Yoshihito Nakayama

Profiling of somatostatin receptor subtype expression by quantitative PCR and correlation with clinicopathological features in pancreatic endocrine tumors.

Objectives: Pancreatic endocrine tumor (PET) presents variable clinical features. Five subtypes of somatostatin receptor (SSTR) are involved in hormone secretion and cell proliferation. In this paper, we explore the correlation between the SSTR subtype messenger RNA (mRNA) expression and clinicopathological features of PET. Methods: Twenty-one cases of PET and 5 cases of pancreatic adenocarcinomas (AC) were studied. Using total RNA extracted from paraffin sections and fresh tissues, SSTR subtype mRNA was quantified by real-time polymerase chain reaction. The hormones and MIB1 index were examined using immunohistochemical techniques. Results: The mRNA levels of SSTR1, SSTR2, SSTR3, and SSTR5 were high in PET compared with AC, whereas the expression of SSTR4 was low in PET and AC. Levels of each subtype did not vary with histological grades. Somatostatin receptor 2 levels in functioning tumors were slightly low compared with nonfunctioning tumors. Four distinct groups of PET were identified by hierarchical cluster analysis, and two of these groups showed reduced SSTR5 with elevation of MIB1 index. Conclusions: The study showed a heterogeneous expression profile of SSTR subtype mRNA and the association of reduction in SSTR5 with high proliferative activity. Such profiling of SSTR subtypes may provide useful information on tumor biology and treatment of PET.

VIP and calcitonin-producing pancreatic neuroendocrine tumor with watery diarrhea: clinicopathological features and the effect of somatostatin analogue.

CONTEXT Pancreatic neuroendocrine tumor (pNET) secretes various peptide hormones; however, calcitonin hypersecretion is rare. Its clinicopathological significance and treatment is still controversial. CASE REPORT A 43 year-old Japanese man presented severe watery diarrhea and a large mass in the pancreatic tail. Blood concentration of VIP was elevated to 649 pg/mL (reference range: 0-100 pg/mL), and calcitonin to 66,700 pg/mL (reference range: 15-86 pg/mL). There was no tumor in other endocrine organs. The resected tumor was composed of 80% calcitonin-positive cells and 10% VIP-positive cells. After the operation, the levels of VIP and calcitonin were decreased to 44 and 553 pg/mL, respectively, and diarrhea was improved. The mRNA of somatostatin receptor (SSTR) subtypes 2, 3 and 5 in the tumor tissue were increased 22.8, 25.1, and 37.0-fold of those of normal pancreas, respectively. At 19 months after the operation, blood calcitonin was again raised to 3,980 pg/mL, and metastatic tumors were found in the liver. With the treatment of long-acting somatostatin analogue, calcitonin was reduced to 803 pg/mL. The patient does not present endocrine symptom, and the size of the metastatic tumors appears stable. CONCLUSION From the world literature to date, co-secretion of VIP and calcitonin was documented in only 10 cases of pNET including the current case. Although VIP is a primary cause of diarrhea in these cases, high level of calcitonin may also influence on the clinical symptoms. Somatostatin analogue suppresses the levels of VIP and calcitonin, and the control proliferation is also expected when tumor cells express SSTRs.

Combination therapy with gemcitabine and nab‑paclitaxel for locally advanced unresectable pancreatic cancer

The aim of the present study was to investigate the early treatment outcomes of combined gemcitabine and nab-paclitaxel treatment for locally advanced unresectable pancreatic cancer (LURPC). The subjects comprised 7 patients with LURPC receiving the abovementioned combination therapy at the Hirosaki University Hospital (Hirosaki, Japan) between January and September, 2015. The clinicopathological factors, adverse events and response to treatment were investigated. To determine whether the cases were unresectable, the National Comprehensive Cancer Network guidelines, version 2. 201,) were applied. The patients underwent a median of 4 (range, 2-7) courses of treatment. The response to treatment was evaluated using the Response Evaluation Criteria In Solid Tumors. The subjects included 1 male and 6 female LURPC patients, with a median age of 71 years (range, 59-78 years). The tumor was located in the head and body of the pancreas in 6 and 1 patients, respectively. No patients achieved a complete response, 5 achieved a partial response, 2 had stable disease, and none exhibited progressive disease. The response rate was 71%. The mean tumor diameter decreased significantly from 35 mm (range, 24-60 mm) prior to treatment to 22 mm (range, 20-35 mm) following treatment. Two patients were downstaged. The mean carbohydrate antigen (CA) 19-9 values decreased significantly from 767 U/ml (range, 14-1,977 U/ml) prior to treatment to 35 U/ml (range, 14-123 U/ml) following treatment. Adverse events classified as grade ≥3 occurred in 4 patients (57%): 3 patients (43%) suffered from neutropenia and 1 patient (14%) developed bilateral cellulitis of the lower extremities. No patients experienced an increase in disease severity, and all were able to continue treatment following temporary withdrawal or dosage reduction. Therefore, combined treatment with gemcitabine and nab-paclitaxel had favorable tumor-reducing effects and was not associated with severe adverse events, suggesting that this is a useful therapeutic strategy for patients with LURPC.

Prognosis based on the revised histological classification by the World Health Organization (2010) for pancreatic neuroendocrine tumors

Background/aim: Pancreatic neuroendocrine tumors (PNETs) are a rare subgroup of tumors, for which the factors predictive of survival and prognosis are not well known. Recently, the European Neuroendocrine Tumors Society (ENETS) proposed the TNM staging and the World Health Organization (WHO) revised its histological classification in 2010. This study aimed to evaluate whether the ENETS staging and the revised WHO classification can predict survival after surgical resection of PNETs. Methods: Twenty consecutive curative resections for PNETs were performed at our institute from 1998 to 2012. The prognostic factors based on the revised WHO histological classification (2010) for survival were retrospectively evaluated using the Kaplan–Meier method. Results: The mean patient age was 60.3 10.9 years. Twelve patients (60%) were diagnosed with functioning tumors and 8 (40%) with nonfunctioning tumors. Surgical methods comprised pancreatoduodenectomy (n 1⁄4 3), distal pancreatectomy (n 1⁄4 5), enucleation (n 1⁄4 9), and central pancreatectomy (n 1⁄4 3). Hepatectomy was performed for 2 patients with synchronous liver metastasis. According to the ENETS staging, 14 (70%), 2 (10%), 2 (10%), and 2 (10%) had stage I, II, III, and IV tumors, respectively. According to the revised WHO histological classification (2010), 13 (65%), 5 (25%), 1 (5%), and 1 (5%) patient was diagnosed with neuroendocrine tumor (NET) G1, NET G2, neuroendocrine carcinoma (NEC), and mixed adenoneuroendocrine carcinoma (MANEC), respectively. Univariate analysis revealed that both the ENETS staging and the revised WHO histological classification (2010) significantly predicted survival after surgical resection for PNETs. Conclusions: The ENETS staging and the revised WHO histological classification (2010) may be useful to predict survival in PNETs. However, because PNETs represent a rare tumor subgroup, more time and a sufficient number of cases are required to confirm its prognostic reliability.