Survival impact of immune cells infiltrating peritumoral area of hepatocellular carcinoma.

Inflammatory and immune cells in the tumor microenvironment are reported to be associated with tumor progression in several cancers. In total, 225 patients who underwent initial and curative hepatectomy for hepatocellular carcinoma (HCC) from 2004 to 2013 were enrolled in this study. Tumor-associated neutrophils (TANs), M2 macrophages (TAMs; tumor-associated macrophages), CD8+ T cells, and regulatory T cells (Tregs) were evaluated by immunohistochemistry (IHC), and their relationships with patient clinicopathological characteristics and prognosis were evaluated. IHC was performed focusing on TANs first. We could not find a relationship between intratumoral and peritumoral TANs and clinicopathological features except for the fibrous capsule and infiltration of tumors into capsule. Next, TAMs, CD8+ cells and Tregs were evaluated by IHC. At the peritumoral area, TANs and TAMs (r = 0.36, p = 0.001) or Tregs (r = 0.16, p = 0.008) showed a positive correlation, whereas TANs and CD8+ cells showed a negative correlation (r = -0.16, p = 0.02). As for survival outcomes, at the peritumoral area, high TANs (p = 0.0398), low CD8+ cells (p = 0.0275), and high TAMs (p = 0.001) were significantly associated with worse overall survival (OS). In addition, high TANs (p = 0.010), and high TAMs (p = 0.00125) were significantly associated with worse disease-free survival (DFS). Finally, we established a risk signature model by combining the expression patterns of these cells. The high-risk signature group had significantly worse OS (p = 0.0277) and DFS (p = 0.0219) compared with those in the low-risk signature group. Our risk signature based on immune cells at the peritumoral area of the HCC can predict patient prognosis of HCC after curative hepatectomy.

Is Portal Vein Embolization Followed by Hepatectomy for Hepatocellular Carcinoma Justified in Patients with Impaired Liver Function?

BACKGROUND: Portal vein embolization (PVE) was developed for patients with insufficient future liver remnant volume and function and has gained relevant support worldwide before major hepatectomy. However, the efficacy of preoperative PVE for hepatocellular carcinoma (HCC) patients with impaired liver function remains uncertain. PATIENTS AND METHODS: Ninety-seven HCC patients who were scheduled for PVE followed by hepatectomy were enrolled in this study. Their short- and long-term outcomes were investigated, according to the liver damage classification defined by the Liver Cancer Study Group of Japan. RESULTS: Of 97 patients who underwent preoperative PVE, 30 (32.4%) could not undergo subsequent hepatectomy. Dropout rate from treatment strategy was significantly higher in patients with liver damage B (n = 13, 61.5%) than in those with liver damage A (n = 84, 26.2%) (P = 0.014). Among the 67 patients who underwent planned hepatectomy after PVE, 53 were categorized to liver damage A, and 14 were categorized to liver damage B at the point of hepatectomy. Although major complication and mortality rates were comparable between the two groups, the cumulative overall survival (OS) and disease-free survival (DFS) after hepatectomy were markedly worse in patients with liver damage B than in those with liver damage A (5-year OS rate: 23.1% vs 74.6%, P = 0.014, 5-year DFS rate: 7.8% vs 33.5%, P = 0.054, respectively). CONCLUSIONS: The treatment strategy of PVE followed by hepatectomy might be a contraindication for HCC patients with impaired liver function categorized as liver damage B because of the higher dropout rate and poorer long-term outcomes after hepatectomy.

High ARHGEF2 (GEF-H1) Expression is Associated with Poor Prognosis Via Cell Cycle Regulation in Patients with Pancreatic Cancer.

BACKGROUND: Pancreatic cancer has an extremely poor prognosis, even after curative resection. Treatment options for pancreatic cancer remain limited, therefore new therapeutic targets are urgently needed. We searched for genes predictive of poor prognosis in pancreatic cancer using a public database and validated the survival impact of the selected gene in a patient cohort. METHODS: We used a public database to search for genes associated with early pancreatic cancer recurrence. As a validation cohort, 201 patients who underwent radical resection in our institution were enrolled. Expression of the target gene was evaluated using immunohistochemistry (IHC). We evaluated growth and invasiveness using small interfering RNAs, then performed pathway analysis using gene set enrichment analysis. RESULTS: We extracted ARHGEF2 from GSE21501 as a gene with a high hazard ratio (HR) for early recurrence within 1 year. The high ARHGEF2 expression group had significantly poorer recurrence-free survival (RFS) and poorer overall survival (OS) than the low ARHGEF2 expression group. Multivariate analysis demonstrated that high ARHGEF2 expression was an independent poor prognostic factor for RFS (HR 1.92) and OS (HR 1.63). In vitro, ARHGEF2 suppression resulted in reduced cell growth and invasiveness. Bioinformatic analysis revealed that ARHGEF2 expression was associated with MYC, G2M, E2F, and CDC25A expression, suggesting that c-Myc and cell cycle genes are associated with high ARHGEF2 expression. IHC revealed a positive correlation between ARHGEF2 and c-Myc expression. CONCLUSIONS: High ARHGEF2 expression is associated with cell cycle progression, and predicts early recurrence and poor survival in patients with pancreatic cancer.

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.

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.

The pivotal predictor of severe postoperative complications of pancreatoduodenectomy: complex links of bacterial contamination from preoperative biliary drainage.

PURPOSE: Preoperative biliary drainage (PBD) prior to pancreatoduodenectomy (PD) is controversial. The aim of this study was to clarify how PBD leads to postoperative complications of PD. METHODS: The subjects of this retrospective study were 230 patients who underwent PD between January, 2008 and January, 2018. We analyzed how PBD was associated with severe postoperative complications (Clavien-Dindo ≥ IIIB) with special reference to its links with bacterial contamination. RESULTS: Preoperative biliary drainage (PBD) was correlated with the contamination of both bile juice collected at surgery (p < 0.001) and ascites collected from the intraperitoneal drain on postoperative day (POD) 3 (p < 0.001). Receiver operating characteristic curve analysis revealed that PBD for longer than 28 days was significantly associated with the contamination of bile juice. Multivariate regression analysis revealed that the contamination of ascites on POD3 was independently associated with severe postoperative complications (Clavien-Dindo ≥ IIIB) (odds ratio 3.52, p = 0.03), although PBD and the contaminated bile juice at surgery were not. CONCLUSIONS: PBD was associated with the contamination of biliary tract and ascites after surgery. The current study revealed that contaminated ascites on POD 3, not PBD by itself, was independently associated with severe postoperative complications after PD.

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.

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.

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.

Risk factors for lymph node metastasis in patients with pancreatic neuroendocrine neoplasms.

BACKGROUND: Although PNENs generally have a better prognosis than pancreatic cancers, some PNENs display malignant behavior including lymph node (LN) metastasis. Complete tumor resection can be the only potentially curative treatment for patients with resectable PNENs. However, the indications for LN dissection are still controversial. Over the last decade, minimally invasive surgery such as laparoscopic pancreatic surgery (LPS) has been increasingly performed for pancreatic tumors including PNENs. AIM: To investigate the risk factors for LN metastasis in PNENs and to select appropriate patients for limited surgery by LPS. METHODS: From April 2001 to December 2019, 92 patients underwent pancreatic resection for PNENs at Kumamoto University Hospital. Finally, 82 patients were enrolled in this study. Using perioperative factors, we examined the predictive factors for LN metastasis in PNENs. RESULTS: Among the 82 patients, the percentage of LN metastasis according to the pathological findings was 12% (10/82 cases). The median tumor size was 12 mm (range: 5-90 mm). The median tumor size in the LN-positive group (37 mm) was significantly larger than that in the LN-negative group (12 mm) (P = 0.0001). Multivariate analyses revealed that larger tumor size (≥ 20 mm) was an independent risk factor for LN metastasis (odds ratio 16.8, P = 0.0062). In patients with small tumors (≤ 10 mm), LN metastasis was not found. CONCLUSION: Larger tumor size (≥ 20 mm) is an independent risk factor for LN metastasis in PNENs. In smaller PNENs (≤ 10 mm), we may be able to choose limited surgery without LN dissection.

Efficacy of Ring Drape and Unused Sterile Instruments for Incisional SSI After Hepatectomy.

BACKGROUND/AIM: The aim of this study was to verify the efficacy of wound protection with a plastic ring wound protector (ring drape) and using new sterile instruments when closing the abdominal wall (wound closure set), both of which were used to prevent incisional surgical site infection (SSI) after hepatectomy. PATIENTS AND METHODS: The incidence of incisional SSIs and the clinical courses of 572 patients who underwent hepatectomy between January 2010 and December 2015 were studied retrospectively. The patients were divided into three period groups according to the period when each infection countermeasure was started. RESULTS: Incisional SSI incidence decreased significantly with additional countermeasures: 1st period 10.1%; 2nd period 2.08% (p=0.0114); 3rd period, 1.63% (1st vs. 3rd period, p=0.0016). A multivariate analysis showed that postoperative bile leakage [odds ratio (OR)=4.12, p=0.012] and not using a ring drape (OR=0.176, p=0.003) were independent factors for incisional SSI. CONCLUSION: Incisional SSI incidence was significantly reduced by using ring drape after hepatectomy.

Intraoperative bile culture helps choosing antibiotics in pancreaticoduodenectomy: Mechanistic profiling study of complex rink between bacterobilia and postoperative complications.

BACKGROUND: Postoperative complications after pancreaticoduodenectomy (PD) is still a major concern. The aim of this study was to propose how to choose antibiotics, based on bacterial sensitivity profiling involved in postoperative complications after PD. METHODS: Two hundred and thirty patients underwent PD between 2008 and 2018 at Kumamoto University Hospital. We enrolled 121 patients who had both intraoperative bile culture and drain culture on postoperative day (POD) 3. The clinical impact of the bacterial profile on postoperative outcome was retrospectively analyzed. RESULTS: Multivariate regression analysis revealed that intraperitoneal contamination on POD3 was independently associated with postoperative complications (odds ratio 2.62, P = .02). The bacteria in intraperitoneal drain on POD3 showed 94.9% similarity with those in bile collected during surgery. The major species were Enterococcus (44.6%) and Enterobacter (38.5%). Enterobacter species caused a higher rate of postoperative complications than others (83% vs 54%, P = .04). Three out of five Enterococcus faecium were resistant to carbapenems that were active against all Gram-negative rods. CONCLUSIONS: Intraperitoneal contamination on POD3, which had similar bacterial species as bile collected during surgery, was correlated with postoperative complications. The bacterial antibiotic sensitivity profile may help selecting optimal antibiotics against infectious postoperative complications in PD.

A case of primary carcinosarcoma of the liver with combined hepatocellular carcinoma and cholangiocarcinoma.

Primary carcinosarcoma of the liver is extremely rare. Here, we report an unusual case of carcinosarcoma of the liver containing combined hepatocellular carcinoma and cholangiocarcinoma. A 66-year-old man with a history of viral hepatitis B was admitted for investigation of multiple liver masses. Dynamic computed tomography revealed a mostly hypoenhancing main tumor with a peripheral ring enhancement and several satellite nodules. After transcatheter arterial chemoembolization and portal vein embolization, an extended right posterior sectionectomy was performed. The resected tumor was macroscopically a simple nodular type, 4.3 × 4.2 cm in diameter, with a dense fibrous capsule. The pathological findings showed that both carcinomatous and sarcomatous elements were present, and diagnosis of carcinosarcoma of the liver was confirmed. The carcinomatous element consisted of hepatocellular carcinoma and cholangiocarcinoma. The sarcomatous element was composed of spindle cells. Immunohistochemical studies demonstrated that cytokeratin AE1/AE3, human serum albumin, cytokeratin 7, and Arginase-1 were partially positive in tumor cells of the carcinomatous element but not in tumor cells of the sarcomatous element. Follow-up for 30 months after surgery has shown no signs of recurrence.

A case of inferior right hepatic vein-right hepatic vein bypass with interrupted inferior vena cava compressed by focal nodular hyperplasia in caudate lobe.

Focal nodular hyperplasia (FNH) is a relatively common benign liver tumor with rare indications to surgery. Budd-Chiari syndrome is a rare condition caused by interrupted hepatic venous outflow in the hepatic veins and inferior vena cava (IVC). A 42-year-old woman was referred to our department with a hepatic tumor. Patient's chief complaint was leg edema. Because of this symptom, it was difficult for the patient to stand for more than 20 min in the evening. Computed tomography (CT) showed a hypervascular mass compressing IVC in the caudate lobe of the liver. Fine needle aspiration was performed, and preoperative diagnosis was focal nodular hyperplasia (FNH). Hepatic resection of the right caudate lobe was performed. Postoperative histological examination revealed that the tumor was FNH. After surgery, the patient's leg edema disappeared, and postoperative CT revealed that severe IVC stenosis was improved. Although there have been several reports of giant FNH causing Budd-Chiari syndrome, this case shows the stenosis of IVC below the root of hepatic veins causing Budd-Chiari-like syndrome without portal hypertension. The location of the tumor considerably attributed to the congestion of venous flow in IVC causing various symptoms and intrahepatic inferior right hepatic vein-right hepatic vein bypass. The surgical indication of FNH is limited in most cases; however, the current report alerts that the location of FNH should be taken into account when monitoring it.

Metabolic shift to serine biosynthesis through 3-PG accumulation and PHGDH induction promotes tumor growth in pancreatic cancer.

Cancer cells craftily adapt their energy metabolism to their microenvironment. Nutrient deprivation due to hypovascularity and fibrosis is a major characteristic of pancreatic ductal adenocarcinoma (PDAC); thus, PDAC cells must produce energy intrinsically. However, the enhancement of energy production via activating Kras mutations is insufficient to explain the metabolic rewiring of PDAC cells. Here, we investigated the molecular mechanism underlying the metabolic shift in PDAC cells under serine starvation. Amino acid analysis revealed that the concentrations of all essential amino acids and most nonessential amino acids were decreased in the blood of PDAC patients. In addition, the plasma serine concentration was significantly higher in PDAC patients with PHGDH-high tumors than in those with PHGDH-low tumors. Although the growth and tumorigenesis of PK-59 cells with PHGDH promoter hypermethylation were significantly decreased by serine starvation, these activities were maintained in PDAC cell lines with PHGDH promoter hypomethylation by serine biosynthesis through PHGDH induction. In fact, DNA methylation analysis by pyrosequencing revealed that the methylation status of the PHGDH promoter was inversely correlated with the PHGDH expression level in human PDAC tissues. In addition to PHGDH induction by serine starvation, PDAC cells showed enhanced serine biosynthesis under serine starvation through 3-PG accumulation via PGAM1 knockdown, resulting in enhanced PDAC cell growth and tumor growth. However, PHGDH knockdown efficiently suppressed PDAC cell growth and tumor growth under serine starvation. These findings provide evidence that targeting the serine biosynthesis pathway by inhibiting PHGDH is a potent therapeutic approach to eliminate PDAC cells in nutrient-deprived microenvironments.

Prognostic Impact of Coagulation Activity in Patients Undergoing Curative Resection for Pancreatic Ductal Adenocarcinoma.

BACKGROUND/AIM: The aim of this study was to elucidate the clinical impact of coagulation disorders on outcomes after curative resection of pancreatic ductal adenocarcinoma. PATIENTS AND METHODS: Preoperative coagulation activity in 135 patients, who had undergone curative resections for pancreatic ductal adenocarcinoma was retrospectively evaluated and the impact on survival outcomes analyzed. RESULTS: A prolonged prothrombin time-international normalized ratio (PT-INR) (≥1.1) was detected in 23/135 patients (17%). Univariate analysis that showed prolonged PT-INR was associated with worse relapse-free (hazard ratio=1.79, p=0.044) and overall (hazard ratio=2.18, p=0.004) survival. Multivariate analyses showed prolonged PT-INR, large tumor (>30 mm), and lymph node metastasis were independent predictors of poor overall survival. CONCLUSION: Prolonged PT-INR may be a predictor of poor prognosis in patients with pancreatic ductal adenocarcinoma who have undergone curative resection. Coagulation disorders may be a therapeutic target for improving outcomes of pancreatic ductal adenocarcinoma.

Renal metastasis from intrahepatic cholangiocarcinoma.

Metastases to the kidney are extremely rare and intrahepatic cholangiocarcinoma (ICC) is difficult to treat. In this study, we report a case of renal metastasis from ICC. A 72-year-old man who had been followed-up for chronic hepatitis C was diagnosed with ICC in the segment 8 and underwent S8 segmentectomy in 2014. During follow-up, the serum levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were slightly elevated, and abdominal contrast-enhanced computed tomography revealed a low-density mass preceded by rim enhancement in the arterial phase measuring 1.5 × 1.5 cm in the segment 6, and a hypovascular mass measuring 2.2 × 2.0 cm in the upper pole of the left kidney in 2017. He underwent partial hepatectomy and partial nephrectomy. Based on postoperative histological findings combined with immunohistochemical analysis, the tumors both in the liver and kidney were diagnosed as recurrent ICC.

Ectopic hepatocellular carcinoma mimicking a retroperitoneal tumor: A case report.

BACKGROUND: An ectopic hepatocellular carcinoma (EHCC) arises from the ectopic liver which is defined as a hepatic organ or tissue not connected to surrounding tissues. EHCC is a rare disease and it is difficult to diagnose preoperatively. Furthermore, the clinical features are not fully elucidated. CASE SUMMARY: A retroperitoneal tumor (6 cm) was located at the dorsal side of the pancreas head on abdominal ultrasonography in an 81-year old woman positive for hepatitis C virus antibody. Contrast enhanced-computed tomography and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging showed viable HCC patterns with early enhancement and delayed washout. The tumor markers - serum alpha-fetoprotein and alpha-fetoprotein-L3% - were increased to 30.1 ng/mL and 83.1%, respectively. Protein induced by vitamin K absence or antagonist-II was within normal levels (17 mAU/mL). Positron emission tomography-computed tomography showed strong accumulation into the tumor (Standardized Uptake Value max: 13.8), and the tumor cytology following endoscopic ultrasound-guided fine needle aspiration showed poorly differentiated carcinoma. Tumor extirpation was performed, and operative findings showed that the retroperitoneal tumor was disconnected from the pancreas and the liver. Swollen lymph nodes near the tumor were histologically normal. On histological examination, the tumor was finally diagnosed as EHCC with Arginase-1 positive expression. CONCLUSION: We report our experience of a rare EHCC which was difficult to diagnose, and we present a review of the literature.