Intestinal commensal microbiota and cytokines regulate Fut2+ Paneth cells for gut defense.

Paneth cells are intestinal epithelial cells that release antimicrobial peptides, such as α-defensin as part of host defense. Together with mesenchymal cells, Paneth cells provide niche factors for epithelial stem cell homeostasis. Here, we report two subtypes of murine Paneth cells, differentiated by their production and utilization of fucosyltransferase 2 (Fut2), which regulates α(1,2)fucosylation to create cohabitation niches for commensal bacteria and prevent invasion of the intestine by pathogenic bacteria. The majority of Fut2- Paneth cells were localized in the duodenum, whereas the majority of Fut2+ Paneth cells were in the ileum. Fut2+ Paneth cells showed higher granularity and structural complexity than did Fut2- Paneth cells, suggesting that Fut2+ Paneth cells are involved in host defense. Signaling by the commensal bacteria, together with interleukin 22 (IL-22), induced the development of Fut2+ Paneth cells. IL-22 was found to affect the α-defensin secretion system via modulation of Fut2 expression, and IL-17a was found to increase the production of α-defensin in the intestinal tract. Thus, these intestinal cytokines regulate the development and function of Fut2+ Paneth cells as part of gut defense.

Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer. METHODS: This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688). FINDINGS: Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0-73·3%) in the observation group compared with 77·1% (70·9-82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51-0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1-57·2%) in the observation group compared with 62·4% (55·6-68·4%) in the S-1 group (HR 0·80, 95% CI 0·61-1·04; two-sided p=0·088). The main grade 3-4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]). INTERPRETATION: Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. FUNDING: The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma.

BACKGROUND AND AIMS: Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC. APPROACHES AND RESULTS: We performed RNA-seq of tumor tissues in 113 patients with nonviral HCC and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into three molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with cadherin-associated protein beta 1 (CTNNB1) mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-ß signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Patients with steatotic HCC, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti-PD-L1 and anti-VEGF antibodies. CONCLUSIONS: Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.

Laparoscopic Portal Vein Ligation and Embolization During First-Stage Hepatectomy for Initially Unresectable Colorectal Liver Metastases.

BACKGROUND: Two-stage hepatectomy (TSH) is the only treatment for the patients with multiple bilobar colorectal liver metastases (CRMs) who are not candidates for one-step hepatectomy because of insufficient future remnant liver volume and/or impaired liver function.1-5 Although laparoscopic approaches have been introduced for TSH,6-8 the postoperative morbidity and mortality remains high because of the technical difficulties during second-stage hepatectomy.9,10 The authors present a video of laparoscopic TSH with portal vein (PV) ligation and embolization, which minimizes adhesions and PV thrombosis risk in the remnant liver, thereby facilitating second-stage hepatectomy. METHODS: Three patients with initially unresectable bilateral CRMs received a median of chemotherapy 12 cycles, followed by conversion TSH. After right PV ligation, laproscopic PV embolization was performed by injection of 100% ethanol into the hepatic side of the right PV using a 23-gauge winged needle. After PV embolization, a spray adhesion barrier (AdSpray, Terumo, Tokyo, Japan)11 was applied. RESULTS: During the first stage of hepatectomy, two patients underwent simultaneous laparoscopic colorectal resection (left hemicolectomy and high anterior resection). In the initial hepatectomy, two patients underwent two limited hepatectomies each, and one patient underwent six hepatectomies in the left lobe. After hepatectomy, all the patients underwent right PV embolization. During the second stage, two patients underwent open extended right hepatectomy (right adrenalectomy was performed because of adrenal invasion in one patient), and one patient underwent laparoscopic extended right hepatectomy. No postoperative complications occurred in the six surgeries. CONCLUSIONS: Laparoscopic TSH with PV embolization is recommended for safe completion of the second hepatectomy.

Unique Biology of Pancreatic Ductal Adenocarcinoma Accompanied by Rapidly Impaired Diabetes: A Favorable Long-Term Survival Following Curative Resection.

BACKGROUND: Pancreatic ductal adenocarcinomas (PDACs) are sometimes diagnosed accompanied by rapidly impaired diabetes (PDAC-RID). Although this type of PDAC may have unusual biological features, these features have not been explained. METHODS: Patients with PDAC who underwent upfront pancreatectomy between 2010 and 2018 were retrospectively reviewed. PDAC-RID was defined as a glycated hemoglobin (HbA1c) value of ≥ 8.0% of newly diagnosed diabetes, and acute exacerbation of previously diagnosed diabetes. Other patients were classified as PDAC with stable glycometabolism (PDAC-SG). Clinicopathological factors, long-term survival rates, and recurrence patterns were evaluated. RESULTS: Of the 520 enrolled patients, 104 were classified as PDAC-RID and 416 as PDAC-SG. There was no significant difference regarding TNM staging, resectability, or adjuvant chemotherapy rate between the groups. However, 5-years cancer-specific survival (CSS) was significantly higher in the PDAC-RID group than in the PDAC-SG group (45.3% vs. 31.1%; p = 0.02). This survival difference was highlighted in relatively early-stage PDAC (≤ pT2N1) (CSS: 60.8% vs. 43.6%; p = 0.01), but the difference was not significant for advanced-stage PDAC. A multivariate analysis of early-stage PDAC showed that PDAC-SG was an independent risk factor of shorter CSS (hazard ratio 1.76; p = 0.02). The hematogenous metastatic rate in early-stage PDAC was lower in the PDAC-RID group than in the PDAC-SG group (18.3% vs. 35.8%; p = 0.01). CONCLUSIONS: PDAC-RID showed a favorable long-term survival rate after curative resection with low hematogenous metastases, which may be due to its unique biology.

Technical Strategy for Pancreatic Body Cancers: A Raison d'etre of Distal Pancreatectomy with Portal Resection.

BACKGROUND: Advancements in multiagent chemotherapy have expanded the surgical indications for pancreatic cancer. Although pancreaticoduodenectomy (PD) with portal vein resection (PVR) has become widely adopted, distal pancreatectomy (DP) with PVR remains rarely performed because of its technical complexity. This study was designed to assess the feasibility of DP-PVR compared with PD-PVR for pancreatic body cancers, with a focus on PV complications and providing optimal reconstruction techniques when DP-PVR is necessary. METHODS: A retrospective review was conducted on consecutive pancreatic body cancer patients who underwent pancreatectomy with PVR between 2005 and 2020. An algorithm based on the anatomical relationship between the arteries and PV was used for optimal surgical selection. RESULTS: Among 119 patients, 32 underwent DP-PVR and 87 underwent PD-PVR. Various reconstruction techniques were employed in DP-PVR cases, including patch reconstruction, graft interposition, and wedge resection. The majority of PD-PVR cases involved end-to-end anastomosis. The length of PVR was shorter in DP-PVR (25 vs. 40 mm; p < 0.001). Although Clavien-Dindo ≥3a was higher in DP-PVR (p = 0.002), inpatient mortality and R0 status were similar. Complete PV occlusion occurred more frequently in DP-PVR than in PD-PVR (21.9% vs. 1.1%; p < 0.001). A cutoff value of 30 mm for PVR length was determined to be predictive of nonrecurrence-related PV occlusion after DP-PVR. The two groups did not differ significantly in recurrence or overall survival. CONCLUSIONS: DP-PVR had higher occlusion and postoperative complication rates than PD-PVR. These findings support the proposed algorithm and emphasize the importance of meticulous surgical manipulation when DP-PVR is deemed necessary.

Fusobacterium Detected in Barrett's Esophagus and Esophageal Adenocarcinoma Tissues.

We examined Fusobacterium nucreatum (F. nucleatum) and whole Fusobacterium species (Pan-fusobacterium) in non-neoplastic Barrett's esophagus (BE) from patients without cancer (n = 67; N group), with esophageal adenocarcinoma (EAC) (n = 27) and EAC tissue (n = 22). F. nucleatum was only detectable in 22.7% of EAC tissue. Pan-fusobacterium was enriched in EAC tissue and associated with aggressive clinicopathological features. Amount of Pan-fusobacterium in non-neoplastic BE was correlated with presence of hital hernia and telomere shortening. The result suggested potential association of Fusobacterium species in EAC and BE, featuring clinicpathological and molecular features.

Potential involvement of oncostatin M in the immunosuppressive tumor immune microenvironment in hepatocellular carcinoma with vessels encapsulating tumor clusters.

AIM: Vessels encapsulating tumor clusters (VETC) represents an adverse prognostic morphological feature of hepatocellular carcinoma (HCC), which is associated with an immunosuppressive tumor immune microenvironment (TIM). However, the underlying factors characterizing the TIM in HCC with a VETC pattern (VETC-positive HCC) remain uncertain. Oncostatin M (OSM), a pleiotropic cytokine of the interleukin-6 family, regulates various biological processes, including inflammation, proliferation, and invasiveness of tumor cells. We aimed to test a hypothesis that OSM is associated with the immunosuppressive TIM of VETC-positive HCC. METHODS: A total of 397 consecutive HCC patients with curative-intent hepatectomy were included. OSM-positive cells and inflammatory cells including CD4-, CD8-, CD163-, and FOXP3-positive cells were immunohistochemically evaluated. We compared VETC-positive and VETC-negative HCCs in terms of the number of these cells. RESULTS: We found the VETC pattern in 62 patients (15.6%). Our analysis revealed a significant decrease in the expression of arginase-1, a marker associated with mature hepatocyte differentiation, in VETC-positive HCC (p = 0.046). The number of tumor-infiltrating OSM-positive cells was significantly low in VETC-positive HCC (p = 0.0057). Notably, in VETC-positive HCC, the number of OSM-positive cells was not associated with vascular invasion, whereas in VETC-negative HCC, an increase in the number of OSM-positive cells was associated with vascular invasion (p = 0.042). CONCLUSIONS: We identified an association between a decrease in OSM-positive cells and the VETC pattern. Additionally, our findings indicate that VETC-positive HCC is characterized by low hepatocyte differentiation and OSM-independent vascular invasion. These findings highlight the potential interaction between VETC-positive HCC cells and their TIM through the reduction of OSM-expressing cells.

Feasibility of Colorectal Endoscopic Submucosal Dissection in Elderly Patients: The Impact of Sarcopenia.

INTRODUCTION: Colorectal cancer is a public health concern associated with high incidence rates. Sarcopenia is a known risk factor for postoperative complications, although an association between increased complications after colorectal endoscopic submucosal dissection (ESD) and sarcopenia remains undocumented. Herein, we aimed to explore the feasibility of colorectal ESD in patients with sarcopenia. METHODS: This retrospective study included 499 patients (69 with and 430 without sarcopenia). We evaluated the short- and long-term outcomes of colorectal ESD. RESULTS: There were no significant differences between the two groups regarding en bloc, R0, or curative resection rates. However, poor bowel preparation was significantly more common in the sarcopenia group. Moreover, patients with sarcopenia exhibited a significant increase in complications (37.7% vs. 10.5%). Multivariate analysis revealed that sarcopenia (odds ratio [OR]: 3.78, 95% confidence interval [Cl]: 1.85-7.73, p < 0.001), anticoagulation therapy (OR: 3.59, 95% Cl: 1.86-6.92, p < 0.001), procedure time (OR: 1.28, 95% Cl: 1.11-1.47, p < 0.001), and resection size (OR: 1.25, 95% Cl: 1.03-1.52, p = 0.02) were significantly correlated with the Common Terminology Criteria for Adverse Events (CTCAE) ≥ grade 2. The correlation between sarcopenia and CTCAE ≥ grade 2 was maintained after matching, resulting in more extended hospital stays in patients with sarcopenia. However, we detected no association between sarcopenia and overall survival and ESD-related death. CONCLUSION: Sarcopenia is a risk factor for complications in colorectal ESD, suggesting that colorectal ESD could be performed for patients with sarcopenia, although much caution should be taken.

Scope transition and early arterial inflow control provide safe and comfortable dissection in robotic distal pancreatectomy.

PURPOSE: We describe details and outcomes of a novel technique for optimizing the surgical field during robotic distal pancreatectomy (RDP) for distal pancreatic lesions, which has become common with potential advantages over laparoscopic surgery. METHODS: For suprapancreatic lymph node dissection and splenic artery ligation, we used the basic center position with a scope through the midline port. During manipulation of the perisplenic area, the left position was used by moving the scope to the left medial side. The left lateral position is optionally used by moving the scope to the left lateral port when scope access to the perisplenic area is difficult. In addition, early splenic artery clipping and short gastric artery dissection for inflow block were performed to minimize bleeding around the spleen. We evaluated retrospectively the surgical outcomes of our method using a scoring system that allocated one point for blood inflow control and one point for optimizing the surgical view in the left position. RESULTS: We analyzed 34 patients who underwent RDP or R-radical antegrade modular pancreatosplenectomy (RAMPS). The left position was applied in 14 patients, and the left lateral position was applied in 6. Based on the scoring system, only the 0-point group (n = 8) had four bleeding cases (50%) with splenic injury or blood pooling; the other 1-point or 2-point groups (n = 13, respectively) had no bleeding cases (p = 0.0046). CONCLUSION: Optimization of the surgical field using scope transition and inflow control ensured safe dissection during RDP.

Management of potential portal vein thrombus during laparoscopic right hemihepatectomy following portal vein embolization.

BACKGROUND: Portal vein embolization (PVE) is often performed prior to right hemihepatectomy (RH) to increase the future liver remnants. However, intraoperative removal of portal vein thrombus (PVT) is occasionally required. An algorithm for treating the right branch of the PV using laparoscopic RH (LRH) after PVE is lacking and requires further investigation. METHODS: In our department, after the confirmation of a lack of extension of PVT to the main portal trunk or left branch on preoperative examination (ultrasound and contrast-enhanced computed tomography), a final evaluation was performed using intraoperative ultrasonography (IOUS). Here we present the cases of eight patients who underwent LRH after PVE and examine the safety of our treatment strategies. RESULTS: IOUS revealed PVT extension into the main portal trunk in two cases. For the other six patients without PVT extension, we continued the laparoscopic procedure. In contrast, in the two cases with PVT extension, we converted to laparotomy after hepatic transection and removed the PVT. The median operation time for hepatectomy was 562 min (421-659 min), the median blood loss was 293 mL (85-1010 mL), no liver-related postoperative complications were observed, and the median length of stay was 10 days (6-34 days). CONCLUSIONS: PVT evaluation and removal are important in cases of LRH after PVE. Our strategy is safe and IOUS is particularly useful for laparoscopically evaluating PVT extension.

Hepatitis C virus modulates signal peptide peptidase to alter host protein processing.

Immunoevasins are viral proteins that prevent antigen presentation on major histocompatibility complex (MHC) class I, thus evading host immune recognition. Hepatitis C virus (HCV) evades immune surveillance to induce chronic infection; however, how HCV-infected hepatocytes affect immune cells and evade immune recognition remains unclear. Herein, we demonstrate that HCV core protein functions as an immunoevasin. Its expression interfered with the maturation of MHC class I molecules catalyzed by the signal peptide peptidase (SPP) and induced their degradation via HMG-CoA reductase degradation 1 homolog, thereby impairing antigen presentation to CD8+ T cells. The expression of MHC class I in the livers of HCV core transgenic mice and chronic hepatitis C patients was impaired but was restored in patients achieving sustained virological response. Finally, we show that the human cytomegalovirus US2 protein, possessing a transmembrane region structurally similar to the HCV core protein, targets SPP to impair MHC class I molecule expression. Thus, SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses.

Does Preoperative Manual Reduction (Omoto Technique) Affect Surgical Outcomes for Calcaneal Fractures? A Multicenter (TRON Group) Retrospective Study.

The Omoto technique is a well-known method that is commonly used for noninvasive manual repair of calcaneal fractures. However, there have been no detailed studies on its clinical outcomes in preoperative closed reduction for surgical cases. This multicenter retrospective study aimed to compare the clinical and radiographic outcomes of calcaneal fractures treated with and without the preoperative Omoto technique, assessing its effectiveness. We extracted 335 patients with calcaneal fracture who underwent surgery between 2015 and 2020 from our multicenter database, named TRON. We evaluated the clinical outcomes using the American Orthopedic Foot and Ankle Society (AOFAS) score, the Böhler angle (BA) for radiographic analysis, and noted any complications. We divided the patients into those managed with the Omoto technique (group O) and those managed without the Omoto technique (group N). Patients were matched by age, sex, and fracture type, resulting in 43 patients per group. The use of the Omoto technique at the time of injury significantly improved the Böhler angle (BA). Furthermore, there were no significant differences in AOFAS, postoperative complications, or BA values at the final follow-up. In conclusion, our study demonstrates that the Omoto technique, when used preoperatively for calcaneal fractures, does not negatively impact the outcomes of subsequent surgical treatments. For patients who prefer to avoid surgery, the Omoto technique can be an effective initial intervention. Additionally, our findings suggest that the Omoto technique may facilitate less invasive surgical options in certain cases.

Comparison of the Outcomes of Plating, Screw Fixation, and Pinning in Sanders Type II Fractures: A Multicenter (TRON) Retrospective Study.

Calcaneus fractures Sanders type II have been historically treated with various modalities. However, few studies compared these procedures directly. The multicenter (TRON group) retrospective study compared the radiographic and clinical outcomes of operative procedures using Kirschner wires (K-wires), cannulated cancellous screws (CCSs) and plates. Between 2014 and 2020, 121 patients with Sanders type II calcaneus fractures were surgically treated in our group using K-wire (Group K: n = 31), CCS (Group C: n = 60) or plate (Group p: n = 30) fixation. We assessed the American Orthopedic Foot and Ankle Society (AOFAS) score and infection after operation as clinical outcomes and Böhler's and Preiss' angles as radiographic outcomes. The AOFAS scores of the 3 groups showed a significant difference, with Group P showing significantly inferior scores to Group C at 6 months postoperatively and at the final follow-up examination (p = .015 and p < .001, respectively). The rate of infection did not differ to a statistically significant extent, but the incidence in Group P tended to be higher in comparison to the other groups. Among the three groups, Böhler's angle did not differ to a statistically significant extent immediately after the operation (p = .113) or at the final follow-up examination (p = .383). Postoperatively, Preiss' angle did not differ to a statistically significant extent (p = .251) but was significantly smaller in the Group C at the final follow-up examination (p = .0331). In Sanders type II calcaneus fracture, CCS fixation may obtain the best functional outcomes.

Neoadjuvant chemotherapy for borderline resectable colorectal cancer liver metastases: a single-institution retrospective study.

INTRODUCTION: This study aimed to extract prognostic factors in patients undergoing neoadjuvant chemotherapy (NAC) for borderline resectable colorectal liver metastasis (BR-CRLM) (tumor size ≥5 cm, number of tumors ≥4, or resectable extrahepatic diseases) and assess validity of this strategy. MATERIALS AND METHODS: Since 2010, patients with BR-CRLM were treated with hepatectomy after six cycles of NAC. Prognostic factors of these patients were evaluated using clinicopathological data. RESULTS: Of 650 patients who underwent initial hepatectomy for CRLM from 2010 to 2018, 246 BR-CRLM cases underwent hepatectomy after NAC (BR-NAC). The 5-year recurrence-free survival rate was 16.7% and the 5-year overall survival rate (5y-OS) was 52.9%. Number of tumors ≥6, carcinoembryonic antigen (CEA) level ≥25 ng/mL, tumor diameter ≥5 cm, and progressive disease (PD) after NAC were identified as independent poor prognostic factors for OS. Patients were divided into four groups according to the number of risk factors, and prognoses of the four groups were well stratified. CONCLUSION: In patients with BR-NAC, number of tumors ≥6, CEA ≥25 ng/mL, tumor diameter ≥5 cm, and PD after NAC were independent poor prognostic factors. Patients with three or four risk factors showed poor prognosis and may need to switch chemotherapy.

Alterations in driving ability and their relationship with morphometric magnetic resonance imaging indicators in patients with amnestic mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Drivers with dementia are at a higher risk of motor vehicle accidents. The characteristics of driving behaviour of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) have not been fully elucidated. We investigated driving ability and its relationship with cognitive function and magnetic resonance imaging (MRI) morphometry indicators. METHODS: The driving abilities of 19 patients with AD and 11 with amnestic MCI (aMCI) were evaluated using a driving simulator. The association between each driving ability parameter and the Mini-Mental State Examination (MMSE) score or voxel-based specific regional analysis system for AD (VSRAD) was assessed. RESULTS: Patients with AD made a significantly higher number of operational errors than those with aMCI in attention allocation in the complex task test (P = 0.0008). The number of operational errors in attention allocation in the complex task test significantly and negatively correlated with MMSE scores in all participants (r = -0.4354, P = 0.0162). The decision time in the selective reaction test significantly and positively correlated with the severity and extent of medial temporal structural atrophy (r = 0.4807, P = 0.0372; r = 0.4862, P = 0.0348; respectively). CONCLUSION: An increase in the operational errors for attention allocation in the complex task test could be a potential indicator of progression from aMCI to AD. Atrophy of the medial temporal structures could be a potential predictor of impaired judgement in driving performance in aMCI and AD. A driving simulator could be useful for evaluating the driving abilities of individuals with aMCI and AD.

Lactic acid bacteria-derived γ-linolenic acid metabolites are PPARδ ligands that reduce lipid accumulation in human intestinal organoids.

Gut microbiota regulate physiological functions in various hosts, such as energy metabolism and immunity. Lactic acid bacteria, including Lactobacillus plantarum, have a specific polyunsaturated fatty acid saturation metabolism that generates multiple fatty acid species, such as hydroxy fatty acids, oxo fatty acids, conjugated fatty acids, and trans-fatty acids. How these bacterial metabolites impact host physiology is not fully understood. Here, we investigated the ligand activity of lactic acid bacteria-produced fatty acids in relation to nuclear hormone receptors expressed in the small intestine. Our reporter assays revealed two bacterial metabolites of γ-linolenic acid (GLA), 13-hydroxy-cis-6,cis-9-octadecadienoic acid (γHYD), and 13-oxo-cis-6,cis-9-octadecadienoic acid (γKetoD) activated peroxisome proliferator-activated receptor delta (PPARδ) more potently than GLA. We demonstrate that both γHYD and γKetoD bound directly to the ligand-binding domain of human PPARδ. A docking simulation indicated that four polar residues (T289, H323, H449, and Y473) of PPARδ donate hydrogen bonds to these fatty acids. Interestingly, T289 does not donate a hydrogen bond to GLA, suggesting that bacterial modification of GLA introducing hydroxy and oxo group determines ligand selectivity. In human intestinal organoids, we determined γHYD and γKetoD increased the expression of PPARδ target genes, enhanced fatty acid ß-oxidation, and reduced intracellular triglyceride accumulation. These findings suggest that γHYD and γKetoD, which gut lactic acid bacteria could generate, are naturally occurring PPARδ ligands in the intestinal tract and may improve lipid metabolism in the human intestine.

Serum DUPAN-2 could be an Alternative Biological Marker for CA19-9 Nonsecretors with Pancreatic Cancer.

OBJECTIVE: This study investigates the use of serum DUPAN-2 in predicting the PC progression in CA19-9 nonsecretors. BACKGROUND: Although we previously reported that serum CA19-9 >500U/ mL is a poor prognostic factor and an indication for enhanced neoadjuvant treatment, there is not a biomarker surrogate that equivalently predicts prognosis for CA19-9 nonsecretors. METHODS: We evaluated consecutive PC patients who underwent pancreatectomy from 2005 to 2019. All patients were categorized as either nonsecretor or secretor (CA19-9 ≤ or >2.0U/mL). RESULTS: Of the 984 resected PC patients, 94 (9.6%) were nonsecretors and 890 (90.4%) were secretors. The baseline characteristics were not statistically different between the 2 groups except for the level of DUPAN-2 (720 vs. 100U/mL, P < 0.001). Survival curves after resection were similar between the 2 groups (29.4 months vs. 31.3 months, P = 0.900). Survival curves of patients with DUPAN-2 >2000U/mL in the nonsecretors and patients with CA19-9 >500U/mL in the secretors were nearly equivalent as well (hazard ratio 2.08 vs. 1.89). In the multivariate analysis, DUPAN-2 >2000U/mL (hazard ratio 2.53, P = 0.010) was identified as independent prognostic factor after resection. CONCLUSION: DUPAN-2 >2000U/mL in CA19-9 nonsecretors can be an unfavorable factor that corresponds to CA19-9 >500U/mL in CA19-9 secretors which is an indicator for enhanced neoadjuvant treatment. The current results shed light on the subset of nonsecretors with poor prognosis that were traditionally categorized in a group with a more favorable prognosis group.

Comprehensive DNA methylation profiling of Barrett's esophagus and esophageal adenocarcinoma in Japanese patients.

Molecular mechanisms of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remain unclear in Japanese patients. Japanese EACs frequently have underlying short length BE: short-segment BE (SSBE), for which, neoplastic potential remains unclear. We performed comprehensive methylation profiling of EAC and BE in Japanese patients, mostly comprised with SSBE. Using three different groups of biopsies obtained from non-neoplastic BE from patients without cancer (n = 50; N group), with EAC (n = 27; ADJ group) and EAC (n = 22; T group), methylation statuses of nine candidate genes (N33, DPYS, SLC16A12, CDH13, IGF2, MLF1, MYOD1, PRDM5, and P2RX7) were examined by the bisulfite pyrosequencing. Reduced representation bisulfite sequencing was performed to characterize the genome-wide methylation status in 32 samples (12 from N, 12 ADJ, and 8 from T groups). In the candidate approach, methylation levels of N33, DPYS, and SLC16A12 were higher in ADJ and T groups compared to that in N group. The ADJ group was an independent factor for higher DNA methylation in non-neoplastic BE. The genome-wide approach demonstrated an increase of hypermethylation from ADJ to T groups relative to N group near the transcription start sites. Among gene groups hypermethylated in ADJ and T groups (n = 645) and T group alone (n = 1438), 1/4 and 1/3 were overlapped with downregulated genes in the microarray data set, respectively. Accelerated DNA methylation is observed in EAC and underlying BE in Japanese patients, mostly comprised with SSBE, highlighting the potential impact of methylation in early carcinogenesis.

Role of Intraoperative Assessment of Proximal Bile Duct Margin Status and Additional Resection of Perihilar Cholangiocarcinoma: Can Local Clearance Trump Tumor Biology? A Retrospective Cohort Study.

BACKGROUND: The aim of this study was to evaluate the clinical implications of the proximal bile duct margin status in resection of perihilar cholangiocarcinoma (PHCC). Intraoperative frozen section (IFS) analysis to assess the bile duct margin status is commonly used during PHCC resection. However, the impact of additional resection after obtaining a positive margin on the long-term outcome remains unclear. PATIENTS AND METHODS: Among the 257 patients who underwent PHCC resection, 190 patients with a negative distal margin were included and analyzed. IFS analysis of the proximal bile duct margin was performed in all patients. A positive margin was defined by the presence of either invasive cancer, or carcinoma, in situ. RESULTS: IFS analysis revealed an initial positive margin in 69 (36%) patients. Among 20 patients who underwent re-resection, only 11 patients achieved a negative margin (secondary R0). An initial positive margin was associated with poor long-term outcomes: recurrence-free survival (RFS) and overall survival (OS) were 16 and 25 months for patients with an initial positive margin, but 47 and 63 months for patients with an initial negative margin, respectively (p < 0.0001). In contrast, there was no difference in RFS or OS between patients with a secondary R0 margin, and those with a final R1 margin (14 vs. 16 months for RFS, p = 0.98, and 23 versus 25 months for OS, p = 0.63, respectively). CONCLUSION: An IFS-positive proximal hepatic duct margin dictates poor long-term outcomes for patients with resectable PHCC. Additional resection has minimal impact on survival, even when negative margin is achieved.