Relationships between radiosensitivity and microvascular density in esophageal carcinoma: significance of hypoxic fraction

PURPOSE: The prognosis and the radiosensitivity of macroscopically infiltrative type of esophageal carcinoma are worse than those of the localized type of esophageal carcinoma treated with irradiation. The aim of this study was to investigate the cause of differences in radiosensitivity and prognosis of esophageal carcinoma according to macroscopic type from the viewpoint of tumor angiogenesis. METHODS AND MATERIALS: A total of 40 surgically resected esophageal carcinoma tissues with good material remaining were selected at random from macroscopically localized type (n = 20) and infiltrative type (n = 20) of esophageal carcinoma. The highest intratumoral microvascular density (h-MVD), average intratumoral microvascular density (a-MVD), Ki67 labeling index, and expression of vascular endothelial growth factor (VEGF) in each section were estimated. RESULTS: h-MVD was significantly (p = 0.0006) greater in the infiltrative type than in the localized type, whereas a-MVD (p = 0.0014) and Ki67 labeling index (p = 0.022) were significantly lower in the infiltrative type than in the localized type. The expression level of VEGF was significantly (p < 0.0001) higher in the infiltrative type. CONCLUSIONS: The generally underdeveloped vascular densities with low proliferation activities (suggesting increase of hypoxic fraction) seemed to be one of the reasons for unfavorable radiosensitivities of infiltrative type of esophageal carcinoma. The infiltrative type of esophageal carcinoma shows a high level of VEGF expression and high activity of tumor angiogenesis. The locally enhanced neovascularization, which occurs frequently in hematogenous metastasis seemed to be one of the reasons for the unfavorable prognosis of the infiltrative type of esophageal carcinoma.     

Weekly paclitaxel and nedaplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer: a phase I/II study

OBJECTIVE: The purpose of this study was to determine the safety and efficacy of nedaplatin and paclitaxel when given concurrently with radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC). METHODS: Nedaplatin was administered at a fixed dose of 20 mg/m(2), and paclitaxel was administered at a starting dose of 30 mg/m(2) with an incremental increase of 5 mg/m(2) until dose-limiting toxicity (DLT) occurred in more than one-third of the patients. The chemotherapy was administered once a week for 6 weeks. The RT was given at a single daily dose of 2 Gy for 5 days per week. The pharmacokinetics of nedaplatin and paclitaxel were investigated. RESULTS: Overall, 20 patients were recruited and assigned to three different treatment groups: group 1 (paclitaxel 30 mg/m(2)), group 2 (paclitaxel 35 mg/m(2)) and group 3 (paclitaxel 40 mg/m(2)). Pulmonary toxicity was the main toxicity which occurred in 16 of 20 patients. In group 3, grades 3 and 4 pulmonary toxicity occurred in two of six patients and grade 3 esophagitis in one patient. The maximum tolerated dose of paclitaxel in this study was 40 mg/m(2) and the recommended dose of paclitaxel was therefore 35 mg/m(2). Four complete and 11 partial responses were observed, resulting in a 75% overall response rate. The area under the concentration-time curve of paclitaxel in group 3 was significantly higher than that in group 1. CONCLUSION: Nedaplatin 20 mg/m(2) and paclitaxel 35 mg/m(2) could be safely administered for NSCLC with concurrent thoracic RT, and this regimen was effective. The most important DLT was pulmonary toxicity.     

A late phase II clinical study of S-1 in patients with progressed, refractory breast cancer

A late phase II clinical study of S-1 against advanced or refractory breast cancer was done by 37 institutes in Japan. S-1 was administered twice daily at 80, 100 or 120 mg/body/day consecutively for 28 days followed by 14 days of rest (1 course). Eighty-three patients were enrolled and 81 were eligible for the study. The response ratio was 42.0% with 6 CR and 28 PR and its 95% confidence interval for the response was 31.1 to 53.5%. The median survival period was 910 days (95% confidence interval was 493-1, 083 days). The observed major adverse reactions (> or = grade 2) were as follows: hematological toxicities: leukopenia 21.0% (17/81), neutropenia 28.4% (23/81), erythropenia 4.9% (4/81); gastrointestinal toxicities: anorexia 9.9% (8/81), nausea and vomiting 12.3% (10/81), diarrhea 8.6% (7/81), stomatitis 1.2% (1/81), and fatigue 8.6% (7/81). The severe adverse reactions (> or = grade 3) were as follows; hematological toxicities: neutropenia 8.6% (7/81), anorexia 4.9% (4/81), fatigue 3.7% (3/81), nausea and vomiting 1.2% (1/81), diarrhea 1.2% (1/81), stomatitis 1.2% (1/81). Grade 4 adverse reactions (neutropenia and fatigue) were observed only in 1 patient. The ratio without hospitalization was 87.7%. These results strongly suggest the superior efficacy and safety of S-1 against patients suffering from advanced, refractory breast cancer. Therefore, S-1 may be a new therapeutic agent to prolong the survival period of breast cancer patients due to its high antitumor activity and low toxicity.     

A devised method of hepatic and splenic arterial infusion chemotherapy after transcatheter peripancreatic arterial embolization for patients with advanced pancreatic cancer

We previously reported the clinical efficacy based on hepatic and splenic arterial infusion chemotherapy (HSAIC) for patients with advanced pancreatic cancer after transcatheter peripancreatic arterial embolization (TPPAE). However, this medical treatment pointed out a few problems in which the method had its complexity and a limited use of embolus micro-coil numbers. Then, we tried to improve the method in solving those problems. In order to reduce the embolus micro-coil numbers for TPPAE, we divided the micro-coil into several parts. We also devised the method of HSAIC. We used one catheter with a side hole, so that the catheter was able to supply a therapeutic drug for arterial infusion chemotherapy, both to the common hepatic artery and splenic artery. The effective rate for eleven cases was 72.7%, and there were no significant differences from the cases treated with the conventional method of TPPAE-HSAIC. Therefore, the devised treatment was considered to be an easy and useful method for TPPAE and HSAIC.     

Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

The putative tumor suppressor CDKN1C is an imprinted gene at 11p15.5, a well-known imprinted region often deleted in tumors. The absence of somatic mutations and the frequent diminished expression in tumors would suggest that CDKN1C expression is regulated epigenetically. It has been, however, controversial whether the diminution is caused by imprinting disruption of the CDKN1C/LIT1 domain or by promoter hypermethylation of CDKN1C itself. To clarify this, we investigated the CpG methylation index of the CDKN1C promoter and the differentially methylated region of the LIT1 CpG island (differentially methylated region (DMR)-LIT1), an imprinting control region of the domain, and CDKN1C expression in esophageal cancer cell lines. CDKN1C expression was diminished in 10 of 17 lines and statistically correlated with the loss of methylation at DMR-LIT1 in all but three. However, there was no statistical correlation between CDKN1C promoter MI and CDKN1C expression. Furthermore, loss of CpG methylation was associated with loss of histone H3 lysine 9 (H3K9) methylation at DMR-LIT1. Histone modifications at CDKN1C promoter were not correlated with CDKN1C expression. The data suggested that the diminished CDKN1C expression is associated with the loss of methylation of CpG and H3K9 at DMR-LIT1, not by its own promoter CpG methylation, and is involved in esophageal cancer, implying that DMR-LIT1 epigenetically regulates CDKN1C expression not through histone modifications at CDKN1C promoter, but through that of DMR-LIT1.     

Famotidine and long QT syndrome

Numerous drugs have been implicated in causing a prolonged QT interval and Torsades de pointes. However, the association of famotidine and acquired long QT syndrome has rarely been reported. We report 2 cases of famotidine-associated acquired long QT syndrome.     

Repeated epicardial coronary artery endothelial injuries lead to a global spontaneous coronary artery spasm

OBJECTIVES: This study was conducted to develop a spontaneous coronary spasm model. MATERIALS AND METHODS: Balloon endothelial denudation was carried out in the epicardial left anterior descending coronary artery (LAD) every 2 weeks, for a total of four times, in 12 pigs. Changes in the denuded site diameter and LAD blood flow caused by acetylcholine or serotonin were assessed before each denudation and at week 8. Blood pressure, electrocardiogram (ECG) from the LAD area and LAD blood flow were monitored continuously in conscious and unrestrained pigs. RESULTS: Spontaneous ECG ST depression with a decrease in LAD blood flow appeared at around 2 weeks. In accordance with this, 0.5 microg/kg acetylcholine induced similar ECG and LAD blood flow changes without denuded site narrowing, suggesting microvascular spasm. Thereafter, ECG ST depression or elevation by serotonin via a denuded site spasm was found after 6 weeks and spontaneous ECG ST changes due to epicardial coronary artery spasm were observed. CONCLUSION: Epicardial coronary artery endothelial injury may induce spontaneous vasospasticity in the downstream coronary microvessels as well as in the denuded portion, suggesting functional abnormality through the entire coronary arterial tree.     

Immunohistochemical study of characteristics of bile duct dysplasia evaluated on the basis of expression of metastasis/invasion-related factors and <Emphasis Type="Italic">p53</Emphasis>

Background/Purpose

Bile duct carcinoma still continues to have an unfavorable prognosis, despite an improved rate of curative resection and the development of surgical techniques. We evaluated the expression of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and intercellular adhesive factors (E-cadherin, α-catenin, β-catenin) in cancer, dysplastic lesions, and normal (nonatypical) epithelia (glandulous ducts) in patients with bile duct carcinoma. Positivity rates for these factors were compared among the three histological types to examine the characteristics of bile duct dysplasia.

Methods

Among 89 patients with bile duct carcinoma resected at our hospital during the past 10 years, we studied 18 patients who concurrently had a cancerous lesion, dysplastic lesion, and normal (nonatypical) epithelia adjoining each other in excised specimens. The immunohistochemical expressions of MMPs, TIMPs, E-cadherin, α-catenin, and β-catenin were investigated.

Results

Positivity rates for MMP-9, TIMP-1, TIMP-2, membrane type (MT) 1-MMP, MT2-MMP, and E-cadherin were significantly higher in cancerous than in normal epithelium. Only the positivity rate for MT1-MMP was significantly higher in dysplasia than in normal epithelium. Positivity for MMP-related factors correlated with the degree of atypia of the bile duct epithelium. Differences between cancer and dysplasia were slightly greater than those between dysplasia and normal epithelium. Likelihood ratios between cancer and dysplasia, cancer and normal epithelium, and dysplasia and normal epithelium were higher than 5 for all metastasis-related factors and higher than 10 for most factors. This finding suggests that a normal-dysplasia-carcinoma sequence underlies the development of bile duct cancer accompanied by dysplasia.

Conclusions

The phenotypic characteristics of dysplasia are closer to those of normal epithelium than to those of cancerous epithelium. A normal-dysplasia-carcinoma sequence is apparently involved in the development of bile duct cancer accompanied by dysplastic cells.