Novel therapies against aggressive differentiated thyroid carcinomas

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Isolated adrenal metastases of papillary thyroid carcinoma

Funding Information: The authors thank the Pathology Department of Instituto Portugu?s de Oncologia de Lisboa Francisco Gentil for providing representative images of the histological slides.publishersversionpublishe

Diffuse sclerosing variant of papillary thyroid carcinoma: outcomes of 33 cases

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Outcomes of lenvatinib therapy in poorly differentiated thyroid carcinoma

Funding Information: Ricardo Rodrigues was granted with a PhD scholarship by iNOVA4Health Research Unit (UIDP/04462/2020; UI/BD/154256/2022). The remaining authors did not receive any specific grant from funding agencies in the public, commercial, or non-for-profit sectors. Publisher Copyright: © 2023 the author(s) Published by Bioscientifica Ltd.Background and objective: Lenvatinib showed promising results in a subgroup of patients with poorly differentiated thyroid carcinoma (PDTC) in the SELECT trial. Our aim was to report the effectiveness and tolerability of lenvatinib in our series of PDTC patients. Methods: Medical records of eight consecutive patients with PDTC treated with lenvatinib in a single center between January 2019 and October 2022 were retrospectively reviewed. Inclusion criteria were PDTC diagnosis based on Turin criteria and evidence of disease progression in the previous 6 months. Results: Eight PDTC patients received an average dose of lenvatinib of 18.1 mg for a median duration of treatment of 10.3 months. The baseline Eastern Cooperative Oncology Group performance status was ≥2 in 50% of patients. Two patients had unresectable primary tumor. Seven patients showed extrathyroidal disease, particularly mediastinal lymph nodes (85.7%), lung (71.4%), and bone (71.4%). The disease control rate was 100%, with partial response and stable disease in 12.5 and 87.5%, respectively. The median time to best overall response was 3 months, and the median duration of response was 7.5 months. Median progression-free survival was 12 months and median overall survival was not reached. At 6, 12, and 18 months, overall survival was 87.5, 71.4, and 57.1%, respectively. All patients experienced drug-related adverse effects (AEs). Four (50%) had dose reductions and two (25%) had temporary treatment interruptions. Lenvatinib was stopped in two patients due to grade ≥3 AEs. Conclusion: Lenvatinib is an effective treatment for real-world PDTC patients. Adequate management of comorbidities and AEs increases treatment tolerability and minimizes dose reductions.publishersversionpublishe

Chronic hypocalcemia due to anti-calcium sensing receptor antibodies

Introduction: Hypoparathyroidism is an entity associated with hypocalcemia, more frequently a consequence of neck surgery. An autoimmune etiology is rare and its diagnosis difficult to establish. Clinical report: 52 year-old woman, with irrelevant past medical history and no significant familial conditions, referred because of hypocalcemia and basal ganglia calcifications, detected in the course of investigation of myalgias. Besides hypocalcemia (4.6 mg/ dL), hyperphosphatemia (8.7 mg/dL), undetectable parathyroid hormone and low urinary calcium, phosphorus and magnesium were present. Molecular analysis of CaSR gene excluded germinal mutations. Anti-calcium sensing receptor antibodies (anti-CaSR) were present. The patient is asymptomatic and normocalcemic under treatment with calcium and vitamin D. Discussion: Although rare, hypocalcemia due to anti-CaSR hypoparathyroidism must be considered in the absence of previous neck surgery, hypocalcemic drugs, familial history or phenotype suggesting a genetic disorder. Low or undetectable parathyroid hormone excludes pseudohypoparathyroidism and anti-CaSR positivity establishes the diagnosis.publishersversionpublishe

a case report

personBACKGROUND: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid tumors. ATC is frequently diagnosed at advanced stages with unresectable disease and palliative care is often indicated. Recently, several patient-tailored therapies for ATC are emerging due to advances in molecular profiling of these tumors. Entrectinib is a potent oral selective inhibitor of neutrotrophic tropomyosin receptor kinase (NTRK), ROS1, and anaplastic lymphoma kinase fusions. The experience regarding ATC and other thyroid carcinomas, particularly in the neoadjuvant setting, is minimal. CASE REPORT: We present a case of a 51-year-old female patient presenting with a bulky mass of the left thyroid lobe measuring 100 × 108 × 80 mm that was considered surgically unresectable. While waiting for next-generation sequence (NGS) profiling, lenvatinib was initiated. There was an initial clinical and imagiologic response; however, progression occurred after 12 weeks, and at this time NGS identified an ETV6-NTRK3 fusion and entrectinib was started. After 12 weeks, tumor diameters reduced to a minimum of 68×60×49 mm, and the patient underwent total thyroidectomy plus central lymphadenectomy. Histological diagnosis confirmed an ATC (pT4a R2 N1a). Adjuvant radiotherapy (RT) (60 Grays) with weekly paclitaxel (45 mg/m2) was then administered followed by maintenance entrectinib 600 mg daily. Fluorodeoxyglucose positron emission tomography performed 3 months after completion of RT showed only non-specific uptake in the posterior wall of the hypopharynx and larynx, suggestive of inflammation. CONCLUSION: We report the first case of an ATC with a dramatic response to neoadjuvant therapy with entrectinib, which enabled surgical resection of an ab initio unresectable tumor.publishersversionpublishe

Coincidence or correlation?

Rationale:Multiple Endocrine Neoplasia type 1 (MEN1) is a familial syndrome that results from the disruption of a tumor suppressor protein called MENIN. Its management is challenging, as MEN1 affects different endocrine tissues and predisposes to both benign and malignant tumors. MENIN-deficient cells have recently been recognized to play a role in triggering autoimmunity. Herein, we present a case of MEN1 with multiple endocrine and autoimmune disorders.Patient concerns:A 50 years old female with a 25 years history of complicated nephrolithiasis presented with primary hyperparathyroidism.Diagnoses:Over several decades, she was diagnosed with recurrent primary hyperparathyroidism, autoimmune thyroiditis, multinodular goiter, pernicious anemia, metastatic gastric type 1 neuroendocrine tumor, macroprolactinemia, gonadotropin deficiency, mucosa-associated lymphoid tissue lymphoma of the thyroid gland, positive anti-calcium sensor receptor antibodies, and BRCA 1/2-negative invasive breast cancer. The autoimmune regulator gene was sequenced, but no pathogenic variants were found. Next-generation sequencing revealed both a pathogenic MEN1 mutation and a benign CDC73 gene variant. Familial genetic screening revealed a large kindred with multiple carriers of one or both genetic variants (MEN1 = 19; CDC73 = 7).Interventions:The patient underwent surgical excision of three parathyroid glands, total thyroidectomy and breast tumorectomy plus tamoxifen, and monthly injections of octreotide. The patient and family members with the MEN1 mutation are under a life-long surveillance program for MEN1 prototypic tumors.Outcomes:The patient was stable and alive during a 24-years follow-up period.Lessons:With the present case, the authors highlight a new interplay between MENIN and the immune system, which may have implications for future targeted life-long surveillance and treatment of MEN1 patients.publishersversionpublishe

a clinical and molecular study

Funding This work was funded by Fundação para a Ciência e Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior (FCT/MCTES, Portugal) through national funds to iNOVA4Health (UIDB/04462/2020 and UIDP/04462/2020) and the Associated Laboratory LS4FUTURE (LA/P/0087/ 2020), by Associação de Endocrinologia Oncológica (AEO), and by Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG). Carolina Pires was granted with a PhD scholarship by FCT - 2020.07120.BD. Ricardo Rodrigues was granted with a PhD scholarship by iNOVA4Health Research Unit - UIDP/04462/2020; UI/BD/ 154256/2022.OBJECTIVES: Anaplastic thyroid carcinoma (ATC) has a poor survival. The combination of Dabrafenib plus Trametinib (DT) had a significant impact in survival of BRAF p.V600E patients. However, durable responses may be compromised by resistance. We aim to present our experience with DT in BRAF positive ATC patients and compare the outcomes with usual therapy, and to study tumor molecular alterations in the DT group. METHODS: Patients treated between May 2018 and April 2022 in a tertiary referral center, assessed for BRAF status were included. Patients were divided in three groups: BRAF p.V600E treated with DT, BRAF wild type (WT) under multimodal therapy (MT), and BRAF WT under compassionate care (CC). Response was assessed monthly in the first 6 months and every 3 months afterwards, by RECIST 1.1. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: Twenty-seven ATC patients were included (DT = 9, MT = 8, and CC = 10). Median OS was 475 days for DT, 156 days for MT, and 39 days for CC (P < .001). At 12 months, only patients in the DT group were alive (71%). Median PFS was 270 days, in the DT group, compared with less than 32 days in BRAF WT (P < .001). No severe adverse events were reported. Molecular profiling showed that in one of the four clinical progressions, a pathogenic NRAS mutation was found. CONCLUSIONS: Our results show a significant real-world efficacy of Dabrafenib plus Trametinib in both survival and recurrence compared with standard treatment, with a good safety profile.publishersversionpublishe

Clinical and molecular characterization of parathyroid carcinoma in multiple endocrine neoplasia type 1

Nineteen cases of parathyroid carcinoma in patients with multiple endocrine neoplasia type 1 have been reported in the literature, of which 11 carry an inactivating germline mutation in the MEN1 gene. Somatic genetic abnormalities in these parathyroid carcinomas have never been detected. In this paper, we aimed to describe the clinical and molecular characterization of a parathyroid carcinoma ident ified in a patient with MEN1. A 60-year-old man was diagnosed with primary hyperparathyroidism during the postoperative period of lung carcinoid surgery. Serum calcium and parathyroid hormone levels were 15.0 mg/dL (8.4–10.2) and 472 pg/mL (12–65), respectively. The patient underwent parathyroid surgery, and histological findings were consistent with parathyroid carcinoma. Analysis of the MEN1 gene by next-generation sequencing (NGS) identified a novel germline heterozygous nonsense pathogen ic variant (c.978C>A; p.(Tyr326*)), predicted to encode a truncated protein. Genetic analysis of the parathyroid carcinoma revealed a c.307del, p.(Leu103Cysfs*16) frameshift truncating somatic MEN1 variant in the MEN1 gene, which is consistent with MEN1 tumor-suppressor role, confirming its involvement in parathyroid carcinoma etiology. Genetic analysis of CDC73, GCM2, TP53, RB1, AKT1, MTOR, PIK3CA and CCND1 genes in the parathyroid carcinoma DNA did not detect any somatic mutations. To our knowledge, this is the firs t report of a PC case presenting both germline (first-hit) and somatic (second-hit) in activation of the MEN1 gene

Clinical and molecular characterisation of metastatic papillary thyroid cancer according to radioiodine therapy outcomes

Funding Information: This study was funded by iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344; UID/Multi/00462; UIDB/04462/2020), a program co-funded by Fundação para a Ciência e Tecnologia/Ministério da Ciência e do Ensino Superior, Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo (SPEDM), and Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG). J.S.-P. was supported by iNOVA4Health – UIDB/04462/2020. M.P. was granted by Liga Portuguesa Contra o Cancro, Núcleo Regional do Sul (LPCC-NRS). R.R. was granted with a PhD scholarship by iNOVA4Health Research Unit - UIDP/04462/2020; UI/BD/154256/2022. C.P. was granted with a PhD scholarship by FCT – 2020.07120.BD. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Purpose: Radioiodine (RAI) therapy remains the gold-standard approach for distant metastatic differentiated thyroid cancer (TC). The main objective of our work was to identify the clinical and molecular markers that may help to predict RAI avidity and RAI therapy response of metastatic lesions in a cohort of papillary thyroid cancer (PTC) patients. Methods: We performed a retrospective analysis of 122 PTC patients submitted to RAI therapy due to distant metastatic disease. We also analysed, through next-generation sequencing, a custom panel of 78 genes and rearrangements, in a smaller cohort of 31 metastatic PTC, with complete follow-up, available RAI therapy data, and existing tumour sample at our centre. Results: The most frequent outcome after RAI therapy was progression of disease in 59.0% of cases (n = 71), with median estimate progression-free survival of 30 months. RAI avidity was associated with PTC subtype, age and stimulated thyroglobulin at first RAI therapy for metastatic disease. The most frequently altered genes in the cohort of 31 PTC patients’ primary tumours were RAS isoforms (54.8%) and TERT promoter (TERTp) (51.6%). The presence of BRAF p.V600E or RET/PTC alterations was associated with lower avidity (p = 0.012). TERTp mutations were not associated with avidity (p = 1.000) but portended a tendency for a higher rate of progression (p = 0.063); similar results were obtained when RAS and TERTp mutations coexisted (p = 1.000 and p = 0.073, respectively). Conclusions: Early identification of molecular markers in primary tumours may help to predict RAI therapy avidity, the response of metastatic lesions and to select the patients that may benefit the most from other systemic therapies.publishersversionepub_ahead_of_prin