Intestinal Microbiome Associated with Efficacy of Atezolizumab and Bevacizumab Therapy for Hepatocellular Carcinoma.

The combination of atezolizumab and bevacizumab has become the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). However, no studies have reported on specific intestinal microbiota associated with the efficacy of atezolizumab and bevacizumab. In this study, we analyzed fecal samples collected before treatment to investigate the relationship between the intestinal microbiome and the efficacy of atezolizumab and bevacizumab. A total of 37 patients with advanced HCC who were treated with atezolizumab and bevacizumab were enrolled. Fecal samples were collected from the patients, and they were divided into responder (n = 28) and non-responder (n = 9) groups. We compared the intestinal microbiota of the two groups and analyzed the intestinal bacteria associated with prognosis using QIIME2. The alpha and beta diversities were not significantly different between both groups, and the proportion of microbiota was similar. The relative abundance of Bacteroides stercoris and Parabacteroides merdae was higher in the responder group than in the non-responder group. When the prognosis was analyzed by the presence or absence of those bacteria, patients without both had a significantly poorer prognosis. Differences in intestinal microbiome are involved in the therapeutic effect of atezolizumab and bevacizumab.

Risk factors for decreased bone mineral density in patients with metabolic dysfunction-associated steatotic liver disease: A cross-sectional study at a health examination center.

BACKGROUND & AIMS: Steatotic liver disease (SLD) is often detected in health examinations. However, although individuals with metabolic dysfunction-associated SLD (MASLD) may have decreased bone mineral density (BMD), the specific risk factors remain unclarified. The objective of this study was to identify the factors associated with decreased BMD in patients with MASLD. METHODS: Individuals who underwent abdominal ultrasonography and BMD measurements at our healthcare center were included. The BMD of the calcaneus was assessed using an AOS-10SA bone densitometer. Decreased BMD was defined as a T-score below -1.0 SD or the administration of osteoporosis treatment. SLD was diagnosed based on specific ultrasonographic criteria. RESULTS: A total of 1410 patients were diagnosed with MASLD. The median age was 52 years. Multivariate analysis using a logistic regression model revealed that the independent predictors of decreased BMD were a low body mass index (BMI) or a small waist circumference (odds ratio (OR): 0.48, 95% confidence interval (CI): 0.34-0.67), hypertriglyceridemia (OR: 1.29, 95% CI: 1.00-1.65), and a weak grip strength (OR: 0.98, 95% CI: 0.97-1.00). Subgroup analyses of individuals aged 50 years or older, men, and individuals with a FIB-4 index of 1.3 or greater revealed that the absence of a high BMI or a large waist circumference was associated with decreased BMD. The subgroup analysis of men revealed that a weaker grip strength was associated with decreased BMD. CONCLUSION: The present study suggested several potential risk factors for decreased BMD in patients with MASLD. Individuals with the abovementioned risk factors should be encouraged to undergo BMD measurement from the perspective of preventive medicine.

A prospective study on the histological evaluation of type 1 autoimmune pancreatitis using endoscopic ultrasound-guided fine needle biopsy with a 19-gauge Franseen needle.

BACKGROUND/PURPOSE: To assess the diagnostic efficacy and safety of endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) using a 19-gauge Franseen needle for autoimmune pancreatitis (AIP). METHODS: Twenty patients suspected of having type 1 AIP were prospectively enrolled and underwent EUS-FNB with a 19-gauge Franseen needle. Their data were compared with those of historical controls: a total of 29 type 1 AIP patients had EUS-FNB with a 22-gauge Franseen needle. RESULTS: Specimens suitable for histological evaluation were obtained from 19 of the 20 patients (95%), and the median total tissue area was 11.9 mm2. The histological diagnosis rate of AIP was 65% (95% CI: 43.2%-82%). Adverse events were observed in three patients (15%), and a switch to 22-gauge needles occurred during transduodenal puncture in two patients. Compared to those punctured with 22-gauge needles, patients punctured with 19-gauge needles had greater prevalence of each characteristic feature of lymphoplasmacytic sclerosing pancreatitis, but the difference was not statistically significant. CONCLUSIONS: EUS-FNB using a 19-gauge Franseen needle demonstrated favorable performance for the histological diagnosis of AIP and allowed for large tissue samples, potentially facilitating pathological diagnosis. However, during transduodenal puncture, maneuverability is reduced; therefore, the needle may need to be selected according to the puncture site.

What is the appropriate method of pathological specimen collection for cholangiocarcinoma detection in primary sclerosing cholangitis?

BACKGROUND: In primary sclerosing cholangitis (PSC), it is important to understand the cholangiographic findings suggestive of malignancy, but it is difficult to determine whether cholangiocarcinoma is present due to modifications caused by inflammation. This study aimed to clarify the appropriate method of pathological specimen collection during endoscopic retrograde cholangiopancreatography for surveillance of PSC. METHODS: A retrospective observational study was performed on 59 patients with PSC. The endpoints were diagnostic performance for benign or malignant on bile cytology and transpapillary bile duct biopsy, cholangiographic findings of biopsied bile ducts, diameters of the strictures and upstream bile ducts, and their differences. RESULTS: The sensitivity (77.8% vs. 14.3%, P = 0.04), specificity (97.8% vs. 83.0%, P = 0.04), and accuracy (94.5% vs. 74.1%, P = 0.007) were all significantly greater for bile duct biopsy than for bile cytology. All patients with cholangiocarcinoma with bile duct stricture presented with dominant stricture (DS). The diameter of the upstream bile ducts (7.1 (4.2-7.2) mm vs. 2.1 (1.2-4.1) mm, P < 0.001) and the diameter differences (6.6 (3.1-7) mm vs. 1.5 (0.2-3.6) mm, P < 0.001) were significantly greater in the cholangiocarcinoma group than in the noncholangiocarcinoma group with DS. For diameter differences, the optimal cutoff value for the diagnosis of benign or malignant was 5.1 mm (area under the curve = 0.972). CONCLUSION: Transpapillary bile duct biopsy should be performed via localized DS with upstream dilation for the detection of cholangiocarcinoma in patients with PSC. Especially when the diameter differences are greater than 5 mm, the development of cholangiocarcinoma should be strongly suspected.

Monoclonal Antibodies Against Mature Interleukin-18 Ameliorate Colitis and Repair Goblet Cell Function.

BACKGROUND: Numerous biological interventions and small molecules are used to treat Crohn's disease; however, the effectiveness of these treatments varies largely. Non-responsiveness to biological therapies is associated with interleukin (IL)-18 gene polymorphisms and high IL-18 expression has been implicated in the pathogenesis of Crohn's disease. AIMS: The aim of this study was to elucidate the expression of precursor and mature IL-18 in patients with Crohn's disease who exhibited varied responses to cytokine-targeted treatments and determine whether selective inhibition of mature IL-18 offers a novel therapeutic avenue. METHODS: We generated a monoclonal antibody that specifically recognizes the neoepitope of caspase-cleaved mature IL-18. Expression of precursor and mature IL-18 was analyzed in patients with Crohn's disease. Anti-mature IL-18 monoclonal antibodies were intraperitoneally administered in an acute colitis mouse model, and the disease activity index, body weight loss, tissue pathology, proinflammatory cytokine expression, goblet cell function, and microbiota composition were assessed. RESULTS: Precursor and mature IL-18 expression was upregulated and goblet cell function was impaired in patients with Crohn's disease who were unresponsive to biological therapies. Administration of anti-mature IL-18 antibodies ameliorated induced colitis by repairing goblet cell function and restoring the mucus layer. CONCLUSIONS: The newly developed monoclonal antibody holds promise as a therapeutic alternative for Crohn's disease.

Endoscopic diagnosis of epithelial subtypes of superficial non-ampullary duodenal epithelial tumors using magnifying narrow-band imaging.

INTRODUCTION: Superficial non-ampullary duodenal epithelial tumors (SNADETs) include low-grade adenoma (LGA) and high-grade adenoma or carcinoma (HGA/Ca), and are classified into two different epithelial subtypes, gastric-type (G-type) and intestinal-type (I-type). We attempted to distinguish them by endoscopic characteristics including magnifying endoscopy with narrow-band imaging (M-NBI). METHODS: Various endoscopic and M-NBI findings of 286 SNADETs were retrospectively reviewed and compared between G- and I-types and histological grades. M-NBI findings were divided into four patterns based on the following vascular patterns; absent, network, intrastructural vascular (ISV), and unclassified. Lesions displaying a single pattern were classified as mono-pattern and those displaying multiple patterns as mixed-pattern. Lesions showing CDX2 positivity were categorized as I-types and those showing MUC5AC or MUC6 positivity were categorized as G-types based on immunohistochemistry. RESULTS: Among 286 lesions, 23 (8%) were G-type and 243 (85%) were I-type. More G-type lesions were located oral to papilla (91.3％ vs 45.6％, P<0.001), and had protruding morphology compared to those of I-types (65.2% vs 14.4%, P<0.001). The major M-NBI pattern was ISV in G-type (78.2% vs 26.3％, P<0.001), and absent for I-type (0% vs 34.5%, P=0.003). Three endoscopic characteristics; location oral to papilla, protruding morphology and major M-NBI pattern (ISV) were independent predictors for G-type. Mixed-pattern was more common in HGA/Ca than LGA for I-type (77.0% vs 58.8%, P＝0.01); however, there was no difference for those in G-type. CONCLUSION: Endoscopic findings including M-NBI is useful to differentiate epithelial subtypes.

Outcomes of immune checkpoint inhibitor-induced liver toxicity managed by hepatologists in a multidisciplinary toxicity team.

AIM: To detect immune-related adverse events (irAEs) early and treat them appropriately, our institute established an irAE-focused multidisciplinary toxicity team in cooperation with various departments. This study aimed to evaluate a consultation system involving a team of hepatologists in terms of its utility for the management of severe immune checkpoint inhibitor (ICI)-induced liver toxicity. METHODS: To analyze the diagnosis and treatment of severe ICI-induced liver toxicity (Grade 2 requiring corticosteroid therapy and Grade 3 or higher), we examined patients' clinical courses before and after the hepatologist consultation system was established (pre-period, September 2014 to February 2019; post-period, March 2019 to March 2023). RESULTS: The median follow-up period was 392 days. Of the 1247 patients with advanced malignancies treated with ICIs, 66 developed severe ICI-induced liver toxicity (n = 22 and 44 in the pre- and post-periods, respectively). In the pre-period, hepatologist consultations were sought for 15/22 patients, whereas in the post-period, 42/44 patients were referred to and treated by hepatologists. The time from the onset of liver toxicity to the consultation was significantly shorter in the post-period than in the pre-period (mean 1.9 vs. 6.5 days, respectively; p = 0.012). The number of patients with a biopsy-confirmed diagnosis of ICI-induced liver toxicity was significantly higher in the post-period than in the pre-period (n = 22 vs. n = 3, respectively; p = 0.006). Finally, there were no cases of immune-related cholangitis in the pre-period, compared to five cases in the post-period. CONCLUSION: A hepatologist consultation system in an irAE-focused multidisciplinary toxicity team is useful for managing severe ICI-induced liver toxicity.

An image-based metal artifact reduction technique utilizing forward projection in computed tomography.

The projection data generated via the forward projection of a computed tomography (CT) image (FP-data) have useful potentials in cases where only image data are available. However, there is a question of whether the FP-data generated from an image severely corrupted by metal artifacts can be used for the metal artifact reduction (MAR). The aim of this study was to investigate the feasibility of a MAR technique using FP-data by comparing its performance with that of a conventional robust MAR using projection data normalization (NMARconv). The NMARconv was modified to make use of FP-data (FPNMAR). A graphics processing unit was used to reduce the time required to generate FP-data and subsequent processes. The performances of FPNMAR and NMARconv were quantitatively compared using a normalized artifact index (AIn) for two cases each of hip prosthesis and dental fillings. Several clinical CT images with metal artifacts were processed by FPNMAR. The AIn values of FPNMAR and NMARconv were not significantly different from each other, showing almost the same performance between these two techniques. For all the clinical cases tested, FPNMAR significantly reduced the metal artifacts; thereby, the images of the soft tissues and bones obscured by the artifacts were notably recovered. The computation time per image was ~ 56 ms. FPNMAR, which can be applied to CT images without accessing the projection data, exhibited almost the same performance as that of NMARconv, while consuming significantly shorter processing time. This capability testifies the potential of FPNMAR for wider use in clinical settings.

Extensive Hepatic Infarction due to Polycythemia Vera.

Polycythemia vera (PV) is one of the three BCR-ABL1-negative myeloproliferative neoplasms characterized by activating mutations in JAK2, which clinically presents as erythrocytosis and has an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia. Splanchnic vein thrombosis is a rare manifestation of venous thromboembolism involving one or more abdominal vessels and is strongly associated with PV. We herein report a case in which hepatic infarction due to PV was saved by conservative treatment.

Gastric ectopic pancreas with a pseudocyst.

Ectopic pancreas (EP) is defined as pancreatic tissue that lacks anatomical or vascular connections to the normal pancreas. EP is generally asymptomatic and is detected incidentally during endoscopy. However, due to pseudocyst formation, inflammation, or malignant transformation, it may cause non-specific gastrointestinal symptoms, such as abdominal pain, abdominal discomfort, nausea, vomiting, and bleeding. Pseudocyst formation in EP may result from the retention of exocrine secretions in the absence of connections between the glandular epithelium and gastric lumen. We herein report a case of EP with a pseudocyst associated with epigastric pain. EP with a pseudocyst, although rare, needs to be considered in a differential diagnosis of cystic lesions of the stomach.

Artificial intelligence-based diagnostic imaging system with virtual enteroscopy and virtual unfolded views to evaluate small bowel lesions in Crohn's disease.

Since even subtle mucosal changes may be depicted using virtual endoscopy created by the three-dimensional reconstruction of MDCT images, we developed a novel diagnostic imaging system that integrates and displays virtual enteroscopy, curved planar reconstruction, and a virtual unfolded view, the width of which changes with increases/decreases in the inner luminal diameter. The system is also equipped with artificial intelligence that superimposes and displays depressed areas, generates an automatic small bowel centerline that connects fragmented small bowel regions, and performs electronic cleansing. We retrospectively evaluated the diagnostic performance of this system for small bowel lesions in Crohn's disease, which were divided into two groups: endoscopically-observable and endoscopically-unobservable. Lesion detection rates for stenoses, longitudinal ulcers with a cobblestone appearance, and scars were excellent in both groups. This system, when used in combination with endoscopy, shows slight mucosal changes in areas in which an endoscope cannot reach due to strictures, thereby extending the range of observation of the small bowel. This system is a useful diagnostic modality that has the capacity to assess mucosal healing and provide extraluminal information.

Identification of the Microbiome Associated with Prognosis in Patients with Chronic Liver Disease.

We investigated the prognostic role of the gut microbiome and clinical factors in chronic liver disease (hepatitis, cirrhosis, and hepatocellular carcinoma [HCC]). Utilizing data from 227 patients whose stool samples were collected over the prior 3 years and a Cox proportional hazards model, we integrated clinical attributes and microbiome composition based on 16S ribosomal RNA sequencing. HCC was the primary cause of mortality, with the Barcelona Clinic Liver Cancer staging system-derived B/C significantly increasing the mortality risk (hazard ratio [HR] = 8.060; 95% confidence interval [CI]: 3.6509-17.793; p < 0.001). Cholesterol levels < 140 mg/dL were associated with higher mortality rates (HR = 4.411; 95% CI: 2.0151-9.6555; p < 0.001). Incertae sedis from Ruminococcaceae showed a protective effect, reducing mortality risk (HR = 0.289; 95% CI: 0.1282 to 0.6538; p = 0.002), whereas increased Veillonella presence was associated with a higher risk (HR = 2.733; 95% CI: 1.1922-6.2664; p = 0.017). The potential of specific bacterial taxa as independent prognostic factors suggests that integrating microbiome data could improve the prognosis and treatment of chronic liver disease. These microbiome-derived markers have prognostic significance independently and in conjunction with clinical factors, suggesting their utility in improving a patient's prognosis.

Characteristics of microbiomes of the saliva, duodenal bulb, and descending portion of superficial nonampullary duodenal epithelial tumors.

INTRODUCTION: Nonampullary duodenal epithelial tumors are rare, but their prevalence is increasing. Various gastrointestinal cancers have been associated with microbiomes. We evaluated the characteristics of the salivary and duodenal microbiomes of patients with nonampullary duodenal epithelial tumors. METHODS: Saliva and biopsy samples from the duodenal bulb and descending portion were obtained from 15 patients with nonampullary duodenal epithelial tumors and 10 controls. Next-generation sequencing was performed to identify bacteria for comparison. RESULTS: Saliva samples had higher Amplicon Sequence Variants (ASVs) and more observed species than duodenal samples. Saliva samples from patients with nonampullary duodenal epithelial tumor were dominated by Bacteroidetes and Prevotella, whereas Proteobacteria and Neisseria were dominant in the control samples. The relative abundance of bacteria was higher in patients with nonampullary duodenal epithelial tumors. Most bacteria were classified as bacteria of oral origin. Oribacterium and Stomatobaculum were significantly higher in the saliva, duodenal bulb, and descending portion of patients with nonampullary duodenal epithelial tumors. CONCLUSION: Patients with nonampullary duodenal epithelial tumors had different salivary and duodenal microbiomes than controls. Bacteria types differed between groups at each site, and most bacteria of oral origin were more abundant in patients with nonampullary duodenal epithelial tumors.

Validating computer applications for calculating spatial resolution and noise property in CT using simulated images with known properties.

The purpose of this study was to evaluate, using simulated images with known property values, how accurately some computer applications for calculating modulation transfer function (MTF), task transfer function (TTF), or noise power spectrum (NPS) in computed tomography (CT) based on widely known techniques produce their results. Specifically, they were three applications applicable to the wire method for MTF calculation, two applications corresponding to the circular edge (CE) and linear edge (LE) methods for TTF, and one application using a two-dimensional Fourier transform for NPS, which are collectively integrated with the software 'CTmeasure' provided by the Japanese Society of CT Technology. Images for the calculation with radial symmetry were generated based on a roll-off type filter function. The accuracy of each application was evaluated by comparing the calculated property with the true one. The calculated MTFs for the wire method accurately matched the true ones with percentage errors of smaller than 1.0%. In contrast, the CE and LE methods presented relatively large errors of up to 50% at high frequencies, whereas the NPS's errors were up to 30%. A closer investigation revealed, however, that these errors were attributable not to the applications but to the insufficiencies in the measurement techniques commonly employed. By improving the measurement conditions to minimize the effects of the insufficiencies, the errors notably decreased, whichvalidated the calculation techniques in the applications we used.

An atypical case of isolated immunoglobulin G4-related sclerosing cholangitis with a cholangiogram resembling primary sclerosing cholangitis.

An asymptomatic 77-year-old man with intrahepatic bile duct dilation was referred to our hospital. Cholangiography revealed alternations between strictures and dilated segments from the right and left hepatic ducts to the lower bile ducts, with findings of a pruned tree, beaded, shaggy appearance, and diverticulum-like outpouching. Histopathology revealed abundant immunoglobulin G4 (IgG4)-positive plasma cells (> 10 per high-power field) with an IgG4/IgG-positive cell ratio of 40-50%. After 2 weeks of steroid therapy, the cholangiography markedly improved. Because the cholangiographic findings resembled those of primary sclerosing cholangitis, steroid therapy proved useful in differentiating IgG4-related sclerosing cholangitis from primary sclerosing cholangitis.