Causality and functional relevance of BRCA1 and BRCA2 pathogenic variants in non-high-grade serous ovarian carcinomas.

The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision-making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high-grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of BRCA1/2 tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of n = 946 EOCs revealed BRCA1/2 PVs in 125 samples (13%), only eight of which were found in non-HGSOC histotypes. Specifically, BRCA1/2 PVs were identified in high-grade endometrioid (3/20; 15%), low-grade endometrioid (1/40; 2.5%), low-grade serous (3/67; 4.5%), and clear cell (1/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re-evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight 'anomalous' cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first 'anomalous' non-HGSOC with a BRCA1/2 PV proved to be a misdiagnosed HGSOC. Next, germline BRCA2 variants, found in two p53-abnormal high-grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53-wildtype low-grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the BRCA1/2 wildtype allele, suggestive of non-causal secondary passenger variants. We conclude that likely causal BRCA1/2 variants are present in high-grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype-directed sequencing. Furthermore, in-depth functional analysis of tumours harbouring BRCA1/2 variants combined with detailed revision of cancer histotypes can serve as a model in other BRCA1/2-related cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Oxidative Stress Predicts Post-Surgery Complications in Gastrointestinal Cancer Patients.

INTRODUCTION: An excessive perioperative inflammatory reaction can lead to more postoperative complications in patients treated for gastrointestinal cancers. It has been suggested that this inflammatory reaction leads to oxidative stress. The most important nonenzymatic antioxidants are serum free thiols. The purpose of this study was to evaluate whether high preoperative serum free thiol levels are associated with short-term clinical outcomes. METHODS: Blood samples were drawn before, at the end of, and 1 and 2 days after surgery of a consecutive series of patients with gastrointestinal cancer. Serum free thiols were detected using a colorimetric detection method using Ellman's reagent. Short-term clinical outcomes were defined as 30-day complications (Clavien-Dindo ≥2) and length of hospital stay. Logistic regression was applied to examine the association between serum free thiol levels and short-term patient outcomes. RESULTS: Eighty-one patients surgically treated for gastrointestinal cancer were included in the study. Median age was 68 (range 26-87) years, and 28% were female. Patients in the lowest tertile of preoperative serum free thiols had a threefold higher risk to develop postoperative complications (odds ratio [OR]: 3.4; 95% confidence interval [CI]:1.1-10.7) and a fourfold higher risk to have an increased length of stay in the hospital (OR 4.0; 95% CI 1.3-12.9) compared with patients in the highest tertile. CONCLUSIONS: Patients with lower preoperative serum free thiol levels, indicating a decrease in extracellular antioxidant capacity and therefore an increase in systemic oxidative stress, are more likely to develop postoperative complications and show a longer in hospital stay than patients with higher serum free thiol levels.

Qualitative Evaluation of Common Quantitative Metrics for Clinical Acceptance of Automatic Segmentation: a Case Study on Heart Contouring from CT Images by Deep Learning Algorithms.

Organs-at-risk contouring is time consuming and labour intensive. Automation by deep learning algorithms would decrease the workload of radiotherapists and technicians considerably. However, the variety of metrics used for the evaluation of deep learning algorithms make the results of many papers difficult to interpret and compare. In this paper, a qualitative evaluation is done on five established metrics to assess whether their values correlate with clinical usability. A total of 377 CT volumes with heart delineations were randomly selected for training and evaluation. A deep learning algorithm was used to predict the contours of the heart. A total of 101 CT slices from the validation set with the predicted contours were shown to three experienced radiologists. They examined each slice independently whether they would accept or adjust the prediction and if there were (small) mistakes. For each slice, the scores of this qualitative evaluation were then compared with the Sørensen-Dice coefficient (DC), the Hausdorff distance (HD), pixel-wise accuracy, sensitivity and precision. The statistical analysis of the qualitative evaluation and metrics showed a significant correlation. Of the slices with a DC over 0.96 (N = 20) or a 95% HD under 5 voxels (N = 25), no slices were rejected by the readers. Contours with lower DC or higher HD were seen in both rejected and accepted contours. Qualitative evaluation shows that it is difficult to use common quantification metrics as indicator for use in clinic. We might need to change the reporting of quantitative metrics to better reflect clinical acceptance.

Automatic Cardiac Structure Contouring for Small Datasets with Cascaded Deep Learning Models.

Cardiac structure contouring is a time consuming and tedious manual activity used for radiotherapeutic dose toxicity planning. We developed an automatic cardiac structure segmentation pipeline for use in low-dose non-contrast planning CT based on deep learning algorithms for small datasets. Fifty CT scans were retrospectively selected and the whole heart, ventricles and atria were contoured. A two stage deep learning pipeline was trained on 41 non contrast planning CTs, tuned with 3 CT scans and validated on 6 CT scans. In the first stage, An InceptionResNetV2 network was used to identify the slices that contained cardiac structures. The second stage consisted of three deep learning models trained on the images containing cardiac structures to segment the structures. The three deep learning models predicted the segmentations/contours on axial, coronal and sagittal images and are combined to create the final prediction. The final accuracy of the pipeline was quantified on 6 volumes by calculating the Dice similarity coefficient (DC), 95% Hausdorff distance (95% HD) and volume ratios between predicted and ground truth volumes. Median DC and 95% HD of 0.96, 0.88, 0.92, 0.80 and 0.82, and 1.86, 2.98, 2.02, 6.16 and 6.46 were achieved for the whole heart, right and left ventricle, and right and left atria respectively. The median differences in volume were -4, -1, + 5, -16 and -20% for the whole heart, right and left ventricle, and right and left atria respectively. The automatic contouring pipeline achieves good results for whole heart and ventricles. Robust automatic contouring with deep learning methods seems viable for local centers with small datasets.

Risk factors for adverse events induced by immune checkpoint inhibitors in patients with non-small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can cause serious immune-related adverse events (irAEs). This study aimed to identify risk factors for all types of irAEs induced by ICIs in patients with non-small-cell lung cancer (NSCLC), by systematic review and meta-analyses. METHODS: A systematic search was performed in Pubmed, Embase and Web of Science by two independent reviewers. Studies were selected that included patients with NSCLC and evaluated characteristics of patients with and without irAEs induced by ICIs. Quality and risk of bias of the selected studies were assessed. Random effects meta-analyses were conducted to estimate pooled odds ratios (ORs) for risk factors of developing all type of irAEs, and separately for pneumonitis, interstitial lung disease and severe irAEs. With the objective of exploring sources of heterogeneity, stratified analyses were performed by quality and region. RESULTS: 25 studies met the inclusion criteria. In total, the data of 6696 patients were pooled. 33 different risk factors for irAEs were reported. irAEs of interest were reported for 1653 (25%) of the patients. Risk factors related to the development of irAEs were: C-reactive protein, neutrophil lymphocyte ratio (NLR), use of PD-1 inhibitor, high PD-L1 expression, an active or former smoking status, ground glass attenuation, and a better treatment response. CONCLUSION: The identified risk factors for the development of these irAEs are mostly related to the alteration of the immune system, proinflammatory states and loss of immunological self-tolerance. Patients identified as having a higher risk for irAEs should be monitored more closely.

Population-based study of morbidity risk associated with pathological complete response after chemoradiotherapy for rectal cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer may induce a pathological complete response (pCR) but increase surgical morbidity due to radiation-induced fibrosis. In this study the association between pCR and postoperative surgical morbidity was investigated. METHODS: Patients in the Netherlands with rectal cancer who underwent nCRT followed by total mesorectal excision between 2009 and 2017 were included. Data were stratified into patients who underwent resection with creation of a primary anastomosis and those who had a permanent stoma procedure. The association between pCR and postoperative morbidity was investigated in univariable and multivariable logistic regression analyses. RESULTS: pCR was observed in 976 (12·2 per cent) of 8003 patients. In 3472 patients who had a primary anastomosis, the presence of pCR was significantly associated with surgical complications (122 of 443 (27·5 per cent) versus 598 of 3029 (19·7 per cent) in those without pCR) and anastomotic leak (35 of 443 (7·9 per cent) versus 173 of 3029 (5·7 per cent) respectively). Multivariable analysis also showed associations between pCR and surgical complications (adjusted odds ratio (OR) 1·53, 95 per cent c.i. 1·22 to 1·92) and pCR and anastomotic leak (adjusted OR 1·41, 1·03 to 2·05). Of 4531 patients with a permanent stoma, surgical complications were observed in 120 (22·5 per cent) of 533 patients with a pCR, compared with 798 (20·0 per cent) of 3998 patients with no pCR (adjusted OR 1·17, 0·94 to 1·46). CONCLUSION: Patients with a pCR in whom an anastomosis was created were at increased risk of developing an anastomotic leak.

ANTECEDENTES: La quimiorradioterapia neoadyuvante (neoadjuvant chemoradiotherapy, nCRT) para el cáncer de recto localmente avanzado puede inducir una respuesta patológica completa (pathological complete response, pCR), pero también puede aumentar la morbilidad quirúrgica debido a la fibrosis inducida por la radiación. En este estudio se investigó la asociación entre pCR y morbilidad quirúrgica postoperatoria. MÉTODOS: Se incluyeron los pacientes con cáncer de recto que recibieron nCRT seguida de resección total del mesorrecto entre 2009 y 2017 en los Países Bajos. Los datos se estratificaron en pacientes en los que se realizó una resección con anastomosis primaria y en los que se realizó una resección con estoma permanente. La asociación entre pCR y morbilidad postoperatoria se investigó mediante análisis de regresión logística univariable y multivariable. RESULTADOS: Se observó una pCR en 976 (12,2%) de 8.003 pacientes. En el grupo de pacientes con anastomosis primaria (n = 3472), la presencia de pCR se asoció significativamente con complicaciones quirúrgicas (n = 122; 27,5% versus n = 598; 19,7% sin pCR) y fuga anastomótica (n = 35; 7,9 % versus n = 173; 5,7% sin pCR). Las asociaciones entre la pCR y las complicaciones quirúrgicas y la pCR y la fuga anastomótica también se confirmaron en los análisis multivariables (razón de oportunidades ajustada, odds ratio, OR ajustado: 1,53; i.c. del 95%: 1,22-1,92; OR ajustado: 1,41; i.c. del 95%: 1,03-2,05, respectivamente). En el grupo con estoma permanente (n = 4.531), se observaron complicaciones quirúrgicas en 120 pacientes (22,5%) en los casos con presencia de pCR en comparación con 798 pacientes (20%) en ausencia de pCR (OR ajustado: 1,17; i.c. del 95%: 0,94-1,46). CONCLUSIÓN: Los pacientes con pCR en los que se realizó una anastomosis tenían mayor riesgo de presentar una fuga anastomótica.

Coverage determinants of breast cancer screening in Flanders: an evaluation of the past decade.

BACKGROUND: Breast cancer (BC) is the most common cancer in women in the developed world. In order to find developing cancers in an early stage, BC screening is commonly used. In Flanders, screening is performed in and outside an organized breast cancer screening program (BCSP). However, the determinants of BC screening coverage for both screening strategies are yet unknown. OBJECTIVE: To assess the determinants of BC screening coverage in Flanders. METHODS: Reimbursement data were used to attribute a screening status to each woman in the target population for the years 2008-2016. Yearly coverage data were categorized as screening inside or outside BCSP or no screening. Data were clustered by municipality level. A generalized linear equation model was used to assess the determinants of screening type. RESULTS: Over all years and municipalities, the median screening coverage rate inside and outside BCSP was 48.40% (IQR: 41.50-54.40%) and 14.10% (IQR: 9.80-19.80%) respectively. A higher coverage rate outside BSCP was statistically significantly (P < 0.001) associated with more crowded households (OR: 3.797, 95% CI: 3.199-4.508), younger age, higher population densities (OR: 2.528, 95% CI: 2.455-2.606), a lower proportion of unemployed job seekers (OR: 0.641, 95% CI: 0.624-0.658) and lower use of dental care (OR: 0.969, 95% CI: 0.967-0.972). CONCLUSION: Coverage rate of BC screening is not optimal in Flanders. Women with low SES that are characterized by younger age, living in a high population density area, living in crowded households, or having low dental care are less likely to be screened for BC in Flanders. If screened, they are more likely to be screened outside the BCSP.

GlycA, a novel pro-inflammatory glycoprotein biomarker is associated with mortality: results from the PREVEND study and meta-analysis.

BACKGROUND: Chronic diseases are associated with an inflammatory response. We determined the association of two inflammatory markers, GlycA and high-sensitivity C-reactive protein (hsCRP), with overall and cause-specific mortality in a cohort of men and women. METHODS: Cox regression analyses were used to examine associations of GlycA and hsCRP with all-cause, cancer and cardiovascular mortality in 5526 subjects (PREVEND cohort; average follow-up 12.6 years). RESULTS: GlycA was associated with all-cause mortality (n = 838), independent of clinical risk factors and hsCRP (hazard ratio 1.43 [95% confidence interval (CI): 1.09-1.87] for top versus bottom quartiles). For hsCRP, the association with all-cause mortality was nonsignificant after adjustment for GlycA. GlycA and hsCRP were associated with cancer mortality in men (n = 248), but not in women (n = 132). Neither GlycA nor hsCRP was independently associated with cardiovascular mortality (n = 201). In a meta-analysis of seven population-based studies, including 8153 deaths, the pooled multivariable-adjusted relative risk of GlycA for all-cause mortality was 1.74 (95% CI: 1.40-2.17) for top versus bottom quartiles. The association of GlycA with all-cause mortality was somewhat stronger than that of hsCRP. GlycA and hsCRP were not independently associated with cardiovascular mortality. The associations of GlycA and hsCRP with cancer mortality were present in men, but not in women. CONCLUSIONS: GlycA is significantly associated with all-cause mortality. GlycA and hsCRP were each not independently associated with cardiovascular mortality. The association of GlycA and hsCRP with cancer mortality appears to be driven by men.

Margin status revisited in vulvar squamous cell carcinoma.

OBJECTIVE: To determine the incidence of local recurrence of vulvar squamous cell carcinoma in relation to tumor- and/or precursor lesion free pathologic margins. METHODS: Consecutive patients with primary vulvar squamous cell carcinoma surgically treated in two Dutch expert centers between 2000 and 2010 were included. All pathology slides were independently reviewed by two expert gynecopathologists, and local recurrence was defined as any recurrent disease located on the vulva. Time to first local recurrence was compared for different subgroups using univariable and multivariable Cox-regression analyses. RESULTS: In total 287 patients with a median follow-up of 80months (range 0-204) were analyzed. The actuarial local recurrence rate ten years after treatment was 42.5%. Pathologic tumor free margin distance did not influence the risk on local recurrence (HR 1.03 (95% CI 0.99-1.06)), neither using a cutoff of eight, five, or three millimeters. Multivariable analyses showed a higher local recurrence rate in patients with dVIN and LS in the margin (HR 2.76 (95% CI 1.62-4.71)), in patients with dVIN in the margin (HR 2.14 (95% CI 1.11-4.12)), and a FIGO stage II or higher (HR 1.62 (95% CI 1.05-2.48)). CONCLUSIONS: Local recurrences frequently occur in patients with primary vulvar carcinoma and are associated with dVIN (with or without LS) in the pathologic margin rather than any tumor free margin distance. Our results should lead to increased awareness among physicians of an ongoing risk for local recurrence and need for life-long follow-up. Intensified follow-up and treatment protocols for patients with dVIN in the margin should be evaluated in future research.

Mindfulness-based stress reduction for menopausal symptoms after risk-reducing salpingo-oophorectomy (PURSUE study): a randomised controlled trial.

OBJECTIVE: To assess the short- and long-term effects of mindfulness-based stress reduction (MBSR) on the resulting quality of life, sexual functioning, and sexual distress after risk-reducing salpingo-oophorectomy (RRSO). DESIGN: Randomised controlled trial. SETTING: A specialised family cancer clinic of the university medical center Groningen. POPULATION: Sixty-six women carriers of the BRCA1/2 mutation who developed at least two moderate-to-severe menopausal symptoms after RRSO. METHODS: Women were randomised to an 8-week MBSR training programme or to care as usual (CAU). MAIN OUTCOME MEASURES: Change in the Menopause-Specific Quality of Life Questionnaire (MENQOL), the Female Sexual Function Index, and the Female Sexual Distress Scale, administered from baseline at 3, 6, and 12 months. Linear mixed modelling was applied to compare the effect of MBSR with CAU over time. RESULTS: At 3 and 12 months, there were statistically significant improvements in the MENQOL for the MBSR group compared with the CAU group (both P = 0.04). At 3 months, the mean MENQOL scores were 3.5 (95% confidence interval, 95% CI 3.0-3.9) and 3.8 (95% CI 3.3-4.2) for the MBSR and CAU groups, respectively; at 12 months, the corresponding values were 3.6 (95% CI 3.1-4.0) and 3.9 (95% CI 3.5-4.4). No significant differences were found between the MBSR and CAU groups in the other scores. CONCLUSION: Mindfulness-based stress reduction was effective at improving quality of life in the short- and long-term for patients with menopausal symptoms after RRSO; however, it was not associated with an improvement in sexual functioning or distress. TWEETABLE ABSTRACT: Mindfulness improves menopause-related quality of life in women after risk-reducing salpingo-oophorectomy.

Mindfulness, cognitive behavioural and behaviour-based therapy for natural and treatment-induced menopausal symptoms: a systematic review and meta-analysis.

BACKGROUND: During menopause women experience vasomotor and psychosexual symptoms that cannot entirely be alleviated with hormone replacement therapy (HRT). Besides, HRT is contraindicated after breast cancer. OBJECTIVES: To review the evidence on the effectiveness of psychological interventions in reducing symptoms associated with menopause in natural or treatment-induced menopausal women. SEARCH STRATEGY: Medline/Pubmed, PsycINFO, EMBASE and AMED were searched until June 2017. SELECTION CRITERIA: Randomised controlled trials (RCTs) concerning natural or treatment-induced menopause, investigating mindfulness or (cognitive-)behaviour-based therapy were selected. Main outcomes were frequency of hot flushes, hot flush bother experienced, other menopausal symptoms and sexual functioning. DATA COLLECTION AND ANALYSIS: Study selection and data extraction were performed by two independent researchers. A meta-analysis was performed to calculate the standardised mean difference (SMD). MAIN RESULTS: Twelve RCTs were included. Short-term (<20 weeks) effects of psychological interventions in comparison to no treatment or control were observed for hot flush bother (SMD -0.54, 95% CI -0.74 to -0.35, P < 0.001, I2  = 18%) and menopausal symptoms (SMD -0.34, 95% CI -0.52 to -0.15, P < 0.001, I2  = 0%). Medium-term (≥20 weeks) effects were observed for hot flush bother (SMD -0.38, 95% CI -0.58 to -0.18, P < 0.001, I2  = 16%). [Correction added on 9 July 2018, after first online publication: there were miscalculations of the mean end point scores for hot flush bother and these have been corrected in the preceding two sentences.] In the subgroup treatment-induced menopause, consisting of exclusively breast cancer populations, as well as in the subgroup natural menopause, hot flush bother was reduced by psychological interventions. Too few studies reported on sexual functioning to perform a meta-analysis. CONCLUSIONS: Psychological interventions reduced hot flush bother in the short and medium-term and menopausal symptoms in the short-term. These results are especially relevant for breast cancer survivors in whom HRT is contraindicated. There was a lack of studies reporting on the influence on sexual functioning. TWEETABLE ABSTRACT: Systematic review: psychological interventions reduce bother by hot flushes in the short- and medium-term.

Neoadjuvant chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: a feasibility and safety study.

BACKGROUND: Standard treatment for colorectal peritoneal carcinomatosis typically involves cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and if possible, postoperative adjuvant chemotherapy. However, a substantial percentage of patients never receive adjuvant chemotherapy because of postoperative complications. Neoadjuvant chemotherapy could be beneficial in this setting, so we assessed its feasibility and safety when used before cytoreductive surgery and HIPEC. METHODS: In this non-randomized, single-center, observational feasibility study, patients were scheduled to receive six cycles of capecitabine and oxaliplatin before cytoreductive surgery and HIPEC. Computed tomography was performed after the third and sixth chemotherapy cycles to evaluate tumor response, and patients underwent cytoreductive surgery and HIPEC if there were no pulmonary and/or hepatic metastases. Postoperative complications, graded according to the Clavien-Dindo classification, were compared with those of a historic control group that received postoperative adjuvant chemotherapy. RESULTS: Of the 14 patients included in the study, 4 and 3 had to terminate neoadjuvant chemotherapy early because of toxicity and tumor progression, respectively. Cytoreductive surgery and HIPEC were performed in eight patients, and the timing and severity of complications were comparable to those of patients in the historic control group treated without neoadjuvant chemotherapy. CONCLUSION: Patients with peritoneal metastases due to colorectal carcinoma can be treated safely with neoadjuvant chemotherapy before definitive therapy with cytoreductive surgery and HIPEC. TRIAL REGISTRATION NUMBER: NTR 3905, registered on 20th march, 2013, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3905.

Characteristics of Lynch syndrome associated ovarian cancer.

OBJECTIVE: To describe clinical characteristics of Lynch syndrome associated ovarian cancer and the efficacy of surveillance in the early detection of these ovarian cancers. METHODS: All Lynch syndrome associated ovarian cancer cases identified in either the Dutch Lynch syndrome registry (DLSR) between 1987 and 2016, and/or the cohort at the University Medical Center Groningen (UMCG) between 1993 and 2016 were included. Clinical data on age at diagnosis, mutation type, histological type, FIGO stage, treatment, follow-up and gynecological surveillance were collected. RESULTS: A total of 46/798 (6%) women in the DLSR and 7/80 (9%) in the UMCG cohort were identified as LS associated ovarian cancer patients. The median age at ovarian cancer diagnosis was 46.0 years (range 20-75 years). The most frequently reported histological type was endometrioid adenocarcinoma (40%; n = 21) and serous carcinoma (36%; n = 19). Most tumors (87%; n = 46) were detected at an early stage (FIGO I/II). Forty-one of 53 (77%) patients were diagnosed with ovarian cancer before LS was diagnosed. In the other 12/53 (23%) women, ovarian cancer developed after starting annual gynecological surveillance for LS; three ovarian cancers were screen-detected in asymptomatic women. Overall survival was 83%. CONCLUSION: Ovarian cancer in women with LS has a wide age-range of onset, is usually diagnosed at an early stage with predominantly endometrioid type histology and a good overall survival. The early stage at diagnosis could not be attributed to annual gynecological surveillance.

Survival analysis of the CEAwatch multicentre clustered randomized trial.

BACKGROUND: The CEAwatch randomized trial showed that follow-up with intensive carcinoembryonic antigen (CEA) monitoring (CEAwatch protocol) was better than care as usual (CAU) for early postoperative detection of colorectal cancer recurrence. The aim of this study was to calculate overall survival (OS) and disease-specific survival (DSS). METHODS: For all patients with recurrence, OS and DSS were compared between patients detected by the CEAwatch protocol versus CAU, and by the method of detection of recurrence, using Cox regression models. RESULTS: Some 238 patients with recurrence were analysed (7·5 per cent); a total of 108 recurrences were detected by CEA blood test, 64 (55·2 per cent) within the CEAwatch protocol and 44 (41·9 per cent) in the CAU group (P = 0·007). Only 16 recurrences (13·8 per cent) were detected by patient self-report in the CEAwatch group, compared with 33 (31·4 per cent) in the CAU group. There was no significant improvement in either OS or DSS with the CEAwatch protocol compared with CAU: hazard ratio 0·73 (95 per cent 0·46 to 1·17) and 0·78 (0·48 to 1·28) respectively. There were no differences in survival when recurrence was detected by CT versus CEA measurement, but both of these methods yielded better survival outcomes than detection by patient self-report. CONCLUSION: There was no direct survival benefit in favour of the intensive programme, but the CEAwatch protocol led to a higher proportion of recurrences being detected by CEA-based blood test and reduced the number detected by patient self-report. This is important because detection of recurrence by blood test was associated with significantly better survival than patient self-report, indirectly supporting use of the CEAwatch protocol.

Complication rates of CT-guided transthoracic lung biopsy: meta-analysis.

OBJECTIVES: To meta-analyze complication rate in computed tomography (CT)-guided transthoracic lung biopsy and associated risk factors. METHODS: Four databases were searched from 1/2000 to 8/2015 for studies reporting complications in CT-guided lung biopsy. Overall and major complication rates were pooled and compared between core biopsy and fine needle aspiration (FNA) using the random-effects model. Risk factors for complications in core biopsy and FNA were identified in meta-regression analysis. RESULTS: For core biopsy, 32 articles (8,133 procedures) were included and for FNA, 17 (4,620 procedures). Pooled overall complication rates for core biopsy and FNA were 38.8 % (95 % CI: 34.3-43.5 %) and 24.0 % (95 % CI: 18.2-30.8 %), respectively. Major complication rates were 5.7 % (95 % CI: 4.4-7.4 %) and 4.4 % (95 % CI: 2.7-7.0 %), respectively. Overall complication rate was higher for core biopsy compared to FNA (p < 0.001). For FNA, larger needle diameter was a risk factor for overall complications, and increased traversed lung parenchyma and smaller lesion size were risk factors for major complications. For core biopsy, no significant risk factors were identified. CONCLUSIONS: In CT-guided lung biopsy, minor complications were common and occurred more often in core biopsy than FNA. Major complication rate was low. For FNA, smaller nodule diameter, larger needle diameter and increased traversed lung parenchyma were risk factors for complications. KEY POINTS: • Minor complications are common in CT-guided lung biopsy • Major complication rate is low in CT-guided lung biopsy • CT-guided lung biopsy complications occur more often in core biopsy than FNA • Major complication rate is similar in core biopsy and FNA • Risk factors for FNA are larger needle diameter, smaller lesion size.

Diagnostic performance of semi-quantitative and quantitative stress CMR perfusion analysis: a meta-analysis.

BACKGROUND: Stress cardiovascular magnetic resonance (CMR) perfusion imaging is a promising modality for the evaluation of coronary artery disease (CAD) due to high spatial resolution and absence of radiation. Semi-quantitative and quantitative analysis of CMR perfusion are based on signal-intensity curves produced during the first-pass of gadolinium contrast. Multiple semi-quantitative and quantitative parameters have been introduced. Diagnostic performance of these parameters varies extensively among studies and standardized protocols are lacking. This study aims to determine the diagnostic accuracy of semi- quantitative and quantitative CMR perfusion parameters, compared to multiple reference standards. METHOD: Pubmed, WebOfScience, and Embase were systematically searched using predefined criteria (3272 articles). A check for duplicates was performed (1967 articles). Eligibility and relevance of the articles was determined by two reviewers using pre-defined criteria. The primary data extraction was performed independently by two researchers with the use of a predefined template. Differences in extracted data were resolved by discussion between the two researchers. The quality of the included studies was assessed using the 'Quality Assessment of Diagnostic Accuracy Studies Tool' (QUADAS-2). True positives, false positives, true negatives, and false negatives were subtracted/calculated from the articles. The principal summary measures used to assess diagnostic accuracy were sensitivity, specificity, andarea under the receiver operating curve (AUC). Data was pooled according to analysis territory, reference standard and perfusion parameter. RESULTS: Twenty-two articles were eligible based on the predefined study eligibility criteria. The pooled diagnostic accuracy for segment-, territory- and patient-based analyses showed good diagnostic performance with sensitivity of 0.88, 0.82, and 0.83, specificity of 0.72, 0.83, and 0.76 and AUC of 0.90, 0.84, and 0.87, respectively. In per territory analysis our results show similar diagnostic accuracy comparing anatomical (AUC 0.86(0.83-0.89)) and functional reference standards (AUC 0.88(0.84-0.90)). Only the per territory analysis sensitivity did not show significant heterogeneity. None of the groups showed signs of publication bias. CONCLUSIONS: The clinical value of semi-quantitative and quantitative CMR perfusion analysis remains uncertain due to extensive inter-study heterogeneity and large differences in CMR perfusion acquisition protocols, reference standards, and methods of assessment of myocardial perfusion parameters. For wide spread implementation, standardization of CMR perfusion techniques is essential. TRIAL REGISTRATION: CRD42016040176 .

Bone mineral density and fractures after surgical menopause: systematic review and meta-analysis.

BACKGROUND: Oophorectomy is recommended for women at increased risk for ovarian cancer. When performed at premenopausal age oophorectomy induces acute surgical menopause, with unwanted consequences. OBJECTIVE: To investigate bone mineral density (BMD) and fracture prevalence after surgical menopause. SEARCH STRATEGY: A literature search of PubMed, EMBASE and Cochrane library was performed with no date restriction. Date of last search was March 1st, 2016. SELECTION CRITERIA: Primary studies reporting on BMD, T-scores or fracture prevalence in women with surgical menopause and age-matched control groups. DATA COLLECTION AND ANALYSIS: Data were extracted on BMD (g/cm2 ), T-scores and fracture prevalence in women with surgical menopause and control groups. Quality was assessed by an adaptation of the Downs and Black checklist. Random effects models were used to meta-analyse results of studies reporting on BMD or fracture rates. MAIN RESULTS: Seventeen studies were included, comprising 43 386 women with surgical menopause. Ten studies provided sufficient data for meta-analysis. BMD after surgical menopause was significantly lower than in premenopausal age-matched women [mean difference lumbar spine, -0.15 g/cm2 (95% CI, -0.19 to -0.11 g/cm2 ); femoral neck, -0.17 g/cm2 (95% CI, -0.23 to -0.11 g/cm2 )] but not lower than in women with natural menopause [lumbar spine, -0.02 g/cm2 (95% CI, -0.04 to 0.00 g/cm2 ); femoral neck, 0.04 g/cm2 (95% CI, -0.09 to 0.16 g/cm2 )]. Hip fracture rate was not higher after surgical menopause compared with natural menopause [hazard ratio: 0.85 (95% CI, 0.70 to 1.04)]. AUTHOR'S CONCLUSIONS: No evident effect of surgical menopause was observed on BMD and fracture prevalence compared with natural menopause. However, available studies are prone to bias and need to be interpreted with caution. TWEETABLE ABSTRACT: Bone health after menopause: no evidence for additional effect of surgical menopause on BMD and fractures.

Primary healthcare use during follow-up after curative treatment for colorectal cancer.

The rising number of colorectal cancer (CRC) survivors is likely to impose a burden on healthcare systems. Effective resource allocation between primary and hospital care to ensure ongoing high-quality care is under discussion. Therefore, it is important to understand the current role of GPs during follow-up care of CRC. This study explores the primary healthcare use of patients 2-6 years after CRC treatment. Annual rates of face-to-face contacts, prescribed medication and referrals were compared between CRC patients and age, gender and GP matched controls in a historical prospective study. Reasons for contacts and prescribed medication were compared based on International Classification of Primary Care and Anatomical Therapeutic Chemical (ATC) Classification System codes, respectively. Negative binomial regression models and non-parametric test were used. Patients showed significantly more face-to-face contacts in the 2nd (63%), 3rd (32%) and 6th (23%) year, more drug prescriptions in the 2nd, 3rd and 6th year, and more referrals in the 2nd and 5th year after diagnosis. Differences in contacts and medication were related to the alimentary tract, blood and blood-forming organs, and psychological problems. This study suggests that GPs already play a substantial role during CRC follow-up and that there may be scope for formal services to be incorporated into the current model of GP care.

A systematic review of the psychological impact of false-positive colorectal cancer screening: What is the role of the general practitioner?

Screening for colorectal cancer (CRC) has both advantages (e.g. reduction in morbidity and mortality) and disadvantages (e.g. false positives and distress). A systematic review was therefore performed to improve our understanding of how false-positive CRC screening results affect patients psychologically (and to make recommendations for primary care). The PubMed, Embase, PsychINFO, CINAHL and Cochrane databases were searched in October 2014 and supplemented in December 2016 to identify studies on the psychological impact of false-positive CRC screening. Original studies were eligible when they assessed psychological impact in a screening setting, provided they also included false-positive CRC screening results. Two authors independently assessed 2,367 available manuscripts and included seven. Heterogeneity in their outcome measures meant that data could not be pooled. Two studies showed that a false-positive CRC screening result caused some moderate psychological distress shortly before and after colonoscopy. The remaining five studies illustrated that the psychological distress of patients with true-positive and false-positive CRC screening results was comparable. We conclude that a false-positive CRC screening result may cause some moderate psychological distress, especially just before or after colonoscopy. We recommend that general practitioners mention this when discussing CRC screening with patients and monitor those with a false-positive outcome for psychological distress.