Máxima Medisch Centrum

Adrenocortical carcinoma (ACC) is a rare and in most cases steroid hormone-producing tumor with variable prognosis. The purpose of these guidelines is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with ACC based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions, which we judged as particularly important for the management of ACC patients and performed systematic literature searches: (A) What is needed to diagnose an ACC by histopathology? (B) Which are the best prognostic markers in ACC? (C) Is adjuvant therapy able to prevent recurrent disease or reduce mortality after radical resection? (D) What is the best treatment option for macroscopically incompletely resected, recurrent or metastatic disease? Other relevant questions were discussed within the group. Selected Recommendations: (i) We recommend that all patients with suspected and proven ACC are discussed in a multidisciplinary expert team meeting. (ii) We recommend that every patient with (suspected) ACC should undergo careful clinical assessment, detailed endocrine work-up to identify autonomous hormone excess and adrenal-focused imaging. (iii) We recommend that adrenal surgery for (suspected) ACC should be performed only by surgeons experienced in adrenal and oncological surgery aiming at a complete en bloc resection (including resection of oligo-metastatic disease). (iv) We suggest that all suspected ACC should be reviewed by an expert adrenal pathologist using the Weiss score and providing Ki67 index. (v) We suggest adjuvant mitotane treatment in patients after radical surgery that have a perceived high risk of recurrence (ENSAT stage III, or R1 resection, or Ki67 >10%). (vi) For advanced ACC not amenable to complete surgical resection, local therapeutic measures (e.g. radiation therapy, radiofrequency ablation, chemoembolization) are of particular value. However, we suggest against the routine use of adrenal surgery in case of widespread metastatic disease. In these patients, we recommend either mitotane monotherapy or mitotane, etoposide, doxorubicin and cisplatin depending on prognostic parameters. In selected patients with a good response, surgery may be subsequently considered. (vii) In patients with recurrent disease and a disease-free interval of at least 12 months, in whom a complete resection/ablation seems feasible, we recommend surgery or alternatively other local therapies. Furthermore, we offer detailed recommendations about the management of mitotane treatment and other supportive therapies. Finally, we suggest directions for future research.

Secondary prevention through comprehensive cardiac rehabilitation has been recognized as the most cost-effective intervention to ensure favourable outcomes across a wide spectrum of cardiovascular disease, reducing cardiovascular mortality, morbidity and disability, and to increase quality of life. The delivery of a comprehensive and 'modern' cardiac rehabilitation programme is mandatory both in the residential and the out-patient setting to ensure expected outcomes. The present position paper aims to update the practical recommendations on the core components and goals of cardiac rehabilitation intervention in different cardiovascular conditions, in order to assist the whole cardiac rehabilitation staff in the design and development of the programmes, and to support healthcare providers, insurers, policy makers and patients in the recognition of the positive nature of cardiac rehabilitation. Starting from the previous position paper published in 2010, this updated document maintains a disease-oriented approach, presenting both well-established and more controversial aspects. Particularly for implementation of the exercise programme, advances in different training modalities were added and new challenging populations were considered. A general table applicable to all cardiovascular conditions and specific tables for each clinical condition have been created for routine practice.

Cardiovascular remodelling in the conditioned athlete is frequently associated with physiological ECG changes. Abnormalities, however, may be detected which represent expression of an underlying heart disease that puts the athlete at risk of arrhythmic cardiac arrest during sports. It is mandatory that ECG changes resulting from intensive physical training are distinguished from abnormalities which reflect a potential cardiac pathology. The present article represents the consensus statement of an international panel of cardiologists and sports medical physicians with expertise in the fields of electrocardiography, imaging, inherited cardiovascular disease, cardiovascular pathology, and management of young competitive athletes. The document provides cardiologists and sports medical physicians with a modern approach to correct interpretation of 12-lead ECG in the athlete and emerging understanding of incomplete penetrance of inherited cardiovascular disease. When the ECG of an athlete is examined, the main objective is to distinguish between physiological patterns that should cause no alarm and those that require action and/or additional testing to exclude (or confirm) the suspicion of an underlying cardiovascular condition carrying the risk of sudden death during sports. The aim of the present position paper is to provide a framework for this distinction. For every ECG abnormality, the document focuses on the ensuing clinical work-up required for differential diagnosis and clinical assessment. When appropriate the referral options for risk stratification and cardiovascular management of the athlete are briefly addressed.

BACKGROUND: The three approaches to hysterectomy for benign disease are abdominal hysterectomy (AH), vaginal hysterectomy (VH), and laparoscopic hysterectomy (LH). Laparoscopic hysterectomy has three further subdivisions depending on the part of the procedure performed laparoscopically. OBJECTIVES: To assess the most beneficial and least harmful surgical approach to hysterectomy for women with benign gynaecological conditions. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials (15 August 2008), CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE (1950 to August 2008), EMBASE (1980 to August 2008), Biological Abstracts (1969 to August 2008), the National Research Register, and relevant citation lists. SELECTION CRITERIA: Only randomised controlled trials comparing one surgical approach to hysterectomy with another were included. DATA COLLECTION AND ANALYSIS: Independent selection of trials and data extraction were employed following Cochrane guidelines. MAIN RESULTS: There were 34 included studies with 4495 women. The benefits of VH versus AH were speedier return to normal activities (mean difference (MD) 9.5 days), fewer febrile episodes or unspecified infections (odds ratio (OR) 0.42), and shorter duration of hospital stay (MD 1.1 days). The benefits of LH versus AH were speedier return to normal activities (MD 13.6 days), lower intraoperative blood loss (MD 45 cc), a smaller drop in haemoglobin (MD 0.55 g/dl), shorter hospital stay (MD 2.0 days), and fewer wound or abdominal wall infections (OR 0.31) at the cost of more urinary tract (bladder or ureter) injuries (OR 2.41) and longer operation time (MD 20.3 minutes). The benefits of LAVH versus TLH were fewer febrile episodes or unspecified infection (OR 3.77) and shorter operation time (MD 25.3 minutes). There was no evidence of benefits of LH versus VH and the operation time (MD 39.3 minutes) as well as substantial bleeding (OR 2.76) were increased in LH. For some important outcomes, the analyses were underpowered to detect important differences or they were simply not reported in trials. Data were absent for many important long-term outcome measures. AUTHORS' CONCLUSIONS: Because of equal or significantly better outcomes on all parameters, VH should be performed in preference to AH where possible. Where VH is not possible, LH may avoid the need for AH however the length of the surgery increases as the extent of the surgery performed laparoscopically increases. The surgical approach to hysterectomy should be decided by the woman in discussion with her surgeon in light of the relative benefits and hazards.

BACKGROUND: Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma. METHODS: TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival. RESULTS: A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression. CONCLUSIONS: In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.).

BACKGROUND: Obesity is increasing rapidly among women all over the world. Obesity is a known risk factor for subfertility due to anovulation, but it is unknown whether obesity also affects spontaneous pregnancy chances in subfertile, ovulatory women. METHODS: We evaluated whether obesity affected the chance of a spontaneous pregnancy in a prospectively assembled cohort of 3029 consecutive subfertile couples. Women had to be ovulatory and had to have at least one patent tube, whereas men had to have a normal semen analysis. Time to spontaneous ongoing pregnancy within 12 months was the primary endpoint. RESULTS: The probability of a spontaneous pregnancy declined linearly with a body mass index (BMI) over 29 kg/m(2). Corrected for possible related factors, women with a high BMI had a 4% lower pregnancy rate per kg/m(2) increase [hazard ratio: 0.96 (95% CI 0.91-0.99)]. CONCLUSIONS: These results indicate that obesity is associated with lower pregnancy rates in subfertile ovulatory women.

INTRODUCTION: Antipsychotics (AP) induce weight gain. However, reviews and meta-analyses generally are restricted to second generation antipsychotics (SGA) and do not stratify for duration of AP use. It is hypothesised that patients gain more weight if duration of AP use is longer. METHOD: A meta-analysis was conducted of clinical trials of AP that reported weight change. Outcome measures were body weight change, change in BMI and clinically relevant weight change (7% weight gain or loss). Duration of AP-use was stratified as follows: ≤6 weeks, 6-16 weeks, 16-38 weeks and >38 weeks. Forest plots stratified by AP as well as by duration of use were generated and results were summarised in figures. RESULTS: 307 articles met inclusion criteria. The majority were AP switch studies. Almost all AP showed a degree of weight gain after prolonged use, except for amisulpride, aripiprazole and ziprasidone, for which prolonged exposure resulted in negligible weight change. The level of weight gain per AP varied from discrete to severe. Contrary to expectations, switch of AP did not result in weight loss for amisulpride, aripiprazole or ziprasidone. In AP-naive patients, weight gain was much more pronounced for all AP. CONCLUSION: Given prolonged exposure, virtually all AP are associated with weight gain. The rational of switching AP to achieve weight reduction may be overrated. In AP-naive patients, weight gain is more pronounced.

BACKGROUND: Aspirin and low-molecular-weight heparin are prescribed for women with unexplained recurrent miscarriage, with the goal of improving the rate of live births, but limited data from randomized, controlled trials are available to support the use of these drugs. METHODS: In this randomized trial, we enrolled 364 women between the ages of 18 and 42 years who had a history of unexplained recurrent miscarriage and were attempting to conceive or were less than 6 weeks pregnant. We then randomly assigned them to receive daily 80 mg of aspirin plus open-label subcutaneous nadroparin (at a dose of 2850 IU, starting as soon as a viable pregnancy was demonstrated), 80 mg of aspirin alone, or placebo. The primary outcome measure was the live-birth rate. Secondary outcomes included rates of miscarriage, obstetrical complications, and maternal and fetal adverse events. RESULTS: Live-birth rates did not differ significantly among the three study groups. The proportions of women who gave birth to a live infant were 54.5% in the group receiving aspirin plus nadroparin (combination-therapy group), 50.8% in the aspirin-only group, and 57.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, -2.6 percentage points; 95% confidence interval [CI], -15.0 to 9.9; aspirin only vs. placebo, -6.2 percentage points; 95% CI, -18.8 to 6.4). Among 299 women who became pregnant, the live-birth rates were 69.1% in the combination-therapy group, 61.6% in the aspirin-only group, and 67.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, 2.1 percentage points; 95% CI, -10.8 to 15.0; aspirin alone vs. placebo -5.4 percentage points; 95% CI, -18.6 to 7.8). An increased tendency to bruise and swelling or itching at the injection site occurred significantly more frequently in the combination-therapy group than in the other two study groups. CONCLUSIONS: Neither aspirin combined with nadroparin nor aspirin alone improved the live-birth rate, as compared with placebo, among women with unexplained recurrent miscarriage. (Current Controlled Trials number, ISRCTN58496168.)

Importance: Colorectal surgery is associated with substantial morbidity rates and a lowered functional capacity. Optimization of the patient's condition in the weeks prior to surgery may attenuate these unfavorable sequelae. Objective: To determine whether multimodal prehabilitation before colorectal cancer surgery can reduce postoperative complications and enhance functional recovery. Design, Setting, and Participants: The PREHAB randomized clinical trial was an international, multicenter trial conducted in teaching hospitals with implemented enhanced recovery after surgery programs. Adult patients with nonmetastasized colorectal cancer were assessed for eligibility and randomized to either prehabilitation or standard care. Both arms received standard perioperative care. Patients were enrolled from June 2017 to December 2020, and follow-up was completed in December 2021. However, this trial was prematurely stopped due to the COVID-19 pandemic. Interventions: The 4-week in-hospital supervised multimodal prehabilitation program consisted of a high-intensity exercise program 3 times per week, a nutritional intervention, psychological support, and a smoking cessation program when needed. Main Outcomes and Measures: Comprehensive Complication Index (CCI) score, number of patients with CCI score more than 20, and improved walking capacity expressed as the 6-minute walking distance 4 weeks postoperatively. Results: In the intention-to-treat population of 251 participants (median [IQR] age, 69 [60-76] years; 138 [55%] male), 206 (82%) had tumors located in the colon and 234 (93%) underwent laparoscopic- or robotic-assisted surgery. The number of severe complications (CCI score >20) was significantly lower favoring prehabilitation compared with standard care (21 of 123 [17.1%] vs 38 of 128 [29.7%]; odds ratio, 0.47 [95% CI, 0.26-0.87]; P = .02). Participants in prehabilitation encountered fewer medical complications (eg, respiratory) compared with participants receiving standard care (19 of 123 [15.4%] vs 35 of 128 [27.3%]; odds ratio, 0.48 [95% CI, 0.26-0.89]; P = .02). Four weeks after surgery, 6-minute walking distance did not differ significantly between groups when compared with baseline (mean difference prehabilitation vs standard care 15.6 m [95% CI, -1.4 to 32.6]; P = .07). Secondary parameters of functional capacity in the postoperative period generally favored prehabilitation compared with standard care. Conclusions and Relevance: This PREHAB trial demonstrates the benefit of a multimodal prehabilitation program before colorectal cancer surgery as reflected by fewer severe and medical complications postoperatively and an optimized postoperative recovery compared with standard care. Trial Registration: trialregister.nl Identifier: NTR5947.

BACKGROUND: The erosion of the early mortality advantage of elective endovascular aneurysm repair (EVAR) compared with open repair of abdominal aortic aneurysm remains without a satisfactory explanation. METHODS: An individual-patient data meta-analysis of four multicentre randomized trials of EVAR versus open repair was conducted to a prespecified analysis plan, reporting on mortality, aneurysm-related mortality and reintervention. RESULTS: The analysis included 2783 patients, with 14 245 person-years of follow-up (median 5·5 years). Early (0-6 months after randomization) mortality was lower in the EVAR groups (46 of 1393 versus 73 of 1390 deaths; pooled hazard ratio 0·61, 95 per cent c.i. 0·42 to 0·89; P = 0·010), primarily because 30-day operative mortality was lower in the EVAR groups (16 deaths versus 40 for open repair; pooled odds ratio 0·40, 95 per cent c.i. 0·22 to 0·74). Later (within 3 years) the survival curves converged, remaining converged to 8 years. Beyond 3 years, aneurysm-related mortality was significantly higher in the EVAR groups (19 deaths versus 3 for open repair; pooled hazard ratio 5·16, 1·49 to 17·89; P = 0·010). Patients with moderate renal dysfunction or previous coronary artery disease had no early survival advantage under EVAR. Those with peripheral artery disease had lower mortality under open repair (39 deaths versus 62 for EVAR; P = 0·022) in the period from 6 months to 4 years after randomization. CONCLUSION: The early survival advantage in the EVAR group, and its subsequent erosion, were confirmed. Over 5 years, patients of marginal fitness had no early survival advantage from EVAR compared with open repair. Aneurysm-related mortality and patients with low ankle : brachial pressure index contributed to the erosion of the early survival advantage for the EVAR group. Trial registration numbers: EVAR-1, ISRCTN55703451; DREAM (Dutch Randomized Endovascular Aneurysm Management), NCT00421330; ACE (Anévrysme de l'aorte abdominale, Chirurgie versus Endoprothèse), NCT00224718; OVER (Open Versus Endovascular Repair Trial for Abdominal Aortic Aneurysms), NCT00094575.

•This updated ESMO Clinical Practice Guideline provides key recommendations on the management of adrenal cancer.•Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe.•Detailed guidance on diagnosis, classification, treatment and follow-up is provided for both adrenocortical carcinoma and malignant phaeochromocytoma.•Recommendations are provided in the text, including levels of evidence and grades of recommendation, where applicable.•Due to the rarity of the adrenocortical carcinoma and malignant phaeochromocytoma, there is a clear recommendation to consult expert centres. Two different primary malignancies can arise from the adrenal gland: adrenocortical carcinoma (ACC) from the adrenal cortex and malignant phaeochromocytoma from the adrenal medulla. Both malignancies are rare. ACC has an estimated incidence of ∼0.5-2 new cases per million people per year.1Kerkhofs T.M. Verhoeven R.H. Van der Zwan J.M. et al.Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993.Eur J Cancer. 2013; 49: 2579-2586Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar,2Kebebew E. Reiff E. Duh Q.Y. et al.Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress?.World J Surg. 2006; 30: 872-878Crossref PubMed Scopus (318) Google Scholar Phaeochromocytomas are catecholamine-producing neuroendocrine tumours arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia. The latter are usually called paraganglioma, leading to the combined term phaeochromocytomas and paragangliomas (PPGLs). The detected incidence of PPGLs is commonly reported at 2-8 per million per year3Pacak K. Eisenhofer G. Ahlman H. et al.Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005.Nat Clin Pract Endocrinol Metab. 2007; 3: 92-102Crossref PubMed Scopus (517) Google Scholar (supplementary information, available at https://doi.org/10.1016/j.annonc.2020.08.2099). All patients with suspected and proven ACC or PPGL should be discussed in a multidisciplinary expert team meeting, at least at the time of initial diagnosis (ideally before surgery) and in case of progressive disease. Every patient with (suspected) ACC or PPGL should undergo careful clinical assessment, including case history, clinical examination for symptoms and signs of adrenal hormone excess. For more details on this topic, we refer to more comprehensive guidelines and reviews.3Pacak K. Eisenhofer G. Ahlman H. et al.Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005.Nat Clin Pract Endocrinol Metab. 2007; 3: 92-102Crossref PubMed Scopus (517) Google Scholar, 4Fassnacht M. Dekkers O.M. Else T. et al.European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2018; 179: G1-G46Crossref PubMed Scopus (403) Google Scholar, 5Lenders J.W. Duh Q.Y. Eisenhofer G. et al.Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.J Clin Endocrinol Metab. 2014; 99: 1915-1942Crossref PubMed Scopus (1471) Google Scholar, 6Amar L. Servais A. Gimenez-Roqueplo A.P. et al.Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma.J Clin Endocrinol Metab. 2005; 90: 2110-2116Crossref PubMed Scopus (283) Google Scholar, 7Fassnacht M. Libe R. Kroiss M. Allolio B. Adrenocortical carcinoma: a clinician's update.Nat Rev Endocrinol. 2011; 7: 323-335Crossref PubMed Scopus (302) Google Scholar, 8Mansmann G. Lau J. Balk E. et al.The clinically inapparent adrenal mass: update in diagnosis and management.Endocr Rev. 2004; 25: 309-340Crossref PubMed Scopus (602) Google Scholar The aims of hormonal evaluation are multiple: (i) hormone assays provide orientation to the nature of the adrenal mass and can be useful to assess presence of malignancy; (ii) a phaeochromocytoma should always be ruled out, because these tumours can induce life-threatening crises, requiring specific management before any intervention; (iii) massive adrenocortical steroid excess can impact short-term survival and quality of life (QoL), requiring specific treatments to block impacts of hormonal excess; (iv) abnormal hormone secretions may serve as biological markers for the follow-up of patients; (v) in case of large bilateral adrenal masses, a systematic assessment of adrenal function is recommended to rule out adrenal insufficiency. Precise hormone assays have been detailed in recent guideline statements,4Fassnacht M. Dekkers O.M. Else T. et al.European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2018; 179: G1-G46Crossref PubMed Scopus (403) Google Scholar,5Lenders J.W. Duh Q.Y. Eisenhofer G. et al.Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.J Clin Endocrinol Metab. 2014; 99: 1915-1942Crossref PubMed Scopus (1471) Google Scholar,9Plouin P.F. Amar L. Dekkers O.M. et al.European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma.Eur J Endocrinol. 2016; 174: G1-G10Crossref PubMed Scopus (251) Google Scholar,10Fassnacht M. Arlt W. Bancos I. et al.Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2016; 175: G1-G34Crossref PubMed Scopus (853) Google Scholar and are summarised in Table 1.Table 1Diagnostic work-up of (suspected) adrenal- or paraganglioma-related malignanciesSpecific questionAssaysIndication(Suspected) ACC Exclusion of glucocorticoid excess?1 mg dexamethasone suppression testAll adrenal masses with no overt Cushing (clinically) Characterisation of glucocorticoid excess?1 mg dexamethasone suppression testFree cortisol in 24-h urineBasal ACTH (plasma)Adrenal masses with clinical signs of Cushing or pathological 1 mg dexamethasone test Sex steroids and steroid precursors excess?DHEA-S17-OH progesteroneAndrostenedioneTestosterone (only in women)17-beta-oestradiol (only in men and postmenopausal women)11-deoxycortisol (if available)Any adrenal mass suspected to be an ACC Mineralocorticoid excess?PotassiumAldosterone/renin ratioAny adrenal masses with hypertension and/or hypokalaemia Extension of the adrenal tumour and evidence for metastases?CT or MRI of abdomen, pelvis and chest (or FDG-PET/CT including full-dose CT)All suspected ACCs Evidence of cerebral metastases?Cerebral MRTOnly if cerebral metastases are suspected Evidence of bone metastasesFDG-PET/CT, bone scan, bone CT or bone MRIOnly if skeletal metastases are suspected(Suspected) PPGL Catecholamine excess?Fractionated metanephrines in 24-h urine or plasma-free metanephrines and methoxytyramineAll adrenal masses and all paraganglioma Extension of the adrenal tumour?CT or MRI of abdomenAll biochemically confirmed phaeochromocytoma Evidence of thoracic metastases?Chest CT (or PET/CT including full-dose CT)All PPGL patients with a 'high risk of metastases'aThe authors suggest being at a 'high risk of metastases' applies to all patients who fulfil one or more of the following criteria: adrenal phaeochromocytoma ≥5 cm or any extra-adrenal paraganglioma or known SDHB germline mutation or plasma methoxytyramine more than threefold above the upper reference limit. Evidence of cerebral metastases?Cerebral MRTOnly if cerebral metastases are suspected Evidence of bone metastasesFDG-PET/CT, DOTATATE-PET/CT, bone scan, bone CT or bone MRIOnly if skeletal metastases are suspectedbSome authors are in favour of carrying out functional imaging to detect bone metastases in all PPGL patients. Additional functional imaging?At least one functional whole-body imaging (i.e. FDG-PET, DOTATATE-PET, MIBG scintigraphy)In all PPGL patients with a 'high risk of metastases'aThe authors suggest being at a 'high risk of metastases' applies to all patients who fulfil one or more of the following criteria: adrenal phaeochromocytoma ≥5 cm or any extra-adrenal paraganglioma or known SDHB germline mutation or plasma methoxytyramine more than threefold above the upper reference limit. Radionuclide therapy possible?MIBG scintigraphy and somatostatin-based imaging (e.g. DOTATATE-PET/CT)In all PPGL patients with evidence for metastases17-OH, 17-hydroxy; ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; CT, computed tomography; DHEA-S, dehydroepiandrosterone sulfate; FDG-PET, 2-fluoro-2-deoxy-d-glucose-positron electron tomography; MIBG, meta-iodobenzylguanidine; MRI, magnetic resonance imaging; MRT, magnetic resonance tomography; PPGL, phaeochromocytoma and paraganglioma; SDHB, succinate dehydrogenase complex iron sulfur subunit B.a The authors suggest being at a 'high risk of metastases' applies to all patients who fulfil one or more of the following criteria: adrenal phaeochromocytoma ≥5 cm or any extra-adrenal paraganglioma or known SDHB germline mutation or plasma methoxytyramine more than threefold above the upper reference limit.b Some authors are in favour of carrying out functional imaging to detect bone metastases in all PPGL patients. Open table in a new tab 17-OH, 17-hydroxy; ACC, adrenocortical carcinoma; ACTH, adrenocorticotropic hormone; CT, computed tomography; DHEA-S, dehydroepiandrosterone sulfate; FDG-PET, 2-fluoro-2-deoxy-d-glucose-positron electron tomography; MIBG, meta-iodobenzylguanidine; MRI, magnetic resonance imaging; MRT, magnetic resonance tomography; PPGL, phaeochromocytoma and paraganglioma; SDHB, succinate dehydrogenase complex iron sulfur subunit B. For all adrenal masses, the diagnosis of phaeochromocytoma should be systematically assessed by measuring plasma-free or urinary-fractionated metanephrines [V, A].5Lenders J.W. Duh Q.Y. Eisenhofer G. et al.Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.J Clin Endocrinol Metab. 2014; 99: 1915-1942Crossref PubMed Scopus (1471) Google Scholar,10Fassnacht M. Arlt W. Bancos I. et al.Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2016; 175: G1-G34Crossref PubMed Scopus (853) Google Scholar Additional measurements of plasma methoxytyramine, a biomarker now increasingly available, provide useful information to assess the likelihood of malignancy.11Eisenhofer G. Lenders J.W. Siegert G. et al.Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status.Eur J Cancer. 2012; 48: 1739-1749Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar In cases of suspected ACC, an extensive steroid hormone work-up is recommended, assessing gluco-, mineralo-, sex- and precursor-steroids ([V, B] (Table 1)).12Arlt W. Biehl M. Taylor A.E. et al.Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors.J Clin Endocrinol Metab. 2011; 96: 3775-3784Crossref PubMed Scopus (305) Google Scholar, 13Taylor D.R. Ghataore L. Couchman L. et al.A 13-steroid serum panel based on LC-MS/MS: use in detection of adrenocortical carcinoma.Clin Chem. 2017; 63: 1836-1846Crossref PubMed Scopus (66) Google Scholar, 14Hines J.M. Bancos I. Bancos C. et al.High-resolution, accurate-mass (HRAM) mass spectrometry urine steroid profiling in the diagnosis of adrenal disorders.Clin Chem. 2017; 63: 1824-1835Crossref PubMed Scopus (63) Google Scholar, 15Schweitzer S. Kunz M. Kurlbaum M. et al.Plasma steroid metabolome profiling for the diagnosis of adrenocortical carcinoma.Eur J Endocrinol. 2018; 180: 117-125Crossref Scopus (40) Google Scholar, 16Kerkhofs T.M. Kerstens M.N. Kema I.P. et al.Diagnostic value of urinary steroid profiling in the evaluation of adrenal tumors.Horm Cancer. 2015; 6: 168-175Crossref PubMed Scopus (65) Google Scholar For best patient care, adequate visualisation of the tumour and potential metastases is essential. For differential diagnosis of an adrenal mass, computed tomography (CT) and magnetic resonance imaging (MRI) are both effective [IV, A]. Although these methods cannot determine the exact entity of the mass, both are able to correctly diagnose a subset of benign tumours—at least when carried out according to state-of-the-art criteria. The single best criterion to diagnose a benign tumour (e.g. adenoma) remains Hounsfield units ≤10 in an unenhanced CT.17Dinnes J. Bancos I. Ferrante di Ruffano L. et al.Management of endocrine disease: imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis.Eur J Endocrinol. 2016; 175: R51-R64Crossref PubMed Scopus (113) Google Scholar However, other imaging criteria, such as rapid washout in 10- or 15-min delayed contrast-enhanced CT, signal intensity loss using opposed-phase MRI, and low 2-fluorine-18 [18F]fluoro-2-deoxy-d-glucose (FDG) uptake in [18F]FDG-positron electron tomography (PET)/CT are also suggestive of a benign tumour. Most ACCs show an inhomogeneous appearance in CT or MRI with irregular margins and irregular enhancement of solid components after intravenous injection of contrasted agent. Detection of local invasion or tumour extension into the inferior vena cava, as well as lymph node or other metastases—including lung and liver—is mandatory before planning any surgery. Therefore, cross-sectional imaging of the chest, abdomen and pelvis is required preoperatively [V, A]. For PPGLs, conventional radiological imaging can be important to determine the presence of metastases. However, neither CT nor MRI can be used to determine whether PPGLs are benign or malignant. Malignancy can only be determined from the presence of metastatic lesions at sites where chromaffin cells are normally absent. Without such evidence, all PPGLs should be considered potentially malignant, with risk dependent on several factors as outlined below. There are a number of functional imaging modalities available for patients with PPGLs (supplementary File, available at https://doi.org/10.1016/j.annonc.2020.08.2099). The indication is twofold: (i) best tumour staging in patients with suspected metastases (e.g. by conventional imaging) or with presumably high risk for metastases; (ii) to evaluate the option of a radionuclide-based therapy in patients with nonresectable PPGL. For assessments of metastatic risk for the first indication the authors suggest the presence of one or more of the following criteria:•tumour size ≥5 cm;•any extra-adrenal paraganglioma;•known succinate dehydrogenase complex iron sulfur subunit B (SDHB) germline mutation; or•plasma methoxytyramine more than threefold above the upper cut-offs of reference intervals. For imaging-based diagnosis of metastatic PPGLs, it is important to avoid confusing metastases with multiple primary tumours that often occur in patients with hereditary PPGL syndromes. Additionally, local recurrences should not be misdiagnosed as metastases. Biopsy of adrenal tumours is usually contraindicated because of the risk of tumour spillage, poor diagnostic power to discriminate benign from malignant adrenocortical tumours and risk of hypertensive crises in phaeochromocytoma. However, a biopsy might be indicated in an adrenal mass without any hormone excess in patients with a history of extra-adrenal cancers to exclude or prove an adrenal metastasis of an extra-adrenal malignancy, and in patients in whom tumour sequencing is desired. The pathological differential diagnosis of adrenal neoplasias in both biopsied and resected specimens is primarily based on morphological features requiring an experienced pathologist [IV, A]. Preferably, a panel of immunohistochemical markers should be applied to aid diagnosis; for example, steroidogenesis factor 1 (SF1) or, alternatively, inhibin-alpha, calretinin and melan-A for identification of adrenocortical tumours and chromogranin A for identification of PPGL [IV, A]. Staining for tyrosine hydroxylase and synaptophysin may also be helpful to highlight PPGL, but positive results for synaptophysin are also possible in adrenocortical tumours. The differential diagnosis between ACC and adenoma may be challenging as no single marker indicates malignancy. The most widely used diagnostic score has been introduced by Weiss18Weiss L.M. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors.Am J Surg Pathol. 1984; 8: 163-169Crossref PubMed Scopus (768) Google Scholar,19Weiss L.M. Medeiros L.J. Vickery Jr., A.L. Pathologic features of prognostic significance in adrenocortical carcinoma.Am J Surg Pathol. 1989; 13: 202-206Crossref PubMed Scopus (653) Google Scholar and includes nine parameters (supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.08.2099) [IV, A]. A score of ≥3 suggests malignancy. In addition, the Ki-67 labelling index, as a marker of proliferative activity, may be useful and is very helpful for prognostic purposes (supplementary Tables S2 and S3, available at https://doi.org/10.1016/j.annonc.2020.08.2099). For phaeochromocytomas, the situation is similarly demanding. Tumour size, SDHB mutation status, extra-adrenal location and plasma methoxytyramine may all be used to indicate risk of metastasis. However, there is no single histological or immunohistochemical parameter that can predict the clinical behaviour of PPGL. Nevertheless, several histological scoring systems have been developed.20Thompson L.D. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases.Am J Surg Pathol. 2002; 26: 551-566Crossref PubMed Scopus (494) Google Scholar, 21Kimura N. Takayanagi R. Takizawa N. et al.Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma.Endocr Relat Cancer. 2014; 21: 405-414Crossref PubMed Scopus (193) Google Scholar, 22Koh J.M. Ahn S.H. Kim H. et al.Validation of pathological grading systems for predicting metastatic potential in pheochromocytoma and paraganglioma.PLoS One. 2017; 12: e0187398Crossref PubMed Scopus (45) Google Scholar, 23Pierre C. Agopiantz M. Brunaud L. et al.COPPS, a composite score integrating pathological features, PS100 and SDHB losses, predicts the risk of metastasis and progression-free survival in pheochromocytomas/paragangliomas.Virchows Arch. 2019; 474: 721-734Crossref PubMed Scopus (19) Google Scholar All these scores have value but none of them has reached general acceptance. Therefore, according to the current World Health Organization (WHO) classification, all PPGLs should be considered to have some malignant potential.24Lloyd R.V. Osamura R.Y. Klöppel G. Rosai J. WHO Classification of Tumours of Endocrine Organs. IARC, Lyon, France2017Google Scholar A definitive diagnosis of malignancy can only be made by the presence of metastases at sites where chromaffin tissue is normally absent (e.g. liver, bone, lungs or lymph nodes), assessed by pathology or imaging, in particular functional imaging. Molecular characterisation of ACC (supplementary File, available at https://doi.org/10.1016/j.annonc.2020.08.2099) and PPGL is an active area of ongoing research. The gene encoding subunit B of the SDHB complex is by far the most important molecular contributor to malignant PPGL, with at least 40% of all cases of metastatic PPGLs carrying mutations of this gene.25Brouwers F.M. Eisenhofer G. Tao J.J. et al.High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing.J Clin Endocrinol Metab. 2006; 91: 4505-4509Crossref PubMed Scopus (256) Google Scholar Inactivation of SDHB reduces function of the succinate dehydrogenase complex, leading to activation of the hypoxia-inducible pathway and a pseudohypoxic state characterised by increased angiogenesis, growth and expression of mitogenic factors,26Jochmanova I. Yang C. Zhuang Z. Pacak K. Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction.J Natl Cancer Inst. 2013; 105: 1270-1283Crossref PubMed Scopus (126) Google Scholar but also to DNA hypermethylation, which is believed to provide a further drive to metastatic progression.27Letouze E. Martinelli C. Loriot C. et al.SDH mutations establish a hypermethylator phenotype in paraganglioma.Cancer Cell. 2013; 23: 739-752Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar At least 35% of PPGLs result from germline mutations of over 18 tumour-susceptibility genes identified to date,28Dahia P.L. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic Rev Cancer. 2014; PubMed Scopus Google Scholar, Jr., T. et of the practice in the diagnosis and management of Relat Cancer. 2018; 25: PubMed Scopus Google Scholar, J. Pacak K. on pheochromocytoma and paraganglioma: a molecular Rev. 2017; PubMed Scopus Google Scholar, N. A. et on diagnostic of hereditary phaeochromocytomas and Rev Endocrinol. 2017; 13: PubMed Scopus Google Scholar, L. J. K. update on the of it to 2019; PubMed Scopus Google Scholar, J. A. S. et in pheochromocytoma and paraganglioma.Endocr Relat Cancer. 2019; 26: PubMed Scopus (63) Google Scholar with in of hypoxia-inducible factors and and carrying a risk of metastatic disease than to other mutations (supplementary Table available at https://doi.org/10.1016/j.annonc.2020.08.2099). is in patients with PPGL to mutations in the SDHB L. J. E. et in pheochromocytoma or functional paraganglioma.J Clin 2005; 23: PubMed Scopus Google Scholar The of all metastatic PPGLs, including disease to SDHB from or PPGLs with Nevertheless, a of of metastatic PPGLs from adrenal tumours that are characterised by of as by increased plasma or urinary M. et of of SDHB mutation in metastatic J Endocrinol. 2015; PubMed Scopus Google Scholar metastatic disease may only after the primary tumour is and in some patients of disease the of recommendations for follow-up of all patients with resected P.F. Amar L. Dekkers O.M. et al.European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma.Eur J Endocrinol. 2016; 174: G1-G10Crossref PubMed Scopus (251) Google Scholar patients with an adrenal tumour suspected to be an ACC or a phaeochromocytoma should undergo careful clinical assessment for signs of adrenal hormone patients with suspected and proven ACC or PPGL should be discussed in a multidisciplinary expert team meeting, at least at the time of initial diagnosis and in case of progressive patients with suspected ACC a comprehensive endocrine work-up to potential excess of and adrenocortical steroid hormone precursors [IV, imaging for patients with suspected ACC includes at least CT or MRI and chest CT (or [IV, of suspected ACC are usually not and should be ACC is by a score ≥3 [IV, A]. diagnosis should be carried out by an experienced endocrine Ki-67 to the risk of patients with suspected PPGL the of plasma or urinary metanephrines [V, A]. of disease is primarily based on (i) the presence of symptoms or other of excess; (ii) adrenal or (iii) to high risk with hereditary or history of all patients with 'high risk of metastases' a chest CT and at least one functional whole-body imaging FDG-PET, DOTATATE-PET, is recommended in to of suspected PPGL are contraindicated in most PPGLs are by the presence of metastasis. However, all PPGLs are considered to have some malignant In the assessment of disease the authors the metastasis by the European Network for the Study of Adrenal Tumours (supplementary Table available at https://doi.org/10.1016/j.annonc.2020.08.2099) [IV, M. S. M. et prognostic value of the International Cancer staging for adrenocortical carcinoma: for a PubMed Scopus (503) Google Scholar because this to be to other staging systems and is by the for International Cancer and R.V. Osamura R.Y. Klöppel G. Rosai J. WHO Classification of Tumours of Endocrine Organs. IARC, Lyon, France2017Google Scholar indicated above for at least a CT of the chest, abdomen and pelvis (or FDG-PET/CT including full-dose is suggest that lymph node with than R. I. et factors in adrenocortical an European Network for the Study of Adrenal 2015; 26: Full Text Full Text PDF PubMed Scopus Google Scholar the of ACC is However, suggest that in patients with of a tumour survival can be as high as M. S. W. et survival in patients with adrenocortical carcinoma by Clin Endocrinol Metab. PubMed Scopus Google Scholar In metastatic ACC, survival is However, in this there is a of patients with long-term M. S. M. et prognostic value of the International Cancer staging for adrenocortical carcinoma: for a PubMed Scopus (503) Google R. I. et factors in adrenocortical an European Network for the Study of Adrenal 2015; 26: Full Text Full Text PDF PubMed Scopus Google Scholar is well established that disease and are the most important prognostic factors in For the European Society of Endocrinology a comprehensive for prognostic factors has been carried out and only the marker Ki-67 and glucocorticoid excess a with [IV, (supplementary Table available at M. Dekkers O.M. Else T. et al.European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors.Eur J Endocrinol. 2018; 179: G1-G46Crossref PubMed Scopus (403) Google T. M. G. Dekkers O.M. of hormonal functional on survival in adrenocortical carcinoma: systematic review and meta-analysis.Eur J Endocrinol. 2018; 179: PubMed Scopus Google Scholar other markers for and survival have been but clinical use In the WHO a tumour staging for PPGL (supplementary Table available at R.V. Osamura R.Y. Klöppel G. Rosai J. WHO Classification of Tumours of Endocrine Organs. IARC, Lyon, France2017Google Scholar Although this staging remains to be the authors

BACKGROUND: Treatment options for tubal ectopic pregnancy are; (1) surgery, e.g. salpingectomy or salpingo(s)tomy, either performed laparoscopically or by open surgery; (2) medical treatment, with a variety of drugs, that can be administered systemically and/or locally by various routes and (3) expectant management. OBJECTIVES: To evaluate the effectiveness and safety of surgery, medical treatment and expectant management of tubal ectopic pregnancy in view of primary treatment success, tubal preservation and future fertility. SEARCH STRATEGY: The Cochrane Menstrual Disorders and Subfertility Group's Specialised Register, Cochrane Controlled Trials Register (up to February 2006), Current Controlled Trials Register (up to October 2006), and MEDLINE (up to October 2006) were searched. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing treatments in women with tubal ectopic pregnancy. DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment was done independently by two reviewers. Differences were resolved by discussion with all reviewers. MAIN RESULTS: Thirty five studies have been analysed on the treatment of tubal ectopic pregnancy, describing 25 different comparisons. SURGERY: Laparoscopic salpingostomy is significantly less successful than the open surgical approach in the elimination of tubal ectopic pregnancy (2 RCTs, n=165, OR 0.28, 95% CI 0.09, 0.86) due to a significant higher persistent trophoblast rate in laparoscopic surgery (OR 3.5, 95% CI 1.1, 11). However, the laparoscopic approach is significantly less costly than open surgery (p=0.03). Long term follow-up (n=127) shows no evidence of a difference in intra uterine pregnancy rate (OR 1.2, 95% CI 0.59, 2.5) but there is a non significant tendency to a lower repeat ectopic pregnancy rate (OR 0.47, 95% 0.15, 1.5). Salpingostomy alone is significantly less successful than when combined with a prophylactic single shot methotrexate (2 RCTs, n=163, OR 0.25, 95% CI 0.08-0.76) to prevent persistent trophoblast. MEDICAL TREATMENT: Systemic methotrexate in a fixed multiple dose intramuscular regimen has a non significant tendency to a higher treatment success than laparoscopic salpingostomy (1 RCT, n=100, OR 1.8, 95% CI 0.73, 4.6). No significant differences are found in long term follow-up (n=74): intra uterine pregnancy (OR 0.82, 95% CI 0.32, 2.1) and repeat ectopic pregnancy (OR 0.87, 95% CI 0.19, 4.1). One single dose intramuscular methotrexate is significantly less successful than laparoscopic salpingostomy (4 RCTs, n=265, OR 0.38, 95% CI 0.20, 0.71). With a variable dose regimen treatment success rises, but shows no evidence of a difference compared to laparoscopic salpingostomy (OR 1.1, 95% CI 0.52, 2.3). Long term follow-up (n=98) do not differ significantly (intra uterine pregnancy OR 1.0, 95% CI 0.43, 2.4, ectopic pregnancy OR 0.54, 95% CI 0.12, 2.4). The efficacy of systemic single dose methotrexate alone is significantly less successful than when combined with mifepristone (2 RCTs, n=262, OR 0.59, 95% CI 0.35, 1.0). The same goes for the addition of traditional Chinese medicine (1 RCT, n=78, OR 0.08, 95% CI 0.02, 0.39). Local medical treatment administered transvaginally under ultrasound guidance is significantly better than a 'blind' intra-tubal injection under laparoscopic guidance in the elimination of tubal ectopic pregnancy (1 RCT, n=36, methotrexate OR 5.8, 95% CI 1.3, 26; 1 RCT, n=80, hyperosmolar glucose OR 0.38, 95% CI 0.15, 0.93). However, compared to laparoscopic salpingostomy, local injection of methotrexate administered transvaginally under ultrasound guidance is significantly less successful (1 RCT, n=78, OR 0.17, 95% CI 0.04, 0.76) but with positive long term follow up (n=51): a significantly higher intra uterine pregnancy rate (OR 4.1, 95% CI 1.3, 14) and a non significant tendency to a lower repeat ectopic pregnancy rate (OR 0.30, 95% CI 0.05, 1.7). EXPECTANT MANAGEMENT: Expectant management is significantly less successful than prostaglandin therapy (1 RCT, n=23, OR 0.08, 95% CI 0.02-0.39). AUTHORS' CONCLUSIONS: In the surgical treatment of tubal ectopic pregnancy laparoscopic surgery is a cost effective treatment. An alternative nonsurgical treatment option in selected patients is medical treatment with systemic methotrexate. Expectant management can not be adequately evaluated yet.

Despite intensive investigation, an underlying cause of miscarriage has not been found in a high proportion of women with a history of recurrent miscarriage. No effective intervention has been identified that improves rates of live birth. Some investigators have suggested that treatment of women with unexplained recurrent miscarriage with aspirin and low-molecular-weight heparin may increase the proportion of live births; the limited data available from randomized controlled trials have been inconsistent. This multicenter, randomized, placebo-controlled trial investigated whether a combination of aspirin with low-molecular-weight heparin or aspirin alone, compared with placebo, would improve the live-birth rate in women with a history of unexplained recurrent miscarriage. The study subjects were 364 women aged 18 to 42 years with a history of unexplained recurrent miscarriage who were trying to conceive or were pregnant less than 6 weeks. Women were randomly assigned to receive combined therapy (n = 123) consisting of daily doses of aspirin 80 mg plus open-label subcutaneous low-molecular-weight heparin (nadroparin) at a dose of 2850 IU, or 80 mg of aspirin alone (n = 120), or placebo (n = 121) either before conception or at a gestational age of less than 6 weeks. The main study outcome measure was the rate of live birth. Secondary outcome measures included rates of miscarriage, obstetrical complications, and maternal and neonatal adverse events. No significant difference between the 3 study groups was found in the proportion of live births (combined therapy, 54.5%; aspirin only, 50.8%; and placebo, 57%); the absolute difference in live-birth rate for combined therapy versus placebo was −2.6 percentage points, with a 95% confidence interval of −15.0 to 9.9; and for the aspirin only versus placebo was −6.2, with a 95% confidence interval of −18.8 to 6.4 (P = 0.63). There was also no significant difference in the live-birth rates among the 299 women in these 3 groups who became pregnant; the rates were 69.1% in the combined therapy group, 61.6% in the aspirin-only group, and 67.0% in the placebo group (P = 0.52). Compared to the other 2 groups, the combined therapy group had a significantly increased tendency for bruising and swelling or itching at the injection site (P < 0.001). These findings demonstrate that neither aspirin combined with nadroparin nor aspirin alone increase the likelihood of a live birth in comparison with placebo among women with unexplained recurrent miscarriage.

BACKGROUND: Colorectal cancer (CRC) is the second most prevalent type of cancer in the world. Surgery is the only curative option. However, postoperative complications occur in up to 50% of patients and are associated with higher morbidity and mortality rates, lower health related quality of life (HRQoL) and increased expenditure in health care. The number and severity of complications are closely related to preoperative functional capacity, nutritional state, psychological state, and smoking behavior. Traditional approaches have targeted the postoperative period for rehabilitation and lifestyle changes. However, recent evidence shows that the preoperative period might be the optimal moment for intervention. This study will determine the impact of multimodal prehabilitation on patients' functional capacity and postoperative complications. METHODS/DESIGN: This international multicenter, prospective, randomized controlled trial will include 714 patients undergoing colorectal surgery for cancer. Patients will be allocated to the intervention group, which will receive 4 weeks of prehabilitation (group 1, prehab), or the control group, which will receive no prehabilitation (group 2, no prehab). Both groups will receive perioperative care in accordance with the enhanced recovery after surgery (ERAS) guidelines. The primary outcomes for measurement will be functional capacity (as assessed using the six-minute walk test (6MWT)) and postoperative status determined with the Comprehensive Complication Index (CCI). Secondary outcomes will include HRQoL, length of hospital stay (LOS) and a cost-effectiveness analysis. DISCUSSION: Multimodal prehabilitation is expected to enhance patients' functional capacity and to reduce postoperative complications. It may therefore result in increased survival and improved HRQoL. This is the first international multicenter study investigating multimodal prehabilitation for patients undergoing colorectal surgery for cancer. TRIAL REGISTRATION: Trial Registry: NTR5947 - date of registration: 1 August 2016.

PURPOSE: To gain insight into the prevalence and severity of chemotherapy-induced neuropathy and its influence on health-related quality of life (HRQOL) in a population-based sample of colorectal cancer (CRC) survivors 2 to 11 years after diagnosis. METHODS: All alive individuals diagnosed with CRC between 2000 and 2009 as registered by the Dutch population-based Eindhoven Cancer Registry were eligible for participation. Eighty-three percent (n = 1,643) of patients filled out the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 and the EORTC QLQ Chemotherapy-Induced Peripheral Neuropathy 20. RESULTS: The five neuropathy subscale-related symptoms that bothered patients with CRC the most during the past week were erectile problems (42% of men), trouble hearing (11%), trouble opening jars or bottles (11%), tingling toes/feet (10%), and trouble walking stairs or standing up (9%). Additionally, patients who received oxaliplatin more often reported tingling (29% v 8%; P = .001), numbness (17% v 5%; P = .005), and aching or burning pain (13% v 6%; P = .03) in toes/feet compared with those not treated with chemotherapy. They also more often reported tingling toes/feet (29% v 14%; P = .0127) compared with those treated with chemotherapy without oxaliplatin. Those with many neuropathy symptoms (eg, upper 10%) reported statistically significant and clinically relevant worse HRQOL scores on all EORTC QLQ-C30 subscales (all P < .01). CONCLUSION: Two to 11 years after diagnosis of CRC, neuropathy-related symptoms are still reported, especially sensory symptoms in the lower extremities among those treated with oxaliplatin. Because neuropathy symptoms have a negative influence on HRQOL, these should be screened for and alleviated. Future studies should focus on prevention and relief of chemotherapy-induced neuropathy.

BACKGROUND: Tubal disease accounts for 20% of infertility cases. Hydrosalpinx, caused by distal tubal occlusion leading to fluid accumulation in the tube(s), is a particularly severe form of tubal disease negatively affecting the outcomes of assisted reproductive technology (ART). It is thought that tubal surgery may improve the outcome of ART in women with hydrosalpinges. OBJECTIVES: To assess the effectiveness and safety of tubal surgery in women with hydrosalpinges prior to undergoing conventional in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, DARE, and two trial registers on 8 January 2020, together with reference checking and contact with study authors and experts in the field to identify additional trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing surgical treatment versus no surgical treatment, or comparing surgical interventions head-to-head, in women with tubal disease prior to undergoing IVF. DATA COLLECTION AND ANALYSIS: We used Cochrane's standard methodological procedures. The primary outcomes were live birth rate (LBR) and surgical complication rate per woman randomised. Secondary outcomes included clinical, multiple and ectopic pregnancy rates, miscarriage rates and mean numbers of oocytes retrieved and of embryos obtained. MAIN RESULTS: = 77%; very low-quality evidence). No study reported on surgical complication rate for this comparison. Transvaginal aspiration of hydrosalpingeal fluid versus laparoscopic salpingectomy No study reported on LBR for this comparison, and there was insufficient evidence to identify a difference in surgical complication rate between groups (Peto OR not estimable; one RCT; n = 160). We are uncertain of the effect of transvaginal aspiration of hydrosalpingeal fluid versus laparoscopic salpingectomy on CPR (RR 0.69, 95% CI 0.44 to 1.07; one RCT; n = 160; very low-quality evidence). AUTHORS' CONCLUSIONS: We found moderate-quality evidence that salpingectomy prior to ART probably increases the CPR compared to no surgery in women with hydrosalpinges. When comparing tubal occlusion to no intervention, we found that tubal occlusion may increase CPR, although the evidence was of low quality. We found insufficient evidence of any effect on procedure- or pregnancy-related adverse events when comparing tubal surgery to no intervention. Importantly, none of the studies reported on long term fertility outcomes. Further high-quality trials are required to definitely determine the impact of tubal surgery on IVF and pregnancy outcomes of women with hydrosalpinges, particularly for LBR and surgical complications; and to investigate the relative efficacy and safety of the different surgical modalities in the treatment of hydrosalpinges prior to ART.

BACKGROUND: Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. OBJECTIVE: The aim of this study was to identify markers with prognostic value for patients in this clinical setting. DESIGN, SETTING, AND PARTICIPANTS: From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified. As an independent validation cohort, 250 patients from three European countries were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS). RESULTS: Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio [HR] for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10-19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone. CONCLUSION: This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.

BACKGROUND: Hyperphosphataemia is associated with increased mortality in patients with chronic kidney disease (CKD) stage IV or on dialysis. Furthermore, in animal studies, elevated plasma phosphate has been shown to be associated with an accelerated decline in renal function. The aim of this study was to determine the association of plasma phosphate with renal function loss and mortality in CKD stage IV-V pre-dialysis patients with GFR <20 ml/min/1.73 m(2). METHODS: Incident pre-dialysis patients were included between 1999 and 2001 in the multi-centre PREPARE study, and followed until 2003 or death. Rate of decline in renal function for each patient was calculated by linear regression using the Modification of Diet in Renal Disease (MDRD) formula to estimate GFR (eGFR). RESULTS: A total of 448 patients were included [mean (SD) age 60 (15) years, eGFR 13 (5.4) ml/min/1.73 m(2), decline in renal function 0.38 (0.95) ml/min/month]. Phosphate concentration at baseline was 4.71 (1.16) mg/dl, calcium 9.25 (0.77) mg/dl and calcium-phosphate product 43.5 (10.9) mg(2)/dl(2). For each mg/dl higher phosphate concentration, the mean (95% CI) decline in renal function increased with 0.154 (0.071-0.237) ml/min/month. After adjustment, this association remained [beta 0.178 (0.082-0.275)]. Seven percent of the patients died. Crude mortality risk was 1.25 (0.85-1.84) per mg/dl increase in phosphate, which increased to 1.62 (1.02-2.59) after adjustment. CONCLUSIONS: High plasma phosphate is an independent risk factor for a more rapid decline in renal function and a higher mortality during the pre-dialysis phase. Plasma phosphate within the normal range is likely of vital importance in pre-dialysis patients.

The purpose of this study was to document the prevalence of diabetes among newly diagnosed cancer patients and to evaluate the influence of diabetes on stage at diagnosis, treatment and overall survival. We performed a population-based analyses of all 58,498 cancer patients newly diagnosed between 1995 and 2002 in the registration area of the Eindhoven Cancer Registry. Stage of cancer, cancer treatment and comorbidities were actively collected by hospital medical records review. Follow-up of all patients was completed until January 1, 2005. Nine percent of all cancer patients had diabetes at the time of cancer diagnosis. The prevalence of diabetes was highest among patients with cancer of the pancreas (19%), uterus (14%) and among young men with kidney cancer (8%). Colon, breast and ovarian cancer patients with diabetes were more often diagnosed with a higher tumour stage (p < 0.05). Patients with diabetes and cancer of the oesophagus, colon, breast and ovary were treated less aggressively compared to those without diabetes (p < 0.05). During the follow-up period 3,902 of 5,555 cancer patients with diabetes died and 29,909 of 52,943 cancer patients without diabetes died. For all cancers combined, in a multivariate cox-regression model, adjusting for age, gender, stage, treatment and cardiovascular disease, patients with diabetes experienced a significant increase in overall mortality (HR = 1.44, 95% CI 1.40-1.49), ranging however from 0 to 40% for different types of cancer, compared to those without diabetes. In conclusion, diabetic cancer patients frequently were treated less aggressively and had a worse prognosis compared to those without diabetes.

<h3>Importance</h3> Although inadequate sleep has a proven negative association with health care outcomes, to date, no large-scale studies have examined sleep in general hospital wards. <h3>Objectives</h3> To assess the subjective quantity and quality of sleep and to identify the hospital-related factors associated with sleep disturbances in hospitalized patients. <h3>Design</h3> For this nationwide, single-day, multicenter, cross-sectional, observational study, which took place on February 22, 2017, all hospitals in the Netherlands were encouraged by word of mouth and conventional and social media to participate in this study. A total of 39 hospitals participated. Included patients were at least 18 years of age, were able to give informed consent, and had spent at least 1 night in a regular-care hospital ward. <h3>Exposures</h3> Hospitalization in a regular-care ward. <h3>Main Outcomes and Measures</h3> Quantity and quality of last night's sleep in the hospital compared with habitual sleep at home the month before hospitalization. The Consensus Sleep Diary and the Dutch-Flemish Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance item bank were used. Complementary questions assessed sleep-disturbing factors. <h3>Results</h3> A total of 2005 patients were included (median age, 68 years; interquartile range, 57-77 years; 994 of 1935 [51.4%] were male [70 patients did not identify their sex]). Compared with habitual sleep at home, the total sleep time in the hospital was 83 minutes (95% CI, 75-92 minutes;<i>P</i> &lt; .001) shorter. The mean number of nocturnal awakenings was 2.0 (95% CI, 1.9-2.1) times at home vs 3.3 (95% CI, 3.2-3.5) times during hospitalization (<i>P</i> &lt; .001). Patients woke up 44 minutes (95% CI, 44-45 minutes;<i>P</i> &lt; .001) earlier than their habitual wake-up time at home. A total of 1344 patients (70.4%) reported having been awakened by external causes, which in 718 (35.8%) concerned hospital staff. All aspects of sleep quality measured using PROMIS questions were rated worse during hospitalization than at home. The most reported sleep-disturbing factors were noise of other patients, medical devices, pain, and toilet visits. <h3>Conclusions and Relevance</h3> This study demonstrated that the duration and quality of sleep in hospitalized patients were significantly affected and revealed many potentially modifiable hospital-related factors negatively associated with sleep. Raising awareness about the importance of adequate sleep in the vulnerable hospital population and introducing interventions to target sleep-disturbing factors may improve healing.