The fundamentals of sex-based disparity in liver transplantation: Understanding can lead to change.

Liver transplantation (LT) is the definitive treatment for end-stage liver disease. Unfortunately, women are disadvantaged at every stage of the LT process. We conducted a literature review to increase the understanding of this disparity. Hormonal differences, psychological factors, and Model for End-Stage Liver Disease (MELD) score inequalities are some pretransplantation factors that contribute to this disparity. In the posttransplantation setting, women have differing risk than men in most major outcomes (perioperative complications, rejection, long-term renal dysfunction, and malignancy) and assessing the two groups together is disadvantageous. Herein, we propose interventions including standardized criteria for LT referral, using an alternate MELD, education for support of women, and motivating women to seek living donors. Understanding sex-based differences will allow us to improve access, tailor management, and improve overall outcomes for all patients, particularly women.

Association between gut colonization of vancomycin-resistant enterococci and liver transplant outcomes.

BACKGROUND: Vancomycin-resistant enterococci (VRE) colonization is common in liver transplant recipients and has been associated with worse posttransplant outcomes. METHODS: We conducted a retrospective cohort study at the University of Alberta Hospital including patients who underwent a liver transplant between September 2014 and December 2017. RESULTS: Of 343 patients, 68 (19.8%) had pretransplant VRE colonization and 27 (27/275, 9.8%) acquired VRE posttransplant, 67% were males and the median age was 56.5 years. VRE colonized patients at baseline had higher MELD scores and required longer posttransplant hospitalization. VRE colonization was associated with increased risk of early acute kidney injury (AKI) (64% vs. 52%, p = .044), clinically significant bacterial/fungal infection (29% vs. 17%, p = .012) and invasive VRE infection (5% vs. 1%, p = .017). Mortality at 2 years was 13% in VRE-colonized versus 7% in noncolonized (p = .085). On multivariate analysis, VRE colonization increased the risk of posttransplant AKI (HR 1.504, 95% CI: 1.077-2.100, p = .017) and clinically significant bacterial or fungal infection at 6 months (HR 2.038, 95% CI: 1.222-3.399, p = .006), and was associated with nonsignificant trend toward increased risk of mortality at 2 years posttransplant (HR 1.974 95% CI 0.890-4.378; p = .094). CONCLUSIONS: VRE colonization in liver transplant patients is associated with increased risk of early AKI, clinically significant infections, and a trend toward increased mortality at 2 years.

Physiologic Reserve Assessment and Application in Clinical and Research Settings in Liver Transplantation.

Physiologic reserve is an important prognostic indicator. Because of its complexity, no single test can measure an individual's physiologic reserve. Frailty is the phenotypic expression of decreased reserve and portends poor prognosis. Both subjective and objective tools have been used to measure one or more components of physiologic reserve. Most of these tools appear to predict pretransplant mortality, but only some predict posttransplant survival. Incorporation of these measures of physiologic reserve in the clinical and research settings including prediction models are reviewed, and the applicability to patient-related outcomes are discussed. Commonly used tools, in patients with cirrhosis, that have been associated with clinical outcomes were reviewed. The strength of subjective tools lies in low-cost, wide availability, and quick assessments at the bedside. A disadvantage of these tools is the manipulative capacity, restricting their value in allocation processes. The strength of objective tests lies in objective measurements and the ability to measure change. The disadvantages include complexity, increased cost, and limited accessibility. Heterogeneity in the definitions and tools used has prevented further advancement or a clear role in transplant assessment. Consistent use of objective tools, including the 6-minute walk test, gait speed, Liver Frailty Index, or Short Physical Performance Battery, are recommended in clinical and research settings.

Post-liver transplantation chronic kidney disease is associated with increased cardiovascular disease risk and poor survival.

Chronic kidney disease (CKD) is common following liver transplantation (LT). We aimed to investigate the frequency, risk factors, and impact of CKD on cardiovascular disease (CVD), graft, and patient survival. We analyzed 752 patients who received LT at the University of Alberta. Development of CKD was defined as eGFR <60 ml/min for greater than 3 months, intrinsic renal disease or presence of end-stage renal disease requiring renal replacement therapy. 240 patients were female (32%), and mean age at LT was 53 ± 11 years. CKD was diagnosed in 448 (60%) patients. On multivariable analysis, age (OR 1.3; P = 0.01), female sex (OR 3.3; P < 0.001), baseline eGFR (OR 0.83; P < 0.001), MELD (OR 1.03; P = 0.01), de novo metabolic syndrome (OR 2.3; P = 0.001), and acute kidney injury (OR 3.5; P < 0.001) were associated with CKD. A higher tacrolimus concentration to dose ratio was protective for CKD (OR 0.69; P < 0.001). CKD was associated with post-transplant CVD (26% vs. 16% P < 0.001), reduced graft (HR 1.4; P = 0.02), and patient survival (HR 1.3; P = 0.03). CKD is a frequent complication following LT and is associated with an increased risk of CVD and reduced graft and patient survival.

Sarcopenia in Cirrhosis: Looking Beyond the Skeletal Muscle Loss to See the Systemic Disease.

Sarcopenia is a common complication of cirrhosis and is defined as a progressive and generalized loss of skeletal muscle mass, strength, and function. Sarcopenia is associated with poor prognosis and increased mortality. How sarcopenia and muscle wasting relate to such poor outcomes requires looking beyond the overt muscle loss and at this entity as a systemic disease that affects muscles of vital organs including cardiac and respiratory muscles. This review explores the pathophysiological pathways and mechanisms that culminate in poor outcomes associated with sarcopenia. This provides a launching pad to identify potential targets for therapeutic intervention and optimization to improve patient outcomes.

Differing Impact of Sarcopenia and Frailty in Nonalcoholic Steatohepatitis and Alcoholic Liver Disease.

Sarcopenia and frailty are commonly encountered in patients with end-stage liver disease and are associated with adverse clinical outcomes, including decompensation and wait-list mortality. The impact of these entities in patients with differing disease etiologies has not been elucidated. We aim to ascertain the change in their prevalence over time on the wait list and determine their impact on hospitalization, delisting, and wait-list survival, specifically for patients with nonalcoholic steatohepatitis (NASH) and alcoholic liver disease (ALD). Adult patients who were evaluated for their first liver transplant from 2014 to 2016 with a primary diagnosis of NASH (n = 136) or ALD (n = 129) were included. Computed tomography scans were used to determine the presence of sarcopenia and myosteatosis. Frailty was diagnosed using the Rockwood frailty index. Patients with NASH had a significantly lower prevalence of sarcopenia (22% versus 47%; P < 0.001) but a significantly higher prevalence of frailty (49% versus 34%; P = 0.03) when compared with patients with ALD at the time of listing. In patients with NASH, sarcopenia was not associated with adverse events, but a higher frailty score was associated with an increased length of hospitalization (P = 0.05) and an increased risk of delisting (P = 0.02). In patients with ALD, univariate analysis showed the presence of sarcopenia was associated with an increased risk of delisting (P = 0.01). In conclusion, sarcopenia and frailty occur with differing prevalence with variable impact on outcomes in wait-listed patients with NASH and ALD.

Sarcopenia in hiding: The risk and consequence of underestimating muscle dysfunction in nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Up to one third of individuals with NAFLD will develop nonalcoholic steatohepatitis (NASH), which is associated with progression to cirrhosis and is rapidly becoming the leading indication for liver transplantation. Sarcopenia is defined as a progressive and generalized loss of skeletal muscle mass, strength, and function. It is observed in up to 60% of patients with end-stage liver disease and portends a poor prognosis. Recent studies have shown that sarcopenia is a novel risk factor for developing NAFLD. Pathophysiological mechanisms relating sarcopenia and NASH may include insulin resistance (IR) and increased inflammation. IR leads to accumulation of triglycerides in both muscle tissue and the liver. It also exacerbates proteolysis and leads to muscle depletion. Chronic inflammation leads to liver injury and progression of fibrosis. The inflammatory milieu also stimulates protein catabolism. Viewing skeletal muscle as an endocrine organ that secretes various salutary myokines may help us understand its role in the development of steatosis. A better understanding of the pathophysiology will aid in developing physical and pharmacological therapeutic interventions. In this review, we will explore the complex inter-relationships between sarcopenia and NASH. We will discuss the impact of sarcopenia in patients with NASH and therapeutic options for the management of sarcopenia. (Hepatology 2017;66:2055-2065).

Tacrolimus and Mycophenolate Mofetil as Second-Line Therapies for Pediatric Patients with Autoimmune Hepatitis.

BACKGROUND: We studied the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy in pediatric patients with autoimmune hepatitis (AIH) who were intolerant or non-responders to standard therapy (corticosteroid and azathioprine). PATIENTS AND METHODS: We performed a retrospective study of data from 13 centers in Europe, USA, and Canada. Thirty-eight patients (< 18 years old) who received second-line therapy (18 MMF and 20 tacrolimus), for a median of 72 months (range 8-182) were evaluated. Patients were categorized into two groups: Group 1 (n = 17) were intolerant to corticosteroid or azathioprine, and group 2 (n = 21) were non-responders to standard therapy. RESULTS: Overall complete response rates were similar in patients treated with MMF and tacrolimus (55.6 vs. 65%, p = 0.552). In group 1, MMF and tacrolimus maintained a biochemical remission in 88.9 and 87.5% of patients, respectively (p = 0.929). More patients in group 2 given tacrolimus compared to MMF had a complete response, but the difference was not statistically significant (50.0 vs. 22.2%, p = 0.195). Biochemical remission was achieved in 71.1% (27/38) of patients by tacrolimus and/or MMF. Decompensated cirrhosis was more commonly seen in MMF and/or tacrolimus non-responders than in responders (45.5 vs. 7.4%, p = 0.006). Five patients who received second-line therapy (2 MMF and 3 tacrolimus) developed side effects that led to therapy withdrawal. CONCLUSIONS: Long-term therapy with MMF or tacrolimus was generally well tolerated by pediatric patients with AIH. Both MMF and tacrolimus had excellent efficacy in patients intolerant to corticosteroid or azathioprine. Tacrolimus might be more effective than MMF in patients failing previous therapy.

The Long Winding Road to Transplant: How Sarcopenia and Debility Impact Morbidity and Mortality on the Waitlist.

Frailty and sarcopenia are common complications of cirrhosis. Frailty has been described as an increased susceptibility to stressors secondary to a cumulative decline in physiologic reserve; this decline occurs with aging or is a result of the disease process, across multiple organ systems. Sarcopenia, a key component of frailty, is defined as progressive and generalized loss of skeletal muscle mass and strength. The presence of either of these complications is associated with increased morbidity and mortality, as these are tightly linked to decompensation and increased complication rates. Recognition of these entities is critical. Studies have shown improvement in muscle strength and function lead to reduced mortality, suggesting both frailty and sarcopenia are modifiable risk factors. In this review we outline the prevalence of frailty and sarcopenia in cirrhosis and the impact on clinical outcomes such as decompensation, hospitalization, and mortality. Existing and potential novel therapeutic approaches for frailty and sarcopenia are also reviewed.

Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis.

BACKGROUND & AIMS: Predniso(lo)ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. METHODS: We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. RESULTS: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. CONCLUSIONS: Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.

Hyperhomocysteinemia is associated with severity of cirrhosis and negative impact after liver transplantation.

BACKGROUND & AIMS: Hyperhomocysteinemia constitutes an independent risk factor for thrombosis and cellular injury promoted by oxidative stress. The clinical significance of hyperhomocysteinemia in cirrhosis and outcomes post-liver transplantation is poorly documented. In this study, we aimed to determine the prevalence of hyperhomocysteinemia in cirrhosis, evaluate its association with thrombosis and severity of liver disease, and its impact on survival after liver transplantation. METHODS: We analysed 450 patients with cirrhosis who received a liver transplant between 2001 and 2010. Data were recovered from medical charts and homocysteine serum levels were determined before liver transplantation in all patients. RESULTS: Median age was 53 years (range, 18-72 years) and 308 patients were males (68%). Cirrhosis aetiology was hepatitis C (37%), autoimmune liver disease (22%), alcohol (16%) and others (25%). The median homocysteine level was 11 µmol/L (range, 4-221 µmol/L) and 165 patients (37%) had hyperhomocysteinemia. The MELD (23 ± 10 vs. 20 ± 9 points, P < 0.001), and Child-Pugh (11 ± 2 vs. 9 ± 2 points, P < 0.001) scores were higher in patients with hyperhomocysteinemia. Episodes of thrombosis occurred in 91 patients (20%), but there was no significant difference in patients with or without hyperhomocysteinemia (19 vs. 21%, P = 0.6). Hyperhomocysteinemia was associated with reduced graft (105 ± 4 vs. 119 ± 2 months; P = 0.005), and patient survival (125 ± 33 vs. 131 ± 2 months; P = 0.006). CONCLUSIONS: Hyperhomocysteinemia is frequently present in patients with cirrhosis and is associated with severe liver disease and reduced graft and patient survival after liver transplantation. The negative impact hyperhomocysteinemia has on graft and patient survival is not related to thrombosis.

Liver transplantation for overlap syndromes of autoimmune liver diseases.

BACKGROUND/AIMS: The term overlap syndrome describes variant forms of autoimmune hepatitis (AIH) that present in combination with either characteristics of primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC). This study analysed the outcomes and evidence of recurrent liver disease after liver transplantation in patients with overlap syndromes compared with patients transplanted for single autoimmune liver disease. METHODS: We evaluated 231 adult patients who received a liver transplant as a result of autoimmune liver diseases; including 103 with PBC, 84 with PSC, 32 with AIH and 12 with overlap syndrome (7 AIH-PBC and 5 AIH-PSC). RESULTS: Patients with overlap syndromes had a higher probability of recurrence than patients with a single autoimmune liver disease (5 years: 53% vs. 17%; 10 years 69% vs. 29%, P = 0.001). Furthermore, median time for recurrence in overlap syndrome was shorter when compared with patients with single autoimmune liver disease (67 ± 20 vs. 172 ± 9 months, P = 0.001). The diagnosis of overlap syndrome was independently associated with a higher risk to develop recurrent disease than patients transplanted with a single disease (HR 3.39, P = 0.007). Median graft survival for overlap syndrome was 123 ± 16 months and 180 ± 8 months in patients with single autoimmune liver diseases (P = 0.9), and median patient survival for overlap syndrome was 135 ± 13 months and 193 ± 8 months in patients with single autoimmune liver disease (P = 0.6). CONCLUSIONS: Patients that received an allograft for end-stage liver disease secondary to overlap syndrome had a higher rate of disease recurrence when compared with transplant recipients with single autoimmune liver disorders, but the overall survival was comparable.

Exception points for liver transplantation: A Canadian review.

Background: Exception points for liver transplant (LT) allocation are used to account for mortality risk not reflected by scoring systems such as the Model for End-Stage Liver Disease with sodium (MELD-Na). Currently, there is no formal policy regarding exception points in Canada, and differences across the country are not well understood. As such, a review of the criteria and exception points granted throughout the country for LT was conducted. Methods: Seven LT centres in five provinces were surveyed (Vancouver, Edmonton, London, Toronto, Montréal, Halifax) regarding the indications and criteria for exception points granted, the number of points granted, how points would be accrued, and the maximum points granted. Results: Programs in British Columbia and Nova Scotia grant variable exception points based on the median MELD-Na score with modifications; Alberta, Ontario, and Quebec grant exception points using specific values based on the indication. Overall, there was significant heterogeneity regarding exception points granted nationally with agreement only for awarding exception points for hepatopulmonary syndrome and polycystic liver disease. The second most common agreed-upon indications for exception points were portopulmonary hypertension and recurrent cholangitis offered by four provinces. Quebec had the most formal criteria for non-cirrhosis-based conditions. Conclusions: There is substantial variance across the country regarding the indications for granting exception points as well as the number of points granted. Future work on developing a national consensus will be important for the development of equity in LT across Canada.

Learning from a rare phenomenon - spontaneous clearance of chronic hepatitis C virus post-liver transplant: A case report.

BACKGROUND: Hepatitis C virus (HCV) can lead to chronic liver damage resulting in cirrhosis and hepatocellular carcinoma. Spontaneous clearance of HCV has been documented after an acute infection in 20%-45% of individuals. However, spontaneously resolved chronic hepatitis C following liver transplant (LT) is rare and has been documented only in a few case reports. The phenomenon of spontaneous clearance of chronic hepatitis C occurs together with other meaningful events, which are typically associated with significant changes in the host immunity. CASE SUMMARY: We report three cases of spontaneous resolution of chronic hepatitis C following liver transplantation. These patients either failed or had no HCV treatment prior to transplant, but had spontaneous resolution of HCV post-LT as documented by undetectable polymerase chain reaction (PCR). Diagnosis of HCV was based on viremia through PCR or liver biopsy. All three patients currently undergo surveillance and have no recurrence of HCV. CONCLUSION: Examining each patient's clinical course, we learned about many viral, host and cellular-factors that may have enhanced the host's immunity leading to spontaneous clearance of HCV. Though HCV treatment has excellent cure rates, understanding this mechanism may provide clinicians with insights regarding timing and duration of treatment.

Post-transplant diabetes mellitus in Canadian liver and renal transplant recipients.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) occurs in 10%-40% of liver and renal transplant recipients. Whether the risk factors for PTDM in liver and renal transplant recipients are similar and whether Indigenous Canadians, who have a high underlying prevalence of diabetes mellitus (DM), are at increased risk of developing PTDM have yet to be determined. OBJECTIVE: To describe and compare those variables associated with PTDM in adult Canadian liver and renal transplant recipients. METHODS: A retrospective chart review of adult liver and renal transplant recipients attending four transplant follow-up clinics in three Canadian provinces was undertaken. RESULTS: De novo PTDM was diagnosed in 184/905 (20.3%) liver and 179/390 (45.9%) renal transplant recipients. Older age, higher pre-transplant BMI, underlying immune-mediated liver disease, lower trough tacrolimus levels and longer duration of follow-up were independently associated with PTDM in liver transplant recipients and non-Caucasian race, higher pre-transplant BMI, and incidence of organ rejection in renal transplant recipients. Compared with Caucasians, Indigenous Canadians who had undergone renal transplantation had a significantly increased prevalence of PTDM (56.5% versus 40.0%, p = 0.035). The prevalence of PTDM in liver transplant recipients was similar in Indigenous Canadians and Caucasians (27.9% versus 20.1%, p = 0.215). CONCLUSIONS: The variables associated with PTDM differ in liver and renal transplant recipients. Compared with Caucasians, Indigenous Canadians undergoing renal transplantation are at increased risk of developing PTDM.

Skeletal Muscle Pathological Fat Infiltration (Myosteatosis) Is Associated with Higher Mortality in Patients with Cirrhosis.

Myosteatosis (pathological fat accumulation in muscle) is defined by lower mean skeletal muscle radiodensity in CT. We aimed to determine the optimal cut-offs for myosteatosis in a cohort of 855 patients with cirrhosis. CT images were used to determine the skeletal muscle radiodensity expressed as Hounsfield Unit (HU). Patients with muscle radiodensity values below the lowest tertile were considered to have myosteatosis. Competing-risk analysis was performed to determine associations between muscle radiodensity and pre-transplant mortality. Muscle radiodensity less than 33 and 28 HU in males and females, respectively, were used as cut-offs to identify myosteatosis. In the univariate analysis, cirrhosis etiology, MELD score, refractory ascites, variceal bleeding, hepatic encephalopathy, sarcopenia and myosteatosis were predictors of mortality. Myosteatosis association with mortality remained significant after adjusting for confounding factors (sHR 1.47, 95% CI 1.17−1.84, p = 0.001). Patients with concurrent presence of myosteatosis and sarcopenia constituted 17% of the patient population. The cumulative incidence of mortality was the highest in patients with concomitant sarcopenia and myosteatosis (sHR 2.22, 95% CI 1.64−3.00, p < 0.001). In conclusion, myosteatosis is common in patients with cirrhosis and is associated with increased mortality. The concomitant presence of myosteatosis and sarcopenia is associated with worse outcomes.

Myosteatosis in Cirrhosis: A Review of Diagnosis, Pathophysiological Mechanisms and Potential Interventions.

Myosteatosis, or pathological excess fat accumulation in muscle, has been widely defined as a lower mean skeletal muscle radiodensity on computed tomography (CT). It is reported in more than half of patients with cirrhosis, and preliminary studies have shown a possible association with reduced survival and increased risk of portal hypertension complications. Despite the clinical implications in cirrhosis, a standardized definition for myosteatosis has not yet been established. Currently, little data exist on the mechanisms by which excess lipid accumulates within the muscle in individuals with cirrhosis. Hyperammonemia may play an important role in the pathophysiology of myosteatosis in this setting. Insulin resistance, impaired mitochondrial oxidative phosphorylation, diminished lipid oxidation in muscle and age-related differentiation of muscle stem cells into adipocytes have been also been suggested as potential mechanisms contributing to myosteatosis. The metabolic consequence of ammonia-lowering treatments and omega-3 polyunsaturated fatty acids in reversing myosteatosis in cirrhosis remains uncertain. Factors including the population of interest, design and sample size, single/combined treatment, dosing and duration of treatment are important considerations for future trials aiming to prevent or treat myosteatosis in individuals with cirrhosis.

Clinical Course and Treatment Implications of Combination Immune Checkpoint Inhibitor-Mediated Hepatitis: A Multicentre Cohort.

BACKGROUND: Immune-related adverse events can occur after treatment with immune checkpoint inhibitors (ICI), limiting treatment persistence. We aimed to evaluate the clinical course of ICI-mediated hepatitis (IMH) associated with combination ipilimumab and nivolumab treatment. METHODS: A retrospective cohort study including consecutive patients with metastatic melanoma treated with ipilimumab and nivolumab between 2013 and 2018 was conducted at two tertiary care centres. IMH was defined by the Common Terminology Criteria for Adverse Events (CTCAE). We determined the proportion of patients developing IMH, and compared the duration, treatment patterns and outcomes, stratified by hepatitis severity. Kaplan-Meier survival analysis was used to evaluate time to hepatitis resolution, and a linear mixed-effects model was used to compare longitudinal outcomes by treatment. RESULTS: A total of 63 patients were included. Thirty-two patients (51%) developed IMH (34% Grade 1-2, 66% Grade 3-4), at a median of 34 days (IQR 20 to 43.5 days) after the first dose. Baseline FIB4 index ≥1.45 was associated with IMH (OR 3.71 [95% CI: 1.03 to 13.38], P = 0.04). Ninety-four per cent (30/32) of patients had liver enzyme normalization after a median duration of 43 days (IQR 26 to 70 days). Corticosteroid use was not associated with faster IMH resolution or less ICI discontinuation. A total of 24 patients died during the study; no deaths were attributable to hepatitis-related complications. Fifty-three per cent (17/32) of patients resumed anti-PD-1 monotherapy and three patients developed IMH recurrence. CONCLUSIONS: Approximately half of the patients treated with combination ipilimumab and nivolumab developed IMH in this cohort. However, most patients experienced uncomplicated IMH resolution.