Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development.

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in patients with various malignancies, however, they are associated with a wide range of immune-related toxicities affecting many organs, including the liver. Immune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a distinctive form of drug induced liver injury (DILI), that differs from most DILI types in presumed underlying mechanism, incidence, and response to therapeutic interventions. Despite increased awareness of ILICI and other immune-related adverse effects of ICIs reflected by recent guidelines for their management in post marketing clinical practice, there is lack of uniform best practices to address ILICI risk during drug development. As efforts to develop safer and more effective ICIs for additional indications grow, and as combination therapies including ICIs are increasingly investigated, there is a growing need for consistent practices for ILICI in drug development. This publication summarizes current best practices to optimize the monitoring, diagnosis, assessment, and management of suspected ILICI in clinical trials using ICI as a single agent and in combination with other ICIs or other oncological agents. It is one of several publications developed by the IQ DILI Initiative in collaboration with DILI experts from academia and regulatory agencies. Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, ILICI detection, approach to a suspected ILICI signal, causality assessment, hepatic discontinuation rules and additional medical treatment.

Changes in the gastric enteric nervous system and muscle: a case report on two patients with diabetic gastroparesis.

BACKGROUND: The pathophysiological basis of diabetic gastroparesis is poorly understood, in large part due to the almost complete lack of data on neuropathological and molecular changes in the stomachs of patients. Experimental models indicate various lesions affecting the vagus, muscle, enteric neurons, interstitial cells of Cajal (ICC) or other cellular components. The aim of this study was to use modern analytical methods to determine morphological and molecular changes in the gastric wall in patients with diabetic gastroparesis. METHODS: Full thickness gastric biopsies were obtained laparoscopically from two gastroparetic patients undergoing surgical intervention and from disease-free areas of control subjects undergoing other forms of gastric surgery. Samples were processed for histological and immunohistochemical examination. RESULTS: Although both patients had severe refractory symptoms with malnutrition, requiring the placement of a gastric stimulator, one of them had no significant abnormalities as compared with controls. This patient had an abrupt onset of symptoms with a relatively short duration of diabetes that was well controlled. By contrast, the other patient had long standing brittle and poorly controlled diabetes with numerous episodes of diabetic ketoacidosis and frequent hypoglycemic episodes. Histological examination in this patient revealed increased fibrosis in the muscle layers as well as significantly fewer nerve fibers and myenteric neurons as assessed by PGP9.5 staining. Further, significant reduction was seen in staining for neuronal nitric oxide synthase, heme oxygenase-2, tyrosine hydroxylase as well as for c-KIT. CONCLUSION: We conclude that poor metabolic control is associated with significant pathological changes in the gastric wall that affect all major components including muscle, neurons and ICC. Severe symptoms can occur in the absence of these changes, however and may reflect vagal, central or hormonal influences. Gastroparesis is therefore likely to be a heterogeneous disorder. Careful molecular and pathological analysis may allow more precise phenotypic differentiation and shed insight into the underlying mechanisms as well as identify novel therapeutic targets.

Postcholecystectomy sphincter of oddi dyskinesia--a diagnostic dilemma--role of noninvasive nuclear and invasive manometric and endoscopic aspects.

BACKGROUND: Persistent abdominal pain after cholecystectomy is not uncommon. Sphincter of oddi dysfunction (SOD) is one of the causes for this entity. However, diagnosing SOD is often difficult. Sphincter of oddi manometry (SOM) is the gold standard. Because it is invasive and needs experienced person to perform, simple noninvasive imaging techniques are needed. Other invasive endoscopic methods also play an important role in difficult cases and before therapeutic intervention. METHODS: Retrospective review of the charts of postcholecystectomy patients who presented with persistent abdominal pain and underwent quantitative hepatobiliary studies (QHBS) as per Sostre et al scoring protocol and simultaneous endoscopic retrograde cholangiopancreatography (ERCP) with SOM between 2003 and 2004. Additional 6 studies with SOM data that had routine nonscoring hepatobiliary study (HBS) were later identified and were included in the study. RESULTS: A total of 24 HBS studies (22 patients) were identified, 19 performed with scoring (Sostre) and 5 with nonscoring methods. ERCP results were available for 16 patients. SOM results were available for 10 patients. Of the 19 who had Sostre's QHBS, 3 were positive and 16 were negative. All 3 QHBS positive patents also had ERCP with SOM findings of SOD. Of the 16 negative Sostre's QHBS, 8 had ERCP with SOM of which 6 had SOD, 1 had no SOD, and 1 was inconclusive. Eight patients who had negative QHBS/ HBS did not undergo further invasive gastrointestinal procedures and were followed conservatively. The rest of 5 patients with negative HBS had ERCP with SOM findings of biliary and pancreatic SOD. CONCLUSIONS: From our limited retrospective review, when QHBS by Sostre's is positive there is good correlation to ERCP with SOM. When negative, the agreement with ERCP with SOM is less. However, correlation of Sostre's QHBS is slightly better than nonscoring HBS. Hence, QHBS by Sostre protocol is a simple, noninvasive, and easy to use initial procedure in the management of postcholecystectomy pain syndromes and when positive can guide the gastrointestinal physicians to proceed to invasive ERCP with SOM with confidence.

An unusual electrocardiogram artifact: what is its source?

A diabetic female presented with nausea and vomiting. Her electrocardiogram showed sinus rhythm with two artifactual spikes, not synchronized with the cardiac rhythm. The patient had an implanted gastric electrical stimulation system for treating her diabetic gastroparesis. Recent DC shock for ventricular fibrillation during coronary angiography caused malfunction of the gastric pacemaker.