Multiple endocrine neoplasia type 2: towards a risk-based approach integrating molecular and biomarker results.

PURPOSE OF REVIEW: Significant advances have transformed our understanding of the molecular biology and natural history of multiple endocrine neoplasia type 2 (MEN2). This progress enacted a paradigm shift with regard to routine neck dissection for medullary thyroid cancer and total adrenalectomy for pheochromoytoma. The purpose of this review is to summarize key molecular and clinical data underpinning the current risk-based approach to MEN2 that integrates molecular and biomarker results. RECENT FINDINGS: Early identification and biochemical monitoring of rearranged during transfection ( RET ) carriers yield important lead time. Within these ' windows of opportunity ', total thyroidectomy alone, avoiding incremental morbidity from node dissection; ' tissue-sparing ' subtotal adrenalectomy, balancing risks of steroid dependency with pheochromocytoma recurrence in adrenal remnants; and parathyroidectomy of enlarged glands only, weighing risks of postoperative hypoparathyroidism against hyperactive parathyroid glands left behind, are adequate therapies. SUMMARY: All that is needed to determine a RET carriers' risk of medullary thyroid cancer, pheochromocytoma and/or primary hyperparathyroidism in the molecular era is patient age, underlying RET mutation, and biomarker levels. As broader testing begins to penetrate healthcare, the needle on population genomic screening and education needs to be moved forward to complete the transition from symptom-based to preventive healthcare.

Axillary Node Metastases of Medullary Thyroid Cancer: A Hallmark of Terminal Disease.

Little is known about axillary node metastasis of medullary thyroid cancer (MTC). To address this, a comparative study of patients with and without axillary node metastases of MTC was conducted. Among 1215 consecutive patients with MTC, 482 patients had node-negative MTC and 733 patients node-positive MTC. Among the 733 patients with node-positive MTC, 4 patients (0.5%) had axillary node metastases, all of which were ipsilateral. Patients with axillary node metastases had 5.7-6.9-fold more node metastases removed, both at the authors' institution (medians of 34.5 vs. 5 metastases; p=0.011) and in total (medians of 57 vs. 10 metastases; p=0.013), developed more frequently distant metastases (3 of 4 vs. 178 of 729 patients, or 75 vs. 24%; p=0.049), specifically to bone (2 of 4 vs. 67 of 729 patients, or 50 vs. 9%; p=0.046) and brain (1 of 4 vs. 4 of 729 patients, or 25 vs. 0.5%; p=0.027), and more often succumbed to cancer-specific death (3 of 4 vs. 52 of 729 patients, or 75 vs. 14%; p=0.005). Altogether, patients with axillary node metastases revealed 4-8-fold more node metastases in the ipsilateral lateral neck (medians of 11 vs. 3 metastases; p=0.021) and in the ipsilateral central neck (medians of 8 vs. 1 metastases; p=0.079) patients without axillary node metastases. Cancer-specific survival of patients with vs. patients without axillary node metastases of MTC was significantly shorter (means of 41 vs. 224 months; plog-rank<0.001). These findings show that patients with axillary node metastases of MTC have massive metastatic dissemination with poor survival.

Clinical Presentation, Treatment, and Outcome of Parathyroid Carcinoma: Results of the NEKAR Retrospective International Multicenter Study.

OBJECTIVE: In this retrospective cohort study, we describe the clinical presentation and workup of parathyroid carcinoma (PC) and determine its clinical prognostic parameters. Primary outcome was recurrence free survival. SUMMARY BACKGROUND DATA: PC is an orphan malignancy for which diagnostic workup and treatment is not established. METHODS: Eighty-three patients were diagnosed with PC between 1986 and 2018. Disease-specific and recurrence-free survivals were estimated with the Kaplan-Meier method. Risk factors for recurrence were identified by binary logistic regression with adjustment for age and sex. Thirty-nine tumors underwent central histopathological review. RESULTS: Renal (39.8%), gastrointestinal (24.1%), bone (22.9%), and psychiatric (19.3%) symptoms were the most common symptoms. Surgical treatment was heterogeneous [parathyroidectomy [PTx)] alone: 22.9%; PTx and hemithyroidectomy: 24.1%; en bloc resection 15.7%; others 37.3%] and complications of surgery were frequent (recurrent laryngeal nerve palsy 25.3%; hypoparathyroidism 6%). Recurrence of PC was observed in 32 of 83 cases. In univariate analysis, rate of recurrence was reduced when extended initial surgery had been performed (P = 0.04). In multivariate analysis low T status [odds ratio (OR) = 2.65, 95% confidence interval (CI) 1.02-6.88, P = 0.045], N0 stage at initial diagnosis (OR = 6.32, 95% CI 1.33-30.01, P = 0.02), Ki-67 <10% (OR = 14.07, 95% CI 2.09-94.9, P = 0.007), and postoperative biochemical remission (OR = 0.023, 95% CI 0.001-0.52, P = 0.018) were beneficial prognostic parameters for recurrence-free survival. CONCLUSION: Despite a favorable overall prognosis, PC shows high rates of recurrence leading to repeated surgery and postoperative recurrent laryngeal nerve palsy and hypoparathyroidism. In view of the reduced recurrence rate in cases of extended surgery, ipsilateral completion surgery may be considered when PC is confirmed.

Clonidine suppression test for a reliable diagnosis of pheochromocytoma: When to use.

OBJECTIVE: In clinical practice, false-positive results in biochemical testing for suspected pheochromocytoma/paraganglioma (PPGL) are not infrequent and may lead to unnecessary examinations. We aimed to evaluate the role of the clonidine suppression test (CST) in the era of analyses of plasma-free metanephrines for the diagnosis or exclusion of PPGL in patients with adrenal tumours and/or arterial hypertension. DESIGN AND METHODS: This single-centre, prospective trial investigated the use of CST in 60 patients with suspected PPGL associated with out-patient elevations of plasma normetanephrine (NMN) and/or metanephrine (MN), in most cases accompanied with hypertension or an adrenal mass. Measurements of plasma catecholamines and free metanephrines were performed by liquid chromatography with electrochemical detection and tandem mass spectrometry, respectively. RESULTS: Forty-six patients entered final analysis (n = 20 with PPGL and n = 26 with a nonfunctional adrenal mass and/or hypertension). CST reliably excluded false-positive baseline NMN results with a specificity of 100%. The sensitivity of CST improved from 85% to 94% when tumours with isolated MN increase (n = 3) were not considered. In patients with elevated baseline NMN (n = 24), CST correctly identified all patients without PPGL. Patients with falsely elevated baseline NMN results (n = 7, 26.9%) exhibited increases of baseline NMN up to 1.7-fold above the upper reference limit. CONCLUSION: CST qualifies as a useful diagnostic tool for differential diagnosis of borderline elevated plasma-free NMN in patients with suspected PPGL. In this context, CST helps to correctly identify all false-positive NMN screening results.

Risk Patterns of Distant Metastases in Follicular, Papillary and Medullary Thyroid Cancer.

This study of 542 patients with follicular thyroid cancer, 366 patients with the follicular variant and 1452 patients with the classical variant of papillary thyroid cancer, and 819 patients with sporadic medullary thyroid cancer operated at a tertiary referral center aimed to determine risk patterns of distant metastasis for each tumor entity, which are ill-defined. On multivariable logistic regression analyses, lymph node metastasis consistently emerged as an independent risk factor of distant metastasis, yielding odds ratios (ORs) of 2.4 and 2.8 for follicular thyroid cancer and the follicular variant of papillary thyroid cancer, and ORs of 5.9 and 6.4 for the classical variant of papillary thyroid cancer and sporadic medullary thyroid cancer. Another independent risk factor consistently associated with distant metastasis, most strongly in follicular thyroid cancer and the follicular variant of papillary thyroid cancer (OR 3.5 and 4.0), was patient age >60 years. Altogether, 2 distinct risk patterns of distant metastasis were identified, which were modulated by other cancer type-dependent risk factors: one with lymph node metastasis as leading component (classical variant of papillary thyroid cancer and sporadic medullary thyroid cancer), and another one with age as leading component (follicular thyroid cancer and the follicular variant of papillary thyroid cancer). Distant metastasis was exceptional in node-negative patients with sporadic medullary thyroid cancer (1.7%) and the classical variant of papillary thyroid cancer (1.4%), and infrequent in node-negative patients with the follicular variant of papillary thyroid cancer (4.4%). These findings delineate windows of opportunity for early surgical intervention before distant metastasis has occurred.

Metastatic risk profile of microscopic lymphatic and venous invasion in papillary thyroid cancer.

OBJECTIVES: The aim of this study was to define the suitability of microscopic lymphatic and venous invasion for prediction of lymph node and distant metastases in papillary thyroid cancer. DESIGN: Stratification by microscopic lymphatic and venous invasion, and multivariable analyses on lymph node and distant metastases including microscopic lymphatic and venous invasion as independent variables. SETTING: Tertiary referral centre. PARTICIPANTS: 422 patients who had ≥5 lymph nodes removed at initial thyroidectomy. MAIN OUTCOME MEASURES: Lymph node and distant metastases. RESULTS: Patients with microscopic lymphatic invasion had larger primary tumours than patients without and more often revealed microscopic venous invasion, multifocal tumour growth and lymph node metastases. Patients with microscopic venous invasion exhibited larger primary tumours than patients without and more commonly had microscopic lymphatic invasion, poor tumour differentiation, lymph node metastases and distant metastases. Prediction of lymph node metastases by microscopic lymphatic invasion was better than prediction of distant metastases by microscopic venous invasion regarding sensitivity (61.0 vs. 33.3%) and positive predictive value (92.6 vs. 20.9%), comparable regarding specificity (89.6 and 93.4%), and worse regarding negative predictive value (51.9 vs. 95.3%) and accuracy (70.1 vs. 87.7%). On multivariable logistic regression analysis, microscopic lymphatic invasion was associated with lymph node metastasis (odds ratio [OR] 11.1) and multifocal tumour growth (OR 2.4), whereas primary tumour size (OR 5.8 for tumours >40 mm relative to tumours ≤20 mm) and multifocal tumour growth (OR 3.1) were associated with distant metastasis. CONCLUSION: Stricter histopathological criteria are warranted to enhance the utility of microscopic vascular invasion for prediction of distant metastases in papillary thyroid cancer.

IGF2BP1 is the first positive marker for anaplastic thyroid carcinoma diagnosis.

Anaplastic thyroid carcinomas (ATC) are rare, but represent the most lethal malignancy of the thyroid. Selective molecular markers and drivers distinguishing ATC from other thyroid carcinomas of follicular origin remain largely unknown, limiting advances in diagnosis and treatment. In a retrospective study, we analyzed gene expression in 36 ATC, 18 poorly differentiated, 132 papillary, and 55 follicular thyroid carcinoma, as well as 124 paired and unpaired normal thyroid tissues in three independent cohorts by RNA-sequencing and immunohistochemistry. RNA-sequencing data in the test cohort suggested selective ATC protein biomarkers. Evaluation of these revealed that ATCs are characterized by the de novo expression of various testis antigens, including melanoma-associated antigen A3 (MAGEA3), but most importantly the oncofetal IGF2 mRNA binding protein 1 (IGF2BP1). Shallow whole genome sequencing essentially excluded that IGF2BP1 upregulation results from gene copy number alterations. Immunohistochemical analyses in all three tumor cohorts confirmed the selective de novo expression of IGF2BP1 protein in ATC. In sum, 75% (27/36) of all tested ATC and 0.5% (1/204) of poorly and well-differentiated thyroid carcinoma tissue samples were positive for IGF2BP1 protein. This indicates that IGF2BP1 protein expression identifies ATC with a diagnostic odds ratio of 612 (95% CI: 74.6-5021). In addition, we found that MAGEA3 is exclusively, although less consistently upregulated in ATC, presenting with an odds ratio of 411 (95% CI: 23.8-7098.7). Importantly, we provide confirmatory evidence that IGF2BP1 and MAGEA3 expression distinguishes ATC from poorly differentiated thyroid carcinoma. IGF2BP1 furthermore identified ATC foci within low-grade follicular thyroid carcinoma. In conclusion, IGF2BP1 represents the most promising single-gene marker available for ATC, followed by MAGEA3, improving on current techniques. Robust markers are essential to help distinguish this high-grade malignancy from other thyroid carcinomas, to guide surgical decision making, therapy and post-resection/therapy monitoring strategies.

Metastatic Risk Profile of Microscopic Lymphatic and Venous Invasion in Medullary Thyroid Cancer.

The metastatic risk profile of microscopic lymphatic and venous invasion in medullary thyroid cancer is ill-defined. This evidence gap calls for evaluation of the suitability of microscopic lymphatic and venous invasion at thyroidectomy for prediction of lymph node and distant metastases in medullary thyroid cancer. In this study of 484 patients with medullary thyroid cancer who had≥5 lymph nodes removed at initial thyroidectomy, microscopic lymphatic and venous invasion were significantly associated with greater primary tumor size (27.6 vs. 14.5 mm, and 30.8 vs. 16.2 mm) and more frequent lymph node metastasis (97.0 vs. 25.9%, and 85.2 vs. 39.5%) and distant metastasis (25.0 vs. 5.1%, and 32.8 vs. 7.3%). Prediction of lymph node metastases by microscopic lymphatic invasion was better than prediction of distant metastases by microscopic venous invasion regarding sensitivity (97.0 vs. 32.8%) and positive predictive value (58.4 vs. 39.2%); comparable regarding negative predictive value (98.5 vs. 90.5%) and accuracy (80.4 vs. 85.1%); and worse regarding specificity (74.1 vs. 92.7%). On multivariable logistic regression, microscopic lymphatic invasion predicted lymph node metastasis better (odds ratio [OR] 65.6) than primary tumor size (OR 4.6 for tumors>40 mm and OR 2.7 for tumors 21-40 mm, relative to tumors≤20 mm), whereas primary tumor size was better in predicting distant metastasis (OR 8.3 for tumors>40 mm and OR 3.9 for tumors 21-40 mm, relative to tumors≤20 mm) than microscopic venous invasion (OR 3.2). These data show that lymphatic invasion predicts lymph node metastases better in medullary thyroid cancer than venous invasion heralds distant metastases.

Distinct Late-Night Salivary Cortisol Cut-Off Values for the Diagnosis of Hypercortisolism.

Due to high morbidity and mortality of untreated hypercortisolism, a prompt diagnosis is essential. Measurement of late-night salivary cortisol provides a simple and non-invasive method. However, thresholds and reference ranges differ among studies. The goal of this study was to define a threshold of late-night salivary cortisol for the diagnosis of hypercortisolism based on the used assay. Moreover, the influence of different aetiologies of hypercortisolism and individual comorbidities were investigated. Prospective analyses of 217 patients, including 36 patients with proven hypercortisolism were carried out. A sum of 149 patients with suspicion of hypercortisolism but negative endocrine testing and 32 patients with hypercortisolism in remission served as control group. Late-night salivary cortisol was measured using an automated chemiluminescence immunoassay. Cut-off values were calculated by ROC analysis. The calculated cut-off value for the diagnosis of hypercortisolism was 10.1 nmol/l (sensitivity 94%; specificity 84%). Only slightly lower thresholds were obtained in patients with suspected hypercortisolism due to weight gain/obesity (9.1 nmol/l), hypertension or adrenal tumours (both 9.8 nmol/l) or pituitary adenomas (9.5 nmol/l). The late-night salivary cortisol threshold to distinguish between Cushing's disease and Cushing's disease in remission was 9.2 nmol/l. The cut-off value for the diagnosis of ectopic ACTH-production was 109.0 nmol/l (sensitivity 50%, specificity 92%). Late-night salivary cortisol is a convenient and reliable parameter for the diagnosis of hypercortisolism. Except for ectopic ACTH-production, thresholds considering different indications for evaluation of hypercortisolism were only slightly different. Therefore, they might only be useful if late-night salivary cortisol results near the established cut-off value are present.

Analysis and outcomes of wrong site thyroid surgery.

BACKGROUND: In thyroid surgery, wrong-site surgery (WSS) is considered a rare event and seldom reported in the literature. CASE PRESENTATION: This report presents 5 WSS cases following thyroid surgery in a 20-year period. We stratified the subtypes of WSS in wrong target, wrong side, wrong procedure and wrong patient. Only planned and elective thyroid surgeries present WSS cases. The interventions were performed in low-volume hospitals, and subsequently, the patients were referred to our centres. Four cases of wrong-target procedures (thymectomies [n = 3] and lymph node excision [n = 1] performed instead of thyroidectomies) and one case of wrong-side procedure were observed in this study. Two wrong target cases resulting additionally in wrong procedure were noted. Wrong patient cases were not detected in the review. Patients experienced benign, malignant, or suspicious pathology and underwent traditional surgery (no endoscopic or robotic surgery). 40% of WSS led to legal action against the surgeon or a monetary settlement. CONCLUSION: WSS is also observed in thyroid surgery. Considering that reports regarding the serious complications of WSS are not yet available, these complications should be discussed with the surgical community. Etiologic causes, outcomes, preventive strategies of WSS and expert opinion are presented.

Surgery for adrenal angiomyelolipoma: an individualized concept.

BACKGROUND: Because adrenal angiomyelolipoma (AAML) is rare and uniformly benign, the indications for surgery are ill defined. METHODS: Among a series of 156 patients with adrenal pathologies surgically treated between 2013 and 2018, 12 patients were operated with the diagnosis of an AAML. The clinical as well as imaging parameters forming the individual indications for surgery were analyzed. RESULTS: Preoperative diagnosis consistent with AAML was made in all 12 patients. The mean size of surgically removed AAML was 82.3 mm (45-150 mm). Gender and affected side were evenly distributed. Local symptoms but lack of radiological signs suspicious for malignancy or size increase were observed in 4 of 12 patients (group 1, 33%). In contrast, 4 of 12 patients (group 2, 33%) showed radiological signs suspicious for malignancy but lacked local symptoms. Additional 4 of 12 patients (group 3, 33%) showed both local symptoms and radiological signs suspicious for malignancy. Patients with local symptoms harbored significantly larger tumors compared to those patients that lacked local symptoms (93.9 mm ± 32.8 vs. 59.3 mm ± 2.7, p = 0.021). Patients with radiologically suspicious signs were older (60 years ± 9.9 vs. 53 years ± 5.4, p > 0.05), and time to surgery was shorter (4.4 months ± 3 vs. 6.0 months ± 3.0, p > 0.05). Importantly, surgical approach was not influenced by tumor size (p = 0.65). However, patients with suspicious imaging were more likely to be operated by conventional open approach (4 of 8 vs. 0 of 4, p = 0.08). The minimal invasive approach was associated with shorter hospital stay (7 days, ± 1.3 vs. 14.2 days, ± 8.8, p = 0.038). All lesions that showed radiological signs suspicious for malignancy proved benign in final histology. CONCLUSION: Large AAML present a clinical challenge. The presence of local symptoms and/or radiological signs suspicious for malignancy identifies three groups of patients that define the concept of an individualized indication for surgery in AAML. A minimal invasive approach can be advocated even for large AAML with radiological signs suspicious for malignancy.

Genotype-specific progression of hereditary medullary thyroid cancer.

Although already 25 years into the genomic era, age-related progression of hereditary medullary thyroid cancer (MTC), the prevalence of which is estimated at one in 80,000 inhabitants, remains to be delineated for most unique RET (REarranged during Transfection) mutations. Included in this study were 567 RET carriers. The age-related progression of MTC across histopathological groups (normal thyroid/C-cell hyperplasia; node-negative MTC; node-positive MTC) was statistically significant for 13 unique RET mutations (p.Cys611Phe/c.1832G > T; p.Cys611Tyr; p.Cys618Ser/c.1852T > A; p.Cys620Arg; p.Cys634Arg; p.Cys634Phe; p.Cys634Ser; p.Cys634Tyr; p.Glu768Asp; p.Leu790Phe/c.2370G > T; p.Val804Met; p.Ser891Ala; p.Met918Thr), whereas two unique RET mutations (p.Cys618Phe; p.Cys634Gly) trended toward statistical significance. When grouped by mutational risk (highest; high; moderate-high; low-moderate; polymorphism), the age-related progression of MTC was significant for all four categories of RET mutations, which differed significantly across and within the three histopathological groups. For high, for moderate-high, and for low-moderate risk RET mutations, the age-related progression of MTC by mutated codon was broadly comparable across and within the three histopathological groups, and essentially unaffected by the amino acid substitutions examined. These data argue in favor of splitting the American Thyroid Association's moderate-risk category into moderate-high and low-moderate risk categories, while emphasizing the need to contradistinguish the latter from rare nonpathogenic polymorphisms.

[Register of Difficult Surgical Situations]. / Register der schwierigen chirurgischen Situationen.

Every surgical problem that increases the likelihood of intraoperative and postoperative complications is considered to be a difficult surgical situation. Based on this definition, Korenkov et al. proposed to classify patients according to the following intraoperative difficulty levels (I to IV): (I) ideal situation (easy to operate, no problems), (II) fairly easy/manageable/simple (some minor difficulties may occur), (III) difficult/problematic (difficult to operate; some operative techniques are considerably more difficult than others), and (IV) very difficult (every operative step is difficult/challenging). Kaafrani et al. proposed a severity classification for intraoperative adverse events. Depending on the severity level, classes range from I (injury requiring no repair) to VI (intraoperative death). Clavien and colleagues published a globally established classification system for postoperative complications. In this classification, the severity of postoperative complications ranges from severity grade I (minimal deviation from the normal postoperative course) to severity grade V (death of patient). Based on the proposed classifications and the problems of individual surgical decision-making, we had the idea to create a Register of Difficult Intraoperative Situations (DIS register). The basic principle of such a register is the collection of an individual expert's experiences. The scientific analysis should focus on patients with apparent modifications in treatment due to difficult intraoperative situations. Registration and processing of enrolled cases will be performed anonymously based on an appropriate IT platform. The main goal of this register is to develop an accessible database for practising surgeons. This will provide an opportunity for every surgeon to find out what other surgeons did in similar situations.

Parathyroid Hormone Levels Predict Long-Term Outcome After Operative Management of Parathyroid Cancer.

The role of parathyroid hormone (PTH) serum levels for prediction of outcome is ill defined for parathyroid cancer, which is a very rare disease. This investigation of 17 consecutive patients with parathyroid cancer, (re-)operated on at a tertiary referral center between 1994 and July 2016, with a mean follow-up of 179.6 months (15 years) aimed to clarify the suitability of PTH serum levels for prediction of clinical outcome after comprehensive operative management of parathyroid cancer. Cancer-specific mortality occurred significantly more often with the performance of sternotomy before or at first operation at this institution (80 vs. 0%; p=0.002); mean PTH serum levels before first operation (1 105 vs. 357 pg/ml; p=0.008; r=0.77) and at most recent follow-up (3 167 vs. 101 pg/ml; p=0.019; r=0.60); and normalization of PTH serum levels at most recent follow-up (0 vs. 64%; p=0.034). For cancer-specific survival, receiver-operating characteristics analysis identified as optimum cut-off point an initial PTH serum level of 700 pg/ml. For local recurrence, no significant associations were found. Kaplan-Meier analysis confirmed that the patients with initial PTH serum levels >700 pg/ml (plog-rank=0.011) and sternotomy (plog-rank<0.001), but not node or lung metastases, had worse cancer-specific survival. Parathyroid cancer is much more an endocrine disease with oncological features than an oncological disease with endocrine features. Operative intervention(s) should be comprehensive and directed at clearing all metabolically active parathyroid tumor deposits early. If surgical cure cannot be reached, it is pivotal to achieve metabolic control, obviating the need for, or facilitating, medical therapy of hypercalcemia, and preserve renal function.

Variability in penetrance of multiple endocrine neoplasia 2A with amino acid substitutions in RET codon 634.

OBJECTIVE: Controversy surrounds the importance of the different amino acids substituting for cysteine in REarranged during Transfection (RET) codon 634 for multiple endocrine neoplasia 2A (MEN 2A). This study aimed to clarify the relevance of these amino acid substitutions for the development of MEN 2A. DESIGN: Cross-sectional study at surgical referral centres in Germany. PATIENTS: Included were 184 carriers of RET mutations in codon 634. MEASUREMENTS: Arginine (79 carriers) and tyrosine (50 carriers) substitutions in codon 634 were compared with each other and, for the first time, gauged against a common reference standard comprising all other amino acid substitutions (phenylalanine, 35 carriers; serine, 12 carriers; glycine, 7 carriers; tryptophan, 1 carrier). RESULTS: Arginine substitutions in codon 634 were associated with higher penetrance of medullary thyroid cancer (MTC; 82% vs 62%; P = 0·010), any phaeochromocytoma (44% vs 15%, P < 0·001), bilateral phaeochromocytoma (32% vs 5%; P < 0·001) and primary hyperparathyroidism (18% vs 5%; P = 0·039) relative to the reference standard. The penetrance rates of any phaeochromocytoma (44% vs 26%; P = 0·041) and bilateral phaeochromocytoma (32% vs 14%; P = 0·035) were also higher with arginine than with tyrosine substitutions. Corrected for multiple testing, the associations of arginine with any phaeochromocytoma and bilateral phaeochromocytoma remained statistically significant. Progression of MTC, evidenced by largest primary tumour diameter, nodal status, distant metastasis and biochemical cure, did not differ by amino acid substitution. CONCLUSIONS: In codon 634, arginine substitutions for cysteine may cause slightly higher penetrance rates of MEN 2A which, overall, are too small to treat carriers differently. The mode of action by which arginine exerts these subtle effects warrants further research.

Continuous intraoperative monitoring of vagus and recurrent laryngeal nerve function in patients with advanced atrioventricular block.

PURPOSE: Intraoperative neuromonitoring of recurrent laryngeal nerve function after stimulation of the vagus nerve has been embraced as a risk minimization tool in thyroid surgery to prevent recurrent laryngeal nerve injury. Because this technology is increasingly used in an elderly and sicker population, the present study was conducted to determine the safety of this method in patients with second- or third-degree atrioventricular block. METHODS: This study aimed at evaluating the feasibility and safety of continuous intraoperative neuromonitoring (CIONM) in patients with second- or third-degree atrioventricular block. RESULTS: A total of six patients (12 nerves at risk), accounting for 0.3 % of all 1800 patients (3049 nerves at risk) who underwent thyroid surgery during the study period, were found to have second- or third-degree atrioventricular block. All these patients maintained normal systolic and diastolic blood pressures; heart rate; and peripheral arterial oxygen saturation before, during, and after CIONM. No clinically relevant changes in heart rate or blood pressure, cardiac arrhythmia, or other hemodynamically important events were noted despite careful monitoring of these patients. There was no interference between the biphasic waveform of the vocal muscle electromyogram and the spikes generated by the implanted cardiac pacemakers. Outcomes were uneventful with normal vocal fold and parathyroid gland function. CONCLUSIONS: Within the limitations of this series and considering experimental, animal, and human data, continuous IONM of the vagus nerve at ≤2 Hz seems to be reasonably safe. Additional research is warranted to confirm these results in larger groups of patients with advanced atrioventricular block.

Radiological features of metastases to the thyroid.

BACKGROUND: Thyroid metastases (TM) are uncommon. Dependent on study design, the reported frequency of TM is in the range of 0.1-6% in different analyses. While clinical and histopathological features of TM were well described in the literature, radiological publications consist predominantly of isolated case reports or small series. PURPOSE: To estimate the prevalence, clinical signs, and radiological appearances of TM. MATERIAL AND METHODS: From 1997 to 2013, a total of 8849 patients with various disorders of the thyroid gland were treated in our institution. In 33 patients TM were diagnosed. Ultrasound (US) images were available in all patients, computed tomography (CT) of the neck in 16 patients, and magnetic resonance imaging (MRI) in nine patients. RESULTS: Clinically, most patients (85%) presented with a painless neck mass. Primary tumors were renal cell carcinoma (79%), colorectal cancer (12%), lung cancer (3%), rhabdomyosarcoma (3%), and breast carcinoma (3%). On US, most lesions were irregular in shape with inhomogenous texture. On CT, all TM were hypodense. On T1-weighted images, most TM were inhomogenously iso-to-hyperintense in comparison to the normal thyroid tissue, and slightly hyperintense on T2-weighted images with an inhomogenous contrast enhancement. CONCLUSION: The prevalence of TM was 0.4%. Most of the TM originated from renal cell carcinoma. The identified radiological features of TM should be taken into consideration in the differential diagnosis of thyroid lesions.

Local recurrence in the neck and survival after thyroidectomy for metastatic renal cell carcinoma.

BACKGROUND: Most investigations of thyroidectomy for metastatic renal cell carcinoma (RCC) are case studies or small series. This study was conducted to determine the contribution of clinical and histopathologic variables to local recurrence in the neck and overall survival after thyroidectomy for RCC metastases. METHODS: The medical records of 140 patients with thyroidectomy for metastatic RCC performed between 1979 and 2012 at 25 institutions in Germany and Austria were analyzed. RESULTS: The median interval between nephrectomy and thyroidectomy was 120 months. Concurrence of thyroid and pancreatic metastases was present in 23 % of the patients and concurrence of thyroid and adrenal metastases in 13 % of the patients. Clinical outcome data were available for 130 patients with a median follow-up period of 34 months. The 5-year overall survival rate was 46 %, and 28 % of patients developed a local neck recurrence at a median of 12 months after thyroidectomy. Multivariate analysis showed that invasion of adjacent cervical structures (hazard ratio [HR] 3.2; p = 0.001), patient age exceeding 70 years (HR 2.5; p = 0.004), and current or past evidence of metastases to nonendocrine organs (HR 2.4; p = 0.003) were independent determinants of inferior overall survival. Conversely, invasion of adjacent cervical structures (HR 12.1; p < 0.0001) and year of thyroidectomy (HR 5.7 before 2000; p < 0.0001) were shown to be independently associated with local recurrence in the neck by multivariate analysis. CONCLUSIONS: Although significant improvement of local disease control in patients with thyroid metastases of RCC has been achieved during the last decade, overall outcome continues to be poor for patients with locally invasive thyroid metastases.

Phosphorylation of pyruvate kinase M2 and lactate dehydrogenase A by fibroblast growth factor receptor 1 in benign and malignant thyroid tissue.

BACKGROUND: Lactate dehydrogenase A (LDHA) and Pyruvate Kinase M2 (PKM2) are important enzymes of glycolysis. Both of them can be phosphorylated and therefore regulated by Fibroblast growth factor receptor 1 (FGFR1). While phosphorylation of LDHA at tyrosine10 leads to tetramerization and activation, phosphorylation of PKM2 at tyrosine105 promotes dimerization and inactivation. Dimeric PKM2 is found in the nucleus and regulates gene transcription. Up-regulation and phosphorylation of LDHA and PKM2 contribute to faster proliferation under hypoxic conditions and promote the Warburg effect. METHODS: Using western blot and SYBR Green Real time PCR we investigated 77 thyroid tissues including 19 goiter tissues, 11 follicular adenomas, 16 follicular carcinomas, 15 papillary thyroid carcinomas, and 16 undifferentiated thyroid carcinomas for total expression of PKM2, LDHA and FGFR1. Additionally, phosphorylation status of PKM2 and LDHA was analysed. Inhibition of FGFR was performed on FTC133 cells with SU-5402 and Dovitinib. RESULTS: All examined thyroid cancer subtypes overexpressed PKM2 as compared to goiter. LDHA was overexpressed in follicular and papillary thyroid cancer as compared to goiter. Elevated phosphorylation of LDHA and PKM2 was detectable in all analysed cancer subtypes. The highest relative phosphorylation levels of PKM2 and LDHA compared to overall expression were found in undifferentiated thyroid cancer. Inhibition of FGFR led to significantly decreased phosphorylation levels of PKM2 and LDHA. CONCLUSIONS: Our data shows that overexpression and increased phosphorylation of PKM2 and LHDA is a common finding in thyroid malignancies. Phospho-PKM2 and Phospho-LDHA could be valuable tumour markers for thyroglobulin negative thyroid cancer.

Trans-sectoral care in patients with colorectal cancer: Protocol of the randomized controlled multi-center trial Supportive Cancer Care Networkers (SCAN).

BACKGROUND: Managing therapy-related side-effects and improving health-related quality of life in patients with colorectal cancer is still challenging. The need for an effective management of adverse events and unmet supportive care needs have been widely discussed. In the past decade, interventions by nursing staff gained more and more importance. Evidence suggests that a majority of patients even in early stages of the disease experience substantial impairments potentially resulting in diminished therapy adherence as well as impaired quality of life. However, evidence for the effectiveness of nurse-led interventions on symptom management and quality of life is still very limited. This especially applies to care transitions between different inpatient and outpatient health care providers throughout the course of treatment and aftercare. METHODS/DESIGN: Supportive Cancer Care Networkers (SCAN) is a prospective randomized controlled trial conducted in eight large and middle-sized German cancer centers and municipal hospitals. The target population is adults with colorectal cancer UICC I-III after initial R-0 resection scheduled for adjuvant chemotherapy or guideline-based aftercare only. 370 patients will be randomly assigned to either intervention or control group. Patients in the intervention group will receive an additional support by specialized oncology nurses for eight weeks after discharge from hospital by telephone, consisting of symptom monitoring, counselling on self-assessment and self-management and dealing with individual resources for coping and psychosocial well-being. The primary endpoint will be health-related quality of life (HRQoL) at eight weeks after discharge from the initial treating hospital. DISCUSSION: The presented SCAN trial is to provide information that will be useful to advance our understanding of complex interdependencies between symptom severity, supportive care needs, functioning and the risk for diminished HRQoL. Most importantly, these patient-reported outcomes are not fully implemented in today's clinical routine practice potentially resulting in therapy cessations and lower chemotherapy treatment rates for colorectal cancer especially in older patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01651832.