Tatsunori Miyata

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.

Repeated hepatic resections and radio-frequency ablations may improve the survival of adult undifferentiated embryonal sarcoma of the liver: report of two cases

Undifferentiated embryonal sarcoma of the liver (UESL) in adults, especially over 30 years old, is quite rare. We report two adult UESL patients that one of them survived 62 months and one is now surviving more than 65 months treated with repeated hepatic resections and radio-frequency ablations. Although UESL is an entirely unusual and aggressive tumor, multidisciplinary treatments including repeated hepatic resections and radio-frequency ablations may provide a longer survival.

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.

Predicting Poorly Differentiated Hepatocellular Carcinoma that Meets the Milan Criteria

Background/Aim: Poorly differentiated hepatocellular carcinoma (HCC) is a malignant phenotype following radiofrequency ablation, but not liver resection. This study aimed to identify prognostic parameters that could predict poorly differentiated HCC. Patients and Methods: Between 2007-2014, 158 HCC patients undergoing liver resection were enrolled that not the Milan criteria. Laboratory data were measured including three tumor markers and inflammatory factors (neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio, and monocyte/lymphocyte ratio. Preoperative parameters to predict poorly differentiated HCC were assessed by multivariate logistic regression analysis. Results: Poorly differentiated HCC was observed in 28 (17.7%) patients. In multivariate analysis, two or three positive tumor markers and high NLR (≥2.33) were independent predictors of poorly differentiated HCC. Recurrence-free and overall survival were comparable despite these significant predictors. Conclusion: The preoperative status of two or three positive tumor markers and high NLR facilitated selecting HCC patients with poorly differentiated disease, which will assist making therapeutic decisions for HCC patients.

Abstract 1770: The association between sarcopenia and cellular senescence of cancer associated fibroblast in pancreatic cancer

Background: Sarcopenia is a syndrome that is characterized by progressive and generalized loss of skeletal muscle mass and strength. Several recent studies have shown that sarcopenia has prognostic significance for patients with malignant disease, including cancers of the esophagus, colon, pancreas and liver. On the other hand, cellular senescence is gaining increased attention from clinicians and researchers, yet incompletely understood role in the development of malignant disease. Previous studies reported that Caveolin-1 expression in cancer associated fibroblast is associated with cancer progression, and it is known in recent years that caveolin-1 plays a major role in controlling cellular senescence. Therefore, we hypothesized that sarcopenia causes cellular senescence of cancer associated fibroblast (CAF). The aim of this study is to clarify the between sarcopenia and cellular senescence of CAF through Caveolin-1 in pancreatic cancer. Methods: All consecutive patients with pancreatic cancer underwent curative resection between January 2004 and December 2014 were enrolled in this retrospective study. Skeletal muscle and visceral fat amount at the third lumbar vertebra (L3) in the inferior direction were quantified using enhanced computed tomography. The patients were divided into two groups, with and without sarcopenia, based on Japan Society of Hepatology guidelines for sarcopenia. Next, Caveolin-1 expression was analyzed by immunohistochemistry (IHC). Moreover, we investigated the relationship between sarcopenia and Caveolin-1 expression. Results: Forty-one (31.5%) of 130 patients were identified with sarcopenia. Kaplan-Meier analysis showed that patients with sarcopenia had a significantly worse cancer specific survival than patients without sarcopenia (3-year-survival: 37.2% vs 50.4%, respectively, p = 0.038). While, a high level of Caveolin-1 expression was detected in 29.2% (38/130) of our samples. High Caveolin-1 expression in CAF significantly correlated with poor prognoses with respect to overall survival (log-rank p = 0.014) and disease-free survival (log-rank p = 0.0015). However, there was no relationship between sarcopenia and IHC score of Caveolin-1 expression in CAF. Conclusion: The present result suggested that sarcopenia and Caveolin-1 expression of CAF in patient with pancreatic cancer is respectively associated with poor prognosis, but not associated each other. Now, we focus on Caveolin-1 expression of CAF, and establish primary cultures of CAF from the pancreatic cancer tissues and examine its function. Citation Format: Kensuke Yamamura, Yo-ichi Yamashita, Yuki Kitano, Kota Arima, Takayoshi Kaida, Tatsunori Miyata, Shigeki Nakagawa, Kosuke Mima, Katsunori Imai, Daisuke Hashimoto, Akira Chikamoto, Hideo Baba. The association between sarcopenia and cellular senescence of cancer associated fibroblast in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1770. doi:10.1158/1538-7445.AM2017-1770

Fetal-type Glycogen Phosphorylase (FGP)Expression in Intestinal Metaplasia as a High Risk Factor of the Development of Gastric Carcinoma

It has been reported that an enzyme-glycogen phosphorylase [EC 2.4.1.1] histochemical re‐ action is observed in differentiated hepatic or muscular tissues and in some proliferating tis‐ sues including fetus and carcinoma [1,2]. In the human stomach, a phosphorylase reaction appears in the undifferentiated gastric epithelium at the midpoint of fetal life, and is not de‐ tected in gastric epithelium after birth.