Shuichi Mitsunaga

Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome.

Because autonomous proliferating cancer cells are often exposed to hypoxic conditions, there must be an alternative metabolic pathway, such as autophagy, that allows them to obtain energy when both oxygen and glucose are depleted. We previously reported finding that autophagy actually contributes to cancer cell survival in colorectal cancers both in vitro and in vivo. Pancreatic cancer remains a devastating and poorly understood malignancy, and hypoxia in pancreatic cancers is known to increase their malignant potential. In the present study archival pancreatic cancer tissue was retrieved from 71 cases treated by curative pancreaticoduodenectomy. Autophagy was evaluated by immunohistochemical staining with anti‐LC3 antibody, as LC3 is a key component of autophagy and has been used as a marker of autophagy. The results showed that strong LC3 expression in the peripheral area of pancreatic cancer tissue was correlated with a poor outcome (P = 0.0170) and short disease‐free period (P = 0.0118). Two of the most significant correlations among the clinicopathological factors tested were found between the peripheral intensity level of LC3 expression and tumor size (P = 0.0098) or tumor necrosis (P = 0.0127). Activated autophagy is associated with pancreatic cancer cells, and autophagy is thought to be a response to factors in the cancer microenvironment, such as hypoxia and poor nutrient supply. This is the first study to report the clinicopathological significance of autophagy in pancreatic cancer. (Cancer Sci 2008; 99: 1813–1819)

Cisplatin and Etoposide as First-line Chemotherapy for Poorly Differentiated Neuroendocrine Carcinoma of the Hepatobiliary Tract and Pancreas

OBJECTIVE The combination chemotherapy consisting of cisplatin and etoposide, one of the standard regimens for small cell lung cancer, has been widely used to treat extrapulmonary poorly differentiated neuroendocrine carcinomas. However, there were no prior reports limited to the hepatobiliary tract and pancreas as the primary sites. METHODS We reviewed the cases in our database from October 1995 to January 2009 and retrospectively examined the clinical data of patients, with unresectable or recurrent poorly differentiated neuroendocrine carcinoma arising from the hepatobiliary tract and pancreas, who received combination chemotherapy with cisplatin and etoposide as the first-line treatment. The chemotherapy regimen consisted of cisplatin 80 mg/m(2) given intravenously on day 1 and etoposide 100 mg/m(2) intravenously on days 1-3, repeated every 3-4 weeks. RESULTS Twenty-one patients were treated with the above regimen of cisplatin and etoposide combination chemotherapy. The primary tumor site was the liver in 2 patients, gallbladder in 8 patients, pancreas in 10 patients and ampulla of Vater in 1 patient. Although no complete responses were obtained, three patients had partial responses, resulting in an overall response rate of 14%. Median progression-free survival was 1.8 months, and median overall survival was 5.8 months. The major adverse events were myelosuppression and gastrointestinal toxicities, with Grade 3 or 4 neutropenia (90%), nausea (33%) and anorexia (24%). CONCLUSIONS Cisplatin and etoposide combination as the first-line chemotherapy for hepatobiliary or pancreatic poorly differentiated neuroendocrine carcinoma had only marginal antitumor activity and relatively severe toxicity compared with previous studies on extrapulmonary poorly differentiated neuroendocrine carcinoma treated with the same regimen.

Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head.

Tumor‐associated macrophages (TAMs) are candidate histological factors in invasive ductal carcinoma (IDC) of the pancreas. Tumor‐associated macrophages can be affected by cancer‐related inflammation and pancreatitis and interact with important invasive behavior in a recurrent manner in pancreatic IDC. These features may help elucidate the aggressiveness of pancreatic IDC. The aim of this study was to characterize TAMs in pancreatic IDC in comparison with chronic pancreatitis (CP) and to reveal TAM‐related factors and the clinical impact of TAMs. CD68 (a pan‐macrophage marker) and CD204 (an M2 macrophage marker) immunohistochemistry was carried out in pancreas head specimens from 107 IDC cases and 11 CP cases. Immunopositive cell areas were calculated at the periphery and center of the tumor. The distributions of macrophages in IDC and CP and the relationship between TAMs and histological tumor factors, survival, and recurrence were evaluated. Macrophages were more frequently observed in the lesion periphery than the center in IDC and CP. The density of macrophages was elevated in IDC compared to CP. Dense M2 macrophages at the tumor periphery were frequently seen in large tumors and showed an independent impact on overall survival and disease‐free time. Early recurrence in the liver or the local manipulated area was associated with high accumulation of peripheral M2 macrophages. More M2 macrophages were seen in IDC than in CP in both the periphery and the center. High numbers of peripheral M2 macrophages were associated with large tumor size, early recurrence in the liver, local recurrence, and shortened survival time in patients with pancreatic IDC. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02411.x, 2012)

Serum levels of IL-6 and IL-1β can predict the efficacy of gemcitabine in patients with advanced pancreatic cancer

Background:With this study, we sought to characterise the impact of pro-inflammatory cytokines on the outcomes of gemcitabine monotherapy (GEM) in patients with pancreatic cancer (PC).Methods:Treatment-naive patients with advanced PC and no obvious infections were eligible for enrolment. All of the patients were scheduled to undergo systemic chemotherapy. Serum pro-inflammatory cytokines were measured using an electro-chemiluminescence assay method before chemotherapy. High cytokine levels were defined as values greater than the median. Clinical data were collected prospectively.Results:Sixty patients who received GEM were included in the analysis. High IL-6 and IL-1β levels were poor prognostic factors for overall survival in a multivariate analysis (P=0.011 and P=0.048, respectively). Patients with both a high IL-6 level and a high IL-1β level exhibited shortened overall and progression-free survival, a reduction in the tumour control rate, and a high dose intensity of GEM compared with patients with low levels of both IL-6 and IL-1β.Conclusion:The serum levels of IL-6 and IL-1β predict the efficacy of GEM in patients with advanced PC.

Detail histologic analysis of nerve plexus invasion in invasive ductal carcinoma of the pancreas and its prognostic impact

Nerve plexus invasion is regarded as one of the most important prognostic factors in invasive ductal carcinoma (IDC) of the pancreas, though nerve plexus invasion has not been evaluated in terms of prognostic impact on the basis of detailed histologic investigation. The purpose of this study was to precisely examine morphologic characteristics of nerve plexus invasion and analyze its prognostic predictive power compared with the well-known prognostic parameters of pancreatic IDCs. The outcome and histologic features of 75 patients with pancreatic IDC in the pancreas head were investigated, and 422 lesions of nerve plexus invasion were evaluated. Tumor cells invading nerve plexus showed a duct-forming differentiated feature and predominantly existed in the perineurium and perineural space. Multivariate analyses revealed that the important prognostic factors, in addition to invasive tumor size and tumor necrosis, were at long distances from nerve plexus invasion to pancreatic capsule and perineural invasion in nerve plexus invasion.

Important prognostic histological parameters for patients with invasive ductal carcinoma of the pancreas

For clinicians, the orthodox histological investigation of patients with invasive ductal carcinoma (IDC) remains important for predicting prognoses. The purpose of the present study was to determine the most important of the known prognostic histological parameters (including fibrotic focus and tumor necrosis), enabling the outcomes of 101 patients with IDC of the pancreas to be predicted accurately. Furthermore, we established a scoring classification consisting of important prognostic histological parameters examined in this study. Multivariate survival analyses showed that invasive tumor size of more than 3 cm, the presence of tumor necrosis, the presence of nerve plexus invasion and lymph vessel invasion scores of 2 or 3 were important prognostic factors. Our scoring classification, consisting of the above four parameters, accurately classified the outcome of patients independent of the invasive tumor size of IDC. We concluded that invasive tumor size of 3 cm or more, the presence of tumor necrosis, the presence of nerve plexus invasion and lymph vessel invasion scores of 2 or 3 are important histological prognostic parameters for patients with IDC of the pancreas. Furthermore, the scoring system consisting of the above four histological parameters is probably a very useful prognostic histological classification for patients with IDC of the pancreas. (Cancer Sci 2005; 96: 858–865)

Japanese phase I study of GC33, a humanized antibody against glypican-3 for advanced hepatocellular carcinoma

GC33 is a humanized mAb against human glypican‐3 (GPC3). In the first‐in‐human study carried out in the USA, GC33 was well tolerated and showed preliminary antitumor activity in patients with advanced hepatocellular carcinoma. This study aimed to assess the safety, tolerability, and pharmacokinetic characteristics of GC33 in Japanese patients with advanced hepatocellular carcinoma. The study design was a conventional 3 + 3 dose‐escalation design to determine the maximum tolerated dose of GC33 given i.v. at 5, 10, or 20 mg/kg weekly. Immunohistochemistry was carried out on tumor biopsies to evaluate GPC3 expression. Thirteen patients were enrolled across the three dose levels, and no patients observed any dose‐limiting toxicity up to the highest planned dose of 20 mg/kg. The most common adverse events were decreased lymphocyte count, decreased natural killer cell count, increased C‐reactive protein, and pyrexia. Grade 3 adverse events (increased blood pressure, decreased lymphocyte count, and decreased platelet count) were observed in two or more patients. The AUCinf showed a dose‐proportional increase from the 5 mg/kg dose group to the 20 mg/kg dose group. The trough concentrations of GC33 appeared to reach a steady state after the fourth to the sixth dose. Seven of the 13 patients showed stable disease, the other six showed progressive disease. Furthermore, three patients showed long‐term stable disease of more than 5 months. In conclusion, GC33 given at up to 20 mg/kg weekly was well tolerated in Japanese patients with advanced hepatocellular carcinoma.

Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

Purpose: To determine the maximum tolerable dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of lenvatinib in patients with advanced hepatocellular carcinoma (HCC). Experimental Design: This multicenter, open-label, phase I, dose-escalation study included patients aged 20 to 80 years, refractory to standard therapy, and stratified by hepatic function measured using Child–Pugh (CP) scores: CP-A (score, 5–6) and CP-B (score, 7–8). Lenvatinib was administered continually once daily for 4-week cycles. MTD was defined as the maximum dose associated with ≤ 1 dose-limiting toxicity (DLT) occurring in cycle 1 among 6 patients. Results: In total, 20 patients (9 in CP-A and 11 in CP-B) were enrolled. The MTD was 12 and 8 mg once daily in CP-A and CP-B, respectively; DLTs included proteinuria, hepatic encephalopathy, and hyperbilirubinemia. The most common grade 3 toxicities included hypertension in CP-A and hyperbilirubinemia in CP-B. Lenvatinib plasma concentration at 24 hours after administration (C24 h) for 12 mg once daily was higher in patients with HCC than in patients with other solid tumors shown in a previous phase I study, but C24 h for 25 mg once daily lenvatinib was comparable. After lenvatinib treatment, the number of circulating endothelial and c-Kit+ cells decreased and the levels of interleukin (IL)-6, IL10, granulocyte-colony stimulating factor, and vascular endothelial growth factor increased (P < 0.05). Partial responses were observed in 3 patients and tumor shrinkage occurred in 14 patients. Conclusions: Lenvatinib (12 mg once daily) demonstrated preliminary efficacy with manageable toxicity and is the recommended dose for phase II studies in patients with HCC and CP-A. Clin Cancer Res; 22(6); 1385–94. ©2015 AACR.

Construction and validation of a prognostic index for patients with metastatic pancreatic adenocarcinoma.

Objectives: To identify prognostic factors in patients with metastatic pancreatic adenocarcinoma. Methods: The relationship between patient characteristics and outcome was examined by multivariate regression analyses of data from 409 consecutive patients with metastatic pancreatic adenocarcinoma who had been treated with a gemcitabine-containing regimen, and we stratified the patients into 3 risk groups according to the number of prognostic factors they had for a poor outcome. A validation data set obtained from 145 patients who had been treated with agents other than gemcitabine was analyzed. The prognostic index was applied the each of the patients. Results: The multivariate regression analyses revealed that the presence of pain, peritoneal dissemination, liver metastasis, and an elevated serum C-reactive protein value significantly contributed to a shorter survival time. The patients were stratified into 3 groups according to their number of risk factors, and their outcomes of the 3 groups were significantly different. When the prognostic index was applied to the validation data set, the respective outcomes of the 3 groups were found to be significantly differed from each other. Conclusions: Pain, peritoneal dissemination, liver metastasis, and an elevated serum C-reactive protein value are important prognostic factors for patients with metastatic pancreatic adenocarcinoma.

Dose–Volume Histogram Analysis of the Safety of Proton Beam Therapy for Unresectable Hepatocellular Carcinoma

PURPOSE To evaluate the safety and efficacy of radiotherapy using proton beam (PRT) for unresectable hepatocellular carcinoma. METHODS AND MATERIALS Sixty consecutive patients who underwent PRT between May 1999 and July 2007 were analyzed. There were 42 males and 18 females, with a median age of 70 years (48-92 years). All but 1 patient had a single lesion with a median diameter of 45 mm (20-100 mm). Total PRT dose/fractionation was 76-cobalt Gray equivalent (CGE)/20 fractions in 46 patients, 65 CGE/26 fractions in 11 patients, and 60 CGE/10 fractions in 3 patients. The risk of developing proton-induced hepatic insufficiency (PHI) was estimated using dose-volume histograms and an indocyanine-green retention rate at 15 minutes (ICG R15). RESULTS None of the 20 patients with ICG R15 of less than 20% developed PHI, whereas 6 of 8 patients with ICG R15 values of 50% or higher developed PHI. Among 32 patients whose ICG R15 ranged from 20% to 49.9%, PHI was observed only in patients who had received 30 CGE (V30) to more than 25% of the noncancerous parts of the liver (n = 5) Local progression-free and overall survival rates at 3 years were 90% (95% confidence interval [CI], 80-99%) and 56% (95% CI, 43-69%), respectively. A gastrointestinal toxicity of Grade ≥2 was observed in 3 patients. CONCLUSIONS ICG R15 and V30 are recommended as useful predictors for the risk of developing PHI, which should be incorporated into multidisciplinary treatment plans for patients with this disease.