Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX.

We evaluated the expression patterns of proapoptotic BAX, antiapoptotic Bcl-2 and p53, the proposed upstream effector of these molecules, as potential prognostic markers in UICC stage III colon cancer by immunohistochemical staining. To identify high-frequency microsatellite instability (MSI+) individuals, we performed single-strand conformation polymorphism-based analysis for BAT26. A total of 188 patients who had received 5-fluorouracil (5-FU)-based adjuvant chemotherapy (5-FU/folinic acid or 5-FU/levamisole) were enrolled. Median follow-up was 84.5 months. We found that BAX, Bcl-2 and p53 protein expressions were high or positive in 59, 70 and 50% of 188 cases, respectively. MSI+ tumours were detected in 9% of 174 evaluable patients. BAX or Bcl-2 was correlated with a higher degree of differentiation or left-sided tumours (P=0.01 or P=0.03, respectively); MSI was correlated with right-sided tumours (P<0.0001). In contrast to p53, Bcl-2, or MSI, low BAX, advanced pN category, low grade of differentiation and treatment with 5-FU/levamisole were univariately associated with poorer disease-free survival (DFS) (P=0.0005, P=0.001, P=0.005 and P=0.01, respectively) and poorer overall survival (OS) (P=0.002, P=0.0001, P=0.003 and P=0.02, respectively). Besides pN category and treatment arm, BAX was an independent variable related to both OS and DFS (P=0.003 and P=0.001, respectively). In both univariate and multivariate analysis, the p53-/BAX high in comparison with the p53+/BAX high subset conferred a significantly improved DFS (P=0.03 and P=0.03, respectively) as well as a marginally improved OS (P=0.07 and P=0.08, respectively). BAX protein expression may be of central significance for clinical outcome to 5-FU-based adjuvant chemotherapy in stage III colon cancer, and bivariate analysis of p53/BAX possibly may provide further prognostic evidence.

Molecular lesions in colorectal cancer: impact on prognosis? Original data and review of the literature.

BACKGROUND: In the Dukes' B and C stages of colorectal carcinoma there are considerable variations in the observed courses of the disease. Since post-operative chemotherapy in patients with Dukes' C (node-positive) colon carcinoma has been demonstrated to be effective in improving overall-survival, a more exact prognosis assessment gains additional significance and therapeutic relevance. DISCUSSION: One also hopes to derive improved prognostic factors from the clarification of the molecular pathogenesis. Because of its frequency and the accessibility and recognizability of its developmental stages colorectal carcinoma is among the best investigated of all solid tumors. Despite a multitude of suggested molecular candidate markers none of these changes has yet been able enter the everyday life of the clinic. However, it is to be expected that some of the molecular alterations presently discussed will gain importance before long in the clinical treatment of patients with colorectal carcinoma. CONCLUSION: Considering also our own findings, this review presents the latest developments in the scientific discussion of the tumor suppressor/oncogenes p53, k-ras, and DCC, biochemical determinants of the 5-fluorouracil metabolism, and defects of the DNA repair system.

The prognostic value of S-phase fraction in preoperative radiotherapy of rectal cancer.

The aim of this study was to analyze the flow cytometric S-phase fraction (SPF) in rectal tumors before and after preoperative radiotherapy (15x2 Gy) and to compare the findings to the clinical outcome. Archival specimens from 84 cases, treated from 1980 to 1988 with S-phase data and complete follow-up were reviewed. There was no significant correlation between SPF and clinicopathological factors. The median SPF for the 26 diploid tumors before irradiation was 6.6%+/-3.1, compared to a significantly higher median for the 58 preirradiated aneuploid tumors (20.3%+/-6.1; p<0.0001). With a median follow-up of 6 years, there was a significant difference in the number of recurrences for aneuploid tumors with a pretreatment SPF < and >20.3 (51.7% vs. 20.7%; p=0.029), which also led to a significant difference in recurrence-free survival (p=0.05). For diploid tumors, a reduction in the percentage of cells in S-phase after radiation resulted in a borderline significant lower number of recurrences (p=0.06). It is concluded that pretreatment S-phase measurements may be of predictive value especially for aneuploid tumors. An alteration in SPF after radiotherapy may also be helpful in predicting outcome and planning therapy.

Alteration of DNA ploidy status and cell proliferation induced by preoperative radiotherapy is a prognostic factor in rectal cancer.

To identify predictors of prognosis after preoperative radiotherapy, DNA ploidy and cell proliferation were investigated in 116 patients with rectal cancer. For flow cytometry, a nuclear suspension was prepared by pepsin digestion of paraffin samples of biopsies taken before preoperative radiotherapy (15 x 2 Gy) and also of the resected rectal tumors after radiotherapy. The median follow-up period was 6 years. The proportion of tumor necrosis was evaluated in histological sections before and after irradiation. There was a significant decrease (74 to 48%) in aneuploid tumors after radiation. Of 86 patients with aneuploid biopsies, 28 revealed no reduction in the proportion of aneuploid tumor cells [group AN(=/increase)], and 58 showed a reduction (mean 48.9%) or complete elimination of aneuploid tumor cells [group AN(decrease/psi)]. The incidence of local or distal failure was significantly reduced in the group AN(decrease/psi) (7.8%/20%), compared with the group AN (=/increase) (27%/54%) and the group of constant diploid tumors (n = 22; 13.6%/31.8 %; P = 0.034). There was a trend of decreased recurrence rate in diploid tumors with a reduced fraction of cells in S-phase after radiotherapy. Survival was significantly increased in group AN(decrease/psi) (P < 0.0001). In a multivariate regression analysis, variables of independent prognostic significance were increased proportion of necrosis after irradiation and DNA ploidy group and the postoperative tumor stage. These results suggest that alterations in tumor DNA ploidy and cell proliferation induced by preoperative radiotherapy might help to identify patients likely to benefit from preoperative radiation in rectal cancer.

Influence of p53 status on prognosis in preoperatively irradiated rectal carcinoma.

BACKGROUND: Even when they are analogous in microscopic and macroscopic appearance, tumors vary in their response rates to radiotherapy. Cell culture and xenograft experiments with colorectal cell lines have demonstrated that wild-type p53 increases radiosensitivity. Hence, the authors investigated, in a well-defined population of patients treated at the same institution, whether p53 status was a prognostic factor in preoperatively irradiated rectal carcinoma patients. METHODS: The p53 status of rectal adenocarcinomas was examined immunohistochemically (with monoclonal antibody DO-1) in preirradiated biopsy samples (n = 100) and corresponding postirradiated resected specimens (n = 97). The mean follow-up was 73.2 months (median, 71.3 months; range, 4.3-157 months). Statistical analysis was performed using the SPSS program (SPSS, Chicago, IL). RESULTS: p53 protein expression was detected in 55 of 100 biopsy samples (> or = 5% nuclear staining). There was essentially no difference in p53 expression between biopsy samples and corresponding resected specimens (54 of 97 vs. 55 of 97). In univariate analysis, p53 immunoreactivity of biopsy samples did not correlate with age, gender, tumor location, TNM stage, pT category, pN category, or histologic grade. Unlike clinicopathologic variables, p53 expression did not have a statistically significant association with local recurrence free, disease free, or overall survival in either univariate (P = 0.91, 0.18, and 0.17, respectively) or multivariate analysis. CONCLUSIONS: In contrast to cell line studies, this immunohistochemical study demonstrates that p53 status is not useful as a prognostic marker in preoperatively irradiated rectal carcinoma.

[Collaboration in tumor after care with the established physician]. / Zusammenarbeit in der Tumornachsorge mit dem niedergelassenen Arzt.

The organization of cancer followup, the investigations and subsequent treatment are the responsibility of only those doctors directly involved. The followup work consists of three types: diagnostic after curative treatment, therapeutic with adjuvant chemotherapy and palliative. The cooperation of hospital doctors and practitioners has proved effective. The patient's data are recorded in the accompanying documentation. The follow-up system has met with high patient compliance (94%). The drop-out rate is 6%. Twenty percent of patients with colorectal cancer who underwent curative surgery had pathologic findings. One half of them could be treated therapeutically or palliatively.

[Concepts in the prevention and treatment of liver metastases of colorectal cancer by regional chemotherapy]. / Konzepte zur Prophylaxe und Behandlung von Lebermetastasen beim colorectalen Carcinom durch regionale Chemotherapie.

Three different treatments of regional chemotherapy in colo-rectal malignancies and their results are presented. 1. Prophylactic chemotherapy with 5-FU--via the recanalized umbilical vein in patients without liver metastases (randomized study since 10/1980). 2. Intraportal adjuvant chemotherapy after resection of liver metastases. 3. Intraarterial chemotherapy in patients with unresectable liver metastases. The regional chemotherapy of the liver in colo-rectal diseases seems to increase the survival rate and the quality of life. The Port-A-Cath-system can be used repeatedly, however, there is a certain rate of complications to be expected.

[Stress tolerance following blunt abdominal trauma and its significance for operational indications and tactics]. / Die Belastbarkeit nach stumpfen Bauchtraumen in ihrer Bedeutung für Operationsindikation und -taktik.

Abdominal trauma in combination with other injuries continues to be a life-threatening risk. In spite of intensive care multiple organ failure can result in death several days postoperatively. The initial respiratory therapy of the injured patients is of outstanding importance to ameliorate the unsatisfying results.

Splenoperitoneal anastomoses after application of collagenase to the splenic capsule of rats.

In 200 Wistar rats the spleen was transposed into a pouch between the muscle layers of the left abdominal wall. Collagenase powder was applied to the spleen surface. After 12 to 24 hours an acute haemorrhagic inflammation was seen. Collaterals developed from the splenic parenchyma to the abdominal wall from the 10th day. They connected the portal venous system with the caval system.

Experimental anastomosis between the parenchyma of spleen and kidney.

The procedure described using UV-irradiation and surgical removement of the renal capsule leads to the development of anastomoses between the spleen and the kidney. The collaterals are able to divert blood from the portal system to the surface of the kidney and then to the renal vein and the iliac veins systems. The procedure is easily performed and well tolerated.