FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurposing for rare cystic fibrosis genotypes.

BACKGROUND: Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF. METHODS: We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators. RESULTS: In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy. CONCLUSION: This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies. ONE-SENTENCE SUMMARY: We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.

Trajectories in quality of life of patients with a fracture of the distal radius or ankle using latent class analysis.

PURPOSE: This prospective study aimed to identify the different trajectories of quality of life (QOL) in patients with distal radius fractures (DRF) and ankle fractures (AF). Secondly, it was examined if subgroups could be characterized by sociodemographic, clinical, and psychological variables. METHODS: Patients (n = 543) completed the World Health Organization Quality of Life assessment instrument-Bref (WHOQOL-Bref), the pain, coping, and cognitions questionnaire, NEO-five factor inventory (neuroticism and extraversion), and the state-trait anxiety inventory (short version) a few days after fracture (i.e., pre-injury QOL reported). The WHOQOL-Bref was also completed at three, six, and 12 months post-fracture. Latent class trajectory analysis (i.e., regression model) including the Step 3 method was performed in Latent Gold 5.0. RESULTS: The number of classes ranged from three to five for the WHOQOL-Bref facet and the four domains with a total variance explained ranging from 71.6 to 79.4%. Sex was only significant for physical and psychological QOL (p < 0.05), whereas age showed significance for overall, physical, psychological, and environmental QOL (p < 0.05). Type of treatment or fracture type was not significant (p > 0.05). Percentages of chronic comorbidities were 1.8 (i.e., social QOL) to 4.5 (i.e., physical QOL) higher in the lowest compared to the highest QOL classes. Trait anxiety, neuroticism, extraversion, pain catastrophizing, and internal pain locus of control were significantly different between QOL trajectories (p < 0.05). CONCLUSIONS: The importance of a biopsychosocial model in trauma care was confirmed. The different courses of QOL after fracture were defined by several sociodemographic and clinical variables as well as psychological characteristics. Based on the identified characteristics, patients at risk for lower QOL may be recognized earlier by health care providers offering opportunities for monitoring and intervention.

Evaluation of monitoring strategies for childhood asthma.

INTRODUCTION: The goal of monitoring pediatric asthma is to obtain and maintain asthma control, which is defined as minimizing asthma symptoms, restrictions to daily activities and the use of rescue medication. Long term goals include reducing the risk of fixed airflow limitation, and preventing asthma exacerbations and side effects of treatment. Several monitoring tools are available but no consensus exists on how to monitor patients in the most optimal way. Areas covered: In this review, we provide an overview of different tools and address general considerations on monitoring childhood asthma. Asthma care should be tailored to the individual patient. The health care professional should decide which monitoring strategy and frequency is optimal for the individual patient. Expert commentary: Personalized medicine should be the key issue in monitoring asthma in children. It is crucial to monitor disease activity and deterioration but there is no monitoring strategy that is clearly superior compared to others: The optimal strategy and frequency will vary between patients. Actually, both treatment and monitoring of pediatric asthma probably benefit from a personalized approach.

A randomized controlled trial to compare a restrictive strategy to usual care for the effectiveness of cholecystectomy in patients with symptomatic gallstones (SECURE trial protocol).

BACKGROUND: Five to 22 % of the adult Western population has gallstones. Among them, 13 to 22 % become symptomatic during their lifetime. Cholecystectomy is the preferred treatment for symptomatic cholecystolithiasis. Remarkably, cholecystectomy provides symptom relief in only 60-70 % of patients. The objective of this trial is to compare the effectiveness of usual (operative) care with a restrictive strategy using a standardized work-up with stepwise selection for cholecystectomy in patients with gallstones and abdominal complaints. DESIGN AND METHODS: The SECURE-trial is designed as a multicenter, randomized, parallel-arm, non-inferiority trial in patients with abdominal symptoms and ultrasound proven gallstones or sludge. If patients meet the inclusion criteria they will be randomized to either usual care or the restrictive strategy. Patients in the usual care group will be treated according to the physician's knowledge and preference. Patients in the restrictive care group will be treated with interval evaluation and stepwise selection for laparoscopic cholecystectomy. In this stepwise selection, patients strictly meeting the preselected criteria for symptomatic cholecystolithiasis will be offered a cholecystectomy. Patients not meeting these criteria will be assessed for other diagnoses and re-evaluated at 3-monthly intervals. Follow-up consists of web-based questionnaires at 3, 6, 9 and 12 months. The main end point of this trial is defined as the proportion of patients being pain-free at 12 months follow-up. Pain will be assessed with the Izbicki Pain Score and Gallstone Symptom Score. Secondary endpoints will be the proportion of patients with complications due to gallstones or cholecystectomy, the association between the patients' symptoms and treatment and work performance, and ultimately, cost-effectiveness. DISCUSSION: The SECURE trial is the first randomized controlled trial examining the effectiveness of usual care versus restrictive care in patients with symptomatic gallstones. The outcome of this trial will inform clinicians whether a more restrictive strategy can minimize persistent pain in post-operative patients at least as good as usual care does, but at a lower cholecystectomy rate. (The Netherlands National Trial Register NTR4022, 17th December 2012) TRIAL REGISTRATION: The Netherlands National Trial Register NTR4022 http://www.zonmw.nl/nl/projecten/project-detail/scrutinizing-inefficient-use-of-cholecystectomy-a-randomized-trial-concerning-variation-in-practi/samenvatting/.

Improvement in survival for patients with synchronous metastatic esophageal cancer in the south of the Netherlands from 1994 to 2013.

BACKGROUND: We assessed the use of external beam radiotherapy, brachytherapy chemoradiotherapy and chemotherapy in patients with metastatic esophageal cancer and evaluated the effect on overall survival. METHODS: We included all patients diagnosed with synchronous metastatic esophageal cancer in the south of the Netherlands between 1 January 1994 and 31 December 2013. Proportions of patients treated with external beam radiotherapy, brachytherapy, chemoradiotherapy and chemotherapy were described with respect to the period of diagnosis, patient and tumor characteristics. Independent risk factors for death were discriminated. RESULTS: A total of 1020 patients were included, 61.5% of these patients received palliative treatment with external beam radiotherapy, chemoradiotherapy, brachytherapy and/or chemotherapy. The use of external beam radiotherapy decreased from 44.5% in 1994 to 22.2% in 2013 (p = 0.0001), whereas the use of chemoradiotherapy increased from 2.9% in 1994 to 19.1% in 2013 (p < 0.0001). The prescription of systemic chemotherapy as single modality increased from 13.9% to 30.5% (p < 0.0001). The use of brachytherapy decreased from 20.9% in 1994 to 7.4% in 2013 (p = 0.0013). The odds of receiving external beam radiotherapy, brachytherapy, chemoradiotherapy and chemotherapy were influenced by different tumor and patient characteristics, such as age, gender, histologic subtype and number of metastatic sites. The median overall survival in patients with metastatic esophageal cancer significantly improved over time from 18 weeks (one-year survival rate 14.4%) in 1994-1998 to 25 weeks (one-year survival rate 22.4%) in 2009-2013. Patients treated with chemoradiotherapy had the most favorable prognosis, followed by patients treated with chemotherapy as a single modality. CONCLUSION: The median overall survival of patients diagnosed with metastatic esophageal cancer improved from 18 weeks in 1994-1998 to 25 weeks in 2009-2013. Although this increase could be attributed to stage migration, our population-based study suggests that major changes in treatment strategies and appropriate patient selection might have played a role as well.

The association between patient's and partner's fatigue in couples coping with colorectal cancer: a longitudinal study.

BACKGROUND: Couples coping with colorectal cancer were monitored during the first year after diagnosis to evaluate the following: (i) levels of patients' and partners' fatigue-hereby comparing their scores to each other and a normative population, (ii) association between patients' and partners' fatigue, (iii) the course of partners' fatigue, and (iv) biopsychosocial predictors of the partners' fatigue, including the patients' level of fatigue. METHOD: Couples (n = 171) preoperatively completed questions regarding age and sex as well as questionnaires assessing neuroticism and trait anxiety. Questionnaires assessing fatigue, anxiety, and depressive symptoms were measured preoperative (time-0) and 3 (time-1), 6 (time-2), and 12 months (time-3) postoperative. Patients' clinical characteristics were retrieved from the Eindhoven Cancer Registry. Descriptive statistics, correlations, and linear mixed effect models were used. RESULTS: Compared with a normative population, partners' fatigue was similar (p > .05), while patients' fatigue was higher at Time-2 and Time-3 (p values <.001). At each time point, correlations between patients' and partners' fatigue were small (r < .30). Partner's course of fatigue was as follows: 18.2 at time-0, 19.0 at time-1, 19.4 at time-2, and 19.2 at time-3 (p = 0.64). Scoring higher on neuroticism (ß = .12) and trait anxiety (ß = .23), and more depressive symptoms (ß = .30) significantly contributed to higher partners' fatigue. CONCLUSION: Trait anxiety, neuroticism, and depressive symptoms predicted higher levels of partners' fatigue, while demographic factors, patients' fatigue, and clinical factors did not. Health professionals are advised to be alert for partners with a vulnerable personality and depressive symptoms. If needed, they can for instance refer to a psychologist for treatment.

The impact of complications on quality of life following colorectal surgery: a prospective cohort study to evaluate the Clavien-Dindo classification system.

AIM: This prospective cohort study was performed to evaluate the impact of complications on quality of life (QOL) in colorectal surgery. The Clavien-Dindo complication classification (CDCC) is promising, but has not been evaluated by relating the classification to patient-reported outcome measures. METHOD: Patients undergoing colorectal surgery were evaluated prospectively 12 months postoperatively using the WHOQOL-BREF questionnaire. Patient data were prospectively recorded and complications were classified using the CDCC. Postoperative QOL in patients with minor and severe complications and patients without complications was compared using a general linear model. Relationships between CDCC and QOL were examined using correlations and multivariate regression. RESULTS: Of 218 patients, 130 (59.6%) had complications. In patients with severe complications there was a greater decrease in overall QOL (P = 0.043), QOL-physical (P < 0.001) and QOL-psychological (P = 0.013) domains in the first six postoperative weeks, whereas patients with minor complications had QOL scores comparable to those of patients without complications. QOL recovered to preoperative levels in all groups at 12 months. Change in QOL at 6 weeks was significantly correlated with CDCC grade, especially in the physical domain (Spearman's rho -0.287, P < 0.001). The presence of severe complications was an independent predictor of overall QOL, QOL-physical and QOL-psychological at 6 weeks. CONCLUSION: Severe complications are associated with reduced postoperative QOL at 6 weeks, but QOL recovers after 12 months. CDCC grade negatively correlates with change in QOL in the early postoperative period. These findings support the theoretical framework of the CDCC.

Technical errors and complications in orthopaedic trauma surgery.

INTRODUCTION: Adverse events and associated morbidity and subsequent costs receive increasing attention in clinical practice and research. As opposed to complications, errors are not described or analysed in literature on fracture surgery. The aim of this study was to provide a description of errors and complications in relation to fracture surgery, as well as the circumstances in which they occur, for example urgency, type of surgeon, and type of fracture. METHODS: All errors and complications were recorded prospectively in our hospital's complication registry, which forms an integral part of the electronic medical patient file. All recorded errors and complications in the complication registry linked to fracture surgery between 1 January, 2000 and 31 December, 2010 were analysed. RESULTS: During the study period 4310 osteosynthesis procedures were performed. In 78 (1.8 %) procedures an error in osteosynthesis was registered. The number of procedures in which an error occurred was significantly lower (OR = 0.53; p = 0.007) when an orthopaedic trauma surgeon was part of the operating team. Of all 3758 patients who were admitted to the surgical ward for osteosynthesis, 745 (19.8 %) had one or more postoperative complications registered. There was no significant difference in the number of postoperative complications after osteosynthesis procedures in which an orthopaedic trauma surgeon was present or absent (16.7 vs. 19.1 %; p = 0.088; OR 0.85). DISCUSSION: In the present study the true error rate after osteosynthesis may have been higher than the rate found. Errors that had no significant consequence may be especially susceptible to underreporting. CONCLUSION: The present study suggests that an osteosynthesis procedure performed by or actively assisted by an orthopaedic trauma surgeon decreases the probability of an error in osteosynthesis. Apart from errors in osteosynthesis, the involvement of an orthopaedic trauma surgeon did not lead to a significant reduction in the number of postoperative complications.

The course of health status and (health-related) quality of life following fracture of the lower extremity: a 6-month follow-up study.

PURPOSE: The aim of this prospective study was to describe the course of health status (HS), health-related quality of life, and quality of life (QOL) in patients with lower extremity fractures (LEF) up to 6 months post-fracture. METHODS: Patients (n = 171; age range 18-100 years) completed the World Health Organization Quality of Life assessment instrument-Bref (WHOQOL-Bref) and the Short Musculoskeletal Function Assessment questionnaire (SMFA) at time of diagnosis (i.e., pre-injury status), 1 week, and 6 months post-fracture. Linear mixed modeling was performed. RESULTS: Interaction effects of time with treatment were detected for the WHOQOL-Bref facet Overall QOL and General health (p = .002) and Physical health (p = .003). Patients did not return to their pre-injury Physical health, Psychological health, and Environment 6 months post-fracture (p < .05). No effects were found for Social relationships. The SMFA subscale Lower extremity dysfunction showed main effects for time and treatment (p < .0001) with full recovery at 6 months (p = .998). An interaction effect of time with treatment was found for Daily life consequences (p < .0001) with nonoperatively treated patients showing full recovery (p = 1.00), whereas surgically treated patients did not (p = .002). CONCLUSIONS: Six months after LEF, patients still experienced impaired physical and psychological health on the WHOQOL-Bref compared to their pre-injury status. However, patients showed full recovery on SMFA Lower extremity dysfunction, indicating that the choice of the questionnaire influences the derived conclusions. LEF did not affect satisfaction with social relationships.

Determinants in decision making for curative treatment and survival in patients with resectable oesophageal cancer in the Netherlands: a population-based study.

BACKGROUND: Preferred treatment for resectable oesophageal cancer is surgery with or without neoadjuvant treatment. However, oesophageal surgery has high morbidity and in vulnerable patients with co-morbidity other treatment modalities can be proposed. We examined determinants in decision making for surgery and factors affecting survival in patients with resectable oesophageal cancer in southern Netherlands. METHODS: All patients with resectable (T1-3, N0-1, M0-1A) oesophageal cancer (n=849) diagnosed between 2003 and 2010 were selected from the population-based data of the Eindhoven Cancer Registry. Logistic regression analysis and multivariable Cox survival analysis were conducted to examine determinants of surgery and survival. RESULTS: Forty-five percent of the patients underwent surgery. In multivariable survival analysis only surgery, chemoradiation alone and tumour stage influenced overall survival (OS). Patients aged ≥ 70 yrs, a low socioeconomic status (SES), one or more co-morbidities, cT1-tumours, cN1-tumours, a squamous-cell carcinoma, and those with a proximal tumour were significantly less often offered surgical resection. Older patients and patients with cT1 tumours were less likely to receive chemoradiation alone. Patients with clinically positive lymph nodes or a proximal tumour were more likely to receive chemoradiation alone. CONCLUSION: Treatment modalities including surgery and chemoradiation alone as well as stage of disease were independent predictors of a better OS in patients with potentially resectable oesophageal cancer. Therefore, the decision to perform potentially curative treatment is of crucial importance to improve OS for patients with potentially resectable oesophageal cancer. Although age and SES had no significant influence on overall survival, a higher age and low SES negatively influenced the probability to propose potentially curative treatment.

Prospective multicentre cohort study of patient-reported outcomes after cholecystectomy for uncomplicated symptomatic cholecystolithiasis.

BACKGROUND: Up to 33 per cent of patients with uncomplicated symptomatic cholecystolithiasis report persistent pain after cholecystectomy. The aim of this study was to determine characteristics associated with patient-reported absence of abdominal pain after cholecystectomy, improved abdominal symptoms, and patient-reported positive cholecystectomy results in a prospective cohort multicentre study. METHODS: Patients aged 18 years or more with symptomatic cholecystolithiasis who had a cholecystectomy between June 2012 and June 2014 in one of three hospitals were included. Before surgery all patients were sent the Gastrointestinal Quality of Life Index (GIQLI) questionnaire and the McGill Pain Questionnaire (MPQ). At 12 weeks after surgery, patients were invited to complete the GIQLI and Patients' Experience of Surgery Questionnaire (PESQ). Logistic regression analyses were performed to determine associations. RESULTS: Questionnaires were sent to 552 patients and returned by 342 before and after surgery. Postoperative absence of abdominal pain was reported by 60·5 per cent of patients. A high preoperative GIQLI score, episodic pain, and duration of pain of 1 year or less were associated with postoperative absence of pain. These factors showed no association with improved abdominal symptoms (reported by 91·5 per cent of patients) or a positive surgery result (reported by 92·4 per cent). CONCLUSION: Preoperative characteristics determine the odds for relief of abdominal pain after cholecystectomy. However, these factors were not associated with patient-reported improvement of abdominal symptoms or patient-reported positive cholecystectomy results, highlighting the variation of internal standards and expectations of patients before cholecystectomy.

Hospital of diagnosis and probability to receive a curative treatment for oesophageal cancer.

BACKGROUND: Surgical treatment of oesophageal cancer in the Netherland is performed in high volume centres. However, the decision to refer patients for curative surgery is made in the referring hospital of diagnosis. The objective of this study was to determine the influence of hospital of diagnosis on the probability of receiving a curative treatment and survival. MATERIAL AND METHOD: All patients with resectable oesophageal cancer (cT1-3, cN0-3, cM0-1A) diagnosed between 2003 and 2010 (n = 849) were selected from the population-based Eindhoven Cancer Registry, an area with ten non-academic hospitals. Multivariate logistic regression analysis was conducted to examine the independent influence of hospital of diagnosis on the probability to receive curative treatment. Furthermore, the effect of hospital of diagnosis on overall survival was examined using multivariate Cox regression analysis. RESULTS: 849 patients were included in the study. A difference in proportion of patients referred for surgery was observed ranging from 33% to 67% (p = 0.002) between hospitals of diagnosis. Multivariate logistic regression analysis confirmed the effect of hospital of diagnosis on the chance of undergo curative treatment (OR 0.1, 95% CI 0.1-0.4). Multivariate Cox regression analysis showed that hospital of diagnosis also had an effect on overall survival, up to hazard ratio (HR) 2.2 (95% CI 1.3-3.7). CONCLUSION: There is a strong relation between hospital of diagnosis and the chance of referring patients with oesophageal cancer for a curative treatment as well as overall survival. Patients diagnosed with oesophageal cancer should be discussed within a regional multidisciplinary expert panel.

Time trends and inter-hospital variation in treatment and axillary staging of patients with ductal carcinoma in situ of the breast in the era of screening in Southern Netherlands.

BACKGROUND: To examine variation in time and place in axillary staging and treatment of patients with ductal carcinoma in situ (DCIS) of the breast. METHODS: Trends in patients with DCIS recorded in the Eindhoven Cancer Registry diagnosed in 1991-2010 (n = 2449) were examined. RESULTS: The use of breast conserving surgery (BCS) went from 17% to 67% in 1991-2010 and administration of radiotherapy after BCS increased to 89%. Axillary lymph node dissection decreased to almost 0%, while sentinel node biopsy was performed in 65% of patients in 2010. The proportion who underwent BCS varied between hospitals from 49% to 80%; the proportion without axillary staging ranged from 21% to 60%. Patients with screen-detected DCIS were more likely to receive BCS. CONCLUSION: There was considerable variation in the use of BCS, radiotherapy, and axillary staging of DCIS over time and between hospitals. Patients with DCIS were more likely to be treated with BCS if their disease was detected by screening.

Psychometric properties of the Dutch Short Musculoskeletal Function Assessment (SMFA) questionnaire in patients with a fracture of the upper or lower extremity.

PURPOSE: This prospective study examined the psychometric properties of the adapted Dutch translation of the Short Musculoskeletal Function Assessment (SMFA) questionnaire in patients with isolated unilateral lower fracture (LEF) or upper extremity fracture (UEF). METHODS: Patients (N = 458) completed the SMFA, WHOQOL-BREF, and the RAND-36 at time of diagnosis (i.e. pre-injury status), 1, and 2 weeks post-fracture. Principal axis factoring was performed, and Cronbach's alpha coefficients (α) and intra-class correlation coefficients (ICC) were calculated. Furthermore, Pearson's product-moment correlations (r), paired t tests, and standardized response means (SRM) were calculated. RESULTS: A three-factor structure was found: Lower extremity dysfunction, Upper extremity dysfunction, and Daily life consequences. This structure was different for patients with LEF versus UEF. ICCs ranged from .68 to .90, and α varied from .81 to .95. The correlations between the SMFA and, respectively, the RAND-36 and WHOQOL-BREF were small to large depending on the SMFA factor combined with fracture location. Responsiveness was confirmed (p < .0001; SRM ranging from .28 to 1.71). CONCLUSIONS: The SMFA has good psychometric properties in patients with fractures. Patients with UEF and LEF could not be regarded as a homogenous group. The development of separate SMFA modules should be considered.

Local recurrence following breast-conserving treatment in women aged 40 years or younger: trends in risk and the impact on prognosis in a population-based cohort of 1143 patients.

AIM: To evaluate trends in the risk of local recurrences after breast-conserving treatment (BCT) and to examine the impact of local recurrence (LR) on distant relapse-free survival in a large, population-based cohort of women aged ≤40 years with early-stage breast cancer. METHODS: All women (n=1143) aged ≤40 years with early-stage (pT1-2/cT1-2, N0-2, M0) breast cancer who underwent BCT in the south of the Netherlands between 1988 and 2010 were included. BCT consisted of local excision of the tumour followed by irradiation of the breast. RESULTS: After a median follow-up of 8.5 (0.1-24.6)years, 176 patients had developed an isolated LR. The 5-year LR-rate for the subgroups treated in the periods 1988-1998, 1999-2005 and 2006-2010 were 9.8% (95% confidence interval (CI) 7.1-12.5), 5.9% (95% CI 3.2-8.6) and 3.3% (95% CI 0.6-6.0), respectively (p=0.006). In a multivariate analysis, adjuvant systemic treatment was associated with a reduced risk of LR of almost 60% (hazard ratio (HR) 0.42; 95%CI 0.28-0.60; p<0.0001). Patients who experienced an early isolated LR (≤5 years after BCT) had a worse distant relapse-free survival compared to patients without an early LR (HR 1.83; 95% CI 1.27-2.64; p=0.001). Late local recurrences did not negatively affect distant relapse-free survival (HR 1.24; 95% CI 0.74-2.08; p=0.407). CONCLUSION: Local control after BCT improved significantly over time and appeared to be closely related to the increased use and effectiveness of systemic therapy. These recent results underline the safety of BCT for young women with early-stage breast cancer.

Inferior survival for young patients with contralateral compared to unilateral breast cancer: a nationwide population-based study in the Netherlands.

To compare overall survival between women with unilateral breast cancer (UBC) and contralateral breast cancer (CBC). Women with UBC (N = 182,562; 95 %) and CBC (N = 8,912; 5 %) recorded in the Netherlands Cancer Registry between 1989 and 2008 were included and followed until 2010. We incorporated CBC as a time-dependent covariate to compute the overall mortality rate ratio between women with CBC and UBC. Prognostic factors for overall death were examined according to age at first breast cancer. Women with CBC exhibited a 30 % increase in overall mortality (Hazard Ratio (HR), 95 % Confidence Interval: 1.3, 1.3-1.4) compared with UBC, decreasing with rising age at diagnosis of first breast cancer (<50 years: 2.3, 2.2-2.5 vs. ≥70 years: 1.1, 1.0-1.1). Women older than 50 years at CBC diagnosis and diagnosed 2-5 years after their first breast cancer exhibited a 20 % higher death risk (1.2, 1.0-1.3) compared to those diagnosed within the first 2 years. In women younger than 50 years, the HR was significantly lower if the CBC was diagnosed >5 years after the first breast cancer (0.7, 0.5-0.9). The prognosis for women with CBC significantly improved over time (2004-2008: 0.6, 0.5-0.7 vs. 1989-1993). Women with CBC had a lower survival compared to women with UBC, especially those younger than 50 years at first breast cancer diagnosis. A tailored follow-up strategy beyond current recommendations is needed for these patients who, because of their age and absence of known familial risk, are currently not invited for population-based screening.

Health status and (health-related) quality of life during the recovery of distal radius fractures: a systematic review.

PURPOSE: Distal radius fractures (DRF) cause long-term functional limitations. A subgroup (21.2 %) will never fully recover after DRF. Therefore, it is important to consider the health status (HS) and (health-related) quality of life (HR)QOL of these patients. The aim of this systematic review was to describe (1) the HS and (HR)QOL outcomes following DRF, (2) sociodemographic, clinical, and psychosocial factors associated with HS and (HR)QOL, and to (3) evaluate the conceptualization of HS and (HR)QOL in these studies. METHODS: A systematic literature search was conducted in Pubmed, Embase, The Cochrane Library, and PsycINFO (January 1976-July 2012). A criteria list was used to assess the methodological quality of the studies. RESULTS: Twenty-six studies were included with a mean quality score of 7.7 (SD = 1.7). The majority of studies had a low methodological quality. Twenty-three studies (88.5 %) focused exclusively on HS and only three studies examined (HR)QOL. However, 34.8 % of the outcomes were labeled as (HR)QOL by the authors, while in fact, HS was assessed. Sex, age, educational level, living situation, and radiocarpal arthritis were associated with HS. In general, no differences were found in HS and (HR)QOL when comparing different treatment modalities. CONCLUSIONS: The focus of outcome research in DRF is mainly on HS instead of (HR)QOL. HS instruments were often mislabeled as (HR)QOL instruments. With inconclusive results of mostly low-quality studies, there is a need for high-quality prospective follow-up studies measuring HS and/or (HR)QOL while using the correct terminology.

Health status, health-related quality of life, and quality of life following ankle fractures: a systematic review.

INTRODUCTION: The number of disabling short- and long-term consequences after ankle fracture (AF) is high. Therefore, it is important to consider the health status (HS), health-related quality of life (HRQOL), and quality of life (QOL) of these patients. The aim of this study was to provide a systematic overview of studies on HS, HRQOL, and QOL in patients with AF. In addition, the conceptualisation of HS, HRQOL, and QOL in these studies was evaluated. METHODS: A systematic literature search was conducted in Pubmed, Embase, The Cochrane Library, and PsycINFO (January 1976 to April 2012). RESULTS: Twenty-three studies were included of which almost half had a cross-sectional design. The assessment of HRQOL or QOL was an explicit objective in 17.4% of the studies. The SF-36 and SMFA were the instruments most often used and measure respectively HS and a combination of HS and HRQOL. However, they had been labelled as functional status. Inconclusive results were reported regarding the predictive value of age, sex, education level, alcohol use, smoking, fracture type, and the role of syndesmotic reduction with regard to HS and HRQOL. Also, inconclusive results were found comparing HS and HRQOL scores of patients with AF with norm population scores and regarding the course of HS and HRQOL over time. The additional value of early mobilisation after AF was not confirmed. CONCLUSIONS: There are few quality studies on HS and HRQOL following AF and results are inconclusive. Future studies should measure these important patient-reported outcomes, including QOL. The concepts HS and HRQOL are not applied in agreement with the content of the instruments and instruments are downgraded to assess functional status. The correct terminology should be used to warrant clear communication in the field.

Increased risks of third primary cancers of non-breast origin among women with bilateral breast cancer.

BACKGROUND: This study examined the risk of third cancer of non-breast origin (TNBC) among women with bilateral breast cancer (BBC; either synchronous or metachronous), focussing on the relation with breast cancer treatment. METHODS: Risk was assessed, among 8752 Dutch women diagnosed with BBC between 1989 and 2008, using standardised incidence ratios (SIR) and Cox regression analyses to estimate the hazard ratio (HR) of TNBC for different treatment modalities. RESULTS: Significant increased SIRs were observed for all TNBCs combined, haematological malignancies, stomach, colorectal, non-melanoma skin, lung, head and neck, endometrial, and ovarian cancer. A 10-fold increased risk was found for ovarian cancer among women younger than 50 years (SIR=10.0, 95% confidence interval (CI)=5.3-17.4). Radiotherapy was associated with increased risks of all TNBCs combined (HR=1.3; 95%CI=1.1-1.6, respectively). Endocrine therapy was associated with increased risks of all TNBCs combined (HR=1.2; 95%CI=1.0-1.5), haematological malignancies (HR=2.0; 95%CI=1.1-3.9), and head and neck cancer (HR=3.3; 95%CI=1.1-10.4). After chemotherapy decreased risks were found for all TNBCs combined (HR=0.63; 95%CI=0.5-0.87). CONCLUSION: Increased risk of TNBC could be influenced by genetic factors (ovarian cancer) or an effect of treatment (radiotherapy and endocrine therapy). More insight in the TNBC risk should further optimise and individualise treatment and surveillance protocols in (young) women with BBC.

The use of endografts to create an endoluminal femoropopliteal bypass after failed above-knee femoropopliteal open bypass surgery.

Redo femoropopliteal bypass surgery is associated with increased morbidity and related to a poorer outcome than primary procedures. Endografts might provide an alternative, avoiding dissection of a previously operated groin. Patients treated with a polytetrafluoroethylene-covered stents for superficial femoral artery occlusive disease between February 2009 and September 2011 were prospectively gathered. Demographics, clinical status, procedural aspects, and follow-up were retrieved. Seventy-four patients were included of which 5 (7%) were treated before with a femoropopliteal bypass. Indication for intervention was Rutherford category 3 in all patients and the median ankle-brachial index (ABI) was 0.68. Technical success was achieved in all cases. The postoperative course was uneventful in all and the ABI increased to 0.95. After a follow-up period of 18 months, 4 of 5 endografts remained patent. The use of endografts after failed femoropopliteal bypass surgery is feasible and safe and could be used to avoid or minimize a difficult and hazardous dissection of a previously operated area.