High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients.

Background: Exosomes arise from viable cancer cells and may reflect a different biology than circulating cell-free DNA (cfDNA) shed from dying tissues. We compare exosome-derived DNA (exoDNA) to cfDNA in liquid biopsies of patients with pancreatic ductal adenocarcinoma (PDAC). Patients and methods: Patient samples were obtained between 2003 and 2010, with clinically annotated follow up to 2015. Droplet digital PCR was performed on exoDNA and cfDNA for sensitive detection of KRAS mutants at codons 12/13. A cumulative series of 263 individuals were studied, including a discovery cohort of 142 individuals: 68 PDAC patients of all stages; 20 PDAC patients initially staged with localized disease, with blood drawn after resection for curative intent; and 54 age-matched healthy controls. A validation cohort of 121 individuals (39 cancer patients and 82 healthy controls) was studied to validate KRAS detection rates in early-stage PDAC patients. Primary outcome was circulating KRAS status as detected by droplet digital PCR. Secondary outcomes were disease-free and overall survival. Results: KRAS mutations in exoDNA, were identified in 7.4%, 66.7%, 80%, and 85% of age-matched controls, localized, locally advanced, and metastatic PDAC patients, respectively. Comparatively, mutant KRAS cfDNA was detected in 14.8%, 45.5%, 30.8%, and 57.9% of these individuals. Higher exoKRAS MAFs were associated with decreased disease-free survival in patients with localized disease. In the validation cohort, mutant KRAS exoDNA was detected in 43.6% of early-stage PDAC patients and 20% of healthy controls. Conclusions: Exosomes are a distinct source of tumor DNA that may be complementary to other liquid biopsy DNA sources. A higher percentage of patients with localized PDAC exhibited detectable KRAS mutations in exoDNA than previously reported for cfDNA. A substantial minority of healthy samples demonstrated mutant KRAS in circulation, dictating careful consideration and application of liquid biopsy findings, which may limit its utility as a broad cancer-screening method.

[Recommended Extension of Indication Criteria for Genetic Testing of BRCA1 and BRCA2 Mutations in Hereditary Breast and Ovarian Cancer Syndrome]. / Doporucení rozsírení indikacních kriterií ke genetickému testování mutací v genech BRCA1 a BRCA2 u hereditárního syndromu nádoru prsu a ovarií.

Genetic testing for hereditary breast and ovarian cancer syndrome is indicated by a genetic counselor on the basis of personal and family history evaluation, with regards to consensual criteria, reflecting the current knowledge. The latest recommendation accepted by Czech Oncology Society and Society of Medical Genetics was published in the supplement 22 to the Journal of Clinical Oncology in 2009. Since the availability of PARP inhibitors for treatment of ovarian cancer in BRCA1/ 2 mutation carriers, an update of these guidelines is urgently needed. Another reason is a higher incidence of other malignancies in high-risk families, such as prostate or pancreatic cancer. The goal is to refine the detection of mutations in selected families, to improve preventive care and collect data necessary for targeted cancer treatment.

[Retrospective NGS Study in High-risk Hereditary Cancer Patients at Masaryk Memorial Cancer Institute]. / Retrospektivní NGS studie u vysoce rizikových pa-cientu s hereditární predispozicí k nádorovému onemocnení v Masarykove onkologickém ústavu.

BACKGROUND: Currently, more than 200 hereditary cancer syndromes have been described, yet, in most countries genetic testing is restricted to a narrow spectrum of genes within a limited group of people tested. METHODS: For this retrospective study we used the TruSight cancer panel (Illumina)--NGS panel targeting 94 cancer predisposition genes in order to analyze 50 high-risk cancer patients with significant personal and family history of cancer who did not carry mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6, TP53 or APC genes. All pathogenic and potentially pathogenic mutations detected by NGS technology have been confirmed by Sanger sequencing. RESULTS: There were several deleterious (frame-shift/nonsense) mutations detected in ATM, BAP1, FANCC, FANCI, PMS2, SBDS, ERCC2, RECQL4 genes. Various pathogenic or potentially pathogenic (missense, predicted splice site, in-frame insertion/deletion) mutations were detected in ATM, BRIP1, CDH1, CHEK2, ERCC2, ERCC3, ERCC4, FANCA, MC1R, MEN1, MRE11A, MUTYH, PALB2, RAD51C, RET, SDHB, STK11. These mutations affect highly conserved protein domains and affect their function as proved by the available functional assays. They were confirmed to be pathogenic as an "Parent No2 " in serious recessive diseases such as Ataxia telangiectasia or Fanconi anemia. The clinical significance of the majority of detected missense variants still remains to be identified. CONCLUSION: Moderate or low penetrance variants are of limited clinical importance. Panel genetic testing in high-risk individuals with cancer provides important information concerning the cause of the investigated cancer, and may assist in the risk assesment and optimal management of the cancer, as well as in further preventive care.

[PALB2 as Another Candidate Gene for Genetic Testing in Patients with Hereditary Breast Cancer in Czech Republic]. / PALB2 jako dalsí kandidátní gen pro genetické testování u pa-cientu s hereditárním karcinomem prsu v Ceské republice.

BACKGROUND: The PALB2 (FANCN) gene was identified as a component of endogenous BRCA2 complex that encodes a DNA repair protein participating along with BRCA1 and BRCA 2 proteins in DNA double-strand break repair. Hereditary PALB2 mutations are associated with an increased risk of breast and pancreatic cancers in heterozygotes. Breast cancer risk for PALB2 mutation carriers has recently been estimated at 33-58% depending on family history of breast cancer; pancreatic cancer risk in carriers of PALB2 mutations has not been precisely quantified, yet. MATERIALS AND RESULTS: Results of a study identifying PALB2 mutations in high-risk, BRCA1/2-negative, breast and/or ovarian cancer patients in the Czech Republic indicate that the frequency of hereditary PALB2 mutations in our population is quite high. Interestingly, almost 20% of all recognized mutations comprised large genomic rearrangements. The highest proportion of PALB2 mutations (comparable with the number of mutations reported for BRCA2) was found in a subgroup of hereditary breast cancer patients (5.5%). Frequency of mutations in an independent group of Czech unselected pancreatic cancer patients was approximately 1.3%. CONCLUSION: Considering the frequency of pathogenic, hereditary PALB2 mutations in our population, their phenotypic similarity to BRCA2, and expected risk of breast cancer associated with PALB2 mutations, its screen-ing (including large genomic rearrangements) should be encouraged in patients from hereditary breast cancer families. The follow-up of pathogenic PALB2 mutation carriers should be similar to that in BRCA2 mutation carriers, enabling early diagnosis, prevention, and possible targeted therapy. Preventive surgical interventions for the carriers could be considered in case of strong family cancer history and evident segregation of a pathogenic mutation with a tumor phenotype. Additional analysis of various cancer patient populations and further meta-analyses will be necessary for accurate assessment of PALB2 gene penetrance and its significance for the risk of pancreatic and other cancers.

[Fanconi Anemia, Complementation Group D1 Caused by Biallelic Mutations of BRCA2 Gene--Case Report]. / Fanconiho anémie, komplementacní skupina D1 v dusledku bialelické mutace genu BRCA2--kazuistika.

Fanconi anemia is a rare autosomal recessive disorder, clinically and genetically heterogeneous, characterized by typical clinical features, such as short stature, microcephaly, skeletal abnormalities, abnormal skin pigmentations, developmental delay and congenital heart, kidney anomalies etc. Pancytopenia leading to bone marrow failure occurs in the first decade. Patients with Fanconi anemia have a high risk of hematologic malignancies and solid tumors. The diagnosis of Fanconi anemia is based on cytogenetic testing for increased rates of spontaneous chromosomal breakage and increased sensitivity to diepoxybutane or mitomycin C. Fanconi anemia is a heterogeneous disorder, at least 15 complementation groups are described, and 15 genes in which mutations are responsible for all of the 15 Fanconi anemia complementation groups have been identified. Unlike other Fanconi anemia complementation groups, for complementation group D1 (FANCD1), the bone marrow failure is not a typical feature, but early-onset leukemia and specific solid tumors, most often medulloblastoma and Wilms tumor, are typical for this complementation group.

Occupational exposure to endocrine disruptors and lymphoma risk in a multi-centric European study.

BACKGROUND: Incidence rates of lymphoma are usually higher in men than in women, and oestrogens may protect against lymphoma. METHODS: We evaluated occupational exposure to endocrine disrupting chemicals (EDCs) among 2457 controls and 2178 incident lymphoma cases and subtypes from the European Epilymph study. RESULTS: Over 30 years of exposure to EDCs compared to no exposure was associated with a 24% increased risk of mature B-cell neoplasms (P-trend=0.02). Associations were observed among men, but not women. CONCLUSIONS: Prolonged occupational exposure to endocrine disruptors seems to be moderately associated with some lymphoma subtypes.

Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium.

BACKGROUND: Type 2 diabetes mellitus has been associated with an excess risk of pancreatic cancer, but the magnitude of the risk and the time-risk relationship are unclear, and there is limited information on the role of antidiabetic medications. PATIENTS AND METHODS: We analyzed individual-level data from 15 case-control studies within the Pancreatic Cancer Case-Control Consortium, including 8305 cases and 13 987 controls. Pooled odds ratios (ORs) were estimated from multiple logistic regression models, adjusted for relevant covariates. RESULTS: Overall, 1155 (15%) cases and 1087 (8%) controls reported a diagnosis of diabetes 2 or more years before cancer diagnosis (or interview, for controls), corresponding to an OR of 1.90 (95% confidence interval, CI, 1.72-2.09). Consistent risk estimates were observed across strata of selected covariates, including body mass index and tobacco smoking. Pancreatic cancer risk decreased with duration of diabetes, but a significant excess risk was still evident 20 or more years after diabetes diagnosis (OR 1.30, 95% CI 1.03-1.63). Among diabetics, long duration of oral antidiabetic use was associated with a decreased pancreatic cancer risk (OR 0.31, 95% CI 0.14-0.69, for ≥15 years). Conversely, insulin use was associated with a pancreatic cancer risk in the short term (OR 5.60, 95% CI 3.75-8.35, for <5 years), but not for longer duration of use (OR 0.95, 95% CI 0.53-1.70, for ≥15 years). CONCLUSION: This study provides the most definitive quantification to date of an excess risk of pancreatic cancer among diabetics. It also shows that a 30% excess risk persists for more than two decades after diabetes diagnosis, thus supporting a causal role of diabetes in pancreatic cancer. Oral antidiabetics may decrease the risk of pancreatic cancer, whereas insulin showed an inconsistent duration-risk relationship.

A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus.

Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0.81, 95% confidence interval (95% CI) = 0.76-0.86, P(combined) = 3.5 × 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.

Occupational exposure to trichloroethylene and risk of non-Hodgkin lymphoma and its major subtypes: a pooled InterLymph [correction of IinterLlymph] analysis.

OBJECTIVES: We evaluated the association between occupational exposure to trichloroethylene (TCE) and risk of non-Hodgkin lymphoma (NHL) in a pooled analysis of four international case-control studies. METHODS: Overall, the pooled study population included 3788 NHL cases and 4279 controls. Risk of NHL and its major subtypes associated with TCE exposure was calculated with unconditional logistic regression and polytomous regression analysis, adjusting by age, gender and study. RESULTS: Risk of follicular lymphoma (FL), but not NHL overall or other subtypes, increased by probability (p=0.02) and intensity level (p=0.04), and with the combined analysis of four exposure metrics assumed as independent (p=0.004). After restricting the analysis to the most likely exposed study subjects, risk of NHL overall, FL and chronic lymphocytic leukaemia (CLL) were elevated and increased by duration of exposure (p=0.009, p=0.04 and p=0.01, respectively) and with the combined analysis of duration, frequency and intensity of exposure (p=0.004, p=0.015 and p=0.005, respectively). Although based on small numbers of exposed, risk of all the major NHL subtypes, namely diffuse large B-cell lymphoma, FL and CLL, showed increases in risk ranging 2-3.2-fold in the highest category of exposure intensity. No significant heterogeneity in risk was detected by major NHL subtypes or by study. CONCLUSIONS: Our pooled analysis apparently supports the hypothesis of an increase in risk of specific NHL subtypes associated with occupational exposure to TCE.

Cigarette smoking and risk of Hodgkin lymphoma and its subtypes: a pooled analysis from the International Lymphoma Epidemiology Consortium (InterLymph).

BACKGROUND: The etiology of Hodgkin lymphoma (HL) remains incompletely characterized. Studies of the association between smoking and HL have yielded ambiguous results, possibly due to differences between HL subtypes. PATIENTS AND METHODS: Through the InterLymph Consortium, 12 case-control studies regarding cigarette smoking and HL were identified. Pooled analyses on the association between smoking and HL stratified by tumor histology and Epstein-Barr virus (EBV) status were conducted using random effects models adjusted for confounders. Analyses included 3335 HL cases and 14 278 controls. RESULTS: Overall, 54.5% of cases and 57.4% of controls were ever cigarette smokers. Compared with never smokers, ever smokers had an odds ratio (OR) of HL of 1.10 [95% confidence interval (CI) 1.01-1.21]. This increased risk reflected associations with mixed cellularity cHL (OR = 1.60, 95% CI 1.29-1.99) and EBV-positive cHL (OR = 1.81, 95% CI 1.27-2.56) among current smokers, whereas risk of nodular sclerosis (OR = 1.09, 95% CI 0.90-1.32) and EBV-negative HL (OR = 1.02, 95% CI 0.72-1.44) was not increased. CONCLUSION: These results support the notion of etiologic heterogeneity between HL subtypes, highlighting the need for HL stratification in future studies. Even if not relevant to all subtypes, our study emphasizes that cigarette smoking should be added to the few modifiable HL risk factors identified.

[Juvenile polyposis syndrome]. / Juvenilný polypózny syndróm.

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by the occurrence of juvenile polyps and predisposition to cancer of the gastrointestinal tract (GIT). Characteristic feature of juvenile polyps are irregular cystic glands filled with mucus not observed in other colorectal cancer syndromes. Germline mutations in the SMAD4 and BMPR1A genes are found in 40% of the JP individuals. Hereditary hemorrhagic telangiectasia (HHT) and higher frequency of gastric polyposis are associated mostly with SMAD4 mutations.

[Hereditary diffuse gastric cancer]. / Hereditární difuzní karcinom zaludku.

Hereditary diffuse gastric cancer is an autosomal dominant syndrome with a high lifetime risk of diffuse gastric cancer and also a high risk of lobular breast carcinoma. Hereditary diffuse gastric cancer (HDGC) is characterized by late presentation and a poor prognosis. The average age of onset of HDGC is 38 years, with a range of 14-69 years. The estimated lifetime risk of developing gastric cancer by age 80 is 67% for men and 83% for women. Many families with HDGC have germline mutations in the E-cadherin (CDH1) gene. We describe indication for genetic testing of germline mutations in CDH1 gene, possibilities of predictive testing, preventive care, prophylactic gastrectomy and preimplantation diagnosis.

[Li-Fraumeni syndrome - a proposal of complex prevention care for carriers of TP53 mutation with total-body MRI]. / Li-Fraumeni syndrom - návrh komplexní preventivní péce o nosice TP53 mutace s pouzitím celotelové magnetické rezonance.

Li-Fraumeni syndrome (LFS) is one of the most serious hereditary cancer syndromes with high risk of malignancy already in childhood. Adrenocortical carcinoma, brain tumor, leukemia, sarcoma are the most frequent malignancies in children. Early breast cancer, brain tumor, sarcoma, skin cancer, gastrointestinal, lung, gynecological, hematological and other malignancies can be seen in adults. Predictive testing in families with detected LFS and TP53 mutation is offered from the age of 18 for various reasons. One of the most important reasons is a very limited effectivity of prevention especially in children, also the possible risk of psychological harm to the child and his family caused by the diagnosis of this syndrome. Progress in diagnostic methods, especially total body MRI, enables to propose preventive care for early cancer diagnoses for children and adults. Biochemical tests, ultrasound, MRI may improve survival of these high risk individuals and support the possibility of predictive testing in children.

[The clinical importance of a genetic analysis of moderate-risk cancer susceptibility genes in breast and other cancer patients from the Czech Republic]. / Klinický význam analýz genu stredního rizika pro hodnocení rizika vzniku karcinomu prsu a dalsích nádoru v Ceské republice.

BACKGROUND: Analysis of the major breast cancer (BC) predisposition genes BRCA1 and BRCA2 enables identification of high-risk individuals. Specialized programs enrolling the carriers of BRCA1/2 mutations facilitate an improvement in prevention and early diagnostics in asymptomatic individuals and rationalize the selection of individualized treatment in case of a BC onset. However, the carriers of mutations in the major predisposition genes represent only approximately 25% of cases among high-risk BC patients. Numerous candidate predisposing genes for breast and other cancers have recently been identified. The risk of cancer development associated with alterations in these genes is lower, and there is a considerable population variability in different regions worldwide. AIM: We have performed mutation analyses of moderate-risk cancer susceptibility genes to evaluate their clinical importance for genetic counseling in high-risk patients suffering from breast and other cancers in the Czech population. RESULTS: Czech oncological patients were analysed for mutation in ATM, CHEK2, NBS1 (NBN) and PALB2 genes. The majority of analyzed individuals represent the population of high-risk BRCA1/2-negative BC patients. CONCLUSIONS: Based on results of this study, we recommend an analysis of recurrent truncating mutations in the CHEK2 gene (the c.1100delC mutation and a large deletion affecting exons 9-10) in BRCA1/2-negative patients from high-risk BC families. A clinical assessment of missense variants in CHEK2 is not suitable. A routine mutation analysis of the ATM and NBS1 (NBN) genes is not recommended in BC patients due to the low frequency of alterations in these genes in the Czech Republic. An identification of truncating mutations in the PALB2 gene is important in BRCA1/2-negative BC patients from families with a strong history of BC (HBC families). The frequency of PALB2 mutations may be comparable to the frequency of mutations in the BRCA2 gene in Czech HBC families.

[The effect of prophylactic mastectomy with recontruction on quality of life in BRCA positive women]. / Vliv profylaktické mastektomie s rekonstrukcí na kvalitu zivota zen s BRCA pozitivitou.

UNLABELLED: It is presumed that bilateral mastectomy is so far the most efficient way how to prevent development of breast carcinoma among BRCA positive patients. This mutilating intervention might be unacceptable for cosmetic reasons for most women. The purpose of this study was to determine the influence of prophylactic mastectomy on the quality of life of BRCA positive patients by comparing results of psychodiagnostic questionnaire methods before surgical intervention and after it. Our data set consisted of 25 BRCA positive healthy women and 19 BRCA positive women in remission. All these patients underwent a reconstructive surgical intervention after mastectomy. Age of patients was 38-55 years. The following questionnaires were used: Life Satisfaction Questionnaire by J. Fahrenberg, M. Myrtek and E. Brähler, Clinical analysis questionnaire by S. E. Kruge and R. B. Cattel, Impact of Event Scale - Revised by D. S. Weiss and C. R. Marmar. RESULTS: Women in remission showed most significant decrease in Financial position category and minor decrease in Work and Employment category and Friends, Acquaintances and Relatives category. Improvement of quality of life was recorded especially in category of Health, Sexuality, Own person, Partnership and in Relationship with own children and there was also a significant improvement to overall life satisfaction. Among healthy patients, there was a significant improvement in category of Health and Own person. Most significant decrease was in dimension of Financial position and Work and employment. Prophylactic mastectomy with reconstruction might be the way of prevention of breast carcinoma because from psychological point of view there is the unambiguously significant fact that there was improvement of perception of own health and own person in both groups of women. These are the quality of life aspects that are considered to be basal and long term stabilizing from the perspective of dynamics of own self and they also systematically influence other aspects of quality of life which are derived from them.

[Surgical prevention of breast carcinoma in patients with hereditary risk]. / Chirurgická prevence karcinomu prsu u pacientek s dedicným rizikem.

BACKGROUND: Women with BRCA1 gene mutation have 85% risk of breast cancer; the risk for BRCA2 carriers is 45%. The aim of the study was to verify if prophylactic mastectomy with immediate breast reconstruction can prevent breast cancer in BRCA positive patients. MATERIAL: There were 100 BRCA positive women in which prophylactic mastectomy with immediate reconstruction, 75 dieps, 25 with implants, performed in period 2000-2011. Group A was composed of healthy, non-affected 41 patients, group B of 59 patients in remission after breast cancer treatment. These groups were compared to group C that consisted of 219 healthy carriers of BRCA1/2, non-operated, from registry of genetic department of the Masaryk Memorial Cancer in Brno, from 2000-2011. METHOD: Follow-up for oncology status was done in September 2011 for all 3 groups. RESULTS: Average follow-up of 21 months revealed that in group A there was no breast cancer, in group B 4 patients died and 2 had treatment for metastases. In group C, there were 16 new cases of breast cancer. CONCLUSION: Bilateral prophylactic mastectomy with immediate reconstruction can be an effective way in breast cancer prevention in healthy carriers of BRCA1/2 mutation. In BRCA positive patients treated for breast cancer, the effect of prophylactic mastectomy is unclear. Their survival is more influenced by their previous disease than by a new tumor in the breast.

[Evaluation of variants of unknown significance in the BRCA2 gene]. / Hodnocení variant nejasného významu v genu BRCA2.

BACKGROUND: Endogenous processes and exogenous agents cause constant DNA damage. DNA double-strand breaks are among the most serious types of damage. They are mainly repaired by homologous recombination, where the BRCA2 protein plays a dominant role. Heterozygous germline BRCA2 mutations predispose to breast, ovarian, pancreatic and other types of cancer. The presence of a pathogenic mutation in patients or their family members warrants close surveillance and prophylactic surgery. Apart from clearly pathogenic mutations, variants leading only to a single amino acid substitution are often identified. Since the influence of these variants on cancer risk is unknown, they represent a major clinical problem. AIMS: The aim of this paper is to summarize the current possibilities of predicting pathogenicity of BRCA2 variants. In some cases, genetic methods are able to classify variants with high probability; however, their use is often limited by low frequency of the variants or inaccessibility of samples for mRNA isolation or DNA from family members. Alternatively, functional assays performed in various cellular models may be employed. Multiple functional tests and cellular models are presented and characterized, including their advantages and limitations. A new model of human syngeneic cell lines developed by the authors is presented, in which one BRCA2 allele is deleted and the variant is introduced into the other allele by homologous recombination. This model has the potential to evaluate function of variants without some of the unwanted effects of the other models. Currently, this model is being applied to variants identified in patients with hereditary cancer predisposition in the Masaryk Memorial Cancer Institute. CONCLUSION: Functional assays in cellular models including a new model of syngeneic cell lines described by the authors have a great potential in evaluating clinical importance of unclassified variants in the BRCA2 gene, especially in cases where genetic tests are not applicable.

[Diagnostics of breast cancer in high-risk women - our own experience]. / Diagnostika nádoru prsu ve skupine rizikových zen - vlastní zkusenosti.

Preventive oncology clinic of MMCI provides complex preventive care for women with high hereditary risk of breast and ovarian cancer due to germline mutations in BRCA1 and BRCA2 genes. Clinical follow-up is also provided to women with mutations in other genes causing a higher risk of different tumors, and also to women with increased lifetime empirical risk of breast cancer due to positive family history. Our clinic was established in 2000 and takes care for about 700 women. The goal of the clinic is to extend the life expectancy of these women to the level of the regular population. The risk of breast cancer can be reduced by prophylactic surgeries. Prophylactic mastectomy and oophorectomy are offered to women at a high risk. Other modality in breast cancer risk reduction is a chemoprevention by Tamoxifen. Most women accept only secondary prevention with the goal of the detection of breast cancer in clinical stage I, where the tumor is smaller than 1 cm and the risk of recurrence is less than 10%. The algorithm of prevention care was changed over the time and our diagnostic methods were improved by magnetic resonance imaging of breasts. During the 11 years of clinical follow-up 32 breast cancers in 31 women were detected. High risk women are examined every 6 month by physical examination, breast ultrasound and MRI plus mammography yearly.

Menstrual and reproductive factors, and hormonal contraception use: associations with non-Hodgkin lymphoma in a pooled analysis of InterLymph case-control studies.

BACKGROUND: The two most common forms of non-Hodgkin lymphoma (NHL) exhibit different sex ratios: diffuse large B-cell lymphoma (DLBCL) occurs more frequently in men and follicular lymphoma (FL) more frequently in women. Looking among women alone, this pooled analysis explores the relationship between reproductive histories and these cancers. MATERIALS AND METHODS: Self-reported reproductive histories from 4263 women with NHL and 5971 women without NHL were pooled across 18 case-control studies (1983-2005) from North America, Europe and Japan. Study-specific odd ratios (ORs) and confidence intervals (CIs) were estimated using logistic regression and pooled using random-effects meta-analyses. RESULTS: Associations with reproductive factors were found for FL rather than NHL overall and DLBCL. In particular, the risk of FL decreased with increasing number of pregnancies (pooled OR(trend) = 0.88, 95% CI 0.81-0.96). FL was associated with hormonal contraception (pooled OR = 1.30, 95% CI 1.04-1.63), and risks were increased when use started after the age of 21, was used for <5 years or stopped for >20 years before diagnosis. DLBCL, on the other hand, was not associated with hormonal contraception (pooled OR = 0.87, 95% CI 0.65-1.16). CONCLUSIONS: Hormonal contraception is associated with an increased risk of FL but not of DLBCL or NHL overall.