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The major lysosomal proteases, Cathepsin B (CTSB), Cathepsin D (CTSD) and Cathepsin L (CTSL), are implicated in autophagic activity. To investigate the role of each cathepsin in the exocrine pancreas, we generated mice in which the pancreas was specifically deficient in Ctsb, Ctsd and Ctsl . Each of these gene knockout (KO) and Ctsb;Ctsl and Ctsd;Ctsl double-knockout (DKO) mice were almost normal. However, we found cytoplasmic degeneration in the pancreatic acinar cells of Ctsb;Ctsd DKO mice, similar to autophagy related 5 ( Atg5 ) KO mice. LC3 and p62 (autophagy markers) showed remarkable accumulation and the numbers of autophagosomes and autolysosomes were increased in the pancreatic acinar cells of Ctsb;Ctsd DKO mice. Moreover, these Ctsb;Ctsd DKO mice also developed chronic pancreatitis (CP). Thus, we conclude that both Ctsb and Ctsd deficiency caused impaired autophagy in the pancreatic acinar cells, and induced CP in mice.

Background Posthepatectomy liver failure (PHLF) remains a severe complication after liver resection. This retrospective study investigated the correlation of three hepatic functional tests and whether 99mTc-galactosyl human serum albumin (99mTc-GSA) scintigraphy and modified albumin–bilirubin (ALBI) score are useful for predicting PHLF. Methods This retrospective cohort study included 413 consecutive patients undergoing hepatectomies between January 2017 and December 2020. To evaluate preoperative hepatic functional reserve, modified ALBI grade, indocyanine green clearance (ICG-R15), and 99mTc-GSA scintigraphy (LHL15) were examined before scheduled hepatectomy. Based on a retrospective chart review, multivariable logistic regression analysis adjusted for confounding factors was performed to confirm that mALBI, ICG-R15, and LHL15 are independent risk factors for PHLF. Results ICG-R15 and LHL15 were moderately correlated ( r  =  − 0.61) but this correlation weakened when ICG-R15 was about ≥ 20. Weak correlations were observed between LHL15 and ALBI score ( r  =  − 0.269) and ALBI score and ICG-R15 ( r  = 0.339). Of 413 patients, 66 (19%) developed PHLF (20 grade A, 44 grade B, 2 grade C). Multivariable logistic regression analyses, major hepatectomy ( P  < 0.001), mALBI grade ( P  = 0.01), ICG-R15 ( P  < 0.001), and Esophagogastric varices ( P  = 0.007) were significant independent risk factors for PHLF. Subgroup analysis showed that ICG-R15 < 19, major hepatectomy, and mALBI grade and ICG-R15 ≥ 19, major hepatectomy, LHL15, and Esophagogastric varices were significant independent risk factors for PHLF ( P  = 0.033, 0.017, 0.02, 0.02, and 0.001, respectively). Conclusion LHL15, the assessment of Esophagogastric varices, and mALBI grade are complementary to ICG-R15 for predicting PHLF risk.

Background A new circulating biomarker superior to carbohydrate antigen 19–9 (CA19-9) is needed for diagnosing pancreatobiliary cancer (PBca). The aim of this study was to identify serum microRNA (miRNA) signatures comprising reproducible and disease-related miRNAs. Methods This multicenter study involved patients with treatment-naïve PBca and healthy participants. The optimized serum processing conditions were evaluated using t -distributed stochastic neighbor embedding ( t -SNE) visualization. Serum miRNA candidates for disease association were selected using weighted gene coexpression network analysis (WGCNA). A miRNA signature combining multiple serum miRNAs was tested in exploratory, validation, and independent validation sets. The synthesis and secretion of diagnostic miRNAs were evaluated using human pancreatic cancer cells. Results In total, 284 (150 healthy and 134 PBca) of 827 serum samples were processed within 2 h of blood collection before freezing, distributed in the same area as that in the t -SNE map, and assigned to an exploratory set. The 193 optimized samples were assigned to either the validation (50 healthy, 47 PBca) or independent validation (50 healthy, 46 PBca) set. Index-1, a combination of five serum miRNAs (hsa-miR-1343-5p, hsa-miR-4632-5p, hsa-miR-4665-5p, hsa-miR-665, and hsa-miR-6803-5p) with disease association in WGCNA, showed a sensitivity and specificity of > 80% and an AUC outperforming that of CA19-9 in the exploratory, validation, and independent validation sets. The AUC of Index-1 was superior to that of CA19-9 (0.856 vs. 0.649, p  = 0.038) for detecting T1 tumors. miR-665, a component of Index-1, was expressed in human pancreatic cancer cells, and its transfection inhibited cell growth. Conclusions The serum miRNA signature Index-1 is useful for detecting PBca and could facilitate the early diagnosis of PBca. These findings can help improve clinical PBca detection by providing an optimized biomarker that overcomes the limitations of the current standard.

PurposeThis study aimed to clarify what hepatocellular carcinoma (HCC) phenotype, as categorized by intraoperative contrast-enhanced ultrasonography (CEUS), showed a high risk of recurrence after hepatic resection.MethodsPatients who underwent initial curative hepatectomy with intraoperative CEUS for a single HCC nodule were retrospectively assigned to three patterns of fine (FI), vascular (VA), and irregular (IR) according to the maximum intensity projection pattern based on intraoperative CEUS. Staining was performed for Ki-67, pyruvate kinase type M2 (PKM2), and vascular endothelial growth factor (VEGF) to assess the tumor proliferative activity, tumor glucose metabolism, and angiogenesis, respectively.ResultsOf 116 patients, 18, 50, and 48 were assigned to the FI, VA and IR patterns, respectively. IR patients demonstrated a significantly worse prognosis for both the recurrence-free survival (RFS) and overall survival (OS) (P = 0.0002, 0.0262, respectively) than did patients with other patterns. A multivariate analysis revealed an IR pattern in intraoperative CEUS to be an independent predictive factor for a poor RFS, and major hepatectomy and an IR pattern were independent predictive factors for a poor OS. An IR pattern was closely related to the tumor size (≥ 3.3 cm) and poor histological differentiation and showed a high Ki-67 index, low VEGF expression, and high PKM2 expression.ConclusionIR-pattern HCCs as classified by intraoperative CEUS may be associated with a higher risk of recurrence and worse outcomes in HCC patients after hepatic resection than other patterns.

PurposeThis study assessed the significance of measuring liver stiffness using virtual touch quantification before hepatectomy to predict posthepatectomy refractory ascites.MethodsA total of 267 patients with hepatocellular carcinoma who underwent hepatectomy were prospectively analyzed. Liver stiffness was defined as the median value of the virtual touch quantification (Vs; m/s) by acoustic radio-force-impulse-based virtual touch.ResultsA multivariate analysis showed that Vs and the aspartate aminotransferase-to-platelet ratio index were independent risk factors for postoperative refractory ascites (odds ratio = 3.27 and 3.08, respectively). The cutoff value for Vs was 1.52 m/s (sensitivity: 59.5%, specificity: 88.6%) as determined by the analysis of the receiver-operating characteristic curve, and the area under the receiver-operating characteristic curve was 0.79. The cutoff value for the aspartate aminotransferase-to-platelet ratio was 0.952 (sensitivity: 65.5%, specificity: 82.9%), and the area under the receiver-operating characteristic curve was 0.75.ConclusionsVs is an independent risk factor for refractory ascites after hepatectomy. The measurement of liver stiffness by virtual touch quantification before hepatectomy can help estimate the risk of postoperative refractory ascites. Nonsurgical treatments should be considered for the management of patients who are at high risk for refractory ascites.

We report a very rare case of a 45-year-old Japanese male patient with hairy cell leukemia-Japanese variant (HCL-JV) expressing CD27. The patient showed a high number of abnormal peripheral lymphocytes, thrombocytopenia, and severe splenomegaly but no lymphadenopathy. Histology of the resected spleen showed small-sized lymphoma cells diffusely infiltrating the red pulp without follicle formation. By immunohistochemistry, lymphoma cells were negative for CD3, CD5, CD8, CD10, CD34, cyclin-D1, and annexin A1 but positive for CD20 and BCL2. BRAF V600E mutation was not observed. Bone marrow aspirate showed preserved normal hematopoietic cells with invasion of lymphoma cells in an interstitial pattern without obvious nodules. The cells had abundant pale cytoplasm and round nuclei with inconspicuous nucleoli. After natural drying, the cells had unevenly distributed microvilli. Flow cytometric analysis demonstrated positivity for CD11a, CD11c, CD19, CD20, CD22, CD27, surface IgG, and λ but not for CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD21, CD23, CD25, CD30, CD34, CD38, CD43, CD56, CD57, CD103, IgD, IgM, and κ. Monoclonal expansion of B cells was confirmed by an immunoglobulin heavy chain (IgH) rearrangement band as demonstrated by Southern blot hybridization. The lymphoma cells had unevenly distributed long, large, and broad-based microvilli, which resembled splenic diffuse red pulp small B cell lymphoma (SDRPL) cells. CD27 expression is extremely rare in HCL-JV, but the young age of the patient and high peripheral WBC counts were similar to HCL-JV, which suggests, in this case, an intermediate disease between SDRPL and HCL-JV.

BackgroundThe optimal approach for the safe implementation and education of robotic pancreaticoduodenectomy (RPD) remains unclear. Prolonged operation time may cause surgeon fatigue and result in perioperative complications. To solve this issue, our department adopted task division by the console surgeon turnover between resection and reconstruction in 2022.MethodsThis study retrospectively investigated consecutive patients who underwent RPD from November 2009 (initial introduction of RPD) to December 2023. The analysis excluded patients who underwent concomitant resection of other organs. The cases performed by a single console surgeon (single approach) were compared with those performed by two or more console surgeons (multiple approach).ResultsThis study analyzed 85 consecutive RPD cases, including 51 with the single approach and 34 with the multiple approach. The operation time was significantly shorter (832 vs. 618 min, p < 0.001), and the postoperative major complication was less frequent (45% vs. 12%, p = 0.003) in the multiple approach group, although less experienced surgeons performed the multiple approach (number of RPD experiences: 19 cases vs. 5 cases, p < 0.001). The console surgeon turnover between the resection and reconstruction resulted in a safe pancreatojejunostomy performed by the less experienced surgeon (number of pancreatic reconstruction experiences: 6.5 vs. 14 cases, p = 0.010). Surgeons who started RPD with a multiple approach observed a reduction in surgical time and a lower incidence of complications earlier than those who started with a single approach.ConclusionTask division during the early introduction phase of RPD using the multiple approach demonstrated potential contributions to improved surgical outcomes and enhanced educational benefits.

BackgroundRobotic pancreaticoduodenectomy (RPD) is technically demanding, and 20–50 cases are required to surpass the learning curve. This study aimed to show our experience of 76 cases from the introduction of RPD and report the changes in surgical results owing to the accumulation of cases and optimization of surgical techniques.MethodsA total of 76 patients who underwent RPD between November 2009 and May 2023 at the Fujita Health University Hospital were divided into three groups: competency (n = 23, Nov 2009–Mar 2020), proficiency (n = 31, Apr 2020–Jun 2022), and mastery (n = 22, Jul 2022–May 2023) phases. In the mastery phase, for the education of new surgeons and maintenance of surgical quality, optimization of the procedure, including hanging maneuver with or without stapling transection of the retropancreatic tissue was implemented. The surgical outcomes were compared between the groups.ResultsThe mean operation time decreased over time despite of the participation of newly started operators in mastery phase [competency: 921.5 min (IQR 775–996 min) vs. proficiency: 802.8 min (IQR 715–887 min) vs. mastery: 609.2 min (IQR 514–699 min), p < 0.001]. Additionally, Clavien–Dindo ≥ grade IIIa complications decreased from 52.2% in competency phase to 35.5% and 9.1% in proficiency and mastery phases, respectively (p = 0.005).ConclusionOperation time and major complications decreased along the learning curve from the introduction of RPD. In addition, optimization of the procedure, including hanging maneuver of the retropancreatic tissue seemed to be effective in reducing operation time and educating new RPD surgeons.

Surgical techniques and outcomes of minimally invasive anatomic liver resection (AR) using the extrahepatic Glissonian approach for hepatocellular carcinoma (HCC) are undefined. In 327 HCC cases undergoing 185 open (OAR) and 142 minimally invasive (MIAR; 102 laparoscopic and 40 robotic) ARs, perioperative and long-term outcomes were compared between the approaches, using propensity score matching. After matching (91:91), compared to OAR, MIAR was significantly associated with longer operative time (643 vs. 579 min, p = 0.028); less blood loss (274 vs. 955 g, p < 0.0001); a lower transfusion rate (17.6% vs. 47.3%, p < 0.0001); lower rates of major 90-day morbidity (4.4% vs. 20.9%, p = 0.0008), bile leak or collection (1.1% vs. 11.0%, p = 0.005), and 90-day mortality (0% vs. 4.4%, p = 0.043); and shorter hospital stay (15 vs. 29 days, p < 0.0001). On the other hand, laparoscopic and robotic AR cohorts after matching (31:31) had comparable perioperative outcomes. Overall and recurrence-free survivals after AR for newly developed HCC were comparable between OAR and MIAR, with potentially improved survivals in MIAR. The survivals were comparable between laparoscopic and robotic AR. MIAR was technically standardized using the extrahepatic Glissonian approach. MIAR was safe, feasible, and oncologically acceptable and would be the first choice of AR in selected HCC patients.