Takahiro Akahori

Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer.

Purpose: The programmed death-1 ligand/programmed death-1 (PD-L/PD-1) pathway has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. In this study, we tried to reveal the clinical importance and therapeutic potential of the PD-L/PD-1 pathway in pancreatic cancer, which is one of the most aggressive and intractable malignant tumors. Experimental Design: We used immunohistochemistry to investigate PD-L expression in 51 patients with pancreatic cancer who underwent surgery and explored the therapeutic efficacy of blocking the PD-L1/PD-1 pathway in murine pancreatic cancer in vivo. Results: PD-L1–positive patients had a significantly poorer prognosis than the PD-L1–negative patients, whereas there was no significant correlation of tumor PD-L2 expression with patient survival. PD-L1 expression was inversely correlated with tumor-infiltrating T lymphocytes, particularly CD8+ T cells. These clinical data have suggested that the PD-L1/PD-1 pathway may be a critical regulator in human pancreatic cancer. Monoclonal antibodies against PD-L1 or PD-1 induced a substantial antitumor effect on murine pancreatic cancer in vivo. PD-L1 blockade promoted CD8+ T-cell infiltration into the tumor and induced local immune activation. Furthermore, the combination of anti–PD-L1 monoclonal antibody and gemcitabine exhibited a significant synergistic effect on murine pancreatic cancer and resulted in complete response without overt toxicity. Conclusion: Our data suggest for the first time that PD-L1 status may be a new predictor of prognosis for patients with pancreatic cancer and provide the rationale for developing a novel therapy of targeting the PD-L/PD-1 pathway against this fatal disease.

Clinical importance of B7-H3 expression in human pancreatic cancer

Background:B7-H3 is a new member of the B7 ligand family and regulates T-cell responses in various conditions. However, the role of B7-H3 in tumour immunity is largely unknown. The purpose of this study was to evaluate the clinical significance of B7-H3 expression in human pancreatic cancer and the therapeutic potential for cancer immunotherapy.Methods:We investigated B7-H3 expression in 59 patients with pancreatic cancer by immunohistochemistry and real-time PCR. Furthermore, we examined the anti-tumour effect of B7-H3-blocking monoclonal antibody in vivo in a murine pancreatic cancer model.Results:Tumour-related B7-H3 expression was abundant in most human pancreatic cancer tissues and was significantly higher compared with that in non-cancer tissue or normal pancreas. Moreover, its expression was significantly more intense in cases with lymph node metastasis and advanced pathological stage. B7-H3 blockade promoted CD8+ T-cell infiltration into the tumour and induced a substantial anti-tumour effect on murine pancreatic cancer. In addition, the combination of gemcitabine with B7-H3 blockade showed a synergistic anti-tumour effect without overt toxicity.Conclusion:Our data show for the first time that B7-H3 may have a critical role in pancreatic cancer and provide the rationale for developing a novel cancer immunotherapy against this fatal disease.

Direct targeting of fibroblast growth factor-inducible 14 protein protects against renal ischemia reperfusion injury

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to have pivotal roles in various inflammatory processes. The TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), has various unique functions under physiological and pathological conditions; however, the therapeutic potential of its direct targeting remains unknown. Here, we found that Fn14 expression was highly upregulated in ischemic renal tissues and tubular epithelial cells of patient biopsies and experimental animal models of renal injury. To clarify the function of Fn14 in ischemia reperfusion injury, we coincubated renal tubular cells with ITEM-2, an anti-Fn14 blocking monoclonal antibody, and found that it inhibited the production of proinflammatory cytokines and chemokines after injury. Furthermore, Fn14 blockade downregulated the local expression of several proinflammatory mediators, reduced accumulation of neutrophils and macrophages in ischemic tissues, and inhibited tubular cell apoptosis. Importantly, Fn14 blockade attenuated the development of chronic fibrosis after ischemia reperfusion injury and significantly prolonged the survival of lethally injured mice. Thus, we conclude that Fn14 is a critical mediator in the pathogenesis of ischemia reperfusion injury.

Effects of pancrelipase on nonalcoholic fatty liver disease after pancreaticoduodenectomy

Postoperative nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD) has recently become recognized. However, the pathoetiology of postoperative NAFLD is largely unknown. Furthermore, the optimal treatment has not been established. The aim of this prospective study was to clarify whether pancrelipase, which contains digestive pancreatic enzymes, could reverse NAFLD.

Prognostic importance of tumour-infiltrating memory T cells in oesophageal squamous cell carcinoma

Memory T cells survive for many months and years and are critically important for host defence in humans. In tumour immunity, they have been also suggested to play a significant role in tumour progression and metastasis. However, the role of memory T cells in actual human cancer remains largely unknown. In this study, the clinical importance of tumour‐infiltrating CD45RO+ memory T cells was investigated in human oesophageal squamous cell carcinoma (OSCC). CD45RO+ T cells were evaluated by immunohistochemistry in primary OSCC tumours from 105 patients. Patients were classified into two groups as CD45RO+hi or CD45RO+lo based on the number of cells stained positively for CD45RO. No significant difference was observed between CD45RO status and several clinicopathological prognostic factors. However, the postoperative overall and disease‐free survival for CD45RO+hi patients was significantly better than for CD45RO+lo patients. Furthermore, there were significant correlations of CD45RO status in the primary tumour with postoperative lymph node and pulmonary recurrence, suggesting that memory T cells may control postoperative metastatic recurrence. Most importantly, CD45RO+ memory T cell status has a significant prognostic value for OSCC independently of conventional tumour–node–metastasis (TNM) classification. Our study may provide a rationale for developing a novel immunotherapy in intentional induction of memory T cells for the treatment of oesophageal cancer.

Proposed preoperative risk factors for early recurrence in patients with resectable pancreatic ductal adenocarcinoma after surgical resection: A multi-center retrospective study

BACKGROUND/OBJECTIVE Although surgical resection remains the only chance for cure in patients with pancreatic ductal adenocarcinoma (PDAC), postoperative early recurrence (ER) is frequently encountered. The purpose of this study is to determine the preoperative predictive factors for ER after upfront surgical resection. METHODS Between 2001 and 2012, 968 patients who underwent upfront surgery with R0 or R1 resection for PDAC at seven high-volume centers in Japan were retrospectively reviewed. ER was defined as relapse within 6 months after surgery. Study analysis stratified by resectable (R) and borderline resectable (BR) PDACs was conducted according to the National Comprehensive Cancer Network guidelines. RESULTS ER occurred in 239 patients (25%) with a median survival time (MST) of 8.8 months. Modified Glasgow prognostic score = 2 (odds ratio (OR) 2.06, 95% confidence interval (CI) 1.05-3.95; P = 0.044), preoperative CA19-9 ≥300 U/ml (OR 1.94, 1.29-2.90; P = 0.003), and tumor size ≥30 mm (OR 1.72, 1.16-2.56; P = 0.006), were identified as preoperative independent predictive risk factors for ER in patients with R-PDAC. In the R-PDAC patients, MST was 35.5, 26.3, and 15.9 months in patients with 0, 1 and ≥2 risk factors, respectively. There were significant differences in overall survival between the three groups (P < 0.001). No preoperative risk factors were identified in BR-PDAC patients with a high rate of ER (39%). CONCLUSIONS There is a high-risk subset for ER even in patients with R-PDAC and a simple risk scoring system is useful for prediction of ER.

Prognostic Significance of Muscle Attenuation in Pancreatic Cancer Patients Treated with Neoadjuvant Chemoradiotherapy

BackgroundEmerging evidences have gradually revealed the skeletal muscle attenuation (MA) was not only reflected the accumulation of lipids in skeletal muscle but also associated with physiological and pathological states. The aim of this study was to evaluate the impact of MA on the prognosis of pancreatic cancer patients treated with neoadjuvant chemoradiotherapy (NACRT).MethodsEighty-three patients with pancreatic cancer who received NACRT were enrolled. Patients were divided according to their Hounsfield units of the skeletal muscle at the third lumbar vertebra in CT. The lower quartile was defined as MA group and the remainder as control group.ResultsThere was no significant difference in overall survival between pre-NACRT MA and control groups. In contrast, patients with post-NACRT MA had a significantly poorer prognosis than patients without. The patients in the post-NACRT MA group were significantly older than patients in the control group. There were no significant differences in most clinicopathological and perioperative factors between both groups. However, patients with post-NACRT MA had a longer hospital stay than patients without. Furthermore, the incompletion rate of the proposed adjuvant chemotherapy was significantly higher in the MA group than control. Importantly, multivariate analysis indicated that post-NACRT MA was an independent prognostic factor.ConclusionsMuscle attenuation may have a significant impact in pancreatic cancer patients treated with multimodal therapy. Therefore, our data may provide new insights into perioperative patient care to improve the prognosis of resectable pancreatic cancer.

Optimal indication of neoadjuvant chemoradiotherapy for pancreatic cancer.

PurposeMuch attention has been paid to preoperative treatment as a new strategy especially for borderline resectable pancreatic cancer (BRPC). The purpose of this study was to define the optimal indication of neoadjuvant chemoradiotherapy (NACRT) for pancreatic cancer.MethodsWe analyzed consecutive 184 patients who had undergone pancreatic resection in Nara Medical University Hospital. Resectability status was classified by NCCN guidelines. Full-dose gemcitabine with concurrent radiation was used as NACRT. We evaluated 85 patients treated with NACRT in comparison with 99 patients without NACRT as control.ResultsThe regimen of NACRT was well tolerated and feasible. The perioperative outcomes were almost comparable. The postoperative complications were significantly less frequent in NACRT group than non-NACRT group. The pathological effects on both resectable and borderline tumors were favorable in NACRT group compared to non-NACRT group. The overall survival of resectable pancreatic cancer was significantly better than that of BRPC regardless of whether the patients were treated with or without NACRT. The prognosis of the patients with NACRT in resectable tumors was significantly better than without, while there was no significant difference in BRPC. Furthermore, multivariate analysis of various factors in the patients with NACRT identified resectability status and completion of adjuvant chemotherapy as independent prognostic factors.ConclusionsNACRT did not improve the prognosis of the patients with BRPC, although it induced substantial pathological antitumor effect. In contrast, the prognosis of resectable pancreatic cancer treated with NACRT was favorable. Therefore, resectable pancreatic cancer may be good indication for multimodal treatment including NACRT.

Factors associated with failure to complete adjuvant chemotherapy in pancreatic cancer

BACKGROUND The importance of completing adjuvant chemotherapy in pancreatic cancer is becoming recognized. However, the clinicopathological factors associated with failure to complete adjuvant chemotherapy remain unclear. METHODS A total of 135 patients were analyzed to identify the factors associated with failure to complete adjuvant chemotherapy. RESULTS Ninety patients completed planned adjuvant chemotherapy, whereas 45 patients failed to complete adjuvant chemotherapy. Lower preoperative prognostic nutritional index, intraoperative blood transfusion, and organ and/or space surgical site infection, and advanced tumor stage were associated with failure to complete adjuvant chemotherapy. Neoadjuvant chemoradiotherapy was associated with significantly lower prognostic nutritional index, less incidence of organ and/or space surgical site infection, and earlier tumor stage, suggesting the conflicting effects of neoadjuvant chemoradiotherapy on completing adjuvant chemotherapy. CONCLUSIONS Several clinicopathological factors including patient conditions and perioperative events were associated with failure to complete adjuvant chemotherapy.

Nectin-4 expression contributes to tumor proliferation, angiogenesis and patient prognosis in human pancreatic cancer

BackgroundNectin-4 belongs to the nectin family that has diverse physiological and pathological functions in humans. Recent studies have also suggested some roles for Nectin-4 in several human cancers. However, the precise roles and clinical relevance of Nectin-4 in tumors are largely unknown.MethodsNectin-4 expression was investigated in 123 patients with pancreatic cancer by immunohistochemistry. Furthermore, we investigated the association of Nectin-4 in pancreatic cancer with tumor proliferation, angiogenesis and immunity by using immunohistochemistry and siRNA interference method.ResultsPatients with high Nectin-4 expression had poorer postoperative prognosis than those with low expression. Importantly, multivariate analysis indicated that Nectin-4 expression had a significant independent prognostic value in pancreatic cancer (HR = 1.721, 1.085-2.730; P = 0.021). Tumor Nectin-4 expression was significantly correlated with Ki67 expression. In addition, siRNA-mediated gene silencing of Nectin-4 significantly inhibited the cell proliferation in human pancreatic cancer cells, Capan-2 and BxPC-3. Furthermore, Nectin-4 expression was also positively correlated with VEGF expression and intratumoral microvessel density. However, there were no significant correlations of tumor Nectin-4 expression with tumor-infiltrating T cells.ConclusionNectin-4 is a significant prognostic predictor, and may play a critical role in pancreatic cancer. Nectin-4 may be novel therapeutic target for pancreatic cancer.