Takahiro Tsuchikawa

Infiltrating regulatory T cell numbers is not a factor to predict patient's survival in oesophageal squamous cell carcinoma

CD4/8 status has been previously reported to be a critical factor in the prognosis of oesophageal squamous cell carcinoma (OSCC). In the current study, we investigated the effect of regulatory T cells (Treg; Foxp3+ lymphocytes) on the status of CD4+ and CD8+ T cells in 122 patients with OSCC. Immunohistochemical analysis of Treg was performed using an antibody against Foxp3. The survival rate for low Foxp3 patients was significantly lower than for high Foxp3 patients (P=0.0028 by log-rank test), but Foxp3 status did not significantly correlate with prognosis in CD4/8(+/+) patients or CD4/8(+/−) or (−/+) patients (P=0.5185 and 0.8479, respectively, by log-rank test). We also found that Foxp3 status correlated with CD4/8 status (P=0.0002 by χ2 test) and that the variance of CD8/CD4 ratio in patients with low Foxp3 was larger than in patients with high Foxp3 (P<0.0001 by F-test). Thus, the results do not support the idea that Treg suppress anti-tumour immunity in patients with OSCC. Rather, the CD8/CD4 ratio and CD4/8 status appear to be critical factors in anti-tumour immunity. Furthermore, Treg numbers correlate with both the CD8/CD4 ratio and the CD4/8 status, suggesting that Treg number is not a factor to predict patients survival in OSCC.

Functional Characterization of an scFv-Fc Antibody that Immunotherapeutically Targets the Common Cancer Cell Surface Proteoglycan CSPG4

Cell surface chondroitin sulfate proteoglycan 4 (CSPG4) is an attractive target for antibody-based cancer immunotherapy because of its role in tumor cell biology, its high expression on malignant cells including cancer-initiating cells, and its restricted distribution in normal tissues. The clinical use of CSPG4 has been hampered by the lack of a CSPG4-specific chimeric, humanized, or fully human monoclonal antibody. To overcome this limitation, we generated a CSPG4-specific fully human single-chain antibody termed scFv-FcC21 and characterized its specificity and antitumor activity. Viable CSPG4(+) melanoma cells were used in a screen of a human scFv phage display library that included CDR3 engineered to optimize antibody binding sites. The scFv antibody isolated was then recombinantly engineered with a human immunoglobulin G1 Fc region to construct the fully human antibody scFv-FcC21, which recognized tumors of neuroectodermal origin, various types of carcinomas, mesotheliomas, and sarcomas as well as myeloid leukemias. scFv-FcC21 inhibited in vitro growth and migration of tumor cells and in vivo growth of human tumor xenografts. These effects were mediated by inhibition of the activation of extracellular signal-regulated kinase and focal adhesion kinase signaling pathways that are critical for tumor cell growth and migration, respectively. Our findings define the CSPG4-specific fully human scFv-FcC21 antibody as a candidate therapeutic agent to target the many types of tumors that express CSPG4.

No-touch resection of hilar malignancies with right hepatectomy and routine portal reconstruction

BACKGROUND/PURPOSE Locoregional recurrence following resection of hilar biliary cancers could be caused by the microscopic dissemination of cancer cells during dissection of the portal vein from the involved bile duct at the hilar region. This retrospective study assessed the feasibility and safety of a new procedure consisting of right-sided hepatectomy, caudate lobectomy, and bile duct resection combined with routine resection of the portal bifurcation to enable no-touch resection of hilar malignancies. METHODS Of 64 patients who underwent right-sided hepatectomy for hilar biliary cancer, the portal bifurcation was routinely resected by the above new procedure in 25 patients, based on preoperative imaging diagnoses. Perioperative outcomes were compared with those in patients who underwent conventional portal reconstruction (n = 18) and with those in patients who had preservation of the portal bifurcation (n = 21). RESULTS Perioperative data from patients with routine portal reconstruction were similar to those in the patients with conventional portal reconstruction and the patients without portal reconstruction. There were no postoperative complications directly related to portal reconstruction. CONCLUSIONS No-touch resection of hilar malignancies with right hepatectomy and the routine use of portal reconstruction was feasible and safe. The oncologic impact of this technique merits further evaluation.

Oncological benefit of preoperative endoscopic biliary drainage in patients with hilar cholangiocarcinoma

Due to advances in endoscopic equipment and techniques, preoperative endoscopic biliary drainage (EBD) has been developed to serve as an alternative to percutaneous transhepatic biliary drainage (PTBD). This study sought to clarify the benefit of EBD in comparison to PTBD in patients who underwent radical resections of hilar cholangiocarcinoma. One hundred and forty‐one patients underwent radical surgery for hilar cholangiocarcinoma between 2000 and 2008 were retrospectively divided into two groups based on the type of preoperative biliary drainage, PTBD (n = 67) or EBD (n = 74). We investigated if the different biliary drainage methods affected postoperative survival and mode of recurrence after median observation period of 82 months. The survival rate for patients who underwent EBD was significantly higher than those who had PTBD (P = 0.004). Multivariate analysis revealed that PTBD was one of the independent factors predictive of poor survival (hazard ratio: 2.075, P = 0.003). Patients with PTBD more frequently developed peritoneal seeding in comparison to those who underwent EBD (P = 0.0003). PTBD was the only independent factor predictive of peritoneal seeding. In conclusion, EBD might confer an improved prognosis over PTBD due to prevention of peritoneal seeding, and is recommended as the initial procedure for preoperative biliary drainage in patients with hilar cholangiocarcinoma.

Preoperative biliary drainage for hilar cholangiocarcinoma: which stent should be selected?

The controversy over whether and how to perform preoperative biliary drainage (PBD) in patients with hilar cholangiocarcinoma (HCA) remains unsettled. Arguments against PBD before pancreatoduodenectomy have recently been gaining momentum. However, the complication-related mortality rate is as high as 10% for patients with HCA who have undergone major liver resection, and liver failure is a major cause of postoperative death. This suggests the need for PBD to treat jaundice in HCA patients scheduled for major surgical resection of the liver and that major surgery should be performed only after the recovery of hepatic function. No definite criteria or guidelines outlining indications for PBD are currently available. In patients with HCA, PBD may be performed by either percutaneous transhepatic biliary drainage (PTBD) or endoscopic biliary drainage (EBD). No consensus, however, has been reached regarding which drainage method is more appropriate. No reported study has compared the effectiveness of PTBD, endoscopic biliary stenting (EBS), and endoscopic nasobiliary drainage (ENBD) in patients with HCA. This review summarizes the results of our study comparing the three methods and outlines the preoperative endoscopic management of segmental cholangitis (SC) in HCA patients undergoing PBD.

The immunological impact of neoadjuvant chemotherapy on the tumor microenvironment of esophageal squamous cell carcinoma.

BackgroundEsophageal cancer is an aggressive cancer with poor prognosis. However, little is known about the immune response in the tumor microenvironment after neoadjuvant chemotherapy.PurposeTo investigate the immunological impact of neoadjuvant chemotherapy in the tumor microenvironment of esophageal squamous cell carcinoma.MethodsEighteen patients with esophageal squamous cell carcinoma with and without neoadjuvant chemotherapy were analyzed using immunohistochemical methods for human leukocyte antigen (HLA) class I heavy chain, CD4-, CD8-, and Foxp3-positive cell infiltration.ResultsThe number of CD4 T cells in the stroma and within the cancer nest was significantly higher in the neoadjuvant chemotherapy group. The number of CD8 T cells in the stroma was significantly higher in the neoadjuvant chemotherapy group. HLA class I expression was more downregulated in the control group compared with the neoadjuvant chemotherapy group.ConclusionNeoadjuvant chemotherapy utilizing 5-fluorouracil and cisplatin in esophageal squamous cell carcinoma is useful to induce CD4 and CD8 T lymphocytes in the tumor microenvironment and to maintain HLA class I expression levels in combination with its direct cytotoxic effects.

Prognostic significance of epithelial-mesenchymal transition-related markers in extrahepatic cholangiocarcinoma : comprehensive immunohistochemical study using a tissue microarray

Background:Epithelial–mesenchymal transition (EMT) is characterised by the loss of cell-to-cell adhesion and gaining of mesenchymal phenotypes. Epithelial–mesenchymal transition is proposed to occur in various developmental processes and cancer progression. ‘Cadherin switch’, a process in which cells shift to express different isoforms of the cadherin transmembrane protein and usually refers to a switch from the expression of E-cadherin to N-cadherin, is one aspect of EMT and can have a profound effect on tumour invasion/metastasis. The aim of this study was to investigate the clinicopathological significance of EMT-related proteins and cadherin switch in extrahepatic cholangiocarcinoma (EHCC).Methods:We investigated the association between altered expression of 12 EMT-related proteins and clinical outcomes in patients with EHCC (n=117) using immunohistochemistry on tissue microarrays.Results:Univariate and multivariate analyses revealed that, in addition to N classification (P=0.0420), the expression of E-cadherin (P=0.0208), N-cadherin (P=0.0038) and S100A4 (P=0.0157) was each an independent and a significant prognostic factor. We also demonstrated that cadherin switch was independently associated with poor prognosis (P=0.0143) in patients with EHCC.Conclusions:These results may provide novel information for selection of patients with EHCC who require adjuvant therapy and strict surveillance.

A new preoperative prognostic scoring system to predict prognosis in patients with locally advanced pancreatic body cancer who undergo distal pancreatectomy with en bloc celiac axis resection: A retrospective cohort study

BACKGROUND Distal pancreatectomy with en bloc celiac axis resection (DP-CAR) provides good local control for locally advanced pancreatic body cancer, but early recurrence still occurs. In this study, we aimed to establish a new scoring system to predict prognosis using preoperative factors in patients with locally advanced pancreatic body cancer who undergo DP-CAR. METHODS Prognostic factors were analyzed using various data collected retrospectively from 50 consecutive patients who underwent DP-CAR. Using these preoperative factors, a scoring system to predict prognosis was established. RESULTS Multivariate analysis identified intraoperative blood loss (≥940 mL; hazard ratio [HR], 25.179; P = .0003), preoperative platelet counts (<150 × 10(9)/L; HR, 7.433; P = .0043), preoperative C-reactive protein (CRP) levels (≥0.4 mg/dL; HR, 7.064; P = .0018), and preoperative carbohydrate antigen 19-9 (CA19-9) levels (≥300 U/mL; HR, 8.197; P = .0053) as independent adverse prognostic factors. For the 3 preoperative factors, preoperative platelet counts <150 × 10(9)/L, preoperative CRP levels ≥0.4 mg/dL, and preoperative CA19-9 levels ≥300 U/mL were allocated 1 point each. The total score was defined as the Preoperative Prognostic Score (PPS). The estimated disease-specific 1- and 5-year survival rates for the 26 patients with PPS0 were 95.7%, and 49.1%, respectively, and for the 15 patients with PPS1, they were 86.7% and not available, respectively. The median survival times for PPS0 and PPS1 were 50.6 and 22.3 months, respectively. In contrast, in the 9 patients with PPS2/3, 1- and 5-year survival rates were 33.3% and 0%, respectively, and median survival time was only 7.7 months. CONCLUSION A new prognostic scoring system using the preoperative platelet count, CRP, and CA19-9 enables preoperative prediction of prognosis and facilitates selection of appropriate treatment for borderline resectable cases of locally advanced pancreatic body cancer.

Portal vein resection using the no-touch technique with a hepatectomy for hilar cholangiocarcinoma

OBJECTIVES To assess the safety and feasibility and discuss the oncological impact of a portal vein resection using the no-touch technique with a hepatectomy for locally advanced hilar cholangiocarcinoma. PATIENTS AND METHODS From 2005 to March 2009, 49 patients with hilar cholangiocarcinoma underwent a major right-sided hepatectomy with curative intent. Portal vein resection was performed using the no-touch technique in 36 patients (PVR group) but the portal vein was not resected in the other 13 patients (NR group). Peri-operative data and histological findings were compared between the two groups. Moreover, tumour recurrence and survival rates after surgery were calculated and compared for each group. RESULTS Although the tumours of the patients in the PVR group were more locally advanced, the residual tumour status and tumour recurrence rate were similar and there was no significant difference in long-term survival between the two groups: 5-year survival rates in the PVR and NR groups were 59% and 51%, respectively (P = 0.353). In-hospital mortality was encountered in 2 of the 49 patients. CONCLUSION A portal vein resection using the no-touch technique with a right-sided hepatectomy had a positive impact on survival and is feasible in terms of long-term outcomes with acceptable mortality.

Down-regulation of Human Leukocyte Antigen class I heavy chain in tumors is associated with a poor prognosis in advanced esophageal cancer patients

The HLA class I antigen processing machinery (APM) plays a crucial role in the anticancer immune response. The aim of this study was to assess the clinical significance of APM components in esophageal cancer. A total of 11 esophageal cancer cell lines were evaluated by Western blot analysis for 13 HLA class I APM components. There was a different expression pattern among cancer cell lines for HLA class I heavy chain (HLA-HC), β2 microglobulin, Tapasin, TAP-1, TAP-2, LMP-7 and LMP-10. Immunohistochemical staining utilizing a tissue microarray method for HLA class I APM expression showing different expression patterns among cell lines was performed for 95 surgical specimens from patients with esophageal cancer. Prognostic factors were the down-regulation of HLA-HC, and the up-regulation of β2 microglobulin and TAP-1 in the cancer tissues. Multivariate analysis using a Cox regression model indicated that the down-regulation of HLA-HC, and up-regulation of TAP-1 in cancer tissues are independent, unfavorable prognostic factors (hazard ratio, 2.361 and 2.297; P=0.0141 and 0.0145, respectively). Although there was no significant difference in survival for selected p-stage I and II patients (n=54) in all APM components, only down-regulation of HLA-HC was an unfavorable prognostic factor by a Cox regression model for selected p-stage III and IV patients (n=41). In conclusion, the current results suggest that the down-regulation of HLA-HC in tumors is especially associated with a poor prognosis among advanced esophageal cancer patients.