Search

In patients with left-sided obstructive colon cancer (LSOCC), a stoma is often constructed as part of primary treatment, but with a considerable risk of becoming a permanent stoma (PS). The aim of this retrospective multicentre cohort is to identify risk factors for a PS in LSOCC and to develop a pre- and postoperative prediction model for PS. Data was retrospectively obtained from 75 hospitals in the Netherlands. Patients who had curative resection of LSOCC between January 1, 2009 to December 31, 2016 were included with a minimum follow-up of 6 months after resection. The interventions analysed were emergency resection, decompressing stoma or stent as bridge-to-elective resection. Main outcome measure was presence of PS at the end of follow-up. Multivariable logistic regression analysis was performed to identify risk factors for PS at primary presentation (T 0) and after resection, in patients having a stoma in situ (T 1). These risk factors were used to construct a web-based prediction tool. Of 2099 patients included in the study (T 0), 779 had a PS (37%). A total of 1275 patients had a stoma in situ directly after resection (T 1), of whom 674 had a PS (53%). Median follow-up was 34 months. Multivariable analysis showed that older patients, female sex, high ASA-score and open approach were independent predictors for PS in both the T 0 and T 1 population. Other predictors at T 0 were sigmoid location, low Hb, high CRP, cM1 stage, and emergency resection. At T 1 , subtotal colectomy, no primary anastomosis, not receiving adjuvant chemotherapy and high pTNM stage were additional predictors. Two predictive models were built, with an AUC of 0.74 for T 0 and an AUC of 0.81 for T 1. PS is seen in 37% of the patients who have resection of LSOCC. In patients with a stoma in situ directly after resection, 53% PS are seen due to non-reversal. Not only baseline characteristics, but also treatment strategies determine the risk of a PS in patients with LSOCC. The developed predictive models will give physicians insight in the role of the individual variables on the risk of a PS and help in informing the patient about the probability of a PS. [ABSTRACT FROM AUTHOR]

Background: With the increasing use of decompressing stoma as a bridge to surgery for left-sided obstructive colon cancer (LSOCC), the timing of restoration of bowel continuity (ROBC) is a subject of debate. There is a lack of data on immediate ROBC during elective resection as an alternative for a 3-stage procedure. This study analysed if immediate ROBC during tumour resection is safe and of any benefit for patients who underwent decompressing stoma for LSOCC., Methods: In a Dutch nationwide collaborative research project, 3153 patients who underwent resection for LSOCC in 75 hospitals (2009-2016) were identified. Extensive data on disease and procedural characteristics, and outcomes was collected by local collaborators. For this analysis, 332 patients who underwent decompressing stoma followed by curative resection were selected. Immediate ROBC during tumour resection was compared to two no immediate ROBC groups, (1) tumour resection with primary anastomosis (PA) with leaving the decompressing stoma in situ, and (2) tumour resection without PA., Results: Immediate ROBC was performed in 113 patients (34.0%) and no immediate ROBC in 219 patients [168 with PA (50.6%) and 51 patients without PA (15.4%)]. No differences at baseline between the groups were found for age, ASA score, cT, and cM. Major surgical complications (8.8% immediate ROBC vs. 4.8% PA with decompressing stoma and 7.8% no PA; P =0.37) and mortality (2.7% vs. 2.4% and 0%, respectively; P =0.52) were similar. Immediate ROBC resulted in a shorter time with a stoma (mean 41 vs. 240 and 314 days, respectively; P <0.001), and fewer permanent stomas (7% vs. 21% and 80%, respectively; P <0.001) as compared to PA with a decompressing stoma or no PA., Conclusion: After a decompressing stoma for LSOCC, immediate ROBC during elective resection appears safe, reduces the total time with a stoma and the risk of a permanent stoma., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Chronic pelvic pain (CPP) is a common multifactorial condition affecting 6%-27% of women aged 18-50 years worldwide. The aim of this randomised controlled trial (RCT) is to investigate the efficacy and safety of botulinum toxin A (BTA) injection compared with placebo injections in the pelvic floor muscles in women with CPP to improve pain, function and quality of life., Methods and Analysis: This is a study protocol for a multicentre, double-blinded placebo controlled RCT conducted in five gynaecology departments across the Netherlands. A total of 94 women over 16 years, with at least 6 months of CPP without anatomical cause and pelvic floor hypertonicity refractory to first-line pelvic floor physical therapy will be included. Participants will be randomised equally to BTA or placebo, both following physical therapy and (re-)education on the pelvic floor at 4, 8, 12 and 26 weeks after intervention. Multiple validated questionnaires focusing on pain, quality of life and sexual function will be collected at baseline and during all follow-up visits. Statistical analysis includes mixed models for repeated measurements., Ethics and Dissemination: Ethical approval (NL61409.091.17) was obtained from Radboud University Medical Research Ethics Committee (MREC) and Central Committee on Research involving human Subjects (CCMO). The findings will be presented through international conferences and peer-reviewed scientific journals., Trial Registration Number: EudraCT number (2017-001296-23), CCMO/METC number: NL61409.091.17., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Pre-test genetic counseling of patients with breast cancer is increasingly being offered by non-genetic healthcare professionals. We aimed to evaluate the experiences of patients with breast cancer receiving pre-test genetic counseling from a non-genetic healthcare professional (i.e., surgeon or nurse)., Methods: Patients who were diagnosed with breast cancer and received pre-test counseling from their surgeon or nurse (mainstream group), and patients who received pre-test counseling from a clinical geneticist (usual care group) were invited to participate in our multicenter study. Between September 2019 and December 2021, patients received a questionnaire after pre-test counseling (T0) and four weeks after receiving their test results (T1) to evaluate psychosocial outcomes, knowledge, discussed topics and satisfaction., Results: We included 191 patients in our mainstream and 183 patients in our usual care group and received, respectively 159 and 145 follow-up questionnaires. Levels of distress and decisional regret were comparable in both groups. Decisional conflict was higher in our mainstream group (p = 0.01), but only 7% had clinically relevant decisional conflict (vs 2% in usual care group). The possible implications of a genetic test on (secondary) breast or ovarian cancer risks were less frequently discussed in our mainstream group (p = 0.03 and p = 0.000, respectively). In both groups knowledge about genetics was comparable, satisfaction was high and the majority of patients in both groups preferred to give both verbal and written consent for genetic testing., Conclusion: Mainstreamed genetic care provides sufficient information for the majority of breast cancer patients to decide about genetic testing with minimal distress., Competing Interests: Declarations of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: To date, both one- and two-stage techniques are used in immediate 'implant-based breast reconstruction' (IBBR) after mastectomy. Because it is still unknown what technique offers the best clinical outcomes, a multicenter retrospective study was conducted to compare both breast reconstruction techniques., Methods: All patients, who underwent a mastectomy followed by immediate one- or two-stage IBBR during 2010 - 2016 were included. Our primary outcome measure was explantation of the 'tissue expander' (TE) and/ or implants within 60 days after breast reconstruction. Secondary outcomes were overall complication rate and secondary corrections., Findings: Among a total of 383 women, TE/ implant explantation rate was higher in one-stage (19.9%) than in two-stage (11.3%) treated patients (p = 0.082). Overall complication rate (35.7% and 19.9% respectively, p = 0.008) and secondary corrections (29.8% and 20.3% respectively, p = 0.156) were also higher in one-stage compared to two-stage IBBR respectively. However, explantation (OR = 1.55; 95%CI = 0.67-3.58, p = 0.301) and complication (OR = 1.85; 95%CI = 0.92-3.37, p = 0.084) rates were comparable in one- and two-stage IBBR in our stratified multivariate logistic regression analyses, when controlling for history of smoking, nipple-sparing mastectomy, neoadjuvant radiation therapy, and removed breast tissue weight. A remarkable outcome in this study is that women treated with prophylactic surgery were more likely to have an explantation of the TE/ implant after a one-stage IBBR (OR = 4.49; 95%CI = 1.10-18.3, p = 0.037) than two-stage IBBR. In contrast, no association between type of IBBR and risk of TE/implants removal was found among women with a therapeutic mastectomy (OR = 0.82; 95%CI = 0.24-2.79, p =  = 0.74)., Conclusion: One- and two-stage IBBR showed a comparable explantation and complication rate in our retrospective study. In one-stage IBBR more secondary corrections were detected. In addition, women who have to decide on a prophylactic mastectomy should be aware of a significantly higher risk of explantation of their implant after one-stage IBBR., Competing Interests: Declaration of Competing Interest None to declare, (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The global push for the use of hydroxychloroquine (HCQ) and chloroquine (CQ) against COVID-19 has resulted in an ongoing discussion about the effectivity and toxicity of these drugs. Recent studies report no effect of (H)CQ on 28-day mortality. We investigated the effect of HCQ and CQ in hospitalized patients on the non-ICU COVID-ward., Methods: A nationwide, observational cohort study was performed in The Netherlands. Hospitals were given the opportunity to decide independently on the use of three different COVID-19 treatment strategies: HCQ, CQ, or no treatment. We compared the outcomes between these groups. The primary outcomes were 1) death on the COVID-19 ward, and 2) transfer to the intensive care unit (ICU)., Results: The analysis included 1064 patients from 14 hospitals: 566 patients received treatment with either HCQ (n = 189) or CQ (n = 377), and 498 patients received no treatment. In a multivariate propensity-matched weighted competing regression analysis, there was no significant effect of (H)CQ on mortality on the COVID ward. However, HCQ was associated with a significantly decreased risk of transfer to the ICU (hazard ratio (HR) = 0.47, 95% CI = 0.27-0.82, p =  0.008) when compared with controls. This effect was not found in the CQ group (HR = 0.80, 95% CI = 0.55-1.15, p =  0.207), and remained significant after competing risk analysis., Conclusion: The results of this observational study demonstrate a lack of effect of (H)CQ on non-ICU mortality. However, we show that the use of HCQ - but not CQ - is associated with a 53% reduction in risk of transfer of COVID-19 patients from the regular ward to the ICU. Recent prospective studies have reported on 28-day, all-cause mortality only; therefore, additional prospective data on the early effects of HCQ in preventing transfer to the ICU are still needed., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Colorectal carcinoma (CRC) has a worldwide incidence of 1.4 million patients and a large share in cancer-related mortality. After curative treatment, the risk of recurrence is 30-65%. Early detection may result in curative treatment. However, current follow-up (FU) examinations have low sensitivity ranging from 49 to 85% and are associated with high costs. Therefore, the search for a new diagnostic tool is justified. Analysis of volatile organic compound in exhaled air through an electronic nose (eNose) is a promising new patient-friendly diagnostic tool. We studied whether the eNose under investigation, the Aeonose™, is able to detect local recurrence or metastases of CRC., Methods: In this cross-sectional study we included 62 patients, all of whom underwent curative treatment for CRC in the past 5 years. Thirty-six of them had no metastases and 26 had extraluminal local recurrence or metastases of CRC, detected during FU. Breath testing was performed and machine learning was used to predict extraluminal recurrences or metastases, and based on the receiver operating characteristics (ROC)-curve both sensitivity and specificity were calculated., Results: The eNose identified extra luminal local recurrences or metastases of CRC with a sensitivity and specificity of 0.88 (CI 0.69-0.97) and 0.75 (CI 0.57-0.87), respectively, with an overall accuracy of 0.81., Discussion: This eNose may be a promising tool in detecting extraluminal local recurrences or metastases in the FU of curatively treated CRC. However, a well-designed prospective study is warranted to show its accuracy and predictive value before it can be used in clinical practice., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Frailty is a geriatric condition that is associated with an increased risk of mortality and functional decline. To date, mainly the Groningen Frailty Indicator (GFI) and Hospital Safety Management (VeiligheidsManagementSysteem [VMS]) frailty score are used to determine frailty in several hospitals in the Netherlands. However, it is yet unknown, which method has the best predictive value on clinical outcomes., Objective: The aim of this study was to investigate the predictive value of GFI and VMS on clinical outcomes among patients who underwent hip fracture surgery., Design: This is a prospective observational cohort study., Methods: We selected all patients aged 70 years or higher, who underwent hip fracture surgery in our general hospital, between November 2014 and November 2015. Among all patients, VMS, GFI and Barthel-20 index (BI) were assessed. McNemar's paired test and Cohen's κ were used to examine the difference and the level of agreement between the two scoring methods. Kaplan-Meier and multivariable regression analyses were performed to determine overall survival and mortality, respectively, 3 years and 30 days after surgery., Results: A total of 280 patients were included in the study. The median follow-up was 25 months. No systematic difference was found between the two methods ( P =0.237), while a fair level of agreement could be measured (κ=0.363 [95% CI =0.23-50]). VMS showed a statistically significant difference in overall survival as compared to nonfrail patients (57 vs 80%, respectively [ P logrank <0.001] with an HR of 3.5 [95% CI =2.1-5.7; P <0.001]). Classification according to GFI yielded a lower but still significant HR 2.3 (95% CI =1.2-4.1; P =0.008)., Conclusion: VMS can be used in classifying frailty, whereby VMS frailty score is associated with clinical outcomes as overall survival mortality in older patients with hip fracture and who underwent surgery., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objectives: Adequate bowel preparation is an important step for an effective colonoscopy. Polyethylene glycol solution (Kleanprep) and sodium picosulphate with a magnesium citrate solution (Picoprep) are bowel cleansing agents registered and available for this purpose. So far, the results of studies comparing the effectiveness of bowel cleansing between the two agents are inconclusive. This may be because of differences in administration regimes and subjective measurement of bowel cleansing.In this single-blinded randomized-controlled trial, the effectiveness of Kleanprep and Picoprep was examined using a split-dose regimen and an objective bowel cleansing score system., Patients and Methods: One hundred and seventy-three consecutive patients referred for outpatient colonoscopy were included, the required number based on power analysis. Eighty-eight patients received Kleanprep; 85 received Picoprep. The primary outcome was the effectiveness of bowel cleansing using the Boston Bowel Preparation Score. The secondary outcome was patient tolerability measured using a questionnaire. An intention-to-treat-analysis was carried out., Results: The overall Boston Bowel Preparation Score between Kleanprep and Picoprep was not significantly different (P=0.182). On reviewing segment scores, there were also no significant differences between Kleanprep and Picoprep. Patients using Picoprep scored significantly better on the aspects of convenience and flavour of the preparation agent compared with patients using Kleanprep (P<0.001). Side effects such as nausea (P=0.011), vomiting (P=0.001), headache (P=0.003) and bloating (P<0.001) were experienced less significantly by patients using Picoprep., Conclusion: The present study did not find a difference in the effectiveness of bowel cleansing between Kleanprep and Picoprep. Both were found to be adequate cleansing agents. Picoprep was significantly better tolerated than Kleanprep. Therefore, we recommend Picoprep as a first-choice regimen for bowel preparation before colonoscopy.

Background: Automated interleukin assays are promising diagnostic aids for early-onset neonatal sepsis, however, reference values for healthy term neonates are incompletely known. The goal of this study is to determine reference values for interleukin-6 (IL-6) and interleukin-8 (IL-8) in cord blood of healthy term neonates., Methods and Findings: Women were recruited from April 2012 to August 2012. IL-6 and IL-8 levels were measured using an automated immunometric assay (Immulite) in cord blood of 93 healthy term newborns, 60 of them were born via vaginal delivery and 33 by elective caesarean section (ECS). A mean value for IL-8 of 8.1 ± 3.0 pg/mL was found in cord blood of healthy term neonates, which apply to both vaginal delivery and ECS. Regarding IL-6, two values apply. For vaginal delivery, a median value of 3.3 pg/mL (range, <2 to 9.53 pg/mL) was found, while for ECS, a median value of <2 pg/mL (range, <2 to 48 pg/mL) applies., Conclusions: We propose a reference value of <14.1 pg/mL for IL-8 (mean + 2SD), applying to vaginally delivered and ECS-delivered healthy term newborns. From a clinical point of view, we also propose one reference value for IL-6 to be applied to vaginally delivered and ECS-delivered healthy term newborns, which is <10.2 pg/mL (97.5th percentile total group). These values have to be validated in larger cohorts of neonates, inclusive of those with and without early-onset neonatal sepsis.

Pneumatic compression and cryotherapy have been successfully being employed in the management of acute tissue damage. The Game Ready System (GRS) combines cyclic compression and cryotherapy. No randomised controlled trial has been performed on the effects of combined cyclic compression and cryotherapy in total hip arthroplasty (THA). We observed postoperative pain, morphine usage, blood loss, wound discharge, patient and medical staff satisfaction, together with the feasibility of a cryocompression machine, total hospital admission time, infection rate, deep vein thrombosis, and short-term prosthesis related problems in this context. Thirty patients, mean age 68 yrs (range 31-83 yrs) undergoing elective hip arthroplasty for end-stage osteoarthritis were included. Control patients (n = 15) received a tricot compression bandage alone, and patients studied received a tricot compression bandage plus intermittent cryocompression therapy 15 times for 30 minutes. Haemoglobin levels on postoperative day (POD) 1 dropped 2.34 mmol/L in the control group and 1,87 mmol/L in the intervention group (p = 0,027). At POD 3 haemoglobin levels were reduced by 2,63 and 2,16 respectively (p = 0,646). A trend occurred towards lower morphine usage, shorter hospital admission time and less wound discharge in the study group. No difference was found in postoperative pain scores. One event of deep venous thrombosis occurred in the control group. Intermittent cryocompression therefore appears to reduce postoperative blood loss. A trend towards less analgesic use, shorter hospital stay, less wound discharge and less pain at 6 weeks postoperatively was also observed.

Background & Aims: Two percent to 4% of all cases of colorectal cancer (CRC) are associated with Lynch syndrome. Dominant clustering of CRC (non-Lynch syndrome) accounts for 1%-3% of the cases. Because carcinogenesis is accelerated in Lynch syndrome, an intensive colonoscopic surveillance program has been recommended since 1995. The aim of the study was to evaluate the effectiveness of this program., Methods: The study included 205 Lynch syndrome families with identified mutations in one of the mismatch repair genes (745 mutation carriers). We also analyzed data from non-Lynch syndrome families (46 families, 344 relatives). Patients were observed from January 1, 1995, until January 1, 2009. End points of the study were CRC or date of the last colonoscopy., Results: After a mean follow-up of 7.2 years, 33 patients developed CRC under surveillance. The cumulative risk of CRC was 6% after the 10-year follow-up period. The risk of CRC was higher in carriers older than 40 years and in carriers of MLH1 and MSH2 mutations. After a mean follow-up of 7.0 years, 6 cases of CRC were detected among non-Lynch syndrome families. The risk of CRC was significantly higher among families with Lynch syndrome, compared with those without., Conclusions: With surveillance intervals of 1-2 years, members of families with Lynch syndrome have a lower risk of developing CRC than with surveillance intervals of 2-3 years. Because of the low risk of CRC in non-Lynch syndrome families, a less intensive surveillance protocol can be recommended., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Several reproductive and hormonal factors are known to be associated with ovarian cancer risk in the general population, including parity and oral contraceptive (OC) use. However, their effect on ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has only been investigated in a small number of studies., Methods: We used data on 2,281 BRCA1 carriers and 1,038 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study to evaluate the effect of reproductive and hormonal factors on ovarian cancer risk for mutation carriers. Data were analyzed within a weighted Cox proportional hazards framework., Results: There were no significant differences in the risk of ovarian cancer between parous and nulliparous carriers. For parous BRCA1 mutation carriers, the risk of ovarian cancer was reduced with each additional full-term pregnancy (P trend = 0.002). BRCA1 carriers who had ever used OC were at a significantly reduced risk of developing ovarian cancer (hazard ratio, 0.52; 95% confidence intervals, 0.37-0.73; P = 0.0002) and increasing duration of OC use was associated with a reduced ovarian cancer risk (P trend = 0.0004). The protective effect of OC use for BRCA1 mutation carriers seemed to be greater among more recent users. Tubal ligation was associated with a reduced risk of ovarian cancer for BRCA1 carriers (hazard ratio, 0.42; 95% confidence intervals, 0.22-0.80; P = 0.008). The number of ovarian cancer cases in BRCA2 mutation carriers was too small to draw definitive conclusions., Conclusions: The results provide further confirmation that OC use, number of full-term pregnancies, and tubal ligation are associated with ovarian cancer risk in BRCA1 carriers to a similar relative extent as in the general population.

Background: Early menarche and late menopause are important risk factors for breast cancer, but their effects on breast cancer risk in BRCA1 and BRCA2 carriers are unknown., Methods: We assessed breast cancer risk in a large series of 1,187 BRCA1 and 414 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study. Rate ratios were estimated using a weighted Cox-regression approach., Results: Breast cancer risk was not significantly related to age at menopause [hazard ratio [HR] for menopause below age 35 years, 0.60 [95% confidence interval (95% CI), 0.25-1.44]; 35 to 40 years, 1.15 [0.65-2.04]; 45 to 54 years, 1.02 [0.65-1.60]; >or=55 years, 1.12 [0.12-5.02], as compared with premenopausal women]. However, there was some suggestion of a reduction in risk after menopause in BRCA2 carriers. There was some evidence of a protective effect of oophorectomy (HR, 0.56; 95% CI, 0.29-1.09) and a significant trend of decreasing risk with increasing time since oophorectomy, but no apparent effect of natural menopause. There was no association between age at menarche and breast cancer risk, nor any apparent association with the estimated total duration of breast mitotic activity., Conclusions: These results are consistent with other observations suggesting a protective effect of oophorectomy, similar in relative effect to that in the general population. The absence of an effect of age at natural menopause is, however, not consistent with findings in the general population and may reflect the different natural history of the disease in carriers.

Purpose: Women who carry germline mutations in the BRCA1 and BRCA2 genes are at greatly increased risk of breast cancer (BC). Numerous studies have shown that moderate to high doses of ionizing radiation are a risk factor for BC. Because of the role of the BRCA proteins in DNA repair, we hypothesized that BRCA carriers might be more sensitive to ionizing radiation than women in the general population., Patients and Methods: A retrospective cohort study of 1,601 female BRCA1/2 carriers was performed. Risk of breast cancer from exposure to chest x-rays, as assessed by questionnaire data, was analyzed using a weighted Cox proportional hazards model., Results: In this cohort, any reported exposure to chest x-rays was associated with an increased risk of BC (hazard ratio [HR] = 1.54; P = .007). This risk was increased in carrier women aged 40 years and younger (HR = 1.97; P < .001) and in women born after 1949 (HR = 2.56; P < .001), particularly those exposed only before the age of 20 years (HR = 4.64; P < .001)., Conclusion: In our series of BRCA carriers, we detected a relatively large effect on BC risk with a level of radiation exposure that is at least an order of magnitude lower than in previously studied medical radiation-exposed cohorts. Although part of this increase may be attributable to recall bias, the observed patterns of risk in terms of age at exposure and attained age are consistent with those found in previous studies. If confirmed, the results have important implications for the use of x-ray imaging in young BRCA1/2 carriers.

Background: Multiparity, young age at first childbirth, and breast-feeding are associated with a reduced risk of breast cancer in the general population. The breast cancer predisposition gene, BRCA1, regulates normal cell differentiation. Because mammary gland cells divide and differentiate during pregnancy, reproductive factors may influence breast cancer risk in BRCA1/2 mutation carriers differently than they do in noncarriers., Methods: We performed a retrospective cohort study of 1601 women in the International BRCA1/2 Carrier Cohort Study cohort, all of whom carried a mutation in BRCA1 or BRCA2. Information on reproductive factors was obtained from a questionnaire. At the time of interview 853 subjects were classified with breast cancer. Data were analyzed by using a weighted cohort approach. All statistical tests were two-sided., Results: There was no statistically significant difference in the risk of breast cancer between parous and nulliparous women. Among parous women, an increasing number of full-term pregnancies was associated with a statistically significant decrease in the risk of breast cancer (Ptrend = .008); risk was reduced by 14% (95% confidence interval [CI] = 6% to 22%) for each additional birth. This association was the same for carriers of mutations in either BRCA1 or BRCA2 and was restricted to women older than 40 years. In BRCA2 mutation carriers, first childbirth at later ages was associated with an increased risk of breast cancer compared with first childbirth before age 20 years (20-24 years, hazard ratio [HR] = 2.33 [95% CI = 0.93 to 5.83]; 25-29 years, HR = 2.68 [95% CI = 1.02 to 7.07]; > or = 30 years, HR = 1.97 [95% CI = 0.67 to 5.81]), whereas in BRCA1 mutation carriers, first childbirth at age 30 years or later was associated with a reduced risk of breast cancer compared with first childbirth before age 20 years (HR = 0.58 [95% CI = 0.36 to 0.94]). Neither history of interrupted pregnancies (induced abortions or miscarriage) nor history of breast-feeding was statistically significantly associated with the risk of breast cancer., Conclusions: BRCA1 and BRCA2 mutation carriers older than 40 years show a similar reduction in breast cancer risk with increasing parity as non-carriers.

The authors propose a novel approach to evaluate the effects of risk factors on disease risks in carriers of high-penetrance alleles in disease susceptibility genes. Most studies to date have utilised data collected on carriers identified through ongoing genetic testing programs. The advantage of this approach is that it allows relatively large numbers of affected and unaffected carriers to be identified rapidly. However, genetic testing is targeted at individuals with a strong family history of disease, so that the selection of carriers is not random with respect to disease status. Risk factors are often analysed by standard cohort analysis methods, but these can be biased in retrospective studies if subjects are selected on the basis of phenotype. To overcome this problem, a weighted cohort approach is proposed, under which individuals are weighted according to certain sampling probabilities in order to mimic a true cohort. The method is illustrated by analyses of data from the International BRCA1/2 Carrier Cohort Study (IBCCS). Simulations demonstrate that the method gives rate ratio estimates that are close to unbiased provided that the absolute disease risks are well estimated. The power to detect associations is, however, reduced compared with an unweighted approach., (Copyright (c) 2005 Wiley-Liss, Inc.)

Germline mutations of the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2, including multiple endocrine type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. The relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyperparathyroidism (HPT) in MEN 2A patients is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the development of HPT has been suggested but is still controversial. To further investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 individuals, carrying mutations at codon 634, namely C634R (65 patients belonging to 10 families), C634Y (80 patients belonging to 11 families), or the less frequent codon 634 mutations [i.e. C634S, C634F, C634G, or C634W (43 patients belonging to 9 families)]. In this series of patients, we defined an overall HPT prevalence of 19.1% and found that this prevalence did not vary significantly, with respect to the nature of the mutation. However, irrespective of the particular mutation, the prevalence of HPT showed a high interfamilial variability. The statistical model that best fitted with the observed data was in favor of the heterogeneity of the risk for HPT, with 40% of the families showing an HPT risk of 34% and 60% of the families showing an HPT risk of 9%. In addition, our study clearly demonstrated that HPT could be an early component of the disease and provided the first estimate of age-specific and mutation-specific HPT penetrance in individuals with mutations of codon 634 of the RET proto-oncogene.

We have identified 79 mutations in BRCA1 in a set of 643 Dutch and 23 Belgian hereditary breast and ovarian cancer families collected either for research or for clinical diagnostic purposes. Twenty-eight distinct mutations have been observed, 18 of them not previously reported and 12 of them occurring more than once. Most conspicuously, a 2804delAA mutation has been found 19 times and has never been reported outside the Netherlands. A common haplotype spanning > or = 375 kb could be identified for each of the nine examined recurrent mutations, indicating the presence of multiple BRCA1 founder mutations in the Dutch population. The 2804delAA mutation has been estimated to have originated approximately 32 generations ago. No specific breast or ovarian cancer phenotype could be assigned to any of the common mutations, and the ovarian cancer incidence among 18 families with the 2804delAA mutation was heterogeneous.