Tsuneo Sasaki

Frequent and Significant K- ras Mutation in the Pancreas, the Bile Duct, and the Gallbladder in Autoimmune Pancreatitis

Objectives: To assess the relationship between autoimmune pancreatitis (AIP) and pancreatic cancer, we analyzed K-ras mutation in the pancreatobiliary tissues of patients with AIP. Methods: An analysis of K-ras mutation and an immunohistochemical study were performed on the pancreas of 8 patients with AIP and 10 patients with chronic alcoholic pancreatitis and on the common bile duct and the gallbladder of 9 patients with AIP. K-ras mutation was analyzed in the pure pancreatic juice from 3 patients with AIP. Results: High-frequency K-ras mutation (2+ or 3+) was detected in the pancreas of all the 8 patients and in the pancreatic juice of the other 2 patients. The mutation in codon 12 of the ras gene was GAT in all the 10 patients. High-frequency K-ras mutation was detected in the common bile duct of 5 patients with AIP and in the gallbladder epithelium of 4 patients with AIP. The K-ras mutation was detected in the fibroinflammatory pancreas, the bile duct, and the gallbladder, with abundant infiltrating IgG4-positive plasma and Foxp3-positive cells of patients with AIP with elevated serum IgG4 levels. Conclusions: Significant K-ras mutation occurs most frequently in the pancreatobiliary regions of patients with AIP. Autoimmune pancreatitis may be a risk factor of pancreatobiliary cancer.

Hepatitis B Virus Reactivation in a Patient With Chronic GVHD After Allogeneic Peripheral Blood Stem Cell Transplantation

We report a patient with fatal hepatitis B virus (HBV) reactivation after treatment for chronic graft-versus-host disease (GVHD) following allogeneic peripheral blood stem cell transplantation to treat chronic myelogenous leukemia. The presence of antibodies to hepatitis B surface antigen (HBsAb) prior to transplantation indicated previous HBV infection. Liver damage first developed 8 months after transplantation with the disappearance of HBsAb. Hepatitis B antigen was first noted during an examination of liver damage that occurred 22 months after transplantation. Retrospective examination of serum by real-time detection polymerase chain reaction (RTD-PCR) revealed HBV in both the first and second episodes of liver damage (89 copies/mL and 2 x 10p6 copies/mL, respectively). HBV may have been reactivated, leading to fatal liver damage in this HBsAb-positive patient. We propose that RTD-PCR-based analysis should be performed to diagnose liver dysfunction after hematopoietic stem cell transplantation.

Nonmyeloablative allogeneic stem cell transplantation for patients with unresectable pancreatic cancer.

Objectives: To clarify whether nonmyeloablative allogeneic stem cell transplantation (NST) can produce the graft versus tumor (GVT) effect in patients with pancreatic cancer. Methods: A pilot trial of NST was conducted in 5 patients with unresectable pancreatic cancer. Preparative conditioning consisted of administration of 60 mg/kg cyclophosphamide on days 6 and 7 before transplantation, followed by 25 mg fludarabine per square meter of body surface on each of the last 5 days prior to transplantation. Cyclosporine was started 4 days before transplantation. Peripheral blood stem cells from the patients’ HLA-identical siblings were transfused into the patients. Results: Complete donor T-cell chimerism in peripheral blood was obtained in 4 patients on day 15 after transplantation. NST resulted in tumor reduction in 2 patients as determined by CT, decreasing levels of tumor markers in 2 patients, pain relief in 2 patients, and a decrease in pleural fluid in 1 patient. Two patients developed acute graft versus host disease (GVHD) of grade II or III and 2 had chronic GVHD involving skin and/or liver. Administration of immunosuppressive drugs for the treatment of GVHD resulted in the elevation of tumor marker levels. Conclusion: These findings are the first to suggest that NST induces a GVT effect on pancreatic cancer.

Safety and efficacy of rasburicase (SR29142) in a Japanese phase II study

The purpose of this study was to investigate the safety profile of SR29142 when administered as a single agent both prior to chemotherapy and during treatment, and to compare the efficacy of SR29142 administered at two dose levels in adult Japanese patients with leukemia or lymphoma. During this open‐label, multicenter, phase II study, patients received SR29142 for 5 days, administered at either 0.15 or 0.20 mg/kg per day. Chemotherapy was started 4–24 h after the first infusion of SR29142. The primary end‐point was overall response rate, defined as the normalization of plasma uric acid to 7.5 mg/dL or less, from 48 h after the first infusion to 24 h after the last infusion of SR29142. SR29142‐related adverse events including hypersensitivity (allergic) reactions were assessed. Overall, 50 patients received SR29142 at either 0.15 mg/kg per day (n = 25) or 0.20 mg/kg per day (n = 25) followed by chemotherapy. The overall response rate was 100.0% (95% confidence interval, 86.3–100.0%) with 0.15 mg/kg and 96.0% (95% confidence interval, 79.6–99.9%) with 0.20 mg/kg. Both dose levels of SR29142 were equally effective at reducing plasma uric acid levels. In six patients, seven drug‐related adverse events of grade 1/2 occurred before chemotherapy. SR29142‐related, hypersensitivity‐associated reactions occurred in three patients, and rash, anorexia, application site pain and pyrexia occurred in one patient each; only five patients (10%) showed anti‐SR29142 antibodies by day 29. In conclusion, SR29142 is effective at reducing plasma uric acid levels with a tolerable safety profile as a single agent both prior to chemotherapy and during treatment. (Trial register: ClinicalTrials.gov, NCT00631579.) (Cancer Sci 2009; 100: 357–362)

Clinical Characteristics of Patients with Autoimmune Pancreatitis with or without Mikulicz's Disease and Mikulicz's Disease Alone

Background/Aims The objective of this study was to compare the clinical characteristics of patients with autoimmune pancreatitis (AIP) with or without Mikuliczs disease (MD) and with MD alone. Methods We investigated the clinical findings in 15 AIP patients with MD (group A+M), 49 AIP only patients (group A), and 14 MD only patients (group M). Results The male-female ratio was significantly higher in group A+M (73%, p<0.05) and group A (78%, p<0.01) than group M (21%). Serum immunoglobulin G (IgG) levels were significantly higher in group A+M than in group A (p<0.01) and group M (p<0.05). Serum IgG4 levels were significantly higher in group A+M than in group A (p<0.01). Other organ involvement was observed in 73% (11/15) of patients in group A+M. The number of patients with diabetes mellitus was significantly higher in group A+M (66%, p<0.01) and group A (51%, p<0.05) than in group M (7%). All of the patients responded well to steroid therapy, but the relapse rate in group A+M (33%) was significantly higher than that in group A (3%, p<0.01). Salivary gland function was impaired in all groups compared with the control group, but the degree of dysfunction was less in group A compared with group A+M and group M. Conclusions The relapse rate of AIP in MD patients was significantly higher than that of AIP in patients without MD.

A New Embryological Theory of the Pancreatic Duct System

Background/Aims: To clarify the anatomy of the pancreatic duct system and to investigate its embryology. Methods: We reviewed pancreatograms of 256 patients with a normal pancreatic head and 36 cases of complete pancreas divisum. Results: Accessory pancreatograms were divided into two patterns. The long-type accessory pancreatic duct (APD) forms a straight line and joins the main pancreatic duct (MPD) at the neck portion of the pancreas. The short-type APD joins the MPD near its first inferior branch. The short-type APD is less likely to have a long inferior branch arising from the APD. The length of the APD from the orifice to the first long inferior branch was similar in the short- and long-type APD. The first long inferior branch from the long-type APD passes through the MPD near the origin of the inferior branch from the MPD. Immunohistochemically, in the short-type APD, the MPD between the junction of the short-type APD and the neck portion originated from the ventral pancreas. Conclusion: The long-type APD represents a continuation of the main duct of the dorsal pancreatic bud. The short-type APD is very likely formed by the proximal main duct of the dorsal pancreatic bud and its long inferior branch, with the main duct of the dorsal pancreatic bud at the point of connection with the main duct of the ventral pancreatic bud being obliterated and replaced by this additional communication.

Second allogeneic peripheral blood stem cell transplantation with fludarabine-based low-intensity conditioning regimen for relapsed myelodysplastic syndrome after allogeneic bone marrow transplantation.

We describe the case of a 51-year-old patient with relapsed myelodysplastic syndrome after allogeneic bone marrow transplantation (BMT), who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) after conditioning with a novel regimen consisting of fludarabine, busulfan, and antithymocyte globulin. The second PBSCT was performed early, at 3 months after the initial allogeneic BMT, but it was well tolerated and complete hematologic remission was documented.The patient did not experience any early transplantation-related organ toxicity but died from opportunistic infection 6 months after the second transplantation. Our experience suggests that this novel regimen may induce remission and could be offered to patients relapsing after the first transplantation; however, the fludarabine-containing regimen might be accompanied by profound immunosuppression.

P2-2-4TREATMENT OUTCOME OF ADVANCED GASTRIC CANCER WITH DOUBLE PRIMARY CANCER

Abstract Purpose: An aging population and advances in diagnostic technology have led to an increase in the incidence of double or multiple primary cancers (DMPC) in patients with inoperable gastric cancer. We thus performed a retrospective analysis to clarify whether we should treat only gastric cancer as therauptic target and ignore other primary cancer in patients with DPMC. Patients and methods: We use Chart Review to identify 454 advanced or metastatic gastric cancer patients who were diagnosed between December 2000 and April 2013. Results: Of 454 patients, 43 patients had DMPC. All of the 43 patients were treated by fluorouracil agent and cisplatin combination therapy. Among these 43 patients, 20 had synchronous primary cancers, and 23 patients were diagnosed gastric cancer over 6 months after diagnosed second primary cancer. Nine of the 20 synchronous DMPC patients were treated regarding only gastric cancer as therapeutic targets, and 11 patients were treated second primary cancers as therapeutic targets in addition to gastric cancer. Six of the 20 patients had DMPC which were applied for fluorouracil agent and cisplatin combination therapy, and the other 14 patients had DPMC that were not adaptive this combination therapy. With a median follow-up of 12 months, no difference in OS was observed between DMPC patients and simple gastric cancer patients (P = 0.49). Likewise, there was no difference in OS between patients treated only gastric cancer and both cancers (P = 0.64). Moreover, no difference in OS was observed between fluorouracil agent and cisplatin combination therapy sensitive DMPC patients and non-sensitive DMPC patients (P = 0.83). All except one of DMPC patients were dead of progression of gastric cancer. Conclusion: We could treat gastric cancer patients with DMPC with fluorouracil drug and cisplatin combination chemotherapy regarding advanced gastric cancer as first therapeutic target

O2-1-6VALIDATION OF AN ENHANCED INTERNATIONAL PROGNOSTIC INDEX(NCCN-IPI)FOR RISK STRATIFICATION OF DLBCL PATIENTS

Abstract Background: The U.S. National Comprehensive Cancer Network Prognostic Index (NCCN-IPI) was recently developed for risk stratification of diffuse large B-cell lymphoma (DLBCL) cases in the rituximab era (Zhou, Blood 2013). It provided better discrimination of risk groups of DLBCL patients than the conventional IPI. We report the validation of NCCN-IPI compared with IPI by using our institution dataset. Methods: We retrospectively analyzed patients with de novo DLBCL referred to our department from September 2004 to March 2013. NCCN-IPI used a maximum of 8 scoring points for categorized age >40-60 (1 pt.), >60-75 (2 pts.) and >75 yrs. (3 pts.), and LDH ratio >1-3 (1 pt.) and ≥3 (2pts.) upper limit of normal, in addition to extranodal disease in major organs (either bone marrow, CNS, liver/GI tract or lung), Ann Arbor stage III/IV and ECOG performance status (≥2), each having a score of 1. Four risk groups were defined: low (L, 0-1 pt.), low-intermediate (L-I, 2-3 pts.), intermediate-high (HI, 4-5 pts.) and high risk (H, ≥6 pts.). Results: A total of 315 patients were identified. Patients characteristics were the following: age (>40-60/ > 60-75/ >75 yes: 24/44/29%); stage III/IV (53%); extranodal disease (47%); LDH (1-3/ > 3 times: 45/14%); and PS ≥2, (31%). On univariate analysis, all characteristics were significant for OS, and were the same on multivariate analysis except for extranodal disease. The 5-year OS estimates between the NCCN-IPI and IPI differed in each risk groups, 100% (95% CI: 100-100%) vs. 91% (82-96%), 84% (74-90%) vs. 78% (63-87%), 59% (46-69%) vs. 46% (29-60%), 25% (12-40%) vs. 24% (11-39%), in L, L-I, H-I, and H risk groups, respectively. Compared to IPI, the 95% CI did not overlap among NCCN-IPI risk group. Conclusions: NCCN-IPI demonstrated improved risk stratification compared to IPI. NCCN-IPI is a valuable prognostic index for DLBCL patients in the rituximab era.

Serial macroangiography applied to the study of lesions of the extremities

The technique of serial macroangiography as applied to lesions of the extremities is described and a number of different conditions are illustrated. It is concluded that macroangiography is more helpful in demonstrating fine vascular structures in tumours and in differentiating malignant from benign conditions.