Recurrent fever leading to the diagnosis of an angiosarcoma of the adrenal gland: a case report.

BACKGROUND: Angiosarcoma of the adrenal gland is a very rare malignant vascular neoplasm. The clinical symptoms are atypical or completely absent. Angiosarcomas of the adrenal gland are therefore often discovered incidentally, and the diagnosis is made histologically after resection. CASE PRESENTATION: A 46-year-old white Spanish male who was a previous smoker and nondrinker and was slightly overweight (92 kg, 176 cm, body mass index 29.7 kg/m2) with no relevant medical history presented to the internal medicine emergency department of our hospital with an unclear 12 cm tumor of the right adrenal gland. Prior to the computed tomography scan, he had had persistent evening fevers for 4 months and unintentional weight loss of 5 kg. The laboratory results showed anemia and an elevated C-reactive protein, but no hormone production. We performed an open adrenalectomy of the right adrenal gland. Finally, the histologic findings revealed an angiosarcoma of the adrenal gland. CONCLUSION: Even though angiosarcomas of the adrenal gland are rare, the differential diagnosis of an angiosarcoma should be considered if a malignant tumor of the adrenal gland is suspected. Treatment decisions should be made on an interdisciplinary basis and preferably in a specialized center. Owing to the rarity of angiosarcomas of the adrenal gland, it is necessary to continue to share clinical experience to gain a better understanding of this particular tumor entity.

Continuous Intraoperative Nerve Monitoring of a Non-Recurrent Laryngeal Nerve: Real-Life Data of a High-Volume Thyroid Surgery Center.

Thyroid surgery is associated with a risk of injury to the recurrent laryngeal nerve, especially in the presence of anatomical variants such as a non-recurrent laryngeal nerve (NRLN). Injury to the nerve leads to transient or permanent vocal cord palsy (VCP). A novel method to prevent VCP is continuous intraoperative nerve monitoring (cIONM), but less is known about the applicability of this method in patients with NRLN. The aim of this study was to evaluate our own data regarding feasibility and detailed characteristics of cIONM in NRLN patients. We performed a monocentric retrospective cohort analysis including clinical data and intraoperative nerve monitoring data (measured by Inomed Medizintechnik GmbH, Emmendingen, 'C2' and 'C2 Xplore' device) of all thyroid surgery patients, showing NRLN between 2014 and 2022. Of 1406 patients who underwent thyroid surgery with cIONM between 2014 and 2022, 12 patients (0.9%) showed NRLN intraoperatively. Notably, cIONM was feasible in eight patients (67%). In all cases the onset latency of the right vagus nerve was shorter (<3.0 ms) than usually expected, suggesting that a short latency might be suitable to distinguish NRLN. None of the patients had a post-operative VCP. Overall, cIONM appears to be feasible and safe in NRLN patients and provides helpful information to prevent VCP.

Evaluation of intraoperative neuromonitoring (IONM) data with the Mainz IONM Quality Assurance and Analysis tool.

BACKGROUND: Intraoperative neuromonitoring is widely used in thyroid and parathyroid surgery to prevent unilateral and especially bilateral recurrent nerve paresis. Reference values for amplitude and latency for the recurrent laryngeal nerve and vagus nerve have been published. However, data quality measures that exclude errors of the underlying intraoperative neuromonitoring (IONM) data (immanent software errors, false data labelling) before statistical analysis have not yet been implemented. METHODS: The authors developed an easy-to-use application (the Mainz IONM Quality Assurance and Analysis tool) using the programming language R. This tool allows visualization, automated and manual correction, and statistical analysis of complete raw data sets (electromyogram signals of all stimulations) from intermittent and continuous neuromonitoring in thyroid and parathyroid surgery. The Mainz IONM Quality Assurance and Analysis tool was used to evaluate IONM data generated and exported from 'C2' and 'C2 Xplore' neuromonitoring devices (inomed Medizintechnik GmbH) after surgery. For the first time, reference values for latency and amplitude were calculated based on 'cleaned' IONM data. RESULTS: Intraoperative neuromonitoring data files of 1935 patients consecutively operated on from June 2014 to May 2020 were included. Of 1921 readable files, 34 were excluded for missing data labelling. Automated plausibility checks revealed: less than 3 per cent device errors for electromyogram signal detection; 1138 files (approximately 60 per cent) contained potential labelling errors or inconsistencies necessitating manual review; and 915 files (48.5 per cent) were indeed erroneous. Mean(s.d.) reference onset latencies for the left vagus nerve, right vagus nerve, recurrent laryngeal nerve, and external branch of the superior laryngeal nerve were 6.8(1.1), 4.2(0.8), 2.5(1.1), and 2.1(0.5) ms, respectively. CONCLUSION: Due to high error frequencies, IONM data should undergo in-depth review and multi-step cleaning processes before analysis to standardize scientific reporting. Device software calculates latencies differently; therefore reference values are device-specific (latency) and/or set-up-specific (amplitude). Novel C2-specific reference values for latency and amplitude deviate considerably from published values.

Approach to risk stratification for papillary thyroid carcinoma based on molecular profiling: institutional analysis.

BACKGROUND: Currently, treatment recommendations for papillary thyroid carcinoma are not based on the genetic background causing tumourigenesis. The aim of the present study was to correlate the mutational profile of papillary thyroid carcinoma with clinical parameters of tumour aggressiveness, to establish recommendations for risk-stratified surgical treatment. METHOD: Papillary thyroid carcinoma tumour tissue of patients undergoing thyroid surgery at the University Medical Centre Mainz underwent analysis of BRAF, TERT promoter and RAS mutational status as well as potential RET and NTRK rearrangements. Mutation status was correlated with clinical course of disease. RESULTS: One hundred and seventy-one patients operated for papillary thyroid carcinoma were included. The median age was 48 years (range 8-85) and 69 per cent (118/171) of patients were females. One hundred and nine papillary thyroid carcinomas were BRAF-V600E mutant, 16 TERT promotor mutant and 12 RAS mutant; 12 papillary thyroid carcinomas harboured RET rearrangements and two papillary thyroid carcinomas showed NTRK rearrangements. TERT promoter mutant papillary thyroid carcinomas had a higher risk of distant metastasis (OR 51.3, 7.0 to 1048.2, P < 0.001) and radioiodine-refractory disease (OR 37.8, 9.9 to 169.5, P < 0.001). Concomitant BRAF and TERT promoter mutations increased the risk of radioiodine-refractory disease in papillary thyroid carcinoma (OR 21.7, 5.6 to 88.9, P < 0.001). RET rearrangements were associated with a higher count of tumour-affected lymph nodes (OR 7950.9, 233.7 to 270495.7, P < 0.001) but did not influence distant metastasis or radioiodine-refractory disease. CONCLUSIONS: Papillary thyroid carcinoma with concomitant BRAF-V600E and TERT promoter mutations demonstrated an aggressive course of disease, suggesting the need for a more extensive surgical strategy. RET rearrangement-positive papillary thyroid carcinoma did not affect the clinical outcome, potentially obviating the need for prophylactic lymphadenectomy.

[Current indications and operative strategy for renal hyperparathyroidism]. / Aktuelle Indikation und operative Strategie beim renalen Hyperparathyreoidismus.

BACKGROUND: Renal hyperparathyroidism results from pathophysiologic changes induced and maintained by terminal renal failure. Surgical treatment is possible using various resection strategies. AIM OF THE WORK (RESEARCH QUESTION): The aim of this work is to illustrate the indications, techniques and resection strategies for surgical treatment of renal hyperparathyroidism. MATERIAL AND METHODS: National and international guidelines regarding the surgical treatment of renal hyperparathyroidism were analyzed. Furthermore, our own practical experience was integrated into the article. RESULTS: While the indications for surgery according to the Surgical Working Group Endocrinology (CAEK) guidelines are given in cases of clinical impairment and renal hyperparathyroidism that cannot be controlled by medication, international guidelines additionally refer to the absolute parathyroid hormone level for deciding for surgery. DISCUSSION: Individual patient consultation is necessary in the case of renal hyperparathyroidism in order to determine the right time for surgical treatment as well as the most suitable surgical technique, taking into account the individual risk profile and other therapeutic perspectives, including renal transplantation.

Controversy Over Liver Transplantation or Resection for Neuroendocrine Liver Metastasis: Tumor Biology Cuts the Deal.

BACKGROUND: In patients with neuroendocrine liver metastasis (NELM), liver transplantation (LT) is an alternative to liver resection (LR), although the choice of therapy remains controversial. In this multicenter study, we aim to provide novel insight in this dispute. METHODS: Following a systematic literature search, 15 large international centers were contacted to provide comprehensive data on their patients after LR or LT for NELM. Survival analyses were performed with the Kaplan-Meier method, while multivariable Cox regression served to identify factors influencing survival after either transplantation or resection. Inverse probability weighting and propensity score matching was used for analyses with balanced and equalized baseline characteristics. RESULTS: Overall, 455 patients were analyzed, including 230 after LR and 225 after LT, with a median follow-up of 97 months [95% confidence interval (CI): 85-110 months]. Multivariable analysis revealed G3 grading as a negative prognostic factor for LR [hazard ratio (HR)=2.22, 95% CI: 1.04-4.77, P =0.040], while G2 grading (HR=2.52, 95% CI: 1.15-5.52, P =0.021) and LT outside Milan criteria (HR=2.40, 95% CI: 1.16-4.92, P =0.018) were negative prognostic factors in transplanted patients. Inverse probability-weighted multivariate analyses revealed a distinct survival benefit after LT. Matched patients presented a median overall survival (OS) of 197 months (95% CI: 143-not reached) and a 73% 5-year OS after LT, and 119 months (95% CI: 74-133 months) and a 52.8% 5-year OS after LR (HR=0.59, 95% CI: 0.3-0.9, P =0.022). However, the survival benefit after LT was lost if patients were transplanted outside Milan criteria. CONCLUSIONS: This multicentric study in patients with NELM demonstrates a survival benefit of LT over LR. This benefit depends on adherence to selection criteria, in particular low-grade tumor biology and Milan criteria, and must be balanced against potential risks of LT.

A 16-Year Single-Center Series of Trachea Resections for Locally Advanced Thyroid Carcinoma.

(1) Background: Infiltration of the aerodigestive tract in advanced thyroid carcinoma determines the prognosis and quality of life. Different stages of tracheal tumor invasion require customization of the surgical concept. (2) Methods: In the period from January 2007 to January 2023, patients who underwent surgery for advanced thyroid carcinomas with trachea resections were included in a retrospective observational study. The surgical resection concepts and operation-associated complications were documented. The overall survival and post-resection survival were analyzed. (3) Results: From 2007 to 2023, at the single-center UMC Mainz, 33 patients (15 female and 18 male) underwent neck surgery with trachea resections for locally advanced thyroid carcinomas. Of these, 14 were treated with non-transmural (trachea shaving) and 19 transmural trachea resections (9 "window" resections, 6 near-circular resections, 3 sleeve resections and 1 total laryngectomy with extramucosal esophageal resection). The two-year postoperative survival rate was 82.0 percent. The two-year recurrence-free survival rate was 75.0 percent (mean follow-up period: 29.2 months). (4) Conclusions: Tracheal resections for locally advanced tumor infiltration are feasible as an element of highly individualized treatment concepts.

Real-world EUROCRINE® registry data challenge the reliability of Bethesda cytopathology for thyroid surgery indication.

Objectives: Fine-needle aspiration cytology (FNAC) is recommended by international guidelines for the preoperative evaluation of suspicious thyroid nodules >1 cm. Despite robust evidence from endocrine centers demonstrating the key role of FNAC results for the indication of surgery, the method is not routinely used in European clinics. The database EUROCRINE®, which was introduced in 2015 with the scope of registering operations of the endocrine system, allows for a large-scale analysis of the current service reality in Europe concerning FNAC use and associated accuracy. Methods: Operations performed to "exclude malignancy", registered from January 2015 to December 2018 in EUROCRINE®, were analyzed. Parameters of accuracy were calculated for FNAC. FNAC results were considered "test positive" in the case of Bethesda category IV, V, and VI, since these categories usually prompt surgical interventions in European centers for thyroid surgery. Bethesda category II and III were considered "test negative". Results: Of 8,791 operations, 5,780 had preoperative FNAC (65.7%). The overall malignancy rate was 28.3% (2,488/8,791). Malignancy rates were 68.8% for Bethesda VI, 69.9% for Bethesda V, 32.6% for Bethesda IV, 28.2% for III, 20.2% for Bethesda II, and 24.5% for Bethesda I. After exclusion of papillary microcarcinomas (PTMCs), the sensitivity of FNAC was 71.7% and specificity 43.5%, the positive predictive value was 29.1% and the negative predictive value 82.7%. Conclusions: Although the indication to "exclude malignancy" was the predominant reason that prompted thyroid resection in the present cohort, FNAC was only used in about 65.7% of cases. When performed, FNAC was associated with unexpectedly low accuracy. Interestingly, in Bethesda II, 20.2% of malignant entities were present (13.3% after the exclusion of PTMCs).

Multiomic analysis of papillary thyroid cancers identifies BAIAP2L1-BRAF fusion and requirement of TRIM25, PDE5A and PKCδ for tumorigenesis.

BACKGROUND: Papillary thyroid carcinoma (PTC) is one of the most common forms of thyroid cancer with a cure rate of over 90% after surgery. However, aggressive forms may still occur, and personalized therapeutic strategies are increasingly required. METHODS: We performed integrated genomic and proteomic analysis of PTC tumor samples from patients who did not harbor BRAF or RAS mutations. We validate the analysis and present in-depth molecular analysis of the identified genetic rearrangement by employing biochemical and cell biological assays. Finally, we employ 3D spheroid models, loss of function studies and chemical inhibitors to target the hitherto upregulated factors. The data are analysed with appropriate statistical tests which are mentioned in the legends section. RESULTS: In a 23-year-old patient with thyroiditis, we identified a novel rearrangement leading to a BAIAP2L1-BRAF fusion that transforms immortalized human thyroid cells in a kinase and CC-domain dependent manner. Moreover, quantitative proteomic analysis of the same patient samples revealed the upregulation of several proteins including the Ubiquitin E3 ligase TRIM25, PDE5A, and PKCδ. Further, in a cohort of PTC patients, we observed higher expression of TRIM25 and PKCδ in the tumor and metastatic lesions, when compared to the matched normal tissue. Inhibition of TRIM25, PDE5A and PKCδ with small molecules or RNA interference affected not only viability and proliferation of BAIAP2L1-BRAF transformed cells, but also the viability, growth and invasion of corresponding 3D spheroid cultures. CONCLUSIONS: Apart from unveiling a novel oncogenic BRAF fusion in PTCs, our data may open a novel avenue of therapeutic targeting in human PTCs.

Second MAFA Variant Causing a Phosphorylation Defect in the Transactivation Domain and Familial Insulinomatosis.

Adult-onset familial insulinomatosis is a rare disorder with recurrent, severe hypoglycemia caused by multiple insulin-secreting pancreatic tumors. The etiology was unclear until the variant p.Ser64Phe in the transcription factor MAFA, a key coordinator of ß-cell insulin secretion, was defined as the cause in two families. We here describe detailed genetic, clinical, and family analyses of two sisters with insulinomatosis, aiming to identify further disease causes. Using exome sequencing, we detected a novel, heterozygous missense variant, p.Thr57Arg, in MAFA's highly conserved transactivation domain. The impact of the affected region is so crucial that in vitro expression studies replacing Thr57 have already been performed, demonstrating a phosphorylation defect with the impairment of transactivation activity and degradation. However, prior to our study, the link to human disease was missing. Furthermore, mild hyperglycemia was observed in six additional, heterozygote family members, indicating that not only insulinomatosis but also MODY-like symptoms co-segregate with p.Thr57Arg. The pre-described MAFA variant, p.Ser64Phe, is located in the same domain, impairs the same phosphorylation cascade, and results in the same symptoms. We confirm MAFA phosphorylation defects are important causes of a characteristic syndrome, thus complementing the pathophysiological and diagnostic disease concept. Additionally, we verify the high penetrance and autosomal dominant inheritance pattern.

Individualized treatment of differentiated thyroid cancer: The value of surgery in combination with radioiodine imaging and therapy - A German position paper from Surgery and Nuclear Medicine. / Individualisierte Behandlung von differenziertem Schilddrüsenkrebs: Der Wert der Operation in Kombination mit Radiojodbildgebung und -therapie ­ Ein deutsches Positionspapier aus der Chirurgie und Nuklearmedizin.

A consensus statement about indications for post-surgical radioiodine therapy (RIT) in differentiated thyroid cancer patients (DTC) was recently published by the European Thyroid Association (ETA) 1. This publication discusses indications for RIT on the basis of an individual risk assessment. Many of the conclusions of this consensus statement are well founded and accepted across the disciplines involved. However, especially from the perspective of nuclear medicine, as the discipline responsible for indicating and executing RIT, some of the recommendations may require further clarification with regard to their compatibility with established best practice and national standards of care. Assessment of the indications for RIT is strongly dependent on the weighing up of benefits and risks. On the basis of longstanding clinical experience in nuclear medicine, RIT represents a highly specific precision medicine procedure of proven efficacy with a favorable side-effect profile. This distinguishes RIT significantly from other adjuvant oncological therapies and has resulted in the establishment of this procedure as a usually well-tolerated, standard safety measure. With regard to its favorable risk/benefit ratio, this procedure should not be unnecessarily restricted, in the interest of offering reassurance to the patients. Both patients' interests and regional/national differences need to be taken into account. We would therefore like to comment on the recent consensus from the perspective of authors and to provide recommendations based on the respective published data.

Clarifying optimal outcome measures in intermittent and continuous laryngeal neuromonitoring.

BACKGROUND: Intraoperative neuromonitoring (IONM) techniques have evolved over the past decade into intermittent IONM (I-IONM) and continuous IONM (C-IONM) modes of application. Despite many prior publications on both types of IONM, there remains uncertainty about what outcomes should be measured for each form of IONM. The primary objective of this paper is to define categories of benefit for I-IONM/C-IONM and to clarify and standardize their reporting outcomes. METHODS: Expert review consensus statement utilizing modified Delphi methodology. RESULTS: I-IONM provides diagnosis, classification, and prevention of nerve injury through accurate and early nerve identification. C-IONM provides real-time information on nerve functional integrity and thus may prevent some types of nerve injury but cannot assist in nerve localization. Sudden mechanisms of nerve injury cannot be predicted or prevented by either technique. CONCLUSIONS: I-IONM and C-IONM are complementary techniques. Future studies evaluating the utility of IONM should focus on outcomes that are appropriate to the type of IONM being utilized.

[Resection strategy for locally advanced thyroid carcinoma]. / Resektionsstrategien beim lokal fortgeschrittenen Schilddrüsenkarzinom.

Advanced thyroid carcinomas with infiltration of the aerodigestive tract are rare but are responsible for approximately 50% of the tumor-specific mortality. Due to impending and frequently life-threatening local complications and in the absence of promising therapeutic alternatives, a resection in curative or palliative intention is indicated if the local tumor is resectable. The resection and especially reconstruction of the trachea represent an extraordinary surgical challenge, require an individualized approach as well as exact knowledge of tracheal resection techniques. The decision for surgery in general, the selection of adequate resection and reconstruction strategies as well as the perioperative management should be accompanied by a particularly experienced interdisciplinary team.

Genetic testing in inherited endocrine disorders: joint position paper of the European reference network on rare endocrine conditions (Endo-ERN).

BACKGROUND: With the development of molecular high-throughput assays (i.e. next generation sequencing), the knowledge on the contribution of genetic and epigenetic alterations to the etiology of inherited endocrine disorders has massively expanded. However, the rapid implementation of these new molecular tools in the diagnostic settings makes the interpretation of diagnostic data increasingly complex. MAIN BODY: This joint paper of the ENDO-ERN members aims to overview chances, challenges, limitations and relevance of comprehensive genetic diagnostic testing in rare endocrine conditions in order to achieve an early molecular diagnosis. This early diagnosis of a genetically based endocrine disorder contributes to a precise management and helps the patients and their families in their self-determined planning of life. Furthermore, the identification of a causative (epi)genetic alteration allows an accurate prognosis of recurrence risks for family planning as the basis of genetic counselling. Asymptomatic carriers of pathogenic variants can be identified, and prenatal testing might be offered, where appropriate. CONCLUSIONS: The decision on genetic testing in the diagnostic workup of endocrine disorders should be based on their appropriateness to reliably detect the disease-causing and -modifying mutation, their informational value, and cost-effectiveness. The future assessment of data from different omic approaches should be embedded in interdisciplinary discussions using all available clinical and molecular data.

Long-term outcome of surgical resection in patients with gastroenteropancreatic neuroendocrine neoplasia: results from a German nation-wide multi-centric registry.

BACKGROUND: Neuroendocrine neoplasia (NEN) are rare and heterogenous tumours. Few data exist on the impact of surgical therapy. MATERIALS AND METHODS: This is a retrospective analysis of prospectively collected data of gastroenteropancreatic NEN in the German NET-Registry (1999-2012). It focuses on patients without distant metastases (limited disease, LD, stage I-IIIB). RESULTS: Data of 2239 patients with NEN were recorded. Median age was 59 years, the gender ratio was 1:1.3 (f:m). A total of 986 patients (44%) had LD, and the 5-year survival rate (5 years) was 77% for all and 90% for patients with LD. A total of 1635 patients (73%) received a surgical therapy (1st to 6th line); the 5 and 10 ysr were 83/65% after and 59/35% without surgery for all patients (p < .001). The resection margins in the LD patients were 76%, 16%, and 3% for R0, R1 and R2, respectively. The 10 ysr was 84%, 59% and 42% for R0, R1 and R2 resections, respectively (p = .021 R0/R1, p < .001 R0/R2). The R0 resection rate was 75% for G1/G2 NET and 67% for G3 NEC. CONCLUSION: The rate of complete tumour resection (R0) in LD is independent of tumour grading, and R0 resection is the key determinant of long-term survival, as demonstrated by the 10 ysr. of 84%. All NEN patients with limited disease should be considered for operation, if possible, as the best 10-year survival is shown after an R0 resection.

Thyroid surgery in children and young adults: potential overtreatment and complications.

PURPOSE: Thyroid nodules in the pediatric population are more frequently associated with malignant thyroid disease than in adult cohorts. Yet, there is a potential risk of surgical overtreatment. With this single center study, an analysis of potential overtreatment for suspected malignant thyroid disease in children and young adults was aimed for. METHODS: In a period from 2005 to 2018, 155 thyroid operations in children and young adults performed at the University Medical Center Mainz, Germany, were analyzed (patient age 3-20 years, 117 female). Cases were categorized for preoperative diagnosis: non-malignant (group I, n = 45) and malignant thyroid disease (group II, n = 110). Postoperative parameters (histology, complication rates) were assessed and compared between groups. RESULTS: 91.1% of group I were histologically benign. 44.5% of group II harbored malignancy. Permanent hypoparathyroidism was documented in group I (2.7%) and in group II (1.4%, p = 1.000). Wound infections were absent in group I but observed in group II (0.9%, p = 1.000). Transient vocal cord palsy was recorded only in group I (2.3%, 2/85 vs. 0/177 nerves at risk, p = 0.104). Permanent vocal cord palsies were absent. CONCLUSION: Preoperative diagnoses were correct in over 90% of group I and in nearly 45% of group II. The high proportion of carcinomas in group II ruled out the issue of potential overtreatment. The risk of severe postoperative complications was equally low in both patient groups.

Proteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas.

Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy. By RNA-seq analysis, we identify a RET rearrangement in the tumour material of a patient who does not harbour any known RAS or BRAF mutations. This new gene fusion involves exons 1-4 from the 5' end of the Trk fused Gene (TFG) fused to the 3' end of RET tyrosine kinase leading to a TFG-RET fusion which transforms immortalized human thyroid cells in a kinase-dependent manner. TFG-RET oligomerises in a PB1 domain-dependent manner and oligomerisation of TFG-RET is required for oncogenic transformation. Quantitative proteomic analysis reveals the upregulation of E3 Ubiquitin ligase HUWE1 and DUBs like USP9X and UBP7 in both tumor and metastatic lesions, which is further confirmed in additional patients. Expression of TFG-RET leads to the upregulation of HUWE1 and inhibition of HUWE1 significantly reduces RET-mediated oncogenesis.