Takeo Nomi

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.

A novel small-molecule compound targeting CCR5 and CXCR3 prevents acute and chronic allograft rejection.

Background. Chemokines and chemokine receptors are critical in leukocyte recruitment, activation, and differentiation. Among them, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 3 (CXCR3) have been reported to play important roles in alloimmune responses and may be potential targets for posttransplant immunosuppression. Methods. Fully major histocompatibility complex (MHC)-mismatched murine cardiac and islet transplant models were used to test the effect in vivo of a novel, small-molecule compound TAK-779 by targeting CCR5 and CXCR3 in acute allograft rejection. An MHC class II mismatched cardiac transplant model was used to evaluate its efficacy in chronic allograft rejection. Intragraft expression of cytokines, chemokines, and chemokine receptors was measured by quantitative real-time polymerase chain reaction and by histological analysis. Results. Treatment of TAK-779 significantly prolonged allograft survival across the MHC barrier in two distinct transplant models. The treatment downregulated local immune activation as observed by the reduced expression of several chemokines, cytokines, and chemokine receptors. Thereby, the recruitment of CD4, CD8, and CD11c cells into transplanted allografts were inhibited. Furthermore, TAK-779 treatment significantly attenuated the development of chronic vasculopathy, fibrosis, and cellular infiltration. Conclusions. Antagonism of CCR5 and CXCR3 has a substantial therapeutic effect on inhibiting both acute and chronic allograft rejection. CCR5 and CXCR3 are functional in the process of allograft rejection and may be potential targets in clinical transplantation in the future.

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.

Learning curve for laparoscopic major hepatectomy

Laparoscopic major hepatectomy (LMH) is evolving as an important surgical approach in hepatopancreatobiliary surgery. The present study aimed to evaluate the learning curve for LMH at a single centre.

Laparoscopy Decreases Pulmonary Complications in Patients Undergoing Major Liver Resection: A Propensity Score Analysis.

Objective:To compare both incidence and types of postoperative pulmonary complications (PPCs) between laparoscopic major hepatectomy (LMH) and open major hepatectomy (OMH). Background:LMHs are increasingly performed. Yet, the benefits of laparoscopy over laparotomy regarding PPCs remain unknown. Methods:In this multi-institutional study, all patients undergoing OMH or LMH between 1998 and 2013 were retrospectively reviewed. Risk factors for PPCs were analyzed on multivariate analysis. Comparison of both overall rate and types of PPCs between OMH and LMH patients was performed after propensity score adjustment on factors influencing the choice of the approach. Results:LMH was performed in 226 (18.6%) of the 1214 included patients. PPCs occurred in 480 (39.5%) patients including symptomatic pleural effusion in 366 (30.1%) patients, respiratory insufficiency in 141 (11.6%), acute respiratory distress syndrome in 84 (6.9%), pulmonary infection in 80 (6.5%), and pulmonary embolism in 47 (3.8%) patients. On multivariate analysis, preoperative hypoprotidemia [hazard ratio (HR): 1.341, 95% confidence interval (CI): 1.001–1.795; P = 0.049], open approach (HR: 2.481, 95% CI: 1.141–6.024; P = 0.024), right-sided hepatectomy (HR: 2.143, 95% CI: 1.544–2.975; P < 0.001), concomitant extrahepatic procedures (HR: 1.742, 95% CI: 1.103–2.750; P = 0.017), transfusion (HR: 2.851, 95% CI: 2.067–3.935; P < 0.001), and operative time more than 6 hours (HR: 1.510, 95% CI: 1.127–2.022; P = 0.006) were independently associated with PPCs. After propensity score matching, the overall incidence of PPCs (13.2% vs 40.5%, P < 0.001), symptomatic pleural effusion (11.6% vs 26.4%, P = 0.003), pleural effusion requiring drainage (1.7% vs 9.9%, P = 0.006), and acute respiratory distress syndrome (1.7% vs 9.9%, P = 0.006) were significantly lower in the laparoscopy group than in the open group. Conclusions:Pure laparoscopy allows reducing PPCs in patients requiring major liver resection.

Risk factors and consequences of conversion in laparoscopic major liver resection.

Although recent reports have suggested potential benefits of the laparoscopic approach in patients requiring major hepatectomy, it remains unclear whether conversion to open surgery could offset these advantages. This study aimed to determine the risk factors for and postoperative consequences of conversion in patients undergoing laparoscopic major hepatectomy (LMH).

Risk factors for complications after laparoscopic major hepatectomy

Although laparoscopic major hepatectomy (MH) is becoming increasingly common in several specialized centres, data regarding outcomes are limited. The aim of this study was to identify the risk factors for postoperative complications of purely laparoscopic MH at a single centre.

Laparoscopic transabdominal with transdiaphragmatic access improves resection of difficult posterosuperior liver lesions

OBJECTIVE We describe the technical details and evaluate the safety, feasibility, and usefulness of a combined lateral and abdominal (CLA) approach for laparoscopic resection of liver segments 7 and 8. BACKGROUND Laparoscopic resection of lesions in the posterosuperior area of segments 7 and 8 is technically challenging, and currently there is no standardized laparoscopic approach. METHODS Through review of a prospectively maintained database, we identified 44 patients who underwent laparoscopic resection of lesions in segment 7 or 8. Twenty-five patients required the CLA approach because their lesions were more posterosuperior and intraparenchymal; 19 patients underwent resection with a regular abdominal-only approach of more accessible anteroinferior lesions. We reviewed operative details and video footage of these operations and compared the outcomes of the 2 groups. RESULTS In the group treated with the CLA approach, deep location was more frequent (88% vs 42%; P = 0.035), median tumor diameter was larger (24.5 mm vs 15 mm; P = 0.114), and the median weight of the excised parenchyma was greater (56.5 g vs 23 g; P = 0.093). Median operative time was longer in the CLA approach group (217.5 minutes vs 165 minutes; P = 0.046), but blood loss, rate of conversion to open surgery, surgical margin status, morbidity, and mortality were similar between the 2 groups. CONCLUSIONS The CLA approach permits safe laparoscopic resection of lesions in the posterosuperior area of segments 7 and 8, allowing surgeons to overcome the difficulties of limited visualization and access to the target lesions.

Clinical Significance of Prostate Stem Cell Antigen Expression in Non-small Cell Lung Cancer

OBJECTIVE Prostate stem cell antigen was originally identified as an overexpressed gene in prostate cancer and its overexpression correlated with disease progression and prognosis. In this study, we investigated the clinical significance and therapeutic potential of prostate stem cell antigen expression in non-small cell lung cancer. METHODS Prostate stem cell antigen expression was examined by immunohistochemistry in 97 primary tumors and 21 metastatic lymph nodes from non-small cell lung cancer patients who underwent curative resection from January 2001 through March 2003. Therapeutic potential of targeting prostate stem cell antigen was further examined by small interfering RNA method using human lung cancer cell line (A549). RESULTS Prostate stem cell antigen protein expression was detected in 94 of 97 primary lesions (97%) and all metastatic lymph nodes. Prostate stem cell antigen expression intensity was positively correlated with advanced pathological T-factor and stage (T1 vs. T2-4, P = 0.014; Stage I vs. Stages II-IV, P = 0.029, respectively). The prognosis of patients with low prostate stem cell antigen expression was significantly better than those with high prostate stem cell antigen expression (5-year disease-free survival rate; 90% vs. 53%, P = 0.001). Finally, small interfering RNA-mediated knockdown of prostate stem cell antigen resulted in the inhibition of lung cancer cell growth. CONCLUSIONS Prostate stem cell antigen is highly expressed in non-small cell lung cancer and may be functionally important for this fatal disease.

Significance and therapeutic potential of prostaglandin E2 receptor in hepatic ischemia/reperfusion injury in mice

Prostaglandin E2 (PGE2) mediates a variety of innate and adaptive immunity through four distinct receptors: EP1‐EP4. It has been suggested that each EP plays a unique and pivotal role in various disease conditions. We investigated the pathophysiological role of EP receptors in hepatic ischemia/reperfusion (I/R) injury. In this study, a 70% hepatic ischemic model was used in male C57BL/6 mice. Selective EP agonists were used to clarify the function of each PGE2 receptor in I/R injury. Although all four receptors were expressed in the naïve liver, EP4 expression was significantly upregulated after hepatic I/R. Although EP1, 2, or 3 agonists did not show any protective effect on liver function, the EP4 agonist significantly inhibited hepatic I/R injury as determined by serological and histological analyses. Furthermore, the EP4 agonist downregulated the local expressions of several proinflammatory cytokines, chemokines, and adhesion molecules in the early phase of reperfusion. In contrast, it augmented the local expression of an anti‐inflammatory cytokine, interleukin 10. Additionally, the neutrophil accumulation was also inhibited by EP4 agonist treatment. Finally, to confirm the therapeutic efficacy of the EP4 agonist in hepatic I/R injury, the nonischemic shunt liver was removed after 120 minutes of ischemia, resulting in the death of 86% of control mice within 48 hours. In sharp contrast, 80% of mice treated with the EP4 agonist survived. In conclusion, the PGE2‐EP4 signaling pathway has an inhibitory role in hepatic I/R injury. An EP4 agonist effectively protects against ischemic injury. (HEPATOLOGY 2005.)