Utility of weekly docetaxel combined with preoperative radiotherapy for locally advanced esophageal cancer from pathological analysis.

Esophageal squamous cell cancer (ESCC) is a high-grade carcinoma that is treated with multidisciplinary approaches, including chemoradiotherapy (CRT) followed by surgery. Despite some success with these therapies, overall survival remains poor. In order to investigate a newer CRT regimen, we designed a comparative study to evaluate preoperative CRT using docetaxel (DOC) or 5-Fluorouracil and cisplatin (FU+CDDP [FP] therapy) for treatment of resectable ESCC. In a retrospective review of patients with resectable, locally advanced ESCC, 95 patients received preoperative CRT between 2001 and 2007. CRT was administered using either FP (n = 40) or DOC (n = 55). Pathological response and clinical outcomes were compared between the two groups. Hazard ratios and time-to-event analyses were used to assess outcomes; the ratios were controlled by multivariate logistic regression analysis of potential prognostic factors, and survival was presented with Kaplan-Meier curves. In the FP group, a significant curative effect was observed on the basis of pathological examination of postoperative lesions. However, the DOC group presented a significantly better prognosis on the basis of cumulative survival rates. Logistic regression analysis revealed that the presence of five or more lymph node metastases was an independent predictor of reduced survival. Patients with lymph node metastasis exhibited a better prognosis in the DOC group than those in the FP group. Preoperative CRT for locally advanced esophageal cancer using DOC results in similar or better long-term outcomes compared with FP-based CRT. Therefore, CRT using DOC is a promising therapy option for esophageal cancer.

[Esophageal cancer surgery; importance of surgical quality control].

In esophageal cancer, the rate of lymphatic metastasis is higher than any other gastrointestinal cancer. The morbidity and mortality rate of esophageal surgery is still high. In order to reduce high morbidity and mortality rate, esophageal cancer surgery is recommended to be performed at a high-volume hospital in Europe and United States. In Japan, "3-field lymph nodes dissection surgery" has been established for complete lymphatic clearance, and the overall survival has improved. This surgical procedure is now recognized as a standard surgery for advanced esophageal cancer by "Japan Esophageal Society". However, even in Japan, the morbidity and mortality rate of esophageal cancer surgery is higher than gastric or colonic cancer surgery. For rationale of esophageal cancer surgery, we have to continue to improve our surgical quality such as preserving bronchial artery or pulmonary branches of the vagal nerve.

Flavopiridol as a radio-sensitizer for esophageal cancer cell lines.

Flavopiridol is a synthetic flavone that has shown an antitumor effect against several cancers. Here, we investigated the in vitro effect of flavopiridol alone and the combined effect of low-dose flavopiridol plus radiation on esophageal squamous cell carcinoma cell lines. Esophageal squamous cell carcinoma cell lines (TE8, TE9 and KE4) were exposed to flavopiridol (0.05-400 nmol/L) for 48 h. Growth inhibition was evaluated by MTT assay, cell cycle distribution was determined by flow cytometry, and cyclin D1, Bcl-2 and Rb protein expression was detected by Western blotting. The effect of 0.05 nmol/L flavopiridol as a radio-sensitizer was determined by clonogenic assay. The IC50 was approximately 110-250 nmol/L. Exposure to 0.05 nmol/L flavopiridol for 48 h increased the G2/M population, while 300 nmol/L increased the G1 population. At a concentration of 300 nmol/L, nuclear fragmentation and chromatin condensation were observed in all three cell lines. Exposure to 300 nmol/L flavopiridol decreased the levels of cyclin D1 and Rb protein in all three cell lines and Bcl-2 protein was also decreased in TE8 and KE4 cells. Moreover, exposure to 0.05 nmol/L flavopiridol slightly decreased the levels of cyclin D1, Rb and Bcl-2 protein in KE4 cells. Flavopiridol treatment (0.05 nmol/L) enhanced the radio-sensitivity in all three cell lines. Low-dose flavopiridol augmented the response of esophageal squamous cell carcinoma cell lines to radiation. Administration of a low dose of flavopiridol could be a potent new therapeutic approach for improving the efficacy of radiotherapy against esophageal cancer.

Successfully treated case of cervical abscess and mediastinitis due to esophageal perforation after gastrointestinal endoscopy.

Perforations of the esophagus are uncommon complications of flexible gastrointestinal endoscopy. Perforations after endoscopy are likely to occur in the cervical esophagus, where fiber insertion is difficult anatomically. The diagnosis should be made as soon as possible, because mediastinitis and sepsis frequently develop following esophageal perforations. The surgical strategies are dependent on the location of the perforations and the condition of the patients. For a successful outcome, surgery is a preferred treatment for most perforation cases, and non-operative treatment, such as antibiotics, parental nutrition, and no food intake by mouth, should be applied carefully.

Histopathologic effects of neoadjuvant therapies for advanced squamous cell carcinoma of the esophagus: multivariate analysis of predictive factors and p53 overexpression.

In 97 patients (60, chemotherapy; 22, chemoradiotherapy; 15, radiotherapy), histopathologic effects were evaluated microscopically, and histologic response rates were compared among three neoadjuvant treatment modalities. Predictive factors for neoadjuvant therapies were analyzed by logistic regression, including the results of p53 immunohistochemical staining. In the chemoradiotherapy group, the pathologic response rate was 86.4%, and was significantly higher than that for chemotherapy (P < 0.0001) or for radiotherapy (P = 0.0031). In patients with normal p53 protein expression, the histopathologic response rate to chemotherapy was 20.0%, a higher rate than that for patients with abnormal p53 overexpression. In the chemoradiotherapy or radiotherapy group, however, the response rates were almost the same, irrespective of p53 oncoprotein status. From multivariate analysis, the neoadjuvant treatment modality itself was identified as the most powerful predictive factor for the effect. Chemoradiotherapy had the most powerful effect on advanced esophageal cancer, and p53 status did not influence the clinical outcome in this group.

Metastatic gastrinoma to the liver 20 years after primary resection.

Gastrinoma is a rare endocrine tumor that is frequently associated with liver metastasis. The liver metastasis is usually seen simultaneously or soon after a primary operation. A 47-year-old woman who had had a total gastrectomy 20 years earlier developed liver metastasis. An interval of this length between surgery and metastasis is extremely rare. The total gastrectomy prevented the patient from developing the usual symptoms of hypergastrinemia that would have enabled early diagnosis of the metastasis. Laboratory examinations on admission revealed a high serum gastrin concentration (1500 pg/ml). Computed tomography showed an irregularly enhanced mass lesion with an uneven, low-density central area in the right anterior inferior segment of the liver. An extended right hepatectomy was performed. Intraoperative ultrasonography showed no abnormalities in the remnant pancreas. Examination of the cut surface of the specimen revealed a yellow, firm, elastic tumor, 55 mm in diameter. The interior of the tumor appeared necrotic. Histopathologically, the tumor was composed of cells with hyperchromatic, dysplastic nuclei arranged in a trabecular pattern with nest formation. Gastrin staining was positive. A histologic diagnosis of metastatic gastrinoma was made. The patient's gastrin concentration returned to normal and she was well at 2-year follow-up.

Cytokine immunotherapy of cancer with controlled release biodegradable microspheres in a human tumor xenograft/SCID mouse model.

A novel biodegradable poly(lactic acid) microsphere formulation was evaluated for in vivo cytokine immunotherapy of cancer in a human tumor xenograft/ severe combined immunodeficiency (SCID) mouse model. Co-injection of interleukin-2 (IL-2)-loaded microspheres with tumor cells into a subcutaneous site resulted in the complete suppression of tumor engraftment in 80% of animals. In contrast, bovine-serum-albumin(BSA)-loaded particles or bolus injections of poly(ethylene glycol)/IL-2 were ineffective in preventing tumor growth. The antitumor effect of IL-2 released by the microspheres was shown to be mediated by the mouse natural killer cells. This is the first evidence that the rejection of human tumor xenografts can be provoked by the sustained in vivo delivery of IL-2 from biodegradable microspheres. The use of poly(lactic acid) microspheres to deliver cytokines to the tumor environment could provide a safer and simpler alternative to gene therapy protocols in the treatment of cancer.

Antitumor immune response of human peripheral blood lymphocytes coengrafted with tumor into severe combined immunodeficient mice.

Here, it is established that human peripheral blood lymphocytes (HuPBLs), injected s.c. with a human lung tumor into severe combined immunodeficient (SCID) mice, engraft and display antitumor cytotoxic activity. Initial studies used HuPBLs from normal donors and an allogeneic tumor cell line derived from biopsy tissue of a patient with a squamous cell carcinoma of the lung. Evidence of HuPBL antitumor activity was revealed by a cell dose-dependent suppression of the tumor xenograft. Tumor suppression was shown to be dependent upon both CD8+ T cells and CD56+ natural killer cells in the donor HuPBLs. By titrating the antitumor activity of HuPBLs in SCID mice with and without cytokines, it was established that interleukin (IL)-12 enhanced the HuPBL-mediated tumor suppression and that IL-2 had a synergistic effect upon the IL-12 enhancement of cytotoxicity. Subsequent studies revealed that a lung cancer patient's PBLs also suppress the growth of the patient's (autologous) tumor when coinjected s.c. with the tumor cells into SCID mice. The patient's antitumor immunity was shown to be mediated by CD8+ T cells and CD56+ natural killer cells. The data presented here indicate that the s.c. coengraftment of HuPBLs and tumor into SCID mice represents a viable model with which to study (and to periodically monitor) patients' immune responses to their tumors for extended periods of time and suggest that this SCID/Winn assay could be used to evaluate novel immunotherapeutic approaches, such as bolus injections of cytokines, cytokine gene therapy, or vaccination strategies for the treatment of human cancer.

Evaluation and optimization of different cationic liposome formulations for in vivo gene transfer.

Five commonly used cationic liposome formulations were tested for their ability to deliver DNA to established subcutaneous human tumor xenografts in SCID mice. Liposomes were complexed with a mammalian expression plasmid containing the bacterial beta-galactosidase gene and delivered to tumors by direct injection. The optimal lipid to DNA ratios in vivo were markedly different than those observed in vitro for each liposome formulation. Tumor size at the time of inoculation also effected transfection efficiency significantly. Of the five liposome formulations tested, DC-Cholesterol was found to be superior to all others in vivo. Even under optimal conditions however, the efficiency of in vivo transfection was low in our system (approximately 0.3%). Implications of these results for in vivo gene therapy of tumors are discussed.

Induction of tumor-specific cytotoxic T lymphocytes and natural killer cells by tumor cells transfected with the interleukin-2 gene.

To study the antitumor effect of local production of interleukin-2 (IL-2) from tumor cells, the poorly immunogenic murine colon cancer cells, colon26, was transfected with murine IL-2 cDNA in a bovine papilloma virus vector. IL-2 gene transfectants (mIL2 + colon26) did not alter their growth rate compared with parental colon26 cells in vitro, but reduced their tumorigenicity in vivo. Immunization with mIL2 + colon26 cells could induce protective immunity against parental colon26 cells. Following intravenous challenges, the colonies of lung metastasis were also inhibited. Moreover, inoculation of mIL2 + colon26 cells slowed the growth of challenged renal cell carcinoma cells, RenCa. Intraperitoneal inoculation of IL-2 gene transfectants generated a large number of peritoneal exudate cells and these cells had a highly cytolytic activity against colon26 and YAC-1. These results suggest that inoculation with IL-2 transfected tumor cells can stimulate not only cytotoxic T lymphocytes but also natural killer cells, and that these cells will act as antitumor effector cells in host animals.