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Background/aim This study aimed to evaluate how NAD(P)H: quinone oxidoreductase-1 (NQO1) affects survival after hepatectomy in patients with colorectal liver metastasis (CRLM). Patients and methods A retrospective analysis was conducted of 88 consecutive patients who underwent hepatectomy for CRLM. Of the 88 patients, preoperative chemotherapy was administered to 30 patients. Immunohistochemistry of the resected specimens was conducted using monoclonal anti-NQO1 antibody. Results NQO1-positive expression in tumor cells of CRLM was associated with worse overall survival (p=0.026) and was an independent adverse prognostic factor in multivariate analysis (hazard ratio=5.296, p=0.007). Among 30 patients who received preoperative chemotherapy, patients with loss of NQO1 expression in non-neoplastic epithelial cells of the bile ducts (NQO1 polymorphism: n=19) showed significantly better response to preoperative chemotherapy for CRLM (p=0.004). Conclusion NQO1-positive expression in tumor cells of CRLM may be an adverse prognostic factor after hepatectomy for CRLM.

BACKGROUND: Activin A receptor type 2A (ACVR2A) is one of the most frequently mutated genes in microsatellite instability-high (MSI-H) gastric cancer. However, the clinical relevance of the ACVR2A mutation in MSI-H gastric cancer patients remains unclear. The aims of this study were to explore the effect of ACVR2A mutation on the tumor behavior and to identify the clinicopathological characteristics of gastric cancer patients with ACVR2A mutations. METHODS: An in vitro study was performed to investigate the biological role of ACVR2A via CRISPR/Cas9-mediated ACVR2A knockout MKN74 human gastric cancer cells. 124 patients with gastric cancer were retrospectively analyzed and relations between MSI status, ACVR2A mutations, and clinicopathological factors were evaluated. RESULTS: ACVR2A knockout cells showed less aggressive tumor biology than mock-transfected cells, displaying reduced proliferation, migration and invasion (P < 0.05). MSI mutations were found in 10% (13/124) of gastric cancer patients, and ACVR2A mutations were found in 8.1% (10/124) of patients. All ACVR2A mutations were accompanied by MSI. The 5-year overall survival rates of ACVR2A wild-type patients and ACVR2A-mutated patients were 57% and 90%, respectively (P = 0.048). Multivariate analysis revealed that older age (P = 0.015), distant metastasis (P < 0.001), and ACVR2A wild-type status (P = 0.040) were independent prognostic factors for overall survival. CONCLUSIONS: Our study demonstrated that gastric cancer patients with ACVR2A mutation has a significantly better prognosis than those without. Dysfunction of ACVR2A in MKN74 human gastric cancer cells caused less aggressive tumor biology, indicating the importance of ACVR2A in the progression of MSI-H tumors.

Background This study aimed to investigate the incidence and distribution of regional lymph node metastasis according to tumor location, and to clarify whether tumor location could determine the extent of regional lymphadenectomy in patients with pathological T2 (pT2) gallbladder carcinoma. Methods In total, 81 patients with pT2 gallbladder carcinoma (25 with pT2a tumors and 56 with pT2b tumors) who underwent radical resection were enrolled. Tumor location was determined histologically in each gallbladder specimen. Results Survival after resection was significantly worse in patients with pT2b tumors than those with pT2a tumors (5-year survival, 72% vs. 96%; p = 0.027). Tumor location was an independent prognostic factor on multivariate analysis (hazard ratio, 14.162; p = 0.018). The incidence of regional lymph node metastasis was significantly higher in patients with pT2b tumors than in those with pT2a tumors (46% vs. 20%; p = 0.028). However, the number of positive nodes was similar between the two groups (median, 2 vs. 2; p = 0.910). For node-positive patients with pT2b tumors, metastasis was found in every regional node group (12%–63%), whereas even for node-positive patients with pT2a tumors, metastasis was observed in regional node groups outside the hepatoduodenal ligament. Conclusions Tumor location in patients with pT2 gallbladder carcinoma can predict the presence or absence of regional lymph node metastasis but not the number and anatomical distribution of positive regional lymph nodes. The extent of regional lymphadenectomy should not be changed even in patients with pT2a tumors, provided that they are fit enough for surgery.

The role of surgery in the management of primary cystic duct carcinoma (CDC) remains unclear especially in advanced disease. This study aimed to evaluate long-term outcomes in patients undergoing surgery for primary CDC. From a multi-institutional database, we identified 41 patients who underwent surgery for primary CDC, defined as a part of gallbladder carcinoma with the tumor centre located in the cystic duct. Of the 41 patients, 31 (75.6%) underwent preoperative biliary drainage for jaundice. Twenty-eight (68.3%) patients underwent extensive resection including major hepatectomy (n = 21), pancreaticoduodenectomy (n = 4), or both procedures (n = 3). Thirty-four (82.9%) patients had ≥ pT3 tumor, while 31 (75.6%) patients had involvement of contiguous organs/structures. Nodal and distant metastasis was found in 26 (63.4%) and 7 (17.1%) patients, respectively. Most patients (90.2%) had perineural invasion. Median overall survival was 23.7 months in all 41 patients. Factors independently associated with both overall and disease-specific survival were pN (P = 0.003 and P = 0.007, respectively) and pM (P = 0.003 and P = 0.013, respectively) classification. Median survival was 75.3, 17.7, and 5.2 months for patients with pN0M0 (n = 14), pN1/2pM0 or pN0pM1 (n = 21), and pN1/2pM1 (n = 6) disease, respectively (P

Background Solitary fibrous tumor (SFT), a mesenchymal fibroblastic tumor with a hypervascular nature, rarely develops in the pelvis. Resection of a giant SFT occupying the pelvic cavity poses an increased risk of developing massive hemorrhage during resection, although surgical resection is the most effective treatment method for this tumor to achieve a potential cure. SFT rarely develops with Doege–Potter syndrome, which is known as a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia (NICTH) secondary to SFT that secretes insulin-like growth factor-II (IGF-II). We present a case of a giant pelvic SFT with Doege–Potter syndrome, which was successfully treated with transcatheter arterial embolization (TAE) followed by surgical resection. Case presentation A 46-year-old woman presented with a disorder of consciousness due to refractory hypoglycemia. Images of the pelvis showed a giant and heterogeneously hypervascular mass displacing and compressing the rectum. Endocrinological evaluation revealed low serum levels of insulin and C-peptide consistent with NICTH. Angiography identified both the inferior mesenteric artery and the bilateral internal iliac artery as the main feeders of the tumor. To avoid intraoperative massive bleeding, super-selective TAE was performed for the tumor 2 days prior to surgery. Hypoglycemia disappeared after TAE. The tumor was resected completely, with no massive hemorrhage during resection. Histologically, it was diagnosed as IGF-II-secreting SFT. Partial necrosis of the rectum in the specimen was observed due to TAE. The patient was followed up for 2 years and no evidence of disease has been reported. Conclusions Preoperative angiography followed by TAE is an exceedingly helpful method to reduce intraoperative hemorrhage when planning to resect SFT occupying the pelvic cavity. Complications related to ischemia should be kept in mind after TAE, which needs to be planned within 1 or 2 days before surgery. TAE for tumors may be an option in addition to medical and surgical treatment for persistent hypoglycemia in Doege–Potter syndrome.

Objectives A number of patients have developed liver failure after the Kasai operation for biliary atresia (BA), even after long-term postoperative course. We report our experience regarding four cases of biliary atresia required and treated with living donor liver transplantation (LDLT) during adulthood. Methods All four patients underwent Kasai operation for BA from 1974 to 1983 and had been followed-up for more than 30 years in our institute. Then, they developed liver failure and treated with LDLT. These four patients’ records were reviewed retrospectively. All data are described using the median value. Results Three female and one male were included. Kasai operation was performed at the age of 61 days. The type of biliary obstruction was type III-b1-ν in all. The survival period of the native liver was 440 months. The age at LDLT was 37 years. The reasons of deterioration of native liver were recurrent cholangitis in two and pregnancy and delivery in other two. The age of living donor was 40 years. Right liver grafts were used in all. Percentage of the real graft volume per standard liver volume was 47%. All patients were alive and overall graft survival rate was 100% at a follow-up period of 65 months after LDLT. Conclusion Even after more than 30 year-survival with native liver after Kasai operation, liver failure may be caused by recurrent cholangitis or pregnancy and delivery. LDLT may be effective treatment for those adult patients if an adequate living donor is available.

Background: NAD(P)H: quinone oxidoreductase-1 (NQO1) is an antioxidant and detoxifying protein, which contributes to chemoresistance in some types of cancer. This study aimed to evaluate how NQO1 affects the response to preoperative chemotherapy and survival after hepatectomy for patients with colorectal liver metastasis (CRLM).Methods: A retrospective analysis was conducted of 88 consecutive patients who underwent curative-intent hepatectomy for CRLM, with a median follow-up period of 65.4 months. Of the 88 patients, preoperative chemotherapy was administered to 30 patients, among which the association between NQO1 status and response to preoperative chemotherapy was evaluated. Immunohistochemistry of the resected specimens was conducted using monoclonal anti-NQO1 antibody.Results: According to NQO1 expression in tumor cells of CRLM, the 88 patients were classified into those with NQO1 expression (the NQO1-positive group) (n = 61) and those with loss of NQO1 expression (the NQO1-negative group) (n = 27). According to NQO1 expression in non-neoplastic epithelial cells of the large intrahepatic bile ducts, which typically show NQO1-positive expression, the 88 patients were classified into the NQO1 non-polymorphism group (positive expression, n = 69) and the NQO1 polymorphism group (loss of expression, n = 19). The NQO1-positive group had significantly worse overall survival than the NQO1-negative group (cumulative 5-year overall survival rate: 66.5% vs. 90.9%, p = 0.026), whereas NQO1 polymorphism status was not associated with overall survival. NQO1-positive expression was an independent adverse prognostic factor in multivariate analysis (hazard ratio: 5.296, p = 0.007). The presence of NQO1 polymorphism (loss of NQO1 expression in non-neoplastic epithelial cells of the large intrahepatic bile ducts) was significantly associated with a better response to preoperative chemotherapy for CRLM (p = 0.004).Conclusions: NQO1-positive expression may be an adverse prognostic factor after hepatectomy for CRLM. NQO1 polymorphism status may be a clinically useful biomarker for predicting the radiological response to preoperative chemotherapy for CRLM.

Outcomes following surgery for advanced gallbladder carcinoma remain unsatisfactory. This study aimed to determine the surgical outcome and effectiveness of adjuvant chemotherapy according to TNM stage in patients with gallbladder carcinoma. A total of 200 patients undergoing surgery for gallbladder carcinoma were enrolled. Clinicopathological data were evaluated and surgical outcomes were compared between patients with and without adjuvant chemotherapy according to TNM stage. The 5-year overall survival (OS) after resection for patients with stage I (n = 27), IIA (n = 18), IIB (n = 28), IIIA (n = 25), IIIB (n = 43), IVA (n = 7), and IVB (n = 52) disease was 90.8%, 94.4%, 73.6%, 33.7%, 57.7%, 14.3%, and 11.8%, respectively (p

A 68-year-old male patient received a living donor kidney transplantation 8 years earlier for end-stage kidney disease secondary to IgA nephropathy. His post-transplantation follow-up had been routinely performed with laboratory examinations, ultrasound, and computed tomography (CT). His kidney graft function had been excellent and stable, as shown by a baseline serum creatinine level of 1.0 mg/dL. At referral, regular follow-up ultrasound and CT showed allograft hydroureteronephrosis. He did not have any complaints, but his physical examination revealed right inguinal bulging that was 3.5 × 3.5 cm. Abdominal enhanced CT revealed transplant allograft hydroureteronephrosis due to ipsilateral herniation of ureteroneocystostomy into the right inguinal canal. His serum creatinine level was slightly elevated (1.1 mg/dL). Then, he underwent an open right inguinal hernia repair. Paraperitoneal allograft hydroureteronephrosis and bladder herniation was confirmed at surgery, and hernioplasty with polypropylene mesh reinforcement was successfully performed. The postoperative course was uneventful. He was discharged on the seventh day after surgery. Six weeks after surgery, CT revealed disappearance of allograft hydroureteronephrosis and no sign of inguinal hernia recurrence with the serum creatinine stable at 1.0 mg/dL. Transplant ureteral obstruction due to inguinal hernia is a rare complication after kidney transplantation. However, transplant ureter or bladder herniation should be considered in the differential diagnosis of graft hydroureteronephrosis for preventing allograft loss.

Background There is no comprehensive agreement concerning the overall performance of radical resection for T1b gallbladder cancer (GBC). This research focused on addressing whether T1b GBC may spread loco-regionally and whether radical resection is necessary. Methods A retrospective analysis was conducted of 1032 patients with GBC who underwent surgical resection at our centre and its affiliated institutions between January 1982 and December 2018. A total of 47 patients with T1b GBC, 29 (62%) of whom underwent simple cholecystectomy and 18 (38%) of whom underwent radical resection with regional lymph node dissection, were enrolled in the study. Results GBC was diagnosed pre-operatively in 16 patients (34%), whereas 31 patients (66%) had incidental GBC. There was no blood venous or perineural invasion in any patient on histology evaluation, except for lymphatic vessel invasion in a single patient. There were no metastases in any analysed lymph nodes. The open surgical approach was more prevalent among the 18 patients who underwent radical resection (open in all 18 patients) than among the 29 patients who underwent simple cholecystectomy (open in 21; laparoscopic in 8) (P = 0.017). The cumulative 10- and 20-year overall survival rates were 65 and 25%, respectively. The outcome following simple cholecystectomy (10-year overall survival rate of 66%) was akin to that following radical resection (64%, P = 0.618). The cumulative 10- and 20-year disease-specific survival rates were 93 and 93%, respectively. The outcome following simple cholecystectomy (10-year disease-specific survival rate of 100%) was equivalent to that following radical resection (that of 86%, P = 0.151). While age (> 70 years, hazard ratio 5.285, P = 0.003) and gender (female, hazard ratio 0.272, P = 0.007) had a strong effect on patient overall survival, surgical procedure (simple cholecystectomy vs. radical resection) and surgical approach (open vs. laparoscopic) did not. Conclusions Most T1b GBCs represent local disease. As pre-operative diagnosis, including tumour penetration of T1b GBC, is difficult, the decision of radical resection is justified. Additional radical resection is not required following simple cholecystectomy provided that the penetration depth is restricted towards the muscular layer and that surgical margins are uninvolved.

Recent progress in genomic analysis using next-generation sequencing technology has enabled the comprehensive detection of mutations and tumor mutation burden (TMB) in patients. A high TMB (TMB-H) tumor is defined as one with high somatic mutational rates, which correlates with clinical responses to certain treatments such as immunotherapies. We determined TMB in lung adenocarcinoma and clarified the characteristics of patients with TMB-H in relation to common driver mutations and smoking history.Genomic aberrations and TMB were determined in Japanese patients with lung adenocarcinoma (n = 100) using next-generation sequencing of 415 known cancer genes. TMB-H was defined as20 mutations per megabase (Mb) of sequenced DNA.The median TMB was 13.5 (5-33) mutations/Mb. Ten of 100 (10%) patients showed TMB-H, and the others showed low TMB (TMB-L). Only two of 10 (20%) patients with TMB-H had one of the common driver mutations (ALK and ERBB2 mutation), whereas 57 of 90 (63%) patients with TMB-L had one of the driver mutations, including ALK, EGFR, ERBB2, ROS, RET, and MET (P 0.05). Notably, no EGFR mutation was observed in patients with TMB-H. Eight of 10 (80%) patients with TMB-H had recent smoking history, whereas only 17 of 90 (19%) patients with TMB-L had recent smoking history (P 0.001).We found that TMB-H is associated with smoking history, whereas TMB-L is associated with the common driver mutations in lung adenocarcinoma, which may impact treatment strategies for these patients.

Although obesity with associated inflammation is now recognized as a risk factor for breast cancer and distant metastases, the functional basis for these connections remain poorly understood. Here, we show that in breast cancer patients and in animal breast cancer models, obesity is a sufficient cause for increased expression of the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P), which mediates cancer pathogenesis. A high-fat diet was sufficient to upregulate expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, along with its receptor S1PR1 in syngeneic and spontaneous breast tumors. Targeting the SphK1/S1P/S1PR1 axis with FTY720/fingolimod attenuated key proinflammatory cytokines, macrophage infiltration, and tumor progression induced by obesity. S1P produced in the lung premetastatic niche by tumor-induced SphK1 increased macrophage recruitment into the lung and induced IL6 and signaling pathways important for lung metastatic colonization. Conversely, FTY720 suppressed IL6, macrophage infiltration, and S1P-mediated signaling pathways in the lung induced by a high-fat diet, and it dramatically reduced formation of metastatic foci. In tumor-bearing mice, FTY720 similarly reduced obesity-related inflammation, S1P signaling, and pulmonary metastasis, thereby prolonging survival. Taken together, our results establish a critical role for circulating S1P produced by tumors and the SphK1/S1P/S1PR1 axis in obesity-related inflammation, formation of lung metastatic niches, and breast cancer metastasis, with potential implications for prevention and treatment. Significance: These findings offer a preclinical proof of concept that signaling by a sphingolipid may be an effective target to prevent obesity-related breast cancer metastasis. Cancer Res; 78(7); 1713–25. ©2018 AACR.

Background The cystic duct has been included in the staging classification scheme for gallbladder cancer since the 2010 publication of the AJCC Cancer Staging Manual (7th edition). To our knowledge, only seven other cases of adenocarcinoma arising in the remnant cystic duct following cholecystectomy have been reported in the English-language literature, and none has been reported as primary early-stage T1b remnant cystic duct cancer (CDC). We report, herein, a case of primary adenocarcinoma arising in the remnant cystic duct in a patient with history of laparoscopic cholecystectomy for gallstone disease. Case presentation An 81-year-old female presented with abdominal pain. Her medical history included a laparoscopic cholecystectomy for cholecystolithiasis two years prior. Jaundice was observed; imaging studies suggested that this was caused by choledocholithiasis. Blood chemistry findings showed severe liver dysfunction. Endoscopic retrograde cholangiography revealed haemobilia from the common bile duct with no evidence of choledocholithiasis. A bile sample showed Papanicolaou class IV cytology. As the extent of tumour spread was undetermined by abdominal ultrasonography and endoscopic ultrasonography, peroral cholangioscopy (POCS) was performed, which revealed tiny papillary lesions within the confluence of cystic duct, and fine granular lesions in the centre of bile ducts, signifying early-stage remnant CDC. Extrahepatic bile duct resection with regional lymphadenectomy was done. Histopathological findings revealed a 42-mm tubular adenocarcinoma originating from the remnant cystic duct with the considerable shallow spread across the extrahepatic bile ducts. It invaded the fibromuscular layer, with no lymphovascular or perineural invasion, no lymph node metastasis (13 nodes examined), and uninvolved surgical resection margin (R0 resection), and was staged as pT1bN0M0, Stage I. Conclusions Primary early-stage T1b remnant CDC is an uncommon condition for which early diagnosis is challenging; if intraoperatively recognized, it can complicate surgery. Our experience of this case and an overview of the English literature suggest that POCS is an efficient tool to diagnosis this tumour and assess its spread along the extrahepatic bile ducts.

Lymphatic metastasis is known to contribute to worse prognosis of biliary tract cancer (BTC). Recently, sphingosine-1-phosphate (S1P), a bioactive lipid mediator generated by sphingosine kinase 1 (SPHK1), has been shown to play an important role in lymphangiogenesis and lymph node metastasis in several types of cancer. However, the role of the lipid mediator in BTC has never been examined. Here we found that S1P is elevated in BTC with the activation of ceramide-synthetic pathways, suggesting that BTC utilizes SPHK1 to promote lymphatic metastasis. We found that S1P, sphingosine and ceramide precursors such as monohexosyl-ceramide and sphingomyelin, but not ceramide, were significantly increased in BTC compared to normal biliary tract tissue using LC-ESI-MS/MS. Utilizing The Cancer Genome Atlas cohort, we demonstrated that S1P in BTC is generated via de novo pathway and exported via ABCC1. Further, we found that SPHK1 expression positively correlated with factors related to lymphatic metastasis in BTC. Finally, immunohistochemical examination revealed that gallbladder cancer with lymph node metastasis had significantly higher expression of phospho-SPHK1 than that without. Taken together, our data suggest that S1P generated in BTC contributes to lymphatic metastasis.

Background We have introduced and performed laparoscope-assisted surgery in living donor hepatectomy. The objective of this study was to investigate the long-term results of laparoscope-assisted living donor hepatectomy. Methods From 2006 to 2016, laparoscope-assisted living donor hepatectomy was performed in 11 patients (laparoscopic group), and conventional open living donor hepatectomy was performed in 40 patients (conventional group). Intraoperative and postoperative complications were evaluated according to the Clavien-Dindo classification and analyzed in the laparoscopic group for comparison with the conventional group. Results The median postoperative follow-up period was 88 months (range, 58–120 months) in the laparoscopic group. One donor in the conventional group died from a motor vehicle crash 16 months after surgery. All others were alive and returned to their preoperative activity level. Regarding intraoperative and early (≤90 days after surgery) postoperative complications, 1 patient (1/11, 9%) showed biliary fistula (Grade IIIa) in the laparoscopic group. In the conventional group, 6 patients (6/40, 15%) showed surgical complications of Grade I in 2 patients and Grade II in 4 patients. Regarding late (>90 days after surgery) postoperative complications, biliary stricture was observed in 1 patient of the laparoscopic group; this patient developed hepatolithiasis 6 years after surgery, and endoscopic lithotomy and extracorporeal shockwave lithotripsy were performed, resulting in successful treatment. Late complications were not observed in the conventional group. Conclusion One donor in the laparoscopic group showed Grade IIIa late complications. The introduction of laparoscopic surgery to living donor hepatectomy should be performed carefully.

Endoscopic management of acute necrotic pancreatitis and walled off necrosis is less invasive than surgical treatment and has become the 1st choice for treating pancreatic necrosis and abscess. We treated a case of acute necrotic pancreatitis and walled off necrosis after auxiliary partial orthotopic living-donor liver transplantation (APOLT). A 24-year-old woman was admitted to our university hospital for removal of the internal biliary stent, which had already been placed endoscopically for the treatment of biliary stricture after APOLT. She had been treated for acute liver failure by APOLT 10 years before. After we removed the internal stent with the use of an endoscopic retrograde approach, she presented with severe abdominal pain and a high fever. Her diagnosis was severe acute pancreatitis after endoscopic retrograde cholangiography (ERC). Her symptoms worsened, and she had multiple organ failure. She was transferred to the intensive care unit (ICU). Immunosuppression was discontinued because infection treatment was necessary and the native liver had already recovered sufficiently. After she had been treated for 19 days in the ICU, she recovered from her multiple organ failure. However, abdominal computerized tomography demonstrated the formation of pancreatic walled off necrosis and an abscess on the 20th day after ERC. We performed endoscopic ultrasonography-guided abscess drainage and repeated endoscopic necrosectomy. The walled off necrosis diminished gradually in size, and the symptoms disappeared. The patient was discharged on the 87th day after ERC. This is the 1st report of a case of acute necrotic pancreatitis and walled off necrosis that was successfully treated by endoscopic management after APOLT.

Recent progress in cancer genome analysis using next-generation sequencing has revealed a high mutation burden in some tumors. The particularly high rate of somatic mutation in these tumors correlates with the generation of neo-antigens capable of eliciting an immune response. Identification of hypermutated tumors is therefore clinically valuable for selecting patients suitable for immunotherapy treatment. There are several known causes of hypermutation in tumors, such as ultraviolet light in melanoma, tobacco smoke in lung cancer, and excessive APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) activity in breast and gastric cancer. In gastrointestinal cancers, one of the leading causes of hypermutation is a defect in DNA mismatch repair, which results in microsatellite instability (MSI). This review will focus on the frequency, characteristics and genomic signature of hypermutated gastrointestinal cancers with MSI. Detection of tumor hypermutation in cancer is expected to not only predict the clinical benefit of immune checkpoint inhibitor treatment, but also to provide better surgical strategies for the patients with hypermutated tumors. Thus, in an era of precision medicine, identification of hypermutation and MSI will play an important role directing surgical and chemotherapeutic treatment.

Background Laparoscopic surgery for patients with portal hypertension is considered to be contraindicated because of the high risk of massive intraoperative hemorrhaging. However, recent reports have shown hand-assisted laparoscopic surgery for devascularization and splenectomy to be a safe and effective method of treating esophagogastric varices with portal hypertension. The aim of this study is to evaluate the efficacy of hand-assisted laparoscopic devascularization and splenectomy (HALS Hassab’s procedure) for the treatment of esophagogastric varices with portal hypertension. Case presentation From 2009 to 2016, seven patients with esophagogastric varices with portal hypertension were treated with hand-assisted laparoscopic devascularization and splenectomy in our institute. Four men and three women with a median age of 61 years (range 35–71) were enrolled in this series. We retrospectively reviewed the medical records for the perioperative variables, postoperative mortality and morbidity, and postoperative outcomes of esophagogastric varices. The median operative time was 455 (range 310–671) min. The median intraoperative blood loss was 695 (range 15–2395) ml. The median weight of removed spleen was 507 (range 242–1835) g. The conversion rate to open surgery was 0%. The median postoperative hospital stay was 21 (range 13–81) days. During a median 21 (range 3–43) months of follow-up, the mortality rate was 0%. Four postoperative complications (massive ascites, enteritis, intra-abdominal abscess, and intestinal ulcer) were observed in two patients. Those complications were treated successfully without re-operation. Esophagogastric varices in all patients disappeared or improved. Bleeding from esophagogastric varices was not observed during the follow-up period. Conclusion Although our data are preliminary, hand-assisted laparoscopic devascularization and splenectomy proved an effective procedure for treating esophagogastric varices in patients with portal hypertension.

Background This study sought to evaluate the prognostic heterogeneity of Stage III (Union for International Cancer Control, seventh edition) gallbladder carcinoma. Methods Of 175 patients enrolled with gallbladder carcinoma who underwent radical resection, 22 were classified with Stage IIIA disease (T3N0M0) and 46 with Stage IIIB disease (T2N1M0 [n = 23] and T3N1M0 [n = 23]). The median number of retrieved lymph nodes per patient was 18. Results This staging system failed to stratify outcomes between Stages IIIA and IIIB; survival after resection was better for patients with Stage IIIB disease than for patients with Stage IIIA disease, with 5-year survival of 54.9% and 41.0%, respectively (p = 0.366). Multivariate analysis for patients with Stage III disease revealed independently better survival for patients with T2N1M0 than for patients with T3N0M0 (p = 0.016) or T3N1M0 (p = 0.001), with 5-year survival of 77.0%, 41.0%, and 31.0%, respectively. When N1 status was subdivided according to the number of positive nodes, 5-year survival in patients with T2M0 with 1–2 positive nodes, T2M0 with ≥3 positive nodes, T3M0 with 1–2 positive nodes, and T3M0 with ≥3 positive nodes was 83.3%, 50.0%, 45.8%, and 0%, respectively (p Conclusions The prognosis of T2N1M0 disease was better than that of T3N0/1M0 disease, suggesting that not all node-positive patients will have uniformly poor outcomes after resection of gallbladder carcinoma. T2M0 with 1–2 positive nodes leads to a favorable outcome after resection, whereas T3M0 with ≥3 positive nodes indicates a dismal prognosis.

e16068Background: Defective homologous recombination (HR) due to genetic aberrations of HR genes contributes to a high response of platinum therapy in ovarian and breast cancers. The aim of this st...

e15647Background: Hypermutation, which is a molecular subtype with high tumor mutation burden (TMB), has been recognized as a biomarker of anti-PD-1 therapy in many cancers. Hypermutation can be de...

Background Long-term graft survival of partial pancreas auto-transplantation after total pancreatectomy has not been clarified. The clinical implications of repeat completion pancreatectomy for locally recurrent pancreatic carcinoma in the remnant pancreas after initial pancreatectomy also have not been clarified. Methods We have previously reported a 61-year-old woman presenting with re-sectable carcinoma of the remnant pancreas at 3 years after undergoing a pylorus-preserving pancreaticoduodenectomy for invasive ductal carcinoma of the pancreas head. We also performed distal pancreas auto-transplantation with the use of a part of the resected pancreas to preserve endocrine function. Results The patient was discharged at 20 days after surgery without any complications. She had been followed regularly in our outpatient clinic. She had been treated with S-1 as adjuvant chemotherapy; 72 months after the completion total pancreatectomy with distal partial pancreas auto-transplantation, the patient was alive without any evidence of the pancreatic carcinoma recurrence. The pancreas graft was still functioning with a blood glucose level of 112 mg/dL, HbA1C of 6.7%, and serum C-peptide of 1.2 ng/mL; and urinary C-peptide was 11.6 μg/d. Conclusions Our patient demonstrated that repeated pancreatectomies can provide a chance for survival after a locally recurrent pancreatic carcinoma if the disease is limited to the remnant pancreas. An additional partial pancreas auto-transplantation was successfully performed to preserve endocrine function. However, the indications for pancreas auto-transplantation should be decided carefully in the context of pancreatic carcinoma recurrence.

e15592 Background: Molecular heterogeneity represents a significant hurdle in realizing precision medicine for gastric cancer (GC). Large-scale whole exome sequencing projects have identified distinct molecular subtypes to help define the heterogeneity of GC. However, it remains unclear whether the targeted gene panel-based sequencing can provide optimum targeted therapies and clinical utility in GC. The aim of this study is to generate comprehensive genomic profiling data and classify Japanese GC into actionable clusters associated with targeted therapies. Methods: FFPE tumor tissues were obtained from surgical or biopsy specimens of 207 Japanese patients with GC. Extracted DNA was subjected to genomic sequencing for 435 cancer related genes including 69 druggable genes with FDA approved targeted therapies. Somatic mutations, copy number alterations (SCNA), microsatellite instability (MSI) and Epstein-Barr virus (EBV) infection were evaluated using sequencing data. Results: Genomic sequencing identified at least one alteration of 435 genes in 194 pts (94%), and that of 69 druggable genes in 141 pts (68%). The most frequently altered druggable gene was ERBB2 (14%), following BRCA2 (11%) and ATM (10%). We successfully classified 207 tumors into four molecular subtypes, similar to the previously report; EBV (4%), MSI (8%), chromosomal instability (58%) and genomically stable subtype (30%). Frequent alterations of druggable genes ( > 5%) were widely observed through these subtypes. To discover the novel classifications associated with targeted therapies, we classified 207 tumors using mutation rate and hierarchical clustering. We identified a hypermutated group (n = 32), and a remaining non-hypermutated group (n = 175) which were sub-divided into six clusters including five actionable ones; ERBB2 (n = 25), CDKN2A and CDKN2B (n = 10), KRAS (n = 10), BRCA2 (n = 9) and ATM cluster (n = 12). Interestingly, we experienced a case of unresectable GC with a remarkable response for anti-HER2 therapy in the ERBB2 cluster. Conclusions: Genomic sequencing using a 435-gene panel has the potential to provide the information of optimum targeted therapies for upcoming precision medicine in Japanese GC.

e23122 Background: Breast cancer is the leading cancer among women both in US and Japan. Triple negative breast cancer (TNBC) is the subset of breast cancers that are negative for estrogen receptor (ER), progesterone receptor, and HER2. While the selective ER modulator tamoxifen or anti-HER2 therapy for breast cancer patients with ER positive or HER2 protein overexpression are the most successful examples of targeted therapies, only limited therapies are available for patients with TNBCs, which are associated with a poor prognosis. Advance in next-generation sequencing enables us to identify actionable driver mutations that can be potentially treated by targeted therapies in each cancer patient. The aim of this study is to examine actionable driver mutations in TNBCs in Japan by comprehensive genomic sequencing (CGS) with 435 gene panel, and compare the driver events in Japan with TCGA database to validate the utility of CGS. Methods: We examined all exons of 435 known cancer genes in Japanese TNBC patients (N = 53) by CGS and evaluated for concordance among independent data obtained from The Cancer Genome Atlas-TNBC whole exome sequencing database (N = 123). Results: Oncogenic driver mutations were identified in 51 of 53 Japanese patients (96%) with TNBC and 36 of 53 patients (67%) harbored mutations in genes associated with FDA-approved targeted therapies, indicating the potential clinical utility of a large gene panel for evaluating patients with TNBC. Among 80 total genetic alterations, frequently mutated genes ( > 10% patients) were TP53, PIK3CA and PTEN. Overall, the mutation spectrum of the Japanese patients is similar to that of the TCGA population, except amplification of MYC. Conclusions: Use of a CGS panel of 435 genes can reliably identify all of the critical mutations in TNBC patients, which are similar as TCGA data. The information derived from CGS can be used to determine the optimal treatment for TNBC patients.

e23191 Background: Microsatellite instability-high status (MSI-H) and alterations in the DNA mismatch repair pathway associate with the efficacy of 5-FU and immune checkpoint inhibitors in patients with gastrointestinal cancers. The activin type II receptor (ACVR2) that binds to the transforming growth factor beta superfamily of ligands is frequently mutated in MSI-H colorectal cancer. However, the incidence of ACVR2 mutations in gastric cancer patients remains unclear. The aim of this study is to reveal the incidence and to examine the association between the MSI-H and ACVR2A mutations in gastric cancer patients. Methods: 124 archived FFPE gastric cancer tissues (stage I-IV), who were operated at Niigata University Medical and Dental Hospital or Niigata Cancer Center Hospital, were analyzed for ACVR2A mutation and MSI status with the NGS-based comprehensive genomic test platform. Clinicopathological characteristics of the patients were also examined. Results: All 124 gastric cancer patients were successfully analyzed. 13 out of 124 patients (10.4%) showed MSI-H status. Interestingly, 10 of 13 MSI-H patients (76.9%) showed ACVR2A mutation, where none (0%) was found among patients with microsatellite stable status (P < 0.001), indicating the strong association between ACVR2A mutation and MSI status in gastric cancer patients. In the ACVR2A mutated group, there was a female predominance (P < 0.05), and cancers of the lower part of the stomach were more common (P < 0.05), compared with the wild type group. Only one of 10 patients with ACVR2A mutation died, and the patients with ACVR2A mutation show a 5-year overall survival rate of 90%. No statistically significant difference in survival was achieved between patients with ACVR2A mutation and wild type; this is probably due to the small number of patients. Conclusions: 10 of 13 MSI-H patients showed ACVR2A mutation. Our results indicate a strong association between ACVR2A mutation and MSI-H in gastric cancer patients.