Naoki Umezaki

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.

Perforation of the esophagus due to thermal injury after laparoscopic radiofrequency ablation for hepatocellular carcinoma: a case for caution

BackgroundSeveral reported complications associated with radiofrequency ablation for liver tumors are due to thermal damage of neighboring organs. We herein report a first case of esophageal perforation due to thermal injury of laparoscopic radiofrequency ablation (RFA).Case presentationA 75-year-old woman was treated repeatedly with RFA (percutaneous and laparoscopic) and transcatheter arterial chemoembolization for hepatocellular carcinoma. One week after laparoscopic RFA for recurrent HCC located in segment 2 of the liver, dysphagia and thoracic pain occurred. Upper gastrointestinal endoscopy revealed a perforated esophageal ulcer at the esophago-gastric junction. Inflammation was localized because of severe intra-abdominal adhesion due to repeat surgery, so we decided to treat the patient conservatively. The perforation of the esophagus gradually scarred, and exacerbation did not occur after restarting oral intake.ConclusionsWhen patients with a history of abdominal surgery or intra-abdominal inflammation undergo thermal ablation therapy, caution is required, as there is a possibility of thermal injury of unexpected organs.

Number of acinar cells at the pancreatic stump predicts pancreatic fistula after pancreaticoduodenectomy

PurposeTo establish if the number of pancreatic acinar cells at the pancreatic cut end is a predictor of postoperative pancreatic fistula (POPF).MethodsThe number of acinar cells was assessed histologically in 121 consecutive patients who underwent pancreaticoduodenectomy (PD) between April, 2012 and July, 2016.ResultsPOPF developed in 23 of the 121 patients. Univariate analysis revealed that male sex, long operating time, high volume of blood loss, soft remnant pancreas, large pancreatic duct, and the number of pancreatic acinar cells were significantly associated with POPF. Multivariate analysis revealed that male sex (p = 0.022) and the number of pancreatic acinar cells (p < 0.0001) were independently associated with POPF. In the receiver operating characteristic (ROC) curve analysis, the area under curve was 0.83895 when the cut off value of the number of pancreatic acinar cells to predict POPF was 890. Sensitivity and specificity of the number of pancreatic acinar cells were 82.6 and 77.6%, respectively.ConclusionsA large number of pancreatic acinar cells at the cut end of the stump is predictive of POPF after PD. Although POPF is associated with multiple factors and the number of acinar cells is only one of these, our study is the first to confirm this common intuition of surgeons, which has not been assessed definitively before.

Prognostic value of LINE-1 methylation level in 321 patients with primary liver cancer including hepatocellular carcinoma and intrahepatic cholangiocarcinoma

Background The methylation level of long interspersed nucleotide element-1 (LINE-1) is a good surrogate marker of the global DNA methylation level. The relationship between LINE-1 methylation level and prognosis in primary liver cancer (PLC) patients remains unclear. Results LINE-1 methylation levels were significantly lower in HCC and cHCC-CC tissues, but not in ICC tissues, than those in noncancerous liver parenchyma (HCC: p < 0.0001; cHCC-CC: p < 0.001; and ICC: p = 0.053). HCC cases with hypomethylated LINE-1 had significantly shorter relapse-free survival (RFS) (log-rank, p = 0.008); however, this was not observed for the cHCC-CC or ICC cases. Multivariate Cox regression analysis revealed a significantly higher HCC recurrence rate in the group with hypomethylated LINE-1 (hazard ratio, 1.62; 95% confidence interval, 1.06–2.58; p = 0.025). Conclusions The genome-wide DNA hypomethylation status estimated via LINE-1 methylation levels might be indicative of poor RFS in patients with HCC but not ICC or cHCC-CC. Methods We evaluated the level of LINE-1 methylation in 321 cases of curatively resected PLC {231 hepatocellular carcinoma (HCC), 19 combined hepatocellular and cholangiocarcinoma (cHCC-CC) and 71 intrahepatic cholangiocarcinoma (ICC)} via pyrosequencing of formalin-fixed paraffin-embedded (FFPE) tissues and examined its prognostic value.

Survival impact of lymphocyte infiltration into the tumor of hepatocellular carcinoma in hepatitis B virus-positive or non-B non-C patients who underwent curative resection: Lymphocyte infiltration in HCC

The prognostic value of lymphocyte infiltration into hepatocellular carcinoma (HCC) is still controversial, and it has not been reported in hepatitis B virus (HBV)‐positive or non‐B non‐C (NBNC) HCC. The aim of this study is to assess the prognostic significance of lymphocyte infiltrate in tumor for HBV‐positive and NBNC HCC patients.

Hepatobiliary and Pancreatic: Hepatocellular carcinoma developed with angiomyolipoma

Hepatocellular carcinoma (HCC) is the most common malignancy of the liver, and it is most commonly caused by a multistep hepatocarcinogenesis preceded by cirrhosis or viral hepatitis. Angiomyolipoma (AML) is considered a rare and oftenmisdiagnosed as HCC to be resected. We herein present a patient who had an extremely rare case of HCC, which newly detected in a large AML. A 42-year-old man with lung cancer was admitted to our hospital and suspected to have AML in left lobe by computed tomography (CT) and positron emission tomography/CT (PET-CT) (Fig. 1a). The patient underwent a left upper lobectomy for lung cancer, and following which, he underwent chemotherapy with cisplatin and vinorelbine. According to our policy and because the diameter of the AML tumor exceeded 5 cm, we intended to perform a hepatectomy, provided that the lung cancer did not recur. Two years after the surgery for lung cancer, a new solid nodule, with a diameter of 4 cm, was detected within the AML tumor by CT. The nodule was suspected to be HCC because serum alpha-fetoprotein (AFP) level was 10.8 ng/mL and AFP-L3 was 74.3%. CT showed the nodule as an enhanced lesion within AML (Fig. 1b). PET-CT showed it as an Fluorodeoxyglucose (FDG)-accumulated mass, with a maximum standardized uptake value of 9.7 (Fig. 1c). We diagnosed this newly developed mass as HCC; therefore, we performed a left hemi-hepatectomy, which included resection of AML. The resected specimen included a large hepatic mass measuring 15 × 10 cm, with a separate encapsulated nodule of 5.5 × 3.0 cm in size (Fig. 1d). During histologic examination, the large hepatic mass was diagnosed as AML and the inner small nodule was diagnosed as moderately differentiated HCC with trabecular arrangement (Fig. 1e). Histologically, HCC and AML elements were not intermingling. In addition, HCC nodule was completely included within the AML mass, and there is no continuity between HCC and non-tumorous liver tissue. Immunohistochemical staining results were as follows: human melanoma black 45 and alpha-smooth muscle actin were positive for AML, and glypican-3 (GP3) was positive for HCC (Fig. 1f–h). Angiomyolipoma is a mesenchymal tumor; however, there is a wide spectrum of opinions about the origin of AML. Bonetti et al. have suggested that AMLmay originate from perivascular epithelioid cells, making it part of a family of perivascular epithelioid cell tumors. Yang et al. reported that renal AML was derived from adhesive cells possessing the characteristics of mesenchymal stem cells (MSCs). Although we do not know how HCC develop within AML, we have three hypotheses. First, HCC developed from hepatocytes in AML. Second, HCC developed from hepatocytes that migrated from the normal liver to AML. Finally, HCC developed from MSCs in AML. In our case, we could not confirm the presence of hepatocytes in AML or the HCC nodule derived from normal liver, making it difficult to support our first and the second hypothesis. Because MSCs can differentiate into hepatocytes, if a hepatic AML contains MSCs, HCC can develop fromMSCs within AML. Therefore, we consider the final hypothesis to be possible. In renal AML, Inomoto et al. reported renal cell carcinoma within AML and made reference to the possibility that the renal cell carcinoma originated in the AML. In summary, we report an unusual case of HCC, which developed with a hepatic AML.

Hepatobiliary and Pancreatic: Portal vein stent for local recurrence of bile duct cancer: Portal vein stent

Extrahepatic portal vein obstruction is one of causes of portal hypertension, and it can cause thrombocytopenia. When an unresectable malignant tumor occurs around portal vein, it may lead thrombocytopenia and complicate chemotherapy and/or radiation therapy. Treatment strategy of this situation has not been established enough. We report a case with a local recurrence of bile duct cancer that caused portal vein stenosis and thrombocytopenia. A 61-year-old woman underwent right hepatectomy and resection of extrahepatic bile duct followed by hepatojejunostomy for hilar bile duct cancer. She received adjuvant chemotherapy with gemcitabine. Five years after the initial operation, enhanced computed tomography revealed a local recurrence around portal vein (Fig. 1a). Because portal hypertension and splenomegaly due to stenosis of the portal vein led thrombocytopenia (7.6 × 10μl), she could not receive chemotherapy. Then a placement of portal vein stent was planned. Percutaneous transhepatic portal vein approach to the stenosis was not feasible, because of steep angle of the portal vein. So, trans-mesenteric vein approach to the portal vein was selected. Through a small abdominal incision, an ileal vein was punctured and a catheter was inserted into the portal vein. A metallic stent (Luminexx® stent, 14 mm–6 cm, BARD Peripheral Vascular, Inc. Tempe, AZ) was placed at the stenosis of the portal vein (Fig. 1b), then the portal vein was expanded. There was no postoperative complication. The platelet was increased (11.7 × 10/μl) 1 month after the placement of the stent. She got able to receive radiation therapy for the recurrent tumor (50.4 Gy), followed by chemotherapy with gemcitabine. The patency of the stent (Fig. 1c) and the platelet count have beenmaintained, and the chemotherapy has been continued for 5 months until now without progression of the tumor. Several studies have reported the clinical efficacy of portal vein stent placement. For thrombocytopenia due to portal hypertension, splenectomy, or partial splenic artery embolization are generally considered effective. Portal vein stent is less invasive compared with splenectomy, and partial splenic artery embolization has a significant risk of splenic abscess. Our report confirmed that portal vein stent for this situation may be feasible.

Acquired factor V deficiency following transcatheter arterial chemoembolization for hepatocellular carcinoma: a case report

Acquired factor V deficiency is a rare condition associated with a wide variety of causes. We herein report the case of a 75-year-old man who developed acquired factor V deficiency associated with gastrointestinal bleeding after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma. Laboratory data revealed prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT) and a significant reduction in the factor V (FV) activity. Infusion of fresh-frozen plasma (FFP) was unable to correct the prolonged PT and APTT. Four weeks after onset, his coagulation parameters improved spontaneously with no particular treatment. The patient developed acquired FV deficiency after TACE treatment using cisplatin, and thus, cisplatin was suspected as the cause of this coagulopathy. If coagulopathy that is not corrected by FFP transfusion after TACE is observed, acquired factor V deficiency, although extremely rare, should be considered.