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Context Long-term data are scarce on large cohorts with sporadic (sMTC) and hereditary medullary thyroid carcinoma (hMTC). Objectives To compare long-term disease-specific survival (DSS) and outcomes between sMTC and hMTC groups. Design Retrospective analysis. Setting German tertiary referral center. Patients A total of 673 patients with MTC that underwent surgery from January 1974 to July 2019. Intervention None (observational study). Main Outcome Measure Differences between sMTC and hMTC in long-term, stage-dependent survival and outcomes. Results Surgery was performed at median ages of 49 years for sMTC (n = 477, 44% male) and 29 years for hMTC (n = 196, 43% male; P < 0.0001). The mean follow-up times were 9.2 ± 8.0 (sMTC) and 14.6 ± 10.3 years (hMTC). Age and tumor stage at diagnosis were significantly different between the 2 groups (P < 0.0001). The sMTC and hMTC groups had different overall DSS (log rank, P = 0.0183), but similar stage-dependent DSS (log rank, P = 0.1242-0.8981). In a multivariate analysis, sMTC and hMTC did not differ in DSS (hazard ratio [HR] = 1.56; 95% CI, 0.94-2.57), but in both groups, a worse DSS was significantly associated with age at diagnosis (HR = 1.04; 95% CI, 1.02-1.05), male sex (HR = 0.49; 95% CI, 0.32–0.76), and stages III and IV at diagnosis (HR = 20.00; 95% CI, 2.74-145.91 and HR = 97.47; 95% CI, 13.07-726.67, respectively). The groups had significantly different (P < 0.0001) outcomes (i.e., cured, minimal residual disease, structural detectable disease, and death), but similar stage-dependent outcomes (P = 0.9449-0.0511), except for stage III (P = 0.0489). Conclusion Patients with sMTC and hMTC had different ages of onset, but similar stage-dependent DSS and outcomes after the MTC diagnosis. This finding suggested that tumor behavior was similar in sMTC and hMTC.

Medullary thyroid carcinoma (MTC) is a rare malignancy and compromises only 3 % of all thyroid carcinomas. MTC cells secret calcitonin, which serves as a sensitive tumor marker for screening and follow-up of MTC. Calcitonin screening in patients with nodular goiter allows for early diagnosis of MTC and surgical curative treatment. In 25 % of patients MTC occurs as an integral part of multiple endocrine neoplasia type 2 (MEN2), an autosomal dominant inherited tumor syndrome. It is caused by germline mutations in the RET protooncogene. In gene carriers early diagnosis and treatment through prophylactic thyroidectomy is possible. MTC is a slowly growing tumor with a good prognosis and 5 and 10 year survival rates up to 80 and 60 %. In the follow-up a dynamic risk stratification allows for a personalized disease management. In symptomatic and progressive metastasizing MTC tyrosine kinase inhibitors are an effective therapy.

Context The clinical relevance of bone metastases (BM) in advanced medullary thyroid carcinoma (MTC) is poorly described. Objective The objectives of this work are to describe the prevalence of BM, frequency of skeletal related events (SREs), and impact of BM morphology and SREs on prognosis, and to assess the role of antiresorptive treatment (ART). Design A retrospective cohort study was conducted. Setting This study was conducted at 4 German referral centers. Patients A total of 1060 MTC patients were included. Main Outcome Measure Main outcome measures include descriptive statistics, overall survival (OS) by the Kaplan-Meier method, and risk factors by Cox proportional hazards modeling. Results A total of 120 of 416 patients (29%) with metastatic MTC had BM, of which 97% had concurrent nonosseous metastases. BM occurred 2.1 years (median, range –0.1 to 20.6 years) after initial diagnosis, were multifocal in 79%, and were located preferentially in the spine (86%) and pelvis (60%). BM morphology was osteolytic in 32%, osteoblastic in 25%, and mixed in 22% of cases (unknown: 21%). Within a median observation period of 26.6 months (range, 0-188 months) after BM diagnosis, 47% of patients experienced one or more SREs (bone radiation 50%, pathological fractures 32%), of which 42% occurred in osteolytic and 17% in osteoblastic BM (P = .047). Presence of osteolytic metastases (hazard ratio 3.85, 95% CI 1.52-9.77, P = .005) but not occurrence of SREs was associated with impaired OS. Among the 36 patients who received ART (no ART: n = 71), SREs were significantly less frequent than in untreated patients (P = .04). Conclusion BM are common in metastatic MTC and most often with an osteolytic morphology and an unfavorable prognosis. The majority of SREs occur in osteolytic metastases and may be prevented by ART.

The aim of this study was to investigate in a longitudinal approach whether levothyroxine (LT4) substitution has a different impact on quality of life (QoL) and thyroid related QoL in younger (60 years) with elevated thyroid-stimulating hormone (TSH) concentrations. The study included male and female patients with newly diagnosed, untreated subclinical hypothyroidism defined by TSH>8 mU/l. Patients were recruited throughout Germany from 2013–2016 and evaluated by clinical assessment, blood sampling and questionnaires for health related QoL and thyroid-disease thyroid-related QoL (ThyPRO) at time of diagnosis and six months after initiation of LT4 treatment. We found significantly lower QoL in both young and old patients with subclinical hypothyroidism compared to age-matched healthy individuals. Higher scores on follow-up were found in all patients irrespective of age, indicating better QoL on LT4 therapy. Analysis of the ThyPRO questionnaire showed that old patients experienced less Emotional Susceptibility, Tiredness, and Impaired Day Life on LT4, while young patients reported less Cognitive Complaints, Emotional Susceptibility, and Impaired Day Life compared to baseline assessment. Hypothyroidism with TSH concentrations>8 mU/l is associated with impairment in general and ThyPRO QoL in young and old age. Older patients benefited from LT4 therapy and remarkably show similar degree of improvement as younger patients, albeit with some thematic variation in ThyPRO QoL. Our data confirm current recommendations on initiation of LT4 substitution and suggest that this should not be withheld in elderly with TSH concentration above 8–10 mU/l.

Summary Objective The aim of this study was to evaluate intraoral scanning (IOS) in infants, neonates, and small children with craniofacial anomalies for its feasibility, scanning duration, and success rate. Impression taking in vulnerable patients can be potentially life-threatening, with the risk of airway obstruction and aspiration of impression material. The advantage of increasingly digitalized dentistry is demonstrated. Materials and methods IOS was captured with the Trios 3® (3Shape, Copenhagen, Denmark) intraoral scanner. The underlying disorders were divided into cleft lip and palate (CLP), Trisomy 21 (T21), Robin Sequence (RS), Treacher Collins syndrome (TC), and isolated mandibular retrognathia (MR). Scan data were analysed by scanning duration, number of images, possible correlations of these factors with the different craniofacial disorders, patient age, and relationship between first and subsequent scans. Clinical experiences with the repeated digital impressions are described. Results Patient data of 141 scans in 83 patients were analysed within an 11-month period. Patients had a median age of 137 days. Median scanning duration was 138 seconds, resulting in a median of 352 images. There was a statistically significant difference in scanning duration (P = 0.001) between infants and neonates. IOS took longest in patients with CLP (537 seconds) and shortest in T21 patients (21 seconds), although there was no statistically significant difference between aetiologies. There was no statistically significant difference between first and subsequent scans in scanning duration. In four cases the IOS had to be repeated, and one patient ultimately required conventional impression taking (all CLP patients; success rate 94%). No severe adverse events occurred. Conclusion IOS is a fast, safe, and feasible procedure for neonates, small children, and infants with craniofacial malformations. One special challenge for both technician and user was identified in patients with CLP, though implementing this new approach of digital impression taking was otherwise found to be highly successful in everyday clinical routine.

Objectives Procalcitonin (PCT) has been suggested as a tumor marker in patients with medullary thyroid carcinoma (MTC). Clinical application data in long term follow-up are missing. Methods 210 serum samples of 169 consecutive patients with MTC (92 sporadic, 77 hereditary, 158 postoperative follow-up, 11 preoperative) were collected between 2018 and 2020. Postoperative patients were stratified into three groups according to their disease status at the end of follow-up: cured (n=51, calcitonin (CT) levels Results The mean ± SD values seen with the three PCT assays in the MTC response groups, cured: Conclusions PCT measured with three different immunoassays is as good as the standard tumor marker CT in the follow-up of MTC but has a superior analytical stability.

Objective Ectopic Cushing's syndrome (ECS) induced by medullary thyroid cancer (MTC) is rare, and data on clinical characteristics, treatment and outcome are limited. Design Retrospective cohort study in three German and one Swiss referral centres. Patients Eleven patients with MTC and occurrence of ECS and 22 matched MTC patients without ECS were included. Measurements The primary endpoint of this study was the overall survival (OS) in MTC patients with ECS versus 1:2 matched MTC patients without ECS. Results The median age at diagnosis of ECS was 59 years (range: 35-81) and the median time between initial diagnosis of MTC and diagnosis of ECS was 29 months (range: 0-193). Median serum morning cortisol was 49 µg/dl (range: 17-141, normal range: 6.2-18). Eight (73%) patients received treatment for ECS. Treatment of ECS consisted of bilateral adrenalectomy (BADX) in four (36%) patients and adrenostatic treatment in eight (73%) patients. One patient received treatment with multityrosine kinase inhibitor (MKI) to control hypercortisolism. All patients experienced complete resolution of symptoms of Cushing's syndrome and biochemical control of hypercortisolism. Patients with ECS showed a shorter median OS of 87 months (95% confidence interval [95% CI]: 64-111) than matched controls (190 months, 95% CI: 95-285). Of the nine deaths, four were related to progressive disease (PD). Four patients showed PD as well as complications and comorbidities of hypercortisolism before death. Conclusion This study shows that ECS occurs in advanced stage MTC and is associated with a poor prognosis. Adrenostatic treatment and BADX were effective systemic treatment options in patients with MTC and ECS to control their hypercortisolism. MKI treatment achieved complete remission of hypercortisolism and sustained tumour control in one treated case.

Background: Management of patients with advanced medullary thyroid cancer (MTC) remains a therapeutic challenge. The multi-tyrosine kinase inhibitors (TKIs) vandetanib and cabozantinib have been approved for the treatment of progressive MTC based on prolonged progression-free survival (PFS) in phase 3 clinical trials. Patients and Methods: To evaluate clinical characteristics, treatment regimens, efficacy, and treatment emergent adverse events (TEAEs) of vandetanib and cabozantinib in MTC patients outside clinical trials at four German tertiary care centers. Forty-eight patients diagnosed between 1990 and 2018 were included. PFS and overall survival (OS) probabilities were estimated using the Kaplan-Meier method and compared by log-rank test. Results: The median age at diagnosis was 46 years (15-80 years); a germ line RET (rearranged during transfection) mutation was known in 6 (13%) patients. Thirty-two (67%) patients showed progressive disease before TKI initiation. Forty-seven (98%) patients were treated with vandetanib and 23 (48%) patients with cabozantinib. Vandetanib was first-line treatment in 41 (85%) patients and cabozantinib in 7 (15%) patients. Partial response was the best response in 12 (26%) patients treated with vandetanib and in 5 (22%) patients treated with cabozantinib. Sixteen (34%) patients treated with vandetanib and 3 (13%) patients treated with cabozantinib had stable disease ≥24 weeks. The median PFS for vandetanib and cabozantinib was 17 months [95% confidence interval, CI, 9.3-24.6 months] and 4 months [CI 3.1-4.9 months], respectively. The 6- and 12-month survival rates were 98% and 86% for vandetanib and 78% and 70% for cabozantinib, respectively. The median OS for vandetanib and cabozantinib was 53 months [CI 43.7-62.3 months] and 24 months [CI 5.9-42.1 months], respectively. In vandetanib-treated patients, the PFS and OS were significantly longer in patients aged ≤60 years at TKI initiation and in patients with ≥5 TEAEs. Additionally, the PFS was longer in the absence of bone metastases. In cabozantinib-treated patients, the PFS was significantly longer in patients experiencing TEAEs and in patients aged ≤60 years, and the OS was significantly longer in patients who had TEAEs and in patients with ≥5 TEAEs. Conclusions: Vandetanib and cabozantinib are effective treatment options in the majority of MTC patients. We hypothesize that the poorer prognosis of cabozantinib-treated patients in our retrospective analysis is most likely due to its use as second-line treatment after treatment failure on vandetanib. However, different degrees of efficacy of the two drugs are possible.

Increasingly frequent and severe droughts pose one of the greatest challenges for dryland pastoralists in the Horn of Africa. Livestock drought insurance (LDI) has been proposed as a means to manage these risks. However, LDI may have unintended side effects, such as inducing unsustainable herd sizes leading to long-term pasture degradation. These issues are infeasible to study empirically given that none of the emerging LDI programs has existed at scale for any extended period of time. Thus, we study the potential long-term effects of LDI on pasture conditions at scale with the help of an agent-based model. We particularly consider the possibility that if insurance is taken up at scale, the quick herd size recovery that insurance enables after droughts can disrupt natural pasture recovery dynamics, with the potential to degrade the long-run carrying capacity of the vegetation. Our results show that, especially if pastures are very sensitive to grazing, insurance can indeed cause and/or intensify ecological instability. Furthermore, unfortunately, these unintended ecological consequences are most likely where insurance is needed the most. Designing the insurance product in the light of these insights may dampen these effects.

There is an increasing need for an assessment of the impacts of land use and land use change (LUCC). In this context, simulation models are valuable tools for investigating the impacts of stakeholder actions or policy decisions. Agricultural landscape generators (ALGs), which systematically and automatically generate realistic but simplified representations of land cover in agricultural landscapes, can provide the input for LUCC models. We reviewed existing ALGs in terms of their objectives, design and scope. We found eight ALGs that met our definition. They were based either on generic mathematical algorithms (pattern-based) or on representations of ecological or land use processes (process-based). Most ALGs integrate only a few landscape metrics, which limits the design of the landscape pattern and thus the range of applications. For example, only a few specific farming systems have been implemented. We conclude that existing ALGs contain useful approaches that can be used for specific purposes, but ideally generic modular ALGs are developed that can be used for a wide range of scenarios, regions and model types. We have compiled features of such generic ALGs and propose a possible software architecture. Considerable joint efforts are required to develop such generic ALGs, but the benefits in terms of a better understanding and development of more efficient agricultural policies would be high.

Mobile pastoralist strategies have evolved over centuries and are well adjusted to the variable climatic conditions of semi-arid regions. However, economic, social, and climatic changes, as well as technical advancements such as truck transportation, have increasingly affected the livelihood of pastoralist households in recent decades. An increase in inequality has been observed between wealthy pastoralists with large herds and impoverished households that are experiencing decreasing herd sizes on the High Plateau in Eastern Morocco, for example. In addition, whereas wealthy pastoralists possess the financial means to use trucks to transport their herds across large distances, the impoverished households are mainly limited to ranges they can travel by foot. This phenomenon can be described as polarization: the emergence of two distinct socio-economic groups with respect to household livestock and monetary resources. The reasons that have led to this polarization, however, are not well understood at present. In this study, we present a multi-agent simulation model to examine the economic, ecological, climatic, and demographic factors driving this polarization. The model captures the feedbacks between pastoralist households, their herds, and the pastures that they use in a common property grazing system. Using this model, we are able to show that heterogeneities in household assets (livestock and monetary resources) are only one cause of polarization. Changes in ecological conditions and the impact of climate and demographic change can also cause polarization, even if households are completely homogeneous in their characteristics.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant hereditary cancer syndrome caused by missense gain-of-function mutations in the RET proto-oncogene on chromosome 10. Specific RET mutations can predispose toward a particular phenotype and clinical course, with strong genotype–phenotype correlations. MEN2 is highly penetrant in medullary thyroid carcinoma (MTC), and it can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. Two different clinical variants of MEN2 are known: MEN2A, which includes the familial subtype, and MEN2B. Treatment includes early thyroidectomy. Recommendations on the timing and extent of surgery are based on the RET mutation risk categories (moderate-, high-, or highest-risk) regarding the age of MTC onset. Early identification of patients with hereditary MTC has improved treatment outcomes. Previously, MTC was diagnosed based on clinical tumors; in contrast, with genetic screening, MTC can be diagnosed at preclinical disease states. This approach has resulted in a high cure rate and a much better prognosis for MTC. However, classification into one of the three RET mutation risk groups for predicting aggressiveness and prognosis has had limited impact. Increasing evidence has shown that patients with RET mutations in different risk classifications exhibit a broad spectrum of MTC aggressiveness during follow-up, with no relevant difference in survival. The specific germline activating mutation of the RET proto-oncogene appears to be the first determinant of the age of MTC onset, but, presumably, different regulatory events determine long-term tumor behavior., The update on MEN2 focuses on genotype-phenotype correlations, on the RET mutation risk categories regarding the age of onset, and on differences in long-term tumor behavior.

Thyroid cancer is the most common endocrine malignancy. Differentiated thyroid cancer (DTC) with the two subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), is the most frequent subtype of thyroid cancer; more rare subtypes are medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC). The incidence of DTC has increased rapidly in recent years due to the more frequent use of imaging methods such as ultrasound of the neck and fine-needle aspiration (FNA) of thyroid nodules. After total thyroidectomy and radioiodine treatment, DTC remains an indolent and curable disease in most patients, whereas the cure rate in MTC is lower and depends on early diagnosis. Most ATCs are incurable. In recent years, there has been great progress in identifying genetic changes in thyroid cancer, and genetic testing of FNA samples or blood samples provides useful information for clinical decision making. Tumor staging, either postoperatively or by imaging, and measuring the tumor markers thyroglobulin for DTC and calcitonin for MTC, allow for dynamic risk-adapted stratification for follow-up procedures. In advanced metastatic thyroid cancer, molecular targeted therapy using tyrosine kinase receptor inhibitors, including sorafenib, lenvantinib, vandetanib, and cabozantinib, helps control tumor progression and prolongs progression-free survival. Using a dynamic risk-stratified approach to manage thyroid cancer, the outcomes for most thyroid cancer patients are excellent compared with those for other cancers. The major challenge in the future is to identify high-risk patients and to treat and monitor them appropriately. Clin Cancer Res; 22(20); 5012–21. ©2016 AACR. See all articles in this CCR Focus section, “Endocrine Cancers: Revising Paradigms.”

Setting a minimum distance between wind turbines and settlements is an important policy to mitigate the conflict between renewable energy production and the well-being of residents. We present a novel approach to assess the impact of varying minimum distances on the wind energy potential of a region, state or country. We show that this impact can be predicted from the spatial structure of the settlements. Applying this approach to Germany, we identify those regions where the energy potential very sensitively reacts to a change in the minimum distance. In relative terms the reduction of the energy potential is maximal in the north-west and the south-east of Germany. In absolute terms it is maximal in the north. This information helps deciding in which regions the minimum distance may be increased without large losses in the energy potential.

Drylands cover 40% of the world's surface and provide the basis for the livelihoods of at least one billion people. Pastoralists in these regions face risk and uncertainty due to highly variable climatic conditions. Therefore, and due to global change, novel risk-coping management strategies have evolved in recent decades. For example, in many pastoral regions in drylands government supplementary feeding programs are commonly introduced as a strategy to address multiple societal challenges related to climate risks, such as poverty alleviation or the maintenance of resilient pastures, in a cost-efficient way. Therefore, it is crucial to assess government supplementation programs from a multi-criteria cost-benefit perspective. Using a generic, ecological–economic simulation model we analyze the potential benefits and threats of supplementary feeding in the form of government subsidies. Our results show that currently practiced supplementary feeding strategies may cause damage in the long term because of unintended side-effects such as degradation and cost explosion. In addition, we present a novel risk-coping strategy that supports farmers and is also both ecologically and economically sustainable. Last but not least, it is shown that government supplementation programs are only cost-efficient if they are regionalized and adapted to the specific ecological characteristics of the rangeland utilization systems in question.

Context Recent data on long-term outcomes and aggressiveness of medullary thyroid carcinoma (MTC) are lacking for patients with multiple endocrine neoplasia type 2 (MEN2). Objectives To analyze the long-term outcomes in MEN2 and compare MTC aggressiveness in three defined RET mutation-risk categories: moderate risk (MOD), high risk (H), and highest risk (HST). Design, Setting Retrospective study of 263 operated patients with MEN2 from one German tertiary referral center from 1979 to 2017 comparing demographic, biochemical, genetic, and outcome parameters Intervention None (observational study) Main Outcome Measure Long-term survival and outcomes in three risk groups Results Surgery was performed at a mean age of 35.3 ± 18.8 (MOD, n = 122), 23.0 ± 15.7 years (H, n = 120), and 14.9 ± 9.3 (HST, n = 21) years (P < 0.05). The mean follow-up was 12.9 ± 9.8 years. Age and tumor stage at diagnosis differed among the three risk groups (P < 0.0001). Multivariate analysis of disease-specific survival (DSS) showed that increasing age [hazard ratio (HR), 1.06; 95% CI, 1.02 to 1.09], stage III/IV at diagnosis (HR, 7.39; 95% CI, 2.39 to 22.8), and HST group (HR, 14.4; 95% CI, 3.32 to 62.6) were significantly associated with worse DSS; the H group was not (P = 0.175). The DSS rates and outcomes were not different between the MOD and H groups (P = 0.179 and P = 0.893, respectively) but were significantly inferior in the HST group (P < 0.0008 and P < 0.0001, respectively). Conclusion MTC in patients with MEN2 showed a clearly different age of onset in the different risk groups. DSS and outcomes after MTC diagnosis were similar in the MOD and H groups, suggesting similar tumor behavior. The HST group had inferior outcomes and survival vs the MOD and or H groups.

Dynamic models have long been a common tool to support management of ecological and economic systems and played a prominent role in the early days of resilience research. Model applications have largely focused on policy assessment, the development of optimal management strategies, or analysis of system stability. However, modeling can serve many other purposes such as understanding system responses that emerge from complex interactions of system components, supporting participatory processes, and analyzing consequences of human behavioral complexity. The diversity of purposes, types, and applications of models offers great potential for social-ecological systems (SESs) research, but has created much confusion because modeling approaches originate from different disciplines, are based on different assumptions, focus on different levels of analysis, and use different analytical methods. This diversity makes it difficult to identify which approach is most suitable for addressing a specific question. Here, our aims are: (1) to introduce the most common types of dynamic models used in SESs research and related fields, and (2) to align these models with SESs research aims to support the selection and communication of the most suitable approach for a given study. To this end, we organize modeling approaches into a reference scheme called "modelling for social-ecological systems research" (ModSES) along two dimensions: the degree of realism and the degree of knowledge integration. These two dimensions capture key challenges of SESs research related to the need to account for context dependence and the intertwined nature of SESs as systems of humans embedded in nature across multiple scales, as well as to acknowledge different problem framings, understandings, interests, and values. We highlight the need to be aware of the potentials, limitations, and conceptual backgrounds underlying the different approaches. Critical engagement with modeling for different aims of SESs research can contribute to developing integrative understanding and action toward enhanced resilience and sustainability.

Livestock grazing in drylands supports pastoral livelihoods but is facing multiple changes including shocks such as severe droughts. Herdsmen specifically cite drought events as a reason for the abandonment of their transhumance practices. The purpose of this study is to assess the relevance of drought as a driving force for losses of livelihood security leading to a specific systemic change - households abandoning transhumant pastoralism.We present and apply a framework for systematic analyses of the social-ecological functioning of pastoral resource use that consists of the following components: (1) A spatially-explicit social-ecological model for analyzing the system dynamics, especially in face of severe drought in connection with other driving forces of variability, (2) an operationalized measure for assessing livelihood security, and (3) a strategy for systematic vulnerability assessments of pastoral households by scenario comparison. This approach is applied to the land use system of the transhumant pastoralists in the High Atlas Mountains of Morocco.The results indicate that drought is the main threat to livelihood security in only a few cases, eventually forcing households to abandon their transhumant lifestyle. Instead, other (endogenous and exogenous) sources of variability were found to be the main driving force for vulnerability, depending on the household characteristics such as income needs and the level of pastoral mobility. We discuss implications on the role of severe drought in connection with other processes of global change such as social change and land use change for livelihood security in pastoral systems.Moreover, on the basis of these findings, we discuss how the relevance of shocks as a driving force of systemic changes in coupled human-nature-systems may be adequately explored. These conclusions concern the interplay of exogenous and endogenous factors, and unintended side-effects of intended changes. We simulate grazing management and assess households' livelihood security.We differentiate pastoral household types by their state of vulnerability.Drought is the main driver for pastoral households to exit in only a few cases.Resource-consumer interaction dominates over the effects of drought.Increasing income needs and less mobility threaten pastoral livelihood security.

Medullary thyroid carcinoma (MTC) is a differentiated neuroendocrine tumor, mostly slowly growing with a relative good prognosis, with an overall 10-year survival of 61–76% [1,2]. Surgery is the only curative therapy for MTC [3]. After surgery, patients with MTC should be assessed regarding the presence of residual disease, the localization of metastases and the identification of progressive disease. Postoperative staging is used to separate low-risk from high-risk patients with MTC [4]. The TNM system utilizes tumor size, extrathyroidal invasion, nodal metastasis and distant spread of cancer. The number of lymph node metastases and involved compartments as well as postoperative serum calcitonin (CTN) and carcinoembryonic antigen (CEA) levels should be documented in addition. The normalization of serum CTN levels postoperatively is associated with an excellent prognosis (10-year survival >95%). In patients with elevated basal serum CTN levels less than 150 pg/ml following thyroid ectomy, persistent or recurrent disease is almost always confined to lymph nodes in the neck. Unfortunately, many patients with MTC who have regional lymph node metastases also have systemic disease and are not cured biochemically despite aggressive surgery, including bilateral neck dissection [3,5]. In patients with higher CTN levels distant metastases are suspected, having a poor prognosis, with only 40% surviving 10 years [6]. If the postoperative serum CTN level exceeds 150 pg/ml patients should be evaluated by imaging procedures including neck and chest CT, contrast-enhanced MRI and ultrasound of the liver, bone scintigraphy, MRI of the bone and PET/CT. One can estimate the growth rate of MTC metastases from sequential imaging studies using response evaluation criteria in solid tumors (RECIST) [7] that document increases in tumor size over time and by measuring serum levels of CTN or CEA over multiple time points to determine the tumor marker doubling time [8,9]. The treatment goals differ depending on the postoperative tumor stage and the parameters of progressive disease [4]. A risk-stratified follow-up with stage-dependent diagnostic approach and therapy is necessary. One of the main challenges remains to find effective adjuvant and palliative options for patients with metastatic disease. Patients with persistent or recurrent 1

The increase in climate risk is of great concern in drylands. Providing livestock with supplementary fodder has become a widely used strategy for coping with this risk. However, its application is controversial. On the one hand, this form of supplementation allows smallholders to avoid a breakdown in animal numbers in times of drought. On the other hand, it keeps herd sizes high and may thus result in rangeland degradation in the long term. This study aims to tackle the question: can supplementary feeding strategies be designed in such a way that they help to reduce livestock asset risk, but avoid or at least reduce unsustainable side effects on pastures? We constructed a stylized ecological–economic simulation model parameterized to a Moroccan case study which incorporates feedbacks between management and vegetation–livestock dynamics under stochastic rainfall. Three supplementation strategies are compared. Furthermore, the impact of socio-economic and climatic change processes, such as price increases for supplementary fodder or rising fluctuations in rainfall, is investigated. Our results show that the conventional supplementation strategy, which supplements in years of forage shortage, reduces livestock asset risk in the short term. However, it can lead to lower pasture productivity and lower yields from pastoralism in the long run. In contrast, a hypothetical strategy which additionally supplements in the year after a drought in order to rest the pasture reduces livestock asset risk and maintains pastures in a better condition without increasing the amount of supplementation. On the methodological level, this study shows the potential of ecological–economic models to assess new management strategies under different processes of global change.

Introduction: The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. Methods: The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document. Results: The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. Conclusions: The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendati...

Context Recent long-term outcomes and survival data are lacking for patients with multiple endocrine neoplasia type 2B (MEN2B). Objectives To analyze long-term MEN2B outcomes and define prognostic factors. Design, Setting, and Participants Retrospective comparative study of 75 patients with MEN2B from two German tertiary referral centers. Patients diagnosed and treated before and after 2000 were compared for demographic, biochemical, surgical, and outcome parameters. Intervention Surgery. Main Outcome measure Long-term survival. Results We identified seven familial and 68 de novo cases of MEN2B; 61 exhibited the RET M918T genotype (2 others exhibited A883F and E768D/L790T mutations). Surgery was performed at a mean age of 16.4 ± 11.2 years. The tumor stages at diagnosis for 71 patients were stage I, 15%; stage II, 6%; stage III, 35%; and stage IV, 44%. The mean follow-up was 9.6 ± 9.0 years. The outcomes were 15 (20%) cured, 9 (12%) with minimal residual disease, 19 (25%) with metastatic disease, and 10 (13%) unknown. Medullary thyroid cancer (MTC) caused 22 deaths (29%) 7.3 ± 6.2 years after diagnosis (mean age, 22.9 ± 10.7 years). The overall survival rates at 5, 10, and 20 years were 85%, 74%, and 58%, respectively. After 2000 (vs before 2000), significantly more patients had stage I and II (32% vs 11%) and more were cured (43% vs 20%), with a higher survival trend (P = 0.058). The only prognostic factor was tumor stage at diagnosis. Conclusions Patients with MEN2B developed MTC at an early age with wide ranging aggressiveness, but the outcome was generally better after 2000 than before 2000.

In ecosystems driven by water availability, plant community dynamics depend on complex interactions between vegetation, hydrology, and human water resources use. Along ephemeral rivers—where water availability is erratic—vegetation and people are particularly vulnerable to changes in each other's water use. Sensible management requires that water supply be maintained for people, while preserving ecosystem health. Meeting such requirements is challenging because of the unpredictable water availability. We applied information gap decision theory to an ecohydrological system model of the Kuiseb River environment in Namibia. Our aim was to identify the robustness of ecosystem and water management strategies to uncertainties in future flood regimes along ephemeral rivers. We evaluated the trade-offs between alternative performance criteria and their robustness to uncertainty to account for both (i) human demands for water supply and (ii) reducing the risk of species extinction caused by water mining. Increasing uncertainty of flood regime parameters reduced the performance under both objectives. Remarkably, the ecological objective (species coexistence) was more sensitive to uncertainty than the water supply objective. However, within each objective, the relative performance of different management strategies was insensitive to uncertainty. The ‘best’ management strategy was one that is tuned to the competitive species interactions in the Kuiseb environment. It regulates the biomass of the strongest competitor and, thus, at the same time decreases transpiration, thereby increasing groundwater storage and reducing pressure on less dominant species. This robust mutually acceptable strategy enables species persistence without markedly reducing the water supply for humans. This study emphasises the utility of ecohydrological models for resource management of water-controlled ecosystems. Although trade-offs were identified between alternative performance criteria and their robustness to uncertain future flood regimes, management strategies were identified that help to secure an ecologically sustainable water supply.

Das medullare Schilddrusenkarzinom (MTC) ist ein langsam wachsender differenzierter neuroendokriner Tumor mit guter Prognose und Lebensqualitat, der durch Operation geheilt werden kann. Patienten mit postoperativ nur leicht erhohtem Calcitonin (Ct) und geringer Tumorlast zeigen oft einen stabilen asymptomatischen Verlauf. Bei einem kleinen Teil der Patienten ist eine rasche Progression zu beobachten. Zur Therapie des fortgeschrittenen, progredienten metastasierenden MTC stehen jetzt Tyrosinkinaseinhibitoren (TKI) zur Verfugung Die Bedeutung und der Stellenwert der neuen TKI-Therapie im Langzeitverlauf von Patienten mit progredientem metastasierendem MTC werden dargestellt. Indikation und alternative Therapie werden anhand aktueller Studien und Leitlinien diskutiert. Als wichtiger Parameter zur Indikation fur TKI bei progredientem Verlauf haben sich die verkurzte Ct-/CEA-Verdopplungszeit und die durch wiederholte Bildgebung gewonnenen RECIST-Kriterien (RECIST: Response Evaluation Criteria in Solid Tumor) bewahrt. Unter Vandetanib und Cabozantinib kommt es zu einer Verlangerung des progressionsfreien Uberlebens sowie Stabilisierung oder Ruckgang der Tumormasse bei tolerablen Nebenwirkungen. Bei starkeren Nebenwirkungen und/oder Einschrankung der Lebensqualitat ist eine Dosisreduktion oder Therapiepause notwendig. TKI sind eine gute Therapieoption fur das progredient metastasierende MTC, allerdings ergeben sich einige ungeloste Probleme: Dauerbehandlung oder intermittierende Therapie, Kombinationstheapie, Second-Line-Therapie nach Therapieversagen, fruherer Therapiebeginn?

Livestock is the most important source of income for pastoral livelihoods in drylands. Pastoralists have developed flexible resource utilization strategies that enable them to cope with the high spatio-temporal resource variability typical to these areas. However, climate change in the form of decreasing mean annual precipitation accompanied by increasing variability has important consequences for rangeland productivity and thus pastoral livelihood security. Here, we use a spatial simulation model to assess impacts of changing precipitation regimes, and to identify limits of tolerance for these changes beyond which pastoral livelihoods cannot be secured. We also examine strategies to control these limits. Our results indicate that: (i) while reduced mean annual precipitation always had negative effects, increased precipitation variability can have negative, none or even positive effects, depending on the vegetation's recovery potential. (ii) Depending on income requirements there are limits of tolerance to decreases in mean annual precipitation beyond which precipitation regimes overcharge the coping capacity of the pastoral household and threaten its livelihood. (iii) There are certain strategies, in particular “Increasing mobility” and “Diversifying income for coping with income risks from pastoralism”, that allow the limits of tolerance to be shifted to a certain extent. We conclude that it is important to consider climate change and human requirements together to create appropriate climate change mitigation strategies in pastoral systems. Our results also shed new light on the discussion on disequilibrium rangeland systems by identifying mechanisms that can support fluctuating but non-degrading herbivore-vegetation dynamics. The paper finishes with remarks on the broader potential of the presented modelling approach beyond rangelands.

Aim Most risk assessments and decisions in conservation are based on surrogate approaches, where a group of species or environmental indicators are selected as proxies for other aspects of biodiversity. In the focal species approach, a suite of species is selected based on life history characteristics, such as dispersal limitation and area requirements. Testing the validity of the focal species concept has proved difficult, due to a lack of theory justifying the underlying framework, explicit objectives and measures of success. We sought to understand the conditions under which the focal species concept has merit for conservation decisions. Location Our model system comprised 10 vertebrate species in 39 patches of native forest embedded in pine plantation in New South Wales, Australia. Methods We selected three focal species based on ecological traits. We used a multiple-species reserve selection method that minimizes the expected loss of species, by estimating the risk of extinction with a metapopulation model. We found optimal reserve solutions for multiple species, including all 10 species, the three focal species, for all possible combinations of three species, and for each species individually. Results Our case study suggests that the focal species approach can work: the reserve system that minimized the expected loss of the focal species also minimized the expected species loss in the larger set of 10 species. How well the solution would perform for other species and given landscape dynamics remains unknown. Main conclusions The focal species approach may have merit as a conservation short cut if placed within a quantitative decision-making framework, where the aspects of biodiversity for which the focal species act as proxies are explicitly defined, and success is determined by whether the use of the proxy results in the same decision. Our methods provide a framework for testing other surrogate approaches used in conservation decision-making and risk assessment.

Context: The A883F germline mutation of the rearranged during transfection (RET) proto-oncogene causes multiple endocrine neoplasia 2B. In the revised American Thyroid Association (ATA) guidelines for the management of medullary thyroid carcinoma (MTC), the A883F mutation has been reclassified from the highest to the high-risk level, although no well-defined risk profile for this mutation exists. Objective: To create a risk profile for the A883F mutation for appropriate classification among the ATA risk levels. Design: Retrospective analysis. Setting: International collaboration. Patients: Included were 13 A883F carriers. Intervention: The intervention was thyroidectomy. Main Outcome Measures: Earliest age of MTC, regional lymph node metastases, distant metastases, age-related penetrance of MTC and pheochromocytoma (PHEO), overall and disease-specific survival, and biochemical cure rate. Results: One and three carriers were diagnosed at age 7 to 9 years (median, 7.5 years) with a normal thyroid and C-cell hyperplasia, respectively. Nine carriers were diagnosed with MTC at age 10 to 39 years (median, 19 years). The earliest age of MTC, regional lymph node metastasis, and distant metastasis was 10, 20, and 20 years, respectively. Fifty percent penetrance of MTC and PHEO was achieved by age 19 and 34 years, respectively. Five- and 10-year survival rates (both overall and disease specific) were 88% and 88%, respectively. Biochemical cure for MTC at latest follow-up was achieved in 63% (five of eight carriers) with pertinent data. Conclusions: MTC of A883F carriers seems to have a more indolent natural course compared with that of M918T carriers. Our results support the classification of the A883F mutation in the ATA high-risk level.

This study aimed to identify factors influencing long-term outcome in complete or partial postoperative hypoparathyroidism (parathyroid hormone ≤10 or10 ng/l, respectively) in medullary thyroid carcinoma (MTC). It was designed as retrospective, long-term follow-up with single-center outpatient visits. Quality of treatment, renal calcification, and function were evaluated. In 33 patients with MTC and postoperative hypoparathyroidism, current medication includes: calcium (73%), calcitriol (73%), alfacalcidol (6%), dihydrotachysterol (3%), and cholecalciferol supplements (21%). Mean hypoparathyroidism duration was 15.9±9.4 years. Initially, 15% of patients received high cholecalciferol dosages. Initial calcium dosages were higher (1 542±1 179 mg/day) than final dosages (1 188 ± 595 mg/day) (p0.05); calcitriol dosages remained constant. Over the median observation period of about 12 years it was found that serum calcium was within the target range (2.0-2.3 mmol/l) in 63% of visits, decreased (2.0 mmol/l) in 20.4%, high-normal (2.4-2.6 mmol/l) in 15.8%, and increased (2.65 mmol/l) in 0.9% of visits. Calcitriol dosages were 0.73±0.22 μg/day and 0.47±0.20 μg/day in patients with complete (n=13) and partial (n=20) hypoparathyroidism, respectively (p=0.008). Renal function decreased slightly during follow-up (eGFR: 102±22 vs. 90±27 ml/min). eGFR was negatively correlated with hypoparathyroidism duration (r=-0.35, p=0.05). Of 9 patients with renal calcification, 5 had received high initial cholecalciferol doses. eGFR was lower in patients with than in those without calcification (77±17 vs. 95±29 ml/min) (p=0.07). At least one tetanic episode occurred in 60.6% of patients, and 9% had repeated tetanic complaints. In conclusion, severity of hypoparathyroidism affects treatment: Partial hypoparathyroidism required lower calcitriol dosages than complete hypoparathyroidism. Renal calcifications occurred more frequently in patients treated initially with high cholecalciferol dosages. Impaired renal function was related to hypoparathyroidism duration and renal calcification.

Summary Background Based on reports of higher frequencies among patients with sporadic medullary thyroid cancer (MTC) relative to external controls, the RET (REarranged during Transfection) variants G691S, L767L, S836S and S904S have been considered disease modifiers, suggesting greater lifetime risks of MTC. Other studies, employing different external controls, failed to confirm this association. Using a complementary approach, this study aimed at exploring differences in clinico-pathological characteristics among patients with sporadic MTC carrying no (wildtype), one (heterozygotes) or both (homozygotes) homologue RET variants in the germline, with wildtype cases acting as internal controls. Methods Included in this investigation were 150 patients with complete genetic information on G691S, L769L, S836S and S904S RET alleles operated on for sporadic MTC at a tertiary referral centre. Results Not one statistically significant dose–response relationship was identified between any RET variant (wildtype vs RET heterozygotes vs homologue RET homozygotes) and patient age at MTC diagnosis, gender, primary tumour size, extrathyroidal extension, numbers of involved and removed lymph nodes, or distant metastasis. L769L and S836S homozygotes, unlike G691S and S904S homozygotes, were either rare or absent, limiting the analyses to comparisons of heterozygosity versus wildtype. On time-to-event analysis, G691S, L769L, S836S or S904S carriers and noncarriers developed MTC at similar rates. Conclusions In carriers and noncarriers of the RET variants G691S, L767L, S836S and S904S, sporadic MTC appeared clinically and pathologically indistinguishable. This observation, along with the inconclusive evidence of previous association studies, calls for larger longitudinal association studies with age- and sex-matched external controls and additional functional studies of RET biology.

Summary Objective Autosomal dominant hypocalcaemia or hypoparathyroidism is caused by activating mutations of the calcium-sensing receptor (CaSR). Treatment with calcium and vitamin D often worsens hypercalciuria and nephrocalcinosis, and renal impairment can result. Our aim was to describe the phenotypic variance of this rare disorder in a large series and to evaluate the outcome after long-term treatment. Design Nationwide retrospective collaborative study. Patients We describe 25 patients (14 men and 11 women), 20 belonging to 11 families and five single cases. Measurements Activating CaSR mutations and clinical and biochemical findings were evaluated. Results Nine different missense mutations of the CaSR, including one novel variant (M734T), were found. Twelve patients (50%) were symptomatic, 9 (36%) had basal ganglia calcifications and 3 (12%) had nephrocalcinosis. Serum calcium was decreased (1·87 ± 0·13 mm), and PTH was decreased (n = 19) or inappropriately low (n = 4). The occurrence of hypocalcaemic symptoms at diagnosis was related to the degree of hypocalcaemia. The occurrence of features like calcification of basal ganglia or kidney calcification did not correlate with the severity of hypocalcaemia or the age at diagnosis. The most common treatment was calcitriol (median dosage 0·6 μg/day), and the mean duration of therapy was 7·1 years (max. 26 years). Hypercalcaemic episodes rarely occurred, and the rate of kidney calcifications was remarkably low (12%). Conclusion This series increases the limited knowledge of mutations and phenotypes of this rare disorder. Mutation analysis of the CaSR gene facilitates patient and family management. Low dosages of calcitriol resulted in less frequent renal calcifications.

ObjectiveHyperparathyroidism-jaw tumour (HPT-JT) syndrome is a rare autosomal dominant cause of benign and malignant parathyroid tumours, ossifying jaw tumours, various cystic and neoplastic renal abnormalities and benign and malignant uterine tumours. Disease-causing mutations have been localised in the tumour suppressor gene CDC73. There is limited information available on the mutations, and resulting phenotypes and long-term follow-up data are especially scarce.DesignWe analysed the clinical data from 16 patients (including three families) carrying mutations in the CDC73 gene. We describe five new mutations/gene variants, the corresponding phenotypes of these carriers and the long-term follow-up.MethodsThe 16 patients were evaluated at an endocrine outpatient clinic and at a surgical department. DNA samples were obtained for sequence analysis of the CDC73 gene.ResultsClinical features of HPT-JT syndrome were detected in 13 of the 15 carriers with germline CDC73 mutations. The major features were benign (n=7; 47%) or cancerous (n=3; 20%) HPT-JT was present in eight cases (53%). Most patients had severe hypercalcaemia, and median serum calcium levels were 3.36 mmol/l. A patient with non-secretory parathyroid carcinoma was included. HPT was diagnosed at a median age of 28.5 years. Mutational analysis of the CDC73 gene identified eight sequence changes, three of them have been reported previously, whereas five are novel: c.1346delG, c.88_94delTTCTCCT, the non-coding variants, c.307+5G>T and c.424−5T>C and c.*12C>A of unknown significance.ConclusionsThis study significantly increases the information available on the mutations and phenotypes of HPT-JT syndrome.

Summary Objective Primary hyperparathyroidism (HPT) is characterised by autonomous secretion of PTH from enlarged parathyroid glands leading, in most patients, to asymptomatic hypercalcaemia. Familial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant disorder caused by inactivating mutations in the calcium-sensing receptor (CaSR) gene; it is characterised by lifelong and usually asymptomatic hypercalcaemia. Establishing the correct diagnosis is important because surgery can be curative in HPT, but ineffective in FHH. There is overlap in the diagnostic criteria for the two disorders and some patients carrying inactivating mutations in the CaSR gene, which is suggestive of FHH, also have HPT with hyperplastic parathyroid glands or adenomas. Design and patients CaSR gene mutations were analysed and clinical and biochemical parameters evaluated in 139 consecutive outpatients presenting with hypercalcaemia and suspected of having HPT. Results Six different mutations of the CaSR gene were found in eight patients. In four patients, classical FHH was suspected based on clinical and biochemical results and was confirmed by the CaSR mutations. In the other four patients, HPT was diagnosed based on the biochemical profile or symptoms; in these four patients, the parathyroids were operated on and single adenomas were histologically confirmed. In all four patients, serum calcium decreased postoperatively; and in three patients, serum calcium normalised postoperatively. The CaSR mutations in these patients were R25X, E250K and Q926R. Conclusion The coexistence of HPT and FHH in four of 139 patients suggests a pathogenetic role of CaSR mutations in HPT. Despite also having a CaSR mutation, these patients benefited from parathyroid surgery.

Medullary thyroid carcinoma (MTC) is the main component of the autosomal dominant cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). MEN 2 is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. In RET-mutation carriers, an age-related progression has been documented from normal C-cells to premalignant C-cell hyperplasia and finally to MTC with or without cervical lymph node metastases. The time required for this neoplastic development as well as penetrance and aggressiveness of disease mainly depends on the specific RET mutation with a strong genotype-phenotype correlation. Recommendations for the timing of prophylactic thyroidectomy are based upon a model that utilizes these genotype-phenotype correlations to stratify mutations into four risk levels. The excellent prognosis for MTC diagnosed at its earliest stage underscores the importance of early diagnosis by RET-mutation analysis for hereditary MTC.

Multiple endocrine neoplasia type 2 (MEN2) is a autosomal dominat inherited tumour-syndrome caused by germline activating mutations of the RET proto-oncogene on chromosome 10. It is clinically characterized by the presence of medullary thyroid carcinoma (MTC), bilateral pheochromocytoma and primary hyperparathyroidism (MEN2A) within a single patient. Three distinct clinical forms have been described depending on the phenotype: the classical MEN 2A, MEN 2B, an association of MTC, pheochromocytoma and mucosal neuroma, (FMTC) familial MTC with a low incidence of other endocrinopathies. Each variant of MEN2 results from different RET gene mutation, with a good genotype phenotype correlation. Genetic testing detects nearly 100% of mutation carriers and is considered the standard of care for all first degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on a classification into four risk levels utilizing the genotype-phenotype correlations. MEN 2 gives a unique model for early prevention and cure of cancer and for stratified roles of mutation-based diagnosis of carriers.

Background About one quarter of all medullary thyroid cancers (MTC) are determined genetically due to a mutation in the RET proto-oncogene. The most common site of mutation is in codon 634. Therapeutic approaches toward patients at risk for the development of MTC identified by family screening programs range from total thyroidectomy to total thyroidectomy with lymphadenectomy of all 4 compartments. Methods We report 17 patients (median age, 13 years; range, 4–36) carrying a mutation in codon 634 of the RET proto-oncogene who were operated on prophylactically at our department. All patients underwent thyroidectomy with bilateral cervicocentral lymphadenectomy. Current calcitonin level, overall survival, and disease-free survival were analyzed by contacting general practitioners and patients. Results Tumor classification was as follows: C-cell hyperplasia, 18% (n = 3); T1 ( 1 cm), 12% (n = 2). Only 2 patients had lymph node metastases (12%). These patients developed recurrent disease (median observation time, 147 months; range, 90–181). In 1 patient, the calcitonin level normalized after unilateral cervicolateral lymphadenectomy. The other patient (9 years old at primary operation) still has a persistently increased serum calcitonin level after 140 months of follow-up despite several operations for MTC. Conclusion Total thyroidectomy with bilateral cervicocentral lymphadenectomy is sufficient as routine “prophylactic therapy” for patients with mutations in codon 634 of the RET proto-oncogene. Cervicolateral lymphadenectomy is indicated if calcitonin remains elevated after primary surgery. Prophylactic thyroidectomy should be performed before the development of lymph node metastases.

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant tumour syndrome caused by germ-line-activating mutations of the RET protooncogene. It is characterised clinically by the presence of medullary thyroid carcinoma (MTC), bilateral pheochromocytoma, and primary hyperparathyroidism (MEN 2A) within a single patient or family. Three distinct clinical forms have been described: (i) classical MEN 2A, (ii) MEN 2B, an association of MTC, pheochromocytoma, and mucosal neuroma, and (iii) familial MTC (FMTC), which is associated with a very low incidence of other endocrinopathies. Each variant of MEN 2 results from a different RET gene mutation, with strong genotype–phenotype correlation. Genetic testing detects nearly 100% of mutation carriers and is considered the standard of care for all first-degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on classification of RET mutations into three risk levels according to genotype–phenotype correlations. MEN 2 provides a unique model for early prevention and cure of cancer and for the stratified roles of mutation-based diagnosis of carriers.

BackgroundIntraoperative parathyroid hormone (PTH) monitoring predicts successful surgery for primary hyperparathyroidism (pHPT). In renal HPT, intraoperative PTH assays can define whether parathyroid resection is adequate.MethodsIntraoperative PTH was measured with two different immunometric assays (Immulite Turbo DPC and ADVIA Centaur assay) in 91 patients undergoing parathyroidectomy for primary (n=57) and renal (n=34) hyperparathyroidism. PTH was monitored preoperatively, 10, 20, and 30 min after parathyroidectomy and 24 h postoperatively.ResultsTen minutes after parathyroidectomy, intraoperative PTH dropped into the normal range (P=0.0082). Twenty minutes after parathyroidectomy for secondary HPT, intraoperative PTH decreased to the normal range in 100% measured with PTH-I compared with 50% measured with PTH-A (P=0.009). Then, 24 h postoperatively, PTH-I and PTH-A levels were within the normal range in all of the successfully treated patients. Both assays correctly identified six patients with persistent disease and another patient with a double adenoma in pHPT.ConclusionsIn patients undergoing parathyroidectomy for primary or renal HPT, PTH levels decreasing to the normal range indicated successful surgery in all of the patients as measured with the PTH-I assay. Comparing the two assays, PTH-I was able to quantify the intraoperative PTH decay more quickly than PTH-A.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant tumour syndrome caused by germline activating mutations of the RET proto-oncogene. It has a strong penetrance of medullary thyroid carcinoma (MTC) and can be associated with bilateral pheochromocytoma and primary hyperparathyroidism (MEN2A) within a single patient or family. Based on the phenotype three distinct clinical forms have been described: (1) classical MEN2A, (2) MEN2B, an association of MTC, pheochromocytoma and mucosal neuroma and (3) familial MTC (FMTC), which is associated with a very low incidence of other endocrinopathies. Each variant of MEN2 results from a different RET gene mutation, with a good genotype-phenotype correlation with regard to aggressiveness of MTC, time of onset of MTC and the presence or absence of other endocrine tumours. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on a classification of RET mutations into three risk levels using the genotype-phenotype correlations. MEN2 provides a unique model for early prevention and cure of cancer and for stratified roles of mutation-based diagnosis of carriers.

Summary Objectives Hereditary medullary thyroid carcinoma (MTC) is caused by germ-line mutations in the RET proto-oncogene. Our study addresses the difference in development of MTC between rare mutations in RET codons 790, 791 and 804. Design We evaluated tumour stage, calcitonin levels, biochemical cure rates and associated endocrinopathies in 153 German/Austrian patients with RET 790 (n = 47), 791 (n = 56) and 804 mutations (n = 50), divided into index- and screening groups. Results Age at diagnosis in index-patients did not differ significantly among the three codon groups (medians of 57, 61 and 53 years). Tumour stage at diagnosis was significantly less advanced with codon 791 (n = 22) than 790 (n = 16) and 804 (n = 16) mutations (P = 0·001). In screening patients, age at diagnosis did not differ significantly among the three groups (medians 19, 24 and 32 years). Tumour stage at diagnosis was also significantly less advanced with codon 791 (n = 34) than 790 (n = 31) and 804 (n = 34) (P = 0·032). Preoperative basal calcitonin levels were significantly lower in codon 791 carriers compared to codon 790 carriers, and cure rates were significantly higher in both index (75%vs. 31%; P = 0·03) and screening patients (100%vs. 75%; P = 0·015). Additional endocrinopathies were observed only with codon 791 carriers (four pheochromocytomas and two hyperparathyroidism). Conclusion There is a significant difference in MTC development with less extensive C-cell disease, higher cure rate and more frequent additional endocrinopathies in carriers of RET codon 791 mutations compared with carriers of codons 790 and 804 mutations. This information should be considered when age of prophylactic thyroidectomy is discussed.

Of 218 women with hirsutism 16 (7%) were found to have partial 21-hydroxylase deficiency, while 38 (17%) had partial 3 beta-hydroxysteroid dehydrogenase deficiency. Six women (3%) had a steroid constellation which resembled that of an augmented adrenarche. In the women with enzyme deficiency over-weight and abnormal menstruations were more frequent (50%) than in those without such deficiency (33%). The degree of hirsutism and age at diagnosis were similar in those with and those without partial enzyme deficiency. Furthermore, the diagnosis of partial enzyme deficiency could only be made with certainty by the ACTH stimulation test, because with sole measurement of basal levels (17-hydroxyprogesterone and 21-desoxycortisol in 21-hydroxylase deficiency, and 17-hydroxypregnenolone and dehydroepiandrosterone in 3 beta-hydroxysteroid dehydrogenase deficiency) the enzyme defects are in most instances not revealed.

OBJECTIVE To determine the importance of the molecular-genetic demonstration of germ-line mutation in the ret protooncogene for therapeutic measures in sporadic and hereditary medullary thyroid carcinoma (MTC). PATIENTS AND METHODS Several molecular-genetic tests were performed on DNA of 35 families with hereditary and 81 patients with the sporadic form of MTC (isolation of genomic DNA; PCR amplification; DNA sequencing: demonstration of mutation in codon 918 with restriction enzyme FOK 1). RESULTS A disease risk was demonstrated in 178 individuals among the 35 families, 159 of whom were investigated by molecular-genetic tests: 84 family members were found to be gene carriers. Germ-line mutation had already been suspected on clinical grounds in 76% of the carriers, 24% being discovered in a presymptomatic stage. Six children among the latter were treated prophylactically by thyroidectomy, histological evidence of C-cell hyperplasia being found in all of them, microcarcinomas in three of the older children. There were four patients among the non-carriers on whom thyroidectomy had been performed previously because of a false-positive pentagastrin-test; but germ-line mutation was now excluded. In one family, with familial MTC in two brothers, no mutation in ret-proto-oncogene has been demonstrated. The members of this family must now, as used to be routine, undergo a pentagastrin-test. Three of the 81 patients with "sporadic" MTC had a germ-line mutation, presumably a new one. CONCLUSION Molecular-genetic tests have further improved the management of families with hereditary MTC and they thus take first place among essential diagnostic procedures. The diagnosis of sporadic MTC can be confirmed by excluding germ-line mutation in the ret-proto-oncogene.

BackgroundHomozygous inactivating mutations of the calcium-sensing receptor (CaSR) lead to neonatal severe hyperparathyroidism (NSHPT), whereas heterozygous inactivating mutations result in familial hypocalciuric hypercalcemia (FHH). It is unknown why in some cases heterozygousCaSRmutations cause neonatal hyperparathyroidism (NHPT) clinically similar to NSHPT but with only moderately elevated serum calcium.MethodsA literature survey was conducted to identify patients with heterozygousCaSRmutations and NHPT. The common NHPT CaSR mutants R185Q and R227L were compared with 15 mutants causing only FHH in the heterozygous state. We studiedin vitrocalcium signaling including the functional consequences of co-expression of mutant and wild-type (wt) CaSR, patients’ phenotype, age of disease manifestation and mode of inheritance.ResultsAll inactivating CaSR mutants impaired calcium signaling of wt-CaSR regardless of the patients’ clinical phenotype. The absolute intracellular calcium signaling response to physiologic extracellular calcium concentrationsin vitroshowed a high correlation with patients’ serum calcium concentrationsin vivo, which is similar in NHPT and FHH patients with the same genotype. Pedigrees of FHH families revealed that paternal inheritanceper sedoes not necessarily lead to NHPT but may only cause FHH.ConclusionsThere is a significant correlation betweenin vitrofunctional impairment of the CaSR at physiologic calcium concentrations and the severity of alterations in calcium homeostasis in patients. Whether a particular genotype leads to NHPT or FHH appears to depend on additional predisposing genetic or environmental factors. An individual therapeutic approach appears to be warranted for NHPT patients.

Objective: Medullary thyroid carcinoma (MTC) is often associated with gain-of-function mutations in the RET proto-oncogene, which is found in all hereditary cases and most sporadic cases. The activated RET receptor tyrosine kinase can be inhibited by tyrosine kinase inhibitors in vitro. We evaluated the efficacy of treatment with imatinib mesylate, a tyrosine kinase inhibitor, in patients with advanced MTC. Design and patients: In this open-label clinical trial, nine patients, eight with sporadic and one with hereditary MTC, with unresectable, measurable, progressive metastases were treated with imatinib mesylate 600 mg daily. The tumour response to imatinib was evaluated after 3, 6 and 12 months by computed tomography and after 1 month by 18F-fluoro-2-deoxy d-glucose position-emission tomographic scanning. The median duration of therapy was 8 months. Results: Overall, stable disease occurred in five patients for up to 6 months and in one patient for up to 12 months, with a median duration of progression-free survival of 6 months. Four patients had progressive disease after 12 months. One patient stopped therapy after 2 weeks because of worsening of diarrhoea. Therapy was well tolerated, although transient mild-to-moderate nausea (n = 3), oedema (n = 3), diarrhoea (n = 2) and skin rash (n = 2) were observed. Conclusion: Imatinib mesylate is well tolerated, no tumour remission was observed, only transient stable disease was achieved in some patients with advanced MTC.

Management strategies in rotational grazing systems differ in their level of complexity and adaptivity. Different components of such grazing strategies are expected to allow for adaptation to environmental heterogeneities in space and time. However, most models investigating general principles of rangeland management strategies neglect spatio-temporal system properties including seasonality and spatial heterogeneity of environmental variables. We developed an ecological-economic rangeland model that combines a spatially explicit farm structure with intra-annual time steps. This allows investigating different management components in rotational grazing systems (including stocking and rotation rules) and evaluating their effect on the ecological and economic states of semi-arid grazing systems. Our results show that adaptive stocking is less sensitive to overstocking compared to a constant stocking strategy. Furthermore, the rotation rule becomes important only at stocking numbers that maximize expected income. Altogether, the best of the tested strategies is adaptive stocking combined with a rotation that adapts to both spatial forage availability and seasonality. This management strategy maximises mean income and at the same time maintains the rangeland in a viable condition. However, we could also show that inappropriate adaptation that neglects seasonality even leads to deterioration. Rangelands characterised by higher inter-annual climate variability show a higher risk of income losses under a non-adaptive stocking rule, and non-adaptive rotation is least able to buffer increasing climate variability. Overall, all important system properties including seasonality and spatial heterogeneity of available resources need to be considered when designing an appropriate rangeland management system. Resulting adaptive rotational grazing strategies can be valuable for improving management and mitigating income risks.

Although the aim of conservation planning is the persistence of biodiversity, current methods trade-off ecological realism at a species level in favour of including multiple species and landscape features. For conservation planning to be relevant, the impact of landscape configuration on population processes and the viability of species needs to be considered. We present a novel method for selecting reserve systems that maximize persistence across multiple species, subject to a conservation budget. We use a spatially explicit metapopulation model to estimate extinction risk, a function of the ecology of the species and the amount, quality and configuration of habitat. We compare our new method with more traditional, area-based reserve selection methods, using a ten-species case study, and find that the expected loss of species is reduced 20-fold. Unlike previous methods, we avoid designating arbitrary weightings between reserve size and configuration; rather, our method is based on population processes and is grounded in ecological theory.

Roads and traffic affect animal populations detrimentally in four ways: they decrease habitat amount and quality, enhance mortality due to collisions with vehicles, prevent access to resources on the other side of the road, and subdivide animal populations into smaller and more vulnerable fractions. Roads will affect persistence of animal populations differently depending on (1) road avoidance behavior of the animals (i.e., noise avoidance, road surface avoidance, and car avoidance); (2) population sensitivity to the four road effects; (3) road size; and (4) traffic volume. We have created a model based on these population and road characteristics to study the questions: (1) what types of road avoidance behaviors make populations more vulnerable to roads?; (2) what types of roads have the greatest impact on population persistence?; and (3) how much does the impact of roads vary with the relative population sensitivity to the four road effects? Our results suggest that, in general, the most vulnerable populations are those with high noise and high road surface avoidance, and secondly, those with high noise avoidance only. Conversely, the least vulnerable populations are those with high car avoidance only, and secondly, high road surface and high car avoidance. Populations with low overall road avoidance and those with high