A multicentre double-blinded randomized controlled trial on the efficacy of laser-assisted hatching in patients with repeated implantation failure undergoing IVF or ICSI.

STUDY QUESTION: Does assisted hatching increase the cumulative live birth rate in subfertile couples with repeated implantation failure? SUMMARY ANSWER: This study showed no evidence of effect for assisted hatching as an add-on in subfertile couples with repeated implantation failure. WHAT IS KNOWN ALREADY: The efficacy of assisted hatching, with regard to the live birth rate has not been convincingly demonstrated in randomized trials nor meta-analyses. It is suggested though that especially poor prognosis women, e.g. women with repeated implantation failure, might benefit most from assisted hatching. STUDY DESIGN, SIZE, DURATION: The study was designed as a double-blinded, multicentre randomized controlled superiority trial. In order to demonstrate a statistically significant absolute increase in live birth rate of 10% after assisted hatching, 294 participants needed to be included per treatment arm, being a total of 588 subfertile couples. Participants were included and randomized from November 2012 until November 2017, 297 were allocated to the assisted hatching arm of the study and 295 to the control arm. Block randomization in blocks of 20 participants was applied and randomization was concealed from participants, treating physicians, and laboratory staff involved in the embryo transfer procedure. Ovarian hyperstimulation, oocyte retrieval, laboratory procedures, embryo selection for transfer and cryopreservation, the transfer itself, and luteal support were performed according to local protocols and were identical in both the intervention and control arm of the study with the exception of the assisted hatching procedure which was only performed in the intervention group. The laboratory staff performing the assisted hatching procedure was not involved in the embryo transfer itself. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were eligible for inclusion in the study after having had either at least two consecutive fresh IVF or ICSI embryo transfers, including the transfer of frozen and thawed embryos originating from those fresh cycles, and which did not result in a pregnancy or as having had at least one fresh IVF or ICSI transfer and at least two frozen embryo transfers with embryos originating from that fresh cycle which did not result in a pregnancy. The study was performed at the laboratory sites of three tertiary referral hospitals and two university medical centres in the Netherlands. MAIN RESULTS AND THE ROLE OF CHANCE: The cumulative live birth rate per started cycle, including the transfer of fresh and subsequent frozen/thawed embryos if applicable, resulted in 77 live births in the assisted hatching group (n = 297, 25.9%) and 68 live births in the control group (n = 295, 23.1%). This proved to be statistically not significantly different (relative risk: 1.125, 95% CI: 0.847 to 1.494, P = 0.416). LIMITATIONS, REASONS FOR CAUTION: There was a small cohort of subfertile couples that after not achieving an ongoing pregnancy, still had cryopreserved embryos in storage at the endpoint of the trial, i.e. 1 year after the last randomization. It cannot be excluded that the future transfer of these frozen/thawed embryos increases the cumulative live birth rate in either or both study arms. Next, at the start of this study, there was no international consensus on the definition of repeated implantation failure. Therefore, it cannot be excluded that assisted hatching might be effective in higher order repeated implantation failures. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated no evidence of a statistically significant effect for assisted hatching by increasing live birth rates in subfertile couples with repeated implantation failure, i.e. the couples which, based on meta-analyses, are suggested to benefit most from assisted hatching. It is therefore suggested that assisted hatching should only be offered if information on the absence of evidence of effect is provided, at no extra costs and preferably only in the setting of a clinical trial taking cost-effectiveness into account. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR 3387, NL 3235, https://www.clinicaltrialregister.nl/nl/trial/26138). TRIAL REGISTRATION DATE: 6 April 2012. DATE OF FIRST PATIENT'S ENROLMENT: 28 November 2012.

Identifying Risk Factors for Recurrence After Cubital Tunnel Release.

PURPOSE: This study investigated specific risk factors for recurrent surgery of ulnar nerve entrapment (ie, ipsilateral clinical symptoms within 5 years after initial cubital tunnel release [CuTR]) in a large cohort. We hypothesized that recurrence is associated with lifestyle variables (eg, smoking, drinking alcohol, a high body mass index [BMI]) or comorbidities). METHODS: A retrospective cohort study was performed using the Current Procedural Terminology codes for all patients who underwent CuTR between January 2012 and November 2018. Demographic data, including sex, age, weight, height, BMI, comorbidities, smoking, and alcohol consumption, were collected. The primary outcome was the need for revision surgery after initial CuTR. Univariate and multivariate analyses were performed to identify potential risk factors for revision surgery. RESULTS: Of the 678 patients who underwent CuTR, 120 patients (18%) needed revision surgery within 5 years. Sixty-six patients required subfascial transposition (55%) and 47 patients (39%) received in situ releases. Also, sex, BMI, smoking, alcohol consumption, and comorbidities (except for spinal disc herniation) were similar between the primary and revision subgroup. Age at first occurrence was significantly lower in the revision group (48 years for revision vs 52 years for primary surgery). Moreover, cervical spinal disc herniation was associated with revision surgery (13% vs 6% in the primary group). CONCLUSIONS: Age and medical history of cervical spinal disc herniation are associated with an increased risk of revision surgery. More importantly, BMI, smoking, alcohol consumption, and other comorbidities are not associated with increased risk of revision surgery within our sample. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Clinical outcome of decompressing colostomy for acute left-sided colorectal obstruction: a consecutive series of 100 patients.

PURPOSE: Aim of our study was to evaluate the outcomes of a consecutive series of patients who were treated with a decompressing colostomy (DC) for acute left-sided colorectal obstruction. METHOD: A consecutive series of 100 patients with acute left-sided colorectal obstruction who underwent DC from January 2015 to August 2020 was retrospectively analyzed. Demographic characteristics, etiology of the obstruction, postoperative morbidity- and mortality rates, DC-related complication and stoma reversal rates were evaluated. RESULTS: Of the 100 included patients, 64 had malignant- and 36 had benign obstruction. The mean age was 69 years, 42% was male, and the ASA score was 2. Morbidity and mortality rates after DC construction were 20 and 2%, respectively. In 39% of the patients, DC ended up as a permanent stoma and in 61% as bridge to surgery (BtS). DC related complication rate was 32%, with a re-intervention rate of 9%. Elective colorectal resection was performed in 59 cases (59%) with subsequent postoperative morbidity rate of 20%. Stoma reversal rate was 77% for the patients who underwent DC as BtS. Stoma reversal was performed in 66% of the patients with benign obstruction and in 36% for oncological obstruction. CONCLUSION: DC as bridge to possible elective resection for acute left-sided colorectal obstruction is an effective strategy with low morbidity and mortality rates and a high stoma reversal rate, especially for benign obstruction. However, DC is less appropriate for patients in whom DC turns out to be a permanent stoma due to a relatively high stoma related complications.

Association between allergen component sensitisation and clinical allergic disease in children.

BACKGROUND: Allergen component sensitisation testing is becoming increasingly important in the diagnosis of peanut allergy. The aim of the present study was to evaluate the relationship between sensitisation and symptoms of allergic disease in children by testing a large panel of inhalants, food allergens, and allergen components. METHODS: For 287 children visiting our laboratory for allergy testing, symptoms of allergic disease were recorded by standardised validated questionnaires. Specific IgE to 11 whole allergens was assessed by ImmunoCAP, and to 112 allergen components by ISAC ImmunoCAP assay. We used latent class analysis (LCA) to distinguish clinical phenotypes. RESULTS: Inhalant and food allergen sensitisation was common, irrespective of the children's allergic symptom type. Less than 10% of the variance in symptom scores was explained by variations in the number of allergens (components) that the child was sensitised to. In LCA, 135 children (50.2%) had mild allergy, with few symptoms and sensitisation to no or few allergens, 74 children (27.5%) had more symptoms and sensitisation to inhalant allergens (respiratory allergy) and 60 children (22.3%) showed polysensitisation to a median of six allergens and had more severe symptoms of different organ systems. Adding allergen component test results to LCA failed to result in identifiable classes of allergic disease in children. CONCLUSIONS: In this group of children with allergic symptoms, referred for allergy testing by their physician, broad screening for allergen component sensitisation did not contribute to distinguishing phenotypes of allergic disease.

High correlation of the Oxford Knee Score with postoperative pain, but not with performance-based functioning.

PURPOSE: The Oxford Knee Score (OKS) is a widely known patient-related outcome measure (PROM) to determine pain and knee functioning before and after total knee arthroplasty (TKA). Self-reported function is mainly influenced by change in pain; therefore, it was hypothesized that the OKS correlates more with pain than with performance-based functioning. METHODS: In a prospective cohort of 88 patients, who had a cementless mobile-bearing TKA, included in a randomized clinical trial, the correlation between the overall OKS, and its subscales for pain (PCS) and function (FCS), with performance-based functioning using the DynaPort® Knee Score (DKS), visual analogue scale score for pain (VAS) and the Knee Society Score (KSS) was evaluated. All scores were measured preoperatively, 6 months and 1 year after surgery. Overall change in outcome over time was analysed until 5 years after surgery. RESULTS: All scores improved over time. The DKS was influenced by sex, preoperative BMI and age. The internal consistency of the OKS PCS increased over time, whereas the OKS FCS remained the same. The mean postoperative OKS FCS showed moderate correlation with the DKS (r = 0.65, p < 0.001), and the mean postoperative OKS and OKS PCS showed high correlation with the VAS (r = -0.79 and r = -0.82, respectively, p < 0.001). The mean postoperative KSS showed high correlations with the OKS (r = 0.80, p < 0.001), the OKS PCS (r = 0.72 p < 0.001) and OKS FCS (r = 0.74, p < 0.001). CONCLUSION: The postoperative OKS and the OKS PCS showed high correlation with pain, but only the postoperative OKS FCS was well correlated with performance-based functioning. This suggests that the OKS is more related to pain and tells us less on postoperative functioning. This is important when the OKS as PROM is used to evaluate the quality of orthopaedic care of patients with TKA. LEVEL OF EVIDENCE: III.

Breast and ovarian cancer risks in a large series of clinically ascertained families with a high proportion of BRCA1 and BRCA2 Dutch founder mutations.

BACKGROUND: BRCA1 or BRCA2 mutations confer increased risks of breast and ovarian cancer, but risks have been found to vary across studies and populations. METHODS: We ascertained pedigree data of 582 BRCA1 and 176 BRCA2 families and studied the variation in breast and ovarian cancer risks using a modified segregation analysis model. RESULTS: The average cumulative breast cancer risk by age 70 years was estimated to be 45% (95% CI 36 to 52%) for BRCA1 and 27% (95% CI 14 to 38%) for BRCA2 mutation carriers. The corresponding cumulative risks for ovarian cancer were 31% (95% CI 17 to 43%) for BRCA1 and 6% (95% CI 2 to 11%) for BRCA2 mutation carriers. In BRCA1 families, breast cancer relative risk (RR) increased with more recent birth cohort (p heterogeneity = 0.0006) and stronger family histories of breast cancer (p heterogeneity < 0.001). For BRCA1, our data suggest a significant association between the location of the mutation and the ratio of breast to ovarian cancer (p<0.001). By contrast, in BRCA2 families, no evidence was found for risk heterogeneity by birth cohort, family history or mutation location. CONCLUSIONS: BRCA1 mutation carriers conferred lower overall breast and ovarian cancer risks than reported so far, while the estimates of BRCA2 mutations were among the lowest. The low estimates for BRCA1 might be due to older birth cohorts, a moderate family history, or founder mutations located within specific regions of the gene. These results are important for a more accurate counselling of BRCA1/2 mutation carriers.

No clinical benefit of titanium nitride coating in cementless mobile-bearing total knee arthroplasty.

PURPOSE: Titanium nitride (TiN) coating of cobalt-chromium-molybdenum (CoCrMo) implants has shown to improve the biomechanical properties of the implant surface and to reduce adhesive wear in vitro. It is yet unknown whether TiN coating of total knee prosthesis (TKP) affects the postoperative clinical outcome of total knee arthroplasty (TKA). METHODS: In a double-blind randomized controlled clinical trial, 101 patients received an uncemented mobile-bearing CoCrMo TKP, either TiN coated or uncoated. Primary outcome measure visual analogue scale (VAS) score for pain, and secondary outcome measures Knee Society Score (KSS), revision rate and adverse events, range of motion of the knee as well as knee circumference and knee skin temperature were assessed 6 weeks, 6 months, 1 year and 5 years postoperative. Repeated measures analysis was used to evaluate the postoperative outcome measures over time. RESULTS: There was no difference between the two groups in VAS score, KSS, revision rate, range of motion of the knee, knee circumference and knee skin temperature. There were no adverse events that could be related to the TiN coating. CONCLUSIONS: TiN-coated TKP does not influence the postoperative outcome of uncemented mobile-bearing TKA regarding postoperative pain, revision rate, range of motion, swelling and temperature of the knee. Therefore, TiN coating of CoCrMo TKP has no clinical benefit on the outcome of cementless mobile-bearing TKA. LEVEL OF EVIDENCE: Therapeutic study, Level I.

Local infiltration analgesia following total knee arthroplasty: effect on post-operative pain and opioid consumption--a meta-analysis.

INTRODUCTION: Local infiltration analgesia (LIA) is a popular method for decreasing post-operative pain after total knee arthroplasty (TKA). The goal of this meta-analysis is to compare the effect of LIA with placebo on the intensity of post-operative pain and the consumption of opioids. METHODS: A search was performed in the PubMed/MEDLINE, Cochrane, EMBASE and TRIP databases. All (quasi)-randomized controlled trials (RCTs) were included. LIA consists of intra-operative infiltration with at least one analgesic component. Data were pooled using Cochrane software. RESULTS: Seven placebo-controlled RCTs were included, involving 405 TKAs. On the first post-operative day, LIA provides an average decrease in VAS scores at rest of 12.3 % compared to placebo. Six RCTs studied opioid consumption in patients following TKA. There was a decrease in opioid consumption of 14.8 % compared to placebo 24 h after surgery. This suggests a reduced pain perception due to LIA. On the second post-operative day, the effect on both outcome measures was diminished and no longer significant. Heterogeneity between the studies was 71 % for pain and 39 % for opioid consumption (p = 0.002 and p = 0.0005). No major complications were reported with the use of LIA. CONCLUSION: LIA might be able to decrease pain and the use of opioids on the first post-operative day following TKA. However, due to the high level of heterogeneity between the studies, no firm conclusions can be drawn. LEVEL OF EVIDENCE: Meta-analysis, Level II.

Timing of restoration of bowel continuity after decompressing stoma, in left-sided obstructive colon cancer: a nationwide retrospective cohort.

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.

Efficacy of botulinum toxin A injection in pelvic floor muscles in chronic pelvic pain patients: a study protocol for a multicentre randomised controlled trial.

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.

Personal Genomes in Practice: Exploring Citizen and Healthcare Professionals' Perspectives on Personalized Genomic Medicine and Personal Health Data Spaces Using a Mixed-Methods Design.

Ongoing health challenges, such as the increased global burden of chronic disease, are increasingly answered by calls for personalized approaches to healthcare. Genomic medicine, a vital component of these personalization strategies, is applied in risk assessment, prevention, prognostication, and therapeutic targeting. However, several practical, ethical, and technological challenges remain. Across Europe, Personal Health Data Space (PHDS) projects are under development aiming to establish patient-centered, interoperable data ecosystems balancing data access, control, and use for individual citizens to complement the research and commercial focus of the European Health Data Space provisions. The current study explores healthcare users' and health care professionals' perspectives on personalized genomic medicine and PHDS solutions, in casu the Personal Genetic Locker (PGL). A mixed-methods design was used, including surveys, interviews, and focus groups. Several meta-themes were generated from the data: (i) participants were interested in genomic information; (ii) participants valued data control, robust infrastructure, and sharing data with non-commercial stakeholders; (iii) autonomy was a central concern for all participants; (iv) institutional and interpersonal trust were highly significant for genomic medicine; and (v) participants encouraged the implementation of PHDSs since PHDSs were thought to promote the use of genomic data and enhance patients' control over their data. To conclude, we formulated several facilitators to implement genomic medicine in healthcare based on the perspectives of a diverse set of stakeholders.

Possible Value of Faecal Immunochemical Test (FIT) When Added in Symptomatic Patients Referred for Colonoscopy: A Systematic Review.

If Colorectal cancer (CRC) is detected and treated early, the survival rate is high. This is one of the reasons that population-based screening programs for the early detection of CRC using the faecal immunochemical test (FIT) started worldwide. These programs compete with regular colonoscopy programs and increase the waiting time for symptomatic patients. However, the literature has shown that the correlation between intestinal complaints and the gain of colonoscopy is poor. The aim of this study is to assess the diagnostic utility of symptoms for the yield (CRC) of colonoscopy and to compare this with the diagnostic utility of FIT when offered to symptomatic patients. METHODS: We performed a systematic review search for CRC as an outcome of colonoscopy in referred symptomatic patients and separately for CRC as an outcome in symptomatic patients with a positive FIT. We searched systematically for clinical trials or observational studies in databases, followed by hand-searching of reference lists. We used random Meta-Disc to evaluate the diagnostic performance, using the exploration of heterogeneity with a variety of test statistics and by computing the pooled estimates. RESULTS: We included 35 studies, with almost 5 million symptomatic patients. In addition, we included nine prospective studies with a positive FIT in symptomatic patients, with more than 5000 patients. Significant heterogeneity was found for every symptom and the outcome of colonoscopy in the effect size of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio. In a random effect model, the pooled sensitivity of colonoscopy in symptomatic patients was very low (25%). However, the pooled sensitivity in symptomatic patients with a positive FIT was 83% and the pooled specificity 77%. A total of 75 symptomatic patients (1.4%) had a false-negative FIT. CONCLUSION: Adding FIT in symptomatic patients seems useful for predicting CRC as an outcome of colonoscopy. FIT seems a potential tool for an improved triage of colonoscopy in symptomatic patients.

Alteration of the Exhaled Volatile Organic Compound Pattern in Colorectal Cancer Patients after Intentional Curative Surgery-A Prospective Pilot Study.

As current follow-up modalities for colorectal carcinoma (CRC) have restricted sensitivity, novel diagnostic tools are needed. The presence of CRC changes the endogenous metabolism, resulting in the release of a specific volatile organic compounds (VOC) pattern that can be detected with an electronic nose or AeonoseTM. To evaluate the use of an electronic nose in the follow-up of CRC, we studied the effect of curative surgery on the VOC pattern recognition using AeonoseTM. A prospective cohort study was performed, in which 47 patients diagnosed with CRC were included, all of whom underwent curative surgical resection. Breath testing was performed before and after surgery using the AeonoseTM. A machine learning model was developed by discerning between the 94 pre-and postoperative breath samples. The training model differentiated between the pre-and postoperative CRC breath samples with a sensitivity and specificity of 0.78 (95%CI 0.61-0.90) and 0.73 (95%CI 0.56-0.86), respectively, with an accuracy of 0.76 (95%CI 0.66-0.85), and an area under the curve of 0.79 (95%CI 0.68-0.89). The internal validation of the test set resulted in an accuracy of 0.75 (95%CI 0.51-0.91) and AUC of 0.82 (95%CI 0.61-1). In conclusion, our results suggest that the VOC pattern of CRC patients is altered by curative surgery in a short period, indicating that the exhaled VOCs might be closely related to the presence of CRC. However, to use AeonoseTM as a potential diagnostic tool in the clinical follow-up of CRC patients, the performance of the models needs to be improved through further large-scale prospective research.

Diagnostic value of radiological staging and surveillance for T1 colorectal carcinomas: A multicenter cohort study.

BACKGROUND: The role of radiological staging and surveillance imaging is under debate for T1 colorectal cancer (CRC) as the risk of distant metastases is low and imaging may lead to the detection of incidental findings. OBJECTIVE: The aim of this study was to evaluate the yield of radiological staging and surveillance imaging for T1 CRC. METHODS: In this retrospective multicenter cohort study, all patients of 10 Dutch hospitals with histologically proven T1 CRC who underwent radiological staging in the period 2000-2014 were included. Clinical characteristics, pathological, endoscopic, surgical and imaging reports at baseline and during follow-up were recorded and analyzed. Patients were classified as high-risk T1 CRC if at least one of the histological risk factors (lymphovascular invasion, poor tumor differentiation, deep submucosal invasion or positive resection margins) was present and as low-risk when all risk factors were absent. RESULTS: Of the 628 included patients, 3 (0.5%) had synchronous distant metastases, 13 (2.1%) malignant incidental findings and 129 (20.5%) benign incidental findings at baseline staging. Radiological surveillance was performed among 336 (53.5%) patients. The 5-year cumulative incidence of distant recurrence, malignant and benign incidental findings were 2.4% (95% confidence interval (CI): 1.1%-5.4%), 2.5% (95% CI: 0.6%-10.4%) and 18.3% (95% CI: 13.4%-24.7%), respectively. No distant metastatic events occurred among low-risk T1 CRC patients. CONCLUSION: The risk of synchronous distant metastases and distant recurrence in T1 CRC is low, while there is a substantial risk of detecting incidental findings. Radiological staging seems unnecessary prior to local excision of suspected T1 CRC and after local excision of low-risk T1 CRC. Radiological surveillance should not be performed in patients with low-risk T1 CRC.

High Yield of Chest X-ray in the Follow-Up of Colorectal Cancer.

PURPOSE: Worldwide, colorectal carcinoma (CRC) has a high incidence and a substantial cancer-related mortality. The recurrence risk is 30-50% and lung metastases are common. Treatment of lung metastases with stereotactic ablative radiotherapy (SABR) or metastasectomy may increase survival. The best modality for thoracic screening in the follow-up, however, remains controversial. In this study, we aimed to unravel the additional value of routine chest X-ray (CXR) for detecting lung metastases during the follow-up of CRC patients treated with curative surgery. METHODS: Between 2013 and 2017, 668 CRC patients were treated with curative intent, of whom 633 patients were included in follow-up, which consisted of CXR, serum Carcino-Embryonic Antigen (CEA) and ultrasound of the liver. Patients who developed lung metastases, diagnosed with CXR and characterised by a normal concomitant serum CEA level, were identified. Number, size and treatment of lung metastases were described. RESULTS: Thirty-four (5.4%) patients developed lung metastases. Seventeen (50%) were detected by CXR without pathological CEA levels. Eleven (65%) of these patients were treated with curative intent, whereas 21% of patients with lung metastases and elevated CEA levels were treated with curative intent (p = 0.049). Higher numbers of lung metastases were associated with a lower chance of curative treatment. CONCLUSIONS: More than 50% of patients with lung metastases on CXR in the follow-up would not have been detected with CEA-triggered imaging only. In addition, patients with colorectal lung metastases without elevated CEA levels were often suitable for curative treatment and, therefore, CXR seems to have additional value within the follow-up of CRC.

One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome.

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.

Body weight and risk of breast cancer in BRCA1/2 mutation carriers.

Obesity is an established risk factor for postmenopausal breast cancer in the general population. However, it is still unclear whether this association also exists in BRCA1/2 mutation carriers. We investigated the association between self-reported anthropometric measures and breast cancer risk in a nationwide retrospective cohort study, including 719 BRCA1/2 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. All time-varying Cox proportional hazards analyses were stratified by menopausal status. For premenopausal breast cancer, no statistically significant associations were observed for any of the anthropometric measures. The association between body mass index (BMI) at age 18 and premenopausal breast cancer risk suggested a trend of decreasing risk with increasing BMI (HR(22.50-24.99 vs. 18.50-22.49) = 0.83, 95% CI = 0.47-1.44 and HR(≥ 25.00 vs. 18.50-22.49) = 0.41, 95% CI = 0.13-1.27). For postmenopausal breast cancer, being 1.67 m and taller increased the risk 1.7-fold (HR = 1.67, 95% CI = 1.01-2.74) when compared to a height <1.67 m. Compared with a current body weight < 72 kg, a current body weight of ≥ 72 kg increased the risk of postmenopausal breast cancer 2.1-fold (95% CI = 1.23-3.59). A current BMI of ≥ 25.0 kg/m², an adult weight gain of 5 kg or more, and a relative adult weight gain of 20% or more were all non-significantly associated with a 50-60% increased risk of postmenopausal breast cancer [HR = 1.46 (0.86-2.51), HR = 1.56 (95% CI = 0.85-2.87), and HR = 1.60 (95% CI = 0.97-2.63), respectively], when compared with having a healthy or stable weight. No associations for body weight or BMI at age 18 were observed. In conclusion, menopausal status seemed to modify the association between body weight and breast cancer risk among BRCA1/2 carriers. We observed no clear association between body weight and premenopausal breast cancer, while overweight and weight gain increased postmenopausal breast cancer risk. Carriers may reduce their risk of postmenopausal breast cancer by maintaining a healthy body weight throughout life.

The validity of Dutch health claims data for identifying patients with chronic kidney disease: a hospital-based study in the Netherlands.

BACKGROUND: Health claims data may be an efficient and easily accessible source to study chronic kidney disease (CKD) prevalence in a nationwide population. Our aim was to study Dutch claims data for their ability to identify CKD patients in different subgroups. METHODS: From a laboratory database, we selected 24 895 adults with at least one creatinine measurement in 2014 ordered at an outpatient clinic. Of these, 15 805 had ≥2 creatinine measurements at least 3 months apart and could be assessed for the chronicity criterion. We estimated the validity of a claim-based diagnosis of CKD and advanced CKD. The estimated glomerular filtration rate (eGFR)-based definitions for CKD (eGFR < 60 mL/min/1.73 m2) and advanced CKD (eGFR < 30 mL/min/1.73 m2) satisfying and not satisfying the chronicity criterion served as reference group. Analyses were stratified by age and sex. RESULTS: In general, sensitivity of claims data was highest in the population with the chronicity criterion as reference group. Sensitivity was higher in advanced CKD patients than in CKD patients {51% [95% confidence interval (CI) 47-56%] versus 27% [95% CI 25-28%]}. Furthermore, sensitivity was higher in young versus elderly patients. In patients with advanced CKD, sensitivity was 72% (95% CI 62-83%) for patients aged 20-59 years and 43% (95% CI 38-49%) in patients ≥75 years. The specificity of CKD and advanced CKD was ≥99%. Positive predictive values ranged from 72% to 99% and negative predictive values ranged from 40% to 100%. CONCLUSION: When using health claims data for the estimation of CKD prevalence, it is important to take into account the characteristics of the population at hand. The younger the subjects and the more advanced the stage of CKD the higher the sensitivity of such data. Understanding which patients are selected using health claims data is crucial for a correct interpretation of study results.

Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome.

BACKGROUND & AIMS: Recent genome-wide association studies have identified common low-risk variants for colorectal cancer (CRC). To assess whether these influence CRC risk in the Lynch syndrome, we genotyped these variants in a large series of proven mutation carriers. METHODS: We studied 675 individuals from 127 different families from the Dutch Lynch syndrome Registry whose mutation carrier status was known. We genotyped 8q24.21, 8q23.3, 10p14, 11q23.1, 15q13.3, and 18q21.1 variants in carriers of a mismatch repair gene mutation. Univariate and multivariate analysis was used to analyse the association between the presence of a risk variant and CRC risk. RESULTS: A significant association was found between CRC risk and rs16892766 (8q23.3) and rs3802842 (11q23.1). For rs16892766, possession of the C-allele was associated with an elevated risk of CRC in a dose-dependent fashion, with homozygosity for CC being associated with a 2.16-fold increased risk. For rs3802842, the increased risk of CRC associated with the C-allele was only found among female carriers, while CRC risk was substantially higher among homozygous (hazard ratio [HR] 3.08) than among heterozygous carriers of the C-allele (HR 1.49). In an additive model of both variants, the risk was significantly associated with the number of risk alleles (HR 1.60 for carriers of 2 or more risk alleles). The effects were stronger in female carriers than in male carriers. CONCLUSION: We have identified 2 loci that are significantly associated with CRC risk in Lynch syndrome families. These modifiers may be helpful in identifying high-risk individuals who require more intensive surveillance.

Physical activity and the risk of breast cancer in BRCA1/2 mutation carriers.

BRCA1/2 mutation carriers have a high lifetime risk of developing breast cancer. Differences in penetrance indicate that this risk may be influenced by lifestyle factors. Because physical activity is one of the few modifiable risk factors, it may provide a target to add to breast cancer prevention in this high-risk population. We examined the association between self-reported lifetime sports activity and breast cancer risk in a nationwide retrospective cohort study, including 725 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. We found a nonsignificantly decreased risk for ever engaging in sports activity (HR = 0.84, 95%CI = 0.57-1.24). Among women who had participated in sports, a medium versus low level of intensity and duration (i.e., between 11.0 and 22.7 mean MET hours/week averaged over a lifetime) reduced the risk of breast cancer (HR = 0.59, 95%CI = 0.36-0.95); no dose-response trend was observed. For mean hours/week of sports activity, a nonsignificant trend was observed (HR(low versus never) = 0.93, 95%CI = 0.60-1.43; HR(medium versus never) = 0.81, 95%CI = 0.51-1.29; HR(high versus never) = 0.78, 95%CI = 0.48-1.29; p (trend overall) = 0.272; p (trend active women) = 0.487). For number of years of sports activity no significant associations were found. Among women active in sports before age 30, mean MET hours/week showed the strongest inverse association of all activity measures (HR(medium versus low) = 0.60, 95%CI = 0.38-0.96; HR(high versus low) = 0.58, 95%CI = 0.35-0.94; p (trend) = 0.053). Engaging in sports activity after age 30 was also inversely associated with breast cancer risk (HR = 0.63, 95%CI = 0.44-0.91). Our results indicate that sports activity may reduce the risk of breast cancer in BRCA1/2 mutation carriers.