Diagnostic and societal impact of implementing the syncope guidelines of the European Society of Cardiology (SYNERGY study).

BACKGROUND: Syncope management is fraught with unnecessary tests and frequent failure to establish a diagnosis. We evaluated the potential of implementing the 2018 European Society of Cardiology (ESC) Syncope Guidelines regarding diagnostic yield, accuracy and costs. METHODS: A multicentre pre-post study in five Dutch hospitals comparing two groups of syncope patients visiting the emergency department: one before intervention (usual care; from March 2017 to February 2019) and one afterwards (from October 2017 to September 2019). The intervention consisted of the simultaneous implementation of the ESC Syncope Guidelines with quick referral routes to a syncope unit when indicated. The primary objective was to compare diagnostic accuracy using logistic regression analysis accounting for the study site. Secondary outcome measures included diagnostic yield, syncope-related healthcare and societal costs. One-year follow-up data were used to define a gold standard reference diagnosis by applying ESC criteria or, if not possible, evaluation by an expert committee. We determined the accuracy by comparing the treating physician's diagnosis with the reference diagnosis. RESULTS: We included 521 patients (usual care, n = 275; syncope guidelines intervention, n = 246). The syncope guidelines intervention resulted in a higher diagnostic accuracy in the syncope guidelines group than in the usual care group (86% vs.69%; risk ratio 1.15; 95% CI 1.07 to 1.23) and a higher diagnostic yield (89% vs. 76%, 95% CI of the difference 6 to 19%). Syncope-related healthcare costs did not differ between the groups, yet the syncope guideline implementation resulted in lower total syncope-related societal costs compared to usual care (saving €908 per patient; 95% CI €34 to €1782). CONCLUSIONS: ESC Syncope Guidelines implementation in the emergency department with quick referral routes to a syncope unit improved diagnostic yield and accuracy and lowered societal costs. TRIAL REGISTRATION: Netherlands Trial Register, NTR6268.

Increased Prevalence of Malignancies in Fibrous Dysplasia/McCune-Albright Syndrome (FD/MAS): Data from a National Referral Center and the Dutch National Pathology Registry (PALGA).

Malignant transformation of fibrous dysplasia lesions has been reported in patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS). Recently, we have observed an increased risk for breast cancer. In this study, the prevalence of skeletal and extraskeletal malignancies in patients with FD/MAS in the Netherlands was assessed by analyzing data from our cohort of FD/MAS patients, the Dutch Pathology Registry (PALGA), and the Netherlands Cancer Registry (NCR). We extracted data on sex, age at diagnosis of FD/MAS, type of FD/MAS, type of malignancy, and age at diagnosis of malignancy and histology of bone and malignant tissue when available, including GNAS-mutation analysis from patients' medical records. Standardized Morbidity Ratios (SMRs) with 95% confidence intervals were calculated. Twelve malignancies were identified in the LUMC FD/MAS cohort and 100 in the PALGA cohort. In this cohort, SMR was increased for osteosarcoma (19.7, 95% CI 3.5-48.9), cervical cancer (4.93, 95%CI 1.7-8.2), thyroid cancer (3.71, 95% CI 1.1-7.8), prostate cancer (3.08, 95% CI 1.8-4.6), and melanoma (2.01, 95%CI 1.2-3.1). SMRs for pancreatic cancer or hepatocellular carcinoma could not be calculated due to low numbers. The small number of malignancies identified in our FD/MAS cohort precluded the calculation of SMRs for our cohort specifically. Our findings show that patients with FD/MAS appear to have an increased risk for osteosarcoma, cervical, thyroid, and prostate cancer and melanoma. However, these data should be interpreted with caution, as true incidence rates of the identified malignancies may be influenced by the inclusion of only patients with histologically confirmed FD/MAS. The etiology of this increased risk for malignancies still needs to be elucidated.

Effect of omission of surgery on survival in patients aged 80 years and older with early-stage hormone receptor-positive breast cancer.

BACKGROUND: Surgery is increasingly being omitted in older patients with operable breast cancer in the Netherlands. Although omission of surgery can be considered in frail older patients, it may lead to inferior outcomes in non-frail patients. Therefore, the aim of this study was to evaluate the effect of omission of surgery on relative and overall survival in older patients with operable breast cancer. METHODS: Patients aged 80 years or older diagnosed with stage I-II hormone receptor-positive breast cancer between 2003 and 2009 were selected from the Netherlands Cancer Registry. An instrumental variable approach was applied to minimize confounding, using hospital variation in rate of primary surgery. Relative and overall survival was compared between patients treated in hospitals with different rates of surgery. RESULTS: Overall, 6464 patients were included. Relative survival was lower for patients treated in hospitals with lower compared with higher surgical rates (90·2 versus 92·4 per cent respectively after 5 years; 71·6 versus 88·2 per cent after 10 years). The relative excess risk for patients treated in hospitals with lower surgical rates was 2·00 (95 per cent c.i. 1·17 to 3·40). Overall survival rates were also lower among patients treated in hospitals with lower compared with higher surgical rates (48·3 versus 51·3 per cent after 5 years; 15·0 versus 19·7 per cent after 10 years respectively; adjusted hazard ratio 1·07, 95 per cent c.i. 1·00 to 1·14). CONCLUSION: Omission of surgery is associated with worse relative and overall survival in patients aged 80 years or more with stage I-II hormone receptor-positive breast cancer. Future research should focus on the effect on quality of life and physical functioning.

ANTECEDENTES: En los Países Bajos cada vez es más frecuente descartar la cirugía en pacientes mayores con cáncer de mama operable. Aunque la omisión de la cirugía puede ser adecuada en pacientes mayores frágiles, ello puede determinar peores resultados en pacientes no frágiles. Por tanto, el objetivo de este estudio fue evaluar el efecto de omitir la cirugía en la supervivencia relativa y en la supervivencia global en pacientes mayores con cáncer de mama operable. MÉTODOS: A partir del Registro de Cáncer de los Países Bajos se seleccionaron las pacientes de ≥ 80 años de edad diagnosticadas de cáncer de mama entre 2003-2009 en estadios 1-2 y con receptores hormonales positivos. Se aplicó un método de variables instrumentales para minimizar los factores de confusión utilizando la tasa de variación hospitalaria de la cirugía primaria. Se compararon las supervivencias relativa y global de las pacientes tratadas en hospitales con diferentes tasas de cirugía. RESULTADOS: Se incluyeron 6.464 pacientes. La supervivencia relativa fue menor en las pacientes tratadas en hospitales con tasas quirúrgicas más bajas en comparación con las tratadas en hospitales con tasas altas (90,2% versus 92,4% a los 5 años y 71,6% versus 88,2% a los 10 años, respectivamente). El exceso de riesgo relativo para las pacientes tratadas en hospitales con tasas quirúrgicas más bajas fue de 2,00 (i.c. del 95% 1,17-3,40). La supervivencia global también fue menor para las pacientes tratadas en hospitales con tasas quirúrgicas más bajas en comparación con las más altas (48,3% versus 51,3% a los 5 años y 15,0% versus 19,7% a los 10 años, respectivamente, cociente de riesgos instantáneos, hazard ratio, HR, ajustado 1,07) i.c. del 95% 1,00-1,14)). CONCLUSIÓN: Omitir la cirugía se asocia con una peor supervivencia relativa y global en pacientes de ≥ 80 años con cáncer de mama en estadios 1-2 y receptores hormonales positivos. Las investigaciones futuras deberían centrarse en el efecto de este enfoque en la calidad de vida y la funcionalidad física.

Metastasis of cutaneous squamous cell carcinoma in organ transplant recipients and the immunocompetent population: is there a difference? a systematic review and meta-analysis.

BACKGROUND: Organ transplant recipients (OTR) have a higher risk of developing cutaneous squamous cell carcinoma (cSCC) compared to the immunocompetent population. Immunosuppression is often stated as a risk factor for metastasis. However, evidence for this is scarce. OBJECTIVES: To investigate the cSCC metastasis risk in OTR and the immunocompetent population by systematically reviewing the literature. METHODS: A systematic review of the literature was performed up to January 2018 using: Medline; Embase; Web of Science and ISI Science Citation Index. Studies assessing cSCC metastasis risk in ORT or immunocompetent cohorts were considered. A pooled risk estimate for metastasis was calculated for the immunocompetent population and OTR separately. RESULTS: The pooled metastasis risk estimate for OTR was, respectively, 7.3% (95% CI 6.2-8.4) for cSCC on total body, and 11.0% (95% CI 7.7-14.8) for cSCC of the head neck area. For the immunocompetent population reported risk estimate analysis showed a pooled metastatic risk of 3.1% (95% CI 2.8-3.4) in total body cSCC and of 8.5% (95% CI 7.3-9.8) in cSCC of the head and neck area. Pooled risk estimate per single cSCC in OTR was 1.3% (95% CI 1.0-1.7) in total body cSCC and 4.0% (95% CI 2.7-5.5) in cSCC of the head and neck area. In the immunocompetent population, these pooled risk estimates were, respectively, 2.4% (95% CI 2.1-2.6) and 6.7% (95% CI 5.7-7.8). CONCLUSIONS: Organ transplant recipients show a higher overall risk of cSCC metastasis compared to the immunocompetent population. Metastasis risks per single cSCC were substantially lower in both groups. However, due to heterogeneity and differences between studies, comparisons are difficult. Comprehensive follow-up studies with defined cohorts are necessary to adequately asses the risk for cSCC metastasis.

Comparison of histological and morphometrical changes underlying subchondral bone abnormalities in inflammatory and degenerative musculoskeletal disorders: a systematic review.

OBJECTIVE: Subchondral bone abnormalities (SBAs) on magnetic resonance imaging (MRI) are observed frequently and associated with disease course in various musculoskeletal disorders. This review aims to map the existing knowledge of their underlying histological features, and to identify needs for future research. DESIGN: We conducted a systematic review following PRISMA guidelines until September 2017, including all studies correlating histological features to on MRI defined SBAs in patients with osteoarthritis (OA), rheumatoid arthritis (RA), spondyloarthritis (SpA) and degenerative disc disease (DDD). Two authors independently retrieved articles and assessed study quality. RESULTS: A total of 21 studies (466 patients) correlated histological features to SBAs in OA (n = 13), RA (n = 3), ankylosing spondylitis (AS) (n = 1) and DDD (n = 4). Reported changes in OA were substitution of normal subchondral bone with fibrosis and necrosis, and increased bone remodeling. In contrast, in RA, AS or DDD fibrosis was not reported and SBAs correlated to an increase in inflammatory cell number. In DDD necrosis was observed. Similar to OA, increased bone remodeling was shown in RA and DDD. The risk of bias assessment showed a lack in described patient criteria, blinding and/or adequate topographic correlation in approximately half of studies. There was heterogeneity regarding the investigated histological features between the different disorders. CONCLUSIONS: Current studies suggest that SBAs correlate to various histological features, including fibrosis, cell death, inflammation and bone remodeling. In the majority of studies most quality criteria were not met. Future studies should aim for high quality research, and consistency in investigated features between different disorders.

Study protocol: a randomised controlled trial on the clinical effects of levothyroxine treatment for subclinical hypothyroidism in people aged 80 years and over.

BACKGROUND: Subclinical hypothyroidism is common in older people and its contribution to health and disease needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial to generate the necessary evidence base. METHODS: The IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial (TRUST) with a near identical protocol and shared research infrastructure. Outcomes will be presented separately for the IEMO and TRUST 80-plus groups, as well as a pre-planned combined analysis of the 145 participants included in the IEMO trial and the 146 participants from the TRUST thyroid trial aged 80 years and over. The IEMO 80-plus thyroid trial is a multi-centre randomised double-blind placebo-controlled parallel group trial of levothyroxine treatment in community-dwelling participants aged 80 years and over with persistent subclinical hypothyroidism (TSH ≥4.6 and ≤ 19.9 mU/L and fT4 within laboratory reference ranges). Participants are randomised to levothyroxine 25 or 50 micrograms daily or matching placebo with dose titrations according to TSH levels, for a minimum follow-up of one and a maximum of three years. Primary study endpoints: hypothyroid physical symptoms and tiredness on the thyroid-related quality of life patient-reported outcome (ThyPRO) at one year. Secondary endpoints: generic quality of life, executive cognitive function, handgrip strength, functional ability, blood pressure, weight, body mass index, and mortality. Adverse events will be recorded with specific interest on cardiovascular endpoints such as atrial fibrillation and heart failure. DISCUSSION: The combined analysis of participants in the IEMO 80-plus thyroid trial with the participants aged over 80 in the TRUST trial will provide the largest experimental evidence base on multimodal effects of levothyroxine treatment in 80-plus persons to date. TRIAL REGISTRATION: Nederlands (Dutch) Trial Register: NTR3851 (12-02-2013), EudraCT: 2012-004160-22 (17-02-2013), ABR-41259.058.13 (12-02-2013).

Expression of p27Kip1 and p18Ink4c in human multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors.

PURPOSE: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27Kip1 and p18Ink4c in MEN1-related tumor development in animal models for MEN1, but their contribution to human MEN1-related pancreatic neuroendocrine tumor development is not known. METHODS: In this study, we characterized protein expression of p27Kip1 and p18Ink4c in human MEN1-related PanNETs by immunohistochemistry. From the nationwide DutchMEN1 Study Group database including > 90% of the Dutch MEN1 population, MEN1-patients, who underwent pancreatic surgery, were selected. A tissue micro-array was constructed with available paraffin tissue blocks, and PanNETs from 61 MEN1 patients were eligible for analysis. RESULTS: Expression of p27Kip1 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18Ink4c (67.3%). No association was found between expression of either p27Kip1 or p18Ink4c and clinic-pathological characteristics. CONCLUSIONS: These findings indicate that loss of p18Ink4c, but not p27Kip1, is a common event in the development of MEN1-related PanNETs. Restoration of p18Ink4c function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.

Value and potential limitations of vertebral fracture assessment (VFA) compared to conventional spine radiography: experience from a fracture liaison service (FLS) and a meta-analysis.

We evaluated the value of VFA in the identification of vertebral fractures using a retrospective study and a meta-analysis. Performance of VFA was adequate in the meta-analysis although this was not demonstrated in our centre. We recommend checking the performance of VFA tools before exclusively relying on this tool. INTRODUCTION: Vertebral fractures are traditionally diagnosed using conventional radiographs of the spine. Vertebral fracture assessment (VFA) has been advocated as an alternative tool in the diagnosis of these fractures. METHODS: We conducted a retrospective study as well as a systematic review and a meta-analysis to evaluate the performance of VFA compared to conventional spinal radiography in patients who had sustained a fracture and thus at risk for osteoporosis. A risk of bias analysis was also performed. RESULTS: The diagnostic study included 542 patients (25% male) with fractures. The sensitivity of low-radiation VFA to detect a patient with a vertebral fracture ≥ Genant grade 2 was 0.77 and its specificity 0.80. Two hundred ninety-seven (55%) patients had ≥1 and 135(25%) ≥3 unevaluable vertebrae. The systematic review identified 16 studies including a total of 3238 subjects (19% male) with a mean age range of 45 to 74 years. Seven studies had a low risk of bias and 9 had an intermediate risk, mainly due to not consecutively including patients. The pooled sensitivity of VFA to detect a patient with a vertebral fracture ≥Genant grade 2 was 0.84 (95% CI, 0.72-0.92) and specificity 0.90 (95% CI, 0.84-0.94). CONCLUSIONS: Our findings from the meta-analysis suggest an adequate performance of VFA for the detection of vertebral fractures. However, we could not demonstrate these findings in our center, especially the specificity. Our data advocate caution with exclusively relying on VFA in the assessment of vertebral fractures without identifying performance and potential limitations of the technique.

Individual and partner's level of occupation and the association with HbA1c levels in people with Type 2 diabetes mellitus: the Dutch Diabetes Pearl cohort.

AIMS: Individual indicators of socio-economic status have been associated with glycaemic control in people with Type 2 diabetes, but little is known about the association between partner's socio-economic status and HbA1c levels. We therefore examined the cross-sectional association between individual and partner's level of occupation on HbA1c levels in people with Type 2 diabetes in the Netherlands. METHODS: We included people with Type 2 diabetes with a partner who were treated in primary, secondary and tertiary care in the Diabetes Pearl cohort. Occupational level was classified according to International Standard Classification of Occupations (ISCO)-08 skill levels. Linear regression analyses were performed stratified for sex, and corrected for age, recruitment centre and diabetes medication. RESULTS: In total, 3257 participants (59.8% men, mean 62.2±9.4 years) were included. For men, having a partner with an intermediate level of occupation was associated with lower HbA1c levels [e.g. ISCO level 3: -2 mmol/mol (95% CI -4;-1) or -0.2% (95% CI -0.4;-0.1)], compared with having a partner of the highest occupational level (ISCO level 4). In women, having an unemployed partner was associated with higher HbA1c levels [14 mmol/mol (95% CI 6; 22) or 1.3% (95% CI 0.6; 2.0)], compared with having a partner of the highest occupational level. CONCLUSIONS: Partner's occupational status provided additional information on the association between socio-economic status and HbA1c levels in people with Type 2 diabetes. Women seemed to benefit from a partner with a higher occupational status, while men seemed to benefit from a partner with a lower status. Because of the cross-sectional nature of the present study, more research is necessary to explore this association.

(131)I-MIBG therapy for malignant paraganglioma and phaeochromocytoma: systematic review and meta-analysis.

BACKGROUND: (131)I-MIBG therapy can be used for palliative treatment of malignant paraganglioma and phaeochromocytoma. The main objective of this study was to perform a systematic review and meta-analysis assessing the effect of (131)I-MIBG therapy on tumour volume in patients with malignant paraganglioma/phaeochromocytoma. METHODS: A literature search was performed in December 2012 to identify potentially relevant studies. Main outcomes were the pooled proportions of complete response, partial response and stable disease after radionuclide therapy. A meta-analysis was performed with an exact likelihood approach using a logistic regression with a random effect at the study level. Pooled proportions with 95% confidence intervals (CI) were reported. RESULTS: Seventeen studies concerning a total of 243 patients with malignant paraganglioma/phaeochromocytoma were treated with (131)I-MIBG therapy. The mean follow-up ranged from 24 to 62 months. A meta-analysis of the effect of (131)I-MIBG therapy on tumour volume showed pooled proportions of complete response, partial response and stable disease of, respectively, 0·03 (95% CI: 0·06-0·15), 0·27 (95% CI: 0·19-0·37) and 0·52 (95% CI: 0·41-0·62) and for hormonal response 0·11 (95% CI: 0·05-0·22), 0·40 (95% CI: 0·28-0·53) and 0·21 (95% CI: 0·10-0·40), respectively. Separate analyses resulted in better results in hormonal response for patients with paraganglioma than for patients with phaeochromocytoma. CONCLUSIONS: Data on the effects of (131)I-MIBG therapy on malignant paraganglioma/phaeochromocytoma suggest that stable disease concerning tumour volume and a partial hormonal response can be achieved in over 50% and 40% of patients, respectively, treated with (131)I-MIBG therapy. It cannot be ruled out that stable disease reflects not only the effect of MIBG therapy, but also (partly) the natural course of the disease.

Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis.

BACKGROUND: Chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD) can be used for palliative treatment of malignant pheochromocytoma and paraganglioma. However, the precise effect of this chemotherapeutic regimen on tumour volume is unclear. The main objective of this study was to perform a systematic review and meta-analysis assessing the effect of chemotherapy with CVD on tumour volume in patients with malignant paraganglioma/pheochromocytoma. METHODS: A literature search was performed in October 2013 to identify potentially relevant studies. Main outcomes were the pooled percentages of complete response, partial response and stable disease after chemotherapy with CVD. A meta-analysis was performed with an exact likelihood approach using a logistic regression. Pooled percentages with 95% confidence intervals (CI) were reported. RESULTS: Four studies concerning a total of 50 patients with malignant paraganglioma/pheochromocytoma reported on treatment with a combination of CVD chemotherapy. A meta-analysis of the effect of chemotherapy on tumour volume showed pooled percentages of complete response, partial response and stable disease of, respectively, 4% (95% CI: 1%-15%), 37%(95% CI: 25%-51%) and 14% (95% CI: 7%-27%). Only two studies concerning a total of 35 patients assessed the response on catecholamine excess; pooled percentages for complete, partial and stable hormonal response were 14% (95% CI: 6%-30%), 40% (95% CI: 25%-57%) and 20% (95% CI: 10%-36%), respectively. Duration of response was also reported in only two studies with a median duration of response of 20 months and 40 months. CONCLUSIONS: Data on the effects of a combination of CVD chemotherapy on malignant paraganglioma/pheochromocytoma suggest that a partial response concerning tumour volume can be achieved in about 37% of patients and a partial response on catecholamine excess in about 40% of patients. However, in the included studies, the protocol when to initiate treatment was not well described. Therefore, it cannot be excluded that the reported effect of chemotherapy on tumour volume reflects the natural course of the disease, at least partially.

The effect of levothyroxine on expression of inflammation-related genes in healthy subjects: a controlled randomized crossover study.

An excess of thyroid hormone leads to a prothrombotic state; however, the underlying pathophysiological mechanisms remain unknown. As evidence points towards an extensive "cross-talk" between the inflammatory and coagulation cascade, inflammation has been claimed as a possible mechanism through which different risk factors trigger venous thrombus formation. We aimed to study changes in expression of inflammation-related genes of the leukocyte RNA expression profile in healthy subjects in response to supraphysiological doses of levothyroxine. In a randomized single-blinded crossover design, 12 healthy volunteers (aged 18-40 years) received levothyroxine and no medication, both for 14 days with a wash-out period of at least 28 days between the periods. Blood was sampled at baseline and day 14 of each study period. MRNA was isolated from whole blood and used for multiplex ligation-dependent probe amplification to study the expression of inflammation-related genes. Compared to the control situation no significant changes were found in the expression of proinflammatory cytokines and mediators after the intake of levothyroxine. The results of this study show that high thyroid hormone levels do not lead to an altered inflammatory profile. This provides evidence against a major role of the inflammatory system as mediator in the effect of thyroid hormone on the coagulation system. The mechanisms by which thyroid hormone may influence coagulation proteins remain to be elucidated.

Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

Background: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). Objective: The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. Design and methods: A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Results: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Conclusion: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. Significance statement: The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

Survival in dialysis patients is different between patients with diabetes as primary renal disease and patients with diabetes as a co-morbid condition.

AIMS/HYPOTHESIS: A previous study in Dutch dialysis patients showed no survival difference between patients with diabetes as primary renal disease and those with diabetes as a co-morbid condition. As this was not in line with our hypothesis, we aimed to verify these results in a larger international cohort of dialysis patients. METHODS: For the present prospective study, we used data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry. Incident dialysis patients with data on co-morbidities (n = 15,419) were monitored until kidney transplantation, death or end of the study period (5 years). Cox regression was performed to compare survival for patients with diabetes as primary renal disease, patients with diabetes as a co-morbid condition and non-diabetic patients. RESULTS: Of the study population, 3,624 patients (24%) had diabetes as primary renal disease and 1,193 (11%) had diabetes as a co-morbid condition whereas the majority had no diabetes (n = 10,602). During follow-up, 7,584 (49%) patients died. In both groups of diabetic patients mortality was higher compared with the non-diabetic patients. Mortality was higher in patients with diabetes as primary renal disease than in patients with diabetes as a co-morbid condition, adjusted for age, sex, country and malignancy (HR 1.20, 95% CI 1.10, 1.30). An analysis stratified by dialysis modality yielded similar results. CONCLUSIONS/INTERPRETATION: Overall mortality was significantly higher in patients with diabetes as primary renal disease compared with those with diabetes as a co-morbid condition. This suggests that survival in diabetic dialysis patients is affected by the extent to which diabetes has induced organ damage.

Diagnostic and therapeutic practices in adult chronic nonbacterial osteomyelitis (CNO).

BACKGROUND: Chronic nonbacterial osteomyelitis (CNO) is a rare, and impactful auto-inflammatory bone disease occurring in children and adults. Clinical care for CNO is challenging, as the condition lacks validated classification criteria and evidence-based therapies. This study aimed to map the current diagnostic and therapeutic practices for CNO in adults, as a first step towards a standardized disease definition and future consensus treatment plans. METHODS: A primary survey was spread among global rheumatological/bone networks and 57 experts as identified from literature (May 2022), covering terminology, diagnostic tools (clinical, radiological, biochemical) and treatment steps. A secondary survey (sent to primary survey responders in August 2022) further queried key diagnostic features, treatment motivations, disease activity and treatment response monitoring. RESULTS: 36 and 23 physicians completed the primary and secondary survey respectively. Diagnosis was mainly based on individual physician assessment, in which the combination of chronic relapsing-remitting bone pain with radiologically-proven osteitis/osteomyelitis, sclerosis, hyperostosis and increased isotope uptake on bone scintigraphy were reported indicative of CNO. Physicians appeared more likely to refer to the condition as synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome in the presence of joint and skin pathology. MRI was most frequently performed, and the preferred diagnostic test for 47%. X-rays were second-most frequently used, although considered least informative of all available tools. Typical imaging features reported were hyperostosis, osteitis, osteosclerosis, bone marrow edema, while degeneration, soft tissue calcification, and ankylosis were not regarded characteristic. Inflammation markers and bone markers were generally regarded unhelpful for diagnostic and monitoring purposes and physicians infrequently performed bone biopsies. Management strategies diverged, including indications for treatment, response monitoring and declaration of remission. Step-1 treatment consisted of non-steroidal anti-inflammatory drugs/COX-2 inhibitors (83%). Common step 2-3 treatments were pamidronate, methotrexate, and TNF-a-inhibition (anti-TNFα), the latter two regarded especially convenient to co-target extra-skeletal inflammation in SAPHO syndrome. Overall pamidronate and anti-TNFα and were considered the most effective treatments. CONCLUSIONS: Following from our survey data, adult CNO is a broad and insufficiently characterized disease spectrum, including extra-osseous features. MRI is the favoured imaging diagnostic, and management strategies vary significantly. Overall, pamidronate and anti-TNFα are regarded most successful. The results lay out current practices for adult CNO, which may serve as backbone for a future consensus clinical guideline.

Electronic reporting of rare endocrine conditions within a clinical network: results from the EuRRECa project.

Objective: The European Registries for Rare Endocrine Conditions (EuRRECa, eurreb.eu) includes an e-reporting registry (e-REC) used to perform surveillance of conditions within the European Reference Network (ERN) for rare endocrine conditions (Endo-ERN). The aim of this study was to report the experience of e-REC over the 3.5 years since its launch in 2018. Methods: Electronic reporting capturing new encounters of Endo-ERN conditions was performed monthly through a bespoke platform by clinicians registered to participate in e-REC from July 2018 to December 2021. Results: The number of centres reporting on e-REC increased to a total of 61 centres from 22 countries. A median of 29 (range 11, 45) paediatric and 32 (14, 51) adult centres had reported cases monthly. A total of 9715 and 4243 new cases were reported in adults (age ≥18 years) and children, respectively. In children, sex development conditions comprised 40% of all reported conditions and transgender cases were most frequently reported, comprising 58% of sex development conditions. The median number of sex development cases reported per centre per month was 0.6 (0, 38). Amongst adults, pituitary conditions comprised 44% of reported conditions and pituitary adenomas (69% of cases) were most commonly reported. The median number of pituitary cases reported per centre per month was 4 (0.4, 33). Conclusions: e-REC has gained increasing acceptability over the last 3.5 years for capturing brief information on new encounters of rare conditions and shows wide variations in the rate of presentation of these conditions to centres within a reference network. Significance statement Endocrinology includes a very wide range of rare conditions and their occurrence is often difficult to measure. By using an electronic platform that allowed monthly reporting of new clinical encounters of several rare endocrine conditions within a defined network that consisted of several reference centres in Europe, the EuRRECa project shows that a programme of e-surveillance is feasible and acceptable. The data that have been collected by the e-reporting of rare endocrine conditions (e-REC) can allow the continuous monitoring of rare conditions and may be used for clinical benchmarking, designing new studies or recruiting to clinical trials.

Use of aspirin postdiagnosis improves survival for colon cancer patients.

BACKGROUND: The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients. METHODS: Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998-2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure. RESULTS: In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63-0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50-0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46-0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79-1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70-2.20; P<0.001). CONCLUSION: Aspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of a placebo-controlled trial that investigates the role of aspirin as adjuvant treatment in colon cancer patients.

Adherence to treatment guidelines and survival in patients with early-stage breast cancer by age at diagnosis.

BACKGROUND: Elderly patients with breast cancer are under-represented in clinical studies. It is not known whether treatment guidelines, based on clinical trials, can be extrapolated to this population. The aim of this study was to assess adherence to treatment guidelines by age at diagnosis, and to examine age-specific survival in relation to adherence to guidelines. METHODS: Patients with early-stage breast cancer aged either less than 65 years, or 75 years or more, diagnosed between 2005 and 2008, were identified from the Netherlands Cancer Registry. Adherence to treatment guidelines for breast and axillary surgery, radiotherapy, chemotherapy and endocrine therapy was determined. Non-adherence to the guidelines was defined as overtreatment or undertreatment. The primary endpoint was overall survival, assessed by means of an instrumental variable, the comprehensive cancer centre region. RESULTS: Some 24 959 patients younger than 65 years and 6561 patients aged 75 years or more were included in the analysis. Median follow-up was 2·8 years. Compared with patients younger than 65 years, those aged at least 75 years were less frequently treated in concordance with guidelines: 62·0 per cent (15 487 patients) versus 55·6 per cent (3647 patients) (P < 0·001). In both age groups, most patients received at least three of five treatment modalities in concordance with guidelines: 98·8 per cent (24 652 patients) and 93·8 per cent (6152 patients) respectively. Analysis of survival using the instrumental variable showed that adherence to guidelines was not associated with overall survival in patients younger than 65 years (P = 0·601) or those aged at least 75 years (P = 0·190). CONCLUSION: Adherence to treatment guidelines was affected by age at diagnosis. However, adherence to the guidelines was not associated with overall survival in either age group.

Publication rates in small German trials remained low five years after trial completion.

OBJECTIVE: To investigate publication rates in small trials and to explore which factors are associated with publication rates in small trials, including sample size, the type and number of primary and secondary outcomes. STUDY DESIGN AND SETTING: We studied a subgroup of 'small' trials from a pre-existing dataset (IntoValue), containing German trials completed between 2009 and 2017. Small trials were defined as phase II-III, III and IV trials with 150 or fewer participants. We performed an updated publication search and collected additional data from online trial records. RESULTS: Out of 499 trials, 325 (65%) trials published their results in a journal article or dissertation. Median time-to-publication was 3.41 years (95% CI: 3.04-4.10). Planned sample size was not associated with publication rates, but the difference between planned and achieved sample size was (per 10% unsuccessfully recruited participants, HR = 0.95, 95% CI: 0.91-1.00). Phase III vs. II-III trials, studied intervention (device vs. other) and clearly vs. unclearly defined primary outcomes predicted a higher likelihood of earlier publication. CONCLUSION: About 35% of small trials in Germany remain unpublished, even after an extensive follow-up period of over 9 years. Publication rates are low and were associated with sample size, trial phase and type of intervention.