Metastases to the central nervous system (CNS) are one of the most common and lethal complications of metastatic melanoma. Historically, melanoma patients with CNS metastases have had dismal outcomes and very limited treatment options. However, the development of more effective targeted, immune, and radiation therapies is now leading to promising new investigations and strategies. Optimizing the development and testing of such strategies will benefit from an improved understanding of the unique molecular features of these tumors and the influence of the brain microenvironment. Accounting for unique clinical features and challenges of CNS metastases will also be critical to making significant clinical impact in patients.

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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 years 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 4 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.

Figure 1. Radiological features of appendicitis and complications. (A) Contrast-enhanced CT image showing a normal-appearing appendix (arrows, coronal view). (B) Contrast-enhanced CT image showing an appendix perforated by a large, rim-enhancing, partially walled-off collection containing multiple small pockets of air adjacent to the cecum, suggesting an abscess with associated mesentery fat stranding (arrows, coronal view)

Immune checkpoint inhibitors (ICIs) have rapidly changed the landscape of oncologic care and are now often used in the front line setting for many types of cancers. These agents attempt to harness the immune system to target cancer cells (ICIs) by releasing inhibition of T cell response against tumor cells. With increasing use of ICIs, a new spectrum of immune-related adverse events (irAEs) has emerged including a number of endocrinopathies. A distinct form of ICI-mediated insulin dependent diabetes (ICI-DM) has become increasingly recognized. To better characterize this disease entity and longer-term consequences, we performed a retrospective review of medical records of patients diagnosed with ICI-DM between April 2014 and July 2020 at the MD Anderson Cancer Center. This cohort of 68 patients represent the largest single institution cohort described to date. Baseline characteristics of our cohort are consistent with what has been reported in other case series and meta-analyses with median age at presentation 61 years old (range 32–83 years old), slight male predominance (59% vs 41%), and strong association with anti-programmed cell death protein 1 (anti-PD-1) therapy (59%). Melanoma was the most commonly represented underlying malignancy (29%). The majority of patients (66%) presented with diabetic ketoacidosis. At presentation, median HbA1c was 7.8 % (n < 5.7%) and median C-peptide was 0.2 ng/ml (range <0.1–3.4). Pancreatic autoantibodies were present in 49% of patients. Median insulin dose was 0.54 units per kg per day[T1] (range 0.25 to 1.07 units per kg) at first follow up suggesting these patients may have varying levels of insulin sensitivity[T2]. On most recent follow up at a median[T3] of 40 weeks (range 8 to 261 weeks), median HbA1c was 7.9% and median insulin requirement remained 0.54 units per kg (range 0.14 to 1.2 units per kg). 22% of patients were on insulin pump therapy[T4]. ICI-DM is an irreversible immune-related adverse endocrinopathy characterized by frequent presentation with fulminant hyperglycemia and DKA, persistent beta cell dysfunction necessitating long term insulin therapy and mixed evidence of beta-cell autoimmunity. Median insulin requirement was more consistent with type 1 diabetes, but a wide range was present. Adequate glycemic control was generally achievable on insulin therapy.