An analysis of a second-line S-1 monotherapy for gemcitabine-refractory biliary tract cancer.

BACKGROUND/AIMS: Gemcitabine is widely used as a first-line therapy for biliary tract cancer (BTC). However, few studies have been conducted to analyze second- line therapies. METHODOLOGY: From 33 patients who had been administered gemcitabine following resection between May 2005 and August 2007, we retrospectively analyzed the safety and efficacy of S-1 in 11 cases who received S-1 as second-line therapy due to recurrence or relapse of the primary disease. RESULTS: Among the adverse events (AEs) observed during S-1 administration, the most common was a decrease in the concentration of hemoglobin, followed by thrombocytopenia. No Grade 4 AEs or worse were detected. In addition, the AEs and their respective severity strongly resembled those of gemcitabine used as a first-line therapy. There were 7 cases that could be evaluated according to RECIST criteria, of which 1 was considered in the partial response and 3 as stable disease. The medians of time to progression after S-1 administration and survival after S-1 administration were 5.6 months and 31 months, respectively. CONCLUSIONS: S-1 could be taken safely as a second-line therapy without provoking severe AEs. By preventing the cessation of S-1 administration due to its AEs, more continued S-1 administration could lead to a better prognosis for BTC.

[Surgery for pancreatic neuroendocrine tumors].

Approximately half of pancreatic neuroendocrine tumors (PNETs) are nonfunctioning, and insulinoma and gastrinoma are frequent forms of functioning tumors. The treatment of patients with PNETs should be based on the consideration that more than half are malignant except for insulinomas. Multiple endocrine neoplasia type 1 (MEN1) is often complicated with gastrinoma. Endoscopic ultrasound and somatostain receptor scintigraphy are useful in diagnosing PNETs, and the selective arterial secretagogue injection test is performed if necessary. WHO2010 is available as a histopathologic grading system of malignancy. Although surgical resection should first be considered as a treatment for PNETs, liver metastasis is a major factor hindering resection. In Japan, the choices of drugs to treat liver metastases are too few. In patients with MEN1 in whom PNETS are frequently multiple, we should perform procedures that preserve pancreatic function, although some patients may require total pancreatectomy for the complete resection of tumors. The indications for total pancreatectomy should be determined individually based on the tumor status and patient age.

Retrospective evaluation of the influence of postoperative tumor marker status on survival and patterns of recurrence after surgery for pancreatic cancer based on RECIST guidelines.

PURPOSE: The purpose of this study was to obtain a comprehensive understanding of the impact of postoperative tumor marker (TM) normalization on survival after pancreatectomy for pancreatic carcinoma. We propose the concept of surgical RECIST based on residual tumor and TM status. METHODS: A total of consecutive patients with pancreatic carcinoma underwent pancreatectomy between August 1, 1989, and August 1, 2008. Pre- and postoperative TM values were available for 194 patients. The relationship between TM status, survival, and other clinical and demographic data was determined with univariate log-rank tests and Cox proportional hazards analysis. RESULTS: Postoperative TM levels remained elevated in 92 patients (47.4%; partial responders). TM levels normalized in 102 patients (52.6%; complete responders). Lymph node metastases, portal vein resection, absence of retroperitoneal clearance, residual tumor, preoperative high CA19-9, and surgical partial response were associated with decreased survival. Nodal stage (P = 0.0227) and surgical RECIST (P = 0.025) were significant predictors of survival. Partial responders had a significantly lower median survival time (P = 0.0008) and significantly higher frequency of hepatic metastasis (P = 0.0299). CONCLUSIONS: Postresection TM normalization is a strong prognostic factor for pancreatic cancer. The efficacy of pancreatic cancer surgery should be evaluated in the context of both local clearance and serum TM kinetics.

Advanced bile duct carcinoma in a 15-year-old patient with pancreaticobiliary maljunction and congenital biliary cystic disease.

We report a case of advanced bile duct carcinoma arising in a 15-year-old female with pancreaticobiliary maljunction and congenital biliary cystic disease. Pancreaticoduodenectomy and partial resection of the liver was performed. Surgical and histopathological findings indicated advanced tubular adenocarcinoma, classified as final stage IVb according to the General rules for surgical and pathological studies on cancer of the biliary tract proposed by the Japanese Society of Biliary Surgery, 5th edition, and stage IV according to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC), 6th edition. She underwent chemotherapy with gemcitabine HCl after discharge. She died of cachexia 14 months after the surgery. Although it is well known that biliary malignancies arise frequently in patients with pancreaticobiliary maljunction, it is uncommon for advanced bile duct carcinoma to occur in a 15-year-old female. We should pay attention to the possibility of biliary malignancy in patients with pancreaticobiliary maljunction and congenital biliary cystic disease, even when the patients are juveniles.

Granulocyte-colony stimulating factor-producing pancreatic cancer: report of a case.

A 74-year-old man was hospitalized for the investigation of fever and severe general fatigue. Laboratory examinations revealed severe leukocytosis, with a leukocyte count of 29 500/mm(3). Computed tomography, ultrasonography, and endoscopic retrograde cholangiopancreatography showed a pancreatic tumor with a diameter of 70 mm. We performed distal pancreatectomy with splenectomy and gastrectomy because there was invasion of the posterior wall of the stomach. The leukocyte count decreased to 16 900/mm(3) immediately following the operation, but it began to increase again a week later, ultimately reaching 213 000/mm(3). We measured the serum granulocyte-colony stimulating factor (G-CSF) concentration and the G-CSF expressions in the resected specimens with immunohistochemistry, the findings of which confirmed the diagnosis of G-CSF-producing pancreatic cancer. G-CSF-producing tumors are considered to be in a category of rare malignant diseases originating in various organs, which carry a poor prognosis. However, G-CSF-producing pancreatic cancer is extremely rare. On postoperative day (POD) 35, an intraabdominal recurrence was detected with marked leukocytosis, and on POD 42 the patient died without receiving postoperative cancer therapy.

[Clinical classification and pathological physiology of acute pancreatitis].

Acute pancreatitis is a protean disease capable of wide clinical variation, ranging from mild discomfort to severe organ failure. Moreover, the inflammatory process may remain localized in the pancreas, spread to regional tissues, or even involve remote organ systems. This variability in presentation and clinical course has plagued the study and management of acute pancreatitis since its original clinical description. However, precise comprehension about the pathological physiology is required for better treatment. We described about the clinical classification and pathological physiology in the general in this

[Chemotherapy for pancreatic cancer].

Pancreatic cancer has one of the worst prognosis of any malignant disease. The National Registry of Japan Pancreas Society has reported that only 13% of patients achieve 5 years survival after surgical resection. The vast majority of patients present with metastatic or unresectable disease. Gemcitabine (GEM) has replaced 5-fluorouracil (5-FU)-based chemotherapy as the standard of care. GEM first generated improvements in symptom control and survival in advanced disease, spurring further research. For locally advanced disease, most recent studies have incorporated GEM into combined-modality therapy. However, subsequent trials have not demonstrated that combinations of other agents with GEM extend clinical benefits yet. Similarly, in surgically resectable disease, current trials are incorporating GEM into adjuvant therapy. According to several clinical trials it has been demonstrated that improvements in locoregional control and survival may be achieved when chemotherapy using 5-FU is added to radiation for locally advanced pancreatic cancer. The new regimen for locally advanced disease has demonstrated that the better outcome is expected by chemoradiation therapy with 5-FU followed by GEM treatment. Furthermore, one of the patients showed the significant regression of pancreas tumor, resulting in the successful surgical resection. In order to develop chemotherapy for pancreatic cancer, we are analyzing mRNA expression of pancreas cancer cell lines and examined their resistant against to GEM. One of the genes is demonstrated to be a responsible for drug sensitivity by clustering analysis.

Restoration of SMAD4 by gene therapy reverses the invasive phenotype in pancreatic adenocarcinoma cells.

SMAD4 is a critical cofactor in signal transduction pathways activated in response to transforming growth factor-beta (TGF-beta)-related ligands, regulating cell growth and differentiation. The roles played by SMAD4 inactivation in tumours highlighted it as a tumour-suppressor gene. However, restoration of the TGF-beta antiproliferative pathway following SMAD4 gene transfer in null-tumour cell lines is controversial. Herein, we report the inhibitory effects of SMAD4 on pancreatic tumour invasion and angiogenesis. Adenoviral transfer of this gene in a panel of SMAD4 homozygous-deleted human pancreatic tumour cell lines restored SMAD4 protein expression and function. Although it did not affect proliferation significantly in vitro, SMAD4 inhibited in vivo tumour growth in immunodeficient mice. In this xenograft setting, differential suppression of tumour growth in vivo was mediated, at least in part, through downregulation of vascular endothelial growth factor and expression of gelatinases. We documented the reduced invasion and angiogenesis histologically and by intravital microscopy, and gained mechanistic insight at the messenger and protein level. Finally, we found a negative reciprocal regulation between SMAD4 and ETS-1. ETS-1 is considered a marker for tumour invasion. Upon SMAD4 deletion, we detected high expression levels of ETS-1 in pancreatic tumour cells, suggesting the shift of the pancreatic tumour toward an invasive phenotype.

Allelic loss of DNA locus of the RET proto-oncogene in small cell lung cancer.

We analyzed all 21 exons of the RET proto-oncogene of paired genomic DNA from tumors and normal tissues in 12 small cell lung cancer (SCLC) patients for the presence of genetic alteration. Polymerase chain reaction single-strand conformation polymorphism analysis and direct sequencing revealed that heterozygosity of the RET proto-oncogene was lost in the tumor tissues of six patients out of eight informative SCLC patients, although point mutation was not evident in any tumors. These results suggest that a deletion of the chromosomal region including the RET proto-oncogene is involved in the pathogenesis of SCLC.

Gene therapy for intraperitoneally disseminated pancreatic cancers by Escherichia coli uracil phosphoribosiltransferase (UPRT) gene mediated by restricted replication-competent adenoviral vectors.

Although patients with unresectable pancreatic tumors have been treated with 5-fluorouracil (5FU)-based combination chemotherapy, the drug resistance of cancer cells presents a crucial therapeutic problem. It was reported that UPRT overcomes 5FU resistance. UPRT catalyzes the synthesis of 5-fluorouridine monophosphate (FUMP) from Uracil and phosphoribosylpyrophosphate (PRPP). The antitumor effect of 5FU is enhanced by augmenting 5-fluorodeoxyuridine monophosphate (FdUMP) converted from FUMP, which inhibits thymidylate synthetase (TS). We first demonstrated that injecting an E1-deficient adenoviral vector (Adv) expressing UPRT (AxCAUPRT) followed by 5-FU treatment resulted in a volume reduction of xenotransplanted human tumors. In examining the therapeutic effect of AxCAUPRT/5-FU against peritoneal dissemination, we found that non-selective gene transduction of AxCAUPRT caused severe adverse effects arising from the increase of F-dUMP in normal intestine. Because the therapeutic gene delivered by a restricted replication-competent Adv lacking 55 kDa E1B protein (AxE1AdB) is speculated to be expressed selectively in tumors, mice with established tumors were injected with AxE1AdB and E1-deleted Adv expressing the lacZ reporter gene (AxCAlacZ). The expression of the reporter gene (lacZ) was selectively enhanced in disseminated tumors. The therapeutic advantage of restricted replication competent Adv that expresses UPRT (AxE1AdB-UPRT) was evaluated in an intraperitoneal disseminated tumor model. To study the anti-tumor effect of AxE1AdB-UPRT/5FU, mice with disseminated AsPC-1 tumors were administered the Adv, followed by the 5FU treatment. It was shown that the treatment with AxE1AdB-UPRT/5FU caused a dramatic reduction of the disseminated tumor burden without toxicity in normal tissues. Our results showed that the AxE1AdB-UPRT/5FU system is a promising tool for intraperitoneal disseminated pancreatic cancer.

A novel bulk-culture method for generating mature dendritic cells from mouse bone marrow cells.

We established a novel culture method for generating dendritic cells (DC) from mouse bone marrow (BM) cells. Unfractionated bulk BM cells were cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 5-7 days and a DC population was isolated by gradient centrifugation with 14.5% (w/v) metrizamide. Through this method, 30-40 x 10(6)/mouse DC with 85-95% purity was obtained on day 7; this yield was higher than those of conventional DC generated by Inaba's method either with GM-CSF alone (conventional-GM DC) or GM-CSF and IL-4 (conventional-GM/4 DC). Bulk-cultured DC have a more matured phenotype than both conventional-GM and -GM/4 DC as shown by higher expression of CD86, MHC class II and CD40. Functional analyses reveal that (1) bulk-DC show less ability in endocytosis than conventional-GM DC and are comparable in IL-12 p70 production with conventional-GM and -GM/4 DC. (2) Bulk-DC exhibit stronger stimulatory capacity in allogeneic T-cell proliferation than conventional DC. (3) By using ovalbumin (OVA) and OVA-specific T-cell receptor (TCR) transgenic mice (DO11.10) system, OVA protein-loaded bulk-DC stimulated CD4 T cells of DO11.10 mice more than conventional-GM DC and comparable with conventional-GM/4 DC. (4) Furthermore, OVA peptide-pulsed bulk-DC stimulated CD4 T cells more than conventional-GM and -GM/4 DC. These data indicate that bulk-DC are functionally more mature than conventional DC. Taken together, bulk-culture method is a simple technique for generating functionally mature BM-DC in large quantities and high purity.