Role of the Intramural Vascular Network of the Extrahepatic Bile Duct for the Blood Circulation in the Recipient Extrahepatic Bile Duct Used for Duct-to-Duct-Biliary-Anastomosis in Living Donor Liver Transplantation.

A duct-to-duct-biliary-anastomosis is the preferred biliary reconstruction technique in liver transplantation; biliary complications remain the major concerns for the technique. We examined the significance of the intramural vascular network of the extrahepatic bile duct (EBD) and its relevant vessels. We microscopically examined the axial sections of the EBD with 5 mm intervals of 10 formalin-fixed deceased livers. The luminal-areas of the 3 and 9 o'clock arteries correlated significantly and positively with the distance from the bifurcation of the right and left hepatic ducts (the 3 o'clock artery, r = 0.42, p < 0.001; the 9 o'clock artery, r = 0.39, p < 0.001); the ratios of the numbers of the intramural vessels to the areas of the corresponding sections of the EBD significantly correlated positively with the distance from the bifurcation of the right and left hepatic ducts (total vessels, r = 0.78, p < 0.001; arterioles, r = 0.52, p < 0.001; venules, r = 0.45, p < 0.001). This study demonstrated that there is a significant locoregional distributional heterogeneity of the intramural vessels among the EBD. The hepatic arteries neighboring the EBD primarily supply the blood flow to the EBD; thus, when the broader isolation of the EBD from the neighboring arteries is necessary, this locoregional distributional heterogeneity of the intramural vessels may render the EBD likely to suffer ischemia of the anastomotic site.

The Prognostic Impact of Primary Tumor Site Differs According to the KRAS Mutational Status: A Study By the International Genetic Consortium for Colorectal Liver Metastasis.

OBJECTIVE: To examine the prognostic impact of tumor laterality in colon cancer liver metastases (CLM) after stratifying by Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status. BACKGROUND: Although some studies have demonstrated that patients with CLM from a right sided (RS) primary cancer fare worse, others have found equivocal outcomes of patients with CLM with RS versus left-sided (LS) primary tumors. Importantly, recent evidence from unresectable metastatic CRC suggests that tumor laterality impacts prognosis only in those with wild-type tumors. METHODS: Patients with rectal or transverse colon tumors and those with unknown KRAS mutational status were excluded from analysis. The prognostic impact of RS versus LS primary CRC was determined after stratifying by KRAS mutational status. RESULTS: 277 patients had a RS (38.6%) and 441 (61.4%) had a LS tumor. Approximately one-third of tumors (28.1%) harbored KRAS mutations. In the entire cohort, RS was associated with worse 5-year overall survival (OS) compared with LS (39.4% vs 50.8%, P = 0.03) and remained significantly associated with worse OS in the multivariable analysis (hazard ratio 1.45, P = 0.04). In wild-type patients, a worse 5-year OS associated with a RS tumor was evident in univariable analysis (43.7% vs 55.5%, P = 0.02) and persisted in multivariable analysis (hazard ratio 1.49, P = 0.01). In contrast, among patients with KRAS mutated tumors, tumor laterality had no impact on 5-year OS, even in the univariable analysis (32.8% vs 34.0%, P = 0.38). CONCLUSIONS: This study demonstrated, for the first time, that the prognostic impact of primary tumor side differs according to KRAS mutational status. RS tumors were associated with worse survival only in patients with wild-type tumors.

The optimal cut-off values for tumor size, number of lesions, and CEA levels in patients with surgically treated colorectal cancer liver metastases: An international, multi-institutional study.

BACKGROUND AND OBJECTIVES: Despite the long-standing consensus on the importance of tumor size, tumor number and carcinoembryonic antigen (CEA) levels as predictors of long-term outcomes among patients with colorectal liver metastases (CRLM), optimal prognostic cut-offs for these variables have not been established. METHODS: Patients who underwent curative-intent resection of CRLM and had available data on at least one of the three variables of interest above were selected from a multi-institutional dataset of patients with known KRAS mutational status. The resulting cohort was randomly split into training and testing datasets and recursive partitioning analysis was employed to determine optimal cut-offs. The concordance probability estimates (CPEs) for these optimal cut offs were calculated and compared to CPEs for the most widely used cut-offs in the surgical literature. RESULTS: A total of 1643 patients who met eligibility criteria were identified. Following recursive partitioning analysis in the training dataset, the following cut-offs were identified: 2.95 cm for tumor size, 1.5 for tumor number and 6.15 ng/ml for CEA levels. In the entire dataset, the calculated CPEs for the new tumor size (0.52), tumor number (0.56) and CEA (0.53) cut offs exceeded CPEs for other commonly employed cut-offs. CONCLUSION: The current study was able to identify optimal cut-offs for the three most commonly employed prognostic factors in CRLM. While the per variable gains in discriminatory power are modest, these novel cut-offs may help produce appreciable increases in prognostic performance when combined in the context of future risk scores.

Impact of intramuscular adipose tissue content on short- and long-term outcomes of hepatectomy for colorectal liver metastasis: a retrospective analysis.

BACKGROUND: Numerous reports regarding sarcopenia have focused on the quantity of skeletal muscle. In contrast, the impact of the quality of skeletal muscle has not been well investigated. METHODS: A retrospective analysis of 115 patients who underwent initial hepatectomy for colorectal liver metastasis between January 2009 and December 2016 in our hospital was performed. Intramuscular adipose tissue content (IMAC) was used to evaluate the quality of skeletal muscle by analysing computed tomography (CT) images at the level of the umbilicus. The impact of poor skeletal muscle quality on short-term and long-term outcomes after hepatectomy for colorectal liver metastasis was analysed. RESULTS: Patients were divided into two groups (high IMAC and normal IMAC) according to their IMAC values, and their backgrounds were compared. There were no significant differences in most factors between the two groups. However, both body mass index (P = 0.030) and the incidence of postoperative complications of Clavien-Dindo grade 3 or worse (P = 0.008) were significantly higher in the high-IMAC group. In multivariate analyses, an operative blood loss > 600 ml (P = 0.006) and high IMAC (P = 0.008) were associated with postoperative complications of Clavien-Dindo grade 3 or worse. Overall survival and recurrence-free survival were significantly lower (P < 0.001 and P = 0.045, respectively) in the high-IMAC group than in the normal IMAC group. In multivariate analyses for poor overall survival, high IMAC was associated with poor overall survival (P < 0.001). CONCLUSIONS: IMAC is a prognostic factor for poor short- and long-term outcomes in patients with colorectal liver metastasis.

Higher Tumor Burden Neutralizes Negative Margin Status in Hepatectomy for Colorectal Cancer Liver Metastasis.

OBJECTIVE: The aim of this study was to examine if the prognostic significance of margin status in hepatectomy for colorectal cancer liver metastasis (CRLM) varies for different levels of tumor burden because hepatectomy indications for CRLM have been recently expanded to include patients with a higher tumor burden in whom achieving an R0 resection is difficult. METHODS: Clinicopathological variables in an exploration cohort of 290 patients receiving hepatectomy in Japan for CRLM were investigated. R0 resection was defined as a margin width > 0 mm. Tumor burden was assessed using the recently introduced Tumor Burden Score (TBS), which was calculated as TBS2 = (maximum tumor diameter in cm)2 + (number of lesions)2. The principal findings were validated using a cohort from the United States. RESULTS: R1 resection rates significantly increased as TBS increased: 4/86 (4.7%) in patients with TBS < 3, 29/171 (17.0%) in patients with TBS ≥ 3 and < 9, and 9/33 (27.3%) in patients with TBS ≥ 9 (p < 0.001). R0 resection was significantly superior to R1 resection in patients with TBS ≥ 5; however, this was not the case for TBS ≥ 6, as confirmed by both univariate and multivariate analyses. Furthermore, prehepatectomy chemotherapy was associated with significantly improved survival for patients with TBS ≥ 8. Analysis of the validation cohort yielded similar results. CONCLUSIONS: R0 resection appeared to have a positive impact on prognosis among patients with low tumor burden; however, this was not the case for patients with high tumor burden. As such, systemic treatment, in addition to surgery, may be central to achieving satisfactory outcomes in the latter patient population.

Our Rationale of Initiating Neoadjuvant Chemotherapy for Hilar Cholangiocarcinoma: A Proposal of Criteria for "Borderline Resectable" in the Field of Surgery for Hilar Cholangiocarcinoma.

BACKGROUND: The concept of "borderline resectable" was recently introduced to the field of surgery for pancreatic cancer, and surgical outcomes for this disease with extremely dismal prognosis have improved since the introduction of this concept. However, no such concept has yet been introduced to the field of surgery for hilar cholangiocarcinoma (HCca). AIM: To determine a definition and criteria for "borderline resectable" in the field of surgery for HCca. PATIENTS AND METHODS: Retrospective analysis of 88 patients undergoing curative-intent surgery for HCca at our institution between May 1992 and December 2008 to clarify independent prognostic factors. RESULTS: Survival outcomes were obtained for these 88 patients, with a 5-year overall survival rate of 31.8%. Independent factors predictive of cancer death were determined by multivariate analysis to be the presence of regional lymph node metastasis (LNM) and pathological confirmed vascular invasion (VI). Cumulative survival rates of 23 patients with both LNM and VI who underwent surgery were significantly worse than those of the remaining 65 surgically treated patients and similar to those of 26 patients who were considered to have unresectable disease and treated with non-surgical multidisciplinary treatment during the same study period. CONCLUSION: Outcomes of surgery for cases of HCca showing regional LNM and VI were no better than those of non-surgical treatment for unresectable disease. Coexistence of these two factors indicates oncologically dismal condition and thus such cases should be considered "borderline resectable." Treatments additional to surgery are required for "borderline resectable" cases to obtain better outcomes.

The Tumor Burden Score: A New "Metro-ticket" Prognostic Tool For Colorectal Liver Metastases Based on Tumor Size and Number of Tumors.

OBJECTIVE: To apply the principles of the Metro-ticket paradigm to develop a prognostic model for patients undergoing hepatic resection of colorectal liver metastasis (CRLM). BACKGROUND: Whereas the hepatocellular "Metro-ticket" prognostic tool utilizes a continuum of tumor size and number, a similar concept of a CRLM Metro-ticket paradigm has not been investigated. METHODS: Tumor Burden Score (TBS) was defined using distance from the origin on a Cartesian plane incorporating maximum tumor size (x-axis) and number of lesions (y-axis). The discriminatory power [area under the curve (AUC)] and goodness-of-fit (Akaike information criteria) of the TBS model versus standard tumor morphology categorization were assessed. The TBS model was validated using 2 external cohorts from Asia and Europe. RESULTS: TBS (AUC 0.669) out-performed both maximum tumor size (AUC 0.619) and number of tumors (AUC 0.595) in predicting overall survival (OS) (P < 0.05). As TBS increased, survival incrementally worsened (5-year OS: zone 1, zone 2, and zone 3-68.9%, 49.4%, and 25.5%; P < 0.05). The stratification of survival based on traditional tumor size and number cut-off criteria was poor. Specifically, 5-year survival for patients in category 1, category 2, and category 3 was 58.3%, 45.5%, and 50.6%, respectively (P > 0.05). The corrected Akaike score information criteria value of the TBS model (2865) was lower than the traditional tumor morphologic categorization model (2905). Survival analysis revealed excellent prognostic discrimination for the TBS model among patients in both external cohorts (P< 0.05). CONCLUSIONS: An externally validated "Metro-ticket" TBS model had excellent prognostic discriminatory power. TBS may be an accurate tool to account for the impact of tumor morphology on long-term survival among patients undergoing resection of CRLM.

Significance of Vascular Resection and Reconstruction in Surgery for Hilar Cholangiocarcinoma: With Special Reference to Hepatic Arterial Resection and Reconstruction.

PURPOSE: The aim of this study was to assess the efficacy of combined resection and reconstruction (CRR) of the hepatic artery (HA) in surgery for hilar cholangiocarcinoma (HC). MATERIALS AND METHOD: Among 172 patients who underwent surgical resection for HC, the following three groups were defined according to the type of vascular reconstruction: VR(-) group, in which neither CRR of the portal vein (PV) nor HA was performed (n = 74); VR-PV group, in which only CRR of the PV was required (n = 54); and VR-A group, in which CRR of the HA was performed either with or without CRR of the PV (n = 44). Clinicopathological variables and clinical outcomes were compared among the three groups. RESULTS: Although the VR-A group showed significantly more advanced disease than other groups, the R0 resection rate was comparable among the three groups (VR(-), 74 %; VR-PV, 80 %; VR-A, 80 %). The 5-year disease-specific survival rate was also comparable among the three groups (VR(-), 45.6 %; VR-PV, 51.2 %; VR-A, 22.3 %), but tended to be worse in the VR-A group than in the other groups. A similar trend was observed in morbidity rate. Lymph node metastasis was more frequent in the VR-A group (59 %) than in the other groups (VR(-), 33.8 %; VR-PV, 50 %). In the VR-A group, lymph node metastasis (p = 0.004) and adjuvant chemotherapy (p = 0.006) were determined to represent independent prognostic factors for survival according to multivariate analysis. CONCLUSION: CRR of the HA was considered efficacious in selected patients; however, long-term outcomes of the VR-A group seem unsatisfactory. Treatments additional to surgery may be necessary in cases requiring CRR of the HA.

[Remarkable Response to Trastuzumab Observed in a Case of Gastric Cancer with HER2-Negative Conversion].

A 64-year-old woman was diagnosed with advanced gastric cancer with solitary liver metastasis. Although the HER2 status of the tumor was IHC2+, no further examination for HER2 status using FISH was performed. Four courses of S-1 and cisplatin chemotherapy were administered. The primary lesion and metastatic lesion were confirmed to have partially regressed. After 4 courses of chemotherapy, an open total gastrectomy, D2 dissection, pancreatosplenectomy, and posterior segmental hepatectomy were performed. Her postoperative course was uneventful. On histopathology, cancer cells were found in the resected stomach and resected liver. However, the HER2 statuses of the resected specimens were negative. After discharge, she received S-1 therapy for 1 year. Upon evaluation 1 year and 1 month postoperatively, the tumor marker CA19-9 was elevated. An enhanced CT scan showed multiple lung metastases and lymph node metastases in the pancreatic tail. Three courses of XELOX therapy(capecitabine and oxaliplatin)were administered. However, tumor marker levels continued to increase, and the metastasis continued to enlarge. Although the HER2 status of the resected site was negative, the HER2 status of the biopsy specimen before chemotherapy was positive on FISH. Therefore, weekly paclitaxel and trastuzumab therapy was initiated and repeated for 6 courses, after which an enhanced CT showed significant reduction(nearly CR)of multiple lung metastases and lymph node metastases. This suggests that HER2-negative conversion had occurred at the resected site. However, the HER2 status of the metastatic sites was considered positive.

Glasgow Prognostic Score Predicts Survival and Recurrence Pattern in Patients With Hepatocellular Carcinoma After Hepatectomy.

BACKGROUND/AIM: The prognostic significance of the Glasgow Prognostic Score (GPS) on outcomes of liver resection for hepatocellular carcinoma (HCC) remains unclear; the aim of the study was to assess its significance. PATIENTS AND METHODS: A total of 480 patients with HCC who underwent liver resection with curative intent at the Yokohama City University Hospital and Medical Center were enrolled in the study. Patients were classified into three groups: GPS-0, C-reactive protein (CRP) ≤1.0 mg/dl serum albumin ≥3.5 g/dl; GPS-1, CRP >1.0 mg/dl or serum albumin <3.5 g/dl; and GPS-2, CRP >1.0 mg/dl, serum albumin <3.5 g/dl. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were analyzed retrospectively. The recurrence pattern was also investigated using GPS. RESULTS: Of the 480 patients, 382 (79.6%), 81 (16.9%), and 17 (3.5%) were assigned to GPS-0, GPS-1, and GPS-2, respectively. Elevated GPS, indocyanine green retention rate at 15 min, and protein induced by vitamin K antagonist-II (PIVKA-II) were significantly associated with a poor OS. Elevated GPS, alpha-fetoprotein, and PIVKA-II were significantly associated with a poor DFS by multivariate analysis. The number of patients with liver-only recurrence in GPS-0, GPS-1, and GPS-2 was 179 (86.1%), 40 (78.4%), and 9 (69.2%), respectively. The number of patients with four or more intrahepatic metastases in the GPS-0, GPS-1, and GPS-2 groups, was 33 (17.9%), 11 (27.5%), and 8 (88.9%), respectively. The number of patients with four or more intrahepatic metastases in the GPS-2 group was significantly higher (p<0.001). CONCLUSION: Preoperative GPS is a useful predictor of OS and recurrence pattern after liver resection with a curative intent for HCC.

Is lymph-node micrometastasis in gallbladder cancer a significant prognostic factor?

BACKGROUND/AIMS: The purpose of our study was to investigate prognostic significance of lymph-node micrometastasis in gallbladder carcinoma. METHODOLOGY: In total, 1,094 lymph nodes from 41 patients who had undergone radical resection with lymph-node dissection, including para-aortic lymph nodes were stained with hematoxylin and eosin (H&E) and immunostained with anti-cytokeratin 7/8 antibody. Micrometastasis in each lymph node was defined as tumor cells that were detectable only by immunohistochemical evaluation and were not detected by H&E staining. RESULTS: Metastases were detected in 163 lymph nodes (14.9%) by H&E staining. Micrometastases were found in 25 of the remaining lymph nodes (2.3%). Among 24 patients with lymph node metastasis based on the H&E staining, 12 had micrometastases. Of the 17 patients in whom lymph-node metastasis was not detected by the H&E staining, one was found to have micrometastasis. Micrometastasis correlated significantly with lymph node metastasis on H&E staining and pN (Tumor-Node-Metastasis 5th ed.). On multivariate analysis of data from 17 node-positive patients who underwent curative resection, micrometastasis and microscopic venous invasion were significant prognostic factors. CONCLUSIONS: Our findings suggest that micrometastasis might be traces of scatter of cancer cells to the whole body rather than an event in an initial stage of the metastasis.

Surgical Indications for Huge Hepatocellular Carcinoma.

BACKGROUND/AIM: This study aimed to retrospectively analyse adverse predictors to identify patients with huge hepatocellular carcinoma who were not appropriate candidates for hepatic resection. PATIENTS AND METHODS: From 551 patients with hepatocellular carcinoma who underwent hepatectomy between 1992 and 2019, 92 were diagnosed with huge hepatocellular carcinoma (diameter >10 cm) and 115 were diagnosed with large hepatocellular carcinoma (diameter=5-10 cm). Clinical features and overall and disease-free survival rates were compared between the two groups. RESULTS: Cumulative overall survival was significantly worse in the huge group than in the large group (p=0.035). In the huge group, multivariate analyses revealed that liver cirrhosis, multiple intrahepatic metastases (≥4), poor histological grade, and macroscopic portal vein invasion were significantly associated with poor prognosis. CONCLUSION: We identified four adverse predictors of survival and determined that patients with two or more predictors are not appropriate candidates for straightforward hepatic resection.

Using Artificial Intelligence to Find the Optimal Margin Width in Hepatectomy for Colorectal Cancer Liver Metastases.

Importance: In patients with resectable colorectal cancer liver metastases (CRLM), the choice of surgical technique and resection margin are the only variables that are under the surgeon's direct control and may influence oncologic outcomes. There is currently no consensus on the optimal margin width. Objective: To determine the optimal margin width in CRLM by using artificial intelligence-based techniques developed by the Massachusetts Institute of Technology and to assess whether optimal margin width should be individualized based on patient characteristics. Design, Setting, and Participants: The internal cohort of the study included patients who underwent curative-intent surgery for KRAS-variant CRLM between January 1, 2000, and December 31, 2017, at Johns Hopkins Hospital, Baltimore, Maryland, Memorial Sloan Kettering Cancer Center, New York, New York, and Charité-University of Berlin, Berlin, Germany. Patients from institutions in France, Norway, the US, Austria, Argentina, and Japan were retrospectively identified from institutional databases and formed the external cohort of the study. Data were analyzed from April 15, 2019, to November 11, 2021. Exposures: Hepatectomy. Main Outcomes and Measures: Patients with KRAS-variant CRLM who underwent surgery between 2000 and 2017 at 3 tertiary centers formed the internal cohort (training and testing). In the training cohort, an artificial intelligence-based technique called optimal policy trees (OPTs) was used by building on random forest (RF) predictive models to infer the margin width associated with the maximal decrease in death probability for a given patient (ie, optimal margin width). The RF component was validated by calculating its area under the curve (AUC) in the testing cohort, whereas the OPT component was validated by a game theory-based approach called Shapley additive explanations (SHAP). Patients from international institutions formed an external validation cohort, and a new RF model was trained to externally validate the OPT-based optimal margin values. Results: This cohort study included a total of 1843 patients (internal cohort, 965; external cohort, 878). The internal cohort included 386 patients (median [IQR] age, 58.3 [49.0-68.7] years; 200 men [51.8%]) with KRAS-variant tumors. The AUC of the RF counterfactual model was 0.76 in both the internal training and testing cohorts, which is the highest ever reported. The recommended optimal margin widths for patient subgroups A, B, C, and D were 6, 7, 12, and 7 mm, respectively. The SHAP analysis largely confirmed this by suggesting 6 to 7 mm for subgroup A, 7 mm for subgroup B, 7 to 8 mm for subgroup C, and 7 mm for subgroup D. The external cohort included 375 patients (median [IQR] age, 61.0 [53.0-70.0] years; 218 men [58.1%]) with KRAS-variant tumors. The new RF model had an AUC of 0.78, which allowed for a reliable external validation of the OPT-based optimal margin. The external validation was successful as it confirmed the association of the optimal margin width of 7 mm with a considerable prolongation of survival in the external cohort. Conclusions and Relevance: This cohort study used artificial intelligence-based methodologies to provide a possible resolution to the long-standing debate on optimal margin width in CRLM.

Mutant KRAS as a prognostic biomarker after hepatectomy for rectal cancer metastases: Does the primary disease site matter?

BACKGROUND: The prognostic implication of mutant KRAS (mKRAS) among patients with primary disease in the rectum remains unknown. METHODS: From 2000 to 2018, patients undergoing hepatectomy for colorectal liver metastases at 10 collaborating international institutions with documented KRAS status were surveyed. RESULTS: A total of 834 (65.8%) patients with primary colon cancer and 434 (34.2%) patients with primary rectal cancer were included. In patients with primary colon cancer, mKRAS served as a reliable prognostic biomarker of poor overall survival (OS) (hazard ratio [HR]: 1.58, 95% CI 1.28-1.95) in the multivariable analysis. Although a trend towards significance was noted, mKRAS was not found to be an independent predictor of OS in patients with primary rectal tumors (HR 1.34, 95% CI 0.98-1.80). For colon cancer, the specific codon impacted in mKRAS appears to reflect underlying disease biology and oncologic outcomes, with codon 13 being associated with particularly poor OS in patients with left-sided tumors (codon 12, HR 1.56, 95% CI 1.22-1.99; codon 13, HR 2.10 95% CI 1.43-3.08;). Stratifying the rectal patient population by codon mutation did not confer prognostic significance following hepatectomy. CONCLUSIONS: While the left-sided colonic disease is frequently grouped with rectal disease, our analysis suggests that there exist fundamental biologic differences that drive disparate outcomes. Although there was a trend toward significance of KRAS mutations for patients with primary rectal cancers, it failed to achieve statistical significance.

Analysis of gene expression profiles in fatal hepatic failure after hepatectomy in mice.

BACKGROUND: We developed 90%-hepatectomized mice that were the fatal model, and analyzed the gene expression profiles using a complementary DNA (cDNA) microarray to clarify the mechanisms of hepatic failure after excessive hepatectomy. MATERIALS AND METHODS: Ribonucleic acid (RNA)s from the remnant hepatic tissue of 70%- and 90%-hepatectomized mice were labeled with fluorescent dyes, and hybridized to the Riken set of 39,168 full-length enriched mouse cDNA arrays. The gene expression profiles in 90%- and 70%-hepatectomized mice were analyzed by scanning date for fluorescent dye signals. RESULTS: The down-regulated genes in 90%-hepatectomized mice were genes activating extracellular matrix (ECM) remodeling (matrix metalloproteinases, laminins, and integrins), genes related to cytokines (tumor necrosis factor α converting enzyme, and Janus kinase 3) that were related to the priming, genes related to growth factor (heparin-binding epidermal growth factor-like growth factor and others), and genes promoting cell cycle progression (cyclin D1, D2, and E2) that were related to the progression of hepatocytes. The up-regulated genes were genes inhibiting ECM remodeling [plasminogen activator inhibitors (PAIs)]. CONCLUSIONS: Hepatic failure after hepatectomy was characterized by the inhibition of hepatic cell cycle priming and progression both induced by ECM remodeling in liver regeneration. Particularly, the overexpression of PAIs was thought to play the major role in the first step of inhibition of ECM remodeling.

Reduction of gender-associated M2-like tumor-associated macrophages in the tumor microenvironment of patients with pancreatic cancer after neoadjuvant chemoradiotherapy.

PURPOSE: This study aimed to investigate gender-dependent antitumor immune response to neoadjuvant chemoradiotherapy (NACRT) in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS: This study enrolled 58 patients (25 females and 33 males) with borderline resectable PDAC who underwent R0 surgical resection after NACRT. The resected tumor specimens were analyzed for tumor-associated macrophages (TAMs); tumor-infiltrating lymphocytes (CD8+ and CD4+ T cells); regulatory T cells; and IRF-5-expressing cells using immunohistochemical staining for CD163, CD204, CD8, CD4, Foxp3, and IRF-5 antigen. The relationship between clinicopathological features and clinical outcomes was evaluated using multivariate Cox proportional hazard analysis. RESULTS: Females had longer overall survival (P = .044) and relapse-free survival (P = .044) than males. The CD204+ TAM number was significantly lower in females than in males (P = .009). No significant difference occurred between female and male patients in other tumor-infiltrating immune cells. IRF-5+ cell number was significantly higher in female patients (P = .002). Negative correlation occurred between CD204+ cells and IRF-5-positive cells (P = .003, r = -.385). CONCLUSIONS: Female gender was an independent prognostic factor possibly due to the greater reduction in CD204+ TAM infiltration in tumors after NACRT. The beneficial effects of NACRT on TAMs' infiltration might be associated with gender-dependent IRF-5 expression.

Subcutaneous switching suture technique for hernia defect closure during laparoscopic ventral and incisional hernia repair.

INTRODUCTION: A vertical penetration of the thread through the abdominal wall for the hernia defect closure in laparoscopic ventral/incisional hernia repair (LVIHR) is difficult especially in the large defect cases when applying the existing techniques. MATERIALS: Sixteen LVIHRs were performed using the suture technique for defect closure we newly developed. SURGICAL TECHNIQUE: With the subcutaneous switching, our technique only requires the suture-passer and easily enables the vertical penetration of the thread through the abdominal muscular wall even in the large defect cases. DISCUSSION: The defect closure in LVIHR tends to be complicated in the large defect cases. Thus, we devised this technique for the easy, reliable, and firm closure even in the large defect cases. Although the sample size was currently very small, we consider that the favorable outcomes have been obtained through our technique because any noticeable complications, such as mesh bulging or recurrence, have not been observed currently.

Treatment of acute exacerbation of liver-cirrhosis-associated portal vein thrombosis with direct-acting oral anticoagulant, edoxaban, used as an initial treatment in the early postoperative period after abdominal surgery: a case report.

BACKGROUND: Cirrhosis-associated portal vein thrombosis (CA-PVT) has been reportedly observed in 5-30% of cirrhotic patients. Moreover, the acute exacerbation of CA-PVT is likely to occur after certain situations, such as a status after abdominal surgery. Safety and efficacy of the direct-acting oral anticoagulant (DOAC) used for cirrhotic patients have been being confirmed. However, use of the DOAC as an initial treatment for CA-PVT appears still challenging especially in the early postoperative period after major surgery in terms of unestablished efficacy and safety in such occasion. CASE PRESENTATION: We herein report a case of the acute exacerbation of CA-PVT in the early postoperative period after abdominal surgery, which was successfully treated with DOAC, edoxaban used as an initial treatment. The patient was a 79-year-old Japanese male with alcoholic cirrhosis. The patient suffered choledocholithiasis and had a mural chronic CA-PVT extending from the superior mesenteric vein to the portal trunk. He underwent open cholecystectomy and choledochotomy. Early postoperative clinical course was uneventful except for abdominal distension due to ascites diagnosed on postoperative day (POD)7 when hospital discharge was planned. Contrast enhancement computed tomography (CE-CT) taken on POD 7 revealed the exacerbation of the CA-PVT. Despite recommendation for extension of hospital admission with low molecular weight heparin treatment, the patient strongly hoped to be discharged. Unwillingly, we selected DOAC, edoxaban, as an initial treatment, which was commenced the day after discharge (POD8). As a result, the remarkable improvement of the exacerbated CA-PVT was confirmed by the CE-CT taken on POD21. Any bleeding complications were not observed. Although a slight residue of the CA-PVT remains, the patient is currently doing well 4 years after surgery and is still receiving edoxaban. Any adverse effects of edoxaban have not been observed for 4 years. CONCLUSIONS: A case of successful treatment of the acute exacerbation of CA-PVT with edoxaban was reported. Moreover, edoxaban has been safely administered in a cirrhotic patient for 4 years. The findings obtained from the present case suggest that DOAC can be used as an initial treatment for CA-PVT even in early postoperative period after major abdominal surgery.

Superiority of Sepsis-3 to Sepsis-2 in the Early Detection of Severe Early Postoperative Sepsis After Living Donor Liver Transplantation.

BACKGROUND: To date, the utility of Sepsis-3 compared to Sepsis-2 in living donor liver transplantation (LDLT) recipients has not been evaluated. We assessed the utility of Sepsis-3 compared to Sepsis-2 and verified the following hypotheses: 1. Sepsis-3-based sepsis (S3BS) corresponds to Sepsis-2-based severe sepsis (S2BSS), and 2. S3BS enables earlier diagnosis of early postoperative sepsis (within 21 postoperative days; EPoS) compared to S2BSS. METHODS: We evaluated 66 LDLT recipients in our institution. Patients with EPoS, who were diagnosed with S3BS and S2BSS, were extracted, and the postoperative day of diagnosing S3BS and S2BSS was identified. RESULTS: EPoS was diagnosed in 14 patients with S3BS (21.2%) and in 15 with S2BSS (22.7%). All but 1 patient with S2BSS corresponded to those with S3BS, with 98.4% overlap. Among the overlapping 14 patients, the comparison between the postoperative days when S3BS and S2BSS occurred demonstrated that S3BS was diagnosed earlier in 7 patients (50%) and on the same day in 4 (28.6%), and S2BSS was diagnosed earlier in 3 (21.4%). Especially in cases with a change in the sequential organ failure assessment (SOFA) immediately after S3BS onset compared to before (ΔSOFA) of ≥ 4 points (n = 6), S3BS was diagnosed earlier in 5 cases (83.3%); in cases with ΔSOFA of 2 to 3 points (n = 8), S3BS was diagnosed earlier only in 2 cases (25.0%). Thus, early diagnosis of S3BS was significantly more common in cases with ≥ 4 points of ΔSOFA (P = .02). CONCLUSIONS: S3BS nearly corresponds to S2BSS and can enable earlier detection of EPoS, especially with a high ΔSOFA.