Shukichi Miyazaki

Gene Therapy for Pancreatic Cancer Using an Adenovirus Vector Encoding Soluble flt-1 Vascular Endothelial Growth Factor Receptor

Introduction Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis. The soluble form of flt-1 VEGF receptor inhibits VEGF activity in a dominant-negative manner. Aim This study demonstrated the regional tumor suppression effect of adenovirus-mediated soluble flt-1 in human pancreatic cancer cells. Methodology The VEGF expression level was examined in nine cell lines. Panc-1 and PK-8 were used as lower- and higher-VEGF-producing cell lines, respectively. The in vitro proliferation of cancer cells infected with adenovirus vectors encoding soluble flt-1 (Adsflt) and control vectors (AdLacZ) was not different. To assess the in vivo tumor growth suppression, cancer cells were inoculated subcutaneously in SCID mice. Adsflt, AdLacZ, or vehicle was injected directly into the tumors. The early process of tumor angiogenesis in a dorsal skinfold chamber was monitored by intravital microscopy. Results In both Panc-1 cells and PK-8 cells, the tumor growth of the Adsflt-treated group was significantly suppressed. The microvessel density, revealed by CD31 immunostaining, was also significantly lower in the Adsflt-treated group. Apoptosis index was higher in the Adsflt group. Immunofluorescence staining revealed the expression of VEGF not only in cancer cells but also in tumor stromal cells. Wild-type cells and AdLacZ-infected cells prompted strong tumor angiogenesis, whereas Adsflt-infected cells failed to exert such an effect. Conclusion These results indicate that antiangiogenic gene therapy using soluble flt-1 might be an effective approach for pancreatic cancer treatment.

Prospective Comparison of Surgery Alone and Chemoradiotherapy With Selective Surgery in Resectable Squamous Cell Carcinoma of the Esophagus

PURPOSE Esophagectomy remains the mainstay treatment for esophageal cancer, although retrospective studies have suggested that chemoradiotherapy (CRT) is as effective as surgery. To determine whether CRT can substitute for surgery as the primary treatment modality, we performed a prospective direct comparison of outcomes after treatment in patients with resectable esophageal cancer who had received CRT and those who had undergone surgery. METHODS AND MATERIALS Eligible patients had resectable T1-3N0-1M0 thoracic esophageal cancer. After the surgeon explained the treatments in detail, the patients selected either CRT (CRT group) or surgery (OP group). The CRT course consisted of two cycles of cisplatin and fluorouracil with split-course concurrent radiotherapy of 60Gy in 30 fractions. Patients with progressive disease during CRT and/or with persistent or recurrent disease after CRT underwent salvage resection. RESULTS Of 99 eligible patients with squamous cell carcinoma registered between January 2001 and December 2005, 51 selected CRT and 48 selected surgery. Of the patients in the CRT group, 13 (25.5%) underwent esophagectomy as salvage therapy. The 3- and 5-year survival rates were 78.3% and 75.7%, respectively, in the CRT group compared with 56.9% and 50.9%, respectively, in the OP group (p = 0.0169). Patients in the OP group had significantly more metastatic recurrence than those in the CRT group. CONCLUSIONS Treatment outcomes among patients with resectable thoracic esophageal squamous cell carcinoma were comparable or superior after CRT (with salvage therapy if needed) to outcomes after surgery alone.

High incidence of reflux esophagitis observed by routine endoscopic examination after gastric pull-up esophagectomy

A gastric tube has been widely used for reconstruction of the esophagus after esophagectomy for esophageal cancer. Reflux esophagitis after esophagectomy is frequently observed. Therefore we retrospectively investigated the risk factors for reflux esophagitis after gastric pull-up esophagectomy in 74 outpatients with thoracic esophageal cancer. Reflux esophagitis was diagnosed endoscopically. Esophagitis was classified according to the Los Angeles classification. Reflux symptoms, medications, and the surgical procedure were reviewed. The relation between reflux symptoms and reflux esophagitis and the influence of the anastomotic site were evaluated. Reflux esophagitis was observed in 53 patients. Severe esophagitis (grade C or D) was found in 75.6% of these patients. Although all patients with esophagitis took antacid agents, histamine receptor-2 blocker was effective in only 35% of them. The correlation between reflux symptoms and reflux esophagitis was not significant. Reflux esophagitis was present in 56.4% of patients with neck anastomosis and in 88.6% of patients with intrathoracic anastomosis (p = 0.0039). We concluded that routine endoscopic examination is necessary after gastric pull-up esophagectomy because reflux esophagitis is not diagnosed based on reflux symptoms. When a gastric tube is used for reconstruction after esophagectomy, neck anastomosis is recommended to lower the risk of reflux esophagitis.

Expression of p53 in human esophageal carcinoma: an immunohistochemical study with correlation to proliferating cell nuclear antigen expression.

Immunolocalization of the nuclear protein p53 tumor suppressor gene product is considered to be one of the best methods of detecting a mutated form of p53. We have studied p53 immunohistochemically by using monoclonal antibody pAb1801 in 15 cases of esophageal squamous cell carcinoma. Immunoreactive p53 was observed in the nuclei of tumor cells in 4% paraformaldehyde-fixed, frozen sections (12 of 15) and paraffin-embedded sections (11 of 15), but not in routinely processed (10% formalin-fixed) specimens. p53 expression was closely correlated with the malignant phenotype, including dysplasia. p53 was not observed in histologically normal mucosa, except in three cases in which scattered immunoreactivity was observed in parabasal and basal cells. Immunostaining of ki67 and proliferating cellular nuclear antigen on adjacent tissue sections revealed that p53 expression was strongly correlated with ki67 and proliferating cellular nuclear antigen in carcinoma and dysplastic cells, but not in normal mucosa, suggesting involvement of the mutated form of p53 in the cell cycle of malignant cells. Immunohistochemical patterns of p53 were not related significantly to clinicopathologic parameters in the cases examined. Therefore, p53 expression was strongly associated with the proliferation of carcinoma cells but not with that of normal cells in esophageal carcinoma.

Radiation therapy combined with cis-diammine-glycolatoplatinum (Nedaplatin) and 5-fluorouracil for untreated and recurrent esophageal cancer.

From January 1999 to November 2000, a total of 24 esophageal cancer patients (17 untreated and 7 recurrent cases) were treated with radiation therapy (60–70 Gy) combined with cis-diammine-glycolatoplatinum (Nedaplatin) (80–120 mg/body) and 5-fluorouracil (5-FU) (500–1,000 mg/body/24 h, continuous infusion for 5 days). Grade III leukocytopenia was observed in 6 (25%) of the patients. Grade III and IV thrombocytopenia was observed in one patient each. The 1-year and 2-year survival rates for definitively irradiated patients were 59% and 39%, respectively, and for patients with postoperative recurrence 69% and 69%, respectively. High-dose radiation combined with Nedaplatin and 5-FU is a safe and effective method for treating esophageal cancer.

Dose escalation study of docetaxel and nedaplatin in patients with relapsed or refractory squamous cell carcinoma of the esophagus pretreated using cisplatin, 5-fluorouracil, and radiation

BackgroundDefinitive chemoradiation with cisplatin (CDDP) and 5-fluorouracil (5FU) has been playing an important role in the treatment of esophageal cancer, but some patients are not curable or have recurrent lesions. However, few chemotherapeutic regimens are available for such patients. Docetaxel and nedaplatin are active for esophageal cancer. We conducted a dose-escalation study of docetaxel and nedaplatin as second line-chemotherapy after definitive chemoradiation in patients with relapsed or refractory squamous cell carcinoma of the esophagus after chemoradiation.MethodsNedaplatin was administered on day 1 and docetaxel was administered on days 1 and 15, every 4 weeks. Dose escalation was based on the dose-limiting toxicity (DLT) observed during the first cycle.ResultsTwelve patients were enrolled. At a docetaxel dose of 30 mg/m2 and a nedaplatin dose of 80 mg/m2, one grade 4 neutropenia occurred and caused one treatment break longer than 2 weeks, but there were few DLTs. At doses of 35 and 80 mg/m2, respectively, two grade 4 neutropenias and one grade 2 thrombopenia occurred and caused three treatment breaks longer than 2 weeks. Therefore, the maximum tolerated dose was established at this dose level. Two grade 3 anorexias and one grade 3 nausea occurred, but other non-hematological toxicities were generally mild. Responses were seen in one-fourth of the 12 patients, including one complete remission.ConclusionThe recommended doses of docetaxel and nedaplatin were 30 and 80 mg/m2, respectively. This combination could be a potential second-line treatment for this target population.

Esophagectomy using a thoracoscopic approach with an open laparotomic or hand-assisted laparoscopic abdominal stage for esophageal cancer: analysis of survival and prognostic factors in 315 patients.

&NA;Survival and prognostic factors were analyzed in 315 patients with esophageal cancer undergoing thoracoscopic-assisted esophagectomy (TAE). The 5-year survival rate of 57.8% was satisfactory, indicating the oncological feasibility of TAE. Perioperative outcomes affected overall survival in the whole cohort but not in the subgroup treated with 2 endoscopic stages. Objective:To estimate the oncological feasibility of thoracoscopic-assisted esophagectomy (TAE) for esophageal cancer and to clarify the prognostic impact of perioperative factors after TAE. Background:Favorable perioperative outcomes of TAE versus open surgery have been demonstrated. However, survival data after TAE in a large cohort are limited, and no information on the prognostic influence of perioperative factors after TAE is available. Methods:Prospectively collected data for 315 patients undergoing TAE for esophageal cancer were analyzed. Survival was compared with the Kaplan-Meier analysis and Cox regression analysis between 2 surgical approaches: thoracoscopic and hand-assisted laparoscopic esophagectomy (THLE) and thoracoscopic and open laparotomic esophagectomy (TOE). Factors affecting overall survival were identified with Cox multivariate regression analysis in the whole cohort and the THLE subgroup. Results:THLE and TOE were performed in 153 and 162 patients, respectively. The overall 5-year survival of the whole cohort was 57.8%, with no difference between the THLE and the TOE group. Multivariate analysis of the 315 patients identified the following prognostic factors: blood loss, blood transfusion, intensive care unit stay, cardiovascular complications, pathological T and N stages, lymphatic invasion, intramural metastasis, and number of metastatic nodes. In the THLE subgroup, cerebral comorbidity, histological subtype, pathological T stage, and number of metastatic nodes were independent prognostic factors. Conclusions:TAE was oncologically feasible. Perioperative factors affected survival in the whole cohort, but did not in the THLE subgroup. However, the reduced perioperative factor effect in this subgroup would be small because the survival rates of the 2 surgical approaches were equal.

Two cases of 18 F-FDG PET/CT findings in acinar cell carcinoma of the pancreas.

The patients consisted of a 60-year-old woman and a 72-year-old man with no significant symptoms, who were both referred to the hospital due to the presence of large pancreatic tumors. They underwent F-18 FDG PET/CT and subsequently a pancreaticoduodenectomy and acinar cell carcinoma in the pancreas was proven histopathologically. In one case, the tumor consisted of a solid component presenting intense FDG uptake and necrotic tissue. In another case, the tumor consisted of cystic and papillary components presenting with weak FDG uptake. This report thus documents 2 cases of acinar cell carcinoma that showed contrasting histopathologic and F-18 FDG PET/CT findings.

Successful Management of Esophagoparaprosthetic Fistula After Aortic Surgery

Aortoesophageal fistula is a relatively rare but highly fatal condition, especially in the case of secondary aortoesophageal fistulas after previous thoracic aortic surgery in which the aortic prosthetic graft itself may be involved in the infection, resulting in an esophagoparaprosthetic fistula. In this report, we describe a complicated case of esophagoparaprosthetic fistula arising after descending thoracic aortic replacement and endovascular pseudoaneurysm repair that was successfully treated by surgical resection and in situ aortic graft replacement using a homograft completely covered with an omental flap, combined with subtotal esophagectomy and staged reconstruction of the alimentary tract. The patient has been doing well for 24 months without signs of recurrent infection.

Esophageal gastrointestinal stromal tumors (GISTs): report of three cases

Esophageal gastrointestinal stromal tumors (GISTs) are very rare. We herein report our experience of three cases of esophageal GISTs. Two women and one man were treated by radical surgery either by thoracoscopic or by thoracotomy and thereafter followed up. Both histopathological and immunohistochemical analyses of tissue specimens showed positive findings for c-kit, which confirmed the diagnosis of GISTs. The malignancy of GISTs remains a clinical problem, and various indicators for the risk for recurrence or metastasis have been reported, such as tumor size, mitotic index, and mutation of the c-kit gene. As the tumor size was markedly large in two cases whereas the other had a high mitotic level, they are thought to have malignant potential. Because all three patients have demonstrated a disease-free status for at least 25 months, surgical therapy seems to be sufficient for such patients. However, further long-term follow-up may be necessary.