Shigeru Marubashi

Clinical Significance of Soluble Intercellular Adhesion Molecule-1 and Interleukin-6 in Patients with Extrahepatic Cholangiocarcinoma

ABSTRACT Purpose/Aim: Although several prognostic factors for extrahepatic cholangiocarcinoma (EHC) have been reported, preoperative prognostic factors have yet to be established. We investigated the serum concentration of angiogenic, inflammatory, and nutritional parameters. Materials and Methods: Twenty-five patients with EHC were enrolled before starting treatment. Preoperative prognostic factors were identified using multivariate analyses. Results: The serum soluble intercellular adhesion molecule-1 (sICAM-1) levels were significantly higher in the patients with EHC (436.0 ± 43.2 ng/ml) than in the healthy volunteers (228.6 ± 22.0 ng/ml) (p <.001). In addition, the serum IL-6 levels were significantly higher in the patients (18.0 ± 5.6 pg/ml) than in the healthy volunteers (5.7 ± 0.8 pg/ml) (p <.05). The serum IL-6 and sICAM-1 showed a strong correlation (r = 0.559) in the patients with EHC (p <.01). The serum IL-6 (area under the curve = 0.764, p =.030, cut-off level = 11.6) and sICAM-1 (area under the curve = 0.818, p =.007, cutoff level = 322.6) were revealed to be useful as prognostic factors by the receiver operating characteristic curves. The high IL-6 group and the high sICAM-1 group showed poorer DSS than those of the respective low groups. In the multivariate analysis, IL-6 (hazard ratio: 1.050, 95% confidence interval: 1.002–1.100, p =.043) and sICAM-1 (hazard ratio: 1.009, 95% confidence interval: 1.002–1.015, p =.009) were independent prognostic factors for DSS. Conclusions: IL-6 and sICAM-1 were independent preoperative prognostic factors in EHC patients, causing continuous inflammation and malnutrition in collaboration with other pro-angiogenic factors.

Role of intratumoral infiltrating macrophages after transarterial immunoembolization for hepatocellular carcinoma.

Preoperative transarterial immunoembolization (TIE) for hepatocellular carcinoma (HCC) is effective for preventing recurrence. We aimed to investigate the intratumoral and peritumoral M1 macrophage‐induced immune response following TIE treatment.

M1 macrophage infiltrations and histological changes in the liver after portal vein embolization using fibrinogen and OK432 in the rat

The mechanism of anti-tumor effect of transarterial Immuno-Embolization (TIE) using OK-432 has not been well elucidated. In this study, we aimed to investigate the tissue injury and immune response after portal venous embolization (PVE) with/without OK-432. Embolic materials (L group: lipiodol, LF group: lipiodol+fibrinogen, LO group: lipiodol+OK-432, LFO group: lipiodol+fibrinogen+OK-432) were administered via the right portal vein in Wistar rats. The histological findings in LFO group demonstrated liver damage with severe architectural changes. The concentrations of CD68(+) cells were observed in a time-dependent manner; it was significantly increased in the LO group on day 1 and in the LFO group on day 3. CD68(+)CD163(-) macrophages significantly increased in the LFO group on day 7 (P<0.05). In conclusion, PVE with fibrinogen and OK-432 markedly increased the CD68(+)CD163(-) infiltrating macrophages around the peri-portal area in the liver. This novel technique could be applied as immune-enhanced chemo-embolization of liver tumors.

Fibrosis-related miRNAs as serum biomarkers for pancreatic ductal adenocarcinoma

We investigated whether serum microRNAs (miRNAs) could be diagnostic or prognostic markers in pancreatic ductal adenocarcinoma (PDAC). We first identified miRNAs showing altered expression in human pancreatic stellate cells (hPSCs) co-cultured with PDAC cells (Panc-1 and BxPC-3) as compared to hPSCs cultured alone. Among the miRNAs with altered expression, let-7d exhibited reduced expression in an in silico analysis of The Cancer Genome Atlas data. Inhibition of let-7d resulted in enhanced expression of fibrosis-related genes. We extracted serum miRNA from 45 PDAC patients and 42 healthy controls and quantified expression let-7d using digital PCR. Based on the level of let-7d expression, we were able to distinguish between PDAC patients and controls. Additionally, reduced let-7d expression correlated with poor overall survival. Thus, fibrosis-related miRNAs may be serum biomarkers for PDAC.

Prognostic impact of soluble intercellular adhesion molecule‑1 in hepatocellular carcinoma

The identification of novel biomarkers for hepatocellular carcinoma (HCC) is of great importance in improving the outcome of patients with HCC. The present study aimed to determine the prognostic significance of the soluble intercellular adhesion molecule (sICAM)-1 in patients with HCC. The present study prospectively collected clinicopathological data from 36 patients with HCC who had undergone successful hepatectomy. An analysis using a receiver operating characteristic (ROC) curve was performed to determine the cut-off value for predicting prognosis. Overall survival (OS), recurrence-free survival (RFS) and potential prognostic factors were analyzed. The ROC curve analysis revealed a sICAM-1 cut-off value of 440 ng/ml. HCC patients with sICAM-1 ≥440 ng/ml exhibited a poorer OS and RFS than those with sICAM-1 <440 ng/ml (P=0.002). sICAM-1 ≥440 ng/ml (hazard ratio=3.623; 95% confidence interval: 1.145-11.458; P=0.028) and Child B (hazard ratio=1.514; 95% confidence interval: 1.066-2.150; P=0.021) were independent prognostic factors for OS, and sICAM-1 ≥440 ng/ml was an independent prognostic factor for RFS (hazard ratio=3.625; 95% confidence interval: 1.233-10.659; P=0.019). Serum sICAM-1 may be a promising predictor for the overall and recurrence-free survival of patients with HCC.

An observation study of the prognostic effect of waiting times in the management of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an aggressive course; therefore, it was hypothesized that waiting times during disease management may serve as a prognostic factor for patients with PDAC. Data for all patients with PDAC who received treatment in Fukushima Medical University Hospital were collected. Median disease-free survival and overall survival time were calculated using the Kaplan-Meier method and utilized as cut-off points to divide the patients into 2 groups: A short and a long survival group. Clinical characteristics, including waiting times, the detection-to-diagnosis waiting time and the diagnosis-to-treatment waiting time, were compared between the 2 survival groups. A total of 149 patients were included in the present study. Among the 72 patients who underwent chemotherapy, no significant differences between the 2 survival groups regarding waiting times were identified; however, the proportion of patients with locally advanced disease and the administration of combination chemotherapy were significantly associated with increased survival. Additionally, no significant differences in the waiting times between the 2 survival groups were identified when evaluating the 79 patients who underwent surgical resection. In conclusion, the results of the present study indicated that detection-to-diagnosis and diagnosis-to-treatment waiting times do not influence the prognosis of patients with PDAC.

Utility of magnetic resonance elastography for predicting ascites in patients with chronic liver disease

This study aimed to evaluate the utility of magnetic resonance elastography (MRE) as a non‐invasive method for predicting ascites in patients with chronic liver disease (CLD).

Prediction of major complications after hepatectomy using liver stiffness values determined by magnetic resonance elastography: Risk of complications after hepatectomy determined by magnetic resonance elastography

Liver fibrosis is a risk factor for hepatectomy but cannot be determined accurately before hepatectomy because diagnostic procedures are too invasive. Magnetic resonance elastography (MRE) can determine liver stiffness (LS), a surrogate marker for assessing liver fibrosis, non‐invasively. The aim of this study was to investigate whether the LS value determined by MRE is predictive of major complications after hepatectomy.

Prognostic influence of endoscopic ultrasound-guided fine needle aspiration in IPMN-derived invasive adenocarcinoma

BackgroundEndoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for mucinous cystic neoplasm of the pancreas carries a potential risk of inducing peritoneal tumor cell dissemination. We investigated the diagnostic yield and safety of EUS-FNA-based cytology of cells obtained from the pancreatic invasion site of intraductal papillary-mucinous neoplasm-derived adenocarcinoma (IPMC).MethodsWe included 22 surgically resected IPMCs and 84 pancreatic ductal adenocarcinomas (PDACs). Among the IPMC cases, 14 did not undergo EUS-FNA before surgical resection. The diagnostic yield of EUS-FNA was compared between IPMC and PDAC. Additionally, prognosis (relapse-free and overall survival time after resection) and the rate of peritoneal dissemination were compared among IPMC with EUS-FNA, IPMC without EUS-FNA, and PDAC. A survival analysis was performed using the Kaplan-Meier method and log-rank test.Results(EUS-FNA diagnosis) There were no significant differences in the number of needle passages (PDAC 2.5 vs. IPMC 2.0 passages, Pu2009=u20090.84) or puncture route (stomach/duodenum: 2/6 vs. 45/39, Pu2009=u20090.29). However, the correct diagnosis rate was significantly higher in PDAC (92.9%) than in IPMC (62.5%) (Pu2009=u20090.03). No procedure-related adverse events occurred. Peritoneal lavage cytology performed during the operation was negative in all cases. (Prognosis) Among IPMC with EUS-FNA, IPMC without EUS-FNA, and PDAC, there were no significant differences in relapse-free survival (21.0 vs. 22.4 vs. 12.5xa0months, respectively; Pu2009=u20090.64) or overall survival time (35.5 vs. 53.1 vs. 35.9xa0months, respectively; Pu2009=u20090.42), and peritoneal dissemination was detected during the observation period in 25%, 28.5%, and 21.4% cases, respectively (Pu2009=u20090.82).ConclusionEven though a correct diagnosis was more difficult to obtain in IPMC than in PDAC, IPMC allows specimens to be obtained without influencing the rate of recurrence and prognosis.

Clinical significance of serum transthyretin level in patients with hepatocellular carcinoma: Transthyretin and prognosis of HCC

Although serum albumin has been reported to be useful as a prognostic biomarker for various malignancies, it is not suitable for prognosis of patients with hepatocellular carcinoma (HCC) due to impaired liver function. We aimed to determine whether serum transthyretin (TTR) level can be used as a novel prognostic biomarker.