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Open access

Marine Sitbon, Porhuoy Chou, Seydou Bengaly, Brigitte Poirot, Marie Laloi-Michelin, Laure Deville, Atanas Pachev, Ahouefa Kowo-Bille, Clement Dumont, and Cécile N Chougnet

The endocrine secretions of carcinomas can be life-threatening. Medullary thyroid carcinoma (MTC) is a rare cancer that is often associated with cortisol secretion, leading to paraneoplastic Cushing’s syndrome. Mutations of the proto-oncogene RET are driver molecular events in 70% of MTC cases. Here, we report a case of a woman, born in 1956, who was diagnosed with sporadic MTC in 2005, with subsequent relapses treated with focal treatments. In April 2019, she presented with severe and rapidly progressive paraneoplastic Cushing’s syndrome associated with lymph node, lung, liver and bone metastases. A supraclavicular lymph node biopsy revealed a somatic p.M918T (c.2753T>C) mutation in exon 16 of the RET proto-oncogene. The patient began treatment with selpercatinib in September 2019. Clinical efficacy was immediate. Chronic diarrhea disappeared within a few days. Clinical hypercorticism quickly disappeared, with quick improvements in muscle and skin conditions and fatigue. Two months after treatment initiation, urinary free cortisol normalized to 42 µg/24 h. Levels of the tumor markers carcinoembryonic antigen (CEA) and calcitonin also greatly decreased from baseline. After 34 months of treatment, selpercatinib elicits sustained clinical, biological and morphological responses. In summary, this case report illustrates the rapid and long-lasting antisecretory effect of selpercatinib associated with tumor control. As Cushing’s syndrome associated with medullary thyroid cancer is associated with poor prognosis, this case report is very encouraging. In addition, this suggests the potential benefit of molecular testing in all cases of medullary thyroid cancer.

Open access

Paolo Cavarzere, Laura Palma, Lara Nicolussi Principe, Monica Vincenzi, Silvana Lauriola, Rossella Gaudino, Virginia Murri, Luigi Lubrano, Giuliana Rossi, Alessia Sallemi, Ermanna Fattori, Marta Camilot, and Franco Antoniazzi

Introduction

Infants of mothers with autoimmune hypothyroidism (AH) are at risk of developing late-onset hypothyroidism, often escaping at newborn screening. This condition might be caused both by the action of maternal antibodies and/or by maternal treatment.

Objectives

The aim of this study is to evaluate the prevalence of AH in the mothers of children born in Veneto region, Italy, and to define what is the most appropriate management for these newborns.

Methods

Newborns of six different hospitals with a mother suffering from AH and with negative neonatal screening for congenital hypothyroidism (CH) were included in the study. Between 15 and 20 days of life, we collected a serum sample for the evaluation of thyroid function (thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3)) and anti-thyroid antibodies. On the same occasion, a capillary blood sampling was performed for a second screening test.

Results

Maternal AH has a prevalence of 3.5%. A total of 291 newborns were enrolled from November 2019 to May 2021. Whereas the 11.4% of infants had a slight elevated serum TSH (>6 mU/L) and required a follow-up, only 2 children presented an elevated TSH level at the second screening test. One of these, with the gland in situ, showed persistently elevated serum TSH levels and required treatment with levothyroxine.

Conclusions

Maternal AH rarely caused neonatal thyroid dysfunction. We suggest to reassess newborns from mothers with AH 15 days after birth by means of a second neonatal screening test. This procedure avoids false negatives due to maternal thyroid status, is less invasive and cheaper than the serum TSH evaluation, and prevents a long follow-up.

Open access

Roberto Fiore, Stefano La Rosa, Silvia Uccella, Deborah Marchiori, and Peter A Kopp

Introduction

Consumptive hypothyroidism is a rare paraneoplastic condition most commonly associated with infantile hemangiomas. It is caused by overexpression of deiodinase type 3 (D3), which leads to preferential conversion of thyroxine to the metabolically inactive reverse triiodothyronine (rT3), paralleled by a decrease of the biologically active T3.

Case presentation

A 46-year-old male patient with previously normal thyroid function was diagnosed with a renal carcinoma with rhabdoid differentiation. He was treated with sunitinib, followed by the immune checkpoint inhibitors ipilimumab and nivolumab, and he developed primary hypothyroidism secondary to thyroiditis. Substitution with unusually high doses of levothyroxine as high as 4.3 µg/kg/day did not normalize his thyroid function. Poor compliance was refuted because there was no improvement after observed administration. He had no malabsorption. Although tyrosine kinase inhibitors can increase the expression of D3, this effect tends to be modest. Therefore, the suspicion of tumor-related consumptive hypothyroidism was raised and supported by low free T3 and elevated rT3 levels. The therapy could not be further modified because the patient opted for palliative care and passed away 12 days later.

Immunohistochemistry of the tumor from a sample obtained prior to systemic therapy documented abundant expression of D3, corroborating the diagnosis of consumptive hypothyroidism.

Conclusions

This observation extends the spectrum of malignancies overexpressing D3. Although rare, increased awareness of this paraneoplastic syndrome is key, if persistent hypothyroidism cannot be explained by compliance issues or malabsorption. Substitution with high doses of levothyroxine, and combination therapy with liothyronine, can correct hypothyroidism in these patients.

Open access

Giulia Brigante, Clara Lazzaretti, Elia Paradiso, Federico Nuzzo, Martina Sitti, Frank Tüttelmann, Gabriele Moretti, Roberto Silvestri, Federica Gemignani, Asta Försti, Kari Hemminki, Rossella Elisei, Cristina Romei, Eric Adriano Zizzi, Marco Agostino Deriu, Manuela Simoni, Stefano Landi, and Livio Casarini

To identify a peculiar genetic combination predisposing to differentiated thyroid carcinoma (DTC), we selected a set of single nucleotide polymorphisms (SNPs) associated with DTC risk, considering polygenic risk score (PRS), Bayesian statistics and a machine learning (ML) classifier to describe cases and controls in three different datasets. Dataset 1 (649 DTC, 431 controls) has been previously genotyped in a genome-wide association study (GWAS) on Italian DTC. Dataset 2 (234 DTC, 101 controls) and dataset 3 (404 DTC, 392 controls) were genotyped. Associations of 171 SNPs reported to predispose to DTC in candidate studies were extracted from the GWAS of dataset 1, followed by replication of SNPs associated with DTC risk (P < 0.05) in dataset 2. The reliability of the identified SNPs was confirmed by PRS and Bayesian statistics after merging the three datasets. SNPs were used to describe the case/control state of individuals by ML classifier. Starting from 171 SNPs associated with DTC, 15 were positive in both datasets 1 and 2. Using these markers, PRS revealed that individuals in the fifth quintile had a seven-fold increased risk of DTC than those in the first. Bayesian inference confirmed that the selected 15 SNPs differentiate cases from controls. Results were corroborated by ML, finding a maximum AUC of about 0.7. A restricted selection of only 15 DTC-associated SNPs is able to describe the inner genetic structure of Italian individuals, and ML allows a fair prediction of case or control status based solely on the individual genetic background.

Open access

Juan Antonio Vallejo Casas, Marcel Sambo, Carlos López López, Manuel Durán-Poveda, Julio Rodríguez-Villanueva García, Rita Joana Santos, Marta Llanos, Elena Navarro-González, Javier Aller, Virginia Pubul, Sonsoles Guadalix, Guillermo Crespo, Cintia González, Carles Zafón, Miguel Navarro, Javier Santamaría-Sandi, Ángel Segura, Pablo Gajate, Marcelino Gómez-Balaguer, Javier Valdivia, Manel Puig-Domingo, Juan Carlos Galofré, Beatriz Castelo, María José Villanueva, Iñaki Argüelles, and Lorenzo Orcajo-Rincón

Background

Up to 30% of differentiated thyroid cancer (DTC) will develop advanced-stage disease (aDTC) with reduced overall survival (OS).

Objective

The aim of this study is to characterize initial diagnosis of aDTC, its therapeutic management, and prognosis in Spain and Portugal.

Methods

A multicentre, longitudinal, retrospective study of adult patients diagnosed with aDTC in the Iberian Peninsula was conducted between January 2007 and December 2012. Analyses of baseline characteristics and results of initial treatments, relapse- or progression-free survival ((RP)FS) from first DTC diagnosis, OS, and prognostic factors impacting the evolution of advanced disease were evaluated.

Results

Two hundred and thirteen patients (median age: 63 years; 57% female) were eligible from 23 hospitals. Advanced disease presented at first diagnosis (de novo aDTC) included 54% of patients, while 46% had relapsed from early disease (recurrent/progressive eDTC). At initial stage, most patients received surgery (98%) and/or radioiodine (RAI) (89%), with no differences seen between median OS (95% CI) (10.4 (7.3–15.3) years) and median disease-specific-survival (95% CI) (11.1 (8.7–16.2) years; log-rank test P = 0.4737). Age at diagnosis being <55 years was associated with a lower risk of death (Wald chi-square (Wc-s) P < 0.0001), while a poor response to RAI to a higher risk of death ((Wc-s) P < 0.05). In the eDTC cohort, median (RP)FS (95% CI) was of 1.7 (1.0–2.0) years after RAI, with R0/R1 surgeries being the only common significant favourable factor for longer (RP)FS and time to aDTC ((Wc-s) P < 0.05).

Conclusion

Identification of early treatment-dependent prognostic factors for an unfavourable course of advanced disease is possible. An intensified therapeutic attitude may reverse this trend and should be considered in poor-performing patients. Prospective studies are required to confirm these findings.

Open access

Liyun Shen, Lei Ye, Wei Zhu, Qin Jiao, Yulin Zhou, Shu Wang, Weiqing Wang, and Guang Ning

Objective

A combination of glucocorticoids with mycophenolate is recommended by current guidelines to boost response to Graves’ orbitopathy (GO) therapy. This study was designed to evaluate the therapeutic effects and safety of methotrexate (MTX) plus reduced (3.0 g) or full-dose (4.5 g) i.v. methylprednisolone (MP) vs full-dose i.v. MP alone.

Design and methods

This was a prospective, randomized, observer-masked, single-center clinical trial conducted in a tertiary clinical center. Ninety-seven patients with active moderate-to-severe GO were screened and 90 patients underwent randomization between April 2018 and Oct 2019. All patients completed 12 weeks of treatment and received clinical assessment. The patients received either MP 4.5 g only, MP 4.5 g plus oral MTX, or MP 3.0 g plus oral MTX. The primary outcome was the CAS response at week 12. Secondary outcomes were adverse events and other individual ophthalmic parameters.

Results

At week 12, 53.3% of MP, 76.7% of reduced MP plus MTX, and 76.7% of MP plus MTX achieved a CAS response, although the difference was not significant (P = 0.1). The overall response rates of the MP group, the reduced MP plus MTX group, and the MP plus MTX group were 43.3%, 53.3%, and 60%, respectively (P = 0.5). Subgroup analysis found that smoking status interacted with marginal significance with treatment effect (P = 0.048). Importantly, adverse event incidence was significantly lower in the reduced MP + MTX group (P = 0.017).

Conclusions

Our study shows that reduced MP plus MTX therapy is effective and safer in treating active and moderate-to-severe GO patients than 4.5 g MP monotherapy.

Open access

Annamaria Erdei, Annamaria Gazdag, Bernadett Ujhelyi, Edit B Nagy, Ervin Berenyi, Eszter Berta, Zita Steiber, Sandor Barna, Emese Mezosi, Miklos Bodor, and Endre V Nagy

Introduction

Dysthyroid optic neuropathy (DON) is a rare, severe form of thyroid eye disease, in which decreased visual acuity is accompanied by characteristic MRI findings. The treatment of DON has always been a challenge.

Case presentation

In a patient in whom visual acuity deteriorated on the left eye, mannitol 20% 200 mL followed by furosemide 40 mg 6 h later, administered daily, were initiated on the day of admission. Visual function by ophthalmology methods, and orbital compartment volumes and water content by MRI were followed. Intravenous diuretics resulted in an immediate therapeutic response. Visual acuity improved from 20/50 to 20/25 after 2 days of treatment. MRI revealed decreasing water content of both the muscle and connective tissue compartments without any volume changes. Subsequently, corticosteroids and orbital irradiation were started. Orbital decompression surgery was not required.

Discussion/conclusion

Edematous swelling of orbital tissues is an established contributor of local pressure increase in thyroid eye disease. Diuretics reduce orbital pressure and, if confirmed by others, may be useful additions to the standard of care in sight-threatening DON.

Open access

Jihwan Yoo, Hee Jun Kim, Seok Mo Kim, and Hun Ho Park

Introduction

Brain metastasis in differentiated thyroid cancer (DTC) is rare (frequency < 1%) and has a poor prognosis. Treatment strategies for brain metastasis are not well established.

Objectives

We conducted a retrospective analysis to identify predictive factors for patient outcomes and verify surgical indications for patients with brain metastasis and DTC.

Methods

The study included 34 patients with pathologically confirmed DTC with brain metastasis from March 2008 to November 2020. The associations between overall survival (OS) and clinical factors were evaluated. Cox regression analysis was used to determine the relationship between clinical factors and OS. To assess the survival benefit of craniotomy, Kaplan–Meier survival analysis was performed for each variable whose statistical significance was determined by Cox regression analysis.

Results

The median OS of the entire patient sample was 11.4 months. Survival was affected by the presence of lung metastasis (P = 0.033) and the number of brain metastases (n  > 3) (P = 0.039). Only the subgroup with the number of brain metastases ≤3 showed statistical significance in the subgroup analysis of survival benefit following craniotomy (P = 0.048).

Conclusions

The number of brain metastases and the existence of lung metastasis were regarded more essential than other clinical factors in patients with DTC in this study. Furthermore, craniotomies indicated a survival benefit only when the number of brain metastases was ≤3. This finding could be beneficial in determining surgical indications in thyroid cancer with brain metastasis.

Open access

Ségolène Hescot, Julien Masliah-Planchon, Pauline du Rusquec, Célia Dupain, Maud Kamal, Vincent Servois, and Ivan Bieche

Open access

Bernadette L. Dekker, Anouk N.a. van der Horst-Schrivers, Adrienne H. Brouwers, Christopher M. Shuford, Ido P. Kema, Anneke C. Muller Kobold, and Thera P Links

Objective: Thyroglobulin(Tg) is an established tumor marker for differentiated thyroid carcinoma (DTC) patients. However, Tg immunoassays can be subject to Tg autoantibody(TgAb) interference resulting in incorrect Tg values. Therefore, Tg measurement with liquid chromatography-tandem mass spectrometry(LC-MS/MS) could be promising in patients with TgAbs. We compared a Tg immunoradiometric assay (Tg-IRMA) and a Tg-LC-MS/MS analytically in the presence of TgAbs. Furthermore, we compared the clinical interpretation of results obtained by both Tg assays in DTC patients with lower TgAbs titers (<10 U/ml) during 131I ablation therapy.

Methods: 118 DTC patients diagnosed between 2006 and 2014 in a University Medical Center were followed with the Tg-IRMA and ARCHITECT Anti-Tg assays. We re-analyzed their samples with a sensitive Tg-LC-MS/MS method (limit of quantification of 0.02 ng/ml). Passing-Bablok regression analysis was performed on samples obtained during 131I ablation therapy and follow-up.

Results: In 304 samples with lower TgAb titers, a good analytical agreement was found between both Tg assays (slope of 1.09 (95% CI 1.05 - 1.16)). Fifty-five samples with potentially interfering TgAbs showed higher Tg-LC-MS/MS values than Tg-IRMA (slope of 1.45 (95% CI 1.12->>100)). In patients (n=91) with lower TgAb titers at the time of 131I ablation therapy, the Tg assays showed a clinical concordance of 91.2%, 87.9%, and 98.9%, respectively, using a Tg cut-off value of 1.0 ng/mL, 2.0 ng/mL and 5.0 ng/mL.

Conclusions: In DTC patients with lower titer TgAbs, Tg-IRMA is still a reliable and useful tumor marker. In DTC patients with potentially interfering TgAbs, Tg-IRMA values are decreased due to TgAb interference.