MEN-2 Syndrome: The Value of Screening and Central Registration; A Study of Six Kindreds in The Netherlands

Since 1975, six families with the MEN-2A syndrome including 66 patients have been identified in The Netherlands. All these patients underwent thyroidectomy for C-cell hyperplasia and/or medullary thyroid carcinoma (MTC); eight were symptomatic (Group A), 51 were relatives of patients found to be affected (Group B), and seven had had a negative screening test that became positive (Group C). To assess the effect of screening, we compared these groups with respect to the occurrence of metastatic MTC at thyroidectomy and the results of the postoperative calcitonin (CT) tests. We found that 87% of Group A, 37% of Group B; and none of Group C had metastatic disease at surgery. The cure rates in these three groups with MEN-2A, as determined by stimulated CT measurement, was 0%, 51%, and 100%, respectively. From these results it may be concluded that screening can lead to the detection of MTC at an earlier stage which in turn could permit curative treatment and improvement of both prognosis and life expectancy. The need for supervision of affected families by central registration to guarantee the continuity of screening is stressed

High-dose intensity-modulated radiotherapy for prostate cancer using daily fiducial marker-based position verification: acute and late toxicity in 331 patients

We evaluated the acute and late toxicity after high-dose intensity-modulated radiotherapy (IMRT) with fiducial marker-based position verification for prostate cancer. Between 2001 and 2004, 331 patients with prostate cancer received 76 Gy in 35 fractions using IMRT combined with fiducial marker-based position verification. The symptoms before treatment (pre-treatment) and weekly during treatment (acute toxicity) were scored using the Common Toxicity Criteria (CTC). The goal was to score late toxicity according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale with a follow-up time of at least three years. Twenty-two percent of the patients experienced pre-treatment grade ≥ 2 genitourinary (GU) complaints and 2% experienced grade 2 gastrointestinal (GI) complaints. Acute grade 2 GU and GI toxicity occurred in 47% and 30%, respectively. Only 3% of the patients developed acute grade 3 GU and no grade ≥ 3 GI toxicity occurred. After a mean follow-up time of 47 months with a minimum of 31 months for all patients, the incidence of late grade 2 GU and GI toxicity was 21% and 9%, respectively. Grade ≥ 3 GU and GI toxicity rates were 4% and 1%, respectively, including one patient with a rectal fistula and one patient with a severe hemorrhagic cystitis (both grade 4). In conclusion, high-dose intensity-modulated radiotherapy with fiducial marker-based position verification is well tolerated. The low grade ≥ 3 toxicity allows further dose escalation if the same dose constraints for the organs at risk will be used

An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients

Background: Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-likeCGH classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents

Impact of prevalent and incident vertebral fractures on utility: results from a patient-based and a population-based sample

Data are scarce on the impact of vertebral fractures (VFX) on utility. The objective of this study was to assess the impact of prevalent and incident VFX on utility in both a patient-based and population-based sample. Data from the Multiple Outcomes of Raloxifene Evaluation (MORE) study (n = 550 for prevalent VFX and n = 174 for incident VFX) and the European Prospective Osteoporosis Study (EPOS) (n = 236) were used. Utility was assessed by the index score of the EQ-5D. In the MORE study, highly statistically significant associations were found between utility and the presence of prevalent VFX (p < 0.001), number of prevalent VFX (p < 0.001), severity of prevalent VFX (p < 0.001), the combination of number and severity of prevalent VFX (p = 0.001) and location of prevalent VFX (p = 0.019). The mean utility was significantly lower among women who suffered an incident VFX (utility = 0.67) than among women who did not (utility = 0.77) (p = 0.005), although utility loss was not significantly different between the two groups (p = 0.142). In EPOS, the combination of number and severity of incident VFX was significantly related to utility (p = 0.030). In conclusion, utility is lower among persons with prevalent and incident VFX, especially in a patient-based sample. Utility loss was not significantly different between women without and with incident VFX

Reproducibility of bone mineral density measurement in daily practice.

BACKGROUND: Bone mineral density (BMD) measurements are frequently performed repeatedly for each patient. Subsequent BMD measurements allow reproducibility to be assessed. OBJECTIVE: To examine the reproducibility of BMD by dual energy x ray absorptiometry (DXA) and to investigate the practical value of different measures of reproducibility in a group of postmenopausal women. METHODS: Ninety five women, mean age 59.9 years, underwent two subsequent BMD measurements of spine and hip. Reproducibility was expressed as smallest detectable difference (SDD), coefficient of variation (CV), and intraclass correlation coefficient (ICC). Sources of variation were investigated by multilevel analysis. RESULTS: The median interval between measurements was 0 days (range 0-45). The mean difference (SD) between the measurements (g/cm(2)) was -0.001 (0.02) and -0.0004 (0.02) at L1-4 and the total hip, respectively. At L1-4 and the total hip, SDD (g/cm(2)) was +/-0.05 and +/-0.04 and CV (%) was 1.92 and 1.59, respectively. The ICC at spine and hip was 0.99. CONCLUSIONS: Reproducibility in the postmenopausal women studied was good. In a repeated DXA scan a BMD change exceeding 2 radical 2CV (%), the least significant change (LSC), or the SDD should be regarded as significant. Use of the SDD is preferable to use of the CV and LSC (%) because of its independence from BMD and its expression in absolute units. Expressed as SDD, a BMD change of at least +/-0.05 g/cm(2) at L1-4 and +/-0.04 g/cm(2) at the total hip should be considered significant

Clinical osteoarthritis of the hip and knee and fall risk: The role of low physical functioning and pain medication

Objective: Several studies have found an increased fall risk in persons with osteoarthritis (OA). However, most prospective studies did not use a clinical definition of OA. In addition, it is not clear which factors explain this risk. Our objectives were: (1) to confirm the prospective association between clinical OA of the hip and knee and falls; (2) to examine the modifying effect of sex; and (3) to examine whether low physical performance, low physical activity and use of pain medication are mediating these relationships. Methods: Baseline and 1-year follow-up data from the European Project on OSteoArthritis (EPOSA) were used involving pre-harmonized data from five European population-based cohort studies (ages 65 85, n = 2535). Clinical OA was defined according to American College of Rheumatology (ACR) criteria. Falls were assessed using self-report. Results: Over the follow-up period, 27.7% of the participants fell once or more (defined as faller), and 9.8% fell twice or more (recurrent faller). After adjustment for confounding, clinical knee OA was associated with the risk of becoming a recurrent faller (relative risk=1.55; 95% confidence interval: 1.10 2.18), but not with the risk of becoming a faller. No associations between clinical hip OA and (recurrent) falls were observed after adjustment for confounding. Use of opioids and analgesics mediated the associations between clinical OA and (recurrent) falls, while physical performance and physical activity did not. Conclusion: Individuals with clinical knee OA were at increased risk for recurrent falls. This relationship was mediated by pain medication, particularly opioids. The fall risk needs to be considered when discussing the risk benefit ratio of prescribing these medicationsSources of support: The Longitudinal Aging Study Amsterdam (LASA) is financially supported by the Dutch Ministry of Health, Welfare and Sports (grant no 311669, grant recipient D.J.H. Deeg). The Pe~nagrande study was partially supported by the National Fund for Health Research (Fondo de Investigaciones en Salud) of Spain (grant no FIS PI 05/1898; FIS RETICEF RD06/0013/1013 and FIS PS09/02143, grant recipients A. Otero, M.V. Castell). The Hertfordshire Cohort Study is supported by the Medical Research Council of Great Britain, Versus Arthritis, the British Heart Foundation and the International Osteoporosis Foundation (grant no MRC_MC_UP_A620_1014, grant recipients C. Cooper, E. Dennison). The Italian cohort was supported by the National Research Council of Italy (CNR), Research Project “Aging: molecular and technological innovations for improving the health of the elderly population" (Prot. MIUR 2867, grant recipient: S. Maggi). The Swedish Twin Registry is managed by Karolinska Institutet and receives funding through the Swedish Research Council (grant no 2017-00641, grant recipient Karolinska Institutet

A risk profile for identifying community-dwelling elderly with a highrisk of recurrent falling: results of a 3-year prospective study

Introduction: The aim of the prospective study reported here was to develop a risk profile that can be used to identify community-dwelling elderly at a high risk of recurrent falling. Materials and methods: The study was designed as a 3-year prospective cohort study. A total of 1365 community-dwelling persons, aged 65 years and older, of the population-based Longitudinal Aging Study Amsterdam participated in the study. During an interview in 1995/1996, physical, cognitive, emotional and social aspects of functioning were assessed. A follow-up on the number of falls and fractures was conducted during a 3-year period using fall calendars that participants filled out weekly. Recurrent fallers were identified as those who fell at least twice within a 6-month period during the 3-year follow-up. Results: The incidence of recurrent falls at the 3-year follow-up point was 24.9% in women and 24.4% in men. Of the respondents, 5.5% reported a total of 87 fractures that resulted from a fall, including 20 hip fractures, 21 wrist fractures and seven humerus fractures. Recurrent fallers were more prone to have a fall-related fracture than those who were not defined as recurrent fallers (11.9% vs. 3.4%; OR: 3.8; 95% CI: 2.3-6.1). Backward logistic regression analysis identified the following predictors in the risk profile for recurrent falling: two or more previous falls, dizziness, functional limitations, weak grip strength, low body weight, fear of falling, the presence of dogs/cats in the household, a high educational level, drinking 18 or more alcoholic consumptions per week and two interaction terms (high educationx18 or more alcohol consumptions per week and two or more previous falls x fear of falling) (AUC=0.71). Discussion: At a cut-off point of 5 on the total risk score (range 0-30), the model predicted recurrent falling with a sensitivity of 59% and a specificity of 71%. At a cut-off point of 10, the sensitivity and specificity were 31% and 92%, respectively. A risk profile including nine predictors that can easily be assessed seems to be a useful tool for the identification of community-dwelling elderly with a high risk of recurrent falling. © International Osteoporosis Foundation and National Osteoporosis Foundation 2006

Investigation of Metallized and Nonmetallized Hydroxyl Terminated Polybutadiene/Hydrogen Peroxide Hybrid Rockets

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77070/1/AIAA-22091-612.pd

Am I the right candidate? Self-ascribed fit of women and men to a leadership position

Women are assumed to show a self-ascribed lack-of-fit to leadership positions compared to men (Heilman, 1983). The present study examined whether this gender difference would diminish when agency is accounted for and whether a stimulus person’s gender would alter women’s self-ascribed fit. German management students (91 women, 95 men) received a fictitious recruitment advertisement for a leadership position that portrayed a man, a woman, or both a man and a woman. Participants indicated their perceptions of agency and suitability to the advertised position. As predicted, women judged themselves as less suitable for the leadership position than men and participants’ self-reported agency mediated this effect. Furthermore, all participants felt most suitable if a male and a female stimulus person were portrayed

Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy

Introduction: BRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mutated breast cancer closely and might also share this hypersensitivity. However, ways to identify HRD in non-BRCA-mutated, estrogen receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2- mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy. Methods: Array comparative genomic hybridization (aCGH) was used to classify breast cancers. Patients with tumors with similar aCGH patterns as BRCA1- and/or BRCA2-mutated breast cancers were defined as having a BRCA-like(CGH) status, others as non-BCRA-like(CGH). Stage-III patients (n = 249) had participated in a randomized controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE90C) chemotherapy. Results: Among patients with BRCA-like(CGH) tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE90C was observed regarding overall survival (adjusted hazard ratio 0.19, 95% CI: 0.08 to 0.48) that was not seen for patients with non-BRCA-like(CGH) tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) (P = 0.004). Half of all BRCA-like(CGH) tumors were ER-positive. Conclusions: Distinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen (BRCA-like(CGH) patients) and those without benefit (non-BRCA-like(CGH) patients)