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.

Consensus Guidelines: Best Practices for the Prevention, Detection and Management of Hepatitis B Virus Reactivation in Clinical Trials with Immunosuppressive/Immunomodulatory Therapy.

Hepatitis B virus reactivation (HBVr) during and after immunosuppressive/immunomodulatory (IS/IM) therapy is associated with significant morbidity and mortality, including hepatic decompensation and acute liver failure. The risk of HBVr with IS/IM has been heterogeneous and often unpredictable. As a result, patients with active or previous HBV infection are often excluded from clinical drug trials of such agents. Thorough screening for HBV infection, antiviral prophylaxis, and careful monitoring for HBVr have proven to be effective in reducing the rate of HBVr and improving its outcome in the context of IS/IM. Therefore, safe enrollment and management of certain HBV-marker-positive patients in clinical trials is possible. There is a great, unmet need for consistent, evidence-based recommendations for best practices pertaining to enrollment, monitoring, and management of HBVr in clinical trial participants receiving IS/IM. The aim of these consensus guidelines is to provide a step-by-step blueprint to safely enroll, monitor and manage the patient with inactive chronic or resolved HBV in IS/IM clinical trials from the time of screening through to the end of post-treatment follow up.

Gastroparesis and gastroparesis-like syndrome: response to therapy and its predictors.

PURPOSE: The natural history and outcome of patients with gastroparesis is not well known. The aim of this study was to identify the clinical or pathophysiological characteristics, if any, that may be helpful in predicting therapeutic response in this condition. METHODS: This is a retrospective study of a cohort of patients who presented to a tertiary referral center with symptoms suggestive of gastroparesis. All patients were evaluated by scintigraphic measurement of gastric emptying and symptoms were scored using a modification of the Gastroparesis Cardinal Symptom Index (GCSI). Treatment generally included conservative measures such as antiemetics, prokinetics, tricyclic antidepressants, and analgesics as well as various more invasive interventions in selected patients. Response to treatment was defined as a change in the overall GCSI score of two-thirds or more as compared with baseline. RESULTS: Out of a total of 93 patients, 69 patients met the eligibility criteria. Of these, 29 patients had diabetes mellitus and 40 patients had gastroparesis of nondiabetic etiology. Out of 69 patients, 49 were responders (71%) and 20 were nonresponders (29%). The cause (diabetic versus nondiabetic) of gastroparesis or the presence of delayed emptying did not correlate with response. However, the severity of stomach distension, bloating subscale score, and the global GCSI score at baseline presentation were predictive of response by multivariate analysis. CONCLUSION: Higher global GCSI score, bloating subscale score, and severity of stomach distension at baseline presentation correlated with an unfavorable response in gastroparetic patients. On the other hand, neither the etiology of gastroparesis nor associated delay in gastric emptying appeared to be important in the clinical response. Patients with symptoms of typical gastroparesis but without delays in gastric emptying may have a distinct syndrome with a greater proportion of males than classical gastroparesis.

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.

Drug Insight: from disturbed motility to disordered movement--a review of the clinical benefits and medicolegal risks of metoclopramide.

Metoclopramide, the only drug approved by the FDA for treatment of diabetic gastroparesis, but used off-label for a variety of other gastrointestinal indications, has many potentially troublesome adverse neurologic effects, particularly movement disorders. In this article, we comprehensively review the indications and side effects of metoclopramide, and describe some common pitfalls and strategies to minimize the medicolegal risks to the prescribing physician. Metoclopramide accounts for nearly a third of all drug-induced movement disorders, a common reason for a malpractice suit. The entire spectrum of drug-induced movement disorders, ranging from subtle to life-threatening, can ensue from its use; akathisia and dystonia are generally seen early in the course of metoclopramide-induced movement disorders, whereas tardive dyskinesia and parkinsonism seem to be more prevalent in chronic users. Female sex, age and diabetes are the major risk factors for metoclopramide-induced movement disorders. It is therefore incumbent on gastroenterologists and other prescribing physicians to become familiar with the adverse neurologic effects associated with the use of metoclopramide, and to take appropriate preventive and defensive measures.

Comorbidities associated with constipation in children referred for colon manometry may mask functional diagnoses.

BACKGROUND: In children with prolonged constipation of unclear pathogenesis or unresponsive to treatment, colon manometry can discriminate between functional fecal retention (FFR) and colon neuromuscular diseases. AIM: To identify the clinical features precipitating referral for colon manometry in children with functional constipation. METHOD: Retrospective medical record review of 173 constipated children (116 male, mean age 6.9 years, range 1-17 years) referred for colon manometry. RESULTS: Manometry was normal in 121 (70%). In those with normal manometry, FFR was identified in 96, irritable bowel syndrome (IBS) in 10, and functional constipation in 15. Of the 96 children FFR, 72 (76%) had comorbid conditions that might have interfered with the clinician's ability to diagnose FFR. Of 52 children with colon neuromuscular disease, only 12 (23%) had comorbid conditions (P < 0.001 compared with FFR). Of children more than 4 years, those with FFR were more likely to have fecal incontinence (44 of 62; 71%) than those with other functional disorders (2 of 19; 10%; P < 0.001) or neuromuscular disease (6 of 23; 26%; P < 0.001). CONCLUSIONS: Two thirds of children referred for colon manometry had normal studies and met criteria for a functional diagnosis. Three quarters of those with functional constipation had a comorbid condition that might alter the history sufficiently to obscure the diagnosis.

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.

Baclofen blocks LES relaxation and crural diaphragm inhibition by esophageal and gastric distension in cats.

Esophageal distension and transient lower esophageal sphincter (LES) relaxation (TLESR) are accompanied by simultaneous relaxation of the LES and inhibition of crural diaphragm. Recent studies indicate that baclofen decreases the frequency of TLESR; however, its effect on the crural diaphragm is not known. We evaluated the effects of baclofen on LES relaxation and crural diaphragm inhibition induced by gastric distension and esophageal distension in cats. Five adult cats underwent surgical implantation of wire electrodes into the crural and costal diaphragm for measurement of their EMG activity, respectively. One week after the surgery, animals were lightly sedated and recordings were performed using a manometry catheter equipped with a 2.5-cm balloon. The effects of baclofen (10 micromol/kg iv) on the graded esophageal distension and gastric distension-induced LES and crural diaphragm responses were studied. Distension of the esophagus and stomach induces relaxation of the LES and inhibition of the crural diaphragm, simultaneously. Baclofen blocks both the esophageal and the gastric distension-induced relaxation of the LES and inhibition of the crural diaphragm. The magnitude of response to baclofen was significantly larger for the crural diaphragm inhibition than for the LES relaxation. Baclofen, a GABA(B) receptor agonist, blocks the reflex inhibitory pathway to the LES and crural diaphragm. The reflex inhibitory pathway to the crural diaphragm is more sensitive to blockade by baclofen than the reflex LES inhibitory pathway.

Relationship between esophageal muscle thickness and intraluminal pressure in patients with esophageal spasm.

We previously showed, in normal subjects, a positive correlation between the esophageal contraction amplitude and peak muscle thickness. The goal of this study was to determine the relationship between esophageal muscle thickness and contraction amplitude in patients with high-amplitude peristaltic and simultaneous contractions. Eleven patients with high-amplitude peristaltic contractions, 8 with diffuse esophageal spasm (DES), 7 with nonspecific (NS) motor disorder of the esophagus, and 10 normal subjects were studied using simultaneous pressure and ultrasound imaging. Pressure was recorded by manometry and ultrasound imaging with a high-frequency ultrasound probe catheter. Recordings were performed in the lower esophageal sphincter (LES) and at 2, 4, 6, 8, and 10 cm above the LES during resting state and swallow-induced contractions. Baseline esophageal muscle was thicker in the distal, compared with the proximal esophagus both in normal subjects and patient groups. Patients with DES and nutcracker esophagus (NC) have a higher baseline muscle thickness compared with normal and NS patients. Correlation between the peak pressure and the peak muscle thickness was weaker in patients with NC and DES compared with normal subjects and patients with NS. Whereas normal subjects have good correlation between delta (difference between peak and baseline) muscle thickness and peak pressures, this relationship was absent in patients with NC and DES. Increase in contraction amplitude in patients with NC and DES was associated with an increase in baseline thickness of esophageal muscularis propria. Increase in baseline thickness was specific to patients with spastic motor disorders and was not seen in patients with NS.