The Impact of Histologic Liver Inflammation on Oncology and the Prognosis of Patients Undergoing Hepatectomy for Hepatocellular Carcinoma.

BACKGROUND: Liver inflammation is a reaction to disease-causing stress in the liver that induces fibrosis and cirrhosis. However, its prognostic impact after hepatectomy remains unclear. This study aimed to evaluate the prognostic and oncologic impacts of liver inflammation on patients after curative hepatectomy for hepatocellular carcinoma (HCC). METHODS: The study enrolled 500 consecutive patients with primary HCC who underwent curative and primary hepatectomy. Patient characteristics and prognoses were evaluated according to histologic liver inflammation assessed by the New Inuyama Classification. RESULTS: Severe liver inflammation (A3) was observed in 97 patients (19.4%) and nonsevere liver inflammation (A0-2) in 403 patients (80.6%). The patients with A3 had a significantly poorer prognosis than those with A0-2 in terms of relapse-free survival (p < 0.0001, log-rank) and overall survival (p = 0.0013, log-rank). The study showed that A3 is an independent poor prognostic factor (hazard ratio, 1.36; 95% confidence interval [Cl], 1.02-1.81; p = 0.039), and that Child-Pugh grade B and multiple tumors are associated with relapse-free survival. Furthermore, The significant predictors of early recurrence (within 2 years after hepatectomy) were A3 (odds ratio, 2.10; 95% CI, 1.25-3.55; p = 0.005), a des-γ-carboxyprothrombin level higher than 40 mAU/mL, and multiple tumors. CONCLUSIONS: Severe liver inflammation was associated with poor short- and long-term prognoses independently of cirrhosis. Controlling liver inflammation in the perioperative period may be essential to improving the prognosis of patients with HCC after hepatectomy.

Major postoperative complications are associated with early recurrence of hepatocellular carcinoma following hepatectomy.

BACKGROUND AND AIM: Early recurrence (ER) is a strong predictor of poor prognosis in patients with hepatocellular carcinoma (HCC) after hepatectomy. The aim of this study was to examine manageable factors associated with ER. METHODS: Overall, 475 consecutive patients with primary HCC who underwent curative hepatectomy were included (R0/R1). We defined ER as recurrence within 2 years after hepatectomy and analyzed predictors for ER. We also defined postoperative complication as Clavien-Dindo classification grade III or IV. RESULTS: ER after hepatectomy was observed in 209 cases (44.0%). Patients with ER had a significantly poor prognosis compared with those with late recurrence (log-rank p < 0.0001) and were more likely to be diagnosed with extrahepatic metastasis (p = 0.009). Significant predictors for ER were des-γ-carboxyprothrombin > 40 mAU/mL (odds ratio (OR) 2.06, 95% confidence interval (CI) 1.36-3.14, p = 0.001), multiple tumors (OR 2.80 95%CI 1.83-4.32, p < 0.0001), cirrhosis (OR 1.53, 95%CI 1.01-2.32, p = 0.043), and postoperative complications (OR 1.72, 95% CI 1.05-2.85, p = 0.032). Blood loss (OR 1.09, 95%CI 1.05-1.13, p < 0.0001) and cirrhosis (OR 1.74, 95%CI 1.05-2.86, p = 0.031) were significant predictors for postoperative complications. CONCLUSIONS: We should pay close attention to surgical associated- and disease-specific factors in hepatectomy for HCC to prevent ER.

MicroRNA-25 Exerts an Oncogenic Function by Regulating the Ubiquitin Ligase Fbxw7 in Hepatocellular Carcinoma.

BACKGROUND: MicroRNA (miRNA) expression abnormalities are implicated in tumor progression. Previous reports have indicated that microRNA-25 (miR-25) acts as a tumor suppressor or oncogene in diverse cancers. However, its molecular mechanisms in hepatocellular carcinoma (HCC) are still unclear. F-box and WD repeat domain 7 (Fbxw7) is a critical tumor suppressor and is one of the most important deregulated proteins of the ubiquitin-proteasome system in cancer. Our objective was to elucidate the role of miR-25 and Fbxw7 in HCC and to clarify the mechanism by which Fbxw7 is regulated. METHODS: Fbxw7 expression was estimated in 210 fixed paraffin-embedded HCC samples by immunohistochemistry, and miR-25 expression was evaluated in 142 frozen HCC tissue samples by quantitative real-time PCR. Oncogenic functions of miR-25 and its role in the regulation of Fbxw7 expression were assayed in vitro. RESULTS: miR-25 was overexpressed in HCC tissue compared with adjacent normal tissue and significantly correlated with a poorer prognosis. Moreover, it was inversely correlated with Fbxw7 expression in HCC tissues. Furthermore, miR-25 inhibition significantly reduced the proliferation, migration, and invasion of HCC cells in vitro. CONCLUSION: miR-25 may promote tumor progression in HCC patients by repression of Fbxw7 and could serve as a promising molecular target for HCC treatment.

Prognostic Value of the Preoperative Tumor Marker Index in Resected Pancreatic Ductal Adenocarcinoma: A Retrospective Single-Institution Study.

BACKGROUND: The prediction of prognostic outcomes can provide the most suitable strategy for patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to evaluate the clinical value of the preoperative tumor marker index (pre-TI) in predicting prognostic outcomes after resection for PDAC. METHODS: For 183 patients who underwent pancreatic resection of PDAC, adjusted carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), pancreatic cancer-associated antigen-2 (DUpan-2), and s-pancreas-1 antigen (SPan-1) were retrospectively evaluated, and the positive number of these markers was scored as the pre-TI. RESULTS: A high pre-TI (≥ 2) was significantly associated with a larger tumor and lymph node metastases, and the patients with a high pre-TI had worse prognostic outcomes in terms of both relapse-free survival (RFS) (P < 0.0001, log-rank) and overall survival (OS) (P < 0.0001, Λlog-rank) than the patients with a low pre-TI. The pre-TI was one of the independent factors of a poor prognosis for RFS (hazard ratio [HR], 2.36; P < 0.0001) and OS (HR, 2.27; P < 0.0001). In addition, even for the patients with normal adjusted CA19-9 values (n = 74, 40.4%), those with the high pre-TI had a significantly poorer prognosis than those with a low pre-TI (RFS: P = 0.002, log-rank; OS: P = 0.031, log-rank). CONCLUSIONS: The pre-TI could be a potent predictive marker of prognostic outcomes for patients with resections for PDAC. Patients with a high pre-TI may need additional strategies to improve their prognosis.

Clinical Significance of PD-L1 Expression in Both Cancer and Stroma Cells of Cholangiocarcinoma Patients.

BACKGROUND: The clinical significance of programmed death 1 and its ligand (PD-L1) as therapeutic targets has been reported previously. This study aimed to investigate the clinical impact of PD-L1 expression in cancer and stroma cells in cholangiocarcinoma (CCA). METHODS: The study enrolled 177 consecutive CCA patients who underwent curative resection between 2005 and 2014. Expression of PD-L1 in CCA and stroma cells was assayed by immunohistochemistry, and their relationships with patient clinicopathologic characteristics and prognoses were evaluated. Tumor-infiltrating immune cells (CD66b+ neutrophils [TANs] and CD163+ M2 macrophages [TAMs]) also were assayed by immunohistochemistry, and their relationship with PD-L1 expression in cancer and stroma cells was evaluated. RESULTS: Among the 177 analyzed CCA cases, PD-L1 expression was identified in cancer cells in 54 cases (30.5%) and in stroma cells in 77 cases (43.5%). The patients with positive PD-L1 expression in cancer and stroma cells had worse overall survival rates than those negative for PD-L1 (cancer cells: hazard ratio [HR] 2.08; P = 0.0004; stroma cells: HR 1.84; P = 0.003). Moreover, the patients with PD-L1-positive cancer cells had higher rates of PD-L1 expression in stroma cells (P < 0.0001) and higher numbers of TANs (P = 0.0003) and TAMs (P = 0.004) than those with low PD-L1 expression. In the multivariate analysis, PD-L1 expression in both cancer and stroma cells (HR 2.20; P = 0.002) was an independent predictor of poor overall survival. CONCLUSIONS: The study showed PD-L1 expressed in both CCA and stromal cells and demonstrated that its expression may affect numbers of TANs and TAMs and play a pivotal role in CCA outcomes.

Endoscopic hepatic resection and endoscopic radiofrequency ablation as initial treatments for hepatocellular carcinoma within the Milan criteria.

PURPOSES: The indication of endoscopic (laparoscopic and thoracoscopic) hepatic resection (HR) has been expanded in the past decade because of its low invasiveness. However, the indications of endoscopic HR and radiofrequency ablation (RFA) have not yet been determined. METHODS: Among the 906 patients hospitalized for the initial treatment of hepatocellular carcinoma (HCC) between 2000 and 2017, 77 underwent endoscopic partial HR (E-pHR), and 94 underwent endoscopic RFA (E-RFA). We compared the short- and long-term outcomes between the E-pHR and E-RFA groups. RESULTS: The patients in the E-RFA group were characterized primarily by an impaired liver function. Among the patients with liver damage B or C, the overall survival (OS) in the E-pHR group was significantly worse than in the E-RFA group (3-year OS: 36% vs. 82%, p = 0.003). CONCLUSION: E-RFA may be recommended for the initial treatment of HCC in patients with a severely impaired liver function. However, E-pHR should be avoided as the initial treatment of HCC in such patients.

Postoperative nonalcoholic fatty liver disease is correlated with malnutrition leading to an unpreferable clinical course for pancreatic cancer patients undergoing pancreaticoduodenectomy.

PURPOSES: This study aimed to clarify the impact of postoperative nonalcoholic fatty liver disease (NAFLD) on the clinical course of patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: One hundred and eight patients with pancreatic cancer undergoing pancreaticoduodenectomy (PD) with curative intent in between 2005 and 2016 were enrolled in this study. Post-PD NAFLD was assessed by computed tomography (CT), which was routinely performed at 3 months, 6 months, and 1 year after surgery. The clinical impact of post-PD NAFLD was examined from an oncological perspective. RESULTS: There were 50 (46.2%) post-PD NAFLD patients. The NAFLD group showed significantly lower CT values at 3 months, 6 months, and 1 year after surgery than those without NAFLD. Patients with NAFLD showed significant body weight loss and a decrease in serum albumin level after surgery compared with those without NAFLD. Consequently, the 70% completion rate of adjuvant chemotherapy with gemcitabine, but not S1, was significantly lower in the NAFLD group than in the non-NAFLD group. The 5-year overall survival and disease-free survival rates were comparable between the two groups. CONCLUSION: Post-PD NAFLD was associated with malnutrition in patients with PDAC, reducing their tolerance to gemcitabine-based adjuvant chemotherapy. Post-PD NAFLD needs to be emphasized and requires special nutritional intervention in patients with PDAC.

Clinical role of serum programmed death ligand 1 in patients with hepatocellular carcinoma: Where does it come from?

PURPOSES: Programmed death ligand 1 (PD-L1) is a key target for the treatment of several malignancies. The present study was conducted to clarify the role of serum PD-L1 in hepatocellular carcinoma (HCC). METHODS: Serum PD-L1 (sPD-L1) was examined by an enzyme-linked immunosorbent assay in 153 patients with HCC who underwent curative hepatectomy at Kumamoto University in 2011-2016. The expression of PD-L1 in tissue (tPD-L1) was investigated by immunohistochemistry. The clinical roles of the PD-L1 expression in both serum and tissue were examined. RESULTS: The sPD-L1 was significantly elevated in HCC patients compared to patients without any malignant or inflammatory disease (234 vs. 93 pg/mL, p < 0.0001). The percentage of the tPD-L1-positive area (%tPD-L1) in the background liver was significantly higher than in the tumor (1.52% vs. 0.48%, p < 0.0001). The %tPD-L1 in the background liver but not in the tumor was significantly correlated with the sPD-L1 level (p = 0.0079). The sPD-L1, %tPD-L1 in the tumor, and %tPD-L1 in the background liver were not correlated with the overall survival after surgery. CONCLUSION: PD-L1-expressing cells in the background liver, but not in the tumor tissue, appeared to contribute to the sPD-L1 level. The sPD-L1 level may thus not indicate the tumor burden in patients with HCC.

Lysyl oxidase induces epithelial-mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has high recurrence rates even after curative hepatectomy. Drug therapy for recurrence of HCC is still limited; therefore, identifying new therapeutic targets is urgently needed. We searched for genes that would predict HCC recurrence from intrahepatic metastasis in an exhaustive DNA microarray database by searching genes associated with high early recurrence rate and having higher expression in the tumor area compared to background liver. We detected lysyl oxidase (LOX) and validated the clinical significance of LOX in 358 patients who underwent hepatectomy. Expression of LOX was evaluated by qRT- PCR, and immunohistochemical (IHC) staining. High LOX expression group had a significantly higher recurrence rate than the low LOX expression group (2-year recurrence rate was 64.0% vs 24.2%, P < .0001 for IHC) and poorer survival rate (5-year rate was 60.1% vs 86.2%, P < .0001 for IHC). Multivariate analysis showed that high LOX expression was an independent risk factor for early recurrence (IHC: HR, 2.52; P < .0001). Bioinformatic analysis showed that LOX expression was associated with hypoxia-inducible factor-1α (HIF-1α) and the hypoxia cascade, suggesting that HIF-1α or hypoxia regulates LOX expression and induces epithelial-mesenchymal transition (EMT). In vitro, LOX and HIF-1α were involved in migration and invasion capability. High LOX expression is associated with EMT markers and predicts early recurrence and poor survival in patients with HCC. These findings indicate that lysyl oxidase could be a potential therapeutic target for early recurrence of HCC.

PD-L1 expression enhancement by infiltrating macrophage-derived tumor necrosis factor-α leads to poor pancreatic cancer prognosis.

Immunotherapy using anti-PD-1/PD-L1 antibodies for several types of cancer has received considerable attention in recent decades. However, the molecular mechanism underlying PD-L1 expression in pancreatic ductal adenocarcinoma (PDAC) cells has not been clearly elucidated. We investigated the clinical significance and regulatory mechanism of PD-L1 expression in PDAC cells. Among the various cytokines tested, tumor necrosis factor (TNF)-α upregulated PD-L1 expression in PDAC cells through NF-κB signaling. The induction of PD-L1 expression was also caused by co-culture with activated macrophages, and the upregulation was inhibited by neutralization with anti-TNF-α antibody after co-culture with activated macrophages. PD-L1 expression in PDAC cells was positively correlated with macrophage infiltration in tumor stroma of human PDAC tissues. In addition, survival analysis revealed that high PD-L1 expression was significantly associated with poor prognosis in 235 PDAC patients and especially in patients harboring high CD8-positive T-cell infiltration. These findings indicate that tumor-infiltrating macrophage-derived TNF-α could be a potential therapeutic target for PDAC.

Multimodal radiofrequency ablation versus laparoscopic hepatic resection for the treatment of primary hepatocellular carcinoma within Milan criteria in severely cirrhotic patients: long-term favorable outcomes over 10 years.

BACKGROUND: Less invasiveness is an important consideration for the treatment of hepatocellular carcinoma (HCC) especially in patients with severe cirrhosis. METHODS: Between April 2000 and September 2016, 100 patients with liver damage B underwent multimodal radiofrequency ablation (RFA; n = 62) or laparoscopic hepatic resection (Lap-HR; n = 38) for primary HCC as defined by the Milan criteria. We compared the operative outcomes and patients' survival between the two groups. RESULTS: The RFA group showed worse liver functions as indicated by indocyanine green retention rate (32.9 vs. 22.4%; p < 0.0001) and serum albumin value (3.3 vs. 3.6 g/dl; p = 0.0029). As expected, RFA was less invasive, as indicated by the differences in operation time (166 vs. 288 min.; p < 0.0001) and blood loss (8 vs. 377 g; p < 0.0001). There was no significant difference in the morbidity rate between the two groups; however, the duration of hospital stay of the RFA group was significantly shorter (7 vs. 11 days; p = 0.0002). There were no significant between-group differences regarding overall or disease-free survival. CONCLUSION: Multimodal RFA for HCC in patients with severe cirrhosis is associated with less invasiveness and shorter hospital stays, with no compromise in the patients' survival. In patients with severe cirrhosis, it may be time to consider changing the standard treatment for primary HCC within the Milan criteria to multimodal RFA.

Sarcopenia Affects Systemic and Local Immune System and Impacts Postoperative Outcome in Patients with Extrahepatic Cholangiocarcinoma.

BACKGROUND: A decrease in skeletal muscle mass and function, defined as sarcopenia, is associated with poor postoperative outcome in patients with cancers. Although systemic or local immune status impacts cancer progression, the relationship between sarcopenia and these statuses remains unclear. The aim of this study is to investigate the clinical impact of sarcopenia and its relationship to immune systems in patients with extrahepatic cholangiocarcinoma (ECC). METHODS: A total of 110 consecutive ECC patients with curative resection between 2005 and 2014 were enrolled. Sarcopenia was determined from skeletal muscle index, assessed by a L3 skeletal muscle mass on axial computed tomography images, and their relationships with patients' clinicopathological characteristics and survival were evaluated. Systemic immune status was calculated using preoperative laboratory data, and tumor-infiltrating (TI) immune cells (CD8+ T cells, CD66b+ neutrophils, CD163+ M2 macrophages) assayed by immunohistochemistry, and their relationship to sarcopenia were evaluated. RESULTS: Sarcopenia was present in 31 patients (28.2%). Patients with sarcopenia had a worse recurrence-free survival (HR 1.87, p = 0.009) and overall survival (OS) (HR 2.47, p = 0.0004) than patients without sarcopenia. Moreover, patients with sarcopenia had a higher level of platelet-lymphocyte ratio (159 vs. 119; p = 0.003) and lower number of TI CD8+ T cells (47 vs. 66 cells/spot; p = 0.03) than patients without sarcopenia. On multivariate analysis, the presence of sarcopenia (HR 2.60, p = 0.0008) was an independent predictor of poor OS. CONCLUSIONS: Our data showed that sarcopenia and systemic or local immune cells may interact with each other and play a pivotal role in clinical outcomes of patients with ECC.

Perioperative Allogeneic Blood Transfusion Does not Influence Patient Survival After Hepatectomy for Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

BACKGROUND: Whether perioperative allogeneic blood transfusion (PABT) negatively influences patient survival after hepatectomy (HR) for hepatocellular carcinoma (HCC) remains controversial. METHODS: Five hundred two patients who underwent HR for initial HCC between 1994 and 2015 were enrolled in this study. All patients were divided into two groups: the PABT group and the non-PABT group. Differences of clinicopathological factors, overall survival (OS), recurrence-free survival (RFS), and the recurrence pattern between the two groups were evaluated. Using propensity score matching for tumor-related factors, liver functions, and surgical factors (total 11 factors), the survival impact of PABT was also analyzed. RESULTS: In the entire cohort, 78 patients (15.5%) received PABT such as red cell concentrate, fresh-frozen plasma, or platelets. OS (5-year OS: 55% vs. 76%; p = 0.0005) and RFS (2-year RFS: 47% vs. 56%; p = 0.0131) were significantly worse in the PABT group. The extrahepatic recurrence happened more frequently in the PABT group (15% vs. 5.4%; p = 0.0039). There were many significant clinicopathological differences between the two groups: more advanced tumor stage (tumor diameter, stage III or IV, microvascular invasion), worse liver functions (albumin, indocyanine green retention rate at 15 min), and more surgical stress (blood loss, operation time) in the PABT group. After propensity score matching, 43 pairs of patients were extracted. In this matched cohort, the survival curves of the PABT and non-PABT groups almost completely overlapped both in OS (5-year OS: 62% vs. 62%; p = 0.4384) and in RFS (2-year RFS: 49% vs. 47%; p = 0.8195). The significant difference of the extrahepatic recurrence rate disappeared in the matched cohort (p = 0.5789). CONCLUSION: Using propensity score matching, we found that PABT does not influence patient survival after HR for HCC.

Significance of neoadjuvant therapy for borderline resectable pancreatic cancer: a multicenter retrospective study.

PURPOSE: Neoadjuvant therapy (NAT) is increasingly used to improve the prognosis of patients with borderline resectable pancreatic cancer (BRPC) albeit with little evidence of its advantage over upfront surgical resection. We analyzed the prognostic impact of NAT on patients with BRPC in a multicenter retrospective study. METHODS: Medical data of 165 consecutive patients who underwent treatment for BRPC between January 2010 and December 2014 were collected from ten institutions. We defined BRPC according to the National Comprehensive Cancer Network guidelines, and subclassified patients according to venous invasion alone (BR-PV) and arterial invasion (BR-A). RESULTS: The rates of NAT administration and resection were 35% and 79%, respectively. There were no significant differences in resection rates and prognoses between patients in the BR-PV and BR-A subgroups. NAT did not have a significant impact on prognosis according to intention-to-treat analysis. However, in patients who underwent surgical resection, NAT was independently associated with longer overall survival (OS). The median OS of patients who underwent resection after NAT (53.7 months) was significantly longer than that of patients who underwent upfront (17.8 months) or no resection (14.9 months). The rates of superior mesenteric or portal vein invasion, lymphatic invasion, venous invasion, and lymph node metastasis were significantly lower in patients who underwent resection after NAT than in those who underwent upfront resection despite similar baseline clinical profiles. CONCLUSIONS: Resection after NAT in patients with BRPC is associated with longer OS and lower rates of both invasion to the surrounding tissues and lymph node metastasis.

Clinical role of fludeoxyglucose (18F) positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with pancreatic neuroendocrine tumors.

PURPOSES: Clinical predictive markers for the malignant potential of pancreatic neuroendocrine tumors (PNETs) are limited without histological investigation. We reported previously that a loss of the regular enhancement pattern in preoperative computed tomography (CT) was correlated with the malignant tumor phenotype. This study aimed to establish whether the metabolic aspect of the tumor evaluated by fludeoxyglucose (18F) positron emission tomography/computed tomography 18F-FDG PET/CT is associated with the tumor imaging characteristics and postoperative oncological outcome. METHODS: Among 77 patients who underwent surgery with curative intent for a PNET at our institution between 2001 and 2017, 24 who received 18F-FDG PET/CT before surgery were enrolled in this study. The clinical importance of the standardized uptake value (SUVmax) was investigated with regard to tumor progression and prognosis after curative surgery. RESULTS: There were four (16%) patients with insulinoma. The mean tumor size was 17 mm and when the median value of the SUVmax (= 2.0) was measured as the cut-off value, the SUVmax ≥ 2.0 group (n = 12) was associated with large tumor size (p = 0.021), high tumor grade (p = 0.015), and irregular pattern on CT (p = 0.0055). The SUVmax was not correlated with age, gender, whether the tumor was functioning or non-functioning, or lymph node metastasis. The SUVmax ≥ 2.0 group had significantly poorer disease-free survival (median, 3.5 vs 16.2 months; p = 0.023) and poorer overall survival (median, 8.8 vs 16.2 months; p = 0.042). CONCLUSION: An SUVmax ≥ 2.0 on 18F-FDG PET/CT might be associated with higher malignant potential of PNETs.

Implication of primary tumor location for the indication of preoperative chemotherapy in patients with colorectal liver metastases.

BACKGROUND: The benefit of preoperative chemotherapy for colorectal liver metastases (CRLM) remains uncertain. The aim was to clarify the effect of preoperative chemotherapy on CRLM according to the primary tumor location. METHODS: Among a total cohort of 163 patients who underwent curative hepatectomy for CRLM, 36 patients had a right-sided and 127 had a left-sided primary tumor. According to the performance of preoperative chemotherapy, survival analysis was conducted and prognostic factors were identified. RESULTS: Preoperative chemotherapy was administered to 17 patients (47.2%) with a right-sided and 74 (58.3%) with a left-sided primary tumor (P = 0.24). Among the patients who received preoperative chemotherapy, overall survival (OS) and disease-free survival (DFS) were similar between patients with right- and left-sided primary tumors (P = 0.36 and P = 0.44, respectively). Among the patients who underwent upfront hepatectomy, the OS and DFS of patients with a right-sided primary tumor were worse than those with a left-sided primary tumor (P = 0.02 and P = 0.025, respectively). Among the patients who underwent upfront surgery, the right-sided primary tumor was identified as an independent poor prognostic factor for OS (hazard ratio 3.44, P = 0.021). CONCLUSION: The existence of a right-sided primary tumor may be an indication of preoperative chemotherapy for patients with CRLM.

Downregulation of 15-hydroxyprostaglandin dehydrogenase by interleukin-1ß from activated macrophages leads to poor prognosis in pancreatic cancer.

Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2. The enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin and is frequently decreased in several types of cancer; however, the molecular mechanisms of 15-PGDH suppression are unclear. The current study was carried out to elucidate the molecular mechanisms and clinical significance of 15-PGDH suppression in PDAC. Here, we showed that interleukin-1ß (IL-1ß), a pro-inflammatory cytokine, downregulates 15-PGDH expression in PDAC cells, and that IL-1ß expression was inversely correlated with 15-PGDH levels in frozen PDAC tissues. We also found that activated macrophages produced IL-1ß and reduced 15-PGDH expression in PDAC cells. Furthermore, the number of CD163-positive tumor-associated macrophages was shown to be inversely correlated with 15-PGDH levels in PDAC cells by immunohistochemical staining of 107 PDAC samples. Finally, we found that low 15-PGDH expression was significantly associated with advanced tumors, presence of lymph node metastasis and nerve invasion, and poor prognosis in PDAC patients. Our results indicate that IL-1ß derived from TAMs suppresses 15-PGDH expression in PDAC cells, resulting in poor prognosis of PDAC patients.

Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma.

BACKGROUND: Inflammation and immune characteristics of the tumour microenvironment have therapeutic significance. The aim of this study was to investigate the clinical impact on disease progression in human extrahepatic cholangiocarcinoma (ECC). METHODS: A total of 114 consecutive ECC patients with curative resection between 2000 and 2014 were enrolled. Tumour infiltrating CD66b+ neutrophils (TANs; tumour associated neutrophils), CD163+ M2 macrophages (TAMs; tumour associated macrophages), CD8+ T cells, and FOXP3+ regulatory T cells (Tregs) were assayed by immunohistochemistry, and their relationships with patient clinicopathological characteristics and prognosis were evaluated. RESULTS: Tumour associated neutrophils were inversely correlated with CD8+ T cells (P=0.0001) and positively correlated with Tregs (P=0.001). High TANs (P=0.01), low CD8+ T cells (P=0.02), and high Tregs (P=0.04) were significantly associated with poor overall survival (OS). A high-risk signature, derived from integration of intratumoural inflammatory and immune cells, was significantly associated with poor recurrence-free survival (P=0.01) and OS (P=0.0008). A high-risk signature was correlated with postoperative distant metastases. Furthermore, a high-risk signature was related to the resistance to gemcitabine-based chemotherapy used after recurrence. CONCLUSIONS: Our data showed that tumour infiltrating inflammatory and immune cells may play a pivotal role in ECC progression and a high-risk signature predicted poor prognosis in ECC patients.

Clinical and Prognostic Features of Patients With Esophageal Cancer and Multiple Primary Cancers: A Retrospective Single-institution Study.

OBJECTIVE: To investigate the clinical and prognostic characteristics of patients with esophageal cancer and multiple primary cancers. SUMMARY BACKGROUND DATA: Patients with esophageal cancer frequently have multiple primary cancers, the presence of which may complicate physicians' decision-making because the clinical and prognostic features of such patients remain unknown. METHODS: This retrospective single-institution study included 538 consecutive patients who had undergone resection of esophageal cancer. The Cox proportional hazard model was used to compute the hazard ratio (HR) for mortality. RESULTS: At the time of surgery, 163 patients (30%) had multiple primary cancers (77, metachronous; 86, synchronous). Multiple primary cancers were significantly associated with alcohol use and tobacco smoking (Brinkman index). Patients with synchronous cancers had significantly shorter overall survival than those without multiple primary cancers (log-rank P = 0.032; univariate HR = 1.53, 95% confidence interval 1.02-2.17, P = 0.040; multivariate HR: 1.61; 95% confidence interval: 1.08-2.36; P = 0.020). Patients with metachronous cancers had similar prognoses to those without multiple primary cancers. The prognostic effect of synchronous cancers on overall survival was particularly prominent in patients with Stage I esophageal cancer (log-rank P = 0.0002). CONCLUSIONS: Multiple primary cancers are associated with a history of tobacco and alcohol use, supporting the concept of field cancerization. Synchronous multiple primary cancers may be an independent predictor of poorer long-term survival in patients undergoing resection of esophageal cancers.

Controlling Nutritional Status (CONUT) score is a prognostic marker for gastric cancer patients after curative resection.

BACKGROUND: Controlling Nutritional Status (CONUT), as calculated from serum albumin, total cholesterol concentration, and total lymphocyte count, was previously shown to be useful for nutritional assessment. The current study investigated the potential use of CONUT as a prognostic marker in gastric cancer patients after curative resection. METHODS: Preoperative CONUT was retrospectively calculated in 416 gastric cancer patients who underwent curative resection at Kumamoto University Hospital from 2005 to 2014. The patients were divided into two groups: CONUT-high (≥4) and CONUT-low (≤3), according to time-dependent receiver operating characteristic (ROC) analysis. The associations of CONUT with clinicopathological factors and survival were evaluated. RESULTS: CONUT-high patients were significantly older (p < 0.001) and had a lower body mass index (p = 0.019), deeper invasion (p < 0.001), higher serum carcinoembryonic antigen (p = 0.037), and higher serum carbohydrate antigen 19-9 (p = 0.007) compared with CONUT-low patients. CONUT-high patients had significantly poorer overall survival (OS) compared with CONUT-low patients according to univariate and multivariate analyses (hazard ratio: 5.09, 95% confidence interval 3.12-8.30, p < 0.001). In time-dependent ROC analysis, CONUT had a higher area under the ROC curve (AUC) for the prediction of 5-year OS than the neutrophil lymphocyte ratio, the Modified Glasgow Prognostic Score, or pStage. When the time-dependent AUC curve was used to predict OS, CONUT tended to maintain its predictive accuracy for long-term survival at a significantly higher level for an extended period after surgery when compared with the other markers tested. CONCLUSIONS: CONUT is useful for not only estimating nutritional status but also for predicting long-term OS in gastric cancer patients after curative resection.