CPMS-improving patient care in Europe via virtual case discussions

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

Proteoglycan-4 Regulates Fibroblast to Myofibroblast Transition and Expression of Fibrotic Genes in the Synovium

Background: Synovial tissue fibrosis is common in advanced OA with features including the presence of stress fiber-positive myofibroblasts and deposition of cross-linked collagen type-I. Proteoglycan-4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and is a major component of synovial fluid. PRG4 is a ligand of the CD44 receptor. Our objective was to examine the role of PRG4-CD44 interaction in regulating synovial tissue fibrosis in vitro and in vivo. Methods: OA synoviocytes were treated with TGF-β ± PRG4 for 24h and α-SMA content was determined using immunofluorescence. Rhodamine-labeled rhPRG4 was incubated with OA synoviocytes ± anti-CD44 or isotype control antibodies and cellular uptake of rhPRG4 was determined following a 30-min incubation and α-SMA expression following a 24-h incubation. HEK-TGF-β cells were treated with TGF-β ± rhPRG4 and Smad3 phosphorylation was determined using immunofluorescence and TGF-β/Smad pathway activation was determined colorimetrically. We probed for stress fibers and focal adhesions (FAs) in TGF-β-treated murine fibroblasts and fibroblast migration was quantified ± rhPRG4. Synovial expression of fibrotic markers: α-SMA, collagen type-I, and PLOD2 in Prg4 gene-trap (Prg4GT) and recombined Prg4GTR animals were studied at 2 and 9 months of age. Synovial expression of α-SMA and PLOD2 was determined in 2-month-old Prg4GT/GT&Cd44−/− and Prg4GTR/GTR&Cd44−/− animals. Results: PRG4 reduced α-SMA content in OA synoviocytes (p \u3c 0.001). rhPRG4 was internalized by OA synoviocytes via CD44 and CD44 neutralization attenuated rhPRG4’s antifibrotic effect (p \u3c 0.05). rhPRG4 reduced pSmad3 signal in HEKTGF- β cells (p \u3c 0.001) and TGF-β/Smad pathway activation (p \u3c 0.001). rhPRG4 reduced the number of stress fiberpositive myofibroblasts, FAs mean size, and cell migration in TGF-β-treated NIH3T3 fibroblasts (p \u3c 0.05). rhPRG4 inhibited fibroblast migration in a macrophage and fibroblast co-culture model without altering active or total TGF-β levels. Synovial tissues of 9-month-old Prg4GT/GT animals had higher α-SMA, collagen type-I, and PLOD2 (p \u3c 0.001) content and Prg4 re-expression reduced these markers (p \u3c 0.01). Prg4 re-expression also reduced α-SMA and PLOD2 staining in CD44-deficient mice. Conclusion: PRG4 is an endogenous antifibrotic modulator in the joint and its effect on myofibroblast formation is partially mediated by CD44, but CD44 is not required to demonstrate an antifibrotic effect in vivo

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

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

Ultrasound-guided placement of central venous catheters: A comprehensive guide for the clinician

Background: Using ultrasound as a guidance tool during central venous catheter placement has repeatedly been shown to improve procedural safety. More recent evidence has shown its potential as a diagnostic modality to detect placement-associated complications. A protocol combining these modalities is lacking. This article uses the Indication, Acquisition, Interpretation and Medical decision-making (I-AIM) model, common to other ultrasound protocols, to provide a systematic ultrasound approach to guide central venous catheter placement and assess potential related complications. It is part of a larger series published in this journal. Methods: Relevant articles were found in a thorough search in PubMed using the MeSH terms: “diagnostic imaging” or “ultrasonography” or “sonography” and “central venous catheter” or “central venous cannulation” and “complications” or “placement procedure”. Studies conducted on patients younger than 18 years and studies conducted in animals were excluded. Two independent researchers evaluated the articles for relevance and quality. The results of the various studies were used to create the following structured ultrasound approach. Recommended approach: Following the I-AIM model, acquiring the most valuable images is subdivided into patient, probe, picture and protocol considerations. Ultrasound guidance during central venous catheter placement should be conducted in four steps: pre-cannulation, confirming patency, dynamic guidance during insertion, and confirmation of intravenous central venous catheter position. After these steps, ultrasound should be used in the diagnostic evaluation of malposition and iatrogenic pneumothorax. Conclusions: This model provides a comprehensive and ready to use ultrasound approach to guide central venous catheter placement and assess potential placement associated complications

Pheochromocytomas detected by biochemical screening in predisposed subjects are associated with lower prevalence of clinical and biochemical manifestations and smaller tumors than pheochromocytomas detected by signs and symptoms

Context: Sporadic pheochromocytomas are detected by clinical signs and symptoms, whereas pheochromocytomas in patients with a known hereditary predisposition for these tumors are detected by repetitive screening for catecholamine excess. Objective: To document the clinical, biochemical, and pathological differences between patients with sporadic pheochromocytomas, detected by signs and symptoms and patients with pheochromocytomas, detected by biochemical screening in established hereditary syndromes. Design: Retrospective follow-up study. Patients and methods: We included 60 consecutive patients diagnosed with pheochromocytoma (pheochromocytomas detected by signs and symptoms: n=28 and pheochromocytomas detected by screening: n=32) in our center. Results: Patients with pheochromocytomas detected by screening presented with less complaints of diaphoresis (P<0.01), palpitations (P=0.01), paleness (P=0.01), nausea (P<0.01), and vomiting (P=0.01) compared with patients with symptomatic pheochromocytomas. Patients with pheochromocytomas detected by screening tended to be younger at the time of diagnosis (41+/-2 vs 47+/-3 years, P=0.07). In addition, patients with pheochromocytomas detected by screening had significantly lower rates of 24-h urinary catecholamine excretion, and considerably smaller tumors (3.7+/-0.5 vs 7.3+/-0.7 cm, P<0.01). Conclusions: Pheochromocytomas detected by screening of patients with a hereditary predisposition have a much lower prevalence of signs and symptoms, lower catecholamine excess, and smaller tumors, compared with sporadic pheochromocytomas, detected by signs and symptoms. These data support the benefits of screening for pheochromocytomas in patients with hereditary syndromes predisposing for these tumors.Hereditary cancer genetic

Pheochromocytomas detected by biochemical screening in predisposed subjects are associated with lower prevalence of clinical and biochemical manifestations and smaller tumors than pheochromocytomas detected by signs and symptoms

Context: Sporadic pheochromocytomas are detected by clinical signs and symptoms, whereas pheochromocytomas in patients with a known hereditary predisposition for these tumors are detected by repetitive screening for catecholamine excess. Objective: To document the clinical, biochemical, and pathological differences between patients with sporadic pheochromocytomas, detected by signs and symptoms and patients with pheochromocytomas, detected by biochemical screening in established hereditary syndromes. Design: Retrospective follow-up study. Patients and methods: We included 60 consecutive patients diagnosed with pheochromocytoma (pheochromocytomas detected by signs and symptoms: n=28 and pheochromocytomas detected by screening: n=32) in our center. Results: Patients with pheochromocytomas detected by screening presented with less complaints of diaphoresis (P<0.01), palpitations (P=0.01), paleness (P=0.01), nausea (P<0.01), and vomiting (P=0.01) compared with patients with symptomatic pheochromocytomas. Patients with pheochromocytomas detected by screening tended to be younger at the time of diagnosis (41+/-2 vs 47+/-3 years, P=0.07). In addition, patients with pheochromocytomas detected by screening had significantly lower rates of 24-h urinary catecholamine excretion, and considerably smaller tumors (3.7+/-0.5 vs 7.3+/-0.7 cm, P<0.01). Conclusions: Pheochromocytomas detected by screening of patients with a hereditary predisposition have a much lower prevalence of signs and symptoms, lower catecholamine excess, and smaller tumors, compared with sporadic pheochromocytomas, detected by signs and symptoms. These data support the benefits of screening for pheochromocytomas in patients with hereditary syndromes predisposing for these tumors.Otorhinolaryngolog

Increased Urinary Excretion of 3-Methoxytyramine in Patients with Head and Neck Paragangliomas

Context: Patients with head-and-neck paragangliomas (HNPGL) are regularly screened for catecholamine excess. The clinical relevance of increased urinary secretion of 3-methoxytyramine is unclear in HNPGL. Objective: The aim of the study was to assess the prevalence and the clinical, biochemical, and radiological presentation of patients with HNPGL with increased urinary excretion of 3-methoxytyramine. Patients and Methods: A total of 136 consecutive patients with HNPGL were included and screened for catecholamine excess by measurement of 24-h urinary excretion of (nor) metanephrine, (nor) epinephrine, vanillylic mandelic acid, dopamine, and 3-methoxytyramine. In patients with catecholamine excess, abdominal/intrathoracic paragangliomas were excluded by I-123-metaiodobenzyl-guanidine scintigraphy, magnetic resonance imaging, and/or computed tomography. Results: Urinary 3-methoxytyramine excretion was increased in 31 of the 136 patients (23%). In 18 of these 31 patients, this was the only sign of biochemical activity of HNPGL. Dopamine excretion was higher in subjects with increased 3-methoxytyramine excretion (1.62 +/- 0.1 mu mol/24 h vs. 2.5 +/- 0.3 mu mol/24 h; P < 0.01). Of the 136 HNPGL patients, 21 (15%) had excessive excretion of at least one catecholamine and/or their metabolites when 3-methoxytyramine excretion was not taken into account. With the inclusion of patients with excessive 3-methoxytyramine excretion, 39 (29%) had excessive catecholamine excretion. Patients with 3-methoxytyramine excess had significantly more complaints of palpitations (P < 0.01), diaphoresis (P = 0.03), collapse (P < 0.05), and a higher pulse rate (P < 0.01). Increased excretion of 3-methoxytyramine was not associated with particular types of HNPGL or genotypes. Conclusions: A substantial number of HNPGL patients have biochemically active tumors, reflected in increased excretion of 3-methoxytyramine, associated with increased dopamine excretion. Some patients only display increased excretion of 3-methoxytyramine, but not of other catecholamines or their metabolites. (J Clin Endocrinol Metab 95: 209-214, 2010)Otorhinolaryngolog

THERAPY OF ENDOCRINE DISEASE: Response and toxicity of small-molecule tyrosine kinase inhibitors in patients with thyroid carcinoma: a systematic review and meta-analysis

Context: Many tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC (DTC) and medullary TC (MTC) patients have not been directly compared. The aim of the present systematic review and meta-analysis was to systematically summarize response and toxicity of TKIs in TC patients. Methods: All major databases were systematically searched for publications on TKIs in TC. Primary endpoint was objective response; secondary endpoints were clinical benefit, percentage TKI dose reduction/discontinuation, hand-foot syndrome, diarrhea, and nausea/vomiting. Meta-analysis was performed using an exact likelihood approach and a logistic regression. Pooled percentages and 95% CIs were reported. Results: In total, 22 publications were included. For DTC patients, gefitinib induced no objective responses. Pooled percentage was highest for pazopanib, 49 (95% CI 33-64)%, and was 17 (95% CI 12-24)% for sorafenib. For MTC, gefitinib and imatinib induced no objective responses, whereas sunitinib induced objective response in 43 (95% CI 14-77)%. For vandetanib and cabozantinib, these numbers were 40 (95% CI 34-46)% and 27 (95% CI 22-32)% respectively. Clinical benefit was found in 53 (95% CI 48-59)% of DTC patients on sorafenib, and in 84 (95% CI 79-88)% and 55 (95% CI 49-61)% of MTC patients on vandetanib and cabozantinib respectively. All TKIs were associated with considerable toxicity. Conclusion: The currently studied TKIs show a modest response, while side effects are not negligible. Therefore, we suggest to solely consider TKIs in TC patients with rapid progressive disease, for whom the benefits of treatment outweigh toxicity