Pathways to therapy resistance: The sheltering effect of the bone marrow microenvironment to multiple myeloma cells.

Multiple Myeloma (MM) is a malignant expansion of plasma cells in the bone marrow (BM), resulting in a disease characterized by symptoms of end organ damage from light chain secretion, crowding of the BM, and bone lesions. Although the past two decades have been characterized by numerous novel therapies emerging, the disease remains incurable due to intrinsic or acquired drug resistance. A major player in MM's drug resistance arises from its intimate relationship with the BM microenvironment (BMME). Through stress-inducing conditions, soluble messengers, and physical adhesion to BM elements, the BMME activates numerous pathways in the myeloma cell. This not only propagates myeloma progression through survival and growth signals, but also specific mechanisms to circumvent therapeutic actions. In this review, we provide an overview of the BMME, the role of individual components in MM survival, and various therapy-specific resistance mechanisms reported in the literature.

Etiology-Specific Effects of Impaired Functional Status on Liver Transplant Outcomes.

BACKGROUND AND AIMS: Pre-liver transplant (LT) functional status is an important determinant of prognosis post LT. There is insufficient data on how functional status affects outcomes of transplant recipients based on the specific etiology of liver disease. We stratified LT recipients by etiology of liver disease to evaluate the effects of functional status on post-LT prognosis in each subgroup. METHODS: 2005-2019 United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) was used to select patients with liver transplant. A total of 14,290 patients were included in the analysis. These patients were stratified by functional status according to Karnofsky Performance Scale (KPS) score: no assistance, some assistance, or total assistance. They were then further divided into six diagnosis categories: metabolic dysfunction-associated steatotic liver disease (MASLD), hereditary disorders, hepatitis C, hepatitis B, autoimmune disease (AID), and alcoholic liver disease (ALD). Primary endpoints included all-cause mortality and graft failure, while secondary endpoints included organ-specific causes of death. Those under the age of 18 and those with non-whole liver or prior liver transplantation were excluded. RESULTS: Patients with MASLD requiring some assistance (aHR: 1.57, 95% CI 1.03-2.39, p = 0.04) and those requiring total assistance (aHR: 2.32, 95% CI 1.48-3.64, p < 0.001) had higher incidences of graft failure compared to those requiring no assistance. Those with MASLD requiring total assistance had a higher all-cause mortality rate than those needing no assistance (aHR: 1.62, 95% CI 1.38-1.89, p < 0.001). Patients with hereditary causes of liver disease showed a lower incidence of all-cause mortality in recipients needing some assistance compared with those needing no assistance (aHR: 0.52, 95% CI 0.34-0.80, p = 0.003). LT recipients with hepatitis C, AID, and ALD all showed higher incidences of all-cause mortality in the total assistance cohort when compared to the no assistance cohort. For the secondary endpoints of specific cause of death, transplant recipients with MASLD needing total assistance had higher rates of death due to general cardiac causes, graft rejection, general infectious causes, sepsis, general renal causes, and general respiratory causes. CONCLUSION: Patients with MASLD cirrhosis demonstrated the worst overall outcomes, suggesting that this population may be particularly vulnerable. Poor functional status in patients with end-stage liver disease from hepatitis B or hereditary disease was not associated with a significantly increased rate of adverse outcomes, suggesting that the KPS score may not be broadly applicable to all patients awaiting LT.

Inpatient Cost Burdens of Treating Chronic Hepatitis B in US Hospitals: A Weighted Analysis of a National Database.

BACKGROUND AND AIMS: This study evaluates the cost burdens of inpatient care for chronic hepatitis B (CHB). We aimed to stratify the patients based on the presence of cirrhosis and conduct subgroup analyses on patient demographics and medical characteristics. METHODS: The 2016-2019 National Inpatient Sample was used to select individuals diagnosed with CHB. The weighted charge estimates were derived and converted to admission costs, adjusting for inflation to the year 2016, and presented in United States Dollars. These adjusted values were stratified using select patient variables. To assess the goodness-of-fit for each trend, we graphed the data across the respective years, expressed in a chronological sequence with format (R2, p-value). Analysis of CHB patients was carried out in three groups: the composite CHB population, the subset of patients with cirrhosis, and the subset of patients without cirrhosis. RESULTS: From 2016 to 2019, the total costs of hospitalizations in CHB patients were $603.82, $737.92, $758.29, and $809.01 million dollars from 2016 to 2019, respectively. We did not observe significant cost trends in the composite CHB population or in the cirrhosis and non-cirrhosis cohorts. However, we did find rising costs associated with age older than 65 (0.97, 0.02), white race (0.98, 0.01), Hispanic ethnicity (1.00, 0.001), and Medicare coverage (0.95, 0.02), the significance of which persisted regardless of the presence of cirrhosis. Additionally, inpatients without cirrhosis who had comorbid metabolic dysfunction-associated steatotic liver disease (MASLD) were also observed to have rising costs (0.96, 0.02). CONCLUSIONS: We did not find a significant increase in overall costs with CHB inpatients, regardless of the presence of cirrhosis. However, certain groups are more susceptible to escalating costs. Therefore, increased screening and nuanced vaccination planning must be optimized in order to prevent and mitigate these growing cost burdens on vulnerable populations.

A Successful 12-Month Trial of a Lumen-Apposing Self-Expandable Metallic Stent on a Benign Recalcitrant After Surgical Stricture.

Gastrojejunal anastomotic strictures are common postsurgical complications that may be treated endoscopically. In some cases, conventional endoscopic dilations may prove ineffective, prompting consideration of covered self-expandable metal stents as the next step. However, the efficacy of these stents may be limited by their risk of migration. Lumen-apposing self-expandable metallic stents pose a lower migration risk because of their unique design and offer a possible off-label solution for recalcitrant strictures. We describe a patient with a postsurgical, gastrojejunal anastomotic stricture refractory to several interventions, who achieved long-lasting remission of symptoms after a 12-month trial of lumen-apposing self-expandable metallic stent placement.

A Diagnostic Dilemma: Metastatic Neuroendocrine Tumor Mimicking Hepatocellular Carcinoma.

Carcinoid syndrome arises from neuroendocrine tumors, characterized by the presence of neurosecretory granules. The diagnosis of carcinoid syndrome involves biochemical testing and various imaging techniques. We report the case of a 62-year-old man with Parkinson's Disease who was found to have new-onset cirrhosis and multiple hepatic lesions with necrosis on CT imaging. These findings were concerning for metastatic malignancy of unknown primary origin. Subsequent MRI characterization of the liver lesions indicated hepatocellular carcinoma as the most likely diagnosis. However, a transthoracic echocardiogram, performed for anasarca and dyspnea on exertion, revealed a thickened tricuspid leaflet, highly suspicious for carcinoid valvulitis. A biopsy of one of the hepatic lesions was consistent with neuroendocrine tumor, confirming the diagnosis of carcinoid syndrome. This case highlights the limitations of diagnostic imaging approaches in distinguishing hepatocellular carcinoma from neuroendocrine tumors.

Diplopia after Sleeve Gastrectomy: The Canary in the Coal Mine.

Wernicke's encephalopathy (WE) is a neurologic emergency requiring timely intravenous thiamine supplementation to prevent permanent neurologic deficits. Historically, the WE diagnosis was limited to individuals with alcohol use disorder. However, it is now widely recognized to occur in patients who are chronically malnourished, post-bariatric surgery, pregnant with hyperemesis gravidarum, and with severe anorexia nervosa. Here we present a young woman who developed WE after undergoing a recent sleeve gastrectomy followed by protracted emesis for several days. This case underscores the importance of performing a thorough neurological review of systems and physical exam in high-risk patients and having a low clinical threshold to initiate appropriate thiamine treatment.

Impact of Inflammatory Bowel Disease Subtypes on the Post-liver Transplant Outcomes of Patients with Primary Sclerosing Cholangitis.

BACKGROUND AND AIMS: Liver transplant patients with primary sclerosing cholangitis often present with concurrent inflammatory bowel disease. The effect of comorbid conditions on post-transplant prognosis was evaluated. METHODS: The 2005-2019 United Network of Organ Sharing Standard Transplant Analysis and Research database was used to identify patients with primary sclerosing cholangitis. Patients were categorized as having Crohn's Disease, ulcerative colitis, unclassified inflammatory bowel disease, or no inflammatory bowel disease. Baseline characteristics were assessed between cohorts, and outcomes were examined using Cox regression. Outcomes included all-cause mortality, graft failure, infection-induced mortality, and organ system-delineated mortality. Supplementary analyses with unique exclusion and stratification criteria were also performed. RESULTS: Among 2829 patients undergoing transplant, 1360 were considered to have ulcerative colitis, 372 were considered to have Crohn's Disease, and 69 were considered to have an unclassified form of inflammatory bowel disease. Primary sclerosing cholangitis patients with some form of inflammatory bowel disease had no increased risk for any outcomes. However, patients with ulcerative colitis had lower risks of general infectious (aHR 0.65 95%CI 0.44-0.95) and sepsis-induced (aHR 0.56 95%CI 0.35-0.91) mortality, whereas patients with Crohn's Disease had higher risks of sepsis-induced mortality (aHR 2.13 95%CI 1.22-3.70). Supplementary analyses showed effect modification by abdominal surgery history and era. CONCLUSION: The type of inflammatory bowel disease in liver transplant patients with primary sclerosing cholangitis was found to portend risk difference for infection-induced mortality, with ulcerative colitis found to be protective and Crohn's Disease predictive of increased mortality secondary to infectious etiologies. These associations warrant further investigation.

Advancement of NF-κB Signaling Pathway: A Novel Target in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and is the third highest among cancer related deaths. Despite modest success with therapy such as gemcitabine, pancreatic cancer incidence remains virtually unchanged in the past 25 years. Among the several driver mutations for PDAC, Kras mutation contributes a central role for its development, progression and therapeutic resistance. In addition, inflammation is implicated in the development of most human cancer, including pancreatic cancer. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is recognized as a key mediator of inflammation and has been frequently observed to be upregulated in PDAC. Several lines of evidence suggest that NF-κB pathways play a crucial role in PDAC development, progression and resistance. In this review, we focused on emphasizing the recent advancements in the involvement of NF-κB in PADC's progression and resistance. We also highlighted the interaction of NF-κB with other signaling pathways. Lastly, we also aim to discuss how NF-κB could be an excellent target for PDAC prevention or therapy. This review could provide insight into the development of novel therapeutic strategies by considering NF-κB as a target to prevent or treat PDAC.

Primary pulmonary neoplasms in children: A report of five cases.

Primary pulmonary neoplasms are uncommon in children and represent a wide spectrum of pathology from benign to malignant. They are quite different in their histopathologic distribution from that of adults. This study was done to analyze the histopathologic spectrum of primary lung tumors in children. All the resected specimens of lung in children over a period of 5 years were studied and only the cases of primary pulmonary neoplasms were further analyzed. There were two cases of inflammatory myofibroblastic tumor. The patients were boys aged 10 and 12 years, respectively. One case of bronchial carcinoid was diagnosed in a boy of 12 years. There were one case each of pleuropulmonary blastoma (PPB) in a girl of 9 years and pulmonary blastoma (PB) in a girl of 2 years of age. In our study, the two cases of inflammatory myofibroblastic tumor had excellent prognosis. However, the cases of PPB and PB were both associated with poor clinical outcome, whereas the case of bronchial carcinoid has been doing well on follow-up.