[Rare hereditary syndromes associated with polyposis and the development of malignant tumors].

UNLABELLED: Familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome are genetic diseases characterized by gastrointestinal polyps, extraintestinal manifestations, and autosomal dominant inheritance. The carriers of these diseases from early childhood are at risk for neoplasias at different sites, which are symptomatic at various ages. AIM: to study the clinical organ-specific manifestations in patients with FAP and Peutz-Jeghers, genetics update and possibilities of diagnosis, monitoring, and treatment of these diseases. MATERIAL AND METHODS: The authors give the results of their examination and follow-up of children with FAP and Peutz-Jeghers hamartoma-polypous syndrome. In addition, current data from PubMed, Medline (including reviews, original articles and case reports) were used. RESULTS: The main clinical organ-specific signs of multiple tumors in FAP and Peutz-Jeghers syndrome are shown. Data on the assessment of a risk for malignant tumors at various sites in the affected patients and their family members at different ages are provided. Each of these syndromes has a dissimilar genetic foundation. FAP is caused by the germline mutations in the APC gene, Peutz-Jeghers syndrome is by the STK11 gene, which predispose individuals to specifically associated neoplasias and require different follow-up strategies. Information on a phenotype-genotype correlation may serve as a reference point for the possible severity and various manifestations of a disease. An update on the molecular pathogenesis of these diseases is considered. CONCLUSION: Molecular genetic testing of the genes associated with FAP and Peutz-Jeghers syndromes makes it possible to timely recognize family members at high risk, to plan therapeutic strategy and to affect the course of a disease. The joint participation of pediatricians, proctologists, oncologists, morphologists, geneticists, and molecular biologists is essential to timely recognize the carriers of the syndromes and a better prognosis in these patients.

[Follicular cell (papillary and follicular) thyroid carcinoma, genetic inheritance, and molecular diagnostic markers].

OBJECTIVE: To determine the genetic forms of follicular cell thyroid carcinoma (FCTC) (papillary and follicular thyroid carcinoma (PTC and FTC)), to identify criteria to individually predict the development of the same disease for relatives, and to assess the role of molecular markers in the diagnosis, prognosis, and treatment of this disease. SUBJECTS AND METHODS: One hundred and ninety adult patients aged 20 to 84 years with histologically verified PTC and FTC and 20 children (12 patients with PTC and 8 with benign thyroid tumors) aged 2 to 16 years were examined. To assess the role of the BRAF gene as a molecular marker for thyroid carcinoma, DNA was isolated from the thyroid tumor tissue of 29 patients, which had been obtained by fine-needle aspiration biopsy (FNAB) and scraping and swabbing the cytological specimen previously showing an area containing tumor cells. A BRAF c.1799T>A (p.V600E) mutation in the FNAB specimens was tested by allele-specific ligation, followed by PCR amplification. RESULTS: The examinees' families were found to have a segregation of benign thyroid tumor and nontumor diseases (13.6%). Neoplasias of different sites were observed in 15% of the patients' relatives. Multiple primary tumors were detected in 6.1% of the patients and in 25% of the examined children (3/12). PTC was ascertained to accumulate as two clinical forms in the families. One form belongs to familial PTC (FPTC) in which two or three generations of relatives in the family are afflicted by only PTC and have a more severe phenotype of the disease. The other includes an association of FPTC with papillary kidney cancer. Furthermore, FPTC and PTC may be a component of multitumor syndromes, such as multiple endocrine neoplasia type 1, Cowden syndrome, and familial adenomatous polyposis. The familial hereditary forms of FCTC were generally revealed in 4.2% of the patients. BRAF v600E mutations were found in only 3 patients with Stages II and III PTC and were not in all the 12 children with PTC. CONCLUSION: The found clinical manifestation of the hereditary forms of FCTC permits the identification of people at high risk for this disease. No correlation between somatic BRAF mutations with a less favorable course in PTC can be noticed because there are few observations. Analysis of published data on the role of molecular markers in FCTC has shown that the existing specific somatic changes complement information in the differential cytological diagnosis when examining FNAB specimens.

Intraperitoneal perfusion chemotherapy with hyperthermia in some malignant ascites.

Intraperitoneal administration of chemotherapeutic drugs with hyperthermia (HIPEC) increases their local effect on malignant peritoneal diseases and reduces systemic cytotoxicity. The most commonly used are cisplatin, doxorubicin, and mitomycin C. A major disadvantage of intraperitoneal chemotherapy is limited penetration of the drug in the tumor lesion depth (1-3 mm). Extended exposure and increased pressure in the abdominal cavity solution increases penetration of the agent into the tumor and hyperthermia has synergy with cytostatic agent on the permeability of cell membranes and metabolism of the drug. Real clinical hyperthermia is achieved at 41 degrees C. Of greatest importance is the concentration of the drug, but crucial for the prognosis is complete cytoreductive surgery. A major disadvantage of the closed technique is the uneven distribution of the perfusion solution in the peritoneal cavity, and the main advantage is better control of the perfusion, keeping of constant hyperthermia of the solution and regular repetition of manipulation, like intravenous chemotherapy. Laparoscopy determines the stage of the tumor process, refines the indications and preoperative selection for HIPEC, monitors the effects of treatment and determines locations for introducing catheters. In the review the results of the inraperitoneal chemotherapy with hyperthermia in gastric, colorectal, ovarian and other cancers are discussed as well as in diffuse malignant peritoneal mesothelioma and others.

Aggressive surgery in the multimodality treatment of liver metastases from colorectal cancer.

PURPOSE: The purpose of this study was to analyze the impact of aggressive surgery concerning resection of liver metastases (LMs) from colorectal cancer (CRC) on morbidity, mortality and survival rates and to establish the benefits of multimodal strategies in increasing the resectability rates of LMs. PATIENTS AND METHODS: From January 2004 - April 2006 184 patients with CRC underwent surgical interventions at our clinic. Thirty-four (18.4%) of them had LMs at the time of initial diagnosis, and 26 patients developed LMs in a certain period of time after resection of the primary CRC. Multimodal therapeutic approach included thermoablation, neoadjuvant chemotherapy and surgery. RESULTS: 44 resections were performed in 29 patients: one-stage resection of the primary CRC and the LMs in 15 (40%) cases, resection and thermoablation after adjuvant chemotherapy in 2 (4.3%), resection after neoadjuvant chemotherapy in 8 (17.2%), two-stage liver resection in 1 (2.15%), resection after recurrence or because of a newfound LM in 3 (6.45%). Five resections of metastases larger than 5 cm, and 4 resections of 4 or more liver metastases were performed. Morbidity rate was 15.9% (bile leakage in 4 patients, liver abscess in 1 and wound disruption in 2). Mortality rate was 2.2% (1 patient). CONCLUSION: Multimodal approach in the treatment of LMs of CRC increases resectability and patient survival and has no influence on morbidity and mortality.

[Hereditary cancer: identification, genetic heterogeneity, medico-genetic consult]. / Nasledstvennyi rak: identifikatsiia, geneticheskaia geterogennost', mediko-geneticheskoe konsul'tirovanie.

The paper deals with a role of inherited factors responsible for the occurrence of malignant tumors. Inherited types of cancer are shown to occur virtually at its sites and averaged 5-15%. Formalized criteria for identifying inherited cancer diseases and their etiological and genetic heterogeneity are presented. A role of genes that genetically predispose to particular forms of cancer is shown, which allows for early (preclinical) diagnosis and prevention of cancer diseases.

[The treatment of cyclic mastalgia--a comparative study between the preparations Bromocriptine and Geritamin]. / Lechenie na tsiklichna mastalgiia--srabnitelno prouchvane mezhdu preparatite Bromocriptin i Geritamin.

The aim of the prospective randomized study was to compare the reduction in cyclical breast pain after treatment with oral bromocriptine for 30 days (42 cases) and Geritamine for 40 days (44 cases). The overall response rate to first group was 78.5% and 64.0% to second group. Nine patients treated with bromocriptine and 15 cases with Geritamine have refractory cyclical mastalgia (not influence). The relapse rate after stopping bromocriptine was 30.3% and was 44.8%, with a mean follow-up of 5 months. The investigators indicate that these agents will be used for a twice per year.

[Genetic-epidemiologic study of adenoma and cancer of the large intestine]. / Genetiko-épidemiologicheskoe issledovanie adenom i raka tolstoi kishki.

A clinical/genealogical study of colorectal adenomas (CRA) and cancer (CRC), and multiple primary malignant tumors (MPMT) was performed. The CRA prevalence in the population was 4.7 +/- 1.4% (single CRA--6.3% and multiple CRA--3.0%). The frequencies of malignant adenomas, 0.7% CRC, and MPMT were 0.7, 0.17 +/- 0.07%, and 0.004 +/- 0.003%, respectively. The prevalence of cancer of the female reproductive organs was also estimated (cancer of uterine body, 0.2 +/- 0.1%; cancer of ovaries, 0.08 +/- 0.1%; cancer of uterine cervix, 0.55 +/- 0.1%; cancer of mammary gland 0.57 +/- 0.1%). The main parameters of the familial inheritance of adenomas, CRC, and MPMT were also studied in general and at various clinical variants of these pathologies. Among the first-degree relatives of patients with solitary and multiple adenomas, the adenoma frequencies were 5.9 +/- 0.6 and 3.7 +/- 0.5%, respectively. The CRC frequency among the first-degree relatives of patients with adenoma was 3.0 +/- 0.6% and the frequency of MPMT was 5.8 +/- 0.6%. On the basis of the data obtained on frequencies of malignant tumors in various groups of relatives, the following conclusions were made: (1) in families of each proband group, specific pathology was accumulated; (2) the familial frequency of malignant tumors increased with an increase in proliferative processes and the severity of a pathology in probands.

[Segregation and genetic-dispersion analysis of predisposition to adenoma and cancer of the large intestine]. / Segregatsionnyi i genetiko-dispersionnyi analiz predraspolozhennosti k adenomam i raku tolstoi kishki.

Segregation analysis of inheritance of adenomas, colorectal cancer (CRC), and multiple primary malignant tumors (MPMT) revealed their low penetrance: from 3.2 to 29% for homozygotes and from 2.0 to 14.4% for heterozygotes. This cast a doubt on the monogenic type of their inheritance, although it formally corresponded to the quasidominant type, i.e., only a fraction of heterozygotes was expressed. Therefore, the multifactorial model of inheritance was tested, which seemed more adequate because genetic heterogeneity of adenomas, CRC, and MPMT was suggested from the data on genetic correlations between various clinical forms. Predisposition to various clinical forms of adenomas, CRC, and MPMT was shown to be specific, i.e., the ratio between genetic and environmental predisposition-determining factors reflected pathogenetic differences between these diseases. However, analysis of variance which revealed genetic (pathogenetic) distinctions between adenomas, CRC, and MPMT is insufficient to confirm complete nosologic identity of each of these clinical forms.

CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations.

Hereditary nonpolyposis colon cancer (HN-PCC) is an autosomally inherited predisposition to cancer that has recently been linked to defects in the human mismatch repair genes hMSH2 and hMLH1. The identification of the causative mutations in HNPCC families is desirable, since it confirms the diagnosis and allows the carrier status of unaffected relatives at risk to be determined. We report six different new mutations identified in the hMSH2 and hMLH1 genes of Russian and Moldavian HNPCC families. Three of these mutations occur in CpG dinucleotides and lead to a premature stop codon, a splicing defect or an amino-acid substitution in an evolutionary conserved residue. Analysis of a compilation of published mutations including our new data suggests that CpG dinucleotides within the coding regions of the hMSH2 and hMLH1 genes are hotspots for single base-pair substitutions.

[Clinico-genetical studies of colonic cancer. III. Primary multiple malignant neoplasms]. / Kliniko-geneticheskie issledovaniia raka tolstoi kishki. Soobshchenie III, Pervichno-mnozhestvennye zlokachestvennye novoobrazovaniia (PMZN).

The results of clinico-genealogic analysis of 46 patients with primary-multiple malignant neoplasms are given (among them 16 patients with primary-multiple malignant neoplasms of colon cancer and 30 patients with one or more neoplasms in combination with different malignant tumors of other organs). The values of segregation rates obtained for primary-multiple malignant neoplasms are lower than theoretically expected for simple monogeneous types of inheritance. The relation analysis of primary-multiple malignant neoplasms and colon cancer revealed that these tumors are likely to appear among relatives of probands under the influence of the same genetic system of determination. Risk of the colon cancer development for relatives of the patients with primary-multiple malignant neoplasms is higher than for relatives of the patients with colon cancer.

[Clinico-genetical studies of colonic cancer. II. Genetic analysis of predisposition to colonic cancer]. / Kliniko-geneticheskie issledovaniia raka tolstoi kishki. Soobshchenie II. Geneticheskii analiz predraspolozheniia k raku tolstoi kishki.

The structure of subjection to different clinical forms of colon cancer and to the morbidity as a whole approximates better the quasi-continued phenotypical model within which the contribution of genetic factors reaches 68-84%, that of incidental medium factors being 16-32%. Genetic study of heterogeneity of colon cancer clinical forms revealed that their pathogenetic community was quite high. However, the origin of colon cancer depends strongly on genetic factors (83.7 +/- 7.3%), in comparison with rectal cancer (67.9 +/- 7.1%). The analysis of colon cancer interrelation with other malignant neoplasms (including specific ones for women--breast and uterus cancer) revealed that the development of another malignant neoplasms was the result of the influence of partially common genes (20-50%) which predetermined the development of colon cancer and other malignant neoplasms. According to the data obtained in this study, the tables of repeated risk have been worked out which may be used for medico-genetic consultation.

[Clinico-genetical analysis of colonic cancer. I. Occurrence, frequency in families and segregation analysis]. / Kliniko-geneticheskoe issledovanie raka tolstoi kishki. Soobshchenie I. Rasprostranennost', semeinoe nakoplenie i segregatsionnyi analiz.

The data on clinico-genealogic studies of colon cancer are presented. 694 families were examined with 432 probands having rectal and 262 colonic carcinoma among them. Clear family accumulation of colon cancer (2.4 +/- 0.35%) as well as other malignant tumors (6.8 +/- 0.6%) (p less than 0.01) was shown among the relatives of the first degree of relation. The values of segregation rates obtained for clinical forms of colon cancer were lower than theoretically expected for simple monogenic types of inheritance. The analysis of incomplete penetration of genotypes showed that, though formally the inheritance of colon cancer and its clinico-anatomical forms may be described by quasi-dominant types of inheritance, the penetration values are very low: from 4.3 to 13.3% for homozygotes and from 2.1 to 6.6% for heterozygotes. It shows that the supposition about the monogenic types of the colon cancer inheritance is doubtful and suggests that the colon cancer is to be regarded on the basis of the multifactorial model.

[The spread of enzootic bovine leukemia via the seminal fluid in certain breeds of bulls]. / Razprostranenie na enzootichnata levkoza po govedata sus semennata technost ot niakoi porodi bitsi.

Studied was the occurrence of enzootic bovine leukosis as dependent on the use of semen of leukosis-affected bulls for the artificial insemination of cows and heifers and their offsprings in the F1 generation on 16 farms. Semen was used of a total of 30 bulls of the Holstein-Friesian, American Brown, and European Black-and-white breeds. The agar gel immuno-diffusion test was employed to establish antibodies to the bovine leukosis virus in the sera of the bulls. On 9 farms with 2,997 cows and heifers that were negative for leukosis antibodies a total of 800 female calves (F1) were born. Serologic investigations of both dams and calves, aged 2 to 5 years revealed no leukosis antibodies. On other 7 farms with 1,717 cows and heifers, among which sporadic carriers of BLV-antibodies were discovered, 713 female offsprings (F1) were born. Seventeen (2.38 per cent) out of these responded positively for BLV antibodies. Twenty-two (3.0 percent) of the dams following calving also showed a positive reaction. Over the 1981-1985 period a total of 1,593 female calves were born as the offsprings of 4,714 cattle on all 16 farms. The percent of the positively responding to leukosis was 1.06, resp., 1.38. These results were considered indicative in ruling out the transmission of enzootic bovine leukosis with semen in the artificial insemination of cows and their F1 offsprings.

[Cancer morbidity of the large intestine and its prognosis in the Moldavian SSR]. / Zabolevaemost' rakom tolstoi kishki i ee prognozirovanie v Moldavskoi SSR.

Colorectal cancer ranks fifth in general cancer morbidity in the Moldavian SSR and second among digestive tumors. Within 1970-1979, the morbidity rate for rectal cancer increased 2.2-fold (from 3.0 to 6.70/0000), cancer of the colon--1.4-fold (from 4.4 to 6.00/0000). Rectal cancer morbidity showed a 4.30/0000 rise in male patients, matched by a 3.20/0000 rise in females. The colonic cancer morbidity rates increased by 1.5 and 1.80/0000, respectively. The results of the analysis of the said indexes suggest that by 1990 the rectal cancer morbidity rate will have reached 8.9 +/- 1.1 and colonic cancer--7.3 +/- 2.40/0000. By 1990, the rate of morbidity for cancer of the large bowel will have surpassed that for stomach cancer and it will rank first among tumors of the digestive tract should the present-day trends of morbidity remain unchanged.