No abstract

Background: Previously, we indicated that stromal genetic instability might contribute to tumorigenesis of both sporadic and ulcerative colitis associated colorectal adenocarcinomas. Considering the established adenoma-adenocarcinoma sequence, in this study we analysed genetic instability in colorectal adenoma cells and surrounding stroma. Methods: In 164 colorectal tumours (34 hyperplastic polyps, 38 tubular adenomas with low grade dysplasia (TA-L), 51 tubular adenomas with high grade dysplasia (TA-H), and 41 invasive carcinomas), epithelial and stromal genetic instability with National Cancer Institute standard microsatellite markers and chromosome 17 (Chr17) markers, were analysed by a combination of laser capture microdissection and GeneScan approaches. Results: While frequencies of both loss of heterozygosity (LOH) and microsatellite instability (MSI) were extremely low in hyperplastic polyps, LOH in tubular adenomas was detected in both epithelial (TA-L 13.2%, TA-H 27.5%) and stromal (5.3% and 5.9%, respectively) elements, along with MSI (5.3% and 13.7%, and 5.3 and 5.9%, respectively). Frequencies of epithelial alterations were higher in TA-H than in TA-L, and greatest in the carcinoma group. On the other hand, frequencies of stromal LOH or MSI were almost constant (5.3% , 17.1%, 5.3% , 17.1%, respectively) in adenomas and invasive carcinomas. In addition, p53 was found to be significantly overexpressed in a greater proportion of TA-L with LOH than in those without genetic instability. Conclusion:The results indicate the presence of genetic alterations in stroma from an early stage of carcinogenesis, accompanied by stepwise increasing genetic instability of epithelia with progression to cancer. Thus microenvironmental changes due to genetic alteration in Chr17 markers in stromal cells may play an important role in colon adenoma and adenocarcinoma development.

In 1963, a strain of SHR rats which developed spontaneously hypertension was isolated from Wistar rats by Okamoto and Aoki (JPN CIRC J 27: 282, 1963).In preliminary studies to investigate T-lymphocyte markers in rats we noted that SHR rats had reduced numbers of rosette forming cells in their thymuses when compared to other rat strains (CELL IMMUNOL 27: 52, 1976). Additional studies were undertaken to more clearly determine if additional impairment of immunological functions existed in this rat strain with hypertension.The percentage of rosette forming cells in the thymus and in the spleen of the eight strains was tested.In seven rat strains, about 60% thymus cells formed rosettes with guinea pig erythrocytes, whereas with the SHR rat strain only 18% of thymus cells formed rosettes.W/Mk rats, the original colony of the SHR rats, had 63% rosette formation.None of the strains showed any rosette forming cells in their spleens.The number of rosette forming cells progressively decreased with age. The blastogenesis of SHR rat lymphocytes to PHA and Con A was less than one fifth to that of the other rat strains including W/Mk rats, the original colony of SHR rats.Lymphocytes from 8-month-old SHR rats had significantly lower blastogenic responses than did lymphocytes of 2-monthold SHR rats. aFour month old rats were used . Table shows the results of antibody responses to SRBC of the SHR and other rat strains using the direct plaque-forming assay. Antibody responses of the 4 month old SHR rats was about one tenth to that of the other 6 rat strains. Delayed type hypersensitivity responses of SHR rats to SRBC were measured using the radioisotopic footpad assay. The footpad reaction of immunized SHR rats was significantly lower than that of immunized WKA rats. Ability of SHR rats to reject alloskin grafts was also investigated.The number of mean survival days of allogeneic skin from F344 rats was significantly prolonged when compared to WKA rats (data not presented). (Summary)The thymuses of young SHR rats before developing hypertension had reduced numbers of immature T-lymphocytes which were detected by the rosette formation test with guinea pig erythrocytes, whereas the thymuses of other eight rat strains tested contained about 60% rosetting cells. The number of rosetting cells progressively decreased with age. The blastogenic responses to PHA of the SHR rat lymphocytes was depressed to less than one fifth when compared to those of other rat strains including W/Mk rats, the original colony of the SHR rats.Other cell-mediated immune responses, including delayed hypersensitivity, allograft rejections, and a cooperation of T-and B-lymphocytes to produce humoral antibody formation were significantly depressed when compared to those of other rat strains. 590

The benefits of immunochemotherapy with a penicillin-treated, lyophilized preparation of Streptococcus pyogenes, OK-432 (Picibanil), were reassessed in patients with resected non-small-cell lung cancer through a meta-analysis based on data from 1,520 patients enrolled in 11 randomized clinical trials. All 11 trials were started before 1991, and the subjects had been followed up for at least 5 years after surgery and randomization. In these trials, standard chemotherapy was compared with the same therapy plus OK-432. The endpoint of interest was overall survival, and analysis was based on intent-to-treat population without patient exclusion. Data were analyzed using the Mantel-Haenszel method. The 5-year survival rate for all eligible patients in the 11 trials was 51.2% in the immunochemotherapy group versus 43.7% in the chemotherapy group. The odds ratio (OR) for overall survival was 0.70 (95% CI = 0.56-0.87, p = 0.0010). Analysis of four trials in which central randomization was performed also reconfirmed a significantly longer survival time for the immunochemotherapy group (OR = 0.66, 95% CI = 0.44-1.00, p = 0.049). Based on these results of meta-analysis, it is postulated that postoperative adjuvant immunochemotherapy using OK-432 might improve the survival of patients after resection of non-small-cell lung cancer.