Review of the clinical development of fexuprazan for gastroesophageal reflux-related disease.

Proton pump inhibitors (PPIs) are a mainstay treatment for acid peptic disorders such as gastroesophageal reflux disease (GERD). Although PPIs are considered first-line medications for acid suppression, they have notable limitations such as requiring acid-mediated activation, short half-life and duration of action, and metabolic variability. Fexuprazan is a newly developed potassium-competitive acid blocker (P-CAB), which inhibits acid generation and secretion in a competitive and reversible manner. Fexuprazan, like other P-CABs, has significantly different pharmacodynamic and pharmacokinetic properties than PPIs with potential advantages including rapid, robust, and durable acid suppression, lack of CYP2C19 metabolism, independence from food intake, and no requirement for activation into an active form. Completed clinical trials of fexuprazan have demonstrated comparable efficacy to PPIs for the healing of erosive esophagitis and relief of GERD-related esophageal symptoms without concerning safety signals. Ongoing clinical trials are evaluating fexuprazan for the prevention of NSAID-induced peptic ulcer disease, non-erosive GERD, and acute and chronic gastritis, as well as healing efficacy and maintenance of erosive esophagitis (EE). Fexuprazan is approved in South Korea for the treatment of EE and at the time of this writing is being considered for regulatory approval in several other countries. In this article, we summarize and discuss the pharmacology, efficacy, and safety of fexuprazan.

Underestimation of Cirrhosis-Related Mortality in the Medicare Eligible Population, 1999-2018.

The burden of cirrhosis may be increasing, especially among the elderly. A recent updated definition of cirrhosis has a >90% positive predictive value for identifying cirrhosis and cirrhosis-related complications.1 We hypothesized that cirrhosis-related mortality is underestimated, and that the elderly are disproportionally impacted. In this study, we aimed to examine trends in liver-related mortality using this updated definition among the elderly and to identify changes by relevant subsets of gender, race, and rurality.

Hepatocellular Carcinoma-Related Mortality in the USA, 1999-2018.

BACKGROUND AND AIMS: The burden of hepatocellular carcinoma (HCC) is increasing, and certain groups may be at higher risk. METHODS: We analyzed trends in HCC-related mortality in the USA (1999-2018) using national death data. Age-adjusted trends in death rates (annual percentage change, APC) were calculated using joinpoint regression analysis. RESULTS: HCC-related death rates increased by 2.1% (95% CI 1.9 to 2.3) annually. Hepatitis C (HCV)-related HCC death rates increased from 1999 to 2012 (8.9%, 95% CI 7.6 to 10.2) followed by a -1.3% (95% CI -3.5 to 0.9) decrease annually. For adults > 65 years, HCV-related HCC death rates increased (7.3% annually, 95% CI 6.5 to 8.1), especially for rural areas (11.1% annually, 95% CI 6.9 to 15.5) with high rates among African-Americans and Hispanics. Increases in non-HCV-related HCC death rates were larger: 13.5% annually (95% CI 3.6 to 24.3, 2005-2010) followed by 4.2% annually (95% CI 2.3 to 6.2, 2010-2018). Annual rates of increase were similar for men (6.8%, 95% CI 5.9 to 7.8) and women (7.0%, 95% CI 5.5 to 8.4) from 1999 to 2018. Rate of increase across races was Whites 8.3% (95% CI 7.2 to 9.4, 1999-2018), African-Americans 11.2% (95% CI -6.6 to 32.3, 2015-2018), and Hispanics 3.7% (95% CI 1.0 to 6.5, 2012-2018). CONCLUSION: HCC-related mortality has increased, driven by increases in non-HCV-related mortality with important demographic and regional trends. In addition, HCV-HCC mortality remains high particularly in older persons and those in rural areas despite advances in HCV therapy. These data underscore the need for targeted approaches to mitigate the burden of HCC-related mortality similar to efforts for other cancers.

Extrahepatic causes of death in cirrhosis compared to other chronic conditions in the United States, 1999-2017.

INTRODUCTION AND OBJECTIVES: Cirrhosis-related mortality is underestimated and is increasing; extrahepatic factors may contribute. We examined trends in cirrhosis mortality from 1999-2017 in the United States attributed to liver-related (varices, peritonitis, hepatorenal syndrome, hepatic encephalopathy, hepatocellular carcinoma, sepsis) or extrahepatic (cardiovascular disease, influenza and pneumonia, diabetes, malignancy) causes, and compared mortality trends with congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD) populations. MATERIALS AND METHODS: A national mortality database was used. Changes in age-standardized mortality over time were determined by joinpoint analysis. Average annual percentage change (AAPC) was estimated. RESULTS: Cirrhosis cohort: From 1999-2017, both liver-related (AAPC 1.3%; 95% confidence interval [CI] 0.7-1.9) and extrahepatic mortality (AAPC 1.0%; 95% CI 0.7-1.2) increased. Cirrhosis vs other chronic disease cohorts: changes in all-cause mortality were higher in cirrhosis (AAPC 1.0%; 95% CI 0.7-1.4) than CHF (AAPC 0.1%; 95% CI -0.5- 0.8) or COPD (AAPC -0.4%; 95% CI -0.6- -0.2). Sepsis mortality was highest in cirrhosis (AAPC 3.6%, 95% 3.2- 4.1) compared to CHF (AAPC 0.6%, 95% CI -0.5- 1.7) or COPD (AAPC 0.8%, 95% CI 0.5- 1.2). Cardiovascular mortality increased in cirrhosis (AAPC 1.3%, 95% CI 1.1- 1.5), declined in CHF (AAPC -2.0%, 95% CI -5.3- 1.3) and remained unchanged in COPD (AAPC 0.1%, 95% CI -0.2- 0.4). Extrahepatic mortality was higher among women, rural populations, and individuals >65 years with cirrhosis. CONCLUSIONS: Extrahepatic causes of death are important drivers of mortality and differentially impact cirrhosis compared to other chronic diseases.

Enterovirus-associated hemophagocytic lymphohistiocytosis with multiorgan failure.

Hemophagocytic lymphohistiocytosis is a highly fatal hyperinflammatory syndrome that is increasingly being recognized in adults. It can be primary or secondary in the setting of malignancy, autoimmune disorders, infections, or acquired immune deficiencies. We present a case of a 50-year-old man with enterovirus-associated multiorgan system dysfunction and hemophagocytic lymphohistiocytosis.

Isolated adrenocorticotrophic hormone deficiency in a patient treated with checkpoint inhibitor therapy.

Treatment of advanced melanoma has significantly improved with the advent of checkpoint inhibitor therapy. With the widespread use of these agents, side effects are being increasingly recognized, including immune-related adverse events. We report the onset of adrenal insufficiency in a patient with advanced melanoma who was exposed to two checkpoint inhibitors: ipilimumab and nivolumab. His symptoms initially resolved with steroid replacement but he was unable to be weaned off hormone replacement and required long-term oral hydrocortisone treatment.

DUETS (Dallas UtErus Transplant Study): Complete report of 6-month and initial 2-year outcomes following open donor hysterectomy.

INTRODUCTION: Uterus transplantation has shown success in treating women with uterine factor infertility who want to carry their own pregnancy. METHODS: We report the medical, sexual, and psychological outcomes of our first cohort of 13 living donor hysterectomies. As we have transitioned from open to robotically assisted hysterectomy, this report represents the complete series of open donor hysterectomies at our center, all with ≥6-month postoperative outcomes. RESULTS: The open donor hysterectomy had a median of a 6.5-hour surgical time, 0.8 L estimated blood loss, 6-day hospital stay, and 28-day sick leave. Three donors had a grade III or IV complications, one reported new-onset psychological symptoms, and 9 experienced transient sexual discomfort. All complications were addressed and resolved, and all donors returned to their presurgical social and physical activities. CONCLUSION: Since uterus transplantation is not life-saving or life-extending, the risks in living uterus donation must be weighed against the benefit of giving another woman the opportunity to give birth to her own child. This report provides data to support more detailed informed consent regarding the medical, psychological, and sexual complications of open living donor hysterectomy and allows for further evaluation of the ethical acceptability of this procedure.

Periprosthetic Femoral Stress Fracture After Bisphosphonate Treatment Resulting in Nonunion Successfully Treated with Teriparatide: A Case Report.

CASE: We present the case of a postmenopausal osteoporotic woman, treated with bisphosphonates, who developed a stress fracture at the tip of a revision femoral component, resulting in nonunion after several operative treatment attempts. The nonunion healed after 7 months of subcutaneous injections of 20 µg/day of teriparatide. CONCLUSION: Teriparatide treatment should be considered for use in recalcitrant stress fractures after total hip arthroplasty.