Starting point for benchmarking outcomes and reporting of pituitary adenoma surgery within the European Reference Network on Rare Endocrine Conditions (Endo-ERN): results from a meta-analysis and survey study.

Objective: The European Reference Network on Rare Endocrine Conditions (Endo-ERN) aims to organize high-quality healthcare throughout Europe, including care for pituitary adenoma patients. As surgery is the mainstay of treatment, we aimed to describe the current surgical practice and published surgical outcomes of pituitary adenoma within Endo-ERN. Design and Methods: Systematic review and meta-analysis of studies reporting surgical outcomes of pituitary adenoma patients within Endo-ERN MTG6 pituitary reference centers between 2010 and 2019. A survey was completed by reference centers on their current surgical practice. Results: A total of 18 out of 43 (42%) reference centers located in 7 of the 20 (35%) MTG6-represented countries published 48 articles. Remission rates were 50% (95% CI: 42-59) for patients with acromegaly, 68% (95% CI: 60-75) for Cushing's disease, and 53% (95% CI: 39-66%) for prolactinoma. Gross total resection was achieved in 49% (95% CI: 37-61%) of patients and visual improvement in 78% (95% CI: 68-87). Mortality, hemorrhage, and carotid injury occurred in less than 1% of patients. New-onset hypopituitarism occurred in 16% (95% CI: 11-23), transient diabetes insipidus in 12% (95% CI: 6-21), permanent diabetes insipidus in 4% (95% CI: 3-6), syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in 9% (95% CI: 5-14), severe epistaxis in 2% (95% CI: 0-4), and cerebrospinal fluid leak in 4% (95% CI: 2-6). Thirty-five (81%) centers completed the survey: 54% were operated endoscopically and 57% were together with an ENT surgeon. Conclusion: The results of this study could be used as a first benchmark for the outcomes of pituitary adenoma surgery within Endo-ERN. However, the heterogeneity between studies in the reporting of outcomes hampers comparability and warrants outcome collection through registries.

The PRolaCT studies - a study protocol for a combined randomised clinical trial and observational cohort study design in prolactinoma.

BACKGROUND: First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal remission rates are approximately 34%. Therefore, many patients require prolonged DA treatment, while side effects negatively impact health-related quality of life (HRQoL). Endoscopic transsphenoidal resection is reserved for patients with severe side effects, or with DA-resistant prolactinoma. Surgery has a good safety profile and high probability of remission and may thus deserve a more prominent place in prolactinoma treatment. The hypothesis for this study is that early or upfront surgical resection is superior to DA treatment both in terms of HRQoL and remission rate in patients with a non-invasive prolactinoma of limited size. METHODS: We present a combined randomised clinical trial and observational cohort study design, which comprises three unblinded randomised controlled trials (RCTs; PRolaCT-1, PRolaCT-2, PRolaCT-3), and an observational study arm (PRolaCT-O) that compare neurosurgical counselling, and potential subsequent endoscopic transsphenoidal adenoma resection, with current standard care. Patients with a non-invasive prolactinoma (< 25 mm) will be eligible for one of three RCTs based on the duration of pre-treatment with DAs: PRolaCT-1: newly diagnosed, treatment-naïve patients; PRolaCT-2: patients with limited duration of DA treatment (4-6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for > 2 years. PRolaCT-O will include patients who decline randomisation, due to e.g. a clear treatment preference. Primary outcomes are disease remission after 36 months and HRQoL after 12 months. DISCUSSION: Early or upfront surgical resection for patients with a limited-sized prolactinoma may be a reasonable alternative to the current standard practice of DA treatment, which we will investigate in three RCTs and an observational cohort study. Within the three RCTs, patients will be randomised between neurosurgical counselling and standard care. The observational study arm will recruit patients who refuse randomisation and have a pronounced treatment preference. PRolaCT will collect randomised and observational data, which may facilitate a more individually tailored practice of evidence-based medicine. TRIAL REGISTRATION: US National Library of Medicine registry (ClinicalTrials.gov) NCT04107480 . Registered on 27 September 2019, registered retrospectively (by 2 months).

Patients with rare endocrine conditions have corresponding views on unmet needs in clinical research.

PURPOSE: European Reference Network on Rare Endocrine Conditions' (Endo-ERN) mission is to reduce and ultimately abolish inequalities in care for patients with rare endocrine conditions in Europe. This study assesses which themes related to rare endocrine conditions are prioritized by patients for clinical research. METHODS: A survey was developed, translated into 22 different European languages, and distributed to patients with rare endocrine conditions. Patients were asked to give priority scores to listed prespecified topics: fertility, heritability, tiredness, daily medicine intake, sleep quality, physical discomfort, and ability to work, partake in social life, and sports. They were also asked to suggest further important areas for research in open fields. RESULTS: After data cleaning, 1378 survey responses were analyzed. Most responses were received from Northern (47%) and Western Europeans (39%), while Southern (11%) and Eastern Europe (2%) were underrepresented. Respondents were most interested in research concerning ability to participate in social life and work. Patients suggested key areas to work: long-term side effects of medical treatments and quality of life. Some priorities differed between disease groups, both for prespecified and open topics and reflected aspects of patients' individual conditions. CONCLUSIONS: With this large survey, Endo-ERN gained insight into patients' unmet needs in scientific research. Patients prioritized research on ability to work and participation in social activities, though needs differ between the disease groups. Clinical experts should incorporate the results of this survey into the design of future studies on rare endocrine conditions. We aim to utilize these results in designing patient-reported outcome measures for the disease areas covered by Endo-ERN.

Access to patient oriented information-a baseline Endo-ERN survey among patients with rare endocrine disorders.

AIM: To perform a baseline survey on condition-specific information access among patients/parents/caregivers with rare endocrine disorders (RD) in Europe. METHODS: Electronic invitation to participate in a survey (19 questions) was sent to 120 patient advocacy groups (PAGs), and further distributed to 32 European countries. RESULTS: A total of 1138 respondents from 22 countries (74% women), aged between 1 year (parents) and 70 years, participated. The Netherlands, France, Germany, Italy and France had highest participation rates. All Main Thematic Groups (MTGs) were represented; the adrenal (32%), pituitary (26%) and thyroid (22%) were the most common. The majority of the respondents got information from their endocrinologist (75%), PAGs (37%) and expert reference centre (22%); 95% received information in their mother tongue. Leaflets (70%), infographics (65%), webinars (60%) and Internet films (55%) were preferred ways of learning. Respondents relied mostly on materials by PAGs and alliances (79%), rather than from specific international RD sites (15%). Fifty-six percent used Facebook, and 37% other social media, with a significant age difference (<40/>40 years) among non-users, 19% vs. 36%, p < 0.0001. Of all, 685 answered questions on informational materials for children-79% wanted materials that can be used by the children themselves. There was significant age difference (<40 years/>40 years) in the willingness to help create new educational materials; 49% vs. 34%, p < 0.001. CONCLUSIONS: Our current patient information access survey provides a sound basis for further planning and execution of educational and teaching activities by Endo-ERN.

CPMS-improving patient care in Europe via virtual case discussions.

PURPOSE: The core task of European Reference Networks (ERNs) is to reduce health care inequalities throughout Europe for all patients with rare and complex conditions. A secure web-based application for virtual consultations, the Clinical Patient Management System (CPMS), was developed by the EU to provide expert specialized care for all these patients. This review analyses the opportunities and difficulties that the implementation of this virtual network implies for physicians as well as for the patients. METHODS: European Reference Network on Rare Endocrine Conditions (Endo-ERN) installed an Operational Helpdesk (OH) to support their members in using CPMS. The OH initiated several actions to facilitate and increase the usage of CPMS. Satisfaction with the system and reasons for low participation rates in virtual case discussions were analyzed by different surveys. RESULTS: The number of CPMS users increased constantly, but the active usage of the system remains insufficient. Main reasons were technical difficulties, lack of time and insufficient awareness about CPMS in experts and patients throughout Europe. Still, outcomes of the virtual discussions are considered useful by involved experts and the discussions have provided topics for educational webinars and research. CONCLUSIONS: CPMS is a secure system with many advantages compared to previous ways of consulting experts but also difficulties that need to be overcome with future strategies. By facilitating its use and increasing awareness among all relevant European experts and patients, CPMS can help to make the existing expertise available for all patients with rare (endocrine) conditions throughout Europe as it was intended.

Impact of a Forced Dose-Equivalent Levothyroxine Brand Switch on Plasma Thyrotropin: A Cohort Study.

Background: Patients with primary hypothyroidism are treated with levothyroxine (LT4) to normalize their serum thyrotropin (TSH). Finding the optimal dosage is a long-lasting process, and a small change can have major impact. Currently, limited data are available on the impact of dose-equivalent substitution between brands. This study aimed to determine the effect of the shortage of the LT4 brand Thyrax® in the Netherlands and the resulting dose-equivalent switch to another brand on plasma TSH concentrations in a large cohort of patients. Methods: Observational cohort study. Two registries representative for the Dutch population containing prescription and laboratory test data: the Nivel Primary Care Database and the PHARMO Database Network. Patients using at least 25 µg Thyrax daily for one year or longer were included. Two cohorts were formed: a switch cohort consisting of patients who switched from Thyrax to an alternative brand, and a Thyrax cohort including patients who continued to use Thyrax. Patients in the switch cohort did switch from Thyrax to a different brand of LT4 in 2016 and had two consecutive TSH measurements on the same dose of LT4, one before and one 6 weeks after the switch. Patients in the Thyrax cohort had two consecutive TSH measurements on the same dose of Thyrax that were 6 weeks apart. Results: In the Thyrax cohort, 19% of euthyroid patients using ≤100 µg had a TSH level outside the reference range at the subsequent measurement compared with 24% in the switch cohort (p < 0.0001). For patients using >100 µg Thyrax, these figures were 24% and 63%, respectively (p < 0.0001). Furthermore, patients using >50 µg Thyrax were four to five times more likely to become hyperthyroid after a dose-equivalent switch to a different brand compared with patients who stayed on Thyrax. Conclusions: In euthyroid patients continuing the LT4 product Thyrax at the same dose, TSH was out of range in 19-24% at least 6 weeks later. A dose-equivalent switch from Thyrax to other LT4 brands induced biochemical signs of overdosing in an even larger proportion (24-63%) of patients. The results indicate that a dose-equivalent LT4 brand switch may necessitate a dose adjustment in a large number of patients.

The evolution of trauma care in the Netherlands over 20 years.

INTRODUCTION: In 1999 an inclusive trauma system was initiated in the Netherlands and a nationwide trauma registry, including all admitted trauma patients to every hospital, was started. The Dutch trauma system is run by trauma surgeons who treat both the truncal (visceral) and extremity injuries (fractures). MATERIALS AND METHODS: In this comprehensive review based on previous published studies, data over the past 20 years from the central region of the Netherlands (Utrecht) was evaluated. RESULTS: It is demonstrated that the initiation of the trauma systems and the governance by the trauma surgeons led to a region-wide mortality reduction of 50% and a mortality reduction for the most severely injured of 75% in the level 1 trauma centre. Furthermore, major improvements were found in terms of efficiency, demonstrating the quality of the current system and its constructs such as the type of surgeon. Due to the major reduction in mortality over the past few years, the emphasis of trauma care evaluation shifts towards functional outcome of severely injured patients. For the upcoming years, centralisation of severely injured patients should also aim at the balance between skills in primary resuscitation and surgical stabilization versus longitudinal surgical involvement. CONCLUSION: Further centralisation to a limited number of level 1 trauma centres in the Netherlands is necessary to consolidate experience and knowledge for the trauma surgeon. The future trauma surgeon, as specialist for injured patients, should be able to provide the vast majority of trauma care in this system. For the remaining part, intramural, regional and national collaboration is essential.

Evaluating the Military Medical Evacuation Chain: Need for Expeditious Evacuation Out of Theater?

BACKGROUND: An important factor within the military medical logistical chain is the capability of expeditious evacuation from point of injury, through a Medical Treatment Facility, to the country of residence where highest level of care can be provided. Although many factors can relate to patient outcome, the evaluation of the medical evacuation chain related to long-term patient outcome can be important for investigating possibilities for performance improvement in this domain. This article aims to provide a means to evaluate the quality of care of the medical evacuation chain. METHODS: Repatriated service members from the Afghan theater between 2004 and 2014 were invited to participate in a survey concerning functional outcome and quality of life using Lower Extremity Functional Scale, Short Form health survey 36, and EuroQol-6D questionnaires. Possible associations between these outcomes were analyzed in respect to duration of medical evacuation from point of injury to arrival in the Dutch military hospital. The duration was dichotomized into within and after 72 hours. Ordinal regression was used to analyze a possible association with duration as a continuous variable. FINDINGS: Sixty percent (28/47) of battle casualties arrived in The Netherlands within 72 hours. For the nonbattle injury cohort this was 30% (7/23). Of those who became ill, 18% (5/28) was evacuated in 72 hours. No significant independent associations between interval duration and measured outcomes were found. CONCLUSION: Repatriated battle casualties had lower outcome scores compared to the disease nonbattle injured service members. Significant differences in functional outcome and quality of life with respect to evacuation duration were not found. Specialized tactical evacuation and en route care capability during strategic evacuation contributed to relative high standards of care. Combined with our results, this could implicate that delivery of the right care to the right patient at the right time is a justifiable paradigm. The main focus of the medical support organization is to offer the highest level of care per echelon as soon as possible in conjunction with facilitating maximum social support through expeditious evacuation out of theater. Further research using semistructured interviews among the direct circle around battle casualties, including caregivers, is needed to provide insight into these complex matters.

Review of military and civilian trauma registries: Does consensus matter?

BACKGROUND: Structural collection of data from combat injuries is important to improve provided care and the outcome of (combat) casualties. Trauma registries are used in civilian and military health care systems for systematic administration of injury data. However, these registries often use different methods of data management, compromising international comparison of trauma systems. The aim of this review is to aid in reaching international (coalition-wide) consensus for compatible data collection methods with uniform definitions, which is needed for transnational research and subsequent improvement of medical support organizations. METHODS: In this descriptive review, we analyzed different data sets from trauma systems within the American-European context, and included data variables from civilian and military trauma registries. These data sets were analyzed to identify a core set of variables fundamental to describing the tactical context, epidemiology, injury mechanism, injury severity, key treatment, and outcome. RESULTS: A total of 1,672 unique variables, of which 536 military specific, were identified and divided in 11 elemental categories of medical care (patient info, incident info, injury diagnoses, prehospital care, emergency department, imaging, surgical treatment, intensive care, ward, discharge and outcome) and three military-specific categories (forward medical evacuation, prehospital medical treatment facility, and discharge out of theater). A total of 203 key variables were identified and considered fundamental for effective (military) trauma research. CONCLUSION: Well-established and reliable trauma registries and databases are fundamental in (military) trauma care. We recommend implementation of a (concurrent) UN/NATO wide registry system with a track and follow-up system to further improve the quality of care and registration of casualties. Further research should focus on real time aids available on the battlefield and direct storage/upload in trauma databases in theater. Ultimately, sound and valid data support medical decision process and evaluation necessary to save lives on the battlefield.