[Molecular etiology of colorectal carcinogenesis, clinical manifestations and therapy]. / Molekulare Ursachen kolorektaler Kanzerogenese, klinische Manifestation und Therapie.

Mutations of tumor suppressor genes, of the mismatch DNA repair system, and of the TGF-beta-II-receptor are the main causes for a higher risk of colorectal cancer. Among mutations of the Ape gene, which characterize the clinical manifestation of the familial polyposis (FAP), point mutations are dominating which create new stop codons or arise from deletions or insertions of nucleotides causing frame shifts. Because the binding site of beta-catenin is localized in the C-terminus of the Ape protein, disturbances result in the cellular signal transfer from its loss. Consequently, the interactions of the usually formed Ape-beta-catenin complex with the cytoskeleton and the cadherin system in the plasma membrane as well as the translocation of beta-catenin into the nucleus cannot be realized. Mutations in the genes of the mismatch DNA repair system and of the TGF-beta-II-receptor, the main defects of the HNPCC (hereditary nonpolyposis colorectal cancer), are exclusively identified in sequences of microsatellites. Because the majority of Apc gene mutations is also localized in repetitive motifs even in CpG islands primary disturbances are to postulate in the methylation pattern of the genes producing germline and somatic mutations. Generally, complexly connected reactions are involved in this cascade of colorectal cancer genesis. This fact explains the relatively late clinical manifestation of the disease and offers the possibility to identify carriers with an increased risk of colorectal cancer development in order to integrate them into a programme of control and preventive medicine. Beside the known treatment by surgery and cytostatics, inhibitors of prostaglandin synthesis gain therapeutic significance. Cancerogenesis can be efficiently suppressed by inhibition of the COX-2-induction (cyclo-oxygenase-2). There is a lack of clinical experience for a decision whether a high intraluminal level of butyrate in the large intestine can delay colorectal carcinogenesis.

Significance of apoptosis in the process of tumorigenesis in colorectal mucosa and adenomas in FAP patients.

The relation between proliferation and apoptosis was studied in colorectal mucosal biopsies (N = 41), tubular adenomas (TA) (N = 104) and tubulovillous adenomas (TVA) (N = 34) from 37 FAP patients. Proliferative activity was determined by cell cycle distribution analysis. In addition, transcriptional capacity was determined by chromatin in situ testing. For both, DNA flow cytometry was used. Cycling cells were identified by immunohistochemical staining with monoclonal antibody Ki67. The existence of subdiploid apoptotic cells was derived from DNA and/or DNA/protein patterns. In a follow-up group, the mucosa is characterised by a balance between proliferation (S % + G2M % = 19) and apoptotic cells (% = 17). The percentage of Ki67 positive cells (16%) corresponds to the percentages mentioned above. In TA, the amount of apoptotic cells remains unaltered, in TVA it decreases to 8%. At the same time, the percentage of Ki67 positive cells increases significantly in both TA and TVA (39%, 42%). With patients who underwent surgery due to clinical signs without histological evidence for malignancy, apoptotic cells in TA continue to decrease significantly (9%), without any changes in cycling cells. Only in the carcinoma-bearing bowel, cycling cells increase to 52%. Here, the percentage of apoptotic cells in TVA reaches the lowest level (5%). A connection between proliferation and apoptosis was observed in mucosa and TVA. The process of tumorigenesis is characterised by a stepwise increase in resistance to apoptosis followed by an increase in cycling cells.

Familial adenomatous polyposis: mutation at codon 1309 and early onset of colon cancer.

The clinical course of familial adenomatous polyposis (FAP) varies considerably between patients. Prediction of the severity of the disease is important in the interest of effective cancer prevention. We examined whether age at diagnosis of FAP due to gastrointestinal symptoms and age at death due to colorectal cancer are related to the site of mutation in the responsible gene. 225 families with FAP were screened for mutations. The deletion of 5 base pairs at codon 1309 within exon 15 (known to be the most common mutation) was identified in 20 families; other mutations within exons 7-15 were found in 49 families. In patients with the 5 base-pair deletion at codon 1309, gastrointestinal symptoms and death from colorectal cancer occurred about 10 years earlier than in patients with other mutations. The 1309 mutation leads to development of colonic polyps at a younger age, thus giving rise to an earlier malignant transformation. This relationship should be taken into account in strategies for preventing cancer in patients with FAP.

[Autoradiography of DNA synthesis in colonic mucosa of patients with familial adenomatosis coli]. / Autoradiografische Untersuchung der DNA-Synthese in der Kolon-Mukosa von Patienten mit familiärer Adenomatosis coli.

In connection with routine endoscopic examinations of 31 patients with familial adenomatosis coli and 28 health kindreds of patients with familial adenomatosis coli we investigated by autoradiography the in vitro incorporation of 3H-thymidine into bioptic mucosal particles from colon and adenomas. Within the 5-year follow-up period there was found a significantly increased labelling index of polyps and the surrounding mucosa in patients with polyposis independing on the time elapsed after operation. In 12 of 28 kindreds the histological normal colonic mucosa showed an increased labelling index too. The prognostic value of these results must be proofed by further controls.

[Cell proliferation of the intestinal mucosa in patients with familial adenomatosis coli. Autoradiography study]. / Zellproliferation der Darmschleimhaut bei Patienten mit familiärer Adenomatosis coli. Autoradiografische Untersuchung.

In connection with routine endoscopic examinations of 31 patients with familial adenomatosis coli and 28 healthy kindreds of patients with familial adenomatosis coli we investigated by autoradiography the in vitro incorporation of 3H-thymidine into bioptic mucosal particles from colon and adenomas. Within the 5-year follow-up period there was found a significantly increased labelling index of polyps and the surrounding mucosa in patients with polyposis independing on the time elapsed after operation. In 12 of 28 kindreds the histological normal colonic mucosa showed an increased labelling index too. The prognostic value of these results must be proved by further controls.

[Early detection of colorectal cancers by detection of occult blood in feces using Krypto-Haem SSW]. / Früherkennung kolorektaler Karzinome durch den Nachweis von okkultem Blut im Stuhl mit Krypto-Haem SSW.

Screening for cancer of the bowels with tests for occult blood in the stools obtained an increasing interest during the last 15 years. In the GDR Krypto-Haem SSW is at the disposal for this purpose. Up to now two larger investigations were performed with this preparation. The results of the studies with Krypto-Haem and Haemoccult were compared as well as questions of the test performance, the secondary diagnostics, the sensitivity of the tests, the compliance and organisation of a screening are treated. From this derived that Krypto-Haem SSW can be recommended as diagnostic test for colorectal tumours within the basic medical care.

[Ultrasound-guided fine needle biopsy in tumor diagnosis]. / Ultraschall-geleitete Feinnadelbiopsie in der Tumordiagnostik.

Ultrasound guided fine needle biopsy led in 92 of 100 patients with suspected tumours to correct diagnostic results which determined the diagnostic and therapeutic management. Ultrasound-tomography may thus in connection with fine needle biopsy enlarge and simplify tumour diagnosis.

DNA ploidy and proliferation characteristics of bowel polyps analysed by flow cytometry compared with cytology and histology.

56 human adenomatous bowel polyps and 44 samples of macroscopically unchanged bowel mucosa taken at a distance of 2-10 cm from the polyp were investigated by histology, cytology, and flow cytometry in respect to their dysplasia grade and DNA distributions. 30 human adenomatous polyps of the same localization were investigated by histology and flow cytometry; in 14 cases in addition to the DNA-patterns per se their changes mediated by heparin, a polyanion, were recorded. Histological and cytological investigations revealed mild dysplasia in 25 cases, moderate dysplasia in 43 cases and severe dysplasia in 18 cases. DNA aneuploidy was correlated with the histological finding of mild dysplasia three times, of moderate dysplasia twice and severe dysplasia five times. All other cases, also macroscopically unchanged bowel mucosa revealed DNA diploidy. In these diploid cases, cell cycle stage analysis yielded a higher proportion of cells in S-phase and G2M phase in adenomas with severe dysplasia in comparison to adenomas with moderate and mild dysplasia (P less than 0.05). Macroscopically unchanged bowel mucosa showed about the same values as adenomas with mild dysplasia. The heparin mediated increase in fluorescence intensity is different for adenomas with mild and moderate dysplasia, and attributed to the latter a higher proliferative activity (P less than 0.05).

[Endoscopic and histologic findings in malignant non-Hodgkin lymphomas of the stomach]. / Endoskopische und histologische Befunde bei malignen Non-Hodgkin-Lymphomen des Magens.

The authors have carried out a retrospective analysis of primary malignant Non-Hodgkin-lymphomas of the stomach verified histologically by surgical specimens, with the patients being submitted preoperatively to a gastroscopy with biopsy. The endoscopic and histological findings are outlined. Endoscopically the diagnosis of a malignant lymphoma was established only once, while an ulcerated carcinoma was diagnosed in almost two-thirds of the cases. The histological diagnosis of a malignant lymphoma was established in 10 cases, and a malignant lymphoma suspected in 6 cases. A carcinoma was diagnosed in 4 patients. The results are compared with the literature data and diagnostic problems discussed.

Characterization of human adenomatous polyps of the colorectal bowel by means of DNA distribution patterns.

64 human adenomatous polyps of the colorectal bowel were investigated by histological examination and by flow cytometrical analysis providing DNA distribution patterns. The histological investigation yielded tubular adenomas (TA) in 41 and tubulo-villous adenomas (TVA) in 23 cases. Epithelial dysplasia or carcinomatous degeneration was found in 23 TA and in 11 TVA. Cell cycle stage analysis revealed no different values for TA and TVA without dysplasia, neither for TA and TVA with mild to moderate dysplasia. TVA with severe dysplasia exhibited a significantly higher proportion of cells with G2M phase DNA content than cases without dysplasia or mild to moderate dysplasia. TA and TVA without dysplasia were characterized by diploid DNA distribution patterns. TA with dysplasia showed aneuploid DNA stem lines in 4 of 20 cases, carcinomas arisen from TA in all 4 cases investigated. TVA with dysplasia were characterized by aneuploid DNA stem lines in 1 of 8 cases, carcinomas arisen from TVA in all 4 cases examined. It may be concluded that the DNA distribution patterns do not attribute different biological values to TA and TVA, 2 groups of adenomatous polyps which are characterized by different histological criteria.

A comparative study of early gastric cancer.

Authors provided a comparative study of early gastric cancers (EGC) which were found in the Cancer Research Centre of the Academy of Medical Sciences of USSR (Group A) and in the Central Institute of Cancer Research of the Academy of Sciences of GDR (Group B). The most frequent EGC-type in group B was type II, while types I and III were more frequent in group A. The rate of lymph node metastases in group A was 4,54% versus 16,2% in group B. Multicentric cancers were more often found in group A. These findings strengthen the opinion that early gastric cancer is not a uniform biological entity. Accuracy of x-ray and gastroscopic diagnoses was higher in group A. This fact surely contributes to the better prognosis of early gastric cancer in this group.

[Colonic cancer screening with KRYPTO-HAEM SSW. The results in 3015 persons]. / Dickdarmkarzinom-Screening mit KRYPTO-HAEM SSW. Ergebnisse an 3015 Personen.

In a factory 3015 individuals have been tested for occult blood in stool using the KRYPTO-HAEM SSW. Test results were positive in 100 individuals (3.3%). Subsequent investigations have revealed 6 carcinomas of the colon, one carcinoid in the cecum and adenomas in 9 cases. Eleven out of the 16 tumors detected were beyond the range of the rectoscope. The test was valued as false-positive in 42 individuals (1.4%). A cecum carcinoma and 5 adenomas were revealed by false-negative findings. The importance of case history and exact diagnostic clarification of a positive test is pointed out. The inclusion of the KRYPTO-HAEM test into basic medical care proved to be an adequate measure for early detection of colorectal tumors.

[Cancer and polyps of the large intestine]. / Krebs und Polypen des Dickdarms.

Incidence and mortality of the carcinoma of the large intestine increase also in the GDR. Carcinomas mostly develop in adenomas of the large intestine in the course of several years. Nowadays the adenoma-carcinoma-sequence is regarded as ascertained. The environmental influences are of decisive importance for the genesis of the colon carcinoma. Apart from this also genetic factors play a part. Villous adenomas more frequently show malignant structures than tubular adenomas. In large adenomas with a diameter of more than 20 mm more frequently invasive carcinomas (20-40%) are found than in small adenomas with a diameter of less than 10 mm (1%). From this is to be derived the demand of the removal of all adenomas of the large intestine with a diameter larger than 5 mm. The method of choice of the treatment is the polypectomy and the technique with the diathermy loop.

[Early detection of gastrointestinal tumors (author's transl)]. / Früherkennung gastrointestinaler Tumoren.

"Early cancers" of stomach and colon have a favourable prognosis, but mass screenings for these tumors with endoscopic or radiographic methods are ineffective and expensive. The simple nonspecific test for occult blood as a suitable method for early detection of stomach and colorectal cancer in high-risk patients seems to be more useful. Some suggestions are given to detect and to control risk groups.

[Screening for colorectal cancer with a test for occult blood in stool (author's transl)]. / Screening auf kolorektalen Krebs mit einem Suchtest auf okkultes Blut im Stuhl.

Results of an occult-blood-test in 1 072 persons are reported. The test, recently registered as KRYPTO-HAEM, was developed by the Central Institute of Molecular Biology of the Academy of Sciences of the GDR. 27 patients (2.5%) had positive findings and by clinical examination 1 carcinoma of the sigmoid colon and 2 adenomas were detected. In 1 case (adenoma of the rectum) the test had a false-negative result. The findings were compared with own experiences with the HAEMOCCULT-Test. The KRYPTO-HAEM-Test is recommended for screening for colorectal tumors.

[Therapeutic aspects of endoscopic polypectomy]. / Therapeutische Aspekte der endoskopischen Polypektomie.

466 endoscopic polypectomies of the upper and lower gastrointestinal tract were analysed according to their curative value. In 254 removed polyps of the upper gastrointestinal tract the result of the histological examination was twice a proof of a carcinoma. One it had to be after-resected, once a carcinoid, five times bleeding polyps were removed. Four times prolapsing gastric polyps were removed in the bulbus duodeni. In these cases intermittent disturbances of the passage could be repaired. Thus the endoscopic polypectomy in the upper gastrointestinal tract was of therapeutic value in 4.3%. In the lower intestinal tract in 204 polypectomies 16 focal carcinomas or invasive carcinomas removed in the healthy tissue, 1 carcinoid and 98 bleeding adenomas were cut away. Thus the coloscopic polypectomy was connected with a therapeutic use in 56.3%. 81.8% of the polyps was tubular, papillary or villous adenomas. Taking into consideration the "adenoma-cancer-sequence", the coloscopic polypectomy must thus be regarded as a prophylactic and curative method, while in the polypectomy in the upper gastrointestinal tract the diagnostic value is in the first place.

Confirmation of cancer diagnosis--methods and problems.

Histo- und cytopathological proof of the diagnosis of cancer is crucial for the choice of an appropriate treatment. In the last decade effective methods for obtaining material from various organs of the body within operation have been developed, especially by new procedures in endoscopy, radiology, sonography and fine needle biopsying allowing further progress in cancer management.