[A Case of Conversion Surgery after SOX plus Nivolumab for Unresectable Advanced Gastric Cancer].

A 63-year-old woman came to our hospital complaining of anemia and weight loss. The abdominal CT showed wall thickening from the upper to lower the body of stomach, and peritoneal dissemination. The EGD revealed a type 3 large tumor extending about 2/3 of the circumference. Adenocarcinoma was detected as a result of biopsy. The patient was diagnosed with unresected gastric cancer(cT4aN+M1, cStage Ⅳ). SOX plus nivolumab was selected as a first-line chemotherapy because of HER2 expression negative. Symptoms such as diarrhea developed, and the treatment was completed until 5 courses. Laparoscopic distal gastrectomy was performed after the disappearance of abdominal dissemination by CT scan and PET. Pathological examination revealed cancer cells were completely disappeared in the tumor, regional lymph nodes and white nodules in the peritoneum, and final diagnosis was ypT0N0M0, ypStage 0(histological effect determination is Grade 3). Six months after the operation, the patient has been free of recurrence.

Phase I study of a novel therapeutic vaccine as perioperative treatment for patients with surgically resectable hepatocellular carcinoma: The YCP02 trial.

AIM: Developing effective adjuvant therapies is essential for improving the surgical outcomes in patients with hepatocellular carcinoma (HCC). Immunotherapy against HCC has become a promising strategy; however, only approximately 30% of all HCC patients respond to immunotherapy. Previously, we generated the novel therapeutic vaccine comprising multi-human leukocyte antigen-binding heat shock protein 70/glypican-3 peptides with a novel adjuvant combination of hLAG-3Ig and poly-ICLC. We also confirmed the safety of this vaccination therapy, as well as its capacity for the effective induction of immune responses in a previous clinical trial. METHODS: In this phase I study, we administered this vaccine intradermally six times before surgery, and 10 times after surgery to patients with untreated, surgically resectable HCC (stage II to IVa). The primary end-points of this study were the safety and feasibility of this treatment. We also analyzed the resected tumor specimens pathologically using hematoxylin-eosin staining and immunohistochemistry for heat shock protein 70, glypican 3, CD8 and programmed death-1. RESULTS: A total of 20 human leukocyte antigen-matched patients received this vaccination therapy with an acceptable side-effect profile. All patients underwent planned surgery without vaccination-related delay. Immunohistochemical analyses revealed that potent infiltration of CD8+ T cells into tumors with target antigen expression was observed in 12 of 20 (60%) patients. CONCLUSIONS: This novel therapeutic vaccine was safe as perioperative immunotherapy for patients with HCC, and has the potential to strongly induce CD8+ T cells infiltration into tumors.

Double cancer of primary hepatic angiosarcoma and hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

AIM: Primary hepatic angiosarcoma (PHA) is extremely rare, and its imaging findings are similar to those of other liver tumors including hepatocellular carcinoma (HCC). Here, we report a case of hepatitis C virus (HCV)-related HCC followed by PHA that showed remarkable clinical response to atezolizumab plus bevacizumab (Atezo/Bev) therapy. CASE PRESENTATION: A 78-year-old man with recurrent HCC had a liver tumor with lymphadenopathy. Although considered as HCC recurrence, microscopic examination of the resected liver and lymph node showed PHA. Three months later, a solitary lung nodule was newly detected and subsequently resected. The pathological diagnosis was poorly differentiated HCC. Therefore, the patient was finally diagnosed with double cancer of PHA and HCC. Thereafter, he developed a new liver tumor with lymphadenopathy and received Atezo/Bev therapy. Liver tumor biopsy was carried out before the treatment. The pathological diagnosis was angiosarcoma. The patient showed a partial response after two courses of Atezo/Bev therapy. CONCLUSION: To our best knowledge, this report is the first case to present HCV-related HCC followed by PHA and to show that Atezo/Bev therapy is beneficial for PHA.

[A Case of Early Pancreatic Cancer Diagnosed from the Finding of Partial Pancreatic Parenchymal Atrophy].

A man in his 80s was referred to our hospital for further examination of partial pancreatic atrophy that was detected incidentally. Various imaging examinations including CT, MRI, and EUS did not reveal any obvious abnormal findings other than the partial pancreatic atrophy. However, cytological examination of serial pancreatic juice aspiration showed atypical cells. The presence of pancreatic intraepithelial carcinoma in the atrophy site was considered, and the patient underwent laparoscopic distal pancreatectomy. Pathological examination of the excised specimen confirmed the presence of high-grade pancreatic intraepithelial neoplasia consistent with the atrophy site, and the patient was diagnosed with pTisN0M0, Stage 0 pancreatic cancer. For the detection of early pancreatic cancer, it is important to be aware of partial pancreatic atrophy on imaging studies.

CD4 and FOXP3 as predictive markers for the recurrence of T3/T4a stage II colorectal cancer: applying a novel discrete Bayes decision rule.

BACKGROUND: We recently reported the relapse-free survival (RFS) significance of the combination of CD4+ and forkhead box P3+ (FOXP3) T-cell densities identified by immunohistochemistry in patients with stage I, II, and III colorectal cancer (CRC) who underwent curative resections. This study was designed to determine the optimal combination of markers that predict recurrence in patients with T factors of T3/T4a stage II CRC by applying a novel Bayes decision rule. METHODS: Using 137 cancer tissue specimens from T3/T4a stage II patients, 12 clinicopathologic and immune factors were analysed as predictive candidates for recurrence. RESULTS: Our study showed that the combination of low CD4+ and low FOXP3+ T-cell densities resulted in extremely poor RFS. CONCLUSIONS: Adjuvant chemotherapy may be considered for patients with a combination of low CD4+ and low FOXP3+ T-cell densities. The discovery of this new prognostic indicator is important for the appropriate management of patients undergoing curative resection for T3/T4a stage II CRC.

Immune Evasion of Hepatoma Cancer Stem-Like Cells from Natural Killer Cells.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Human hepatoma cell line-derived CSLCs may possess immune evasion properties, especially from NK cell-mediated immunity.

Surgical shunt ligation for a congenital extrahepatic portosystemic shunt with pulmonary hypertension: A case report.

INTRODUCTION AND IMPORTANCE: 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. CASE PRESENTATION: 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. CLINICAL DISCUSSION: 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. CONCLUSION: 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.

Elevated expression of RAB3B plays important roles in chemoresistance and metastatic potential of hepatoma cells.

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.

[Surgical Resection of Gastric GIST Liver Metastasis with Giant Cystic Mass-A Case Report].

The patient is a woman in her 80s who underwent a partial gastrectomy for a gastric GIST 14 years ago. This time, she presented our department with upper abdominal distention and computed tomography revealed an 18 cm-sized cystic lesion in the left lobe of the liver. Since a nodule enhancement was observed in the cyst, malignant disease such as hepatic cystadenocarcinoma could not be ruled out and surgical resection was performed. Pathological examination revealed liver metastasis of gastric GIST. In Japan, only 14 cases have been reported showing such late recurrence with liver metastasis more than 10 years after resection of a primary tumor, including our case. In addition, the cystic finding in this case made preoperative diagnosis difficult because a needle biopsy could not be performed to obtain a pathological diagnosis.

Antibiotic Usage Reduced Overall Survival by over 70% in Non-small Cell Lung Cancer Patients on Anti-PD-1 Immunotherapy.

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.

Hepatic artery resection and reconstruction using the right gastroepiploic artery during pancreaticoduodenectomy in advanced pancreatic cancer.

PURPOSE: 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. METHODS: We report two cases of pancreatic cancer with hepatic artery resection and reconstruction using the right gastroepiploic artery during pancreaticoduodenectomy after neoadjuvant therapy. RESULTS: 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. CONCLUSION: Hepatic artery reconstruction using the right gastroepiploic artery in pancreatic cancer might be technically safe and might become one of the alternative options.

Pancreatic Cancer Stem-Like Cells With High Calreticulin Expression Associated With Immune Surveillance.

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.

Short- and Long-Term Outcomes of Simultaneous Hepatic Artery Resection and Reconstruction for Perihilar Cholangiocarcinoma.

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.

[A Case of Anastomotic Recurrence of Rectal Cancer Treated by Laparoscopic Total Pelvic Exenteration after Neoadjuvant Chemoradiation].

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.

[A Case of Gastrointestinal Stromal Tumor of the Lower Rectum That Enabled Minimally Invasive Surgery with Imatinib Mesylate as Neoadjuvant Chemotherapy].

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.

Laparoscopic resection reduces superficial surgical site infection in liver surgery.

BACKGROUND: Laparoscopic liver resection is beneficial compared to open liver resection. This study aimed to evaluate whether laparoscopic liver resection could reduce postoperative infections. METHODS: 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. RESULTS: 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). CONCLUSIONS: Using the laparoscopic approach for partial resections and left lateral sectionectomies for liver tumors, the superficial incisional surgical site infection rate could be reduced.

[A Resected Case of Advanced Lower Rectal Cancer with Neoadjuvant Chemotherapy by FOLFOXIRI plus Cetuximab].

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.

[A Case of Intrahepatic Cholangiocarcinoma in the Elderly Patient with Curative Resection after Neoadjuvant Chemotherapy].

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.