Genetic and Molecular Biomarkers in Aggressive Pheochromocytomas and Paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are rare neoplasms producing catecholamines that occur as hereditary syndromes in 25-40% of cases. To date, PPGLs are no longer classified as benign and malignant tumors since any lesion could theoretically metastasize, even if it occurs only in a minority of cases (approximately 10-30%). Over the last decades, several attempts were made to develop a scoring system able to predict the risk of aggressive behavior at diagnosis, including the risk of metastases and disease recurrence; unfortunately, none of the available scores is able to accurately predict the risk of aggressive behavior, even including clinical, biochemical, and histopathological features. Thus, life-long follow-up is required in PPGL patients. Some recent studies focusing on genetic and molecular markers (involved in hypoxia regulation, gene transcription, cellular growth, differentiation, signaling pathways, and apoptosis) seem to indicate they are promising prognostic factors, even though their clinical significance needs to be further evaluated. The most involved pathways in PPGLs with aggressive behavior are represented by Krebs cycle alterations caused by succinate dehydrogenase subunits (SDHx), especially when caused by SDHB mutations, and by fumarate hydratase mutations that lead to the activation of hypoxia pathways and DNA hypermethylation, suggesting a common pathway in tumorigenesis. Conversely, PPGLs showing mutations in the kinase cascade (cluster 2) tend to display less aggressive behavior. Finally, establishing pathways of tumorigenesis is also fundamental to developing new drugs targeted to specific pathways and improving the survival of patients with metastatic disease. Unfortunately, the rarity of these tumors and the scarce number of cases enrolled in the available studies represents an obstacle to validating the role of molecular markers as reliable predictors of aggressiveness.

Development of an ontology for laparoscopic transabdominal adrenalectomy via a comprehensive modified Delphi survey and its validation on a multicentric pilot data set for surgical training and future video analysis with machine learning algorithms.

Surgical technique is essential to ensure safe minimally invasive adrenalectomy. Due to the relative rarity of adrenal surgery, it is challenging to ensure adequate exposure in surgical training. Surgical video analysis supports auto-evaluation, expert assessment and could be a target for automatization. The developed ontology was validated by a European expert consensus and is applicable across the surgical techniques encountered in all participating centres, with an exemplary demonstration in bi-centric recordings. Standardization of adrenalectomy video analysis may foster surgical training and enable machine learning training for automated safety alerts.

Management of surgical diseases of Primary Hyperparathyroidism: indications of the United Italian Society of Endocrine Surgery (SIUEC).

A task force of the United Italian society of Endocrine Surgery (SIUEC) was commissioned to review the position statement on diagnostic, therapeutic and health­care management protocol in parathyroid surgery published in 2014, at the light of new technologies, recent oncological concepts, and tailored approaches. The objective of this publication was to support surgeons with modern rational protocols of treatment that can be shared by health-care professionals, taking into account important clinical, healthcare and therapeutic aspects, as well as potential sequelae and complications. The task force consists of 12 members of the SIUEC highly trained and experienced in thyroid and parathyroid surgery. The main topics concern diagnostic test and localization studies, mode of admission and waiting time, therapeutic pathway (patient preparation for surgery, surgical treatment, postoperative management, management of major complications), hospital discharge and patient information, outpatient care and follow-up, outpatient initial management of patients with pHPT.

Italian Guidelines for the Management of Sporadic Primary Hyperparathyroidism.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of sporadic primary hyperparathyroidism (PHPT) in adults. PHPT management in pregnancy was not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) and Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for the clinical practice recommendations. RESULTS: The present GL provides recommendations about the roles of pharmacological and surgical treatment for the clinical management of sporadic PHPT. Parathyroidectomy is recommended in comparison to surveillance or pharmacologic treatment in any adult (outside of pregnancy) or elderly subject diagnosed with sporadic PHPT who is symptomatic or meets any of the following criteria: • Serum calcium levels >1 mg/dL above the upper limit of normal range. • Urinary calcium levels >4 mg/kg/day. • Osteoporosis disclosed by DXA examination and/or any fragility fracture. • Renal function impairment (eGFR <60 mL/min). • Clinic or silent nephrolithiasis. • Age ≤50 years. Monitoring and treatment of any comorbidity or complication of PHPT at bone, kidney, or cardiovascular level are suggested for patients who do not meet the criteria for surgery or are not operated on for any reason. Sixteen indications for good clinical practice are provided in addition to the recommendations. CONCLUSION: The present GL is directed to endocrinologists and surgeons - working in hospitals, territorial services or private practice - and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Tumor Grade and Molecular Characteristics Associated with Survival in Sporadic Medullary Thyroid Carcinoma.

Background: The International Medullary Thyroid Carcinoma Grading System (IMTCGS) divides medullary thyroid carcinoma (MTC) into two categories, high- and low-grade tumors, which has a profound impact on patient outcomes. The aim of this study was to explore the association between IMTCGS grading, clinical data, and molecular status in sporadic MTC. Methods: A retrospective cohort study was performed on consecutive sporadic MTCs from patients undergoing initial surgery between January 2000 and January 2022 at the Padua Endocrine Surgery Unit. Clinical, pathological, and follow-up data were collected, tumors were graded, and somatic mutations of RET and RAS genes were analyzed. Patient outcomes were based on Ct levels and MTC-related deaths. Survival analyses were carried out employing the Kaplan-Meier method and the log-rank test. A Cox proportional hazard regression model was employed for multivariable survival analysis with the following covariates: somatic RET mutation, MTC stage at diagnosis, sex, age at diagnosis, and IMTCGS grade. Results: We included 141 consecutive sporadic MTCs. The median follow-up was 80.0 months (interquartile ranges: 41.5-122.5 months). Seventeen patients (12.1%) died from disease-related causes. 107/141 (76.9%) were classified as low-grade tumors, 32/141 (23.1%) as high-grade. Patients carrying a RET mutation had more aggressive features and shorter disease-specific survival (DSS) (p = 0.001) and were more frequently classified high-grade than low-grade MTC (p < 0.001). At multivariable survival analysis, only IMTCGS grading was independently associated with DSS (hazard ratio 8.8 [confidence interval: 2.7-28.3], p = 0.005). RET mutations, in particular RET-M918T, were more frequent in high-grade than in low-grade MTC (68.8% vs. 29.4% mutated in RET, 46.9% vs. 12.7% mutated in RET-M918T; p < 0.001). None of the high-grade tumors was mutated in the RAS gene, but the mutation was present in 11.8% of low-grade tumors. Conclusions: IMTCGS grading was associated with DSS independently of other clinical, pathological, and molecular factors. Moreover, MTC grading was associated with RET and RAS patterns, which explains, at least in part, the molecular basis of the aggressive behavior of high-grade MTC.

Water and Electrolyte Content in Salt-Dependent HYpertension in the SKIn (WHYSKI): Effect of Surgical Cure of Primary Aldosteronism.

 INTRODUCTION: This study will test the hypothesis that primary aldosteronism (PA) involves alterations in Na+, K+, and water content in the skin that are corrected by adrenalectomy. AIM AND METHODS: In skin biopsies, we will measure the content of Na+, K+, water, by physical-chemical methods and the osmotic-stress-responsive transcription factor Tonicity-responsive Enhancer Binding Protein (TonEBP, NFAT5) mRNA copy number by droplet digital PCR, in sex-balanced cohorts of 18 -75-year-old consecutive consenting patients with unilateral and bilateral PA, primary (essential) hypertension, and normotension. Before surgery, the patients with unilateral PA will receive the mineralocorticoid receptor antagonist (MRA) canrenone at doses that correct hypokalemia and high blood pressure values. They will be reassessed in an identical way one month after surgical cure, while off MRA. PA patients not selected for adrenalectomy will similarly be assessed at diagnosis and follow-up while on stable MRA treatment. Since a pilot study showed a direct correlation of dry weight (DW) with skin electrolytes and water content and significant differences of biopsy DW between surgery and follow-up, meaningful comparison of the skin cations and water content and TonEBP mRNA copy number, between specimen obtained at different time points, will require DW- and total mRNA-adjustment, respectively. CONCLUSION: This study will provide novel information on the skin Na+, K+ and water content in PA, the paradigm of salt-dependent hypertension, and novel knowledge on the effect of surgical cure of hyperaldosteronism. The TonEBP-mediated regulation of Na+, K+ and water content in the skin will also be unveiled. TRAIL REGISTRY: Trial Registration number: NCT06090617. Date of Registration: 2023-10-19.

Total adrenalectomy versus subtotal adrenalectomy for bilateral pheochromocytoma: meta-analysis.

BACKGROUND: Bilateral pheochromocytomas are rare and often heritable. Total adrenalectomy leads to a definitive oncological cure, with subsequent definitive hypocortisolism. Subtotal adrenalectomy is a possible alternative. The aim of this study was to assess the effects of total adrenalectomy and subtotal adrenalectomy on bilateral pheochromocytoma in terms of post-surgical rate of recurrence, metastatic disease, and steroid dependence. METHODS: Systematic searches in the bibliographic databases PubMed, Embase, and Europe PMC were performed for 1945 to 1 June 2023. PRISMA guidelines were followed and the PICO strategy was applied to English-language studies comparing subtotal adrenalectomy with total adrenalectomy. A random-effects model was used to assess the different outcomes for studies with high heterogeneity. The Newcastle-Ottawa scale and the Risk Of Bias In Non-randomized Studies of Interventions ('ROBINS-I') tool were used to assess quality and risk of bias. RESULTS: From a total of 12 909 studies, 1202 patients (from 10 retrospective studies) were eligible for the meta-analysis. In six studies, including 1176 patients, the recurrence rate after subtotal adrenalectomy and total adrenalectomy was 14.1 versus 2.6 per cent respectively (OR 4.91, 95 per cent c.i. 1.30 to 18.54; P = 0.020; I2 72 per cent). In nine studies, including 1124 patients, the rate of post-surgical steroid dependence was 93.3 versus 11.6 per cent after total adrenalectomy and subtotal adrenalectomy respectively (OR 0.003, 95 per cent c.i. 0.0003 to 0.03; P < 0.00001; I2 66 per cent). Based on two studies, including 719 patients, no differences were evident regarding the occurrence of post-surgery metastatic disease. CONCLUSION: Subtotal adrenalectomy leads to less post-surgical primary adrenal insufficiency, but leads to a higher postoperative recurrence rate. Future prospective randomized studies, with clear eligibility criteria, are needed to confirm these results.

Parathyroid Retrospective Analysis of Neoplasms Incidence (pTRANI Study): An Italian Multicenter Study on Parathyroid Carcinoma and Atypical Parathyroid Tumour.

BACKGROUND: Parathyroid cancer (PC) is a rare sporadic or hereditary malignancy whose histologic features were redefined with the 2022 WHO classification. A total of 24 Italian institutions designed this multicenter study to specify PC incidence, describe its clinical, functional, and imaging characteristics and improve its differentiation from the atypical parathyroid tumour (APT). METHODS: All relevant information was collected about PC and APT patients treated between 2009 and 2021. RESULTS: Among 8361 parathyroidectomies, 351 patients (mean age 59.0 ± 14.5; F = 210, 59.8%) were divided into the APT (n = 226, 2.8%) and PC group (n = 125, 1.5%). PC showed significantly higher rates (p < 0.05) of bone involvement, abdominal, and neurological symptoms than APT (48.8% vs. 35.0%, 17.6% vs. 7.1%, 13.6% vs. 5.3%, respectively). Ultrasound (US) diameter >3 cm (30.9% vs. 19.3%, p = 0.049) was significantly more common in the PC. A significantly higher frequency of local recurrences was observed in the PC (8.0% vs. 2.7%, p = 0.022). Mortality due to consequences of cancer or uncontrolled hyperparathyroidism was 3.3%. CONCLUSIONS: Symptomatic hyperparathyroidism, high PTH and albumin-corrected serum calcium values, and a US diameter >3 cm may be considered features differentiating PC from APT. 2022 WHO criteria did not impact the diagnosis.

Long-Term Outcomes after Surgery for Pheochromocytoma and Sympathetic Paraganglioma.

BACKGROUND: The prognosis of pheochromocytoma and sympathetic paraganglioma (PHEO/sPGL) is difficult to predict at the time of diagnosis and long-term follow-up data are scarce, especially for apparently benign and sporadic variants. The aim of the study was to analyze the long-term outcomes in PHEO/sPGL patients. METHODS: A monocentric series of 170 patients who underwent surgery for PHEO/sPGL was analyzed. RESULTS: The study cohort included 91 female and 79 males with a median age of 48 years (range 6-83). The majority of PHEO/sPGL cases were considered apparently benign at the time of diagnosis; evident malignant behavior was found in 5% of cases. The overall 10-year risk of recurrence was 13%, but it rose up to 33% at 30 years. The risk of new tumor recurrence was higher in patients with hereditary tumors, but the risk was still significant in patients with apparently sporadic variants (20-year risk: 38% vs. 6.5%, respectively; p < 0.0001). The risk of metastatic recurrence was higher in patients with locally aggressive tumors at diagnosis, but the risk was present also in apparently benign variants (5-year risk: 100% vs. 1%, respectively; p < 0.0001). CONCLUSIONS: Lifelong follow-up is required not only for hereditary PHEO/sPGL but also for apparently benign and sporadic tumors at diagnosis because of the risk of long-term recurrent disease.

Validation of miRNAs as diagnostic and prognostic biomarkers, and possible therapeutic targets in medullary thyroid cancers.

Introduction: Medullary thyroid cancer (MTC) is a rare type of neuroendocrine tumor that produces a hormone called calcitonin (CT). Thyroidectomy is the preferred treatment for MTC, as chemotherapy has been shown to have limited effectiveness. Targeted therapy approaches are currently being used for patients with advanced, metastatic MTC. Several studies have identified microRNAs, including miR-21, as playing a role in the development of MTC. Programmed cell death 4 (PDCD4) is a tumor suppressor gene that is an important target of miR-21. Our previous research has shown that high levels of miR-21 are associated with low PDCD4 nuclear scores and high CT levels. The aim of this study was to investigate the potential of this pathway as a novel therapeutic target for MTC. Methods: We used a specific process to silence miR-21 in two human MTC cell lines. We studied the effect of this anti-miRNA process alone and in combination with cabozantinib and vandetanib, two drugs used in targeted therapy for MTC. We analyzed the effect of miR-21 silencing on cell viability, PDCD4 and CT expression, phosphorylation pathways, cell migration, cell cycle, and apoptosis. Results: Silencing miR-21 alone resulted in a reduction of cell viability and an increase in PDCD4 levels at both mRNA and protein levels. It also led to a reduction in CT expression at both mRNA and secretion levels. When combined with cabozantinib and vandetanib, miR-21 silencing did not affect cell cycle or migration but was able to enhance apoptosis. Conclusion: Silencing miR-21, although not showing synergistic activity with TKIs (tyrosine kinase inhibitors), represents a potential alternative worth exploring as a therapeutic target for MTC.

Therapeutic Plasma Exchange for the Treatment of Hyperthyroidism: Approach to the Patient with Thyrotoxicosis or Antithyroid-Drugs Induced Agranulocytosis.

Primary hyperthyroidism is an endocrine disorder characterized by excessive thyroid hormone synthesis and secretion by the thyroid gland. Clinical manifestations of hyperthyroidism can vary from subclinical to overt forms. In rare cases, hyperthyroidism may represent a clinical emergency, requiring admission to an intensive care unit due to an acute and severe exacerbation of thyrotoxicosis, known as a thyroid storm. First-line treatment of hyperthyroidism is almost always based on medical therapy (with thioamides, beta-adrenergic blocking agents, glucocorticoids), radioactive iodine or total thyroidectomy, tailored to the patient's diagnosis. In cases of failure/intolerance/adverse events or contraindication to these therapies, as well as in life-threatening situations, including a thyroid storm, it is necessary to consider an alternative treatment with extracorporeal systems, such as therapeutic plasma exchange (TPE). This approach can promptly resolve severe conditions by removing circulating thyroid hormones. Here we described two different applications of TPE in clinical practice: the first case is an example of thyrotoxicosis due to amiodarone treatment, while the second one is an example of a severe adverse event to antithyroid drugs (agranulocytosis induced by methimazole).

CT Texture Analysis of Adrenal Pheochromocytomas: A Pilot Study.

Radiomics is a promising research field that combines big data analysis (from tissue texture analysis) with clinical questions. We studied the application of CT texture analysis in adrenal pheochromocytomas (PCCs) to define the correlation between the extracted features and the secretory pattern, the histopathological data, and the natural history of the disease. A total of 17 patients affected by surgically removed PCCs were retrospectively enrolled. Before surgery, all patients underwent contrast-enhanced CT and complete endocrine evaluation (catecholamine secretion and genetic evaluation). The pheochromocytoma adrenal gland scaled score (PASS) was determined upon histopathological examination. After a resampling of all CT images, the PCCs were delineated using LifeX software in all three phases (unenhanced, arterial, and venous), and 58 texture parameters were extracted for each volume of interest. Using the Mann-Whitney test, the correlations between the hormonal hypersecretion, the malignancy score of the lesion (PASS > 4), and texture parameters were studied. The parameters DISCRETIZED_HUpeak and GLZLM_GLNU in the unenhanced phase and GLZLM_SZE, CONVENTIONAL_HUmean, CONVENTIONAL_HUQ3, DISCRETIZED_HUmean, DISCRETIZED_AUC_CSH, GLRLM_HGRE, and GLZLM_SZHGE in the venous phase were able to differentiate secreting PCCs (p < 0.01), and the parameters GLZLM_GLNU in the unenhanced phase and GLRLM_GLNU and GLRLM_RLNU in the venous differentiated tumors with low and high PASS. CT texture analysis of adrenal PCCs can be a useful tool for the early identification of secreting or malignant tumors.

The role of procalcitonin in the follow-up of medullary thyroid cancer.

Objective: Calcitonin (Ct) represents the most important biochemical marker of medullary thyroid cancer (MTC), but has certain limits. We analyzed the performance of procalcitonin (ProCt) in follow-up MTC patients. Methods: In this monocentric and retrospective study, we consecutively obtained ProCt and Ct values from all MTC patients that we visited during the period from April 2021 to May 2022. Patients were defined as having structural evidence of disease (29/90, 32.2%) irrespective of Ct values or, in its absence, as not evident disease (NED) if Ct was ≤10 ng/L (47/90, 52.2%), or minimal residual disease if Ct was >10 ng/L (14/90, 15.6%). Results: Ct and ProCt values were highly correlated (r = 0.883, P < 0.01). Median ProCt values differed between NED, minimal residual disease, and structural disease, being 0.04 ng/mL, 0.26 ng/mL, and 1.98 ng/mL, respectively (P < 0.01). ProCt was undetectable (<0.04 ng/mL) in 40/47 (85.1%) of NED patients, in 3/14 (21.4%) patients with minimal residual disease and in none of the patients with a structural disease (P < 0.01). Among the 11 patients with detectable but ≤10 ng/L Ct and undetectable ProCt values, none had a structural disease. The most accurate cut-off of ProCt to distinguish between the presence or absence of a structural disease was >0.12 ng/mL (P < 0.01, area under the curve: 0.963), with the following sensitivity, specificity, positive predictive value, and negative predictive value (NPV): 100%, 83.61%, 74.4%, and 100.0%. Conclusions: ProCt and Ct have a high correlation in MTC follow-up. ProCt may be useful as an adjunct to Ct, especially for its NPV concerning the structural disease.

Prophylactic and Early Thyroidectomy in RET Germline Mutation Carriers in Pediatric and Adult Population: Long-Term Outcomes of a Series of 63 Patients.

Prophylactic and early thyroidectomy in RET germline mutation carriers allows the removal of the thyroid before medullary thyroid carcinoma (MTC) develops, or while it is still confined to the gland. This study was aimed to assess the clinicopathological features in RET carriers according to the age at surgery and the long-term outcomes after prophylactic and early thyroidectomy. A retrospective analysis of 63 operated asymptomatic RET carriers diagnosed after familial genetic screening was performed. Twenty-one RET carriers were operated at pediatric (<18 yrs) and 42 at adult (≥18 yrs) age. Serum preoperative calcitonin levels were significantly lower in pediatric compared to adult patients (p = 0.04); moreover, adult RET carriers had a greater frequency of microMTC at pathology (p = 0.009). Permanent postoperative morbidity occurred in 9.5% of patients, without differences between the two groups. Biochemical postoperative cure was achieved in all patients. At a median follow-up of 14 years, all C-cell hyperplasia patients are disease-free; conversely, biochemical, and structural recurrence of disease occurred in three adults and one pediatric patient with microMTC. The independent predictive factors of MTC were the age at surgery, the preoperative calcitonin level and the RET mutational risk profile (p < 0.02). In conclusion, prophylactic and early thyroidectomy are safe and effective procedures in achieving definitive cure in most RET carriers. However, since recurrences may occur at long-term in case of microMTC, thyroidectomy should be possibly performed earlier to prevent microMTC development.

The Overall Survival and Progression-Free Survival in Patients with Advanced Adrenocortical Cancer Is Increased after the Multidisciplinary Team Evaluation.

We aimed to evaluate the role of adrenal multidisciplinary team evaluation (MTE) in affecting the overall survival (OS) and progression-free survival (PFS) in patients with adrenocortical carcinoma (ACC). We included in a retrospective monocentric study 47 patients with ACC. We divided our cohort into group 1 (without adrenal-MTE discussion, ACC diagnosis from 2004 to 2012, n = 14) and group 2 (diagnosis and beginning of treatments after 2013, all discussed in the adrenal MTE, n = 33). OS was defined by the survival between the first and the last visit, while PFS as the time from the first visit to the progression of the disease. Kaplan−Meier curves were used to compare OS and PFS between Group 1 and Group 2. Group 1stages III−IV (n = 10) presented a shorter median OS than Group 2stages III−IV (25 patients, 4 vs. 31 months, p = 0.023). Likewise, the median PFS was lower in Group 1 as compared to Group 2 (2.9 vs. 17.2 months, p < 0.001). The gain in PFS (6 months) was also confirmed in stage III-IV patients (2.9 vs. 8.7 months, respectively, for Group 1 and Group 2, p = 0.02). Group 1 presented a median PFS of 4 months, while the median PFS of Group 2 was 14.7 months (p = 0.128). In conclusion, we found a significant gain in terms of survival in patients after the MTE discussion in 2013. Therefore, ACC patients should be referred to a tertiary center, ideally from the time of diagnosis, to promptly apply all available treatments, according to the single patient's clinical history and based on multidisciplinary management.

Overexpression of miR-375 and L-type Amino Acid Transporter 1 in Pheochromocytoma and Their Molecular and Functional Implications.

Pheochromocytoma (Pheo) is a tumor derived from chromaffin cells. It can be studied using 18F-dihydroxyphenylalanine (DOPA)-positron emission tomography (PET) due to its overexpression of L-type amino acid transporters (LAT1 and LAT2). The oncogenic pathways involved are still poorly understood. This study examined the relationship between 18F-DOPA-PET uptake and LAT1 expression, and we explored the role of miR-375 and putative target genes. A consecutive series of 58 Pheo patients were retrospectively analyzed, performing 18F-DOPA-PET in 32/58 patients. Real-time quantitative PCR was used to assess the expression of LAT1, LAT2, phenylethanolamine N-methyltransferase (PNMT), miR-375, and the major components of the Hippo and Wingless/Integrated pathways. Principal germline mutations associated with hereditary Pheo were also studied. Pheo tissues had significantly higher LAT1, LAT2, and PNMT mRNA levels than normal adrenal tissues. MiR-375 was strongly overexpressed. Yes-associated protein 1 and tankyrase 1 were upregulated, while beta-catenin, axin2, monocarboxylate transporter 8, and Frizzled 8 were downregulated. A positive relationship was found between 18F-DOPA-PET SUV mean and LAT1 gene expression and for 24 h-urinary norepinephrine and LAT1. This is the first experimental evidence of 18F-DOPA uptake correlating with LAT1 overexpression. We also demonstrated miR-375 overexpression and downregulated (Wnt) signaling and identified the Hippo pathway as a new potentially oncogenic feature of Pheo.

The GIP/GIPR axis in medullary thyroid cancer: clinical and molecular findings.

The improper expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) and the GIP/GIPR axis activation has been increasingly recognized in endocrine tumors, with a potential diagnostic and prognostic value. A high tumor-to-normal tissue ratio (T/N ratio) of GIPR was reported both in humans' and in rats' medullary thyroid cancer (MTC), suggesting a direct link between the neoplastic transformation and the mechanism of receptor overexpression. In this study, we evaluated the potential diagnostic and prognostic significance of GIPR expression in a large cohort of MTC patients by correlating GIPR mRNA steady-state levels to clinical phenotypes. The molecular effect of GIP/GIPR axis stimulation in MTC-derived cells was also determined. We detected GIPR expression in ~80% of tumor specimens, especially in sporadic, larger, advanced-stage cancers with higher Ki-67 values. GIPR stimulation induced cAMP elevation in MTC-derived cells and a small but significant fluctuation in Ca2+, both likely associated with increased calcitonin secretion. On the contrary, the effects on PI3K-Akt and MAPK-ERK1/2 signaling pathways were marginal. To conclude, our data confirm the high T/N GIPR ratio in MTC tumors and suggest that it may represent an index for the degree of advancement of the malignant process. We have also observed a functional coupling between GIP/GIPR axis and calcitonin secretion in MTC models. However, the molecular mechanisms underlying this process and the possible implication of GIP/GIPR axis activation in MTC diagnosis and prognosis need further evaluation.

Can ultrasensitive thyroglobulin immunoassays avoid the need for ultrasound in thyroid cancer follow-up?

PURPOSE: Differentiated thyroid cancer (DTC) is the most common endocrine neoplasm, with a rising incidence and a long life expectancy. It has recently been suggested that patients with low- and intermediate-risk DTC with a good response to treatment at one year could be followed up using only highly sensitive immunoassays for thyroglobulin (Tg). The aim of this study was to examine the serum Tg levels in a series of DTC patients with histologically proven persistent or recurrent diseases. METHODS: The study involved 50 consecutive patients being routinely followed up at our center, whose clinical, histological, and biochemical data were retrospectively collected. RESULTS: The false-negative rate of ultrasensitive serum Tg assay was 14.3% (5/35) overall, and limited to anti-thyroglobulin autoantibodies (TgAb)-negative patients. Among them, only one patient had an excellent response to treatment at one-year follow-up and was diagnosed with a 4 mm recurrence, after more than seven years of periodic ultrasounds. The size of the neck lesion documented in the histological report was slightly larger in patients with detectable as opposed to negative Tg values (P < 0.05). CONCLUSIONS: Serum highly sensitive Tg is undetectable in a proportion of patients with a proven persistent or recurrent DTC. The reasons behind this phenomenon are still unknown. However, in low/intermediate-risk patients cured at one-year follow-up, highly sensitive Tg without neck US seems an appropriate strategy for patients' management.