MC before ICI exposure, 10 had sufficient data to be included in the study. Melanoma (40%) and lung cancer (30%) were the most prevalent cancer types, with 70% of stage IV cancer. Patients received either anti-programmed death 1 regimen (8, 80%) or anti-programmed death ligand 1 agent (2, 20%). Six patients (60%) had collagenous colitis, and 4 (40%) had lymphocytic colitis. The median time from MC diagnosis to ICI initiation was 4 years, with 1 patient on budesonide within 2 months of ICI initiation. Eight patients (80%) developed colitis exacerbations after ICI  and required selective immunosuppression. One patient received a compassionate-use fecal transplantation. The median time from ICI to colitis exacerbation was 14 days, with 40% and 50% of patients experiencing grade 3 diarrhea and grade 2 colitis, respectively, leading to hospitalization in 3 patients. Six patients received steroids and vedolizumab with no colitis recurrence. Of 8 patients who had colitis exacerbation, 6 resumed ICI therapy afterward; with 5 receiving concomitant vedolizumab for secondary prophylaxis. CONCLUSION: Our findings suggest that ICI exposure increases the risk of exacerbation of underlying colitis necessitating and responding to potent immunosuppression therapy.

Clinical Characteristics and Outcomes of Patients with Positive Celiac Serology and Cancer Therapy Exposure.

Objectives: The prevalence of celiac disease (CD) among cancer patients is unknown, yet new cases of CD occur after cancer therapy exposure. The aim of this study was to describe the clinical course and endoscopic features of patients with positive celiac serology (PCS) post-cancer therapy exposure (PCTE) as compared to those with no cancer therapy exposure (NCTE). Methods: A retrospective study of adult patients with PCS at MD Anderson Cancer Center between March 2009 and May 2020. Patients with positive tTG IgA, tTG IgG, and/or EMA IgA were categorized into cases with NCTE and PCTE. Clinical course, endoscopic and histologic features, and treatments were compared between the two groups. Results: Of the 4,345 patients screened for celiac serology, 21 (0.5%) met inclusion criteria. 12 were PCTE, with a median time of 258 days (173-930 days) from initiation of the last cancer therapy. Those PCTE had a higher rate of diarrhea (75% vs 22%, p = 0.030), malnutrition and death. A gluten-free diet was initiated in 82% PCTE vs 89% NCTE, with the majority experiencing symptom resolution. There were no significant differences in endoscopic and histologic features. 17 patients met criteria for CD diagnosis. Conclusions: Our findings suggest that CD may be under-diagnosed in cancer patients. Patients with PCS after cancer therapy may present with diarrhea, nutritional deficiencies, and malnutrition, yet a gluten-free diet may be efficacious in treatment management. Therefore, CD should be considered when treating cancer patients. Given the relative proximity of PCS to cancer therapy exposure, future studies should investigate the association of cancer and cancer therapy with the development of CD.

Upper Gastrointestinal Bleeding From Aberrant Right Subclavian Artery-Esophageal Fistula.

Background: The most common aortic arch abnormality is an aberrant right subclavian artery (ARSA). ARSA-esophageal fistula is a rare sequela that can present with a life-threatening upper gastrointestinal (GI) bleed. Case Report: We report the case of an 88-year-old male who presented with signs of upper GI bleeding. Esophagogastroduodenoscopy demonstrated extrinsic compression of the upper third of the esophagus with ulceration. Imaging studies revealed ARSA posterior to the esophagus with pseudoaneurysm formation. These findings confirmed an upper GI bleed secondary to ARSA-esophageal fistula. The patient underwent prompt embolization of the ARSA pseudoaneurysm, followed a few days later by coil embolization of the ARSA pseudoaneurysm. Despite these interventions, the patient continued to have bleeding with anemia. He and his family opted to avoid any further interventions and instead pursued comfort care. The patient was discharged to hospice and died 3 months later. Conclusion: ARSA-esophageal fistula is a rare but potentially lethal cause of upper GI bleeding. Initial signs and symptoms can be subtle, but the presence of a GI bleed requires immediate stabilization. Surgical interventions have been shown to have longer-lasting success, but endovascular repair may be an option for patients who are deemed unfit for surgery but still require prompt stabilization. Regardless of the intervention, mortality rates for ARSA-esophageal fistula are high.

An Opioid-Sparing Protocol Improves Recovery Time and Reduces Opioid Use After Laparoscopic Sleeve Gastrectomy.

PURPOSE: The current literature is sparse on post discharge pain management for bariatric surgical patients. This study aimed to determine if an opioid-sparing protocol could decrease opioid use during the postoperative period (hospital to home). MATERIALS AND METHODS: In this retrospective cohort study, we implemented an opioid-sparing protocol in January 2018, for patients undergoing laparoscopic sleeve gastrectomy (LSG) at our institution. We compared recovery time, pain scores (in hospital and at home), and perioperative opioid use between the historic control group (February 2017 to December 2017) and the opioid-sparing group (January 2018 to December 2018). A p value of < .05 was considered statistically significant. RESULTS: The study included 400 patients (200 in each group), and 165 participated in the phone survey. Baseline characteristics were similar, except the control group had a higher body mass index and body weight. The average recovery time was significantly shorter in the opioid-sparing group (18.9 versus 35.3 days, P = .043). There was no significant difference in mean postoperative pain scores in the hospital or at home. The opioid-sparing group required significantly fewer opioids postoperatively (10.4 versus 16.1 morphine milligram equivalents, P < .001). Only 1 out of the 200 patients in the opioid-sparing arm requested an opioid prescription after discharge. CONCLUSION: Implementation of an opioid-sparing protocol improved recovery time and reduced postoperative opioid use in the hospital and after discharge without changing perceived pain in patients undergoing LSG.

A Rare Case of Non-Prosthetic Aortic Valve Infectious Endocarditis Caused by Achromobacter xylosoxidans.

BACKGROUND Achromobacter xylosoxidans is a ubiquitous environmental gram-negative bacterium, very resistant to antibiotics. Endocarditis caused by these bacteria is extremely rare, with only 20 cases described in the literature to our knowledge. Mortality rates are high, and treatment usually involves a combination of antibiotics and surgery. Nosocomial infections predominate with a strong association between bacteremia and immunosuppression. CASE REPORT A 19-year-old immunocompetent male presented with endocarditis He had interatrial and interventricular communication corrected at age 11 months and aortic coarctation correction at age 10. Initial echocardiogram showed a possible interventricular patch infection, which was later ruled out. He was treated initially for endocarditis with a combination of antibiotics, but because he remained febrile after appropriate antibiotic treatment, surgery was performed. The patient had a favorable outcome after surgery and was asymptomatic on follow-up. CONCLUSIONS Endocarditis caused by A. xylosoxidans is extremely rare. To date, only 20 cases of IT have been reported in the literature, of which only two involved a native valve. Given the scarcity of cases reported, there is no consensus on the best treatment.

Implementation of community and facility-based HIV self-testing under routine conditions in southern Eswatini.

OBJECTIVES: WHO recommends HIV self-testing (HIVST) as an additional approach to HIV testing services. The study describes the strategies used during phase-in of HIVST under routine conditions in Eswatini (formerly Swaziland). METHODS: Between May 2017 and January 2018, assisted and unassisted oral HIVST was offered at HIV testing services (HTS) sites to people aged ≥ 16 years. Additional support tools were available, including a telephone hotline answered 24/7, HIVST demonstration videos and printed educational information about HIV prevention and care services. Demographic characteristics of HIVST users were described and compared with standard blood-based HTS in the community. HIVST results were monitored with follow-up phone calls and the hotline. RESULTS: During the 9-month period, 1895 people accessed HIVST and 2415 HIVST kits were distributed. More people accessed HIVST kits in the community (n = 1365, 72.0%) than at health facilities (n = 530, 28.0%). The proportion of males and median age among those accessing HIVST and standard HTS in the community were similar (49.3%, 29 years HIVST vs. 48.7%, 27 years standard HTS). In total, 34 (3.9%) reactive results were reported from 938 people with known HIVST results; 32.4% were males, and median age was 30 years (interquartile range 25-36). Twenty-one (62%) patients were known to have received confirmatory blood-based HTS; of these, 20 (95%) had concordant reactive results and 19 (95%) were linked to HIV care at a clinic. CONCLUSION: Integration of HIVST into existing HIV facility- and community-based testing strategies in Eswatini was found to be feasible, and HIVST has been adopted by national testing bodies in Eswatini.

OBJECTIFS: L'OMS recommande l'autotest du VIH (HIVST) comme approche supplémentaire des services de dépistage du VIH. L'étude décrit les stratégies utilisées lors de l'introduction progressive du VIHST dans des conditions de routine à Eswatini (anciennement le Swaziland). MÉTHODES: Entre mai 2017 et janvier 2018, des HIVST orales assistées et non assistées ont été proposés dans les sites des services de dépistage du VIH (HTS) aux personnes âgées de 16 ans et plus. Des outils de soutien supplémentaires étaient disponibles, notamment une permanence téléphonique répondue 24h/24 et 7j/7, des vidéos de démonstration sur le HIVST et des informations éducatives imprimées sur les services de prévention et de soins du VIH. Les caractéristiques démographiques des utilisateurs du VIHST ont été décrites et comparées aux tests sanguins standard des HTS dans la communauté. Les résultats des HIVST ont été contrôlés par des appels téléphoniques de suivi et la hotline. RÉSULTATS: Au cours de la période de 9 mois, 1895 personnes ont eu accès au VIHST et 2415 kits VIHST ont été distribués. Plus de personnes ont eu accès aux kits VIHST dans la communauté (n = 1365, 72,0%) que dans les établissements de santé (n = 530, 28,0%). La proportion d'hommes et l'âge médian parmi ceux qui accèdent au VIHST et au HTS standard dans la communauté étaient similaires (49,3%, 29 ans VIHST vs 48,7%, 27 ans HTS standard). Au total, 34 (3,9%) résultats réactifs ont été signalés chez 938 personnes avec des résultats connus pour le VIHST; 32,4% étaient des hommes et l'âge médian était de 30 ans (intervalle interquartile 25-36). 21 patients (62%) ont reçu un test sanguin de confirmation HTS; parmi ceux-ci, 20 (95%) avaient des résultats réactifs concordants et 19 (95%) ont été reliés aux soins du VIH dans une clinique. CONCLUSION: L'intégration du HIVST dans les structures existantes de dépistage du VIH et les stratégies de dépistage à Eswatini s'est avérée réalisable, et le HIVST a été adopté par les organismes nationaux de dépistage à Eswatini.

Using Computerized Physician Order Entry to Ensure Appropriate Vaccination of Patients with Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a disorder in which an aberrant immune response in a genetically susceptible host, with influences from environmental factors, leads to intestinal inflammation. Vaccines against influenza and pneumococcal pneumonia are indicated for all patients with IBD, while vaccines such as hepatitis A and B, human papillomavirus, and meningococcal meningitis are only indicated for patients with specific risk factor profiles. Some vaccines are contraindicated for patients receiving immunosuppressive medications; typically, these are live or live attenuated vaccines such as measles-mumps-rubella, varicella zoster, and herpes zoster. Given the importance of ensuring patients with IBD are properly vaccinated, we designed a quality improvement project to determine the perceived barriers to ordering these vaccines and to make the process easier. METHODS: At the outset of the study, providers in our gastroenterology department who treat patients with IBD received a survey about vaccinations. Based on the preintervention survey responses, we created an order panel in our electronic medical record (Epic Systems Corporation) to facilitate vaccination ordering. This order panel prompted physicians to order the vaccinations and informed them of contraindications. At the end of the 2-month implementation period, we distributed a second survey to assess the utility of the order panel. RESULTS: Respondents generally agreed that the Epic SmartSet order panel made vaccinations easier to order, ensured physician confidence in ordering vaccinations, was helpful for use in practice, made the clinic more efficient, and reminded physicians which vaccinations are contraindicated because of immunosuppression. Respondents were divided regarding whether a greater number of patients with IBD were actually receiving vaccinations after the order panel was implemented. CONCLUSION: We used the order entry function in Epic to facilitate vaccination ordering for patients with IBD. Our results indicate that the order panel we built made ordering vaccinations easier and more efficient compared to the previous process. We hope this order panel promotes improved patient care and becomes a future area of study for how Epic and other electronic health records may be used.