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Contains fulltext : 125819.pdf (Publisher’s version ) (Closed access) Abstract Objective: To determine the reasons for women's anxiety and psychological stress before and during colposcopy, in order to define strategies to decrease their stress. Methods: Qualitative study with 15 women participating in four focus groups between April 2011 and April 2012. All participants were diagnosed with a cervical cytological abnormality and attended a gynecologist's clinic to undergo colposcopy. The focus group interview was audio-taped and transcribed verbatim. The data were analyzed using qualitative content analysis to identify themes. Results: Psychological stress before colposcopy was seen as being caused by unsatisfactory explanation of abnormal cervical smears and the colposcopy procedure itself. Additionally, a fear of cancer, pain and discomfort, embarrassment, waiting time in the hospital, and a longer interval between referral and the actual colposcopy appointment increased psychological stress and anxiety. Women indicated that more detailed and practical information about the cervical smear result and the colposcopy procedure may reduce stress and anxiety. Conclusion: In order to minimize the adverse psychological consequences of an abnormal cervical smear and colposcopy, timely, practical and detailed information needs to be provided to the women, and waiting and access times need to be as short as possible. These measures may reduce the psychological stress and anxiety, however some stress and anxiety will always remain, and may even be desirable in order to ensure proper follow-up of abnormal cervical smears.

Item does not contain fulltext Vulvar squamous cell carcinoma, its precursor lesions (usual and differentiated vulvar intraepithelial neoplasia) and lichen sclerosus are rare diseases that may have a large impact on the lives of affected women and their partners. Proper identification is vital, but the lesions are sometimes difficult to diagnose because of their rarity and variety of symptoms. High quality of care and proper treatment is important in order to minimize the morbidity and mortality caused by these lesions. This review gives an outline of the latest insights regarding the current evidence in this area and unresolved issues. Additionally, it highlights the improvements that should be made in order to optimize prevention and identification of (pre-)malignant vulvar lesions and to increase the quality of care for these patients.

Contains fulltext : 187523.pdf (Publisher’s version ) (Closed access) BACKGROUND The risk of recurrent oncological disease due to the reintroduction of cancer cells via autotransplantation of cryopreserved ovarian tissue is unknown. METHODS A systematic review of literature derived from MEDLINE, EMBASE and the Cochrane Library was conducted. Studies on follow-up after autotransplantation; detection of cancer cells in ovarian tissue from oncological patients by histology, polymerase chain reaction or xenotransplantation; and epidemiological data on ovarian metastases were included. RESULTS A total of 289 studies were included. Metastases were repeatedly detected in ovarian tissue obtained for cryopreservation purposes from patients with leukaemia, as well as in one patient with Ewing sarcoma. No metastases were detected in ovarian tissue from lymphoma and breast cancer patients who had their ovarian tissue cryopreserved. Clinical studies indicated that one should be concerned about autotransplantation safety in patients with colorectal, gastric and endometrial cancer. For patients with low-stage cervical carcinoma, clinical data were relatively reassuring, but studies focused on the detection of metastases were scarce. Oncological recurrence has been described in one survivor of cervical cancer and one survivor of breast cancer who had their ovarian tissue autotransplanted, although these recurrences may not be related to the transplantation. CONCLUSIONS It is advisable to refrain from ovarian tissue autotransplantation in survivors of leukaemia. With survivors of all other malignancies, current knowledge regarding the safety of autotransplantation should be discussed. The most reassuring data regarding autotransplantation safety were found for lymphoma patients.

Contains fulltext : 124525.pdf (Publisher’s version ) (Closed access) BACKGROUND: Despite the excellent prognosis of Federation Internationale de Gynecologie et d'Obstetrique (FIGO) stage I, type I endometrial cancers, a substantial number of patients experience recurrence and die from this disease. We analyzed the value of immunohistochemical L1CAM determination to predict clinical outcome. METHODS: We conducted a retrospective multicenter cohort study to determine expression of L1CAM by immunohistochemistry in 1021 endometrial cancer specimens. The Kaplan-Meier method and Cox proportional hazard model were applied for survival and multivariable analyses. A machine-learning approach was used to validate variables for predicting recurrence and death. RESULTS: Of 1021 included cancers, 17.7% were rated L1CAM-positive. Of these L1CAM-positive cancers, 51.4% recurred during follow-up compared with 2.9% L1CAM-negative cancers. Patients bearing L1CAM-positive cancers had poorer disease-free and overall survival (two-sided Log-rank P < .001). Multivariable analyses revealed an increase in the likelihood of recurrence (hazard ratio [HR] = 16.33; 95% confidence interval [CI] = 10.55 to 25.28) and death (HR = 15.01; 95% CI = 9.28 to 24.26). In the L1CAM-negative cancers FIGO stage I subdivision, grading and risk assessment were irrelevant for predicting disease-free and overall survival. The prognostic relevance of these parameters was related strictly to L1CAM positivity. A classification and regression decision tree (CRT)identified L1CAM as the best variable for predicting recurrence (sensitivity = 0.74; specificity = 0.91) and death (sensitivity = 0.77; specificity = 0.89). CONCLUSIONS: To our knowledge, L1CAM has been shown to be the best-ever published prognostic factor in FIGO stage I, type I endometrial cancers and shows clear superiority over the standardly used multifactor risk score. L1CAM expression in type I cancers indicates the need for adjuvant treatment. This adhesion molecule might serve as a treatment target for the fully humanized anti-L1CAM antibody currently under development for clinical use.

Contains fulltext : 118802.pdf (Publisher’s version ) (Closed access) OBJECTIVE: In endometrial carcinoma, myometrial invasion is a well known predictor of recurrence, and important in the decision making for adjuvant treatment. According to the FIGO staging system, myometrial invasion is expressed as invasion of of the myometrium (50%MI). It has been suggested to use the absolute depth of invasion (DOI), or the tumor free distance to the serosa (TFD). The aim of this study was to compare DOI, 50%MI, and TFD. METHODS: All patients diagnosed with endometrioid endometrial carcinoma at the RUNMC, and the CWH from 1999 to 2009 were included. Histologic slides were reviewed for histologic type and grade, DOI, 50%MI, and TFD. After review, 335 patients were identified. DOI, 50%MI, and TFD were evaluated for their prediction of clinicopathologic characteristics. RESULTS: The prediction of recurrence was best performed by DOI when compared to TFD, with an area under the ROC curve of 0.726, and 0.638 respectively. The optimal cut-off value for DOI was 4mm. DOI independently correlated with recurrence of disease, and death of disease. TFD was associated with advanced age and large tumor diameter. DOI was the best predictor of progression-free and disease-specific survival next to 50%MI and TFD (HR 3.15, 95%CI 1.16-8.56) and (HR 10.35, 95%CI 1.23-86.93). CONCLUSIONS: DOI showed better predictive performance than TFD, and was more strongly correlated with clinicopathologic parameters than TFD and 50%MI. Possibly, DOI should substitute 50%MI as measure to express myometrial invasion in daily clinical practice. External validation is mandatory to confirm the proposed cut-off value of 4mm.

Item does not contain fulltext DNA-testing for BRCA1/2 or Lynch syndrome is possible from the age of 18 years, although surveillance usually starts at 25. Some patients regret their decision of testing before age 25. This retrospective study evaluates whether the testing age should be above 25 years to prevent adverse effects such as regret or decisional conflict, by determining the percentage and characteristics of patients reporting these problems. 111 of 219 patients (51 %) tested for BRCA1/2 mutations or Lynch syndrome between 18 and 25 years from July 1996 to February 2011, returned self-report surveys. Primary measures were regret, decisional conflict and family influence. Secondary measures included quality of life (QoL), coping style, impact of genetic testing, and risk perception. Median age was 27 [21-40] years, with 86 % female. 73 % was tested for BRCA1/2, 27 % for Lynch syndrome. Only 3 % reported regret, however 39 % had moderate (32 %) to severe (7 %) decisional conflict. Regression analysis revealed that decisional conflict was associated with more monitoring/neutral coping style (p < 0.03) or paternal/no family mutation (p < 0.02); there were no differences in QoL, impact or risk perception. 42 % were mutation carriers, showing equal decisional conflict to non-carriers. 68 % would recommend testing

Contains fulltext : 118139.pdf (Publisher’s version ) (Closed access) PURPOSE: The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology. METHODS: We used data from 21 case-control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model. RESULTS: Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03-1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39-2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12-1.50). For these histological types, consistent dose-response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer. CONCLUSIONS: Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease.

Contains fulltext : 118729.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Currently, human chorionic gonadotropin (hCG) follow-up after evacuation of hydatidiform moles is essential to identify patients requiring chemotherapeutic treatment for gestational trophoblastic neoplasia (GTN). We propose a model based on linear regression of postevacuation serum hCG concentrations for the prediction of GTN. METHODS: One hundred thirteen patients with at least 3 serum samples from days 7 to 28 after evacuation were selected from the Dutch Central Registry for Hydatidiform Moles (1994-2009). The slopes of the linear regression lines of the first 3 log-transformed serum hCG and free beta-hCG values were calculated. Receiver operating characteristic curves were constructed to calculate areas under curve (AUCs). RESULTS: The slope of the hCG regression line showed an AUC of 0.906 (95% confidence interval, 0.845-0.967). Gestational trophoblastic neoplasia could be predicted in 52% of patients with GTN at 97.5% specificity (cutoff, -0.020). Twenty-one percent of patients with GTN could be predicted before diagnosis according to the International Federation of Gynecology and Obstetrics 2000 criteria. The slope of free beta-hCG showed an AUC of 0.844 (95% confidence interval, 0.752-0.935), 69% sensitivity at 97.5% specificity, and 38% of patients with GTN could be predicted before diagnosis according to the International Federation of Gynecology and Obstetrics criteria. CONCLUSIONS: The slope of the linear regression line of hCG proved to be a good test to discriminate between patients who will achieve spontaneous disease remission and patients developing GTN. The slope of free beta-hCG seems to be a better predictor for GTN than the slope of hCG. Although this model needs further validation for different assays, it seems a promising way to predict the more aggressive cases of GTN.

Contains fulltext : 127334.pdf (Publisher’s version ) (Closed access) PURPOSE: The aim of this study was to examine the expression of established stem cell markers in ascites and tumor tissue obtained from ovarian cancer patients. METHODS: Mononuclear cells present in ascites were collected by density gradient centrifugation. Intracellular flowcytometry was used to assess the putative presence of stem cell markers. RT-PCR was used to detect full length Oct4A, a splice variant Oct4B, implicated in glioma and breast cancer, Oct4 pseudogenes and c-Myc. Genes were cloned and sequenced to determine putative mutations. Confocal laser scanning microscopy was performed to localize the markers in ascites cells as well as in tumor tissue. Material from carcinomas other than epithelial ovarian carcinoma served as control. RESULTS: A small quantity of cells in ascites and in tumor tissue of ovarian cancer patients was detected that expresses c-Myc, Oct4A and Nanog. Besides Oct4A, present in the nucleus, also the cytoplasmic resident Oct4B splice variant was detected. Remarkably, c-Myc was found partially in the cytoplasm. Since no mutations in c-Myc were found that could explain the cytoplasmic localization, we hypothesize that this is due an IL-6 induced c-Myc shuttle factor. CONCLUSIONS: The expression of stem cell genes was detected in a small proportion of tumor cells present in ascites as well as in tumor tissue. IL-6 plays an important role in the induction of c-Myc.

Objective: To assess the value of breast MRI in size assessment of breast cancers in high risk patients, including those with a BRCA 1 or 2 mutation. Guidelines recommend invariably breast MRI screening for these patients and therapy is thus based on these findings. However, the accuracy of breast MRI for staging purposes is only tested in sporadic cancers. Methods: We assessed concordance of radiologic staging using MRI with histopathology in 49 tumors in 46 high risk patients (23 BRCA1, 12 BRCA2 and 11 Non-BRCA patients). The size of the total tumor area (TTA) was compared to pathology. In invasive carcinomas (n = 45) the size of the largest focus (LF) was also addressed. Results: Correlation of MRI measurements with pathology was 0.862 for TTA and 0.793 for LF. TTA was underestimated in 8(16%), overestimated in 5(10%), and correctly measured in 36(73%) cases. LF was underestimated in 4(9%), overestimated in 5(11%), and correctly measured in 36(80%) cases. Impact of BRCA 1 or 2 mutations on the quality of size estimation was not observed. Conclusions: Tumor size estimation using breast MRI in high risk patients is comparable to its performance in sporadic cancers. Therefore, breast MRI can safely be used for treatment planning. (C) 2013 Elsevier Ireland Ltd. All rights reserved

The phase 3 RECORD-1 study demonstrated clinical benefit of everolimus over placebo (median progression-free survival: 4.9 mo compared with 1.9 mo, p0.001) in treatment-resistant patients with metastatic renal cell carcinoma (mRCC). However, the Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate was low.To explore the potential role of tumor burden response to everolimus in predicting patient survival.RECORD-1 patients with at least two tumor assessments (baseline and weeks 2-14) were included (n=246).A multivariate Cox proportional hazard model was used to assess the impact of various prognostic factors on overall survival (OS). Components of RECIST progression were explored using univariate Cox regression.The baseline sum of longest tumor diameters (SLD) and progression at weeks 2-14 were prognostic factors of OS by multivariate analysis. Univariate analysis at weeks 2-14 demonstrated that growth of nontarget lesions and appearance of new lesions were predictive of OS (p0.001). This retrospective analysis used data from one arm of one trial; patients in the placebo arm were excluded because of confounding effects when they crossed over to everolimus.This analysis identified baseline SLD as a predictive factor of OS, and the appearance of a new lesion or progression of a nontarget lesion at first assessment after baseline also affects OS in patients with mRCC treated with everolimus.

Contains fulltext : 126182.pdf (Publisher’s version ) (Closed access) AIM: Previous studies showed an increase in incidence of vulvar intraepithelial neoplasia (VIN), the premalignant lesion of Vulvar Squamous Cell Carcinoma (VSCC). Furthermore, during the last decades treatment of VSCC became less radical. Considering these changes the aim of this study was to describe trends of incidence and survival of patients with VSCC in the Netherlands. METHODS: All patients with VSCC diagnosed between 1989 and 2010 (n=4614) were selected from the Netherlands Cancer Registry. Trends in age-adjusted incidence rates were evaluated by calculating the estimated annual percentage change (EAPC). Joinpoint regression analysis was used to detect changes in trends. Five-year relative survival rates were calculated for four time periods. RESULTS: The incidence of VSCC has increased since 2002 (EAPC 5.0; 95% confidence interval (CI): 2.7-7.7%). In women aged

Contains fulltext : 118440.pdf (Publisher’s version ) (Open Access) During cancer genetic counseling, different items which counselors consider important are discussed. However, relatively little empirical evidence exists regarding the needs and preferences of counselees. In this study needs and preferences were assessed from counselees with a personal and/or family history of colorectal cancer (CRC), who were referred for genetic counseling regarding CRC. They received a slightly modified version of the QUOTE-GENE(ca) questionnaire prior to their first visit to the Hereditary Cancer Clinic. Response rate was 60 % (48/80 participants). Counselees rated the importance of 45 items assessing their needs and preferences regarding the content and process of genetic counseling. Participants rated the items regarding discussion of information about their familial CRC risk (100 %) and preventive options (98 %) as important or very important. Fewer participants rated items concerning general information on genetics as important. Sensitive communication during counseling was considered very important by a large percentage of counselees. Generally, no major differences were seen between participants in relation to individual characteristics. Our data suggest that focusing on familial CRC risk and surveillance options, in combination with sensitive communication may lead to better satisfaction with genetic counseling.

Contains fulltext : 117502.pdf (Publisher’s version ) (Closed access) Human papillomavirus (HPV) is a necessary factor in the development of cervical intraepithelial neoplasia and cervical cancer. However, HPV is also a very common sexually transmitted virus and many women clear their infection. To study HPV incidence and clearance, 2,065 women, aged 18-29 years, were followed for 12 months and were asked to provide a self-collected cervico-vaginal sample and fill-out a questionnaire every 3 months. For HPV DNA detection, the SPF10 -DEIA LiPA25 system was used. Incidence rates of any-type high-risk HPV and low-risk HPV were 17.0 per 1,000-person months, and 14.3 per 1,000-person months, respectively. HPV types 16, 52, 51 and 31 had the highest type-specific incidence rates. HPV incidence was increased in singles, and women having a new relationship. A higher number of lifetime sex partners, and a higher frequency of sexual contacts in the past 3 months was associated with an increased HPV incidence. The overall clearance of the newly detected type-specific high-risk HPV infections and low-risk HPV infections was 61.2% and 69.0%, respectively. Having a sexual relationship compared to being single, and a higher sexual age both positively influenced the clearance of any-type high-risk HPV. Among the women infected with HPV 16, the women who had a co-infection had a lower proportion of clearance of HPV 16. In conclusion, in this young Dutch study population, HPV incidence rates are not related to age and comparable to other western countries. Clearance was only independently related to factors associated with sexual behavior, either past or current.

Contains fulltext : 125202.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Epithelial ovarian cancer in women 40 years or younger is rare; diagnosis at this age justifies referral for genetic testing. We evaluated clinical data, family history, and risk of identifying BRCA1/2 mutations in women with early-onset epithelial ovarian cancer. MATERIALS/METHODS: Women 40 years or younger with epithelial ovarian cancer tested for BRCA1/2 mutation at our department of human genetics between 1996 and 2012 were included. The rate of BRCA1/2 mutation was obtained; carriers were compared to noncarriers regarding clinical data. RESULTS: Ten (19%) of 52 women had a BRCA1/2 mutation. This mutation was detected in 67% of women with and in 9% of the women without first-degree relatives with breast and/or ovarian cancer (P < 0.001; Fisher exact test). The median age at diagnosis was lower in the noncarriers compared to the carriers (30 vs 38 years; P = 0.014). Among the BRCA1/2 mutation carriers, 60% had serous tumors, 80% had moderately to poorly differentiated tumors, and 70% had International Federation of Gynecology and Obstetrics stage III/IV compared to 55%, 43%, and 45%, respectively, in the noncarriers. CONCLUSIONS: The risk of finding a BRCA1/2 mutation in women 40 years or younger is comparable to women of all ages with epithelial ovarian cancer. Prior probability of finding a BRCA1/2 mutation in these young women is largely determined by their family history, which can help caregivers in informing ahead of genetic counseling and testing.

Contains fulltext : 118506.pdf (Publisher’s version ) (Closed access) Molecular pathology is an integral part of daily diagnostic pathology and used for classification of tumors, for prediction of prognosis and response to therapy, and to support treatment decisions. For these reasons, analyses in molecular pathology must be highly reliable and hence external quality assessment (EQA) programs are called for. Several EQA programs exist to which laboratories can subscribe, but they vary in scope, number of subscribers, and execution. The guideline presented in this paper has been developed with the purpose to harmonize EQA in molecular pathology. It presents recommendations on how an EQA program should be organized, provides criteria for a reference laboratory, proposes requirements for EQA test samples, and defines the number of samples needed for an EQA program. Furthermore, a system for scoring of the results is proposed as well as measures to be taken for poorly performing laboratories. Proposals are made regarding the content requirements of an EQA report and how its results should be communicated. Finally, the need for an EQA database and a participant manual are elaborated. It is the intention of this guideline to improve EQA for molecular pathology in order to provide more reliable molecular analyses as well as optimal information regarding patient selection for treatment.

Purpose Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6. Patients and Methods Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene–specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk. Results The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers. Conclusion The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.

Contains fulltext : 108161.pdf (Publisher’s version ) (Closed access) Background We present normograms for human chorionic gonadotropin (hCG) regression in patients with high-risk gestational trophoblastic neoplasia (GTN) successfully treated with multiagent chemotherapy in order to predict treatment resistance. Patients and methods We collected data for 46 patients with high-risk GTN treated with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) who had hCG values available. Patients were classified as having methotrexate (MTX)-resistant disease (n = 22) or primary high-risk disease (n = 24). The 10th, 50th and 90th percentiles of the hCG before every chemotherapy course were calculated and plotted in normograms. Results Half of the patients treated for MTX-resistant disease and primary high-risk disease had normal hCG levels before the third and sixth course of chemotherapy, respectively. In patients with MTX-resistant disease, the 90th percentile line fell below normal before the start of the fourth course, whereas in patients with primary high-risk disease this was not the case until the eighth course of chemotherapy. Conclusion Resistance to EMA/CO treatment for high-risk GTN, as illustrated by examples, could be predicted using normograms for hCG resistance. Normograms differed depending on the indication for multiagent chemotherapy due to much higher initial hCG values in patients with primary high-risk disease compared with those treated for MTX-resistant disease.

Contains fulltext : 110221.pdf (Publisher’s version ) (Closed access) Patients with double primary cancer (DPC) of the ovary and endometrium are considered to have a better prognosis than patients with only epithelial ovarian cancer (EOC). The aim of this study was to clarify the difference in prognosis by comparing clinicopathologic characteristics and survival. From the population-based database of the nationwide Netherlands Cancer Registry, women diagnosed between 1996 and 2006 with EOC were identified. Within this database of all EOC patients in 11 hospitals, the DPC patients were identified. Differences in characteristics between EOC-only and DPC patients were tested using Pearson chi tests and t-tests. Differences in overall survival were analyzed by Kaplan-Meier survival analyses and log-rank tests. Multivariable Cox regression analyses were performed to study the factors that influence survival. Among 1105 EOC patients, 29 (2.6%) DPC patients were identified. DPC patients were more often premenopausal (P

Item does not contain fulltext An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.

Contains fulltext : 107891.pdf (Publisher’s version ) (Closed access) Hereditary diffuse gastric cancer (HDGC) is a relatively rare disorder, with a mutated CDH1 gene as the only known cause. Carriers of a germline mutation in CDH1 have a lifetime risk of >80% of developing diffuse gastric cancer. As periodic gastric surveillance is of limited value in detecting early stages of HDGC, prophylactic gastrectomy is advised for this patient group. Little is known about other types of familial gastric cancer. The Dutch working group on hereditary gastric cancer has formulated guidelines for various aspects of medical management for families and individuals at high risk of developing gastric cancer, including criteria for referral, classification, diagnostics, and periodic gastric surveillance. These guidelines are not limited to HDGC and are therefore partially complementary to the guidelines on hereditary diffuse gastric cancer of the international gastric cancer linkage consortium (IGCLC 2010). In order to optimize the care and increase the knowledge on hereditary gastric cancer it is important to centralize medical care for these patients. National and international collaboration is warranted to improve the quality of research by increasing the size of study cohorts.

Contains fulltext : 108625.pdf (Publisher’s version ) (Open Access) The aim of this study was to evaluate the adequacy of family history taking in epithelial ovarian cancer (EOC) patients and to identify factors that determine adequacy. Furthermore, the validity of family history taking was assessed by comparison with self-administered questionnaires. Medical records of all 1,112 EOC patients registered by the nation-wide cancer registry and diagnosed in eleven Dutch hospitals between 1996 and 2006 were reviewed. Adequate family history taking was defined as a written notification of the presence or absence of relatives with breast or ovarian cancer. Factors that were correlated with family history taking were identified using univariable and multivariable logistic regression. 147 patients filled in a postal questionnaire. An adequate family history was taken in 41% of all cases. Younger age, an academic hospital and having undergone surgery and/or chemotherapy were associated with adequate family history taking. The comparison with self-administered questionnaires showed a disagreement in 64% mainly due to missing data in medical records. Documentation on family history is either absent or inadequate in the medical records in the majority of EOC patients. These data urge for better uptake of hereditary cancer risk assessment. Different strategies for this assessment like improved family history taking and genetic testing in EOC patients should be explored.

ObjectiveThe pathogenesis of serous ovarian carcinoma (SOC) is still unknown. Recently, endometrial intraepithelial carcinoma (EIC) was proposed to be the precursor lesion of SOC. This study examines the model of EIC as precursor for SOC.MethodsCases of SOC with a noninvasive or superficially invasive serous lesion, a hyperplastic lesion with/without atypia, or EIC in the endometrium were selected for inclusion in this study. Tissue sections from both ovaries, the fallopian tubes, and the uterus were extensively reviewed by an expert gynecopathologist. For both EIC and SOC, immunostaining for p53, Ki-67, estrogen receptor, and progesterone receptor; TP53 mutation analysis; and in situ ploidy analysis were performed.ResultsNine cases of SOC with concurrent EIC in the endometrium were identified. Immunostaining for p53, Ki-67, estrogen receptor, and progesterone receptor revealed almost identical expression patterns and similar intensities in each pair of EIC and coincident SOC. Identical TP53 mutations were found in SOC and coinciding EIC in 33% of the cases, suggesting a clonal origin. DNA ploidy analysis, as a marker for neoplastic progression, demonstrated an increased number of aneuploid nuclei in SOC compared to their corresponding EIC (P = 0.039). In addition, the mean amount of DNA per nucleus in SOC was higher (ie, more aneuploid) compared to EIC (P = 0.039).ConclusionThis study provides a first indication of EIC as possible precursor lesion for SOC. This finding could have major clinical implications for future ovarian cancer management and underscores EIC as a possible target for early SOC detection and prevention.

Item does not contain fulltext Revertant mosaicism is an infrequently observed phenomenon caused by spontaneous correction of a pathogenic allele. We have observed such reversions caused by mitotic recombination of mutant TERC (telomerase RNA component) alleles in six patients from four families affected by dyskeratosis congenita (DC). DC is a multisystem disorder characterized by mucocutaneous abnormalities, dystrophic nails, bone-marrow failure, lung fibrosis, liver cirrhosis, and cancer. We identified a 4 nt deletion in TERC in a family with an autosomal-dominant form of DC. In two affected brothers without bone-marrow failure, sequence analysis revealed pronounced overrepresentation of the wild-type allele in blood cells, whereas no such skewing was observed in the other tissues tested. These observations suggest that this mosaic pattern might have resulted from somatic reversion of the mutated allele to the normal allele in blood-forming cells. SNP-microarray analysis on blood DNA from the two brothers indeed showed independent events of acquired segmental isodisomy of chromosome 3q, including TERC, indicating that the reversions must have resulted from mitotic recombination events. Subsequently, after developing a highly sensitive method of detecting mosaic homozygosity, we have found four additional cases with a mosaic-reversion pattern in blood cells; these four cases are part of a cohort of 17 individuals with germline TERC mutations. This shows that revertant mosaicism is a recurrent event in DC. This finding has important implications for improving diagnostic testing and understanding the variable phenotype of DC.

Contains fulltext : 109223.pdf (Publisher’s version ) (Open Access) According to the Dutch Guideline on Hereditary Colorectal Cancer published in 2008, patients with recently diagnosed colorectal cancer (CRC) should undergo microsatellite instability (MSI) testing by a pathologist immediately after tumour resection if they are younger than 50 years, or if a second CRC has been diagnosed before the age of 70 years, owing to the high risk of Lynch syndrome (MIPA). The aim of the present MIPAPS study was to investigate general distress and cancer-specific distress following MSI testing. From March 2007 to September 2009, 400 patients who had been tested for MSI after newly diagnosed CRC were recruited from 30 Dutch hospitals. Levels of general distress (SCL-90) and cancer-specific distress (IES) were assessed immediately after MSI result disclosure (T1) and 6 months later (T2). Response rates were 23/77 (30%) in the MSI-positive patients and 58/323 (18%) in the MSI-negative patients. Levels of general distress and cancer-specific distress were moderate. In the MSI-positive group, 27% of the patients had high general distress at T1 versus 18% at T2 (p = 0.5), whereas in the MSI-negative group, these percentage were 14 and 18% (p = 0.6), respectively. At T1 and T2, cancer-specific distress rates in the MSI-positive group and MSI-negative group were 39 versus 27% (p = 0.3) and 38 versus 36% (p = 1.0), respectively. High levels of general distress were correlated with female gender, low social support and high perceived cancer risk. Moderate levels of distress were observed after MSI testing, similar to those found in other patients diagnosed with CRC. Immediately after result disclosure, high cancer-specific distress was observed in 40% of the MSI-positive patients. 01 juni 2012

Contains fulltext : 110066.pdf (Publisher’s version ) (Open Access) OBJECTIVE: A precursor lesion for ovarian carcinoma, tubal intraepithelial carcinoma (TIC), has been identified in BRCA-mutation carriers undergoing prophylactic bilateral salpingo-oophorectomy (pBSO). Other lesions were also identified in fallopian tubes, but different terminology, interpretation, and lack of knowledge of normal epithelium, have hampered to unravel their possible role in carcinogenesis. The aim of this study is to classify tubal epithelial lesions in BRCA-mutation carriers and controls to enable comparison of prevalence, area of localization, and possible malignant potential. METHODS: Two hundred twenty-six BRCA1/2-mutation carriers were included; ovaries and fallopian tubes, embedded completely, were reviewed. Controls included 105 women who underwent BSO for non-malignant reasons. Tubal epithelial lesions included the following categories: hyperplasia, minor epithelial atypia, TIC, and invasive carcinoma. RESULTS: Tubal neoplasia was identified in 7.1% (invasive carcinoma, 0.9%; TIC, 6.2%) of BRCA-mutation carriers compared to none in controls (p=0.004, Fisher's exact test). Hyperplasia and minor epithelial atypia were identified in 41.6% BRCA-mutation carriers and compared to 58.1% in controls (p=0.005, Pearson's chi square). Invasive carcinoma and TIC showed preference for the fimbrial ends (p=0.027, Pearson's chi square), while hyperplasia and minor epithelial atypia displayed more variation in localization. CONCLUSIONS: Invasive tubal carcinoma and TIC were limited to BRCA-mutation carriers, whereas hyperplasia and minor epithelial atypia were commonly found in both BRCA-mutation carriers and controls. It is suggested that hyperplasia and minor atypia represent variations of normal tubal epithelium instead of premalignant lesions. Furthermore, total salpingectomy is strongly recommended as most but not all TIC occurred in the fimbriae. 01 oktober 2012

Item does not contain fulltext Objective: We determined the clinical utility of preoperative serum CA-125 as predictor of extra-uterine disease and as prognosticator for survival in patients with uterine papillary serous carcinoma (UPSC).Methods: Patients diagnosed with UPSC, identified between 1992 and 2009, and with preoperative CA-125 measurement were included. A receiver operator characteristic (ROC) curve was used to quantify marker performance. Overall and progression free survival were analyzed using the Kaplan-Meier method. Regression analyses were used to investigate the association of preoperative CA-125 levels and other clinicopathological variables with the presence of extra-uterine disease and the effects on survival.Results: Sixty-six patients met the study criteria. Using ROC, the CA-125 concentration of 45 U/mL as cutoff level provided the best sensitivity (75%) and specificity (74%) for extra-uterine disease, with a positive predictive value of 86%. Survival was significantly longer in patients with preoperative CA-125 45 U/mL remained significantly associated with extra-uterine disease (OR=6.30, 95% CI 1.93-20.62). Furthermore, advanced FIGO stage (HR=4.53, 95% CI 1.50-13.62) and preoperative CA-125 >45 U/mL (HR=3.12, 95% CI 1.13-8.73) were associated with decreased survival.Conclusion: Preoperative elevated serum CA-125 is an independent predictor for the presence of extra-uterine disease and an independent risk factor for survival in UPSC patients.

Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods:IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06–1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39–3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28–2.70; class I HR, 0.86; 95%CI, 0.69–1.09; Pdifference, 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). Conclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(8); 1362–70. ©2012 AACR.

Item does not contain fulltext OBJECTIVE: A randomised controlled trial (RCT) demonstrated that cognitive behaviour therapy (CBT) for fatigue during curative cancer treatment was effective shortly after cancer treatment. This study aimed to identify which patient characteristics predict fatigue improvement after CBT. In addition, the long-term effectiveness was investigated. METHODS: Patients with various malignancies participated in the RCT (n = 210). Participants were assessed before cancer treatment (T1), postintervention (T2), which was at least 2 months after cancer treatment, and after 1-year follow-up (T3). Monthly fatigue assessments were completed between T2 and T3. A regression analysis with interactions was performed to determine if domains of quality of life (EORTC-QLQ-C30) functioning (Health Survey Short Form-36) or psychological distress (Symptom Checklist-90) moderated the effect of CBT on fatigue. Analyses of covariance were used to study the long-term effectiveness of CBT. RESULTS: Fatigue at T2 was predicted by a significant interaction between self-reported cognitive functioning and CBT. No interactions were found between other domains of quality of life, functioning, psychological distress and CBT. At T3, no significant difference on fatigue was found between CBT and usual care. Exploratory analyses showed that the difference nearly reached significance until 7 months postintervention. CONCLUSIONS: Patients who experienced more concentration and memory problems at T1 benefited more from CBT for fatigue and are indicators. After a year of follow-up, the effect of CBT for fatigue was no longer observed, and the effect on fatigue seemed to be diminished 7 months postintervention. The implication is that CBT for fatigue should be offered to patients with cancer with the highest chance to benefit. Copyright (c) 2011 John Wiley & Sons, Ltd.

Contains fulltext : 110060.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The aim of this study was to describe trends in survival and therapy in advanced stage epithelial ovarian cancer (EOC) in the Netherlands and to determine if changes in therapy affected survival. METHODS: All EOC patients diagnosed in the Netherlands during 1989-2009 were selected from the Netherlands Cancer Registry. Differences in treatment over time were tested by the Cochran-Armitage trend test. Multivariable relative survival analyses were performed to test whether changes in treatment are associated with survival. RESULTS: 23,399 EOC patients were diagnosed, of whom 15,892 (67.9%) in advanced stage (stage >/= 2b). In advanced stage patients, the proportion receiving (neo-)adjuvant chemotherapy and optimal debulking (residuals /= 75 years) a stable proportion (approximately 28%) did not receive any treatment. Five-year relative survival in advanced stage patients increased from 18% in 1989-1993 to 28% in 2004-2009. In the multivariable model survival improved over time (relative excess risk (RER) of 2004-2009 was 0.71, 95% CI 0.67-0.75 compared to 1989-1993). This RER attenuated to 0.85 (95% CI 0.80-0.90) and 0.91 (95% CI 0.83-0.99) with inclusion of treatment variables in the model (surgery with chemotherapy or optimal surgery with chemotherapy, respectively). This suggests that the improvement was mainly, although not entirely, caused by changes in treatment. CONCLUSION: Treatment in advanced stage EOC patients in the Netherlands improved over the last two decades; more patients received (neo)adjuvant chemotherapy and underwent optimal debulking surgery. Changes in treatment led to partial improvement of survival in EOC patients. 01 juni 2012

Item does not contain fulltext OBJECTIVE: The Risk of Malignancy Index (RMI) is a simple scoring system to standardize and improve the preoperative evaluation of adnexal masses. Since 1990, three versions of the RMI have been validated in different clinical studies. Recently, a fourth version of the RMI (RMI-4) was introduced that includes tumor size as an additional parameter. The aim of this study was to validate the ability of RMI-4 to discriminate between non-invasive lesions and invasive malignant adnexal masses, and to compare its performance with RMI-3. STUDY DESIGN: Women scheduled for surgery for an adnexal mass between 2005 and 2009 in 11 hospitals were included. Ultrasonographic characteristics, menopausal status and serum CA 125 level were registered preoperatively, and combined into the RMI. The performances of RMI-3 and RMI-4 were assessed and statistically tested for differences. RESULTS: A total of 643 patients were included: 469 benign, 73 borderline and 101 malignant tumors. The RMI-3 had a sensitivity of 76%, specificity of 82%, positive and negative predictive values (PPV and NPV) of 45% and 95%, and an accuracy of 81%. The RMI-4 had a sensitivity of 74%, specificity of 79%, PPV of 40%, NPV of 94%, and an accuracy of 78%. The accuracy of RMI-3 was significantly higher than the accuracy of RMI-4 (p=.001). Both models had an area under the curve of 0.86. CONCLUSION: Both RMI-3 and RMI-4 were able to discriminate between non-invasive lesions and invasive malignant adnexal masses, with similar performances. Including tumor size in the RMI does not improve its performance.

Contains fulltext : 110453.pdf (Publisher’s version ) (Closed access) CDH1 mutation carriers have a strongly increased risk of developing gastric cancer (GC) and lobular breast cancer (LBC). Clinical data of GC cases and surgical and histological data of prophylactic gastrectomies and mastectomies of all 10 Dutch CDH1 mutation families were collected. In vitro functional assays were performed to analyze the nature of the newly found missense mutation c.1748T>G (p.Leu583Arg). Ten different CDH1 mutations were found. Functional assays gave strong arguments for the pathogenic nature of the p.Leu583Arg mutation. The pedigrees comprised 36 GC cases (mean age 40 years, range 20-72 years) and one LBC case. Twenty-nine/37 carriers alive, aged 18-61 years, underwent prophylactic gastrectomy. Invasive GC-foci and premalignant abnormalities were detected in 2 and 25 patients, respectively. In four patients GC/signetring cell (SRC) foci were diagnosed at preoperative gastroscopy. Long-standing presence of SRCs without progression to invasive carcinoma was shown in two others. Multifocal LBC/LCIS was found in the two prophylactic mastectomy specimens. Clefts of lip and/or palate (CL/P) were reported in seven individuals from three families. The age at onset and aggressiveness of GC is highly variable, which has to be included in counseling on planning prophylactic gastrectomies. The incidence of LBC is expected to increase and prophylactic mastectomy needs to be considered. The relationship between CL/P and CDH1 needs further study to inform future parents from hereditary diffuse gastric cancer (HDGC) families adequately.

Item does not contain fulltext OBJECTIVE: To determine the factors that influence the use of frozen section analysis in adnexal masses and the factors that predict malignancy. METHODS: The study participants were women scheduled for adnexal mass surgery in 11 hospitals between 2005 and 2009. Factors that potentially influenced the use of frozen section analysis and potentially predicted malignancy were studied, such as menopausal status, CA 125 level, ultrasound characteristics, presence of adhesions, and tumor size. We used univariable and multivariable analyses to assess the factors. RESULTS: A total of 670 patients were included in the study. The frozen section analyses for 323 patients (48%) showed 206 benign, 55 borderline, and 62 malignant adnexal masses. The CA 125 level, locularity of the tumor, and presence of solid areas predicted both the use of frozen section analysis and the presence of malignancy. The presence of adhesions predicted malignancy, but not the use of frozen section analysis. Menopausal status and tumor size predicted the use of frozen section analysis, but not malignancy. CONCLUSION: Menopausal status and tumor size are associated with more use of frozen section analysis, but they have not been identified as factors associated with malignancy. Frozen section analysis is useful when the CA 125 levels are greater than 35 units/mL and when there are multilocular tumors, solid areas on ultrasonography, and adhesions revealed during surgery.

Contains fulltext : 97608.pdf (Publisher’s version ) (Closed access) BACKGROUND: The Dutch Health Council recently recommended the introduction of a colorectal cancer (CRC) screening programme by faecal occult blood testing (FOBT) for individuals aged 55-75 at population risk of CRC. Individuals at an increased familial CRC risk (>/= 2 times population risk) should be identified at a younger age, so they and their relatives can receive earlier, more intensive surveillance instead of FOBT. AIMS: To determine the percentage of participants with a positive FOBT in a CRC screening programme with an increased familial CRC risk. METHODS: In a population-based study, 10,569 individuals aged 50-75 received an FOBT. Individuals with a positive FOBT were invited for colonoscopy and familial risk assessment. Participants with an average familial CRC risk were compared to those with an increased risk. Increased familial CRC risk was defined as a cumulative lifetime risk of CRC of at least 10%. RESULTS: Of 6001 participants, 430 had a positive FOBT, of whom 324 (63% males; mean age 63 years) completed colonoscopy and familial risk assessment. CRC (n=22) and/or advanced adenomas (n=122) were found in 133 participants. Familial CRC risk was increased in 6% of participants with a positive FOBT. No significant differences were found between participants with an average versus an increased familial CRC risk. CONCLUSION: Six percent of participants with a positive FOBT had an increased familial CRC risk. Identifying at-risk participants enables them and their relatives to undergo regular colonoscopies. Adding familial risk assessment to FOBT screening may thus prevent a substantial number of CRCs.

Contains fulltext : 96762.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Patients treated for ovarian cancer with curative intent receive an intensive follow-up program in the years after treatment. However, the aimed improved survival through early detection of recurrence is subject to debate. Theoretically, the survival benefit depends on the lead time and the preclinical detection rate and on the effectiveness of recurrence treatment. This systematic review aimed at determining the effectiveness of early detection of recurrent ovarian cancer. METHODS: A systematic literature search in PubMed, EMBASE, MEDLINE, and the Cochrane Library was performed for articles published in 1985 to 2009 in English, German, or Dutch, excluding editorials, letters, and case reports. RESULTS: In total, 67 articles were included. Of 4 observational studies and 1 randomized controlled trial, only 1 observational study reported a better survival for patients who attended routine follow-up compared with those who did not. The sensitivity of cancer antigen 125 for a preclinical recurrence, based on 38 articles using 35 U/mL as a cutoff level, was 65%, with a median lead time of 3 months (range, 1-7 months). Seven studies showed that, on average, 67% (ranging from 20% to 80%) of the 798 relapsed patients had no clinical symptoms when recurrent ovarian cancer was diagnosed. CONCLUSIONS: Routine follow-up may detect 2 of 3 recurrences asymptomatically with a lead time of 3 months. Recurrence treatment may extend survival by several months, but published studies did not show a survival advantage of early detection by routine follow-up examinations. Therefore, the content and aims of routine follow-up should be reconsidered, whereas routine cancer antigen 125 testing with the aim to improve life expectancy should be omitted.

Item does not contain fulltext OBJECTIVE: Serum cancer antigen (CA) 125 is the only biomarker used frequently in women with or at risk for ovarian cancer. However, the same reference level is used before and after (prophylactic) bilateral salpingo-oophorectomy (BSO). We evaluated the effect of BSO on CA125 level in BRCA mutation carriers and tested which factors interact with the change in CA125 level. METHODS: All women who participated in the Nijmegen gynecological screening program and underwent prophylactic BSO were included. Information was obtained on age, smoking, menopausal state, previous hysterectomy and breast cancer, histopathological examination of the adnexa, hormone therapy use, and CA125 level before and after surgical operation. Ovarian volume was calculated. The logarithmic-transformed CA125 levels were used in a linear mixed model to study the relative change in CA125 level and possible interaction. RESULTS: In 60 women, a relative decrease of 18% in CA125 level after BSO was found (P < 0.01). The median serum CA125 level was 10.15 U/mL before and 8.36 U/mL after BSO. Menopausal state interacted with CA125 before and after the surgical operation (P < 0.01). In addition, ovarian volume did not explain the difference in CA125 level (P = 0.94). CONCLUSIONS: BRCA mutation carriers show a relative decrease in CA125 level after BSO. Menopausal state interacts with CA125. Ovarian volume was excluded as a confounder. Possibly, the hormonal effect of ovaries plays a role in the CA125 level. Our study suggests that not the reference level of 35 U/mL but a lower level, as already suggested for postmenopausal women, should be applied to women after a salpingo-oophorectomy.

Background CHARGE syndrome is a highly variable, multiple congenital anomaly syndrome, of which the complete phenotypic spectrum was only revealed after identification of the causative gene in 2004. CHARGE is an acronym for ocular coloboma, congenital heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear anomalies associated with deafness. This typical combination of clinical features is caused by autosomal dominant mutations in the CHD7 gene. Objective To explore the emerging phenotypic spectrum of CHD7 mutations, with a special focus on the mild end of the spectrum. Methods We evaluated the clinical characteristics in our own cohort of 280 CHD7 positive patients and in previously reported patients with CHD7 mutations and compared these with previously reported patients with CHARGE syndrome but an unknown CHD7 status. We then further explored the mild end of the phenotypic spectrum of CHD7 mutations. Results We discuss that CHARGE syndrome is primarily a clinical diagnosis. In addition, we propose guidelines for CHD7 analysis and indicate when evaluation of the semicircular canals is helpful in the diagnostic process. Finally, we give updated recommendations for clinical surveillance of patients with a CHD7 mutation, based on our exploration of the phenotypic spectrum and on our experience in a multidisciplinary outpatient clinic for CHARGE syndrome. Conclusion CHARGE syndrome is an extremely variable clinical syndrome. CHD7 analysis can be helpful in the diagnostic process, but the phenotype cannot be predicted from the genotype.

Contains fulltext : 95971.pdf (Publisher’s version ) (Closed access) OBJECTIVES: The aims of this study were to investigate human papillomavirus (HPV) genotypes in women with cervical intraepithelial lesions and cervical cancer (CC) in Honduras and to identify epidemiological cofactors that contribute to the development of CC. METHODS: Among the 289 patients analyzed, 139 had low-grade squamous intraepithelial lesion (LSIL), 60 had high-grade squamous intraepithelial lesion (HSIL), and 90 had CC. RESULTS: The HPV DNA was detected in 113 women (81%) with LSIL, in 58 women (97%) with HSIL, and in 84 women (93%) with CC. Twenty-five HPV genotypes were found. Human papillomavirus type 16 was detected in 41% of women with CC, in 35% of women with HSIL, and in 24% of women with LSIL. Human papillomavirus type 18 was found in 9% of women with CC, in 4% of women with HSIL, and 5% of women with LSIL. CONCLUSION: Therefore, implementation of the prophylactic vaccines against HPV genotypes 16 and 18 has the potential of preventing at least a quarter of LSIL, one third of HSIL, and about half of CC cases in Honduras.

Contains fulltext : 98458.pdf (Publisher’s version ) (Closed access) OBJECTIVE: We investigated whether providing targeted information on an individual level by mail and by phone reduces anxiety in women referred to the colposcopy clinic. DESIGN: Randomised controlled trial. POPULATION: Women referred to the colposcopy clinic. METHODS: Between December 2007 and April 2010, 169 patients with abnormal smear results were randomised into two study arms. Group A received individually targeted information about the diagnosis and procedure by mail and phone. Group B received the standard folder about colposcopies alone. Patients were requested to fill out a questionnaire prior to their first colposcopy appointment. MAIN OUTCOME MEASURES: The questionnaire included the hospital anxiety and depression scale (HADS), and the Spielberger state-trait anxiety inventory (STAI), as well as a short self-administered questionnaire. RESULTS: Twenty women were excluded from further analyses after randomisation, leaving 149 women for evaluation. The median STAI state anxiety score was high (50.0), but there was no significant difference in median STAI state anxiety and HADS anxiety scores between both groups. However, knowledge about human papillomavirus and the colposcopy procedure did significantly increase in group A (P = 0.004). CONCLUSIONS: Anxiety levels before primary colposcopy are surprisingly high, and are not reduced following individually targeted information given before colposcopy.

Contains fulltext : 95926.pdf (Publisher’s version ) (Open Access) It is well known that the genital skin may be affected by psoriasis. However, little is known about the prevalence and clinical appearance of genital psoriasis, and genital skin is often neglected in the treatment of psoriatic patients. We performed an extensive systematic literature search for evidence-based data on genital psoriasis with respect to epidemiology, aetiology, clinical and histopathological presentation, diagnosis and treatment. Three bibliographical databases (PubMed, EMBASE and the Cochrane Library) were used as data sources. Fifty-nine articles on genital psoriasis were included. The results show that psoriasis frequently affects the genital skin, but that evidence-based data with respect to the efficacy and safety of treatments for genital psoriasis are extremely limited. An advised treatment paradigm for genital psoriasis, based on the levels of evidence, is: first-line: (weak) topical corticosteroids; second-line: vitamin D preparations or tar-based treatments.

Summary Background Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6 , and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3′ end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM -expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions. Methods We obtained clinical data for 194 carriers of a 3′ end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6 , or a combined EPCAM–MSH2 deletion. Findings 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65–85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM–MSH2 deletion (69% [95% CI 47–91], p=0·8609) or mutations in MSH2 (77% [64–90], p=0·5892) or MLH1 (79% [68–90], p=0·5492), but was higher than noted for carriers of MSH6 mutation (50% [38–62], p EPCAM deletions had a 12% [0–27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM–MSH2 deletion (55% [20–90], p MSH2 (51% [33–69], p=0·0006) or MSH6 (34% [20–48], p=0·0309), but did not differ significantly from that noted for MLH1 (33% [15–51], p=0·1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer. Interpretation EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers. Funding Sacha Swarttouw-Hijmans Foundation, Dutch Cancer Society, Deutsche Krebshilfe (German Cancer Aid), Hong Kong Cancer Fund, Hungarian Research Grant OTKA, Norwegian EEA Financial Mechanism (Hungarian National Institute of Oncology), and US National Cancer Institute.

Item does not contain fulltext Lichen sclerosus is considered to be the precursor lesion of vulvar squamous cell carcinoma, of which only 2-5% progress to squamous cell carcinoma. Differentiated vulvar intraepithelial neoplasia (VIN) has been proposed to be the direct precursor lesion, but this is a recently recognized, and a difficult to diagnose, entity, which may easily be mistaken for a benign dermatosis. The aim of this study was to test the hypothesis that of all lesions that have been diagnosed as lichen sclerosus in the past, a part might currently be diagnosed as differentiated VIN, and to identify histopathological differences between lichen sclerosus lesions with and without progression to vulvar squamous cell carcinoma. All lichen sclerosus slides were revised by two expert gynecopathologists and histopathological characteristics were documented. After revision of lichen sclerosus biopsies without progression (n = 61), 58 were reclassified as lichen sclerosus. Revision of lichen sclerosus biopsies with progression yielded concordant diagnoses in 18 of 60 cases (30%). Of 60 lesions, 25 (42%) were reclassified as differentiated VIN. The median time from differentiated VIN to vulvar squamous cell carcinoma was shorter (28 months) than that from lichen sclerosus to vulvar squamous cell carcinoma (84 months) (P < 0.001). Lichen sclerosus that progressed to squamous cell carcinoma, but did not meet the criteria for differentiated VIN, more often showed parakeratosis (P = 0.004), dyskeratosis (P < 0.001), hyperplasia (P = 0.048) and basal cellular atypia (P = 0.009) compared with lichen sclerosus without progression. In conclusion, differentiated VIN diagnosis has been frequently missed and is associated with rapid progression to squamous cell carcinoma. Patients with lichen sclerosus with dyskeratosis and parakeratosis, hyperplasia and/or basal cellular atypia should be kept under close surveillance as these lesions also tend to progress to squamous cell carcinoma.

Aims: Tamoxifen is metabolized by cytochrome P450s, with an important role for CYP2D6. Recently, we demonstrated in 80 patients that CYP2C19*2 is associated with increased survival in breast cancer patients using tamoxifen. Here, we aimed to confirm this in a large group of 499 patients. Materials & methods: A total of 499 estrogen receptor-positive primary breast tumor specimens of advanced disease patients treated with first-line tamoxifen were genotyped for CYP2C19*2 and *17 variant alleles, with primary end point time-to-treatment failure (TTF). Effects of CYP2C19, independent of treatment, were analyzed in 243 primary systematic untreated patients. Results: CYP2C19*2 hetero- and homozygote patients combined showed significantly longer TTFs (hazard ratio [HR]: 0.72; 95% CI: 0.57–0.90; p = 0.004). In multivariate analysis, including CYP2D6*4 status, CYP2C19*2 remained independently associated with TTF (HR: 0.73; 95% CI: 0.58–0.91; p = 0.007). In untreated patients, the CYP2C19*17 allele was significantly associated with a longer disease-free interval (HR: 0.66; 95%CI: 0.46–0.95; p = 0.025). Conclusion: CYP2C19 genotyping is potentially important for tamoxifen therapy for advanced disease and for breast cancer prognosis. Original submitted 14 February 2011; Revision submitted 8 April 2011

Background: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies. Methods: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated. Results: The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71–1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59–1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk. Conclusion: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers. Impact: Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk. Cancer Epidemiol Biomarkers Prev; 20(5); 1032–8. ©2011 AACR.

Contains fulltext : 96128.pdf (Publisher’s version ) (Closed access) In Europe, the use of anti-EGFR monoclonal antibodies is restricted to Kirsten RAS (KRAS) wild-type colorectal tumors. Information on the KRAS status of the patients tumor is thus key for clinical practice; however, there is little guidance or definition on which KRAS mutations to assess and how to assess them. To ensure the consistency and the quality of KRAS test results in Europe, an interlaboratory control network needs to be set up. This pilot study aimed to identify the variables that need to be assessed in a quality control scheme and to provide a first assessment in a selected set of laboratories. Fourteen different tumor cases were circulated between 13 laboratories by a central laboratory acting as the referent for the mutation status determination. This study illustrated that of 13 experienced laboratories that perform KRAS testing only ten correctly identified the KRAS in all 14 cases that were circulated. There was no harmonization in DNA isolation and KRAS mutation detection method between the laboratories. These results indicate that future standardization is needed in KRAS mutation detection methodology. An expansion of the European Society of Pathology KRAS program could identify areas of difficulty in KRAS testing and provide the basis for harmonization.

Contains fulltext : 96007.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The objective of this study is to determine the incidence and time trends of gestational trophoblastic disease (GTD) in The Netherlands using population-based data. METHODS: Data on patients with a pathologically confirmed diagnosis of GTD from 1995 to 2008 were obtained from PALGA, a national archive containing all histopathology reports in The Netherlands. Data on number of deliveries were obtained from the Database of Statistics Netherlands. RESULTS: During the study period, 4249 GTD patients were registered. Overall incidence rates of hydatidiform mole (HM), choriocarcinoma and placental site trophoblastic tumor (PSTT) were 1.34 per 1000 deliveries, 3.1 per 100,000 deliveries, and 1.0 per 100,000 deliveries, respectively. Incidence rates of HM increased from 1.02 per 1000 deliveries in 1995 to 1.56 per 1000 in 2001, an increase of 0.091 per year (95% CI 0.081-0.101). After 2001 incidence rates remained constant (increase per year -0.010, 95% CI -0.045-0.024). Maternal age and ethnicity are known to influence the risk of HM. Highest incidences were observed in women under 20 and over 40years of age. The proportion of deliveries accounted for by women over 40years of age increased from 1.5% to 2.9%, whereas women under 20 accounted for 1.5% of deliveries. The proportion of live births of Asian descent increased from 2.6% to 3.7%. CONCLUSION: The incidence of GTD in The Netherlands increased significantly from 1995 to 2008. This can partially be explained by increased maternal age and increased proportion of live births of Asian descent. Part of the increase might result from improved diagnostic techniques. However, these factors do not seem to account for the total observed increase and part of the increase therefore remains unexplained.

Item does not contain fulltext Uterine papillary serous carcinoma (UPSC) is an aggressive variant of endometrial cancer. Owing to its rarity, most clinicians are unfamiliar with the clinical aspects and management of UPSC. Furthermore, little prospective evidence exists regarding how best to treat this subset of patients. In anticipation of prospective clinical trials, this article summarizes the latest results of various clinical management options in the different substages of UPSC, with a special focus on the effects of cytoreductive surgery, comprehensive surgical staging and different adjuvant treatment options in relation to recurrence rate and survival outcome.

Item does not contain fulltext BACKGROUND: The bachelor-master (BaMa) structure was introduced in medical schools in The Netherlands since 2003 and in Utrecht University in 2006. AIM: The aim of this study was to determine whether conferring a bachelor degree at the end of 3 years of medical school influences the career considerations of the students. METHODS: Two cohorts (BaMa and pre-BaMa) of medical students at Utrecht University were approached to fill out questionnaires in 2008 and 2009, about their career plans and whether a bachelor degree would affect these plans. RESULTS: In 2008, two-thirds of the students in both cohorts indicated that they considered a temporary stop. In 2009, the BaMa cohort showed substantially less interest in such a stop than the pre-BaMa cohort. Very few students considered a permanent stop. Comparison of third year pre-BaMa students (2008 cohort) with third year BaMa students (2009 cohort) revealed adjusted odds ratios of 2.34 (95% CI 1.34-4.09) for a temporary stop and 1.33 (95% CI 0.51-3.42) for a definitive stop. CONCLUSION: Awarding a bachelor degree in the BaMa structure does not encourage students to interrupt or discontinue their medical study, to transfer to another master programme or to transfer to another medical school.

Contains fulltext : 88721.pdf (Publisher’s version ) (Open Access) We investigated success factors for the introduction of a guideline on recognition of Lynch syndrome in patients recently diagnosed with colorectal cancer (CRC) below age 50 or a second CRC below age 70. Pathologists were asked to start microsatellite instability (MSI) testing and report to surgeons with the advice to consider genetic counselling when MSI test or family history was positive. A multicentre cluster-randomised controlled trial (ClinicalTrials.gov, number NCT00141466) was performed in 12 pathology laboratories (clusters), serving 29 community hospitals. All received an introduction to the new guideline. In the intervention group, surgeons received education and tumour test result reminders; pathologists were provided with inclusion criteria cards, an electronic patient inclusion reminder system and feedback on inclusion. Two hundred sixty-six CRC patients were eligible for recognition as at risk for Lynch syndrome. The actual recognition was 18% more successful in the intervention as compared to the control arm (77% (120 of 156) compared to 59% (65 of 110)), with an adjusted odds ratio (OR) = 2.8 (95% confidence interval (CI) 1.1-7.0). The electronic reminder system for pathologists was most strongly associated with recognition of high-risk patients, OR = 4.2 (95% CI 1.7-10.1). An electronic reminder system for pathologists appeared effective for adherence to a new complex guideline and will enhance the recognition of Lynch syndrome. 01 juni 2010

Contains fulltext : 88517.pdf (Publisher’s version ) (Closed access) To identify molecularly defined subgroups in multiple myeloma, gene expression profiling was performed on purified CD138(+) plasma cells of 320 newly diagnosed myeloma patients included in the Dutch-Belgian/German HOVON-65/GMMG-HD4 trial. Hierarchical clustering identified 10 subgroups; 6 corresponded to clusters described in the University of Arkansas for Medical Science (UAMS) classification, CD-1 (n = 13, 4.1%), CD-2 (n = 34, 1.6%), MF (n = 32, 1.0%), MS (n = 33, 1.3%), proliferation-associated genes (n = 15, 4.7%), and hyperdiploid (n = 77, 24.1%). Moreover, the UAMS low percentage of bone disease cluster was identified as a subcluster of the MF cluster (n = 15, 4.7%). One subgroup (n = 39, 12.2%) showed a myeloid signature. Three novel subgroups were defined, including a subgroup of 37 patients (11.6%) characterized by high expression of genes involved in the nuclear factor kappa light-chain-enhancer of activated B cells pathway, which include TNFAIP3 and CD40. Another subgroup of 22 patients (6.9%) was characterized by distinct overexpression of cancer testis antigens without overexpression of proliferation genes. The third novel cluster of 9 patients (2.8%) showed up-regulation of protein tyrosine phosphatases PRL-3 and PTPRZ1 as well as SOCS3. To conclude, in addition to 7 clusters described in the UAMS classification, we identified 3 novel subsets of multiple myeloma that may represent unique diagnostic entities.