Rorc-mediated deletion of Tfam, a mitochondrial transcription factor, causes tuft cell and type 2 immunity-driven small intestine (SI) lengthening in mice. Here, we report an indispensable role for T helper 2 (Th2) cells in this process. High-fat diet (HFD) reverts SI lengthening in Tfamf/fRorc-cre mice by suppressing IL-13-producing Th2 cells and IL-17-producing Th2 cells and group 2 innate lymphoid cells (ILC2s). HFD reduces conventional GATA3-/loRORγt+ ILC3s but promotes GATA3+RORγt+ ILCs, especially in Tfamf/fRorc-cre mice. Compared with conventional ILC3s, GATA3+RORγt+ ILCs express type 2 cytokines and increase cell proliferation but decrease cell death with metabolic re-programming. Single-cell transcriptional analyses indicate that GATA3+RORγt+ ILCs represent a distinct population, different from IL-17- natural ILC2s, IL-17+ inflammatory ILC2s, or conventional ILC3s. GATA3+RORγt+ ILCs produce IL-17 but not IL-22, resulting from competition of the aryl hydrocarbon receptor (Ahr) with GATA3 at the Il22 locus. Tfamf/fRorc-cre mice on HFD have worsened dextran sodium sulfate (DSS)-induced colitis. These data highlight the role of ILC metabolism in intestinal tissue remodeling and inflammation.

Two morphologic subtypes of intrahepatic cholangiocarcinoma (iCCA), small duct and large duct, are now recognized, and importantly, these subtypes are associated with distinct molecular pathways and therapeutic options. Initial studies demonstrated the feasibility of morphologic subclassification and helped characterize the immunoprofile of the subtypes. However, few studies have been undertaken in Western countries where incidence of the subtypes is likely distinct from that in the East. To address this, 48 tumors from a North American cohort, consisting of 29 iCCAs, 18 extrahepatic CCAs (eCCAs), and 1 tumor of unclear origin (liver vs. gallbladder growing into liver) were classified by morphologic criteria as large duct (19 tumors), small duct (13 tumors), or indeterminate (13 tumors; all iCCAs). Notably, only 3 iCCAs were classified as large duct. Additionally, we evaluated the utility of common biomarkers to aid in subclassification, given that a significant portion of iCCAs were challenging to classify (e.g., indeterminate morphology). Tumors were screened for expression of mucicarmine, epithelial membrane antigen (EMA), monoclonal (mCEA), polyclonal CEA (pCEA), N-cadherin, CD56, and albumin by in situ hybridization (ALB-ISH). Of these, pCEA, CRP, N-cadherin, and ALB-ISH showed statistically significant differences between large and small duct types (P < 0.0028), with high specificity (>= 88 %) and at least moderate sensitivity (>= 60 %). Eleven of the 13 morphologically indeterminate tumors could be classified based on their expression of these 4 markers. Four additional large duct iCCAs were subsequently obtained from a second North American institution and assessed for pCEA, N-cadherin, and albumin expression. Combining these data with the initial cohort of large duct iCCAs (total of 7 large duct iCCAs) showed similar biomarker associations. In conclusion, in this Western cohort, 55 % of iCCAs (16 of 29) could be subclassified as large or small duct type based on morphology alone. With the aid of the 4-marker panel, 93 % of iCCAs (27 of 29) could be classified. Unlike in East Asian cohorts, the vast majority of iCCAs (88 %) was small duct type, and hepatolithiasis was not observed. CRP, N-cadherin, and ALB-ISH were found to be specific for small duct iCCA, whereas diffuse, strong expression of pCEA showed specificity for large duct tumors. This is the first report to highlight the utility of pCEA to subclassify iCCAs. Additionally, in cases in which the primary site (within the biliary tract) was unclear, CRP, ALB-ISH, N-cadherin, and pCEA were helpful in distinguishing iCCA from eCCA.

Hepatic adenomas occur most commonly in women between the ages of 20 and 40 years, but rarely they occur in older aged persons, including those 60 years of age or older. This group of adenomas, however, has not been systemically examined. Twenty-six hepatic adenomas in persons 60 years of age or older were studied, along with a control group of 50 hepatic adenomas in persons aged 30 to 39. Hepatic adenomas in persons 60 or more years of age were found in 21 women and 5 men, while the control group had 44 women and 6 men. Subtyping the adenomas in persons 60 years or older showed the following results: 18 HNF1A -inactivated adenomas (69%), 4 inflammatory adenomas (15%), and 4 unclassified adenomas (15%). In contrast, the control group showed a significantly different pattern ( P =0.003), with a greater percentage of inflammatory adenomas (28, 56%), fewer HNF1A- inactivated adenomas (8, 16%), and more unclassified adenomas (14, 28%). Atypia and malignant transformation within the hepatic adenomas was studied next. Of the hepatic adenomas in persons age 60 or greater, 3 (12%) showed atypical histologic features, and 6 (23%) had a malignant transformation. In contrast, for hepatic adenomas in the control group, only 4 (8%) adenomas showed atypical histologic features, and 3 (6%) had undergone malignant transformation. In addition, the hepatic adenomas that were atypical or showed early malignant transformation were less likely to have beta-catenin activation in patients over 60 (2/9 cases) compared with those between 30 and 39 years (5/7 cases). Myxoid change and heavy lipofuscin deposition were also more common in adenomas in older aged persons. In conclusion, hepatic adenomas in persons 60 years of age or older are enriched for HNF1A -inactivated adenomas and have a higher frequency of malignant transformation. Malignant transformation, however, is less likely to develop through activation of the beta-catenin pathway.

Prostate‐specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68Ga‐PSMA‐11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68Ga‐PSMA‐11 PET was prospectively performed in patients with treatment‐naïve HCC on a digital PET scanner using cyclotron‐produced 68Ga. Uptake was graded qualitatively and semi‐quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor‐associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10‐5) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = −0.753; P = 1.58 × 10‐6). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68Ga‐PSMA‐11 standardized uptake value: SUVmax (median [range] 9.2 [4.9‐28.4]), SUVmean 4.7 (2.4‐12.7), and tumor‐to‐liver background ratio 2 (1.1‐11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68Ga‐PSMA‐11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

RORγt + lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A ( Tfam ) in RORγt + lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt + lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt + lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.

Importance Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline DICER1 putative loss-of-function (pLOF) variants in an unselected clinical cohort. Objective To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline DICER1 pLOF variants via genome-first ascertainment. Design, Setting, and Participants This cohort study classifies DICER1 variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018. Main Outcomes and Measures Prevalence of germline DICER1 variation; penetrance of malignant tumors and thyroid disease in carriers of germline DICER1 variation; structured, manual review of electronic health records; and DICER1 sequencing of available tumors from an associated cancer registry. Results A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline DICER1 pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with DICER1 pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first) DICER1 studies published to date. DICER1 pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3; P = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7; P = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline DICER1 hotspot variant was apparently healthy on electronic health record review. The term DICER1 did not appear in any of the medical records of the 25 participants with a pLOF DICER1 variant, even in those affected with a known DICER1-associated tumor or thyroid phenotype. Conclusions and Relevance This cohort study was able to ascertain individuals with germline DICER1 variants based on a genome-first approach rather than through a previously established DICER1-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation.

Purpose The clinical utility of screening unselected individuals for pathogenic BRCA1/2 variants has not been established. Data on cancer risk management behaviors and diagnoses of BRCA1/2 -associated cancers can help inform assessments of clinical utility. Methods Whole-exome sequences of participants in the MyCode Community Health Initiative were reviewed for pathogenic/likely pathogenic BRCA1/2 variants. Clinically confirmed variants were disclosed to patient–participants and their clinicians. We queried patient–participants’ electronic health records for BRCA1/2 -associated cancer diagnoses and risk management that occurred within 12 months after results disclosure, and calculated the percentage of patient–participants of eligible age who had begun risk management. Results Thirty-seven MyCode patient–participants were unaware of their pathogenic/likely pathogenic BRCA1/2 variant, had not had a BRCA1/2 -associated cancer, and had 12 months of follow-up. Of the 33 who were of an age to begin BRCA1/2 -associated risk management, 26 (79%) had performed at least one such procedure. Three were diagnosed with an early-stage, BRCA1/2 -associated cancer—including a stage 1C fallopian tube cancer—via these procedures. Conclusion Screening for pathogenic BRCA1/2 variants among unselected individuals can lead to occult cancer detection shortly after disclosure. Comprehensive outcomes data generated within our learning healthcare system will aid in determining whether population-wide BRCA1/2 genomic screening programs offer clinical utility.

Myxoid hepatic adenomas are a rare subtype of hepatic adenomas with distinctive deposition of extracellular myxoid material between the hepatic plates. A total of 9 cases were identified in 6 women and 3 men with an average of 59±12 years. The myxoid adenomas were single tumors in 5 cases and multiple in 4 cases. In 1 case with multiple adenomas, the myxoid adenoma arose in the background of GNAS -mutated hepatic adenomatosis. Myxoid hepatic adenomas had a high frequency of malignant transformation (N=5 cases). They were characterized at the molecular level by HNF1A inactivating mutations, leading to loss of LFABP protein expression. In addition, myxoid adenomas had recurrent mutations in genes within the protein kinase A (PKA) pathway or in genes that regulate the PKA pathway: GNAS , CDKN1B (encodes p27), and RNF123 . In sum, myxoid adenomas are rare, occur in older-aged persons, have a high risk of malignant transformation, and are characterized by the combined inactivation of HNF1A and additional mutations that appear to cluster in the PKA pathway.

The orphan chemoattractant receptor GPR15 is important for homing T lymphocytes to the large intestine, thereby maintaining intestinal immune homeostasis. However, the molecular mechanisms underlying the regulation of GPR15 expression remain elusive. Here, we show a central role of the aryl hydrocarbon receptor (Ahr) in promoting GPR15 expression in both mice and human, thus gut homing of T lymphocytes. Mechanistically, Ahr directly binds to open chromatin regions of the Gpr15 locus to enhance its expression. Ahr transcriptional activity in directing GPR15 expression was modulated by two transcription factors, Foxp3 and RORγt, both of which are expressed preferentially by gut regulatory T cells (Tregs) in vivo. Specifically, Foxp3 interacted with Ahr and enhanced Ahr DNA binding at the Gpr15 locus, thereby promoting GPR15 expression. In contrast, RORγt plays an inhibitory role, at least in part, by competing with Ahr binding to the Gpr15 locus. Our findings thus demonstrate a key role for Ahr in regulating Treg intestinal homing under the steady state and during inflammation and the importance of Ahr-RORγt-Foxp3 axis in regulating gut homing receptor GPR15 expression by lymphocytes.

Undifferentiated carcinoma of the esophagus and gastroesophageal junction is a recently recognized entity in the fifth edition of the World Health Organization Classification of Digestive Tumors and is diagnostically challenging, particularly on small biopsies. SMARCA4 and SMARCA2 are chromatin remodeling genes with key roles in oncogenesis. We retrieved 14 cases of SMARCA4/SMARCA2-deficient undifferentiated carcinoma of the gastroesophageal junction and esophagus from the authors’ institutions. The tumors showed similar histologic findings: the sheet-like proliferation of tumor cells characterized by discohesion, large nuclei, and prominent macronucleoli with many tumor cells exhibiting a rhabdoid appearance. In 8 cases, adjacent specialized intestinal metaplasia was noted and 3 cases exhibited adjacent high-grade dysplasia. Immunohistochemically, tumors variably expressed keratins and disclosed loss of expression of SMARCA4 in 12 and SMARCA2 in 7 cases. In 2 cases SMARCA2 alone was lost without SMARCA4 loss. A mutant p53 immunohistochemical pattern was seen in 4 of 4 cases, 3 of which showed diffuse, strong nuclear expression, and 1 case displayed a complete loss of nuclear expression of p53, including invasive carcinoma and associated dysplasia, when present. Limited clinical follow-up was available, but 3 patients died of disease within 0.6, 2, and 7 months of diagnosis. We present the first series of undifferentiated carcinoma of the esophagus and gastroesophageal junction with this characteristic morphology associated with loss of SMARCA4 and/or SMARCA2 expression. This tumor type likely arises from dedifferentiation of a lower grade carcinoma in some cases, and Barrett esophagus and appears to be associated with an aggressive clinical course.

A 78-year-old woman with a history of type 2 diabetes mellitus, chronic kidney disease stage 4, hypertension, atrial fibrillation, grade 1 follicular lymphoma, gastroesophageal reflux disease, and iron deficiency anemia presented with several months of transfusion-dependent anemia. Medications included oral ferrous sulfate, insulin, spironolactone, clonidine, metoprolol, simvastatin, omeprazole, and apixaban. In the past several months, she had been receiving weekly darbepoetin alfa injections and requiring 4 blood transfusions a month. Bone marrow biopsy was unrevealing for any primary hematologic etiology. She underwent double balloon anterograde enteroscopy for further evaluation of potential gastrointestinal bleeding that revealed gastric antral vascular ectasia and nonbleeding small angioectasias. Additionally, gastric body, duodenal, and mild jejunal abnormal hyperpigmentation were seen. Biopsies of the jejunum revealed small bowel mucosa with hemosiderin-laden macrophage collections in the lamina propria. This confirmed the diagnosis of pseudomelanosis (Figure 1). Small bowel pseudomelanosis is a rarely described endoscopic finding usually found incidentally with unknown clinical significance.1Zakaria A. Abdu B. Al Share B. Manabat M. Ngo K. Pseudomelanosis intestine "from pylorus to jejunum": a rare endoscopic finding in a patient with GI bleeding.J Family Med Prim Care. 2018; 7: 1120-1122PubMed Google Scholar, 2Thure Caire M. Kalan S. Brady P. Gill J. Pseudomelanosis of the stomach and duodenum: an uncommon endoscopic finding.Endosc Int Open. 2014; 2: E191-E192Crossref PubMed Google Scholar, 3Samiullah S. Bhurgri H. Babar A. Samad F. Choudhary M.M. Demyen M. Peppered and rare—gastric and duodenal pseudomelanosis: a case series.Pak J Med Sci. 2017; 33: 757-760PubMed Google Scholar It is characteristically described as flat speckled pigmented mucosa, commonly in the duodenum. Histology findings include dark pigmented inclusions in macrophages of the lamina propia with varying degrees of iron1Zakaria A. Abdu B. Al Share B. Manabat M. Ngo K. Pseudomelanosis intestine "from pylorus to jejunum": a rare endoscopic finding in a patient with GI bleeding.J Family Med Prim Care. 2018; 7: 1120-1122PubMed Google Scholar,2Thure Caire M. Kalan S. Brady P. Gill J. Pseudomelanosis of the stomach and duodenum: an uncommon endoscopic finding.Endosc Int Open. 2014; 2: E191-E192Crossref PubMed Google Scholar staining (Figure 2). It has previously been associated with gastrointestinal hemorrhage, chronic kidney disease, diabetes mellitus, hypertension, and various medications including iron supplements, β-blockers, diuretics, and hydralazine.1Zakaria A. Abdu B. Al Share B. Manabat M. Ngo K. Pseudomelanosis intestine "from pylorus to jejunum": a rare endoscopic finding in a patient with GI bleeding.J Family Med Prim Care. 2018; 7: 1120-1122PubMed Google Scholar, 2Thure Caire M. Kalan S. Brady P. Gill J. Pseudomelanosis of the stomach and duodenum: an uncommon endoscopic finding.Endosc Int Open. 2014; 2: E191-E192Crossref PubMed Google Scholar, 3Samiullah S. Bhurgri H. Babar A. Samad F. Choudhary M.M. Demyen M. Peppered and rare—gastric and duodenal pseudomelanosis: a case series.Pak J Med Sci. 2017; 33: 757-760PubMed Google Scholar Our patient had several conditions and medications that have been previously associated with small bowel pseudomelanosis. In contrast, there have been cases in patients without any associated medications or conditions.3Samiullah S. Bhurgri H. Babar A. Samad F. Choudhary M.M. Demyen M. Peppered and rare—gastric and duodenal pseudomelanosis: a case series.Pak J Med Sci. 2017; 33: 757-760PubMed Google Scholar There are no guidelines for surveillance of this endoscopic finding.1Zakaria A. Abdu B. Al Share B. Manabat M. Ngo K. Pseudomelanosis intestine "from pylorus to jejunum": a rare endoscopic finding in a patient with GI bleeding.J Family Med Prim Care. 2018; 7: 1120-1122PubMed Google Scholar

Regulatory T cells (Tregs) are pivotal for immune suppression. Cellular metabolism is important for Treg homeostasis and function. However, the exact role of mitochondrial respiration in Tregs remains elusive. Mitochondrial transcription factor A (Tfam) is essential for mitochondrial respiration and controls mitochondrial DNA replication, transcription, and packaging. Here, we show that genetic ablation of Tfam in Tregs impairs Treg maintenance in non-lymphoid tissues in the steady state and in tumors. Tfam-deficient Tregs have reduced proliferation and Foxp3 expression upon glucose deprivation in vitro. Tfam deficiency preferentially affects gene activation in Tregs through regulation of DNA methylation, with enhanced methylation in the TSDR of the Foxp3 locus. Deletion of Tfam in Tregs affects Treg homing and stability, resulting in tissue inflammation in colitis, but enhances tumor rejection. Thus, our work reveals a critical role of Tfam-mediated mitochondrial respiration in Tregs to regulate inflammation and anti-tumor immunity.

Background and study aims Endoscopic ultrasound-guided liver biopsy uses a 19-gauge (G) needle for parenchymal liver biopsies. We evaluated tissue yields with a 22G fine-needle biopsy (FNB) versus 19G FNA fine-needle aspirate (FNA) device. Patients and methods Biopsies were obtained from 20 patients using the 19G FNA and 22G FNB randomizing each in a cross-over fashion with a blinded outcome assessor. Tissue adequacy for histologic evaluation was the primary outcome, or the proportion of specimens obtaining pathologic diagnosis (portal structures ≥ 5 or length of the longest piece ≥ 15 mm). Additional secondary outcomes included portal and centrilobular inflammation/fibrosis, length of the longest piece, aggregate specimen length, and small (< 5 mm), medium (5 - 8 mm) and large (> 8 mm) fragments. Results were compared in a per needle basis. Patients with cirrhosis were excluded. Results Eighty biopsies (40 each 19G FNA and 22G FNB) were obtained. Tissue adequacy was greater for the 19G FNA (88 %) versus 22G FNB (68 %), ( P = 0.03). There was no difference in total portal structures for the 19G FNA (7.4) and 22G FNB (6.1), ( P = 0.28). There was no difference in pre-processing outcomes. After processing, length of the longest piece was higher for the 19G FNA (9.1 mm) versus 22G FNB (6.6 mm), ( P = 0.02). More total post-processing small fragments 29.9 versus 20.7, ( P = 0.01) and fewer large fragments 1.0 versus 0.4 for the 22G FNB ( P = 0.01) were detected. Conclusions Tissue adequacy was higher for the 19G FNA versus 22G FNB needle. The 22G FNB needle produced samples more prone to fragmentation during specimen processing.

Intestinal innate lymphoid cells (ILCs) contribute to the protective immunity and homeostasis of the gut, and the microbiota are critically involved in shaping ILC function. However, the role of the gut microbiota in regulating ILC development and maintenance still remains elusive. Here, we identified opposing effects on ILCs by two Helicobacter species, Helicobacter apodemus and Helicobacter typhlonius , isolated from immunocompromised mice. We demonstrated that the introduction of both Helicobacter species activated ILCs and induced gut inflammation; however, these Helicobacter species negatively regulated RORγt + group 3 ILCs (ILC3s), especially T-bet + ILC3s, and diminished their proliferative capacity. Thus, these findings underscore a previously unknown dichotomous regulation of ILC3s by Helicobacter species, and may serve as a model for further investigations to elucidate the host–microbe interactions that critically sustain the maintenance of intestinal ILC3s.

In patients with non-alcoholic fatty liver disease (NAFLD), all-cause mortality increases with fibrosis stage. Liver biopsy (LB), performed predominantly in the right lobe, assesses fibrosis, however, right lobe LB may not be sufficient due to histological variation in different lobes. Endoscopic ultrasound (EUS) allows for biopsy of right and left liver lobes in the same setting. This retrospective study assessed for histologic variability amongst left and right liver lobe (L:R) specimens obtained via EUS at a tertiary care center. Between January 2012 and December 2015, 38 NAFLD patients underwent LB, in whom both lobes were sampled. L:R agreement was near-perfect for steatosis (κ = 0.816, 95% CI 0.674, 0.958), good for ballooning (κ = 0.740, 95% CI 0.565, 0.916) and moderate for lobular inflammation (κ = 0.401 95% CI 0.110, 0.692) and fibrosis (κ = 0.473, 95% CI 0.275, 0.672). Intra-observer variability assessed by blinded repeat slide readings was almost perfect for fibrosis and steatosis (κ = 1, 95% CI 1, 1 and κ = 0.939, 95% CI 0.881, 0.997 respectively) and substantial for lobular inflammation (κ = 0.725, 95% CI 0.584, 0.866). Only right lobe assessment underestimated fibrosis in 21%, inflammation in 13%, and steatosis and ballooning in 8% cases. These data indicate that in NAFLD, due to regional variation, EUS-guided bi-lobar LB improves assessment of disease activity and fibrosis.

Background and Aims: As EUS-guided liver biopsy sampling (EUS-LB) becomes more widely used, further studies have investigated ways to improve tissue yields. Use of a heparin-primed needle may lead to less clotting of blood within the needle, improve tissue recovery, and decrease fragmentation. The purpose of this study was to prospectively evaluate wet suction using a heparin-primed needle for EUS-LB. Methods: This was a prospective crossover study evaluating wet suction for EUS-LB in parenchymal liver disease. The primary outcome was specimen adequacy, defined by an aggregate specimen length >= 15 mm and >= 5 complete portal tracts (CPTs). Secondary outcomes included number of CPTs, length of the longest piece, aggregate specimen length, and number of small (<= 4 mm), medium (5-8 mm), and large (>= 9 mm) fragments. Adverse events were tracked at 7 and 30 days. Results: One hundred twenty biopsy specimens were collected from 40 participants (3 specimens per patient). Specimen adequacy occurred in 39 wet heparin (98%), 37 dry heparin (93%), and 30 dry needle biopsy samples (80%; 95% confidence interval [CI],.14-. 18; P = .01). There was no difference between dry needle techniques. Length of the longest piece was 8.9 mm for wet heparin and 5.8 mm for dry techniques (95% CI,.33-1.53; P = .003). Aggregate specimen length was 49.2 mm for wet heparin and 23.9 mm for dry heparin (95% CI, -46.34 to 44.94; P = .003). Mean CPT count was 7.0 for wet heparin versus 4.0 for dry (95% CI,.74-6.26; P = .01). There were more medium (2.0 vs 1.0; 95% CI,.06-1.24; P =. 03) and large (1.0 versus 0.0; 95% CI,.33-1.53; P =. 003) fragments with wet suction with no difference in small fragments between groups. Conclusions: The use of wet suction EUS-LB demonstrated improved tissue adequacy compared with dry needle techniques. (Clinical trial registration number: NCT03103997.)

Colonic adenomas are common, but those containing high-grade dysplasia (HGDA) are encountered infrequently. There is limited data on the clinical presentation, and endoscopic features of these worrisome lesions.

ObjectivesInconsistent data on detection of albumin expression by ribonucleic acid (RNA) in situ hybridization have been reported. We investigated the utility of RNAscope (Advanced Cell Diagnostics, Hayward, CA) in detection of albumin in hepatocellular carcinomas (HCCs), intrahepatic cholangiocarcinomas (ICCs), and carcinomas from various organs using manual and automated staining.MethodsRNAscope for albumin detection was performed on 482 cases on tissue microarray sections and on 22 cases of ICC, including 14 surgical resection and eight core biopsy specimens.ResultsThirty-six of 37 (97%) HCCs had detectable mRNA, whereas all non-HCC and non-ICC cases, except one lung adenocarcinoma, were negative for albumin. Fourteen of 22 ICCs (64%) were positive for albumin.ConclusionsRNAscope for albumin is highly sensitive and specific for identifying HCCs and is highly specific and moderately sensitive for detection of ICCs; however, rare carcinomas (non-HCC, non-ICC, and those with no hepatoid histomorphology) can also have aberrant expression of albumin.

Non-invasive testing often leads to a conclusive diagnosis for liver diseases, but liver biopsy remains an important method for determining the etiology and stage in some cases. Endoscopic ultrasound guided-liver biopsy (EUS-LB) using a 19gauge (g) needle has been shown to be a safe and effective method for performing parenchymal liver biopsy. In this study we compared the yield of a 22g fine needle biopsy (FNB) needle compared to a conventional 19g needle. We predicted that the 19 and 22g FNB needle would demonstrate similar diagnostic accuracy, with less visible blood for the 22g needle.