[Importance of Measuring the Urine Protein/Creatinine Ratio in Patients with Advanced Hepatocellular Carcinoma Receiving Atezolizumab plus Bevacizumab Treatment].

INTRODUCTION: When we administer atezolizumab plus bevacizumab treatment to patients with advanced hepatocellular carcinoma, we often encounter inconsistent results between the qualitative dipstick urinalysis and the urine protein/creatinine ratio(UPCR)measurements. In this study, we investigated the relationship between qualitative dipstick urinalysis and UPCR in these patients, and assessed whether incorporating UPCR into the testing protocol could prevent unnecessary interruptions during bevacizumab treatment. SUBJECTS AND METHODS: This study analyzed 298 urine samples collected from 61 patients of advanced hepatocellular carcinoma, who were treated with atezolizumab plus bevacizumab at our institution between October 1, 2020, and August 31, 2021. We used UPCR as an alternative test to the 24-hour urine protein and set the discontinuation criteria for bevacizumab at a UPCR of 2.0 or higher. RESULTS: Among the 41 samples that tested positive for 2+ on the dipstick test, only one(2.4%)had a UPCR exceeding 2.0. Additionally, among the 44 samples that showed a 3+ result, 24 samples(54.5%)had a UPCR higher than 2.0. If our decision to discontinue bevacizumab had been based on a dipstick urinalysis result of 2+, we could have continued administering bevacizumab in 97.6%(40/41)of the cases. Even if the decision had been based on a dipstick urinalysis result of 3+, we could have continued administering bevacizumab in almost half of the cases(45.5%, 20/44). CONCLUSIONS: Our findings suggest that the addition of UPCR to the qualitative dipstick urinalysis during atezolizumab plus bevacizumab treatment for patients with advanced hepatocellular carcinoma could help prevent unnecessary interruptions of bevacizumab and offer more clinical benefits in real-world practice, compared to using qualitative dipstick urinalysis alone.

Three Molecular Developmental Pathways of Remnant Pancreatic Cancer after Resection: A Nationwide Project Study of Japan Pancreas Society.

OBJECTIVE: This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection. SUMMARY BACKGROUND DATA: Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown. METHODS: Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated. RESULTS: These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways. CONCLUSION: Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs.

Levels of 5α-reductase gene in intestinal lavage fluid decrease with progression of colorectal cancer.

Introduction. Colorectal cancer (CRC) is a leading cause of cancer deaths, closely linked to the intestinal microbiota and bile acid metabolism. Secondary bile acids, like deoxycholic and lithocholic acid, are associated with increased CRC risk due to their disruption of vital cellular functions. In contrast, isoallolithocholic acid (isoalloLCA) shows potential health benefits, highlighting the complex role of bile acids in CRC. A specific primer set was previously developed to amplify homologs of the 5α-reductase gene (5ar), which are involved in the biosynthesis of isoalloLCA, thereby enabling the estimation of abundance of 5ar (5ar levels) in the intestine.Hypothesis/Gap Statement. We hypothesized that 5ar levels in the intestine are associated with CRC.Aim. This study aimed to investigate intestinal 5ar levels and compare them across different stages of the adenoma-carcinoma sequence, providing insights into novel strategies for monitoring CRC risk.Methodology. DNA was extracted from intestinal lavage fluids (ILF) collected during 144 colonoscopies. Next-generation sequencing (NGS) was employed to examine the sequence of 5ar homologues, using a specific primer set on DNA from seven selected ILFs - four from carcinoma patients and three from individuals with non-neoplastic mucosa. Additionally, we used quantitative PCR (qPCR) to measure 5ar levels in all 144 DNA samples.Results. We conducted 144 colonoscopies and categorized patients according to the adenoma-cancer sequence: 52 with non-neoplastic mucosa, 69 with adenomas and 23 with carcinoma. Analysis of 292,042 NGS-derived 5ar sequences revealed the seven most prevalent amplicon sequence variants, each 254 base pairs in length. These closely matched or were identical to 5ar sequences in Bacteroides uniformis, Phocaeicola vulgatus and Phocaeicola dorei. Furthermore, qPCR analysis demonstrated significantly lower 5ar levels in the carcinoma group compared to those in the non-neoplastic mucosa group (P = 0.0004). A similar, though not statistically significant, trend was observed in the adenoma group (P = 0.0763), suggesting that 5ar levels decrease as CRC progresses.Conclusion. These findings indicate that PCR-based monitoring of 5ar levels in intestinal samples over time could provide a non-invasive, rapid and cost-effective method for assessing an increased risk of CRC.

Contributions of endoscopic ultrasonography-guided tissue acquisition (EUS-TA) to the diagnostics of biliary stricture and gallbladder lesions.

Endoscopic ultrasonography (EUS) provides high spatial resolution and more detailed images than other diagnostic modalities. Furthermore, EUS-guided tissue acquisition (EUS-TA), such as EUS-guided fine needle aspiration or biopsy (EUS-FNA/FNB), is an indispensable tool in pancreaticobiliary disease diagnostics, supporting a conclusive pathological diagnosis. In this review, we evaluate the current status and the usefulness of EUS-TA for the diagnostics of the following biliary tract diseases: (A) biliary stricture diagnostics, (B) biliary tract cancer (BTC) itself, and (C) staging of advanced BTC. Previous reports have shown that EUS-FNA for biliary lesions is a safe procedure that is useful in differentiating biliary cancer from benign lesions and in the staging of BTC. On the other hand, the diagnostic performance of EUS-TA for bile duct lesions is reported to be similar to that of transpapillary biopsy. Overall, EUS-TA for biliary lesions may be a safe and effective method, but it should be performed with an understanding of the risk of serious adverse events such as bile leakage and peritoneal dissemination of cancer. It is recommended for distal biliary stricture lesions for which endoscopic retrograde cholangiopancreatography cannot confirm the diagnosis or gallbladder lesions if they do not require the needle to pass through the biliary lumen.

Protocol for a Multi-Center Confirmatory Trial to Evaluate the Differential Diagnostic Performance of Contrast-Enhanced Ultrasonography Using Perflubutane in Patients with a Pancreatic Mass: A Multicenter Prospective Study.

For pancreatic masses, an evaluation of their vascularity using contrast-enhanced ultrasonography can help improve their characterization. This study was designed to evaluate the utility and safety of contrast-enhanced transabdominal ultrasonography (CE-TUS) and endoscopic ultrasonography (CE-EUS) in the diagnosis of pancreatic masses including solid or cystic masses. This multi-center comparative open-label superiority study is designed to compare Plain (P)-TUS/EUS alone with P-TUS/P-EUS plus CE-TUS/CE-EUS. Three hundred and one patients with a total of 232 solid pancreatic masses and 69 cystic masses were prospectively enrolled. The primary endpoints are to compare the diagnostic accuracy between P-TUS/P-EUS alone and P-TUS/P-EUS plus CE-TUS/CE-EUS for both the TUS and EUS of solid pancreatic masses, and to compare the diagnostic accuracy between P-EUS alone and P-EUS plus CE-EUS in cystic pancreatic masses. The secondary endpoints are to compare the diagnostic sensitivity and specificity of P-TUS/P-EUS alone and P-TUS/P-EUS plus CE-TUS/CE-EUS for pancreatic solid/cystic masses, and the accuracy of P-TUS alone and P-TUS plus CE-TUS for pancreatic cystic masses. Other secondary endpoints included comparing the diagnostic sensitivity, specificity, and accuracy of CE-TUS, CE-EUS and CE-computed tomography (CT) for solid/cystic pancreatic masses. The safety, degree of effective enhancement, and diagnostic confidence obtained with CE-TUS/CE-EUS will also be assessed.

Co-administration of the prebiotic 1-kestose and the paraprobiotic Lactiplantibacillus plantarum FM8 in magellanic penguins promotes the activity of intestinal Lactobacillaceae and reduces the plc gene levels encoding Clostridium perfringens toxin.

Despite the well-known potential health benefits of prebiotics and non-viable probiotics (paraprobiotics) in various animal species, research regarding their use in penguins is scarce. Our study aimed to investigate the impact of a combined administration of prebiotics and paraprobiotics (referred to here as "parasynbiotics") on the gut microbiome and overall health of Magellanic penguins (Spheniscus magellanicus). The parasynbiotics consisted of 1-kestose, which is a fructooligosaccharide comprising sucrose and fructose, and heat-killed Lactiplantibacillus plantarum FM8, isolated from pickled vegetables. It was administered to eight penguins aged <3 years (Young-group) and nine penguins aged >17 years (Adult-group) for 8 weeks. Results from 16S rRNA sequencing revealed that compared to baseline, parasynbiotic administration significantly decreased the relative abundance of intestinal Clostridiaceae_222000 in both groups and significantly increased that of Lactobacillaceae in the Young-group. Quantitative real-time polymerase chain reaction revealed a significant decrease in the plc gene levels encoding alpha-toxin of Clostridium perfringens in the Young-group after parasynbiotic administration (P=0.0078). In the Young-group, parasynbiotic administration significantly increased the plasma levels of total alpha-globulin (P=0.0234), which is associated with inflammatory responses. Furthermore, exposure of dendritic cells to heat-killed L. plantarum FM8 promoted the secretion of interleukin 10, a major anti-inflammatory cytokine. Overall, parasynbiotic administration enhanced the activity of gut Lactobacillaceae, decreased the levels of C. perfringens and its toxin encoding plc gene, and reduced inflammatory response in penguins. These results provide novel insights into the potential benefits of parasynbiotics for improving penguin health.

Effects of 1-kestose on microbiome changes caused by vonoprazan: a randomized, double-blind, placebo-controlled pilot study.

BACKGROUND AND AIM: Potassium-competitive acid blockers more strongly suppress the gastric acid barrier than proton pump inhibitors and cause dysbiosis. However, preventive measures in this regard have not been established. We aimed to evaluate whether 1-kestose, a known prebiotic, was effective at alleviating dysbiosis caused by potassium-competitive acid blockers. METHODS: Patients scheduled to undergo endoscopic resection for superficial gastroduodenal tumors were enrolled and randomized 1:1 to receive either 1-kestose or placebo. All patients were started on potassium-competitive acid blocker (vonoprazan 20 mg/day) and took 1-kestose 10 g/day or placebo (maltose) 5 g/day for 8 weeks. The primary outcome was the effect of 1-kestose on potassium-competitive acid blocker-induced alterations in the microbiome. The fecal microbiome was analyzed before and after potassium-competitive acid blocker treatment via MiSeq (16S rRNA gene V3-V4 region). RESULTS: Forty patients were enrolled, and 16 in each group were analyzed. In the placebo group, the Simpson index, an alpha diversity, was significantly decreased and relative abundance of Streptococcus was significantly increased by 1.9-fold. In the kestose group, the Simpson index did not change significantly and relative abundance of Streptococcus increased 1.3-fold, but this was not a significant change. In both groups, no adverse events occurred, ulcers were well healed, and pretreatment and posttreatment short-chain fatty acid levels did not differ. CONCLUSIONS: The potassium-competitive acid blocker caused dysbiosis in the placebo group; this effect was prevented by 1-kestose. Thus, 1-kestose may be useful in dysbiosis treatment.

A stag beetle knife can achieve stabler and safer endoscopic submucosal dissection in the esophagus.

Background and study aims Esophageal endoscopic submucosal dissection (ESD) has a higher complication rate than gastric ESD. Scissor-type devices, including the stag beetle (SB) knife, are reportedly safer and have shorter procedure times than tip devices. To clarify the characteristics of the SB knife, we compared the treatment outcomes of esophageal ESD with a tip-type knife to those with an SB knife combination. Patients and methods Between January 2016 and March 2023, clinical data from 197 lesions in 178 patients who underwent esophageal ESD were analyzed retrospectively. Every lesion was assigned to either the tip-type group or the SB group based on the devices with which the submucosa was initially dissected. We compared procedure time and complications and analyzed the risk of muscular exposure using multivariate analysis. Results Procedure time was not significantly different between the tip-type and SB groups (60.3±42.2 min vs. 58.8±29.1 min). The variation in procedure time was significant according to F test P =0.002). Incidence of muscular exposure was significantly lower in the SB group than in the tip-type group (24.5% vs. 11.1%, P =0.016). These differences were significant in resected specimens larger than 21 mm. Procedure time over 60 minutes (odds ratio [OR] 2.5, 95% confidence interval [CI]: 1.15-5.42, P =0.02) was a risk factor for muscular exposure, and submucosal dissection with an SB knife was a safety factor (OR 0.4, 95% CI: 0.18-0.89, P =0.02). Conclusions Performing esophageal ESD with an SB knife is a safe procedure with less variation in procedure time and less muscule exposure.

The role of contrast-enhanced endoscopic ultrasound for biliary diseases.

Contrast-enhanced endoscopic ultrasound (CE-EUS) has emerged as a promising diagnostic modality for assessing biliary diseases. CE-EUS is a noninvasive imaging technique that utilizes contrast agents to enhance the visualization of blood vessels and perfusion within target tissues. In the context of biliary diseases, CE-EUS allows for improved characterization of biliary lesions, aiding in differential diagnosis and treatment planning. This review highlights several key findings regarding the usefulness of CE-EUS in biliary disease assessment and therapeutic procedures.

Use of contrast-enhanced harmonic endoscopic ultrasonography for the diagnosis of pancreatic cystic lesions.

Endoscopic ultrasonography (EUS) provides high spatial and contrast resolution and is a useful tool for evaluating the pancreato-biliary regions. Recently, contrast-enhanced harmonic EUS (CH-EUS) has been used to evaluate lesion vascularity, especially for the diagnosis of pancreatic tumors. CH-EUS adds two major advantages when diagnosing pancreatic cystic lesions (PCL). First, it can differentiate between mural nodules and mucous clots, thereby improving the accurate classification of PCL. Second, it helps with evaluation of the malignant potential of PCL, especially of intraductal papillary mucinous neoplasms by revealing the vascularity in the mural nodules and solid components. This review discusses the use and limitations of CH-EUS for the diagnosis of PCL.

Combined oral intake of short and long fructans alters the gut microbiota in food allergy model mice and contributes to food allergy prevention.

BACKGROUND: It has become clear that the intestinal microbiota plays a role in food allergies. The objective of this study was to assess the food allergy-preventive effects of combined intake of a short fructan (1-kestose [Kes]) and a long fructan (inulin ([Inu]) in an ovalbumin (OVA)-induced food allergy mouse model. RESULTS: Oral administration of fructans lowered the allergenic symptom score and alleviated the decreases in rectal temperature and total IgA levels and increases in OVA-specific IgE and IgA levels induced by high-dose OVA challenge, and in particular, combined intake of Kes and Inu significantly suppressed the changes in all these parameters. The expression of the pro-inflammatory cytokine IL-4, which was increased in the allergy model group, was significantly suppressed by fructan administration, and the expression of the anti-inflammatory cytokine IL-10 was significantly increased upon Kes administration. 16 S rRNA amplicon sequencing of the gut microbiota and beta diversity analysis revealed that fructan administration may induce gut microbiota resistance to food allergy sensitization, rather than returning the gut microbiota to a non-sensitized state. The relative abundances of the genera Parabacteroides B 862,066 and Alloprevotella, which were significantly reduced by food allergy sensitization, were restored by fructan administration. In Parabacteroides, the relative abundances of Parabacteroides distasonis, Parabacteroides goldsteinii, and their fructan-degrading glycoside hydrolase family 32 gene copy numbers were increased upon Kes or Inu administration. The concentrations of short-chain fatty acids (acetate and propionate) and lactate were increased by fructan administration, especially significantly in the Kes + Inu, Kes, and Inu-fed (Inu, Kes + Inu) groups. CONCLUSION: Combined intake of Kes and Inu suppressed allergy scores more effectively than single intake, suggesting that Kes and Inu have different allergy-preventive mechanisms. This indicates that the combined intake of these short and long fructans may have an allergy-preventive benefit.

Incidence and clinical relevance of postoperative diarrhea after minimally invasive gastrectomy for gastric cancer: a single institution retrospective study of 1476 patients.

PURPOSE: Postoperative diarrhea (PD) remains one of the significant complications. Only a few studies focused on PD after minimally invasive surgery. We aimed to investigate PD after minimally invasive gastrectomy for gastric cancer. METHODS: A total of 1476 consecutive patients with gastric cancer undergoing laparoscopic or robotic gastrectomy between 2009 and 2019 at our institution were retrospectively reviewed. PD was defined as continuous diarrhea for ≥ 2 days, positive stool culture, or positive clostridial antigen test. The incidence, causes, and related clinical factors were analyzed. RESULTS: Of the 1476 patients, the median age was 69 years. Laparoscopic and robotic approaches were performed in 1072 (72.6%) and 404 (27.4%), respectively. Postoperative complications with Clavien-Dindo classification grade of ≥ IIIa occurred in 108 (7.4%) patients. PD occurred in 89 (6.0%) patients. Of the 89 patients with PD, Clostridium difficile, enteropathogenic Escherichia coli, and methicillin-resistant Staphylococcus aureus were detected in 24 (27.0%), 16 (33.3%), and 7 (14.6%) patients, respectively. Multivariate analysis revealed that age ≥ 75 years (OR 1.62, 95% CI [1.02-2.60], p = 0.042) and postoperative complications (OR 6.04, 95% CI [3.54-10.32], p < 0.001) were independent risk factors for PD. In patients without complications, TG (OR 1.88) and age of ≥ 75 years(OR 1.71) were determined as independent risk factors. CONCLUSION: The incidence of PD following minimally invasive gastrectomy for gastric cancer was 6.0%. Older age and TG were obvious risk factors in such a surgery, with the latter being a significant risk even in the absence of complications.

Clinical Outcomes With Lenvatinib in Patients Previously Treated With Atezolizumab/Bevacizumab for Advanced Hepatocellular Carcinoma.

BACKGROUND/AIM: The combination of atezolizumab plus bevacizumab (Atz/Bev) has become widely used as a first-line therapy for advanced hepatocellular carcinoma (HCC). However, for post-Atz/Bev therapy, evidence on the outcomes of molecular targeted agents, such as lenvatinib, is limited. The present study aimed to assess the clinical effectiveness of lenvatinib on advanced HCC in patients who had previously undergone Atz/Bev treatment. PATIENTS AND METHODS: Twenty patients with HCC, who received lenvatinib after Atz/Bev treatment, were enrolled in the study. In particular, we examined the impact of adverse events (AEs), such as anorexia and general fatigue. During the treatment, lenvatinib dosages were adjusted or temporarily discontinued in response to AEs. Treatment outcomes were retrospectively evaluated. RESULTS: The objective response rate (ORR) and disease control rate (DCR) for lenvatinib treatment were 25.0% and 95.0%, respectively, according to the Response Evaluation Criteria in Solid Tumors. The median progression-free survival (PFS) was 6.0 months, and the median overall survival (OS) was 10.5 months. Eleven patients experienced anorexia or fatigue, leading to a reduction in the dose of lenvatinib but not to a significant difference in the time to drug discontinuation. Importantly, there were no significant differences between the 11 anorexia/fatigue-suffering patients and the nine other patients with regard to PFS and OS. CONCLUSION: Lenvatinib can be efficacious and safe for treating advanced HCC patients previously treated with Atz/Bev, and AEs such as anorexia and general fatigue can be effectively managed without losing lenvatinib's therapeutic benefits.

Contrast-enhanced endoscopic ultrasound for swollen lymph nodes.

Endoscopic ultrasound (EUS) is an important tool for the evaluation of lymphadenopathy, especially in intra-thoracic or intra-abdominal regions. EUS also provides tissue diagnosis via EUS fine-needle aspiration or biopsy. To select the target for biopsy or aspiration, conventional B-mode images are used for the evaluation, but this approach still lacks diagnostic accuracy. Contrast-enhanced EUS has been used to evaluate the vascularity of lesions. Most malignant lymphadenopathy shows heterogenous enhancement or defect of enhancement, while quantitative studies using time-intensity curves in contrast-enhanced harmonic EUS show a rapid decline in enhancement pattern. These findings are useful as an auxiliary method for tissue diagnosis or in cases in which tissue diagnosis is contraindicated.