Serologic Presentation of Lamotrigine-Induced Lupus.

This paper discusses the presentation of a rare drug side effect, a case of drug-induced lupus presenting with weight loss, weakness, hepatitis, and pancreatitis. A 24-year-old male with a history of major depressive disorder and childhood seizures presented to the ER with symptoms of abdominal pain, significant weight loss, and weakness. Initial workup revealed acute pancreatitis, elevated liver function enzymes (LFTs), and abnormal anti-double-stranded DNA antibody (anti-dsDNA) 1 : 640. He showed no classical clinical signs of lupus including rash, arthritis, or photosensitivity. He had multiple hospitalizations in the previous 6 months for excessive weight loss, malnutrition, weakness, and altered mental status. He had been taking lamotrigine for seizure prevention and mood stabilization while on a selective serotonin reuptake inhibitor (SSRI) and had a decline in health since the lamotrigine dose was increased. Antihistone antibodies were positive suggesting a drug-induced lupus syndrome. We hope to bring awareness to the possible rare complication of lamotrigine-induced lupus.

Targeting FGFR in intrahepatic cholangiocarcinoma [iCCA]: leading the way for precision medicine in biliary tract cancer [BTC]?

Introduction: The increasing availability of next-generation DNA sequencing (NGS) opens the opportunity to tailor therapies to potential targets. Intrahepatic cholangiocarcinoma (iCCA) has the most actionable genomic targets of the hepatobiliary malignancies, including mutations in Isocitrate Dehydrogenase (IDH) and Fibroblast Growth Factor Receptor (FGFR), particularly FGFR2. With the recent accelerated approval of pemigatinib and several trials currently underway, FGFR2 inhibition will set the mold for tailored therapies in hepatobiliary cancer.Areas covered: We review the current standard of therapy for iCCA, the genomic targets, and the role of FGFR inhibitors in developing the treatment landscape. The FGFR mechanism of actionand use of IDH1/2 inhibition and immunotherapy in iCCA are also discussed. We queried the PubMed and ClinicalTrials.gov databases, along with conference proceedings for relevant data.Expert opinion: While more mature data are needed from the trials in progress, currently published analyses show survival benefit with FGFR2 inhibitors in patients positive for FGFR2 fusion who have failed the standard of care. Infigratinib, futibatinib, pemigatinib and derazantinib have all demonstrated promising activity iCCA patients harboring FGFR2 fusion. Eventually, head-to-head trials will be needed to fully understand the benefits of each agent and the role of reversible versus irreversible FGFR2 inhibitors.

Recent Advances in Systemic Therapies for Advanced Hepatocellular Carcinoma.

PURPOSE OF REVIEW: This paper aims to summarize the data of recently completed and key ongoing clinical trials of systemic agents for advanced hepatocellular carcinoma (aHCC). In particular, the review focuses on ongoing checkpoint inhibitor combination trials and promising studies combining tyrosine kinase inhibitors with checkpoint inhibitors. RECENT FINDINGS: The recently approved combination of atezolizumab and bevacizumab based on the IMbrave150 trial has shown the most potential with the highest overall survival of any systemic agent in HCC to date, surpassing sorafenib. Despite COVID-19 delays, other promising trials that involve combining VEGF-directed therapy and checkpoint inhibition, cancer vaccines, phosphatidylserine, YIV-906, and oncolytic and immunotherapeutic vaccinia virus are actively recruiting patients. SUMMARY: After almost a 10-year dormancy, the list of potential systemic treatment options for aHCC is growing rapidly. Given the promising data from the IMbrave150 trial, the combination of atezolizumab and bevacizumab is now the new first-line therapy. We discuss the change in landscape, the new second- and third-line systemic treatments in aHCC, and the ongoing clinical trials for newer agents including combination therapies.

Male Sex Is Associated With Higher Rates of Liver-Related Mortality in Primary Biliary Cholangitis and Cirrhosis.

BACKGROUND AND AIMS: The impact of sex on the postcirrhosis progression of primary biliary cholangitis (PBC) has not been well defined. Prior studies have suggested that men have worse outcomes but present at more advanced stages of fibrosis than women. This observation, however, has been limited by small numbers of men and even fewer patients with cirrhosis. APPROACH AND RESULTS: We investigated the association of sex with the development of all-cause and liver-related mortality or transplantation, decompensation, and hepatocellular carcinoma (HCC), using competing-risk time-updating Cox proportional hazards models in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. In a cohort of 532 participants (418 male) with PBC-related cirrhosis with a total follow-up of 3,231.6 person-years (PY) from diagnosis of compensated cirrhosis, male participants had a higher unadjusted rates of death or transplantation (8.5 vs. 3.8 per 100 PY; P < 0.0001), liver-related death or transplantation (5.5 vs. 2.7 per 100 PY; P < 0.0001), decompensation (5.5 vs. 4.0 per 100 PY; P = 0.002), and HCC (0.9 vs. 0.3 per 100 PY; P < 0.0001). After adjusting for confounders, male sex was associated with a higher risk of death or transplantation (adjusted hazard ratio, 1.80; 95% CI, 1.01-3.19; P = 0.046), and liver-related death or transplantation (subhazard ratio, 2.17; 95% CI, 1.15-4.08; P = 0.02). A sensitivity analysis that defined ursodeoxycholic acid response as normalization of alkaline phosphatase and total bilirubin revealed similar findings. CONCLUSIONS: In patients with PBC and well-compensated cirrhosis, male sex is associated with a higher risk of both death and liver-related death or transplantation.

Update on the Evaluation and Management of Portal Hypertension.

The development of clinically significant portal hypertension (CSPH) in patients with chronic liver disease is an important predictor of varices, variceal hemorrhage, ascites, hepatic encephalopathy, and death. The nomenclature of compensated advanced chronic liver disease, revised from compensated cirrhosis, recognizes the importance of portal hypertension (PH), rather than the histologic finding of cirrhosis, in clinical outcomes. Recent advances in the field have focused on the development of noninvasive methods, including transient elastography (TE), magnetic resonance elastography, and multiparametric magnetic resonance imaging, for predicting PH. TE is evolving to be the most widespread clinical tool to estimate PH, with a liver stiffness (LS) measurement cutoff of greater than or equal to 25 kilopascals (kPa) ruling in CSPH, and that of less than 15 kPa combined with a platelet count of greater than 150 × 109/L ruling out CSPH. Extending utilization of TE to not only LS measurement but also splenic stiffness measurement using the same probes may augment the sensitivity of detecting CSPH and thus selecting candidates warranting endoscopic evaluation for high-risk varices. With respect to management of PH, the role of nonselective ß blockers continues to evolve and may extend beyond variceal bleed in preventing decompensation and development of ascites. Statins have a burgeoning well of data supporting their use, but large, prospective, controlled trials with clinical endpoints are awaited. Further data are still warranted regarding the use of long-term albumin therapy to prevent complications of PH.

Case of anti-Zic4 antibody-mediated cerebellar toxicity induced by dual checkpoint inhibition in head and neck squamous cell carcinoma.

Combined checkpoint inhibition therapy targeting the programmed cell death 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 pathways has been a successful approach in the treatment of metastatic melanoma, leading to its investigation in the treatment of head and neck squamous cell carcinoma (HNSCC) with PD-L1 expression. Despite the potential for excellent responses, an increased rate of autoimmune neurological toxicity and paraneoplastic conditions has been observed when using these treatment modalities. We present the case of a patient with metastatic HNSCC treated with combination ipilimumab/nivolumab who experienced severe cerebellar ataxia with a positive screen for the anti-Zic4 antibody. This is the first case, to our knowledge, of anti-Zic4 antibody-mediated cerebellar toxicity reported in association with HNSCC. Although the patient experienced an impressive partial response with dual checkpoint inhibition, he suffered grade 4 neurotoxicity. Despite exciting advances in cancer immunotherapy, clinicians must be aware of the rare, debilitating and possibly previously undescribed paraneoplastic and autoimmune toxicities that may occur.

Pigment Epithelium-Derived Factor Declines in Response to an Oral Glucose Load and Is Correlated with Vitamin D and BMI but Not Diabetes Status in Children and Young Adults.

BACKGROUND: Pigment epithelium-derived factor (PEDF) is associated with obesity and diabetes complications in adults, yet little is known about PEDF in younger individuals. We investigated the relationship between PEDF and various metabolic biomarkers in young healthy volunteers (HV) and similar-aged patients with diabetes (type 1 and type 2). METHODS: A fasting blood sample was collected in 48 HV, 11 patients with type 1 diabetes (T1D), and 11 patients with type 2 diabetes (T2D) 12-25 years of age. In 9 healthy subjects, PEDF was also serially measured during a frequently sampled oral glucose tolerance test (OGTT). RESULTS: PEDF was positively correlated with BMI and systolic blood pressure and negatively correlated with vitamin D. Upon multivariable analysis, BMI and vitamin D were independent predictors of PEDF. Prior to adjustment, PEDF was highest in T2D patients (7,168.9 ± 4417.4 ng/mL) and lowest in individuals with T1D (2,967.7 ± 947.1 ng/mL) but did not differ by diagnosis when adjusted for BMI and vitamin D. Among volunteers who underwent an OGTT, PEDF declined by ∼20% in response to an oral glucose load. CONCLUSION: PEDF was acutely regulated by a glucose load and was correlated with BMI but not with diabetes. The negative correlation with vitamin D, independent of BMI, raises the question whether PEDF plays a compensatory role in bone matrix mineralization.