Hepatocellular Carcinoma With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma in the Absence of Cirrhosis.

This report describes a rare case of hepatocellular carcinoma (HCC) concurrent with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without traditional risk factors, such as hepatic fibrosis or chronic hepatitis. Initially presenting with hematuria, incidental imaging revealed a liver lesion, later diagnosed as moderately differentiated HCC. Notably, the patient had no history of well-established risk factors of HCC including viral hepatitis or liver cirrhosis. CLL/SLL was unexpectedly discovered in the surgical specimen during the hepatectomy. This case challenges traditional perceptions of HCC etiology, suggesting a potential link between HCC and CLL/SLL even without established risk factors.

Safety and Efficacy of Fully Covered Self-Expandable Metal Stents for Benign Upper Gastrointestinal Strictures Beyond the Esophagus.

Background Stents utilized for pyloric, duodenal, or anastomotic malignant strictures are generally uncovered and are not retrievable. Taewoong Medical created a through-the-scope stent that is fully covered, retrievable, and can be placed beyond the esophagus for benign gastroduodenal strictures as an alternative to surgical approaches. The aim of this paper is to examine the safety and efficacy of short-term, fully covered, self-expanding metal stents (FC-SEMS) in refractory benign strictures of the pylorus, duodenum, and gastrojejunal anastomosis. Methodology This multicenter case series was conducted at four hospitals from January 2018 through December 2020. Patients presenting with benign strictures of the pylorus, duodenum, or gastrojejunal anastomosis were entered into the study. A therapeutic channel scope was utilized to place FC-SEMS to open strictures. The stents were removed a few weeks later. A four-point gastric outlet obstruction scoring system (GOOSS) was used to record improvement. Results Statistically significant improvement in GOOSS was found between the pre-procedure and the four-week follow-up. Conclusions Fully covered, retrievable metal stents appear safe and effective in the management of refractory benign pyloric, duodenal, and anastomotic strictures. This may provide a less invasive option in the management of these strictures compared to surgery.

Utilization of Antireflux Mucosectomy and Resection and Plication: A Novel Approach for the Management of Recurrent Gastroesophageal Reflux Disease after Prior Nissen Fundoplication or Transoral Incisionless Fundoplication.

Background: Nissen Fundoplication (NF) and Transoral Incisionless Fundoplication (TIF) are established procedures for the treatment of gastroesophageal reflux disease (GERD). However, the surgically induced plication can loosen over time. This multicenter study aims to evaluate the safety and efficacy of Antireflux Mucosectomy (ARMS) and Resection and Plication (RAP) in symptomatic patients with prior NF or TIF that has become loose. Patients and methods: Eighteen patients were enrolled in the study. Ten had prior TIF, while eight had prior NF. Half of these patients had a Hill Grade 3 Valve while the other half had a Hill Grade 2 valve. Endoscopic submucosal dissection (ESD) was performed in six patients, while endoscopic mucosal resection (EMR) was performed in twelve patients. A follow-up endoscopy was performed at 4-12 weeks. Results: At follow-up, 11 patients had a Hill Grade 1 valve, and seven patients had a Hill Grade 2 valve. All patients had improvement in symptoms for up to 32 months. Conclusions: In this pilot study, ARMS/RAP appears to be an effective option in patients who had prior NF or TIF with recurrent GERD symptoms.

Endoscopic Ultrasound-Guided Botox Injection for Refractory Anal Fissure.

Background: Anal fissures cause severe pain and can be difficult to treat. Medical therapy is initially used, followed by sigmoidoscopy-guided botox injections if the medical therapy is not successful. With this technique, however, it is not clear whether botox is injected into the muscle layer or submucosa. Aim: To evaluate the efficacy of EUS-guided botox injection directly into the internal sphincter. Methods: Consecutive patients with chronic anal fissure refractory to conventional endoscopic botulinum toxin type A injection were enrolled in the study. EUS was performed using a linear array echoendoscope, and a 25 G needle was used to inject botox. All patients were followed up at one- and two-month intervals. Results: Eight patients with chronic anal fissures were included in the study. Six patients had an excellent response to botox at the two-month interval using a visual analog pain scale, while one patient had a moderate response with a pain score reduction of 40%. One patient had no response. No complications were noted. An improvement in visual analog scale (pre-score > post-score) was statistically significant at the p < 0.01 level. Conclusion: EUS-guided botox injection into the internal sphincter appears to be a promising technique for patients with refractory anal fissure with pain.

Hepatocellular Carcinoma: Understanding the Inflammatory Implications of the Microbiome.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. It is well known that repeated inflammatory insults in the liver can cause hepatic cellular injury that lead to cirrhosis and, ultimately, hepatocellular carcinoma. Furthermore, the microbiome has been implicated in multiple inflammatory conditions which predispose patients to malignancy. With this in mind, we explore the inflammatory implications of the microbiome on pathways that lead to HCC. We also focus on how an understanding of these underlying inflammatory principles lead to a more wholistic understanding of this deadly disease, as well as potential therapeutic implications.

Endoscopic management of tumors of minor ampulla: a multicenter study.

Background and study aims Papillary and duodenal carcinoma are aggressive cancers with poor 5-year survival rates. Papillectomy is a well-established treatment for early-stage carcinoma of the major papilla. Tumors arising in the minor papilla are relatively rare and there is little research available on the endoscopic management of these tumors. Patients and methods The purpose of this study was to establish the safety and efficacy of endoscopic papillectomy in the management of minor papillary tumors. A total of six patients undergoing ERCP for papillectomy for minor papillary tumor at four hospitals were included in this study over a period of 5 years. Results Papillectomy was technically successful in all six patients. Pathology revealed adenoma in three patients, adenoma with high-grade dysplasia in one patient, carcinoma in one patient, and carcinoid tumor in one patient. For follow-up, one patient had an additional tumor identified at 2 years which was found to be a recurrence of the original adenoma. This patient was treated with repeat papillectomy with no further evidence of recurrence. Conclusions In our pilot study, we demonstrate that endoscopic papillectomy appears safe and effective in the management of minor papillary tumors.

An Unusual Presentation of Multiple Myeloma: A 71-Year-Old Female With a Single Lytic Lesion of Her Appendicular Skeleton.

Multiple myeloma is a devastating illness with a hallmark of end-organ damage. The clinical presentation of multiple myeloma often includes the involvement of CRAB (hypercalcemia, renal failure, anemia, bone lesions) symptoms. We present a case of a patient who did not exhibit the typical presentation of multiple myeloma making her case unique and her diagnosis more difficult. In addition to the CRAB criteria, typical symptomatology includes constipation, pain, fatigue, and peripheral sensory issues. The purpose of this case report is to bring awareness to both multiple myeloma and this particular presentation. The patient is a 71-year-old female with a past medical history of hypertension, hypothyroidism, and rheumatoid arthritis who presented with a chief complaint of right shoulder pain. The patient's initial labs were significant for a total protein of 9.3, albumin of 3.4, corrected calcium of 9.3, hemoglobin 10.6 (with baseline near 11-12), and creatinine of 1.0 (baseline of 1.0). The patient's right upper extremity X-rays were significant for a right humeral fracture. The patient had a serum kappa/lambda ratio of 15.94. Bone marrow biopsy revealed 50% kappa-restricted cells, consistent with a diagnosis of multiple myeloma. The patient's subsequent bone survey and CT scan were negative for any additional lesions. The patient had subsequent radiation therapy followed by maintenance therapy with bortezomib, lenalidomide, and dexamethasone with improvement in her symptoms. MM is a complex pathophysiological disease and equally as complex in diagnosis as the presentation is varied and sometimes obscure as noted in the case presented here. Although bone lytic lesions are part of the CRAB criteria, it is rare for them to present in patients with MM in an isolated manner with no corresponding lab abnormalities. With this case, we aim to shed light upon an atypical presentation of MM, notably one that solely involves a pathological fracture in a non-axial distribution.

Missed at Birth: A Rare Case of Acute Pancreatitis Secondary to Congenital Diaphragmatic Hernia.

Acute pancreatitis is a common gastrointestinal cause of hospitalizations across the world. The most common etiologies of acute pancreatitis include gallstones, excessive alcohol use, hypertriglyceridemia, or, rarely, trauma. Traction-induced pancreatitis is an uncommon but previously reported cause of acute pancreatitis. We present a 60-year-old male with a past medical history of cerebral palsy who presented to our facility with acute pancreatitis secondary to a congenital diaphragmatic hernia.

Exploring the Inflammatory Pathogenesis of Colorectal Cancer.

Colorectal cancer is one of the most commonly diagnosed cancers worldwide. Traditionally, mechanisms of colorectal cancer formation have focused on genetic alterations including chromosomal damage and microsatellite instability. In recent years, there has been a growing body of evidence supporting the role of inflammation in colorectal cancer formation. Multiple cytokines, immune cells such T cells and macrophages, and other immune mediators have been identified in pathways leading to the initiation, growth, and metastasis of colorectal cancer. Outside the previously explored mechanisms and pathways leading to colorectal cancer, initiatives have been shifted to further study the role of inflammation in pathogenesis. Inflammatory pathways have also been linked to some traditional risk factors of colorectal cancer such as obesity, smoking and diabetes, as well as more novel associations such as the gut microbiome, the gut mycobiome and exosomes. In this review, we will explore the roles of obesity and diet, smoking, diabetes, the microbiome, the mycobiome and exosomes in colorectal cancer, with a specific focus on the underlying inflammatory and metabolic pathways involved. We will also investigate how the study of colon cancer from an inflammatory background not only creates a more holistic and inclusive understanding of this disease, but also creates unique opportunities for prevention, early diagnosis and therapy.

A Pilot Randomized-Controlled Trial on the Effect of CPAP Treatment on Glycemic Control in Gestational Diabetes: Study Design and Methods.

Background: Gestational diabetes (GDM) is associated with adverse short- and long-term maternal and fetal outcomes. Observational data support a link between sleep-disordered breathing (SDB) during pregnancy and GDM. However, it is unknown whether treatment of SDB with continuous positive airway pressure (CPAP) improves glucose control in this patient population. In addition, CPAP adherence and feasibility as a treatment option in pregnancy is unknown. This pilot randomized, controlled trial aims to primarily determine the feasibility of CPAP treatment in pregnant women with SDB and GDM. This study is also investigating the effect of SDB treatment on 24-h glucose profiles as an exploratory outcome. Objectives: To describe the study methodology in this ongoing study of pregnant women with GDM and SDB. Patients and Methods: Pregnant women with GDM and SDB defined by apnea-hypopnea index (AHI) ≥10 (Chicago Scoring Criteria) on level 2 polysomnography are randomized to either auto titrating CPAP (experimental group) or a nasal dilator strip (control group) until delivery. The primary outcome, objectively-assessed adherence to CPAP, is measured over the course of the treatment period using device-specific software. Recruitment and retention rates will be calculated to assess the feasibility for planning future trials. Twenty-four hour glucose profiles are measured over a 72-h period using the continuous glucose monitoring (CGM) system, before and after the intervention. Conclusion: The results of this study will be highly informative to determine whether CPAP is a feasible treatment for pregnant women with GDM and SDB, a specialized population at risk for substantial comorbidity. The trial results will ultimately be useful in planning future SDB treatment trials in pregnancy and GDM. The study is registered on clinicaltrials.gov (NCT02245659).

Exosomal Cargo Properties, Endothelial Function and Treatment of Obesity Hypoventilation Syndrome: A Proof of Concept Study.

STUDY OBJECTIVES: Longitudinal studies support the usage of positive airway pressure (PAP) therapy in treating obstructive sleep apnea (OSA) to improve cardiovascular disease. However, the anticipated benefit is not ubiquitous. In this study, we elucidate whether PAP therapy leads to immediate improvements on endothelial function, a subclinical marker of cardiovascular status, by examining the effect of circulating exosomes, isolated from patients before and after PAP therapy, on naive endothelial cells. METHODS: We isolated plasma-derived circulating exosomes from 12 patients with severe OSA and obesity hypoventilation syndrome (OHS) before and after 6 weeks of PAP therapy, and examined their effect on cultured endothelial cells using several in vitro reporter assays. RESULTS: We found that circulating exosomes contributed to the induction and propagation of OSA/OHS-related endothelial dysfunction (ie, increased permeability and disruption of tight junctions along with increased adhesion molecule expression, and reduced endothelial nitric oxide synthase expression), and promoted increased monocyte adherence. Further, when comparing exosomes isolated before and after PAP therapy, the disturbances in endothelial cell function were attenuated with treatment, including an overall cumulative decrease in endothelial permeability in all 12 subjects by 10.8% (P = .035), as well as detection of a subset of 4 differentially expressed exosomal miRNAs, even in the absence of parallel changes in systemic blood pressure or metabolic function. CONCLUSIONS: Circulating exosomes facilitate important intercellular signals that modify endothelial phenotype, and thus emerge as potential fundamental contributors in the context of OSA/OHS-related endothelial dysfunction. Exosomes may not only provide candidate biomarkers, but are also a likely and plausible mechanism toward OSA/OHS-induced cardiovascular disease. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov, Title: AVAPS-AE Efficacy Study, URL: https://clinicaltrials.gov/ct2/show/NCT01368614, Identifier: NCT01368614.

Exosomes and Metabolic Function in Mice Exposed to Alternating Dark-Light Cycles Mimicking Night Shift Work Schedules.

Sleep is an important modulator of metabolic function. Disruptions of sleep in circadian rhythm are common in modern societies and are associated with increased risk of developing cardiometabolic disorders. Exosomes are ubiquitous extracellular vesicles that may play a mechanistic role in metabolic derangements. We hypothesized that alternating dark-light cycles mimicking shift work in mice would alter fecal microbiota and colonic epithelium permeability and alter plasma exosome cargo and metabolic function. C57BL/6 mice were randomly assigned to (i) control day light (CL), or (ii) inverted dark-light every 2 weeks for 8 weeks (IN). Body weight, fat mass and HOMA-IR were measured, along with Tregs, metabolic, and resident macrophages in visceral white adipose tissue (vWAT). Fecal water samples were incubated with confluent colonic epithelium cell cultures in electric cell-substrate impedance sensing (ECIS) arrays, and plasma exosomes were added to differentiated adipocytes and insulin-induced pAKT/AKT expression changes were assessed by western blots. Mice exposed to IN showed elevated HOMA-IR, and their fecal samples showed altered microbiota which promote increased permeability of the colonic epithelial cell barrier. Plasma exosomes decreased pAKT/AKT responses to exogenous insulin compared to CL, and altered expression of circadian clock genes. Inflammatory macrophages (Ly-6chigh) were increased in IN-exposed vWAT, while Tregs were decreased. Thus, gut microbiota and the cargo of plasma exosomes are altered by periodic shifts in environmental lighting, and effectively alter metabolic function, possibly via induction of systemic inflammation and altered clock expression in target tissues. Further exploration of exosomal miRNA signatures in shift workers and their putative metabolic organ cell targets appears warranted.

Activation of the Integrated Stress Response and Metabolic Dysfunction in a Murine Model of Sleep Apnea.

Intermittent hypoxia (IH) induces activation of the integrated stress response (ISR), but its role in IH-induced visceral white adipose tissue (vWAT) insulin resistance is unknown. CHOP is activated by chronic ISR, whereas GADD34 dephosphorylates the subunit of translation initiation factor 2 (eIF2α), leading to termination of the ISR. We hypothesized that CHOP/Gadd34 null mice would not manifest evidence of insulin resistance after IH exposures. Eight-week-old CHOP/GADD34-/- (double mutant [DM]) and wild-type (WT) littermates were randomly assigned to IH or room air (RA) exposures for 6 weeks. Glucose and insulin tolerance tests were performed, and regulatory T cells (Tregs) and macrophages in vWAT were assessed. Phosphorylated eIF2α:total eIF2α, ATF4, XBP1 expression, and insulin-induced pAKT/AKT expression changes were examined in vWATs. Single GADD34-/- and PERK+/- mice were also evaluated. Body weight and vWAT mass were reduced in DM and WT mice after IH. M1/M2 macrophages and inflammatory macrophages (Ly-6chigh) were significantly increased in WT vWAT but remained unchanged in DM mice. Tregs were significantly decreased in WT vWAT but not in DM mice. Systemic insulin and glucose tolerance tests revealed insulin resistance in IH-WT but not in IH-DM mice. Similarly, decreased pAKT/AKT responses to exogenous insulin emerged in IH-WT compared with RA-WT mice, whereas no significant differences emerged in IH-DM compared with DM-RA. Chronic ISR activation appears to contribute to the insulin resistance and vWAT inflammation that characteristically emerge after long-term IH exposures in a murine model of obstructive sleep apnea.

Aorta macrophage inflammatory and epigenetic changes in a murine model of obstructive sleep apnea: Potential role of CD36.

Obstructive sleep apnea (OSA) affects 8-10% of the population, is characterized by chronic intermittent hypoxia (CIH), and causally associates with cardiovascular morbidities. In CIH-exposed mice, closely mimicking the chronicity of human OSA, increased accumulation and proliferation of pro-inflammatory metabolic M1-like macrophages highly expressing CD36, emerged in aorta. Transcriptomic and MeDIP-seq approaches identified activation of pro-atherogenic pathways involving a complex interplay of histone modifications in functionally-relevant biological pathways, such as inflammation and oxidative stress in aorta macrophages. Discontinuation of CIH did not elicit significant improvements in aorta wall macrophage phenotype. However, CIH-induced aorta changes were absent in CD36 knockout mice, Our results provide mechanistic insights showing that CIH exposures during sleep in absence of concurrent pro-atherogenic settings (i.e., genetic propensity or dietary manipulation) lead to the recruitment of CD36(+)high macrophages to the aortic wall and trigger atherogenesis. Furthermore, long-term CIH-induced changes may not be reversible with usual OSA treatment.

Visceral White Adipose Tissue after Chronic Intermittent and Sustained Hypoxia in Mice.

Angiogenesis, a process induced by hypoxia in visceral white adipose tissues (vWAT) in the context of obesity, mediates obesity-induced metabolic dysfunction and insulin resistance. Chronic intermittent hypoxia (IH) and sustained hypoxia (SH) induce body weight reductions and insulin resistance of different magnitudes, suggesting different hypoxia inducible factor (HIF)-1α-related activity. Eight-week-old male C57BL/6J mice (n = 10-12/group) were exposed to either IH, SH, or room air (RA). vWAT were analyzed for insulin sensitivity (phosphorylated (pAKT)/AKT), HIF-1α transcription using chromatin immunoprecipitation (ChIP)-sequencing, angiogenesis using immunohistochemistry, and gene expression of different fat cell markers and HIF-1α gene targets using quantitative polymerase chain reaction or microarrays. Body and vWAT weights were reduced in hypoxia (SH > IH > RA; P < 0.001), with vWAT in IH manifesting vascular rarefaction and increased proinflammatory macrophages. HIF-1α ChIP-sequencing showed markedly increased binding sites in SH-exposed vWAT both at 6 hours and at 6 weeks compared with IH, the latter also showing decreased vascular endothelial growth factor, endothelial nitric oxide synthase, P2RX5, and PAT2 expression, and insulin resistance (IH > > > SH = RA; P < 0.001). IH induces preferential whitening of vWAT, as opposed to prominent browning in SH. Unlike SH, IH elicits early HIF-1α activity that is unsustained over time and is accompanied by concurrent vascular rarefaction, inflammation, and insulin resistance. Thus, the dichotomous changes in HIF-1α transcriptional activity and brown/beige/white fat balance in IH and SH should enable exploration of mechanisms by which altered sympathetic outflow, such as that which occurs in apneic patients, results in whitening, rather than the anticipated browning of adipose tissues that occurs in SH.

Chronic Sleep Disruption Alters Gut Microbiota, Induces Systemic and Adipose Tissue Inflammation and Insulin Resistance in Mice.

Chronic sleep fragmentation (SF) commonly occurs in human populations, and although it does not involve circadian shifts or sleep deprivation, it markedly alters feeding behaviors ultimately promoting obesity and insulin resistance. These symptoms are known to be related to the host gut microbiota. Mice were exposed to SF for 4 weeks and then allowed to recover for 2 weeks. Taxonomic profiles of fecal microbiota were obtained prospectively, and conventionalization experiments were performed in germ-free mice. Adipose tissue insulin sensitivity and inflammation, as well as circulating measures of inflammation, were assayed. Effect of fecal water on colonic epithelial permeability was also examined. Chronic SF-induced increased food intake and reversible gut microbiota changes characterized by the preferential growth of highly fermentative members of Lachnospiraceae and Ruminococcaceae and a decrease of Lactobacillaceae families. These lead to systemic and visceral white adipose tissue inflammation in addition to altered insulin sensitivity in mice, most likely via enhanced colonic epithelium barrier disruption. Conventionalization of germ-free mice with SF-derived microbiota confirmed these findings. Thus, SF-induced metabolic alterations may be mediated, in part, by concurrent changes in gut microbiota, thereby opening the way for gut microbiome-targeted therapeutics aimed at reducing the major end-organ morbidities of chronic SF.

Effect on Intermittent Hypoxia on Plasma Exosomal Micro RNA Signature and Endothelial Function in Healthy Adults.

STUDY OBJECTIVE: Intermittent hypoxia (IH) is associated with increased risk of cardiovascular disease. Exosomes are secreted by most cell types and released in biological fluids, including plasma, and play a role in modifying the functional phenotype of target cells. Using an experimental human model of IH, we investigated potential exosome-derived biomarkers of IH-induced vascular dysfunction. METHODS: Ten male volunteers were exposed to room air (D0), IH (6 h/day) for 4 days (D4) and allowed to recover for 4 days (D8). Circulating plasma exosomes were isolated and incubated with human endothelial monolayer cultures for impedance measurements and RNA extracted and processed with messenger RNA (mRNA) arrays to identify gene targets. In addition, immunofluorescent assessments of endothelial nitric oxide synthase (eNOS) mRNA expression, ICAM-1 cellular distribution were conducted. RESULTS: Plasma exosomal micro RNAs (miRNAs) were profiled. D4 exosomes, primarily from endothelial sources, disrupted impedance levels compared to D0 and D8. ICAM-1 expression was markedly upregulated in endothelial cells exposed to D4 exosomes along with significant reductions in eNOS expression. Microarray approaches identified a restricted and further validated signature of exosomal miRNAs in D4 exosomes, and mRNA arrays revealed putative endothelial gene target pathways. CONCLUSIONS: In humans, intermittent hypoxia alters exosome cargo in the circulation which promotes increased permeability and dysfunction of endothelial cells in vitro. A select number of circulating exosomal miRNAs may play important roles in the cardiovascular dysfunction associated with OSA by targeting specific effector pathways.

Extracellular microvesicle microRNAs in children with sickle cell anaemia with divergent clinical phenotypes.

Sickle cell anaemia (SCA) is the most frequent genetic haemoglobinopathy, which exhibits a highly variable clinical course characterized by hyper-coagulable and pro-inflammatory states, as well as endothelial dysfunction. Extracellular microvesicles are released into biological fluids and play a role in modifying the functional phenotype of target cells. We hypothesized that potential differences in plasma-derived extracellular microvesicles (EV) function and cargo from SCA patients may underlie divergent clinical trajectories. Plasma EV from SCA patients with mild, intermediate and severe clinical disease course were isolated, and primary endothelial cell cultures were exposed. Endothelial cell activation, monocyte adhesion, barrier disruption and exosome cargo (microRNA microarrays) were assessed. EV disrupted the endothelial barrier and induced expression of adhesion molecules and monocyte adhesion in a SCA severity-dependent manner compared to healthy children. Microarray approaches identified a restricted signature of exosomal microRNAs that readily distinguished severe from mild SCA, as well as from healthy children. The microRNA candidates were further validated using quantitative real time polymerase chain reaction assays, and revealed putative gene targets. Circulating exosomal microRNAs may play important roles in predicting the clinical course of SCA, and in delineation of individually tailored, mechanistically-based clinical treatment approaches of SCA patients in the near future.