Several endogenous and exogenous aggravating factors have been implicated in patients with refractory asthma. The aim of the present study was to identify which comorbid factors are associated with frequent asthma exacerbation in patients with refractory asthma. Thirteen clinical and environmental factors possibly associated with asthma exacerbation were analyzed using a systematic protocol in 63 patients with refractory asthma, as defined by American Thoracic Society criteria, as well as in 65 patients with well-controlled asthma. Aspirin intolerance, psychological dysfunction, recurrent respiratory infection, and hormonal effects were significantly more prevalent in patients with refractory asthma compared with patients with well-controlled asthma. Factors found to be significantly associated with frequent exacerbation during the previous year in Japanese patients with refractory asthma were psychological dysfunction, aspirin intolerance, gastroesophageal reflux, and recurrent respiratory infection. Thus, rigorous treatment of these comorbid factors may result in improvements in refractory asthma.

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The purpose of this study was to identify a predictor of the curative effect of preoperative chemoradiotherapy (CRT) followed by surgery in patients with esophageal squamous cell carcinoma (SCC). We investigated the correlation between the type of variations in serum SCC-antigen (SCC-Ag) levels during preoperative CRT and the response to preoperative CRT. A total of 30 patients with pathological stage I, II or III SCC who underwent a complete thoracoscopic esophagectomy were enrolled in this study. They were administered preoperative CRT, consisting of chemotherapy with a combination of low dose nedaplatin and 5-fluorouracil, and concurrent radiotherapy with a total dose of 30-40Gy. Serum samples were obtained before the initiation of preoperative CRT and after the completion of all the CRT courses (before the surgery). Patients who experienced a ≥20% increase in the serum SCC-Ag level during preoperative CRT had a lower disease-free survival rate than those with no increase. However, the overall survival rates did not significantly vary between the 2 groups of patients. These findings were also present among patients whose serum SCC-Ag levels were below the cut-off value (1.5 ng/dL). In conclusion, the type of variations in serum SCC-Ag levels appears to be useful for predicting the recurrence of esophageal SCC.

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Isolated tumor cells are often found in the regional lymph nodes of colorectal cancer, although their prognostic significance remains unclear. There isolated cells may be derived from undifferentiated cancer cells or small cell clusters (“budding”) at the invasive front. The current study explored the intermediate part of this cancer cell pathway from budding cancer cells to regional lymph nodes. Immunohistochemistry with an anti-cytokeratin antibody was used to examine 864 lymph nodes from 43 budding-positive patients with TNM stage II colorectal cancer. Clinicopathological features were compared between tumors with isolated tumor cells and those without isolated tumor cells. The frequency and number of isolated tumor cells in lymphatic vessels were also assessed by immunostaining with the anti-human lymphatic endothelial cell D2-40 antibody. Isolated tumor cells were detected in 18 lymph nodes (2%) from 11 patients (23% of total patients). Those tumors having isolated tumor cells in lymph nodes were characterized by depth of tumor invasion, lymphatic invasion, and pattern of tumor growth. Multivariate analysis showed that only lymphatic invasion was independently associated with the presence of isolated tumor cells. Further immunostaining of the gamma2 chain of laminin-5 showed that the degree of budding was closely related to the number of isolated tumor cells. Furthermore, the gamma2 chain of laminin-5 was expressed in most of budding cancer cells, cancer cells in lymphatic vessels, and the isolated tumor cells in the regional lymph nodes, with all showing similar expression patterns. This study suggested that isolated tumor cells are derived from budding cells at the invasive front derived from cancer cells in lymphatic vessels.

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The majority of colorectal carcinomas develop from preexisting polypoid adenomas, although some colorectal carcinomas can arise from flat or depressed neoplasias. In general, flat or depressed lesions are smaller than polypoid adenomas. The aim of this study is to clarify clinicopathologic characteristics of small advanced colorectal carcinoma. Patients with small advanced carcinoma were retrospectively recruited from 1,078 consecutive patients who had undergone surgical resection. Small advanced carcinomas were defined as those where the tumor size was 2cm or less in diameter and where the tumor had invaded the muscularis propria (pT2) or beyond (pT3-4). These carcinomas were classified as polypoid growth (PG) or non-polypoid growth (NPG) carcinomas. Among the 1,078 carcinoma cases there were 58 (5.4%) cases of small advanced carcinoma of which 13 (22%) were PG carcinomas and 45 (78%) were NPG carcinomas. The prevalence of pT3 invasion was significantly higher in NPG (17 of 45; 38%) than in PG carcinomas (1 of 13; 8%, P=0.04). The incidence of vascular invasion was also significantly higher in NPG (40 of 45; 89%) than in PG carcinomas (8 of 13, 62%; P=0.02). Approximately 80% of small advanced colorectal carcinomas were NPG carcinomas. A review of the clinicopathologic characteristics of small NPG carcinomas demonstrated that these tumors have a high incidence of vascular invasion with infiltration into deep tissue layers.

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We evaluated the galectin-3 expression patterns and their clinicopathologic significance in patients with gastric cancer. The study included 89 patients with gastric cancer that had been surgically resected. Based on Lauren's classification, 36 patients had intestinal-type cancer and 53 patients had diffuse-type cancer. Lymph node metastasis was observed in 47 patients. The expression of galectin-3 was determined immunohistochemically. Galectin-3 expression was observed in all 89 patients. Comparison of the groups of patients showing a high expression level of galectin-3 (high-expression group) and a low level of galectin-3 expression (low-expression group) showed that the low-expression group had significantly poorly differentiated tumors (P=0.0223) , more advanced histologic T factor (P=0.0236) , and higher rates of lymph node metastasis (P=0.0003). Moreover, when the staining patterns in the high-expression group were classified as diffuse or scattered, significantly poorly differentiated tumors (P < 0.0001) , more advanced histologic T factor (P=0.0165) , and higher rates of lymph node metastasis were observed in the subgroup with the scattered pattern of staining. Moreover, for intestinal-type cancer in the high-expression group, the rate of lymph node metastasis was significantly higher (P=0.001) in the scattered staining pattern subgroup. Our results suggest that tumor growth and metastasis rate are low if galectin-3 is expressed widely and diffusely in the tumor, and that the function of galectin-3 is to inhibit cancer growth. In contrast, prognosis is poor when galectin-3 is expressed in either a small area or over a large area but in a scattered pattern.

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Infection with hepatitis C virus (HCV) is associated with lymphoproliferative disorders (LPD). Several abnormalities of LPD markers and clonal expansion of B cells are observed not only in HCV infected patients with LPD but also in asymptomatic patients, suggesting that reliable markers for B cell proliferation are required. Recently, serum B cell activating factor (BAFF) has been reported as a marker of B cell proliferation. Serum BAFF levels in European patients with HCV infection were reported higher than those in healthy subjects. In this study, we assessed serum BAFF levels in 75 Japanese patients with chronic hepatitis C (CH-C) and analyzed the associated factors with high levels of BAFF. Results showed that serum BAFF levels in patients with CH-C were higher than those in control subjects (1,560.5±153.1 vs. 891.4±55.6pg/ml, P < 0.001). Interferon-based therapy rapidly increased levels of BAFF during the therapy. BAFF levels were neither correlated with levels of other LPD markers (cryoglobulinemia, rheumatoid factor, complement 4 and CH₅₀) nor the B-cell clonality. Decreased number of platelets and cirrhosis were correlated with high levels of serum BAFF, suggesting that the progression of liver diseases might induce the release of BAFF. Serum BAFF levels in patients with other liver diseases, autoimmune hepatitis and primary biliary cirrhosis, were also higher than those in controls (AIH, 1,084.8±77.6, P < 0.05; PBC, 1,970.3±202.6pg/ml, P < 0.001). In conclusion, HCV infection and/or the progression of hepatic inflammation stimulate the release of BAFF. This release is further enhanced by interferon which is associated with the development of LPD and autoimmune diseases.

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The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2) affect the metabolism of alcohol. The inactive ALDH2*1/2*2 heterozygote genotype increases the risk of esophageal squamous cell carcinoma because of accumulation of acetaldehyde. The aim of this prospective study was to investigate whether daily alcohol consumption and the genetic polymorphisms of ALDH2 were risk factors for esophageal squamous intraepithelial neoplasia, as low-grade intraepithelial neoplasia (LGIN) is considered to be an initial lesion of esophageal squamous cell carcinoma. Lugol chromoendoscopy was performed in 400 subjects at Showa University Hospital from January 2004 to August 2008. The effects of smoking, alcohol consumption, and ALDH2 genotype were evaluated in subjects with high-grade intraepithelial neoplasia (HGIN) , LGIN, and controls without neoplasia. Of the 400 subjects, 32 (8%) had HGIN, 21 (5%) had LGIN, and 347 (87%) were controls. There were no significant differences in the proportion of male subjects, or the prevalence of smoking, drinking, or the ALDH2*1/2*2 genotype between LGIN subjects and controls. In contrast, the prevalence of ALDH2*1/2*2 was significantly higher in HGIN (24/32, 75%) than in LGIN subjects (8/21, 38%; P = 0.007). Furthermore, the prevalence of alcohol consumption plus ALDH2*1/2*2 differed significantly between HGIN (20/25, 80%) and LGIN (3/12, 25%; P = 0.001) , while there was no significant difference between LGIN and controls. Daily alcohol consumption and the ALDH2*1/2*2 genotype were not risk factors for LGIN, however, alcohol consumption was a high-risk factor for HGIN in subjects with ALDH2*1/2*2.

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