Predictive score for identifying intrahepatic cholangiocarcinoma patients without lymph node metastasis: a basis for omitting lymph node dissection.

BACKGROUND: This study aimed to develop a predictive score for intrahepatic cholangiocarcinoma (ICC) in patients without lymph node metastasis (LNM) using preoperative factors. METHODS: A retrospective analysis of 113 ICC patients who underwent liver resection with systemic lymph node dissection between 2002 and 2021 was conducted. A multivariate logistic regression analysis was used as a predictive scoring system for node-negative patients based on the ß coefficients of preoperatively available factors. RESULTS: LNM was observed in 36 patients (31.9%). Four factors were associated with LNM: suspicion of LNM on MDCT (odds ratio [OR] 13.40, p < 0.001), low-vascularity tumor (OR 6.28, p = 0.005), CA19-9 ≥500 U/mL (OR 5.90, p = 0.010), and tumor location in the left lobe (OR 3.67, p = 0.057). The predictive scoring system was created using these factors (assigning 3 points for suspected LNM on MDCT, 2 points for CA19-9 ≥500 U/mL, 2 points for low vascularity tumor, and 1 point for tumor location in the left lobe). A score cutoff value of 4 resulted in 0.861 sensitivity and a negative predictive value of 0.922 for detecting LNM. Notably, no patients with peripheral tumors and a score of ≤3 had LNM. CONCLUSION: The developed scoring system may effectively help identify ICC patients without LNM.

Double hepatic vein reconstruction during extended anatomical resection of segment 8 for colorectal liver metastasis.

BACKGROUND: Hepatic vein reconstruction (HVR) is occasionally necessary for resecting hepatic malignancies to ensure surgical margins while preserving remnant liver function [1]. Reports of multiple HVR are rare due to the highly technical demanding procedure and high risk of morbidity [2]. We introduce our procedure of double HVR for metastatic liver tumors invading the right hepatic vein (RHV) and middle hepatic vein (MHV). METHODS: The patient was a 66-year-old man with colorectal liver metastasis in segment 8, invading RHV and MHV. Due to impaired liver function, extended right hemihepatectomy was unsuitable. Thus, extended anatomical resection of segment 8 with double HVR was performed. The liver was completely mobilized and the RHV and MHV were secured. After liver parenchyma dissection, the specimen was connected by RHV and MHV (Fig. 1). The MHV was dissected and reconstructed using a right superficial femoral vein graft while the RHV remained connected [3]. Reconstruction of the MHV was performed on the posterior wall of the proximal side, followed by the anterior wall, using 4-point supporting threads. Anastomosis was performed by the over-and-over suture method. On the distal side, two-point supporting threads were applied. After specimen removal, the RHV was resected and reconstructed in the same manner using a left internal jugular vein graft [4]. RESULTS: The patient was discharged on postoperative day 14 with no signs of liver failure. Computed tomography performed six months after surgery revealed no graft occlusion (Fig. 2). CONCLUSION: In appropriately selected patients, this technique may be a useful option for preserving the remnant liver function.

Efficacy of lymph node dissection for duodenal cancer according to the lymph node station.

Background: Lymph node metastasis (LNM) is associated with poor prognosis in patients with duodenal cancer (DC). However, the efficacy and optimal extent of lymph node (LN) dissection have not been thoroughly discussed. Methods: A total of 98 consecutive patients with DC who underwent surgical resection (pancreatoduodenectomy, n = 55; partial resection, n = 32; pancreas-sparing total duodenectomy, n = 9) were retrospectively analyzed. The LN stations located upstream of the lymphatic flow were defined as Np stations according to tumor location, whereas the others were defined as Nd stations. The association between the dissection of each LN station and survival outcome was investigated using the efficacy index (EI; percentage of metastases to lymph nodes in each station multiplied by the 5-year survival rate of metastatic cases). Results: The survival of patients with LNM at the Nd stations (n = 6) was significantly worse than that of patients with LNM only at the Np stations (n = 20) (relapse-free survival, median survival time [MST], 6.0 vs. 48.4 months, p < 0.001; overall survival, MST, 15.1 vs. 96.0 months, p < 0.001). Multivariate analysis identified LNM at Nd stations as an independent prognostic factor for overall survival (hazard ratio 9.92; p = 0.015). The Np stations had a high EI (range, 8.34-20.88), whereas the Nd stations had an EI of 0, regardless of the tumor location. Conclusions: LN dissection of the Np stations contributed to acceptable survival, whereas LNM of the Nd stations led to poor survival, possibly reflecting advanced tumor progression to systemic disease in patients with DC.

Tumor vascularity on contrast-enhanced computed tomography as a predictive marker of metastatic potential for small nonfunctioning pancreatic neuroendocrine tumors.

BACKGROUND: Although surgical resection is generally suggested for nonfunctioning pancreatic neuroendocrine tumors, observation can be proposed for carefully selected patients with small tumors. However, the indications for observation remain unclear. METHODS: This retrospective study included 77 patients with nonfunctioning pancreatic neuroendocrine tumors, including small tumors (≤2.0 cm, n = 41), who received pancreatectomy. The ratio of the mean computed tomography value of a tumor in the late arterial/equilibrium phase (computed tomography a/e ratio) was used to evaluate tumor vascularity. Pathologic examinations of small tumors were conducted. The associations among the computed tomography a/e ratio, pathologic findings, and survival outcomes were investigated. RESULTS: Small tumors were pathologically categorized by the degree of fibrosis as follows: medullary (n = 20), intermediate (n = 11), and fibrotic (n = 10). The fibrotic type had significantly lower computed tomography a/e ratios than the medullary type (median, 1.42 vs 2.03, P < .001). The median number of vessels with microscopic venous invasion was significantly higher in the fibrotic type than in the medullary type (4.5 vs 0.0, P < .001). The cutoff value of the computed tomography a/e ratio for predicting microscopic venous invasion was determined to be 1.54 by the receiver operating characteristic curve (area under the curve, 0.832; sensitivity, 80.0%; specificity, 83.9%; accuracy, 82.9%). Microscopic venous invasion was an independent prognostic factor for relapse-free survival in overall patients (hazard ratio 5.18, P = .017). CONCLUSION: The computed tomography a/e ratio may be a useful predictor of the metastatic potential of nonfunctioning pancreatic neuroendocrine tumors and may help decide the indications of observation for small nonfunctioning pancreatic neuroendocrine tumors.

Feasibility of S-1 adjuvant chemotherapy after major hepatectomy for biliary tract cancers: An exploratory subset analysis of JCOG1202.

INTRODUCTION: Major hepatectomy (MH) may produce the impaired liver function and affect the feasibility of adjuvant chemotherapy in terms of early period after the surgery, but there have not been detailed investigations. JCOG1202 (UMIN000011688) is a randomized phase III trial demonstrating the superiority of adjuvant S-1 chemotherapy for biliary tract cancer (BTC). The aim of this study is to examine the influence of MH for BTC on adjuvant S-1. MATERIALS AND METHODS: Of the total 424 patients, 207 received S-1 (S-1 arm) while the remaining 217 were not. We compared MH with non-major hepatectomy (NMH) for BTC. RESULTS: In the S-1 arm, 42 had undergone MH, and 165 had undergone NMH. MH had similar pretreatment features to NMH, including the proportion of biliary reconstruction, to NMH, except for a lower platelet count (17.7 vs. 23.4 × 104/mm3, p < 0.0001) and lower serum albumin level (3.5 vs. 3.8 g/dL, p < 0.0001). The treatment completion proportion tended to be lower for MH than for NMH (59.5 % vs. 75.8 %; risk ratio, 0.786 [95 % confidence interval, 0.603-1.023], p = 0.0733), and the median dose intensity was lower as well (88.7 % vs. 99.6 %, p = 0.0358). The major reasons for discontinuation were biliary tract infections and gastrointestinal disorders after MH. The frequency of grade 3-4 biliary tract infection was 19.0 % in MH vs. 4.2 % in NMH. CONCLUSION: The treatment completion proportion and dose intensity were lower in MH than in NMH. Caution should be exercised against biliary tract infections and gastrointestinal disorders during adjuvant S-1 after MH for BTC.

Impact of Mutations in Subunit Genes of the Mammalian SWI/SNF Complex on Immunological Tumor Microenvironment.

BACKGROUND/AIM: Recently, inactivating somatic mutations of SWI/SNF chromatin-remodeling genes in cancers have been reported. However, few studies have been performed regarding the immunological analysis of the tumor microenvironment (TME) in chromatin remodeling complex gene-mutated tumors. In the present study, we identified cancer patients harboring various mammalian SWI/SNF complex mutations and investigated the immunological features in those mutated cancers. PATIENTS AND METHODS: Cancer patients harboring any type of chromatin remodeling complex gene mutation were selected and clinicopathological features were compared between chromatin remodeling complex gene expression-low and expression-high groups. Specifically, expression levels of immune response-associated genes and cancer-associated genes were compared between the SMARCA4 expression-low and expression-high groups using volcano plot analysis. RESULTS: Among cancers harboring PBRM1, SAMRACA4 and ARID2 gene mutations, T-cell marker and mature B-cell marker genes were up-regulated in the tumor. Specifically, T-cell effector genes (CD8B, CD40LG), central memory marker genes (CD27, CCR7) and mature B-cell marker genes (CD20, CD38, CD79 and IRF4) were up-regulated, and cancer-associated genes including MYB, MYC and AURKB genes were down-regulated in the SMARCA4 expression-low group. Remarkably, heatmap of gene expression and immunohistochemistry (IHC) data demonstrated that the tertiary lymphoid structure (TLS) gene signature of mature B cells was up-regulated in SMACA4 gene-mutated stomach cancers. CONCLUSION: These results suggest that immune tumor microenvironment status, such as mature B cell recruitment featuring the TLS gene signature and immune activation mediated by cancer signal down-regulation, might contribute to the classification of SMARCA4 gene-mutated tumors as immune checkpoint blockade therapy-sensitive target tumors.

Prognostic impact of the distance from the root of splenic artery to tumor in the patients with pancreatic body or tail cancer.

BACKGROUND: The impact of the distance from the root of splenic artery to tumor (DST) on the prognosis and optimal surgical procedures in the patients with pancreatic body/tail cancer has been unclear. METHODS: We retrospectively analyzed 94 patients who underwent distal pancreatectomy (DP) and 17 patients who underwent DP with celiac axis resection (DP-CAR) between 2008 and 2018. RESULTS: The 111 patients were assigned by DST length (in mm) as DST = 0: n = 14, 0

Efficacy of combined use of Suvorexant and Ramelteon in preventing postoperative delirium: a retrospective comparative study.

BACKGROUND: Suvorexant and ramelteon have been presented as useful for preventing postoperative delirium. Previous studies reported on the comparison with benzodiazepine hypnotics which have been known for the risk for inducing delirium, but the comparison with patients not taking any hypnotics has not been reported yet. Therefore, we assessed the incidence rates for postoperative delirium comparing cancer patients who received preoperative combined administration with suvorexant and ramelteon and those not taking any hypnotics. METHODS: Among 110 cancer patients who underwent surgeries at the Division of Hepato-Biliary-Pancreatic Surgery at the Shizuoka Cancer Center between April 1, 2017 and June 30, 2020, 50 patients who received combined administration with suvorexant and ramelteon from 7 days prior to their surgeries and 60 patients who did not take any hypnotics including suvorexant and ramelteon were classified. They were retrospectively observed during the 7 days from their surgeries onward to compare the cumulative incidence rates for postoperative delirium. RESULTS: The cumulative incidence rate for postoperative delirium during the 7 days in the combined-administration group was 14.0% (7/50), while that for the no-hypnotic group was 36.7% (22/60), which proved that the incidence rate for the former was significantly low (OR: 0.28, 95%CI: 0.11-0.73, P = 0.009). CONCLUSIONS: The present study suggests that the preventive combined administration with suvorexant and ramelteon starting from the preoperative period for cancer patients can be effective in lowering the incidence rate for postoperative delirium. TRIAL REGISTRATION: Retrospectively registered.

Endoscopic nasobiliary drainage versus endoscopic biliary stenting for preoperative biliary drainage in patients with malignant hilar biliary obstruction: Propensity score-matched multicenter comparative study.

OBJECTIVES: For preoperative biliary drainage (PBD) of malignant hilar biliary obstruction (MHBO), current guidelines recommend endoscopic nasobiliary drainage (ENBD) due to the higher risk of cholangitis after endoscopic biliary stenting (EBS) during the waiting period before surgery. However, few studies have supported this finding. Therefore, we aimed to compare the outcomes of preoperative ENBD and EBS in patients with MHBO. METHODS: Patients with MHBO who underwent laparotomy for radical surgery after ENBD or EBS were included from retrospectively collected data from 13 centers (January 2014 to December 2018). We performed a 1:1 propensity score matching between the ENBD and EBS groups. These patients were compared for the following: cholangitis and all adverse events (AEs) after endoscopic biliary drainage (EBD) until surgery, time to cholangitis development after EBD, postsurgical AEs, and in-hospital death after surgery. RESULTS: Of the 414 patients identified, 355 were analyzed in this study (226 for ENBD and 129 for EBS). The matched cohort included 63 patients from each group. The proportion of cholangitis after EBD was similar between the two groups (20.6% vs. 25.4%, P = 0.67), and no significant difference was observed in the time to cholangitis development. The proportions of surgical site infections, bile leaks, and in-hospital mortality rates were similar between the groups. CONCLUSION: For PBD of MHBO, the proportion of AEs, including cholangitis, after EBD until surgery was similar when either ENBD or EBS was used.

Benefit of lymph node dissection for perihilar and distal cholangiocarcinoma according to lymph node stations.

BACKGROUND: The benefits of lymph node (LN) dissection at each station have not previously been fully investigated in perihilar cholangiocarcinoma (PHCC) and distal cholangiocarcinoma (DCC). METHODS: The efficacy index (EI) was calculated in patients who underwent surgery for PHCC (n = 134) and DCC (n = 135) by multiplying the frequency of metastasis to the LN station and the 5-year overall survival (OS) rate of patients with metastasis to that station. RESULTS: In PHCC, the frequency of metastasis, 5-year OS rates, and the EI in para-aortic LNs (4.7%, 0%, and 0, respectively) and posterior pancreaticoduodenal LNs (8.1%, 0%, and 0, respectively) were lower than those in hepatoduodenal ligament LNs (30.1%, 24.1%, and 7.25, respectively) and LNs along the common hepatic artery (CHA) (16.2%, 15.0%, and 2.43, respectively). In DCC, these values were lower in LNs along the CHA (6.4%, 0%, and 0, respectively) than in the posterior pancreaticoduodenal LNs (31.2%, 34.5%, and 10.8, respectively), the hepatoduodenal ligament LNs (14.8%, 15.2%, and 2.25, respectively), and para-aortic (4.0%, 25.0%, and 0.99, respectively) LNs. CONCLUSIONS: According to the EI, this study raises concerns about the effectiveness of dissection in the posterior pancreaticoduodenal LNs in PHCC and LNs along the CHA in DCC.

Randomized phase II trial of chemoradiotherapy with S-1 versus combination chemotherapy with gemcitabine and S-1 as neoadjuvant treatment for resectable pancreatic cancer (JASPAC 04).

OBJECTIVE: The aim of the present study was to investigate which treatment, neoadjuvant chemoradiotherapy (NAC-RT) with S-1 or combination neoadjuvant chemotherapy with gemcitabine and S-1 (NAC-GS), is more promising as neoadjuvant treatment (NAT) for resectable pancreatic cancer in terms of effectiveness and safety. METHODS: In the NAC-RT with S-1 group, the patients received a total radiation dose of 50.4 Gy in 28 fractions with oral S-1. In the NAC-GS group, the patients received intravenous gemcitabine at a dose of 1000 mg/m2 with oral S-1 for two cycles. The primary endpoint was the 2-year progression-free survival (PFS) rate. The trial was registered with the UMIN Clinical Trial Registry as UMIN000014894. RESULTS: From April 2014 to April 2017, a total of 103 patients were enrolled. After exclusion of one patient because of ineligibility, 51 patients were included in the NAC-RT with S-1 group, and 51 patients were included in the NAC-GS group in the intention-to-treat analysis. The 2-year PFS rate was 45.0% (90% confidence interval [CI]: 33.3%-56.0%) in the NAC-RT with S-1 group and 54.9% (42.8%-65.5%) in the NAC-GS group (p = .350). The 2-year overall survival rate was 66.7% in the NAC-RT with S-1 group and 72.4% in the NAC-GS group (p = .300). Although leukopenia and neutropenia rates were significantly higher in the NAC-GS group than in the NAC-RT with S-1 group (p = .023 and p < .001), other adverse events of NAT and postoperative complications were comparable between the two groups. CONCLUSION: Both NAC-RT with S-1 and NAC-GS are considered promising treatments for resectable pancreatic cancer.

Comparison of Cefazolin and Ceftriaxone as Antimicrobial Prophylaxis in Pancreatoduodenectomy with Preoperative Drainage: Incidence of Surgical Site Infection and Susceptibility of Bacteria in Bile.

BACKGROUND: The optimal perioperative antimicrobial agent for preventing surgical site infection (SSI) in pancreatoduodenectomy (PD) with preoperative biliary drainage (PBD) remains unclear. METHODS: We retrospectively reviewed 288 patients who underwent PD after PBD between 2010 and 2020 at our institution. Patients were classified into two groups according to the perioperative antimicrobial agent used (cefazoline [CEZ] group [n = 108] and ceftriaxone [CTRX] group [n = 180]). The incidence of SSI, type of bacteria in intraoperative bile culture (IBC), and antimicrobial susceptibility to prophylactic antimicrobial agents were analyzed. RESULTS: The incidence of incisional SSI was significantly lower in the CTRX group than in the CEZ group (18% vs. 31%, P = 0.021), whereas the incidence of organ/space SSI in the two groups did not differ to a statistically significant extent (35% vs. 44%, P = 0.133). Gram-negative rod (GNR) bacteria in the IBC showed better antimicrobial susceptibility in the CTRX group than in the CEZ group. In multivariate analysis, antimicrobial resistance due to GNR was a significant risk factor for incisional SSI (odds ratio, 3.50; P < 0.001). CONCLUSIONS: CTRX had better antimicrobial coverage than CEZ for GNR cultured from intraoperative bile samples. In addition, CTRX provides better antimicrobial prophylaxis than CEZ against superficial SSI in patients with PD after PBD. TRIAL REGISTRATION NUMBER: This study was not a clinical trial and had no registration numbers.

Morbidity after left trisectionectomy for hepato-biliary malignancies: An analysis of the National Clinical Database of Japan.

BACKGROUND: The aim of this study was to analyze the nationwide surgical outcome of a left trisectionectomy (LT) and to identify the perioperative risk factors associated with its morbidity. METHODS: Cases of LT for hepato-biliary malignancies registered at the Japanese National Clinical Database between 2013 and 2019 were retrospectively reviewed. Statistical analyses were performed to identify the perioperative risk factors associated with a morbidity of Clavien-Dindo classification (CD) ≥III. RESULTS: Left trisectionectomy was performed on 473 and 238 cases of biliary and nonbiliary cancers, respectively. Morbidity of CD ≥III and V occurred in 45% and 5% of cases with biliary cancer, respectively, compared with 26% and 2% of cases with nonbiliary cancer, respectively. In multivariable analyses, biliary cancer was significantly associated with a morbidity of CD ≥III (odds ratio, 1.87; p = .018). In subgroup analyses for biliary cancer, classification of American Society of Anesthesiologists physical status (ASA-PS) 2, portal vein resection (PVR), and intraoperative blood loss ≥30 mL/kg were significantly associated with a morbidity of CD ≥III. CONCLUSIONS: Biliary cancer induces severe morbidity after LT. The ASA-PS classification, PVR, and intraoperative blood loss indicate severe morbidity after LT for biliary cancer.

Surrogacy of Recurrence-free Survival for Overall Survival as an Endpoint of Clinical Trials of Perioperative Adjuvant Therapy in Hepatobiliary-pancreatic Cancers: A Retrospective Study and Meta-analysis.

OBJECTIVE: To assess the correlation between recurrence-free survival (RFS) and overall survival (OS) in the hepato-biliary-pancreatic (HBP) surgical setting in order to validate RFS as a surrogate endpoint. SUMMARY BACKGROUND DATA: Reliable surrogate endpoints for OS are still limited in the field of HBP surgery. METHODS: We analyzed patients who underwent curative resection for HBP disease (986 patients with pancreatic ductal adenocarcinoma [PDAC], 1168 with biliary tract cancer [BTC], 1043 with hepatocellular carcinoma [HCC], and 1071 with colorectal liver metastasis [CRLM]) from September 2002 to June 2022. We also conducted meta-analyses of randomized controlled trials of neoadjuvant or adjuvant therapy to validate the surrogacy in PDAC and BTC. RESULTS: Correlation coefficients between RFS and OS were low for HCC (ρ = 0.67) and CRLM (ρ = 0.53) but strong for PDAC (ρ = 0.80) and BTC (ρ = 0.75). In a landmark analysis, the concordance rates between survival or death at 5 years postoperatively and the presence or absence of recurrence at each time point (1, 2, 3, and 4 y) were 50%, 70%, 74%, and 77% for PDAC and 54%, 67%, 73%, and 78% for BTC, respectively, both increasing and reaching a plateau at 3 years. In a meta-analysis, the correlation coefficients for the RFS hazard ratio and OS hazard ratio in PDAC and BTC were ρ = 0.88 (P < 0.001) and ρ = 0.87 (P < 0.001), respectively. CONCLUSION: Three-year RFS can be a reliable surrogate endpoint for OS in clinical trials of neoadjuvant or adjuvant therapy for PDAC and BTC.

Conversion surgery for advanced jejunal adenocarcinoma with multiple peritoneal metastases: a case report.

BACKGROUND: Small bowel cancer (SBC) is a rare malignancy that is often diagnosed at an advanced stage. Palliative chemotherapy is the standard treatment for patients with metastatic SBC. The relevant literature on conversion surgery in patients who have responded favorably to chemotherapy is limited. CASE PRESENTATION: A 64-year-old man was diagnosed with jejunal carcinoma with multiple peritoneal metastases. After implanting an expandable metallic stent at the primary site, the patient underwent 6 months of FOLFOX therapy, resulting in a clinical complete response. Chemotherapy was continued, and four years after the initiation of therapy, the patient showed no evidence of disease progression. Nevertheless, anemia of continuous minor hemorrhages from the stent site and general malaise of chemotherapy got progressively worse during treatment. After confirming negative ascites cytology and the absence of peritoneal metastasis via staging laparoscopy, the patient underwent partial jejunectomy. Pathologically, no residual tumor was detected in the resected specimen. The postoperative course was uneventful, and the patient remained free of recurrence for 30 months after surgery without chemotherapy. CONCLUSION: Although infrequent, conversion surgery may be a valid therapeutic option for selected cases of SBC with peritoneal metastasis.

Novel Benchmark Values for Open Major Anatomic Liver Resection in Non-cirrhotic Patients: A Multicentric Study of 44 International Expert Centers.

OBJECTIVE: This study aims at establishing benchmark values for best achievable outcomes following open major anatomic hepatectomy for liver tumors of all dignities. BACKGROUND: Outcomes after open major hepatectomies vary widely lacking reference values for comparisons among centers, indications, types of resections, and minimally invasive procedures. METHODS: A standard benchmark methodology was used covering consecutive patients, who underwent open major anatomic hepatectomy from 44 high-volume liver centers from 5 continents over a 5-year period (2016-2020). Benchmark cases were low-risk non-cirrhotic patients without significant comorbidities treated in high-volume centers (≥30 major liver resections/year). Benchmark values were set at the 75th percentile of median values of all centers. Minimum follow-up period was 1 year in each patient. RESULTS: Of 8044 patients, 2908 (36%) qualified as benchmark (low-risk) cases. Benchmark cutoffs for all indications include R0 resection ≥78%; liver failure (grade B/C) ≤10%; bile leak (grade B/C) ≤18%; complications ≥grade 3 and CCI ® ≤46% and ≤9 at 3 months, respectively. Benchmark values differed significantly between malignant and benign conditions so that reference values must be adjusted accordingly. Extended right hepatectomy (H1, 4-8 or H4-8) disclosed a higher cutoff for liver failure, while extended left (H1-5,8 or H2-5,8) were associated with higher cutoffs for bile leaks, but had superior oncologic outcomes, when compared to formal left hepatectomy (H1-4 or H2-4). The minimal follow-up for a conclusive outcome evaluation following open anatomic major resection must be 3 months. CONCLUSION: These new benchmark cutoffs for open major hepatectomy provide a powerful tool to convincingly evaluate other approaches including parenchymal-sparing procedures, laparoscopic/robotic approaches, and alternative treatments, such as ablation therapy, irradiation, or novel chemotherapy regimens.

Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557-558 Deletion Mutations.

Gastrointestinal stromal tumors (GIST) with KIT exon 11 deletions involving in codons 557-558 (KIT Δ557-558) exhibit higher proliferation rates and shorter disease-free survival times compared with GISTs with other KIT exon 11 mutations. We analyzed 30 GIST cases and observed genomic instability and global DNA hypomethylation only in high-risk malignant GISTs with KIT Δ557-558. Whole-genome sequencing revealed that the high-risk malignant GISTs with KIT Δ557-558 (12 cases) had more structural variations (SV), single-nucleotide variants, and insertions and deletions compared with the low-risk, less malignant GISTs with KIT Δ557-558 (six cases) and the high-risk (six cases) or low-risk (6 cases) GISTs with other KIT exon 11 mutations. The malignant GISTs with KIT Δ557-558 showed higher frequency and significance in copy number (CN) reduction on chromosome arms 9p and 22q, and 50% of them had LOH or CN-dependent expression reduction in CDKN2A. In addition, SVs with driver potential were detected in 75% of them, in which AKT3 and MGMT were recurrently identified. Genome-wide DNA methylation and gene expression analyses showed global intergenic DNA hypomethylation, SNAI2 upregulation, and higher expression signatures, including p53 inactivation and chromosomal instability, as characteristics of malignant GISTs with KIT Δ557-558 that distinguished them from other GISTs. These genomic and epigenomic profiling results revealed that KIT Δ557-558 mutations are associated with increased genomic instability in malignant GISTs. Significance: We present genomic and epigenomic insights into the malignant progression of GISTs with KIT exon 11 deletions involving in 557-558, demonstrating their unique chromosomal instability and global intergenic DNA hypomethylation.

Liver abscess caused by Clostridium perfringens after left hepatic trisectionectomy for perihilar cholangiocarcinoma: a case report.

BACKGROUND: Clostridium perfringens sepsis has been reported to have a rapid onset and severe clinical outcome. We herein report a case of C. perfringens sepsis associated with massive intravascular hemolysis after left hepatic trisectionectomy for perihilar cholangiocarcinoma. CASE PRESENTATION: A 72-year-old woman underwent left hepatic trisectionectomy for perihilar cholangiocarcinoma. Her postoperative course was uneventful except for bile leakage. She was discharged on postoperative day (POD) 35. On POD 54, she was readmitted because of abdominal pain with a high fever. Although her vital signs were stable on arrival at the hospital, a laboratory examination showed a severe inflammatory reaction and hemolysis, and she had developed disseminated intravascular coagulation. Abdominal contrast-enhanced computed tomography showed a 70-mm irregular shape and low-density containing air in liver segment 6, which suggested a liver abscess. The abscess was immediately drained of pus containing air. The pus showed multiple Gram-positive bacilli, and two blood cultures showed Gram-positive bacilli and hemolysis. Empirical antibiotic therapy with vancomycin and meropenem was started because C. perfringens was detected from the preoperative bile culture. Four hours after arrival, tachypnea and decreased oxygen saturation were observed. Her general condition deteriorated rapidly with significant hypoglycemia, progressive acidosis, anemia, and thrombocytopenia. Despite rapid drainage and empiric therapy, she died six hours after her arrival. At autopsy, the abscess consisted of coagulation necrosis of liver cells with inflammatory cell infiltration, and clusters of Gram-positive large bacilli were observed in the necrotic debris. C. perfringens was detected in the drainage fluid and blood culture. She was diagnosed with a liver abscess and severe sepsis caused by C. perfringens and treated promptly, but the disease progressed rapidly and led to her death. CONCLUSIONS: Sepsis caused by C. perfringens can progress rapidly and lead to death in a few hours, so prompt treatment is needed. When patients who have undergone highly invasive hepatobiliary-pancreatic surgery show hemolysis and hepatic abscesses with gas, C. perfringens should be considered the most likely bacterium.

ASO Author Reflections: Prognostic Role of Preoperative Duke Pancreatic Monoclonal Antigen Type 2 Values in Patients with Pancreatic Cancer: Focusing on the Usefulness in Patients with Normal CA19-9.

Pancreatic cancer (PC) is one of the most aggressive cancer types, and carbohydrate antigen (CA) 19-9 has been the most useful biomarker for its surveillance and prognosis prediction. However, CA19-9 may not be sufficiently prognostic in some patients, such as Lewis antigen-negative phenotype (Le[a-b-]) patients who secrete little or no CA19-9. Duke pancreatic monoclonal antigen type 2 (DUPAN-2) has been proposed as a complementary marker to CA19-9 in PC patients, but its utility in Le(a-b-) patients has only been reported in a limited number of cases. In a retrospective analysis of 224 PC patients who underwent surgery, the present study investigated the utility of DUPAN-2 in combination with CA19-9. The study subjects were divided into three groups based on their CA19-9 and DUPAN-2 levels. The normal CA19-9/high DUPAN-2 group had significantly larger tumors and a higher frequency of microscopic vascular invasion, perineural invasion, and recurrence than the normal CA19-9/normal DUPAN-2 group. Both the disease-free survival and disease-specific survival (DSS) of patients in the normal CA19-9/high DUPAN-2 group were significantly shorter than those in the normal CA19-9/normal DUPAN-2 group, and comparable with those in the high CA19-9 group. The results suggest that DUPAN-2 may be useful as a complementary biomarker to CA19-9 in PC, especially in patients who have normal CA19-9 levels. However, since this was a single-center, retrospective study, multicenter studies are needed to confirm the findings and determine the optimal cut-off value for patients with normal CA19-9 levels.