Effectiveness and safety of lenvatinib in a series of advanced well-differentiated thyroid carcinomas from a single tertiary cancer center and literature review.

BACKGROUND: Treatment of advanced differentiated thyroid carcinoma (DTC) remains a challenge as 25-50% of patients with locally invasive or distant metastatic disease become refractory to radioiodine (RAI) therapy. Tyrosine kinase inhibitors (TKI) are increasingly used in this setting. The SELECT trial demonstrated that lenvatinib, a multikinase inhibitor, significantly improved progression free survival (PFS) compared to placebo. Our aim was to report the effectiveness and safety of lenvatinib in our series of patients with advanced DTC. METHODS: A total of 25 patients with advanced DTC followed at a single tertiary center from January of 2016 to January of 2022 were retrospectively reviewed. RESULTS: Patients were treated with a mean daily dose of lenvatinib of 16.9 mg for a mean of 9.1 months. Median estimated PFS was 31.3 months. One patient achieved complete response. The objective response rate (ORR) was 40% and the disease control rate was 84%. The mean change in summed longest diameter of target lesions from baseline to nadir was -36.9%. Lenvatinib prolonged the tumor volume doubling time in 86.7% patients. Interestingly, we found that patients treated with a lower dose of lenvatinib (<16.9 mg daily) had a significantly higher PFS and ORR than patients treated with higher dosages (>16.9 mg). Adverse events were frequently reported. CONCLUSIONS: Our results confirm the effectiveness of lenvatinib in the management of patients with advanced DTC and support the need to adjust the dosage of lenvatinib to patient´s performance status and comorbidities.

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

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.

Clinical significance of papillary thyroid carcinoma with solid/trabecular growth.

OBJECTIVE: The clinical relevance of solid/trabecular (ST) growth in papillary thyroid carcinoma (PTC) is unclear. In this study, we investigated the impact of any amount of ST growth on tumour characteristics and patient outcomes. Furthermore, we evaluated whether ST growth per se affected patients' prognosis in the absence of aggressive features, namely vascular invasion. DESIGN: We analysed 222 PTC patients followed up for more than 5 years in the Department of Endocrinology of the Instituto Português de Oncologia de Lisboa Francisco Gentil from 2002 to 2020. All PTC cases with any percentage of ST growth were included and compared with PTC without ST growth (1:2). Carcinomas with high-grade features were excluded. RESULTS: There were 74 PTC cases with ST growth and 148 without ST growth (median follow-up of 9.3 years). PTC-ST was associated with larger tumour size (p = 0.001) and increased frequency of vascular invasion (p < 0.001) compared with PTC. However, PTC-ST did not exhibit a higher incidence of extrathyroidal extension (p = 1.000) or lymph node metastasis (p = 0.433). Despite the significantly higher prevalence of distant metastasis in PTC-ST compared with PTC (p = 0.043), the significance is lost when the cases with vascular invasion were excluded (p = 0.347). The total radioiodine activity was higher in PTC-ST than in PTC (p = 0.008). Recurrence rates were similar between groups (p = 0.755). The 10-year overall survival and disease-free survival rates for PTC-ST were 94.6% and 98.6%, respectively, similar to the PCT without ST growth (p = 0.097 and p = 0.333, respectively). There was no evidence of an association between the presence of an ST component (p = 0.201) with the risk of death or recurrence, whereas the presence of distant metastasis significantly increased the risk of these events (hazard ratio 10.14, p < 0.001). CONCLUSIONS: The presence of ST growth was associated with several aggressive clinicopathological features. However, the risk of cancer recurrence and death for PTC-ST were similar to PTC. In the absence of vascular invasion, the clinical impact of ST growth alone is negligible.

Preoperative serum inflammation-based scores in medullary thyroid cancer.

INTRODUCTION: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) are prognostic factors in several tumours, though little is known in medullary thyroid cancer (MTC). OBJECTIVE: To evaluate the association between preoperative NLR, PLR and SII with MTC clinicopathological and molecular features, and their predictive value for lymph node and distant metastasis. METHODS: We retrospectively analysed 75 patients with MTC who underwent surgery at our institution. The familial form of MTC was found in 12% of patients. RESULTS: In our cohort, 56% were females, the median age at diagnosis was 57 years (44-69), the median tumour diameter was 25mm (15-50); 21.3% were multifocal and 34.7% had extrathyroidal extension. Lymph node and distant metastasis were observed in 36 (48.0%) and 8 (10.7%) patients, respectively. Higher NLR was associated with preoperative calcitonin, angioinvasion, extrathyroidal extension, moderate/severe fibrosis; higher PLR was associated with extrathyroidal extension and advanced T stages; lower SII and NLR were associated with biochemical cure after surgery. Increased PLR, NLR and SII were associated with advanced MTC stages. In the univariate analysis, only NLR was associated with lymph node metastasis (odds ratio (OR)=2.69, 95% confidence interval (CI): 1.50-5.84; p=0.004); however, in the multivariate model, NLR was no longer a predictive factor for lymph node metastasis. None of these serum inflammatory markers predicted the occurrence of distant metastasis. CONCLUSION: In conclusion, NLR, PLR and SII are associated with aggressive MTC, but do not predict lymph node or distant metastasis.

Malignant Hypercalcemia Due to the Ectopic Production of Calcitriol by an Abdominal Liposarcoma.

Hypercalcemia of malignancy (HM) is a common form of paraneoplastic syndrome associated with a poor prognosis of the disease. In solid tumors, HM occurs mainly due to the production of parathyroid hormone-related peptide (PTHrP). We present a case of a 60-year-old male with a 25 cm retroperitoneal liposarcoma diagnosed with severe hypercalcemia (16.8 mg/dL) by a preoperative blood sampling. Hypercalcemia workup showed suppressed parathyroid hormone (PTH), normal PTHrP, and high 1,25-dihydroxyvitamin D (1,25(OH)2D) serum levels. After surgery, hypercalcemia and calcitriol levels normalized. Immunohistochemical analysis of the tumor showed 1α-hydroxylase expression by tumor cells. To our knowledge, this is the first case of liposarcoma-associated hypercalcemia caused exclusively by the ectopic production of calcitriol. Despite being a rare cause of hypercalcemia, measuring 1,25(OH)2D should be considered in the workup of a patient with high serum calcium levels, suppressed PTH, and normal PTHrP.

Endocrine complications after hematopoietic stem cell transplantation during childhood-Results from a close follow-up in a cohort of 152 patients.

CONTEXT: Haematopoietic stem cell transplantation (HSCT) is a therapeutic option for numerous haematologic diseases and solid tumours. Increasing indications for HSCT and reduction in associated mortality have been raising the number of paediatric HSCT survivors and their long-term toxicities. OBJECTIVE: To characterize the endocrine disorders developed after HSCT. DESIGN AND PATIENTS: Retrospective analysis of 152 patients submitted to HSCT in paediatric age with at least 24 months of follow-up at our endocrine late-effects clinics. RESULTS: Patients were followed up for 9.9 (interquartile range [IQR]: 12.2) years. The median age at HSCT was 7.5 (IQR: 9) years. At least one endocrine complication was observed in 65.1% of the patients. Primary hypogonadism was detected in 34.2%. Female gender (p < .001), HSCT > 10 years old (p = .01) and chemotherapy before HSCT (p < .001) were identified as risk factors for developing gonadal dysfunction. Growth hormone deficiency (GHD) occurred in 23.0% with a mean stature Z-score at diagnosis of -1.8 ± 1.4. GHD was associated with cranial (p < .001) and HSCT < 10 years old (p ≤ 0.001). Patients who were exposed to total body irradiation (TBI) were at higher risk for primary hypothyroidism (22.3%) (p = .01), thyroid nodules (17.1%) (p < .001), thyroid carcinoma (5.3%) (p < .001), dyslipidaemia (19.1%) (p < .001) and disturbance of carbohydrate metabolism (19.1%) (p < .001). CONCLUSION: At least one endocrine complication was diagnosed in 65.1% of patients, with gonadal dysfunction being the most prevalent. The conditioning regimen with TBI was a risk factor for the development of several endocrine disorders. This study is one of the largest series evaluating the endocrine disorders among survivors of paediatric HSCT and intends to reinforce the importance of routine follow-up of these patients.

Adrenal findings in FDG-PET: analysis of a cohort of 1021 patients from a cancer center.

PURPOSE: The use of FDG-PET for cancer staging has led to the increasing incidence of adrenal lesions, which are usually a clinical challenge. We aimed to characterize the adrenal lesions found in FDG-PET of patients followed in a cancer center. METHODS: Retrospective analysis was conducted of all FDG-PET studies performed in our center in the last 10 years. Exams reporting adrenal lesions in the CT component and/or anomalous adrenal FDG uptake were selected. Cases were characterized by the clinical, laboratory, imaging, and pathological findings. RESULTS: We identified 27,427 FDG-PET studies. Of those, 7.6% reported adrenal findings. We included 1364 exams corresponding to 1021 patients. Only 15.6% of the patients were referred to the Endocrinology Department and 38% of the lesions were not studied. In 38.9% of the studied patients, malignant lesions were present, including metastases in 37.5%, carcinoma in 1.2%, and other malignant tumors in 0.4%. The median SUVmax of malignant lesions was significantly higher than the SUVmax of the benign findings (p < 0.05). We also observed a higher median SUVmax in adrenal metastases than in adenomas (p < 0.05). There was a tendency for higher SUVmax of adrenal carcinomas when compared with other malignant lesions (p = 0.066). The median SUVmax was not different between pheochromocytomas and other tumors (p > 0.05). CONCLUSION: Occult adrenal lesions discovered during FDG-PET/CT are common in the cancer context and are frequently benign. SUVmax may be a useful tool in the workup of adrenal lesions but with several important caveats.

Entrectinib in the neoadjuvant setting of anaplastic thyroid cancer: a case report.

Background: 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.

Precocious and accelerated puberty in children with neurofibromatosis type 1: results from a close follow-up of a cohort of 45 patients.

PURPOSE: Central precocious puberty (CPP) in neurofibromatosis type 1 (NF1) occurs mainly in association with optic pathway glioma (OPG), but it can also develop in the absence of OPG. The aim of this study was to analyze the prevalence of puberty disorders in children with NF1 and its association with OPG and its location. METHODS: A retrospective study of 45 children with NF1 (68.9% boys) followed at our center between 2008 and 2020 was conducted. A cerebral MRI scan was performed in all children. We analyzed auxological, laboratory, and imaging data of children with CPP or accelerated puberty (AP). Treatments used for CPP/AP and their effect on height were also evaluated. RESULTS: The prevalence of puberty disorders in our cohort was 17.8% (male to female ratio of 7:1). CPP and AP were diagnosed in 8/45 (17.8%) NF1 children. Among children with puberty disorders, 5/8 (62.5%) had an OPG with chiasm involvement, 1/8 (12.5%) had an isolated optic nerve tumor, and 2/8 (25%) did not have any evidence of OPG on MRI. Fisher's exact test showed an association between CPP/AP and chiasm OPG (p = 0.025). Treatment with triptorrelin was initiated in 5/8 children, of whom four attained final predicted height. CONCLUSION: Our study confirms the higher prevalence of CPP/AP in NF1 patients, as well as an association between chiasm OPG and puberty disorders. However, CPP/AP also occurred in the absence of OPG with an incidence of 9.1%. Comprehensive evaluation of every child with NF1 regardless of the presence of OPG is therefore essential.

Giant retrosternal goitre causing lung atelectasis.

Not required for Clinical Vignette.

Clinical outcomes of a cohort of 271 patients with lung metastases from differentiated thyroid carcinoma.

CONTEXT: Lung is the most common site of distant metastases from differentiated thyroid carcinoma (DTC). OBJECTIVE: To investigate the outcomes of a cohort of patients with DTC and lung metastases (LM). METHODS: A retrospective analysis of a cohort of 271 patients with LM was performed. RESULTS: The female-to-male ratio was 1:1 and the median follow-up time was 5.9 (1.1-38.4) years. Papillary thyroid carcinoma (PTC) was the most frequent type (83.4%), mainly the classic variant, followed by follicular thyroid carcinoma (FTC, 10.3%) and Hürthle cell carcinoma (HTC, 6.3%). The prevalence of PTC, FTC and HCC was different between the micronodular and macronodular LM groups [87.4%, 6.3% and 6.3% vs. 74.6%, 19.0% and 6.3%, respectively (p = .013)]. Only 5.0% of the patients had LM diagnosed after a period of remission. LM were submitted to radioactive iodine treatment (RAIT) in 84.5% (52.8% showed 131 iodine avid metastases). Complete remission was only achieved in 12.2%. Micronodular disease and age <55 years at LM diagnosis were associated with a better prognosis (p < .05). We found no difference in survival between patients with LM treated or not with RAIT. However, in patients submitted to RAIT, there was a tendency for longer survival in the group of patients with 131 I avid lesions. CONCLUSION: The classic variant of PTC was the most frequent histology found in LM of DTC. LM are rarely diagnosed in the follow-up when complete remission is achieved after surgery and 131 I. Younger age at LM diagnosis and a micronodular pattern are associated with a better prognosis.

X-linked hypophosphataemic rickets: Report of a novel PHEX mutation and cinacalcet as adjuvant therapy in the mineral metabolism control.

X-linked hypophosphataemic rickets (XLH) is a rare disease caused by a mutation in the phosphate-regulating neutral endopeptidase (PHEX) gene, located on the X chromosome. This gene encodes the phosphate-regulating endopeptidase, and its inactivation leads to increased levels of circulating phosphatonins responsible for renal phosphate loss. The treatment for XLH is still carried out with long-term administration of phosphate and calcitriol, which can be complicated by hyperparathyroidism, nephrocalcinosis, renal failure, and hypertension. We describe the case of a four-decade follow-up patient with XLH. When she was diagnosed, at 19 years, due to bone pain and deformities, she was put on therapy with phosphorus and cholecalciferol. Despite the clinical improvement, serum phosphorus remained difficult to control. At the age of 44 years, she developed tertiary hyperparathyroidism and was submitted to parathyroidectomy. Five years later, parathyroid hyperfunction recurred. This time, cinacalcet was started, 30 mg alternating with 60 mg/day. Currently, she is 59-years old and remains with controlled mineral metabolism. The genetic study of this patient revealed a nonsense heterozygous mutation (c.501G>A) in PHEX gene that was not previously described. In this case, the off-label use of cinacalcet resulted in the normalisation of serum parathormone and phosphorus levels, eliminated recurrent secondary hyperparathyroidism, which aggravates the bone fragility inherent to XLH, and prevented a new parathyroidectomy. This report also adds important information to the genetic basis of XLH with the identification of a new nonsense mutation of the PHEX gene.

Avidity and Outcomes of Radioiodine Therapy for Distant Metastasis of Distinct Types of Differentiated Thyroid Cancer.

CONTEXT: The recommendations for radioactive-iodine treatment (RAIT) in metastatic differentiated thyroid cancer (DTC) are mostly based in the experience with papillary histotype and do not consider the differences within the distinct types of DTC, in terms of RAIT uptake and response. OBJECTIVE: This work aims to investigate the association between histology and RAIT avidity and response, and to evaluate whether histotype was an independent prognostic factor in progression-free survival (PFS) and disease-specific survival (DSS) after RAIT for distant metastatic disease. METHODS: A retrospective analysis was conducted of all DTC patients who underwent RAIT for distant metastatic disease, from 2001 to 2018, at a thyroid cancer referral center. We included 126 patients: 42 (33.3%) classical variant papillary thyroid cancer (cvPTC), 45 (35.7%) follicular variant PTC (fvPTC), 17 (13.5%) follicular thyroid cancer (FTC) and 22 (17.5%) Hürthle cell carcinoma. Main outcome measures included RAIT avidity and response. RESULTS: RAIT avidity was independently associated with histology (P < .001) and stimulated thyroglobulin (Tg) at first RAIT for distant lesions (P = .007). Avidity was lowest in HCC (13.6%), intermediate in cvPTC (21.4%), and highest in fvPTC (75.6%) and FTC (76.5%). Regarding RAIT response, HCC and FTC were not different; both showed significantly more often progression after RAIT than fvPTC and cvPTC. Histology influenced PFS (P = .014), but tumor type was not a significant prognostic factor in DSS. Instead, age at diagnosis, resection status, and stimulated Tg at the first RAIT were significantly associated with DSS. CONCLUSION: DTC histotype influenced RAIT avidity and PFS. It is crucial to better detect the metastatic patients that may benefit the most from RAIT.

Outcomes of Thyrotropin Alfa Versus Levothyroxine Withdrawal-Aided Radioiodine Therapy for Distant Metastasis of Papillary Thyroid Cancer.

Background: Thyrotropin alfa (rhTSH) is not currently approved by the Food and Drug Administration or European Medicines Agency for the preparation of radioactive iodine therapy (RAIT) in patients with distant metastatic papillary thyroid cancer (PTC). There are only a few studies comparing rhTSH with levothyroxine withdrawal (LTW) in this context. Our main aim was to compare the two methods of RAIT preparation in terms of avidity and structural/biochemical response in distant metastatic PTC. We also intended to evaluate whether the two methods of RAIT preparation represented independent prognostic factors for progression-free survival (PFS) and disease-specific survival (DSS) in this subset of patients. Methods: We performed a retrospective analysis of all patients with PTC treated with RAIT for distant metastatic disease between 2006 and 2018. We included 95 PTC patients-27 (28.4%) had LTW and 68 (71.6%) had rhTSH for RAIT. Results: The two groups presented similar clinicopathological characteristics, except for median age at PTC diagnosis, which was higher in the rhTSH group (p = 0.001), but the median age at first RAIT for distant metastatic disease was not different between the two methods of preparation, 63 years old (interquartile range [IQR] 23) in the LTW group versus 70 (IQR 26.75), p = 0.06. Avidity was similar between the two groups (p = 0.973). Median estimate PFS (p = 0.076) and DSS (p = 0.084) were also similar between LTW and rhTSH. Regarding RAIT-related side effects, only 1 (3.7%) patient and 5 (7.4%) patients in the LTW and rhTSH groups, respectively, reported sialadenitis (p = 0.670). Conclusions: There were no differences between the two methods of RAIT preparation regarding avidity and clinical response. rhTSH may be used as an alternative method of preparation for RAIT in patients with known distant lesions, as it presents similar clinical outcomes to LTW and a good safety profile.

Is Gonadal Therapy a Promoter of Breast Cancer? Incidence of Breast Cancer in a Cohort of Survivors of Oncological Diseases Treated with Gonadal Steroids.

There is a great controversy about hormonal replacement therapy in women among the members of the scientific community. Cancer survivors have sometimes had their ovary function totally or partially destroyed, thus affecting their development and quality of life. In this study, we were looking for adverse effects caused, eventually, by estroprogestative therapy in a cohort of supplemented survivors. The occurrence of breast cancer was our main concern. Ours is a retrospective study based on the clinical records of 174 survivors of several cancer diseases. Their median ages within each of the following time frames were: diagnosis - 22 years old; start of endocrine treatment - 26 years old, and duration of treatment - 12 years old. Evaluation was composed of breast cancer assessment, osteopenia and osteoporosis incidence, and vascular events. We have found a very low incidence of breast cancer as well as of vascular events. After treatment, a high percentage of our sample displayed bone mass improvement.

Diagnosis, treatment, and survival analysis of adrenocortical carcinomas: a multicentric study.

INTRODUCTION: Current guidelines specify controversial areas in adrenocortical carcinomas (ACC), such as optimal follow-up time after remission and identification of prognostic markers. We aim to address these topics by analyzing four reference centers in our country. METHODS: Cross-sectional multicentric study of 69 patients (mean age: 51.7 ± 16.7 years-old; women, 72.5%). Kaplan-Meier survival curves and Cox regression analysis were used to calculate overall survival and its predictors. RESULTS: Thirty-eight individuals (55.0%) had hormonal autonomous production, and 40.6% of the patients presented with metastasis. Surgery was performed in 84.1% of them. Most of these patients (72.4%) were then assigned to adjuvant therapy, while 27.6% were actively surveilled. Among patients undergoing surgery, those who achieved transient remission presented a longer survival time (66 months) than those who never reached the disease-free status (21 months) (p = 0.021). One patient presented with recurrence more than 7 years after complete tumor resection. The lowest overall survival was observed in patients (n = 11) assigned to palliative care since diagnosis (9 months). Tumor stage was identified as the only independent predictor of survival in our cohort (p = 0.006). Five-year survival was 67% for tumors confined to the adrenal space (stage I/II), 56% for locally advanced disease (stage III), and 0% for metastatic disease (stage IV). CONCLUSION: This study reinforces the dismal prognosis of ACC, the need for long-term follow-up, and tumor stage as the most important survival predictor. Reviewing medical records in such rare conditions is an opportunity to identify insufficiencies and to improve medical care.

Anaplastic Thyroid Cancer: Clinical Picture of the Last Two Decades at a Single Oncology Referral Centre and Novel Therapeutic Options.

Anaplastic thyroid cancer (ATC) is a rare tumour but also one of the most lethal malignancies. Therapeutic modalities have usually been limited, but clinical trials with new drugs are now being implemented. The aims of this study were to analyse the clinical presentation, therapeutic modalities and independent prognostic factors for survival. We also reviewed the most recent literature on novel ATC therapies. We performed a retrospective analysis of 79 patients diagnosed between 2000 and 2018. Variables with impact on survival were identified using the Cox proportional-hazard regression model. At presentation, 6.3% had thyroid-confined disease, 30.4% evidenced extrathyroidal extension and 60.8% were already metastatic. Surgery was feasible in 41.8% and radiotherapy was applied to 35.4%, with those receiving >45 Gy having longer estimated survival (p = 0.020). Chemotherapy, either conventional or with tyrosine kinase inhibitors, was performed in 17.7% and 7.6%, respectively. Multimodality therapy with surgery, radiotherapy and chemotherapy/tyrosine kinase inhibitors (TKI) had the greatest impact on disease specific survival (DSS), providing a risk reduction of death of 96.9% (hazard ratio (HR) = 0.031, 0.005-0.210, p < 0.001). We concluded that most of these patients join reference centres at advanced stages of disease and multimodality treatment may offer the best chances for prolonging survival.

Establishment and characterization of a new patient-derived anaplastic thyroid cancer cell line (C3948), obtained through fine-needle aspiration cytology.

PURPOSE: Anaplastic thyroid cancer (ATC) is among the most aggressive and unresectable tumors, presenting a bad prognosis. A better comprehension of the functional and molecular mechanisms behind the aggressiveness of this cancer, as well as new biomarkers for aggressiveness, prognosis, and response to therapy are required. However, owing to their irresectability, ATC tissue is not always accessible. Here we describe the establishment and characterization of a new patient-derived cell line, obtained from an unresectable ATC through fine-needle aspiration cytology (FNAC). METHODS: The morphology, expression of epithelial and thyroid markers, cytogenetic, mutational and gene expression profiles, doubling time, and drug-resistance profile of the new cell line, designated C3948, were investigated using several methodologies: immunostaining, karyotype analysis, comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH), next-generation sequencing (NGS), Sanger sequencing, gene expression microarrays, cell counting, and IC50 determination. RESULTS: Results indicate that C3948 cell line has a histological phenotype representative of original ATC cells and a completely aberrant karyotype with many chromosomal losses and gains; harbors mutated TP53, STK11, and DIS3L2 genes; presents a gene expression profile similar to C643 ATC commercial cell line, but with some unique alterations; has a doubling time similar to C643; and the IC50 profile for paclitaxel, doxorubicin, and cisplatin is similar to C643, although higher for cisplatin. CONCLUSIONS: These observations are consistent with a typical ATC cell profile, supporting C3948 cell line as a novel preclinical model, and FNAC as a useful approach to better study anaplastic thyroid cancer, including testing of new anticancer therapies.