Gallstones in patients with severe motor and intellectual disability.

BACKGROUND: Asymptomatic gallbladder stones may be detected with ultrasound; some gallstones produce symptomatic diseases, such as cholecystitis, cholangitis, or pancreatitis. Identifying the clinical features of symptomatic gallstones may help prevent severe complications by providing intervention for asymptomatic gallstones. We aimed to investigate risk factors associated with developing symptomatic disease in pediatric patients with severe motor and intellectual disabilities (SMID). METHODS: This retrospective study enrolled 30 patients with SMID who were treated at the Nara Medical University between March 2016 and March 2019. We examined the prevalence of gallstones, and the rate at which associated symptoms of gallstones were observed in patients. Furthermore, we compared the clinical features of patients with and without gallstones. RESULTS: Among 30 patients with SMID, 7 (23%) had gallstones, with 6 (86%) of them being symptomatic: 3 patients had acute pancreatitis and 3 had cholecystitis or cholangitis. Among 23 patients without gallstones, 2 had acute pancreatitis and 2 had biliary sludge. Patients with gallstones had significantly lower daily calorie intake than those without gallstones (P = 0.042). Furthermore, the incidence of gallstones was higher in patients who received total parenteral nutrition than in those who did not (P = 0.031). Comparative analysis between symptomatic and asymptomatic patients was not performed because almost all cases were symptomatic. CONCLUSION: Gallstones were detected in 23% of patients with SMID. The gallstones were symptomatic at a very high rate. Considering this fact, patients with SMID should be surveyed for gallstones; careful management may be needed in such patients.

Potential role of the PD-L1 expression and tumor-infiltrating lymphocytes on neuroblastoma.

PURPOSE: The programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway has garnered much attention for its roles in clinical oncology. The aim of this study was to examine the clinical impact of the PD-L1 expression and tumor-infiltrating lymphocytes (TILs) on neuroblastoma. METHODS: We evaluated the PD-L1 expression and TIL status in 31 patients with neuroblastoma who underwent a biopsy or resection by an immunohistochemical analysis. Furthermore, we performed the serial analysis of the PD-L1 status before and after chemotherapy in 15 patients. RESULTS: Among the 31 cases, 11 (35%) showed a positive PD-L1 expression. The survival analysis showed a trend toward an association between PD-L1 positivity and a decreased overall survival. PD-L1 positivity tended to be associated with higher levels of tumor markers. In the serial analysis of the PD-L1 status, positivity was noted in 8 of 15 patients before chemotherapy and 6 after chemotherapy. Notably, all four patients with a positive PD-L1 status both before and after chemotherapy had recurrence, and 3 of them died during the follow-up period. CONCLUSION: Our findings suggest that the PD-L1 tumor expression might be a good biomarker for the treatment of neuroblastoma patients, especially for advanced neuroblastoma.

Risk Factors for Unresectable Recurrence After Up-Front Surgery for Colorectal Liver Metastasis.

BACKGROUND: There is no clear evidence that preoperative chemotherapy for resectable colorectal liver metastasis (CRLM) is superior to up-front surgery (UFS). The aim of this study was to identify the risk factors associated with poor prognosis after UFS for CRLM. METHODS: Data about consecutive patients with CRLM who underwent liver resection at Nara Medical University Hospital between January 2000 and December 2015 were retrieved from a prospective database. Recurrence that developed within 2 years after liver resection and could not be surgically resected was defined as unresectable recurrence (UR). Preoperative risk factors associated with UR after UFS were analyzed. Among the patients with the identified risk factors, the patients who were treated with UFS were compared with those who received preoperative chemotherapy via propensity score-matching analysis. RESULTS: There were 167 patients treated with UFS, and 71 of them developed UR (the UR group). The overall survival (OS) rate of the UR group was significantly worse than that of the non-UR group (5-year survival rate: 3.8 vs. 66.8%, p < 0.001). Multivariate analysis identified a primary colorectal cancer N factor of N2-3 as a risk factor for UR (hazard ratio 2.72, p = 0.004). Propensity score-matching analysis demonstrated that among patients with N2-3 primary colorectal cancer the post-initial treatment OS of the patients treated with UFS was significantly worse than that of the patients who received preoperative chemotherapy (5-year survival rate: 11.1 vs. 30.0%, p = 0.046). CONCLUSIONS: Patients with CRLM with a primary colorectal cancer N factor of N2-3 should be considered for preoperative chemotherapy.

Risk Factors for Postoperative Ascites in Patients Undergoing Liver Resection for Hepatocellular Carcinoma.

BACKGROUND: Postoperative ascites is a common complication after liver resection. This study aimed to identify the risk factors for ascites in patients after liver resection and the relationship between postoperative ascites and other complications. METHODS: We retrospectively analyzed data that were obtained from 266 patients who underwent liver resection for treating hepatocellular carcinoma between 2008 and 2015. Postoperative ascites was defined as a daily ascitic fluid drainage exceeding 500 mL on postoperative day 3 or later. The participants were categorized and analyzed with respect to the presence or absence of postoperative ascites. RESULTS: Overall, 17 (6.4%) patients developed postoperative ascites. A multivariate analysis identified that three significant factors-serum albumin, platelet count, and operation duration-were associated with the development of postoperative ascites. Sixteen (94.1%) of the 17 patients with postoperative ascites experienced other associated complications. The patients with ascites had more pleural effusion (70.6 vs. 17.7%, P < 0.001) than the patients without ascites. Postoperative morbidity, except for pleural effusion, was similar between the groups. The postoperative hospital stay duration was significantly longer in patients with ascites than in those without ascites. CONCLUSIONS: Postoperative ascites frequently occurred in patients with decreased liver functional reserve. Moreover, the presence of ascites was associated with significantly increased pleural effusion rates, and postoperative hospital stay duration was significantly prolonged.

The Administration of Celecoxib as an Analgesic after Liver Resection Is Safe.

BACKGROUND: There are a few studies that have evaluated postoperative analgesia. The aim of this study was to evaluate the safety of administering celecoxib to manage postoperative pain after liver surgery. METHODS: The cases of patients who underwent liver resection at Nara Medical University from April 2008 to December 2015 were retrospectively analyzed. From January 2013 to December 2015, celecoxib was routinely administered (600 mg/day on postoperative day (POD) 2 and 400 mg/day from POD 3-7), whereas celecoxib was not administered from April 2008 to December 2012. The patients' baseline characteristics, the operative procedures, and postoperative complications were analyzed. RESULTS: In total, 207 patients were administered celecoxib (celecoxib group), whereas 246 were not (non-celecoxib group). The preoperative serum total bilirubin and creatinine levels and indocyanine green retention rate at 15 min values of the 2 groups were similar. Similar incidences of overall and major complications (Clavien-Dindo classification ≥grade IIIa) were seen in both groups (33.8 vs. 36.2%, p = 0.601 and 12.1 vs. 12.6%, p = 0.866, respectively). No significant differences in the incidences of gastrointestinal bleeding, acute renal failure, or portal vein thrombosis were observed between the groups. CONCLUSIONS: The use of celecoxib for postoperative analgesia in the early period after liver resection is safe.

A decrease in the prognostic nutritional index is associated with a worse long-term outcome in gastric cancer patients undergoing neoadjuvant chemotherapy.

PURPOSE: The aim of this study was to evaluate the prognostic impact of the prognostic nutritional index (PNI) in gastric cancer patients undergoing neoadjuvant chemotherapy (NAC). METHODS: This study reviewed 54 patients with gastric cancer who underwent NAC and a subsequent R0 gastrectomy. The PNI before starting NAC and before gastrectomy were calculated using the following formula: 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count (per mm3). A multivariate analysis was performed to identify the predictors of overall survival (OS). RESULTS: The mean pre-NAC and preoperative PNI were 48.3 ± 5.1 and 48.2 ± 4.7, respectively (p = 0.934). The PNI decreased after NAC in 31 patients (57.4%). The pre-NAC PNI and preoperative PNI were not significantly associated with the OS rate. The 3-year OS rate in patients with the decreased PNI values was significantly lower than that in the patients whose PNI values were either maintained or increased (41 vs. 76.4%, p = 0.003). A multivariate analysis revealed that a decreased PNI value was an independent predictor of a poor OS (p = 0.006). CONCLUSIONS: Decreased PNI values were associated with worse long-term outcomes in gastric cancer patients undergoing NAC.

The safety of the early removal of prophylactic drainage after liver resection based solely on predetermined criteria: a propensity score analysis.

BACKGROUND: Prophylactic drainage after liver resection remains a common practice amongst hepatic surgeons. However, there is little information about the optimal timing of drain removal. METHODS: From April 2008 to December 2012 (conventional group), the drains were removed based on the treating surgeon's view. From January 2013 to April 2016 (ERP group), the drains were removed on POD 3 if the bile concentration of the drain discharge was less than three times the serum bilirubin on POD 3, and the amount of drain discharge was <500 ml on POD 3. The postoperative outcomes of the two groups were compared using one-to-one propensity score-matching analysis. RESULTS: One hundred nine patients were extracted from ERP group (n = 226) and conventional group (n = 246). The time to drain removal was significantly shorter in the ERP group than in the conventional group (3 days vs. 5 days, P < 0.001). The frequency of delayed bile leakage or the appearance of symptomatic abdominal fluid collection after drain removal did not differ between the two groups (3% vs. 4%, P = 0.791). CONCLUSION: Drain removal on POD 3 based on the volume and bile concentration is safe.

The prognosis of liver resection for patients with four or more colorectal liver metastases has not improved in the era of modern chemotherapy.

BACKGROUND AND OBJECTIVES: The impact of perioperative chemotherapy on patients with multiple colorectal liver metastases (CRLM) remains unclear. We attempted to examine whether the introduction of modern chemotherapies has improved the prognosis of patients that undergo liver resection for ≥4 CRLM. METHODS: Between January 1990 and December 2013, 194 patients underwent liver resection for CRLM at our institution. The outcomes of the patients with ≥4 and 1-3 CRLM were compared before and after 2005, when modern chemotherapies were introduced to Japan. RESULTS: There were 50 and 144 patients with ≥4 (Group 1) and 1-3 (Group 2) CRLM, respectively. The overall survival (OS) rate of Group 1 was significantly worse than that of Group 2 (P = 0.0007). The OS rate of Group 2 was significantly better after 2005 than before 2004 (P = 0.039), while no such differences were observed in Group 1. Multivariate analysis identified three prognostic factors in Group 1: a serum carcinoembryonic antigen level of ≥20 ng/ml (P = 0.018), a serum cancer antigen 19-9 level of ≥100 U/ml (P = 0.018), and a primary colorectal cancer N factor of ≥N2 (P = 0.023). CONCLUSIONS: The prognosis of patients with ≥4 CRLM that undergo liver resection has not improved despite the development of modern chemotherapies. J. Surg. Oncol. 2016;114:959-965. © 2016 Wiley Periodicals, Inc.

[A Case of Advanced Hepatocellular Carcinoma, Its Disease Progression Could Be Controlled by Multimodal Treatment].

The patient was a 73-year-old man, diagnosed with advanced huge hepatocellular carcinoma with a tumor thrombus extending into the inferior vena cava and extrahepatic metastases. Radiation therapy(50 Gy)was applied for the bone metastases, primary tumor, and tumor thrombus, and the patient received a cisplatin transcatheter arterial infusion(100mg/ body, 5 courses). Sorafenib was administered orally once the local lesion was under control. The tumor showed a partial response according to the RECIST criteria, but the tumor thrombus in the inferior vena cava almost disappeared. The presence of a tumor thrombus in the inferior vena cava must be regarded as an oncologic emergency. Acisplatin transcatheter arterial infusion and radiation therapy may be treatment options for unresectable cases.

[Huge Hepatocellular Carcinoma with Portal Vein and Inferior Vena Cava Thrombi Treated with Curative Liver Resection and Perioperative Hepatic Arterial Infusion Chemotherapy - A Case Report].

The prognosis of hepatocellular carcinoma(HCC)with main portal vein(MPV)and/or the inferior vena cava(IVC)tumor thrombi is dismal. The management of HCC with severe tumor thrombus is complicated. In this study, we report a case of HCC with tumor thrombi in the MPV and IVC that was successfullytreated via liver resection and perioperative hepatic arterial infusion chemotherapy(HAI). A 68-year-old man was referred to our institution to treat huge HCC lesion in the right lobe of the liver. Abdominal computed tomography(CT)revealed a tumor(12 cm in diameter)in the right hepatic lobe and tumor thrombi in the MPV and IVC. The patient was initiallytreated with HAI(cisplatin 100mg/body). After 3 courses of HAI, the tumor was dramaticallyreduced in size, and the thrombus in the IVC had disappeared; however, the thrombus in the MPV remained. Therefore, we performed right hepatectomy, wedge resection of the IVC, combined resection of the MPV, and portal vein reconstruction. The histopathological findings of the resected specimen revealed that viable cancer cells were observed onlyin an 8×8mm lesion. Subsequently, HAI was performed as adjuvant therapy for 3 courses. The patient died of other causes 2 years 3 months after surgery. There was no sign of recurrence at the time of death. This case suggested that perioperative HAI and liver resection mayrepresent an effective treatment strategyfor HCC with severe tumor thrombus.

Engineering functional two- and three-dimensional liver systems in vivo using hepatic tissue sheets.

Hepatic tissue engineering using primary hepatocytes has been considered a valuable new therapeutic modality for several classes of liver diseases. Recent progress in the development of clinically feasible liver tissue engineering approaches, however, has been hampered mainly by insufficient cell-to-cell contact of the engrafted hepatocytes. We developed a method to engineer a uniformly continuous sheet of hepatic tissue using isolated primary hepatocytes cultured on temperature-responsive surfaces. Sheets of hepatic tissue transplanted into the subcutaneous space resulted in efficient engraftment to the surrounding cells, with the formation of two-dimensional hepatic tissues that stably persisted for longer than 200 d. The engineered hepatic tissues also showed several characteristics of liver-specific functionality. Additionally, when the hepatic tissue sheets were layered in vivo, three-dimensional miniature liver systems having persistent survivability could be also engineered. This technology for liver tissue engineering is simple, minimally invasive and free of potentially immunogenic biodegradable scaffolds.

Nonalcoholic fatty liver disease developed after pancreatoduodenectomy for solid pseudopapillary neoplasm in a 10-year-old girl: a case report.

BACKGROUND: Solid pseudopapillary neoplasms of the pancreas are rare. Moreover, pancreatoduodenectomy (PD) and postoperative care are not common in pediatric surgery. Herein, we report a case of PD and nonalcoholic fatty liver disease (NAFLD) after PD and present a literature review. CASE PRESENTATION: A 10-year-old girl with a suspected liver tumor was referred to our hospital. Echography, enhanced computed tomography and magnetic resonance imaging showed that the tumor coexisted with the solid and cystic parts of the pancreatic head. Since the patient was a young woman and the imaging findings were consistent with that of pancreatic solid pseudopapillary neoplasms (SPNs), we diagnosed her with pancreatic SPN. Thereafter, PD was performed, and she was discharged 10 days after the operation. Although her postoperative course was mostly uneventful, she experienced few episodes of abdominal pain and diarrhea before hospital discharge. These symptoms subsequently became more frequent and severe. The patient was urgently readmitted to the hospital for watery steatorrhea and lower abdominal colic pain. Her serum aspartate aminotransferase and alanine aminotransferase levels were elevated, and a fatty liver was detected on echography. The patient was diagnosed with steatorrhea, peristaltic pain, and NAFLD after PD. Pancrelipase (containing pancreatic digestive enzymes), antidiarrheal agents, and probiotics were started. Dosage increase of these drugs reduced the defecation frequency and abdominal pain and switched diarrhea to loose stools. However, more lipids in meals or more meals caused diarrhea and abdominal pain. Therefore, the doses of these drugs were further increased, and another antidiarrheal agent, loperamide hydrochloride, was added. Exocrine pancreatic enzymes supplementation and careful follow-up should prevent NAFLD progression after PD. At present, the patient has occasional abdominal pain, but has tangible soft stools once or twice a day. Although echography still shows a mottled fatty liver, her hepatic enzymes are only mildly elevated. CONCLUSIONS: Pediatric PD is rare, and residual pancreatic function is usually sufficient, unlike in adult cases. However, we experienced a case of NAFLD after PD for a pediatric pancreatic SPN, in which pancreatic enzyme supplementation effectively improved this condition. Further attention must be paid to worsening of NAFLD that can develop nonalcoholic steatohepatitis.

A case of perforated multiple gastric duplication cysts with five-layered appearance on ultrasonography.

A case of perforated multiple gastric duplication cysts is presented. One of the gastric duplication cysts without perforation was seen on ultrasonography (US) with the following specific findings of gastric duplication cysts: a five-layered appearance, fold-like structures in the wall, and blood supply from the gastroepiploic artery. Other cysts with perforation presented with irregular and thin walls with a lack of the "double-wall sign" on US. These characteristic findings may be specific to perforated multiple gastric duplication cysts.

Laparoscopic mucosectomy for gastric duplication cysts that communicated with the spleen in a 10-year-old girl: A case report.

We report a case of laparoscopic mucosectomy for gastric duplication cysts that communicated with the spleen. A 10-year-old girl visited a local hospital with a chief complaint of intermittent left abdominal pain that had lasted for about 2 months. We diagnosed two gastric duplication cysts by ultrasonography and planned a laparoscopic extirpation. The elliptical masses were found in the splenic hilum and were 5 and 3 cm in diameter. The bigger one communicated with the spleen, so cystectomy could not be performed. Considering the risk of hemorrhage and the patient's age, we performed a mucosectomy rather than a partial splenectomy. The patient had an uneventful postoperative course. We histologically diagnosed gastric duplication cysts. Laparoscopic mucosectomy is a useful procedure for gastric duplication cysts that communicate with the spleen.

Generation of functional gut-like organ from mouse induced pluripotent stem cells.

Induced pluripotent stem (iPS) cells have the pluripotency to differentiate into broad spectrum derivatives of all three embryonic germ layers. However, the in vitro organ differentiation potential of iPS cells to organize a complex and functional "organ" has not yet been demonstrated. Here, we demonstrate that mouse iPS cells have the ability to organize a gut-like organ with motor function in vitro by a hanging drop culture system. This "induced gut (iGut)" exhibited spontaneous contraction and highly coordinated peristalsis accompanied by a transportation of contents. Ultrastructural analysis identified that the iGut had large lumens surrounded by three distinct layers (epithelium, connective tissue and musculature). Immunoreactivity for c-Kit, a marker of interstitial cells of Cajal (ICCs, enteric pacemaker cells), was observed in the wall of the lumen and formed a distinct and dense network. The neurofilament immunoreactivity was identified to form large ganglion-like structures and dense neuronal networks. The iGut was composed of all the enteric components of three germ layers: epithelial cells (endoderm), smooth muscle cells (mesoderm), ICCs (mesoderm), and enteric neurons (ectoderm). This is the first report to demonstrate the in vitro differentiation potential of iPS cells into particular types of functional "organs." This work not only contributes to understanding the mechanisms of incurable gut disease through disease-specific iPS cells, but also facilitates the clinical application of patient-specific iPS cells for novel therapeutic strategies such as patient-specific "organ" regenerative medicine in the future.

Adult hepatoblastoma successfully treated with multimodal treatment.

PURPOSE: Adult hepatoblastoma is rare and the prognosis is extremely poor. Although surgery offers the only chance for cure, it often recurs even after complete resection. To date, no therapeutic strategy has been established. We report here a rare case of adult hepatoblastoma successfully treated with multimodal treatment. METHODS: A 25-year-old female who had been suffering from right hypochondriac pain was referred to our hospital. Preoperative diagnosis was adult hepatoblastoma. Huge liver tumor was initially deemed unresectable. An intensive chemotherapy including arterial chemoinfusion using interventional-radiological technique resulted in a remarkable tumor reduction. Furthermore, lung metastasis that had later appeared was completely treated with additional chemotherapy. Then she underwent curative surgery at 8 months after initial treatment. RESULTS: The pathological diagnosis was well-differentiated hepatoblastoma. The postoperative course was uneventful and she received short-course adjuvant chemotherapy. She survived for over 4 years after diagnosis. CONCLUSIONS: To our knowledge, this is the first report demonstrating long-term survival of a patient with initially unresectable adult hepatoblastoma. Our new therapeutic strategy may provide new insights into the treatment of this fatal disease.

ADAMTS13 activity decreases after hepatectomy, reflecting a postoperative liver dysfunction.

BACKGROUND/AIMS: The precise mechanism and prophylactic strategy of deteriorated hepatic function after liver surgery have not been fully understood. The substrate of ADAMTS13, unusually large von Willebrand factor multimers, is produced in vascular endothelial cells at liver injury, leading to platelet aggregation. The decrease of plasma ADAMTS13 activity may involve not only the formation of platelet thrombi in the liver, but also subsequent progression of liver dysfunction through a microcirculatory disturbance. This study evaluated changes of plasma ADAMTS13 activity and its clinical relevance in patients with hepatectomy. METHODOLOGY: Plasma ADAMTS13 activity and its related parameters were sequentially determined after hepatectomy in 70 patients. RESULTS: ADAMTS13 activity significantly decreased preoperative 67.0 +/- 30.6 to 48.1 +/- 24.6% after hepatectomy (p < 0.0001). Pringle's maneuver for longer than 45 minutes (p = 0.0007) and major hepatectomy (p = 0.0002) were significantly associated with the decrease of ADAMTS13 activity to less than 40%. The decreased ADAMTS13 activity reflected postoperative thrombocytopenia (p = 0.0028) and hyperbilirubinemia (p < 0.05). CONCLUSIONS: Plasma ADAMTS13 activity significantly decreased after hepatectomy due to ischemic injury together with liver mass reduction, reflecting a postoperative liver dysfunction. Monitoring of ADAMTS13 activity may be useful to prevent further development of the liver failure after hepatectomy.

A neonate with umbilical arteriovenous malformation showing hemorrhagic shock from massive umbilical hemorrhage.

We describe herein the case of a 3-day-old male neonate with umbilical arteriovenous malformation showing umbilical hemorrhage. The patient was born after 38 weeks and 3 days of gestation with a birth weight of 2784 g. Sudden massive umbilical hemorrhage occurred on day 3. Cardiopulmonary arrest developed, but the patient was successfully rescued by immediate cardiopulmonary resuscitation. An umbilical venous catheter was inserted for blood access. However, umbilical hemorrhage continued and hemostasis was difficult. Congenital bleeding disorders were excluded based on laboratory findings. Ultrasonography on day 15 revealed a mass with rich blood supply directly under the umbilicus. Umbilical arteriovenous malformation was suspected from abdominal contrast-enhanced computed tomography on day 17. Excision of the arteriovenous malformation was performed on day 29. The mass was connected to three arteries including the umbilical arteries, with the umbilical vein flowing out from the mass. Umbilical arteriovenous malformation was diagnosed from evidence during the operation and pathological findings. Umbilical arteriovenous malformations are rare and often discovered by heart failure symptoms, but rare cases present with umbilical bleeding, as in this report. Umbilical arteriovenous malformation must be taken into consideration as along with congenital bleeding disorders when massive umbilical hemorrhage is identified.

Successful in vivo propagation of factor IX-producing hepatocytes in mice: potential for cell-based therapy in haemophilia B.

Cell-based therapies using isolated hepatocytes have been proposed to be an attractive application in the treatment of haemophilia B due to the normal production of coagulation factor IX (FIX) in these particular cells. Current cell culture technologies have largely failed to provide adequate isolated hepatocytes, so the present studies were designed to examine a new approach to efficiently proliferate hepatocytes that can retain normal biological function, including the ability to synthesize coagulation factors like FIX. Canine or human primary hepatocytes were transplanted into urokinase-type plasminogen activator-severe combined immunodeficiency (uPA/SCID) transgenic mice. Both donor hepatocytes from canines and humans were found to progressively proliferate in the recipient mouse livers as evidenced by a sharp increase in the circulating blood levels of species-specific albumin, which was correlated with the production and release of canine and human FIX antigen levels into the plasma. Histological examination confirmed that the transplanted canine and human hepatocytes were able to proliferate and occupy >80% of the host livers. In addition, the transplanted hepatocytes demonstrated strong cytoplasmic staining for human FIX, and the secreted coagulation factor IX was found to be haemostatically competent using specific procoagulant assays. In all, the results from the present study indicated that developments based on this technology could provide sufficient FIX-producing hepatocytes for cell-based therapy for haemophilia B.

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.