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Background The prognosis of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is very poor, and the optimal treatment remains controversial. The aim of this study was to examine the safety and feasibility of our multimodal treatment. Methods This was a single-institution, retrospective case series. From 2013 to 2018, induction hepatic arterial infusion chemotherapy (HAIC) with concurrent radiotherapy (RT) was given to 20 consecutive patients with HCC harboring PVTT in the main portal trunk or first branch, even with intrahepatic and extrahepatic metastasis. When the cancers including thrombus and metastatic disease were well-controlled, surgical resection was considered. When macroscopic complete resection was achieved, two courses of HAIC were added as adjuvant therapy, whereas patients who had remnant disease after surgery were provided treatment according to the type of lesion. Results No treatment-related deaths were noted. The objective response rate and disease control rate were 35.0% and 65.0%, respectively. After induction treatment, 10 of 20 patients underwent surgery. Postoperative complications (Clavien-Dindo Grade III or more) were observed in three cases, and median postoperative hospital stay was 15.5 days. Median survival time of all 20 patients was 14.5 months, and that in patients who underwent surgery was significantly longer than that in patients with unresectable HCC (19.5 months vs 9.0 months, p = 0.0018). Conclusions Induction treatment followed by surgery was safe and feasible for HCC with massive PVTT. Surgical resection might be oncologically appropriate for selected patients after induction treatment even with advanced stage HCC.

Objective Pancreatic cancer stem-like cells (P-CSLCs) are thought to be associated with poor prognosis. Previously, we used proteomic analysis to identify a chaperone pro-phagocytic protein calreticulin (CALR) as a P-CSLC-specific protein. This study aimed to investigate the association between CALR and P-CSLC. Methods PANC-1-Lm cells were obtained as P-CSLCs from a human pancreatic cancer cell line, PANC-1, using a sphere induction medium followed by long-term cultivation on laminin. To examine the cancer stem cell properties, subcutaneous injection of the cells into immune-deficient mice and sphere formation assay were performed. Cell surface expression analysis was performed using flow cytometry. Results PANC-1-Lm showed an increased proportion of cell surface CALR-positive and side-population fractions compared with parental cells. PANC-1-Lm cells also had higher frequency of xenograft tumor growth and sphere formation than PANC-1 cells. Moreover, sorted CALRhigh cells from PANC-1-Lm had the highest sphere formation frequency among tested cells. Interestingly, the number of programmed death-ligand 1-positive cells among CALRhigh cells was increased as well, whereas that of human leukocyte antigen class I-positive cells decreased. Conclusion In addition to the cancer stem cell properties, the P-CSLC, which showed elevated CALR expression on the cell surface, might be associated with evasion of immune surveillance.

Introduction: Because surgical resection with simultaneous hepatic artery (HA) resection and reconstruction for perihilar cholangiocarcinoma (PHC) is technically demanding, the surgical indication for this challenging procedure is controversial. Thus, this study aimed to evaluate the efficacy of simultaneous HA resection and reconstruction for PHC. Methods: Between January 2002 and January 2018, 13 patients with PHC underwent surgical intervention with simultaneous resection and reconstruction of the HA at Yamaguchi University Hospital (Ube, Japan) and Osaka University Hospital (Suita, Japan). Results: There were 2 cases (15.4%) of 90-day postoperative mortality. Nine patients (69.2%) developed major postoperative complications (Clavien-Dindo classification ≥IIIa). Curative resections (R0) were achieved in 8 cases (61.5%). The median survival time (MST) and 1- and 3-year survival rates after resection (including in-hospital deaths) were 20.9 months and 61.5 and 10.3%, respectively. The MST and 1- and 2-year survival rates of 8 patients who underwent R0 resection were significantly better than those of the other 5 patients (24.2 vs. 10.2 months, 75.0 vs. 40.0%, and 50.0 vs. 0.0%, respectively, p = 0.0228). Conclusions: Simultaneous HA resection and reconstruction is technically possible and may provide long-term survival in selected patients with locally advanced PHC.

Aim The impact of sustained virologic response (SVR) on surgical outcomes for patients with hepatitis C virus (HCV)‐related hepatocellular carcinoma (HCC) remains controversial. This study aimed to evaluate the influence of SVR on long‐term surgical outcomes after hepatectomy. Methods This multicenter study included 504 patients who underwent curative resection for HCV‐related HCC. Patients with a history of HCC treatment, HBV infection, poor liver function, and tumor with major vascular invasion were excluded. Long‐term surgical outcomes (overall survival [OS] and recurrence‐free survival [RFS]) among patients who achieved SVR before hepatectomy (Pre‐SVR group: 58 patients), after hepatectomy (Post‐SVR group: 54 patients), and without SVR (Non‐SVR group: 186 patients) were compared after adjusting for 13 confounding factors. Using the surgically resected specimens, comparison of the pathological changes in liver fibrosis between the first and second hepatectomy were analyzed. Results Patients with SVR were younger, had better liver function, and less liver fibrosis compared to patients without SVR. Propensity score‐matched OS and RFS were significantly better in Pre‐SVR group than Non‐SVR group (P = .029 and P = .009, respectively). Inverse probability‐weighted OS and RFS were also significantly better in the Post‐SVR group (P = .001 and P = .021, respectively) than in the Non‐SVR group. Histopathological evaluation revealed that only the patients with SVR had regression of liver fibrosis (P, Although the achievement of sustained virologic response (SVR) is essential for improving survival in patients with hepatitis C virus (HCV) infection, its importance on surgical outcomes for HCV‐related hepatocellular carcinoma (HCC) is still controversial. In this multicenter study, we demonstrated the importance of achieving SVR before or after hepatectomy for improving long‐term surgical outcomes. These results can encourage patients with HCV‐related HCC to undergo antiviral therapy regardless of the timing.

A proteomic analysis of hepatocellular carcinoma (HCC) has revealed that Heat Shock Protein 70 (HSP70) is among the cancer antigen proteins of HCC. Moreover, we confirmed that HSP70 was highly expressed in HCC by immunohistochemical staining. Based on these results, we developed an HSP70 mRNA-transfected dendritic cell (DC) therapy for treating unresectable or recurrent HCC, and the phase I trial was completed successfully. Thus, we aimed to investigate the safety and efficacy of this therapy as a postoperative adjuvant treatment after curative resection for HCC to prevent recurrence by conducting a phase I/II randomized controlled clinical trial. Patients (n = 45) with resectable HCC of stages II–IVa were registered and randomly assigned into two groups (DC group: 31 patients, control group: 14 patients) before surgery. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were safety and overall survival. The DC therapy was initially administered at approximately 1 week after surgery, and twice every 3–4 weeks thereafter. No adverse events specific to the immunotherapy were observed in the DC group. There was no difference in DFS between the DC and control groups (p = 0.666). However, in the subgroup with HSP70-expressing HCC, DFS of the DC group tended to be better (p = 0.090) and OS of the DC group was significantly longer (p = 0.003) than those of the control group. The HSP70 mRNA-transfected DC therapy was performed safely as an adjuvant therapy. The prognosis of HSP70-expressing HCC cases could be expected to improve with this therapy.

Background Hepatocellular carcinoma (HCC) with tumour thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA) is a rare advanced disease state with a poor prognosis. The aim of this study was to examine survival after surgical resection. Methods Patients with HCC and TT of either the IVC or RA, who underwent liver resection between February 1997 and July 2017, were included. Their short‐ and long‐term outcomes and surgical details were analysed retrospectively. Results Thirty‐seven patients were included; 16 patients had TT in the IVC below the diaphragm, eight had TT in the IVC above the diaphragm, and 13 had TT entering the RA. Twelve patients had advanced portal vein TT (portal vein invasion (Vp) greater than Vp3 and Vp4), ten had bilobar disease, and 12 had extrahepatic disease. There were no in‐hospital deaths, although two patients died within 90 days. Median survival did not differ between patients who had resection with curative intent (18·7 months) and those with residual tumour in the lung only (20·7 months), but survival was poor for patients with residual tumour in the liver (8·3 months). Conclusion Liver resection with thrombectomy for advanced HCC with TT in the IVC or RA is safe and feasible, leading to moderate survival., Hepatocellular carcinoma with tumour thrombus in the inferior vena cava or right atrium is an advanced disease state with a poor prognosis. This retrospective study examined the survival benefits of surgical resection for patients with this rare condition. Liver resection with thrombectomy in these patients was safe and feasible, especially for those who had a curative resection or residual tumour in the lung only. Liver resection for HCC with caval thrombi is feasible with moderate survival

Background This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor effects of a novel vaccination therapy comprising multi-HLA-binding heat shock protein (HSP) 70/glypican-3 (GPC3) peptides and a novel adjuvant combination of hLAG-3Ig and Poly-ICLC against metastatic gastrointestinal cancers. Methods HSP70/GPC3 peptides with high binding affinities for three HLA types (A*24:02, A*02:01, and A*02:06) were identified with our peptide prediction system. The peptides were intradermally administered with combined adjuvants on a weekly basis. This study was a phase I dose escalation clinical trial, which was carried out in a three patients’ cohort; in total, 11 patients were enrolled for the recommended dose. Results Seventeen patients received this vaccination therapy without dose-limiting toxicity. All treatment-related adverse events were of grades 1 to 2. Peptide-specific CTL induction by HSP70 and GPC3 proteins was observed in 11 (64.7%) and 13 (76.5%) cases, respectively, regardless of the HLA type. Serum tumor marker levels were decreased in 10 cases (58.8%). Immunological analysis using PBMCs indicated that patients receiving dose level 3 presented with significantly reduced T cell immunoglobulin and mucin-domain containing-3 (TIM3)-expressing CD4 + T cells after one course of treatment. PD-1 or TIM3-expressing CD4 + T cells and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT)-expressing CD8 + T cells in PBMCs before vaccination were negative predictive factors for survival. Conclusions This novel peptide vaccination therapy was safe for patients with metastatic gastrointestinal cancers.

A 49-year-old man came to our department for the purpose of scrutinizing liver tumor. CA19-9 and CA125 increased, and AFP and PIVKA-Ⅱ were within the normal range. CT showed a large number of early ring enhanced tumor, and a tumor thrombus in the left branch of the portal vein. Tumor biopsy revealed adenocarcinoma. Chemotherapy(gemcitabine, cisplatin plus S-1: GCS)was performed for intrahepatic cholangiocarcinoma(r/o combined hepatocellular carcinoma and cholangiocarcinoma). Lenvatinib was administered because portal vein tumor thrombus and PIVKA-Ⅱ increased after GCS therapy. Two months later, CA19-9 and PIVKA-Ⅱ were decreased and portal vein tumor thrombus was shrunk. Extended left hepatectomy was performed for the purpose of disease control. Histopathological examination revealed some hepatocellular carcinoma components in intrahepatic cholangiocarcinoma. Tumor thrombus was vitrified and necrotic. After hepatectomy, administration of lenvatinib was continued for the residual lesion, and no significant tumor growth was observed.

This case pertains to a female patient in her 60s who was diagnosed with carcinoma in the cecum with lung, ovarian, and peritoneal metastases. She complained of abdominal distension and poor feeding because her ascites and ovarian metastasis worsened 18 months after chemotherapy initiation. Repeated cytologic examination of the ascitic fluid revealed no malignant cells. Therefore, Pseudo-Meigs' syndrome was suspected. Bilateral salpingo-oophorectomy was performed as palliative surgery because of the patient's reduced capacity to perform activities of daily living(ADL)due to ascites. After palliative surgery, her ascites disappeared, and she was able to better perform ADL. Further, chemotherapy was resumed. The patient remains well 10 months after surgery. This case highlights the importance of considering Pseudo-Meigs' syndrome in patients with massive ascites and ovarian metastasis, because surgical resection can improve their quality of life.

An 80 year-old woman with anorexia and jaundice was diagnosed with mass-forming intrahepatic cholangiocarcinoma, lymph node metastasis, common hepatic duct strictures, and obstructive jaundice. PET-CT showed FDG accumulation in the primary lesion(SUVmax 19.0)and swollen lymph nodes. Her ADL and major organ functions were judged to be sufficient for treatment. After treatment for jaundice, she received a total of 6 courses of gemcitabine, cisplatin plus S-1(GCS)therapy as neoadjuvant chemotherapy(NAC). Her first treatment was an 80% dose of GCS, but she was subsequently diagnosed with Grade 4 thrombocytopenia(CTCAE v5.0). The dose of gemcitabine was further reduced, and no adverse events of Grade 3 or higher were observed thereafter. After NAC, PET-CT showed decreased FDG accumulation in the primary lesion(SUVmax 3.3)and normalization of FDG accumulation in the lymph nodes. Extended right hepatectomy and biliary reconstruction were performed as radical resection(R0). The final diagnosis was pT2, N0, M0, Stage Ⅱ. After hepatectomy, her anorexia and poor ADL persisted. She was discharged to her home 151 days after her surgery.

Although the current standard of care for patients with lower rectal cancer in Japan includes total mesorectal resection with lateral lymph node dissection, postoperative local and distant recurrence rates are high. Multidisciplinary treatment is important to improve the prognosis. A man in his 30s was diagnosed with lower rectal cancer due to bloody stool and referred to our department. He was diagnosed as cT3N3M0, cStage Ⅲc with right obturator lymph node metastasis. Four courses of neoadjuvant chemotherapy(NAC)with FOLFOXIRI plus cetuximab were performed. Because Grade 3 neutropenia was observed in the first cycle(CTCAE v5.0), pegfilgrastim was administered in the second and subsequent cycles, and NAC was completed without dose reduction. The patient underwent laparoscopy-assisted intersphincteric rectal resection and D3+rtLD2 dissection. Histopathological resection margins were negative, and the resection was R0. Lymph node metastasis was found only in No. 263d-rt, and the pathological diagnosis was ypT3N3M0, pStage Ⅲc. Histological evaluation of response to treatment was Grade 2. The postoperative course was good and the patient was discharged on postoperative day 15. The patient received 8 courses of adjuvant chemotherapy with mFOLFOX6 from the 7th postoperative week and is alive and recurrence-free 6 months after surgery.

Poor prognosis in liver cancer is due to its high frequency of intrahepatic metastasis. Cancer stem-like cells (CSLCs), which possess the properties of stemness, tumor initiation capability, and resistance to therapy, also exhibit metastatic potential. Immune surveillance plays an important role in the accomplishment of metastasis. Herein, the property of immune evasion in CSLCs was investigated.Sphere cells were induced as CSLCs using a sphere induction medium containing neural survival factor-1. The expression of genes involved in immune evasion was determined using RNA-sequencing for sphere and parental cells followed by validation using flow cytometric analysis and ELISA. Susceptibility to natural killer (NK) cell-mediated cytotoxicity was examined by a chromium release assay. A xenograft model using BALB/c nu/nu mice was used to assess tumor growth. Gene set enrichment analysis was performed for interpreting RNA sequencing.The cell surface expressions of PD-L1, PD-L2, and CEACAM1 were upregulated and those of ULBP1 and MICA/MICB were downregulated in SK-sphere, CSLCs derived from SK-HEP-1, compared with that in parental cells. Levels of soluble MICA were elevated in conditioned medium from SK-sphere. Expression of HLA class I was not downregulated in SK-sphere. The susceptibilities to NK cell-mediated killing and secreted perforin were significantly lower in both CSLCs derived from SK-HEP-1 and HLE than in parental cells. Tumors formed upon inoculation of SK-sphere in immunodeficient mice harboring NK cells were larger than those formed upon inoculation of parental cells.Human hepatoma cell line-derived CSLCs may possess immune evasion properties, especially from NK cell-mediated immunity.

Background Cancer stem cells (CSCs) are thought to play important roles in carcinogenesis, recurrence, metastasis, and therapy-resistance. We have successfully induced cancer stem-like sphere cells (CSLCs) which possess enhanced chemoresistance and metastatic potential. To enable the development of targeted therapy against CSLCs, we identified a gene responsible for this phenotype in CSLC. Methods Human hepatoma cell line SK-HEP-1 was used for CSLC induction with a unique sphere inducing medium, and HuH-7 cells were used as non-sphere forming cells in the same condition. RNA-sequencing was performed followed by validation with quantitative RT-PCR and western blotting. Knockdown experiments were done by using CRISPR-Cas9 genome-editing, and the rescue experiments were performed using the expressing plasmid vector. Chemoresistance and liver metastasis of the cells, was studied following the splenic injection of cells to severely immune deficient mice and evaluated using the MTS assay. Quantification of exosomes in the medium was done using ELISA. Results RAB3B was identified as an up-regulated gene in both CSLCs and prognostically poor hepatocellular carcinoma (HCC) by RNA-sequencing. RAB3B-KD cells showed altered CSLC phenotypes such as sphere formation, chemoresistance, and metastatic potentials, and those were rescued by RAB3B complementation. Increased exosome secretion was observed in CSLCs, and it was not observed in the RAB3B-KD cells. In addition, the RAB3B expression correlated with the expression of ABCG2, APOE, LEPR, LXN, and TSPAN13. Conclusion The up regulation of RAB3B may play an important role in the chemoresistance and metastatic potential of CSLCs.

BACKGROUND/AIM There is an increasing use of immunotherapy for non-small cell lung cancer (NSCLC) patients. The present study analysed the effect of antibiotic use on the outcome of NSCLC patients undergoing treatment with anti-programmed cell death-1 (anti-PD-1) immunotherapy. PATIENTS AND METHODS This was a retrospective study of 69 NSCLC patients. Eighteen out of 69 patients received antibiotics within 21 days before or within 21 days after start of anti-PD-1 therapy. RESULTS Patients treated with anti-PD-1 antibodies receiving antibiotics had greatly decreased objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) compared to those who did not use antibiotics. Multivariate analysis showed that antibiotic treatment of patients on anti-PD-1 antibody therapy was an independent negative predictive factor of PFS; however, it was not a significant independent predictive factor of OS. CONCLUSION Use of antibiotics within 21 days before and after anti-PD-1 treatment initiation in patients with NSCLC strongly reduced OS and PFS, suggesting the two treatments should not be combined.

A 67-year-old woman was admitted with melena. A colonoscopy detected a 50 mm submucosal tumor close to the dentate line. We diagnosed the rectal gastrointestinal stromal tumor by EUS-FNA. With the expectation of tumor shrinkage and strong hope of the patient, we started imatinib mesylate as neoadjuvant chemotherapy. A CT scan after 3 months after administration of imatinib mesylate showed the reduction of the size to 35 mm. We operated transanal endoscopic surgery considering the localization of the tumor. From histopathological findings, the tumor was low risk in the modified-Fletcher classification, and low risk in the Miettinen classification. Eight months after the operation, no recurrence was observed without further adjuvant chemotherapy. In this case, we were able to resect the tumor without injuring the film of tumor by operating transanal endoscopic surgery, because of tumor shrinkage with imatinib mesylate as neoadjuvant chemotherapy. I considered that using imatinib mesylate preoperatively was contributed to minimally invasive surgery.

Patient is 69-year-old man, who underwent a high anterior resection with laparoscopic support for rectal cancer. The patient was diagnosed with anastomotic recurrent rectal cancer after 14 months after surgery. The pelvic MRI scan showed invasion of the prostate and seminal vesicles, so NACRT was performed. Tumors were found to have decreased in size, although there was still some residual invasion of the prostate and seminal vesicle. Laparoscopic total pelvic exenteration (Lap-TPE), and combined excision of the anal elevator muscle and bladder were performed. Preoperative diagnosis was ycT4b, N0, M0, ycStage Ⅱ, and pathological diagnosis was pT4b (prostate and seminal vesicles), INF b, Ly2, v2, Pn1b, pPM0, pDM0, pRM0, and pN0. Laparoscopic surgery allowed to operate safely, with minimal blood loss and a good field of vision. After postoperative adjuvant chemotherapy, lung and liver metastasis appeared after 6 months after surgery, but there was no local recurrence. The patient is treated with chemotherapy, and the metastases are under control. The patient is survive 17 months after Lap-TPE.

The patient was a woman in her 80s. Operative treatment was performed for papillary thyroid cancer(pT3N0M0)13 years ago. A follow-up CT scan 1 year ago revealed a skin, lung, and lymph node metastasis. At the same time, a tumor with a size of 24 mm was initially observed in the tail of the pancreas, which was considered to be pancreatic metastasis of thyroid papillary cancer and was followed up. Only the pancreatic lesions tended to gradually increase, although other lesions did not increase. Therefore, the patient was referred to our department. It was difficult to diagnose preoperatively. Thus, diagnostic and therapeutic laparoscopic distal pancreatectomy with splenectomy was performed. The pathological diagnosis was dedifferentiated liposarcoma. Postoperatively, a Grade B pancreatic fistula was observed, but the patient recovered conservatively and was discharged on postoperative day 55. Primary liposarcoma of the pancreas is extremely rare, and few cases have been reported. Primary liposarcoma of the pancreas is very difficult to diagnose preoperatively by only diagnostic imaging.

Congenital extrahepatic portosystemic shunt (CEPS) presents with various symptoms due to abnormal communication between the portal venous system and inferior vena cava. And Klippel-Trenaunay-Weber syndrome is another rare congenital disorder characterized by vascular malformations.A 16-year-old male with Klippel-Trenaunay-Weber syndrome was referred to our hospital for surgical treatment of pulmonary hypertension due to CEPS since childhood. Dyspnea had developed about two years before presentation at our hospital and gradually worsened. Right heart catheterization had revealed pulmonary hypertension and a high cardiac output state associated with a portosystemic shunt. Although pulmonary vasodilators improved the dyspnea, pulmonary hypertension remained. The patient was then referred to our hospital for surgical shunt occlusion. The results of the preoperative and intraoperative shunt occlusion tests were within acceptable limits. Therefore, primary shunt ligation was performed. There were no postoperative complications. Continuous intravenous vasodilator was tapered off four months after discharge. No additional or increased doses of medications were required for four years after surgery.Surgical shunt ligation for CEPS is effective but can cause acute portal hypertension. Primary shunt ligation could be performed without complications according to the criteria for safe shunt occlusion.Surgical portosystemic shunt ligation could be performed safely and ameliorated pulmonary hypertension. Patients with CEPS, especially young patients, should be referred to a tertiary center while asymptomatic, and early therapeutic intervention is necessary.

Background Only few studies in literature have analyzed the clinical effects of peritoneal lavage status in biliary tract cancers. Aim We aimed to assess the effect of cytology-positive peritoneal lavage on survival for patients with biliary tract cancer who underwent curative resection. Methods The KHBO1701 study was a multi-institutional retrospective study that assessed the clinical effects of peritoneal lavage cytology in biliary tract cancers. Using clinicopathological data from 11 Japanese institutions, we compared long-term outcomes between patients with cytology-positive and cytology-negative peritoneal lavage. Results Of 169 patients who underwent curative resection, 164 were cytology-negative, and five were cytology-positive. The incidence of portal invasion and preoperative carbohydrate antigen 19-9 levels were higher in the cytology-positive group than in the cytology-negative group. The incidence of peritoneal metastatic recurrence was also higher, and overall survival tended to be worse in the cytology-positive group. In contrast, recurrence-free survival was similar between the cytology-negative and cytology-positive groups. Conclusions The positive status of peritoneal lavage cytology could moderately affect the survival of patients with biliary tract cancers. Given that surgical resection is the only curative treatment option, it may be acceptable to resect biliary tract cancers without other non-curative factors, regardless of peritoneal lavage cytology status.

Surgical resection is the only curative treatment for pancreatic cancer. Arterial resection and reconstruction during pancreaticoduodenectomy for advanced pancreatic cancer remain controversial due to a high rate of complications. We report two cases of pancreatic cancer with hepatic artery resection and reconstruction using the right gastroepiploic artery during pancreaticoduodenectomy after neoadjuvant therapy. The patients underwent pancreaticoduodenectomy with resection of the right hepatic and common hepatic arteries. Achieving direct anastomosis was difficult; therefore, we planned hepatic artery reconstruction using the right gastroepiploic artery. We performed the reconstruction using an interrupted suture with end-to-end anastomosis. The first patient developed a postoperative pancreatic fistula, while the postoperative course of the second patient was uneventful. However, there were no adverse events related to the arterial reconstruction. R0 resection was achieved, and postoperative computed tomography revealed good patency of the reconstructed artery. Hepatic artery reconstruction using the right gastroepiploic artery in pancreatic cancer might be technically safe and might become one of the alternative options.

Laparoscopic liver resection is beneficial compared to open liver resection. This study aimed to evaluate whether laparoscopic liver resection could reduce postoperative infections. This study included 125 and 115 patients with liver tumors who underwent open and pure laparoscopic partial resections or left lateral sectionectomies, respectively. Propensity score matching and stabilized inverse probability of treatment weighting were carried out to compare the postoperative infectious complication rates between the two groups. Patients with tumors located in Couinaud segment 1, 7, or 8; with tumors adjacent to major vessels; or who underwent repeated resections were more likely to receive open resection. After propensity score matching, the superficial incisional surgical site infection rate tended to be lower in the laparoscopic liver resection group than in the open liver resection group. Moreover, overall infectious complication rate and superficial incisional surgical site infection rate were lower in the laparoscopic group (the cohort formed by the stabilized inverse probability of treatment weighting). Using the laparoscopic approach for partial resections and left lateral sectionectomies for liver tumors, the superficial incisional surgical site infection rate could be reduced.

Background and aims Imaging diagnosis of gallbladder cancer remains difficult to achieve preoperatively. We developed a novel approach based on laparoscopic whole‐layer cholecystectomy (LWLC) and laparoscopic gallbladder bed dissection (LGBD) for total biopsy, for ultimately determining the optimal treatment strategy for suspected gallbladder cancer detected on preoperative imaging. Here, we describe a case series of patients who underwent this procedure at our institution. Methods We retrospectively examined clinicopathological data of consecutive patients with suspected gallbladder carcinoma at Yamaguchi University Graduate School of Medicine from September 2016 to July 2018 on which a laparoscopic approach was used. Preoperative imaging findings suggestive of gallbladder cancer were defined as follows: elevated lesion >10 mm in diameter, increasing tumor size over time compared with the previous imaging, sessile lesion, irregular wall thickness lesion mimicking cancer, elevated lesion with dense enhancement, or positive results on fluorodeoxyglucose positron emission tomography. LWLC was performed for early‐stage or suspected malignant lesions without liver invasion, and LGBD was performed for lesions with an unclear border between the gallbladder and the liver. When postoperative pathological examination revealed the presence of gallbladder cancer invading into the subserosal layer, additional gallbladder bed resection and regional lymphadenectomy were considered. Patient characteristics, perioperative findings, pathological findings, and postoperative outcomes of patients who underwent LWLC or LGBD were reviewed retrospectively, and the short‐term outcomes of the laparoscopic approach were analyzed. Results Fifteen consecutive patients were included in the study. The median age of the patients was 63 years (IQR 42‐76 years); 7 patients were males. We performed LWLC in 12 cases and LBGD in 3 cases. Median (IQR) operation time was 159 (140‐193) min and median blood loss was 10 (5–30) mL. No bile leakage caused by intraoperative perforation of the gallbladder was seen. Median hospital stay was 7 (5–9) days. Only one patient developed postoperative complications (abdominal abscess). Histologically, gallbladder cancer was diagnosed in five cases (pT1a, n = 2; pT2, n = 3), and two of the pT2 patients underwent additional open surgery. Conclusions Our laparoscopic‐based approach for suspected gallbladder cancer might represent a safe strategy and could play an important role in defining the optimal treatment strategy.

Cancer immunotherapy, including vaccination, is considered a major scientific and medical breakthrough. However, cancer immunotherapy does not result in durable objective responses against colorectal cancer (CRC). To improve the efficacy of immunotherapy, the present study investigated several biomarkers for selecting patients who were expected to respond well to immunotherapy. Firstly, a comprehensive proteomic analysis was performed using tumor tissue lysates from patients enrolled in a phase II study, in which five human leukocyte antigen (HLA)-A*24:02-restricted peptides were administered. Sialic acid-binding immunoglobulin type lectin (Siglec)-7 was identified as a potential predictive biomarker. Subsequently, this biomarker was validated using western blot analysis, and immunofluorescence using tissue samples from the patients enrolled in the phase II study. The expression levels of Siglec-7 detected by immunofluorescence were quantified and their association with overall survival (OS) in patients treated with the peptide vaccine was examined. Furthermore, considering the important role of tumor-infiltrating lymphocytes (TILs) for CRC prognosis, the densities of CD3+, CD4+, CD8+ and forkhead box P3 (FOXP3)+ T cells in CRC tissues were examined and compared with Siglec-7 expression. The mean expression levels of Siglec-7 were significantly higher in patients with poor prognosis, with an OS of ≤2 years, as shown in comprehensive proteomic analysis (P=0.016) and western blot analysis (P=0.025). Immunofluorescence analysis demonstrated that Siglec-7 was expressed in intratumoral macrophages. The OS in patients with high Siglec-7 expression was significantly shorter than in that in patients with low Siglec-7 expression (P=0.017) in the HLA-A*24:02-matched patients. However, this difference was not observed in the HLA-unmatched patients. There was no significant difference in OS between patients according to the numbers of TILs, nor significant correlation between TILs and Siglec-7 expression. In conclusion, Siglec-7 expression in macrophages in tumor tissue may be a novel predictive biomarker for the efficacy of immunotherapy against metastatic CRC.

A 67-year-old man was admitted with melena. A colonoscopy detected advanced rectal cancer, and a CT scan revealed invasion of the seminal vesicle and prostate. Given the wild-type RAS status of the tumor, we administered 6 courses of XELOX plus cetuximab as neoadjuvant chemotherapy. After treatment, the tumor had shrunk, and the rectum had narrowed. Later, following a diagnosis of coronary artery disease, colostomy was performed. The patient was treated for the coronary artery disease for 2 months. Following treatment, tumor progression was detected, and hence, the patient was treated with the same chemotherapy regimen for 4 more courses. We performed a laparoscopic assisted abdominoperineal resection of the rectum with combined resection of the seminal vesicle and prostate. Pathological examination revealed a complete response to treatment. Six months after the operation, no recurrence was observed without further adjuvant chemotherapy.

The patient was a 17-year-old woman. An abnormal urinalysis was observed, and abdominal echography showed a pancreatic cystic mass. At the first examination, computed tomography(CT)and endoscopic ultrasound(EUS)showed a unilocular cystic mass of 60mm in size in the pancreatic body and tail, and no malignant findings were observed. After 14 months, CT and positron emission tomography-computed tomography(PET-CT)showed that the cystic mass had a mural nodule with FDG accumulation, and presence of a tumor in hepatic S8 with FDG accumulation. Laparoscopic distal pancreatectomy and hepatic subsegmentectomy of S8 were performed for diagnostic and therapeutic purposes. The pathological diagnosis was mucinous cystadenocarcinoma(MCC)and metastatic liver cancer in the form of MCC. S-1 was administered after surgery. Nine months after resection, multiple metastatic liver tumors were found, and GEM plus nab-PTX was administered. After 2 courses of treatment, the patient is still alive without new lesions.

A 64-year-old man presented with dysphagia. Esophagogastroduodenoscopy revealed a submucosal tumor of 52mm in size at the lower thoracic esophagus. Biopsy yielded a pathological diagnosis of c-kit-positive esophageal gastrointestinal stromal tumor(GIST). We started neoadjuvant therapy with imatinib to avoid excessive surgical invasion. After 6 months of treatment, CT revealed a reduction in tumor size to 27 mm. We performed laparoscopic lower esophagectomy, proximal gastrectomy, double-tract reconstruction, and complete tumor resection. Neoadjuvant imatinib therapy was effective for the esophageal GIST.

The patient was a 66-year-old man presenting with epigastric pain and jaundice. PET-CT demonstrated limited-accumulation on the tumor at the head of the pancreas, diagnosed as borderline resectable adenosquamous carcinoma. The patient was treated with preoperative chemoradiation therapy with 2 courses of gemcitabine followed by administration of S-1 and gemcitabine for 13 months, which reduced the tumor size. After preoperative therapy, pancreaticoduodenectomy was performed. Histopathological examination revealed that no viable tumor cells were detected in the pancreas or lymph nodes, and the patient had achieved a pathological complete response. Postoperative adjuvant chemotherapy was not performed, and the patient is still alive without recurrence for 66 months after surgery.

Background Colorectal cancer is the third most common cancer worldwide. If biomarkers can be identified in liquid biopsy, diagnosis and treatment can be optimized even when cancerous tissues are not available. The purpose of this study was to identify proteins from liquid biopsy that would be useful as markers of poor prognosis. Methods First, we comprehensively analyzed serum proteins to identify potential biomarkers and focused on serum lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). The relationship between LOX-1 and the prognosis of patients with colorectal cancer has not been reported. Next, we validated this marker using serum samples from 238 patients with colorectal cancer by ELISA and 100 tissue samples by immunohistochemical staining. Results The optimal cut-off value of serum LOX-1 was 538.7 pg/mL according to time-dependent receiver operating characteristics curve analysis. The overall survival of patients with high levels of serum LOX-1 was significantly poorer than that of individuals with low levels of LOX-1 in the training and test datasets. In multivariate analysis for overall survival, serum LOX-1 was an independent prognostic factor identified in liquid biopsy (hazard ratio = 1.729, p = 0.027). The prognosis of patients with high LOX-1 expression in tumor tissues was significantly poorer than that of individuals with low expression (p =0.047 ). Additionally, inflammatory factors such as white blood cell count, C-reactive protein level, neutrophil/lymphocyte ratio, and monocyte/lymphocyte ratio were significantly higher in the group with high serum LOX-1 levels. Conclusions Serum LOX-1 might be a useful biomarker of poor prognosis in colorectal cancer.

Objectives We previously described adoptive immunotherapy (AIT) with cytotoxic T lymphocytes (CTLs) stimulated by the mucin 1 (MUC1)-expressing human pancreatic cancer cell line YPK-1 (MUC1-CTLs) and demonstrated that MUC1-CTLs might prevent liver metastasis. In the present study, we combined gemcitabine (GEM) and AIT for the treatment of pancreatic cancer. Methods A total of 43 patients who underwent radical pancreatectomy received treatment with MUC1-CTLs and GEM. After surgery, MUC1-CTLs were induced and administered intravenously 3 times, and GEM administered according to the standard regimen for 6 months. The patients whose relative dose intensity of GEM was 50% or more and who received 2 or more MUC1-CTL treatments were used as the adequate treatment group (n = 21). Results In the adequate treatment group, disease-free survival was 15.8 months, and overall survival was 24.7 months. Liver metastasis was found only in 7 patients (33%), and local recurrence occurred in 4 patients (19%). The independent prognostic factor of long-term disease-free survival on multivariate analysis was the average number of CTLs administered (P = 0.0133). Conclusions The combination therapy with AIT and GEM prevented liver metastasis and local recurrence. Moreover, the disease free-survival was improved in patients who received sufficient CTLs.

Cancer stem-like cells (CSLCs) in solid tumors are thought to be resistant to conventional chemotherapy or molecular targeting therapy and to contribute to cancer recurrence and metastasis. In this study, we aimed to identify a biomarker of pancreatic CSLCs (P-CSLCs). A P-CSLC-enriched population was generated from pancreatic cancer cell lines using our previously reported method and its protein expression profile was compared with that of parental cells by 2-D electrophoresis and tandem mass spectrometry. The results indicated that a chaperone protein calreticulin (CRT) was significantly upregulated in P-CSLCs compared to parental cells. Flow cytometry analysis indicated that CRT was mostly localized to the surface of P-CSLCs and did not correlate with the levels of CD44v9, another P-CSLC biomarker. Furthermore, the side population in the CRThigh /CD44v9low population was much higher than that in the CRTlow /CD44v9high population. Calreticulin expression was also assessed by immunohistochemistry in pancreatic cancer tissues (n = 80) obtained after radical resection and was found to be associated with patients' clinicopathological features and disease outcomes in the Cox proportional hazard regression model. Multivariate analysis identified CRT as an independent prognostic factor for pancreatic cancer patients, along with age and postoperative therapy. Our results suggest that CRT can serve as a biomarker of P-CSLCs and a prognostic factor associated with poorer survival of pancreatic cancer patients. This novel biomarker can be considered as a therapeutic target for cancer immunotherapy.

Background Cancer stem cells are thought to play important roles in carcinogenesis, recurrence, metastasis, and therapy-resistance. We have successfully induced cancer stem-like sphere cells (CSLCs) from hepatoma cell lines using a unique medium. Methods The human hepatoma cell line SK-HEP-1 was used as parental cells for CSLC induction. To assess the chemoresistance and liver metastasis, MTS assay and splenic injection were performed, respectively. RNA-seq analysis followed by gene set enrichment analysis (GSEA) was performed with cell line derivatives and clinical specimens of hepatoma. Protein expressions were conducted by western blotting, flow-cytometry, or ELISA. Knock-out experiments was accomplished by CRISPR-Cas9 genome-editing. Following rescue experiments were performed with an expression vector. Results The obtained CSLCs showed increased metastatic potentials and resistance to anti-cancer drugs including molecularly targeted drugs for liver cancer. Regarding immune resistance, CSLCs showed increased proportion of positive cells for PD-L1 and PD-L2. In contrast to decreased membrane-bound MICA/MICB, increased soluble MICA in the medium were observed in CSLCs compared to those from the parental cells. As a result of integrated analysis with RNA-seq, a RAB3B was identified as an up-regulated gene in both CSLCs and poor prognostic liver cancers. Mono-allelic RAB3B knock-out cells showed altered sphere formation, significantly lower chemoresistance, and metastatic potential than that of parental cells, and those were rescued by the complementation of RAB3B. The knock-out cells also showed decreased PD-L1 and PD-L2 expressions in sphere induction medium than those in cells cultured with normal medium. GSEA following RNA-seq with the derivative cells revealed that negative enrichment of G2M checkpoint and positive enrichment of interferon response in CSLCs. Conclusions Our induced CSLCs showed characteristic phenotypes such as metastatic ability, chemo- and immune-resistances. The up-regulation of RAB3B may plays important roles in CSLCs. Legal entity responsible for the study Ryouichi TSUNEDOMI. Funding Japan Society for the Promotion of Science. Disclosure All authors have declared no conflicts of interest.

We have performed a combination therapy of hepatic arterial infusion chemotherapy(HAIC), radiation therapy(RT), and surgical resection for the treatment of hepatocellular carcinoma(HCC)with portal vein tumor thrombosis(PVTT)since 2013. We retrospectively analyzed 36 patients with HCC with PVTT who underwent hepatectomy between 1995 and 2016 to evaluate the clinical outcomes. Ten patients received preoperative HAIC, 7 underwent RT, and 14 received postoperative HAIC. The median survival time(MST)was 19.3 months, and the MST was significantly longer in the patients who underwent curative resection than those in patients who did not. In the non-curative resection group, postoperative HAIC prolonged the survival.

A 77-year-old man underwent a follow-up examination after distal gastrectomy. Contrast-enhanced computed tomography revealed a tumor of the pancreatic body and tail that contacted the common hepatic artery/celiac artery. Subsequently, the tumor was diagnosed as a borderline resectable pancreatic cancer. After chemoradiation therapy, the tumor was considered resectable. Preoperative angiography with intraoperative contrast-enhanced ultrasonography and indocyanine green fluorescence imaging confirmed blood flow in the residual stomach. Postoperatively, ischemic necrosis of the residual stomach was not observed. After distal gastrectomy, distal pancreatectomy with en bloc celiac axis resection was performed to safely and curatively address the cancer of the pancreatic body and tail.

Case 1: A 64-year-old man with a chiefcomplaint ofbloody stools was seen in our hospital. He underwent an extended right lobe resection for hilar cholangiocarcinoma 3 years ago and was in the middle of chemotherapy for multiple metastases. Case 2: A 69-year-old man with a chiefcomplaint ofbloody emesis and stools was seen. He underwent left hepatic trisegmentectomy for hilar cholangiocarcinoma and ligation of the right portal vein for postoperative portal venous thrombus 6 months ago. After careful examination, the patients in both cases were diagnosed with bleeding of the jejunal varices formed at the site ofhepaticojejunostomy. The patient in Case 1 underwent percutaneous transhepatic obliteration ofvarices and the patient in Case 2 underwent transileocolic vein obliteration ofvarices. After hepatobiliary pancreatic surgery with biliary tract reconstruction, we should be aware of ectopic varices during differential diagnosis of gastrointestinal bleeding.

Our previous study reported the effectiveness of the product of tumor number and size (NxS factor) as a predictor of the prognosis of patients with hepatocellular carcinoma (HCC) following hepatectomy. The aim of the present study was to validate the prognostic value of scoring systems based on the NxS factor for HCC. The records of 940 patients who underwent hepatectomy for HCC at Osaka University Graduate School of Medicine and Osaka International Cancer Institute were analyzed. The discriminatory abilities of the mathematical integrated model for tumor staging (MITS) score, which combines the NxS factor with liver function, and known prognostic systems, including the Japan Integrated Staging system, the Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program and the Tokyo system, were compared. Firstly, the present study demonstrated that a higher NxS factor was associated with decreased disease-free survival (DFS) and overall survival (OS) in patients with HCC (P

A 30-year-old primigravid woman without a history of thrombocytopenia was referred to our hospital because of severe thrombocytopenia (1,000 thrombocytes/µl) at 16 weeks of gestation and diagnosed with idiopathic thrombocytopenic purpura (ITP). There was no improvement in the platelet count after treatment with 0.5-1.0 mg/kg/day prednisolone, and the 400 mg/day intravenous immunoglobulin (IVIg) administered for 5 days gradually became ineffective; therefore, a laparoscopic splenectomy was performed at 25 weeks of gestation. The increase in the platelet count after the splenectomy was temporary, but the effects of IVIg therapy improved, and the patient received IVIg therapy seven times in total during her pregnancy. Her platelet count ranged between 10,000 and 70,000/µl after the splenectomy, compared with5,000/µl before the surgery. The patient underwent an elective cesarean section at 34 weeks of gestation without any significant bleeding. The baby was diagnosed with thrombocytopenia at birth (34,000 thrombocytes/µl) and was administered only one dose of IVIg, which increased the baby's platelet count to a normal level after 14 days. The patient's platelet count also increased after delivery. Splenectomy and repeated IVIg therapy can be considered for refractory severe ITP during pregnancy.

The optimal treatment for hepatocellular carcinoma (HCC) should be selected based on tumor conditions, liver functional reserve, and performance status. Surgical treatment, such as liver resection and liver transplantation, is the most favorable treatment method; however, its indication criteria differ according to each country’s guidelines. In Western countries, liver resection is indicated only for early-stage HCC patients with Barcelona-Clinic Liver Cancer staging classification (BCLC) 0/A. While in Asian countries, liver resection is one of the treatment options for advanced HCC, such as BCLC B/C. Recently, the treatment of HCC is about to enter a drastic transitional period. It started with the widespread use of minimally invasive surgery for HCC, followed by a high rate of hepatitis C virus eradication with the advent of direct acting antivirals and developing a multidisciplinary treatment for highly advanced HCC. As a result, the importance of liver resection for HCC is increasing, and it is time to reconsider the criteria for selecting treatment methods for HCC patients. This article outlines current topics in the surgical treatment of HCC.

Cancer stem-like cells (CSLCs) in solid tumors are resistant to conventional chemotherapy and molecularly targeted therapy, which is thought to contribute to cancer recurrence and metastasis. The present study aimed to identify biomarkers for pancreatic CSLCs (P-CSLCs). Using our previously reported methods, P-CSLC-enriched populations were generated from pancreatic cancer cell lines. The protein expression profiles of these populations were compared with those of parental cells using two-dimensional electrophoresis, tandem mass spectrometry, flow cytometry and immunohistochemistry. Protein expression in surgical specimens was also evaluated for relationships with clinical outcomes. A lysosomal cysteine protease, cathepsin B (CTSB), was significantly upregulated in P-CSLCs compared with that in the parental cells, as shown using western blotting. Flow cytometry analysis also confirmed that CTSB was more highly expressed on the surface of P-CSLCs compared with that on parental cells. Moreover, PCLCs had elevated cellular secretions of CTSB compared with the parental cells. Finally, CTSB expression was evaluated in 69 resected tumor specimens, and high expression was associated with the patients' clinicopathological features and surgical outcomes. The present results suggested that CTSB is a biomarker for poor survival in patients with pancreatic cancer, which is possibly associated with P-CSLCs. This novel biomarker may also have potential as a therapeutic target.

Background: Even with curative resection, the recurrence rate of HCC remains high, and effective adjuvant therapies are not currently available. Our previous Phase I study with novel therapeutic peptides and immune adjuvants demonstrated safety, antigen-specific CTL induction in PBMC, and a sign of efficacy (ASCO 2017 Abstract # 3086). We thus started a Phase I study of the same vaccination therapy as a perioperative immunotherapy setting in patients with resectable HCC (jRCTs061180058). Methods: Two mg each of HLA-A*24:02, 02:01, or 02:06-restricted HSP70- and GPC3-derived peptides, in combination with hLAG-3Ig (1.0 mg) + poly-IC:LC (1.4 mg) were injected intradermally at four sites of the inguinal and axillary regions every week for 6 weeks before surgery. Patients subsequently received 10 injections of adjuvant immunotherapy over 4 months. Surgical specimens and PBMCs were analyzed by mass cytometry (CyTOF), using 66 antibodies to monitor T-cell exhaustion, T-cell activation, and effector Treg induction. Tumor specimens were also subjected to HE staining and immunohistochemical staining for CD3, CD8, PD1, HSP70, and GPC3. Results: Nine patients were treated with preoperative vaccination, and resected surgical specimens and PBMC were examined. Pathohistological analysis revealed three response types: “hot cellular immunity”, “intermediate fumoral immunity”, and “cold response”. In three patients, massive infiltration of CD8+ and PD1+ T cells accompanied necrotic and fibrous regions, in which the targeted tumor antigens HSP70 and GPC3 were highly expressed, representing “hot cellular immunity”. Regarding “intermediate”, three patients showed necrotic regions with infiltrating macrophages. HSP70 and/or GPC3 were also highly expressed, but little infiltration of lymphocytes was evident. In the remaining three patients, “cold response” manifested as tumor comprising a pseudo-glandular pattern with no infiltration of T cells or macrophages. Two of these three patients showed no expression of targeted tumor antigens. CyTOF analysis of the tumors also revealed the percentages of CD3+ cells among live cells and of PD1+ cells among CD8+ cells were extremely low in cold response. However, this trend was not observed in PBMCs, suggesting the critical importance of TIL analysis. Conclusions: This novel therapeutic peptide and immune adjuvant combination induced sustained immune cell infiltration into tumor microenvironments, especially in those presenting target tumor-associated antigens with a non-pseudo-glandular type. Our novel immunotherapy may convert cold tumors into hot tumors containing PD1+ lymphocytes. Combining this novel strategy with PD (L) 1 antibody may be warranted. Citation Format: Masao Nakajima, Shoichi Hazama, Koji Tamada, Keiko Udaka, Shun Doi, Michiie Sakamoto, Akira Saito, Shiro Akinaga, Hiroto Matsui, Yoshitaro Shindo, Satoshi Matsukuma, Yukio Tokumitsu, Shinobu Tomochika, Michihisa Iida, Shin Yoshida, Ryouichi Tsunedomi, Yuki Nakagami, Nobuaki Suzuki, Shigeru Takeda, Hiroaki Nagano. Immunological and histopathological tumor responses to a novel neoadjuvant peptide vaccine targeting HSP70 and GPC3 antigens in patients with resectable HCC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT251.