Development of a pediatric differentiated thyroid carcinoma registry within the EuRRECa project: rationale and protocol.

Background: Although differentiated thyroid carcinoma (DTC) is the most frequent endocrine pediatric cancer, it is rare in childhood and adolescence. While tumor persistence and recurrence are not uncommon, mortality remains extremely low. Complications of treatment are however reported in up to 48% of the survivors. Due to the rarity of the disease, current treatment guidelines are predominantly based on the results of small observational retrospective studies and extrapolations from results in adult patients. In order to develop more personalized treatment and follow-up strategies (aiming to reduce complication rates), there is an unmet need for uniform international prospective data collection and clinical trials. Methods and analysis: The European pediatric thyroid carcinoma registry aims to collect clinical data for all patients ≤18 years of age with a confirmed diagnosis of DTC who have been diagnosed, assessed, or treated at a participating site. This registry will be a component of the wider European Registries for Rare Endocrine Conditions project which has close links to Endo-ERN, the European Reference Network for Rare Endocrine Conditions. A multidisciplinary expert working group was formed to develop a minimal dataset comprising information regarding demographic data, diagnosis, treatment, and outcome. We constructed an umbrella-type registry, with a detailed basic dataset. In the future, this may provide the opportunity for research teams to integrate clinical research questions. Ethics and dissemination: Written informed consent will be obtained from all participants and/or their parents/guardians. Summaries and descriptive analyses of the registry will be disseminated via conference presentations and peer-reviewed publications.

Real-world-effectiveness of biological treatment for severe chronic rhinosinusitis with nasal polyps.

BACKGROUND: During the last two years, three different monoclonal antibodies have been approved in many countries for the treatment of patients suffering from severe chronic rhinosinusitis with nasal polyps (CRSwNP). Their efficacy has been demonstrated through large double-blind placebo-controlled clinical studies. Until now, only very limited reports on real-world data regarding this therapy have been published. METHODS: This per protocol analysis included patients with an indication for biological treatment because of uncontrolled CRSwNP, despite long-term nasal steroid treatment, systemic steroid use and/ or endonasal sinus surgery. Baseline data on demographics, medical history and comorbidities, polyp score, quality of life and sense of smell (using Sniffin' Sticks) were assessed and a treatment with either dupilumab or omalizumab was started. The patients were followed up after three and six months. The changes in polyp score, quality-of-life measures and olfaction were noted. RESULTS: 70 consecutive patients were evaluated during the study. Of the patients, 49 were treated with dupilumab and 21 with omalizumab. The polyp score decreased significantly after three and six months, and the quality-of-life parameters and olfaction increased. More than 90% of patients showed a moderate to excellent response to the therapy and there was no difference in the overall response between the two treatments. Olfaction improved in two thirds of the patients, but one third was still anosmic after six months treatment. CONCLUSIONS: This real-world study shows the effectiveness of the monoclonal antibodies dupilumab and omalizumab in the treatment of severe CRSwNP. Nasal polyp scores and quality-of-life parameters as well as measured olfactory function were improved after just three months. The response after guideline-based criteria was insufficient only in 5 patients of this cohort.

Raman and fluorescence micro-spectroscopy applied for the monitoring of sunitinib-loaded porous silicon nanocontainers in cardiac cells.

Nanomaterials are a central pillar in modern medicine. They are thought to optimize drug delivery, enhance therapeutic efficacy, and reduce side-effects. To foster this technology, analytical methods are needed to validate not only the localization and distribution of these nanomaterials, but also their compatibility with cells, drugs, and drug release. In the present work, we assessed nanoparticles based on porous silicon (pSiNPs) loaded with the clinically used tyrosine kinase inhibitor sunitinib for their effectiveness of drug delivery, release, and toxicity in colon cancer cells (HCT 116 cells) and cardiac myoblast cells (H9c2) using Raman micro-spectroscopy, high-resolution fluorescence microscopy, along with biological methods for toxicological effects. We produced pSiNPs with a size of about 100 nm by grinding mesoporous silicon layers. pSiNPs allowed an effective loading of sunitinib due to their high porosity. Photoluminescence properties of the nanoparticles within the visible spectrum allowed the visualization of their uptake in cardiac cells. Raman micro-spectroscopy allowed not only the detection of the uptake and distribution of pSiNPs within the cells via a characteristic silicon Raman band at about 518-520 cm-1, but also the localization of the drug based on its characteristic molecular fingerprints. Cytotoxicity studies by Western blot analyses of apoptotic marker proteins such as caspase-3, and the detection of apoptosis by subG1-positive cell fractions in HCT 116 and MTT analyses in H9c2 cells, suggest a sustained release of sunitinib from pSiNPs and delayed cytotoxicity of sunitinib in HCT 116 cells. The analyses in cardiac cells revealed that pSiNPs are well tolerated and that they may even protect from toxic effects in these cells to some extent. Analyses of the integrity of mitochondrial networks as an early indicator for apoptotic cellular effects seem to validate these observations. Our study suggests pSiNPs-based nanocontainers for efficient and safe drug delivery and Raman micro-spectroscopy as a reliable method for their detection and monitoring. Thus, the herein presented nanocontainers and analytical methods have the potential to allow an efficient advancement of nanoparticles for targeted and sustained intracellular drug release that is of need, e.g., in chronic diseases and for the prevention of cardiac toxicity.

A randomized, open-label, multicenter study of switching to brolucizumab with or without a loading dose for patients with suboptimal anatomically controlled neovascular age-related macular degeneration-the FALCON study.

BACKGROUND: Treatment initiation with brolucizumab, a new potent anti-vascular endothelial growth factor (VEGF) agent, is typically performed with three monthly injections (loading dose) and has been well studied in treatment-naïve patients. However, no clinical data are available yet on whether or not anti-VEGF pretreated patients also benefit from a loading dose. In the clinical setting, different heterogeneous treatment patterns are used as no clinical trial has addressed this so far in a head-to-head comparison. Therefore, the FALCON study is investigating whether patients with unsatisfactory response to previous anti-VEGF treatments benefit from a loading dose at the switch to brolucizumab treatment. METHODS: FALCON is a 52-week, two-arm, randomized, open-label, multicenter, multinational study in patients with residually active neovascular age-related macular degeneration (nAMD) who will be randomized 1:1 and started with brolucizumab 6 mg loading (three monthly loading doses) or brolucizumab 6 mg non-loading (one initial injection) and consecutive treatment every 12 weeks, respectively. The primary objective is to demonstrate non-inferiority of the non-loading vs. loading arm in mean change of best-corrected visual acuity (BCVA) from baseline to the mean value at week 40 to week 52. Secondary objectives include the assessment of anatomical outcomes, treatment intervals, safety and tolerability. RESULTS: FALCON will be the first study to assess treatment initiation with an anti-VEGF agent in a switch situation with or without loading dose in patients with nAMD. CONCLUSIONS: The results will support the optimization of treatment of patients with previous unsatisfactory anti-VEGF response. Therefore, we expect to see an impact on current clinical practice which has been established for more than a decade. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04679935, date of registration-22-Dec 2020; EUDRACT number: 2019-004763-53, date of registration-03 Dec 2019.

[Medicolegal aspects of primary and renal hyperparathyroidism]. / Medikolegale Aspekte der Chirurgie des primären und renalen Hyperparathyreoidismus.

BACKGROUND: Compared with malpractice claims in thyroid surgery, expert medico-legal reviews of surgery performed for hyperparathyroidism (HPT) that aim to prove or rebut surgical malpractice are rare. The aim of this analysis was to describe typical risk patterns for possible treatment errors and to generate recommendations for avoiding these treatment errors. MATERIAL AND METHODS: A total of 12 surgical expert medico-legal reviews, which were carried out by order of 9 arbitration boards and 3 courts between 1997 and 2020 were evaluated. RESULTS: If the indications for surgical treatment of hyperparathyroidism were present, the failure to identify a parathyroid adenoma or hyperplastic parathyroid glands was in the majority of cases not rated as a surgical treatment error, especially in atypical localizations. Unilateral recurrent laryngeal nerve palsy and postoperative bleeding cannot always be prevented, despite maximum diligence. In contrast, bilateral recurrent laryngeal nerve palsy can be prevented when intraoperative neuromonitoring is correctly applied. A lack of patient information regarding postoperatively persistent HPT, postoperative hypoparathyroidism following the removal of inconspicuous parathyroid glands and nonindicated lobectomy or total thyroidectomy, mostly performed under the assumption of an intrathyroid parathyroid adenoma, represented avoidable malpractice issues. CONCLUSION: Advanced knowledge of the pathophysiology of the disease and the anatomy of the parathyroid glands as well as the establishment of intraoperative and perioperative standards can prospectively greatly reduce avoidable errors in the surgical treatment and postoperative care of HPT.

Cross Disciplinary Role Agreement is Needed When Coordinating Long-Term Opioid Prescribing for Cancer: a Qualitative Study.

BACKGROUND: Cancer pain is highly prevalent and often managed in primary care or by oncology providers in combination with primary care providers. OBJECTIVES: To understand interdisciplinary provider experiences coordinating opioid pain management for patients with chronic cancer-related pain in a large integrated healthcare system. DESIGN: Qualitative research. PARTICIPANTS: We conducted 20 semi-structured interviews with interdisciplinary providers in two large academically affiliated VA Medical Centers and their associated community-based outpatient clinics. Participants included primary care providers (PCPs) and oncology-based personnel (OBPs). APPROACH: We deductively identified 94 examples of care coordination for cancer pain in the 20 interviews. We secondarily used an inductive open coding approach and identified themes through constant comparison coming to research team consensus. RESULTS: Theme 1: PCPs and OBPs generally believed one provider should handle all opioid prescribing for a specific patient, but did not always agree on who that prescriber should be in the context of cancer pain. Theme 2: There are special circumstances where having multiple prescribers is appropriate (e.g., a pain crisis). Theme 3: A collaborative process to opioid cancer pain management would include real-time communication and negotiation between PCPs and oncology around who will handle opioid prescribing. Theme 4: Providers identified multiple barriers in coordinating cancer pain management across disciplines. CONCLUSIONS: Our findings highlight how real-time negotiation about roles in opioid pain management is needed between interdisciplinary clinicians. Lack of cross-disciplinary role agreement may result in delays in clinically appropriate cancer pain management.

Superiority of continuous over intermittent intraoperative nerve monitoring in preventing vocal cord palsy.

BACKGROUND: Continuous intraoperative nerve stimulation (IONM) with uninterrupted monitoring is likely better than intermittent IONM in preventing vocal cord palsy after thyroid surgery. METHODS: This was a comparative study of intermittent versus continuous IONM in patients with benign and malignant thyroid disease treated at a tertiary centre over 10 years. Early postoperative and permanent vocal cord palsy rates were estimated. Multivariable logistic regression analysis was used to quantify the contributions of clinical and histopathological variables to early postoperative and permanent vocal cord palsy. RESULTS: A total of 6029 patients were included, of whom 3139 underwent continuous and 2890 intermittent IONM. Based on nerves at risk (5208 versus 5024 nerves), continuous IONM had a 1·7-fold lower early postoperative vocal cord palsy rate than intermittent monitoring (1·5 versus 2·5 per cent). This translated into a 30-fold lower permanent vocal cord palsy rate (0·02 versus 0·6 per cent). In multivariable logistic regression analysis, continuous IONM independently reduced early postoperative vocal cord palsy 1·8-fold (odds ratio (OR) 0·56) and permanent vocal cord palsy 29·4-fold (OR 0·034) compared with intermittent IONM. One permanent vocal cord palsy per 75·0 early vocal cord palsies was observed with continuous IONM, compared with one per 4·2 after intermittent IONM. Early postoperative vocal cord palsies were 17·9-fold less likely to become permanent with continuous than intermittent IONM. CONCLUSION: Continuous IONM is superior to intermittent IONM in preventing vocal cord palsy.

Targeted use of intraoperative frozen-section analysis lowers the frequency of completion thyroidectomy.

BACKGROUND: The impact of intraoperative frozen section (iFS) analysis on the frequency of completion thyroidectomy for the management of thyroid carcinoma is controversial. Although specialized endocrine centres have published their respective results, there are insufficient data from primary and secondary healthcare levels. The aim of this study was to analyse the utility of iFS analysis. METHODS: In the Prospective Evaluation Study Thyroid Surgery (PETS) 2 study, 22 011 operations for benign and malignant thyroid disease were registered prospectively in 68 European hospitals from 1 July 2010 to 31 December 2012. Group 1 consisted of 569 patients from University Medical Centre (UMC) Mainz, and group 2 comprised 21 442 patients from other PETS 2 participating hospitals. UMC Mainz exercised targeted but liberal use of iFS analysis for suspected malignant nodules. iFS analysis was compared with standard histological examination regarding the correct distinction between benign and malignant disease. The percentage of completion thyroidectomies was assessed for the participating hospitals. RESULTS: iFS analysis was performed in 35.70 per cent of patients in group 1 versus 21.80 per cent of those in group 2 (risk ratio (RR) 1.6, 95 per cent c.i. 1.5 to 1.8; P < 0.001). Sensitivity of iFS analysis was 75.0 per cent in group 1 versus 63.50 per cent in group 2 (RR 1.2, 1.2 to 1.3; P = 0.040). Completion surgery was necessary in 8.10 per cent of patients in group 1 versus 20.8 per cent of those in group 2 (RR 0.4, 0.2 to 0.7; P = 0.001). CONCLUSION: iFS analysis is a useful tool in determining the appropriate surgical management of thyroid disease. Targeted use of iFS was associated with a significantly higher sensitivity for the detection of malignancy, and with a significantly reduced necessity for completion surgery.

Management of primary and renal hyperparathyroidism: guidelines from the German Association of Endocrine Surgeons (CAEK).

BACKGROUND AND AIMS: The purpose of this review is to provide updated recommendations for the surgical management of primary (pHPT) and renal (rHPT) hyperparathyroidism, formulating a new guideline of the German Association of Endocrine Surgeons (CAEK). METHODS: Evidence-based recommendations for the diagnosis and therapy of pHPT and rHPT were assessed by a multidisciplinary panel using PubMed for a comprehensive literature search together with a structured consensus dialogue (S2k guideline of the Association of the German Scientific Medical Societies, AWMF). RESULTS: During the last 20 years, a variety of new preoperative localization procedures, such as sestamibi-SPECT, 4D-CT, and various PET/CT procedures, were established for pHPT. High-resolution imaging, together with intraoperative parathyroid hormone (IOPTH) measurement, enabled focused or minimally invasive surgery to become the most favored surgical technique. Patients with pHPT and nonlocalizing imaging have a higher risk of multiglandular disease. Surgical therapy provides very high cure rates, with a clear relation to the surgeon's experience in parathyroid procedures. Reoperative parathyroidectomy, children with pHPT or familial forms, and parathyroid carcinoma are addressed and require special surgical expertise. A multidisciplinary team of experienced nephrologists, transplant, and endocrine surgeons should assess the diagnosis and treatment of renal HPT. CONCLUSION: Surgery is the only curative treatment for pHPT and should be considered for all patients with pHPT. For rHPT, a more selective approach is required, and parathyroidectomy is indicated only when conservative treatment options fail. In parathyroid carcinoma, the adequacy of local resection influences local disease control.

[Extent of resection in intrathyroidal medullary thyroid cancer]. / Resektionsausmaß beim intrathyreoidalen medullären Schilddrüsenkarzinom.

Improvements in preoperative diagnostic modalities in conjunction with highly sensitive calcitonin assays, ultrasound and functional imaging modalities and differentiated genetic testing for detection of hereditary forms, have enabled detection and resection of medullary thyroid carcinoma at an increasingly earlier stage. These developments open up possibilities to deescalate primary surgery adapted to these stages and avoid surgical overtreatment in locally limited tumor growth: thus, promoting a shift from routinely recommended total thyroidectomy with bilateral central lymph node dissection in favor of limited unilateral thyroid resection. Prerequisites for limited thyroid resection include clinical evidence that the tumor is sporadic, unifocal and confined to the thyroid. Corresponding calcitonin levels should also indicate that a biochemical cure will be achieved after unilateral resection. A decisive structural prerequisite for such a limited concept is the low threshold availability of intraoperative frozen section analysis that reliably detects and evaluates a medullary thyroid carcinoma and can assess a breach of the thyroid capsule and desmoplasia with certainty.

Prediction of biochemical cure in patients with medullary thyroid cancer.

BACKGROUND: The impact of number of node metastases versus metastatic lymph node ratio versus AJCC node category on biochemical cure in medullary thyroid cancer (MTC) is not well defined. METHODS: Multivariable logistic regression analysis was used to determine clinical and histopathological variables that contribute to biochemical cure in node-positive MTC. RESULTS: Some 584 of 1026 patients with MTC underwent systematic lymph node dissections for node-positive disease; 27·4 per cent (54 of 197) were biochemically cured after the initial operation and 13·5 per cent (42 of 310 patients) after repeat surgery. Cured patients had significantly less extrathyroid extension (11-14 versus 33·2-55·6 per cent), fewer lymph node metastases (median 2-4 versus 12-16), a lower metastatic lymph node ratio (median 0·05-0·08 versus 0·23-0·28), and were less likely to have AJCC pN1b disease (56-76 versus 89·9-91·6 per cent) and distant metastases (0 versus 28·4-37·1 per cent) than patients who were not cured. Biochemical cure curves advanced steadily up to 7-12 node metastases and a metastatic lymph node ratio of 0·33, eventually levelling off after 16-17 node metastases and metastatic lymph node ratios of 0·45-0·65. In logistic regression analysis, number of lymph node metastases (odds ratio (OR) 17·24 for more than 20 metastases, OR 5·28 for 11-20 metastases, OR 2·22 for 6-10 metastases), preoperative basal serum calcitonin (OR 6·24 for over 1000 pg/ml), reoperation (OR 5·34) and extrathyroid extension (OR 2·42) independently predicted failure to reach biochemical cure. CONCLUSION: Number of lymph node metastases, unlike metastatic lymph node ratio or AJCC node category, determines likelihood of biochemical cure after initial and repeat surgery for node-positive MTC.

ANTECEDENTES: El impacto del número de metástasis ganglionares versus la relación de ganglios linfáticos metastásicos (metastatic lymph node ratio, MLNR) versus el estadio ganglionar según el American Joint Committee on Cancer (AJCC) sobre la curación bioquímica en el cáncer medular de tiroides (medullary thyroid cancer, MTC) no está bien definido. MÉTODOS: Se utilizaron análisis de regresión logística multivariable y análisis estratificados de Kaplan-Meier para determinar las variables clínicas e histopatológicas que contribuyen a la curación bioquímica en el MTC con ganglios positivos. RESULTADOS: En total, 584 de 1.026 pacientes con MTC se sometieron a disecciones sistemáticas de los ganglios linfáticos en caso de enfermedad con ganglios positivos, el 27,4% (54 de 197 pacientes) de los cuales se curaron bioquímicamente después de la cirugía inicial y el 13,5% (42 de 310 pacientes) después de la reintervención quirúrgica. Los pacientes curados tuvieron una extensión extratiroidea significativamente menor (11,1-14% versus 33,2-55,6%), menos metástasis en los ganglios linfáticos (2-4 versus 12-16 metástasis), una MLNR más baja (0,05-0,08 versus 0,23-0,28), una menor frecuencia de estadio ganglionar AJCC pN1b (55,6-76 versus 89,9-91,6%) y no tenían metástasis a distancia (0% versus 28,4-37,1%), Las curvas de tiempo hasta la curación bioquímica avanzaron de manera constante hasta las metástasis de 7 a 12 ganglios y una MLNR de 0,33, y finalmente se nivelaron después de las metástasis de 16 a 17 ganglios y una MLNR de 0,45 a 0,65. En la regresión logística, el número de metástasis en los ganglios linfáticos (razón de oportunidades, odds ratio, OR 17,2 para > 20 metástasis, OR 5,3 para 11-20 metástasis y OR 2,2 para 6-10 metástasis), la calcitonina sérica basal preoperatoria (OR 6,2 para> 1000 pg/mL), la reoperación (OR 5,4) y la extensión extratiroidea (OR 2,4) predijeron de forma independiente el fracaso para alcanzar la curación bioquímica, CONCLUSIÓN: El número de metástasis en los ganglios linfáticos, a diferencia de la MLNR y del estadio ganglionar AJCC, determina la probabilidad de curación bioquímica después de la cirugía inicial y la reintervención para el MTC con ganglios positivos.

[Intraoperative measurement of parathyroid hormone in hyperparathyroidism]. / Intraoperative Parathormonmessung bei Hyperparathyreoidismus.

Intraoperative parathyroid hormone (IOPTH) determination is based on the short half-life of parathyroid hormone (PTH) and the rapid analytical technology. The IOPTH provides functional information regarding correction of the overproductive state in hyperparathyroidism (HPT) and is superior to macroscopic evaluation of the parathyroid gland (PG) as well as any (intraoperative frozen section) form of histology (so-called biochemical frozen section). In this article the relevance and evaluation of IOPTH is defined for the most important forms of HPT, for primary HPT, renal secondary and tertiary HPT, multiple endocrine neoplasia type 1 (MEN1) and parathyroid carcinoma and clinical scenarios based on the currently available data. It becomes apparent that the additional benefits of IOPTH depend on diverse prerequisites of the specific type of HPT, the diagnostics as well as individual patient factors and strategic considerations for resection. Overall, the costs for IOPTH are comparably low and seem to be justified with respect to the gain in quality. In the hands of specialized endocrine surgeons IOPTH is an essential tool for intraoperative decision-making and quality assurance.

Implementing routine communication about costs of cancer treatment: perspectives of providers, patients, and caregivers.

OBJECTIVES: Rising costs in oncology care often impact patients and families directly, making communication about costs and financial impacts of treatment crucial. Cost expenditures could offer opportunities for estimation and prediction, affording personalized conversations about financial impact. We sought to explore providers', patients', and caregivers' preferences towards implementing communication about cost, including when, how, and by whom such information might be provided. METHODS: We conducted semi-structured phone interviews with a diverse population including 12 oncology providers, 12 patients, and 8 patient caregivers (N = 32). The constant comparative method was used to identify mutually agreed upon themes. RESULTS: Participant groups differed in their concerns surrounding cost communication, namely whether they want to receive this information and how such information might impact provider and patient treatment decisions. All participants agreed that oncology providers should not be leading cost conversations. Patients and caregivers identified social workers or financial advisors as most equipped to communicate about cost. Participants emphasized timely cost conversations, ideally around the time of diagnosis. Participants favored various metrics of financial impact beyond overall costs of care including disability, days lost from work, and out-of-pocket expenses. CONCLUSION: Cost transparency should be incorporated into usual care; however, there are several challenges to making cost conversations a part of everyday practice. Patients and family members need resources related to cost to aid in decision-making and those delivering cost information should have competency in oncology, financial advisement, and patient-centered care.

Angiotensin converting enzymes ACE and ACE2 in thyroid cancer progression.

Angiotensin-converting enzymes, ACE and ACE2, play not only a pivotal role in the regulation of blood pressure, but are involved in the processes of pathophysiology, including thyroid dysfunction or progression of several neoplasia such as cancers of skin, lungs, pancreas and leukemia. However, their role in the thyroid carcinogenesis remains unknown. We examined in this study the expression of ACE and ACE2 in thyroid tissues and their possible employment as biomarkers for thyroid cancer progression. Thyroid tissues, including 14 goiters (G), 12 follicular adenomas (FA), 10 follicular thyroid carcinomas (FTC), 14 papillary thyroid carcinomas (PTC) and 11 undifferentiated thyroid carcinomas (UTC), were subjected to RT-PCR and protein analyses with primers or antibodies specific for ACE and ACE2, respectively. FA revealed significantly increased ACE compared to other groups and FTC was significantly higher than UTC. ACE2 was significantly increased in PTC in comparison to G, FA and UTC, and in FTC as compared to G. The ratio ACE/ACE2 decreased, while ACE2/ACE increased with the differentiation grade of thyroid carcinoma. ACE was significantly diminished in individuals older than 50. Both ACEs were significantly diminished in M1 patients, ACE2 additionally in higher tumor masses. ACE and ACE2 are regulated within thyroid benign and malignant tissues. As the transcript ratio between both enzymes correlate proportional with the differentiation status of thyroid cancer, ACE and ACE2 may serve as new markers for thyroid carcinoma.

[Disfiguring neurinoma of the nose tip and the columella-rhinosurgical aspects]. / Dysfigurierendes Neurinom der Nasenspitze und der Columella ­ rhinochirurgische Aspekte.

Neurinomas in the nose and the nasal sinuses are rare. In the present work, we present an exceedingly rare case of a disfiguring neurinoma involving the nasal columella. Treatment of choice is complete resection of the tumor. For an optimal view for tumor resection and esthetic and functional reconstruction, we recommend an open surgical approach.

Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure.

Heart failure (HF) is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. Indeed, survival rates for HF are worse than many common cancers and have not improved over time. Tadalafil is a clinically relevant drug that blocks phosphodiesterase 5 with high specificity and is used to treat erectile dysfunction. Using a sheep model of advanced HF, we show that tadalafil treatment improves contractile function, reverses transverse tubule loss, restores calcium transient amplitude and the heart's response to catecholamines. Accompanying these effects, tadalafil treatment normalized BNP mRNA and prevented development of subjective signs of HF. These effects were independent of changes in myocardial cGMP content and were associated with upregulation of both monomeric and dimerized forms of protein kinase G and of the cGMP hydrolyzing phosphodiesterases 2 and 3. We propose that the molecular switch for the loss of transverse tubules in HF and their restoration following tadalafil treatment involves the BAR domain protein Amphiphysin II (BIN1) and the restoration of catecholamine sensitivity is through reductions in G-protein receptor kinase 2, protein phosphatase 1 and protein phosphatase 2 A abundance following phosphodiesterase 5 inhibition.

Surgical therapy of adrenal tumors: guidelines from the German Association of Endocrine Surgeons (CAEK).

BACKGROUND AND AIMS: Previous guidelines addressing surgery of adrenal tumors required actualization in adaption of developments in the area. The present guideline aims to provide practical and qualified recommendations on an evidence-based level reviewing the prevalent literature for the surgical therapy of adrenal tumors referring to patients of all age groups in operative medicine who require adrenal surgery. It primarily addresses general and visceral surgeons but offers information for all medical doctors related to conservative, ambulatory or inpatient care, rehabilitation, and general practice as well as pediatrics. It extends to interested patients to improve the knowledge and participation in the decision-making process regarding indications and methods of management of adrenal tumors. Furthermore, it provides effective medical options for the surgical treatment of adrenal lesions and balances positive and negative effects. Specific clinical questions addressed refer to indication, diagnostic procedures, effective therapeutic alternatives to surgery, type and extent of surgery, and postoperative management and follow-up regime. METHODS: A PubMed research using specific key words identified literature to be considered and was evaluated for evidence previous to a formal Delphi decision process that finalized consented recommendations in a multidisciplinary setting. RESULTS: Overall, 12 general and 52 specific recommendations regarding surgery for adrenal tumors were generated and complementary comments provided. CONCLUSION: Effective and balanced medical options for the surgical treatment of adrenal tumors are provided on evidence-base. Specific clinical questions regarding indication, diagnostic procedures, alternatives to and type as well as extent of surgery for adrenal tumors including postoperative management are addressed.

Time to calcitonin normalization after surgery for node-negative and node-positive medullary thyroid cancer.

BACKGROUND: It remains unclear when postoperative serum calcitonin levels should be measured in patients with medullary thyroid cancer (MTC) and, specifically, whether this decision should be based on the preoperative calcitonin level or nodal status. METHODS: A cohort of patients with previously untreated MTC was studied. Kaplan-Meier analyses, stratified by preoperative calcitonin level, nodal status and number of nodal metastases, were performed to determine time to calcitonin normalization after initial surgery, with statistical analysis by means of the log rank test. RESULTS: Some 213 patients with node-negative and 182 with node-positive MTC were included in the study. Postoperative calcitonin levels normalized in a mean of 3·5 versus 3·7 days respectively among patients with preoperative calcitonin levels of 10-100 pg/ml (P = 0·815); 4·8 versus 5·3 days in those with preoperative calcitonin levels of 100·1-500 pg/ml (P = 0·026); 5·3 versus 9·9 days in patients with preoperative calcitonin levels of 500·1-1000 pg/ml (P = 0·004); and 6·6 versus 57·7 days among those with preoperative calcitonin levels exceeding 1000 pg/ml (P < 0·001). Calcitonin levels normalized in a mean of 4·7 days when nodal metastasis was not present, 5·2 days in those with one to five nodal metastases, 7·0 days in patients with six to ten nodal metastases, and 57·1 days among patients with more than ten nodal metastases. Postoperative calcitonin normalization curves paralleled each other in patients with node-negative MTC, but diverged in those with node-positive disease and with more nodal metastases. CONCLUSION: Calcitonin levels typically normalize within 1 week; and within a fortnight in those with node-positive MTC and preoperative calcitonin levels of 500·1-1000 pg/ml. With node-positive MTC and preoperative calcitonin levels exceeding 1000 pg/ml, and with more than ten nodal metastases, calcitonin normalization takes longer.

[Work sampling in ophthalmological clinical studies. A multicenter field study]. / Zeiterfassung in ophthalmologischen klinischen Studien. Eine multizentrische Feldstudie.

BACKGROUND: Work in clinical studies is generally more elaborate and therefore more time-consuming in comparison to the clinical routine. The purpose of this study was to systematically investigate the time consumption in the German ophthalmological clinical trial centers. METHODS: The members of the working group of the German Ophthalmology Society clinical study centers (Arbeitsgemeinschaft DOG Klinische Studienzentren) were asked to fill in three questionnaires about best estimations for the time spent on study-related procedures and administration. Additionally, work sampling was performed for each employee at each study center over a period of 3 weeks. RESULTS: The questionnaires were completed by 9 of the 11 centers. Overall, 5504 working hours were recorded. On an average working day, the time spent for both documentation and administration averaged 4 h each. Operative interventions consumed a significant amount of time (2.8 h), as did ophthalmological examinations (2.5 h) and obtaining informed consent (1.5 h). The recorded time consumption for visual acuity testing, informed consent and documentation was well aligned with the best estimates of the three questionnaires. By contrast, interventions, ophthalmological examinations and biomaterial sample handling were underrated in the best estimations. DISCUSSION: A considerable amount of time in clinical studies is spent on documentation and administration. From work sampling, ophthalmological examinations and biomaterial sampling turned out to be surprisingly time consuming. This is probably due to preparation and postprocessing tasks. It is important to consider this when calculating the overall costs of a clinical study. In addition, many administrative activities cannot be attributed to specific patients and can therefore not be compensated on the basis of case payments alone. Additional remuneration is required to fully cover the costs in an ophthalmological study center.

[Surgical treatment options for cervical paragangliomas]. / Chirurgische Therapieoptionen bei zervikalen Paragangliomen.

The therapies available for the rare tumor entity of cervical paraganglioma (PG) are currently undergoing a paradigm shift. The treatment of choice for small carotid body tumors, malignant and active endocrine tumors is surgical resection; however, for locally advanced carotid body tumors and vagal PG, surgical therapy should be critically evaluated. Due to the immediate proximity of these hypervascularized tumors to the caudal cranial nerves, there is a risk of severe nerve damage with a significant impairment of quality of life after resection, particularly for locally advanced cervical PG, emphasizing further the importance of a restrictive surgical strategy. External radiotherapy can provide an equivalent primary therapeutic option with respect to the rate of recurrence and is accompanied by a lower morbidity. The slow rate of tumor progression and the multifocality of the familial variant of cervical PG or significant comorbidities in older, asymptomatic patients warrant a less aggressive treatment strategy for these tumors. When a wait and scan approach is implemented, a closely monitored radiological and clinical re-evaluation is of upmost importance. In a multidisciplinary approach the following critical points require consideration before a therapy is implemented,: size and location of the tumor, progression rate, genetic background, patient age and general condition, relevant comorbidities, the presence of synchronous PG and/or vasoactive catecholamine-producing tumors. Although best practice algorithms for the treatment of cervical PG have already been devised, recent innovative developments have led to more patient-tailored, individualized treatment approaches.