Embolization of iliac metastasis during lenvatinib treatment in patient with advanced Hürthle cell thyroid carcinoma

Lenvatinib is a tyrosine kinase inhibitor (TKI) with antiproliferative and antiangiogenic effects indicated for the treatment of progressive, locally advanced or metastatic progressive thyroid carcinoma, refractory to radioactive iodine therapy. Antiangiogenic therapies induce ischemic necrosis of tumor tissue, with increased risk of hemorrhagic complications. The management of hemorrhagic risk is based on precautionary measures and for any surgical procedure, it is advised to interrupt the treatment in order to avoid complications. 'Flare-up' of tumor activity may follow TKI interruption. However, it is not known if continuing TKIs during minimally invasive interventions is safe. We report here the first case in which an embolization of metastasis is performed without interrupting lenvatinib treatment. The procedure was successful and free of complications

embolization of iliac metastasis during lenvatinib treatment in patient with advanced hurthle cell thyroid carcinoma

Lenvatinib is a tyrosine kinase inhibitor (TKI) with antiproliferative and antiangiogenic effects indicated for the treatment of progressive, locally advanced or metastatic progressive thyroid carcinoma, refractory to radioactive iodine therapy. Antiangiogenic therapies induce ischemic necrosis of tumor tissue, with increased risk of hemorrhagic complications. The management of hemorrhagic risk is based on precautionary measures and for any surgical procedure, it is advised to interrupt the treatment in order to avoid complications. 'Flare-up' of tumor activity may follow TKI interruption. However, it is not known if continuing TKIs during minimally invasive interventions is safe. We report here the first case in which an embolization of metastasis is performed without interrupting lenvatinib treatment. The procedure was successful and free of complications

Thyroid autoimmunity and hypothyroidism are associated with deep molecular response in patients with chronic myeloid leukemia on tyrosine kinase inhibitors

Abstract Purpose: Thyroid alterations including de novo appearance of thyroid autoimmunity are adverse efects of tyrosine kinase inhibitors, used in solid and hematologic cancer therapy, but the relationship between thyroid alterations during this treatment and the outcome of chronic myeloid leukemia remains unclear. Aim of this study was to investigate whether the presence of thyroid alterations may afect the clinical outcome of chronic myeloid leukemia on tyrosine kinase inhibitors. Methods: We evaluated thyroid function and autoimmunity in 69 chronic myeloid leukemia patients on long-term therapy looking at the association between thyroid abnormalities and disease molecular response. Results: Overall, 24 of 69 (34.8%) had one or more thyroid abnormalities during therapy. A high percentage of patients (21/69, 30.4%) showed thyroid autoimmunity (positive thyroid autoantibodies with ultrasound hypoechogenicity), while clinical and subclinical hypothyroidism and subclinical hyperthyroidism were, respectively, found in 4 of 69 (5.8%) and 3 of 69 (4.3%) of cases. Second-generation tyrosine kinase inhibitors resulted signifcantly associated (14/32, 43.7%) with Hashimoto’s thyroiditis, compared to frst generation (7/37, 18.9%; p=0.03). Interestingly, we also found a signifcant association between euthyroid (14/26, 53.8%) and hypothyroid Hashimoto’s thyroiditis (4/26, 15.4%) in patients with deep molecular response, as compared to euthyroid (3/43, 7%; p=0.0001) and hypothyroid (0/43, 0%; p=0.02) Hashimoto’s thyroiditis patients with major molecular response. Conclusions: Our study confrms and extends our knowledge on the tyrosine kinase inhibitors efects on thyroid, showing that thyroid autoimmunity is frequently observed in chronic myeloid leukemia patients on long-term therapy and is associated with a better oncological response

Thyrospheres from B-CPAP cell line with BRAF and TERT promoter mutations have different functional and molecular features than parental cells

Human thyroid cancer derived cell lines are widely used to study the mechanisms involved in thyroid carcinogenesis. However, there is limited availability of non-cross-contaminated cancer cell lines derived from papillary thyroid carcinoma (PTC), and the B-CPAP cell line is one of the few such lines. B-CPAP cells have been genetically and cytogenetically well-characterized, but details of their stemness features remain uncertain. Considering that this cell line is extensively used for in vitro studies on thyroid tumorigenesis, we broaden its functional and molecular profiles as well as the tumorigenic capacity. We used functional assays (sphere-forming capacity and efficiency), assessed self-renewal and propagation efficiency and tested in vivo tumorigenicity in Hsd:Athymic Nude-Foxn1nu mice. Expression of markers of stemness, differentiation, and epithelial-mesenchymal transition were estimated at RNA and protein levels in adherent parental cells and sphere-forming cells. Functional aspects and stemness features were compared with normal thyrocytes. Protein expression of xenograft tumors was evaluated by immunohistochemistry. B-CPAP sphere-forming cells were able to form thyrospheres theoretically indefinitely in an appropriate serum-free medium, reverting to the adherent parental cell phenotype when cultured in differentiation medium. Different expression of ALDH1-A1 and CD44 stemness markers and TTF-1 and CK19 differentiation markers allowed discrimination between isolated sphere-forming cells and adherent parental cells, indicating that sphere-forming cells retained stem-like features. In keeping with these observations, tumorigenicity assays confirmed that, relative to parental adherent cells, thyrospheres had enhanced capacity to initiate xenograft tumors. Thyrospheres from normal cell line retained very low functional capacity, as well as different stemness markers expression compared to tumor thyrospheres. Our findings may constitute a useful background to develop an in vitro model for assessing the origin and progression of papillary thyroid carcinoma bearing BRAFV600E and TERT promoter mutations

Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features

The aim of this study was to carry out genetic screening of the MEN1, CDKN1B and AIP genes, both by direct sequencing of the coding region and multiplex ligation-dependent probe amplification (MLPA) assay in the largest monocentric series of Italian patients with Multiple Endocrine Neoplasia type 1 syndrome (MEN1) and Familial Isolated Hyperparathyroidism (FIHP). The study also aimed to describe and compare the clinical features of MEN1 mutation-negative and mutation-positive patients during long-term follow-up and to correlate the specific types and locations of MEN1 gene mutations with onset and aggressiveness of the main MEN1 manifestations. A total of 69 index cases followed at the Endocrinology Unit in Pisa over a period of 19 years, including 54 MEN1 and 15 FIHP kindreds were enrolled. Seven index cases with MEN1 but MEN1 mutation-negative, followed at the University Hospital of Cagliari, were also investigated. FIHP were also tested for CDC73 and CaSR gene alterations. MEN1 germline mutations were identified in 90% of the index cases of familial MEN1 (F-MEN1) and in 23% of sporadic cases (S-MEN1). MEN1 and CDC73 mutations accounted for 13% and 7% of the FIHP cohort, respectively. A CDKN1B mutation was identified in one F-MEN1. Two AIP variants of unknown significance were detected in two MEN1-negative S-MEN1. A MEN1 positive test best predicted the onset of all three major MEN1-related manifestations or parathyroid and gastro-entero-pancreatic tumors during follow-up. A comparison between the clinical characteristics of F and S-MEN1 showed a higher prevalence of a single parathyroid disease and pituitary tumors in sporadic compared to familial MEN1 patients. No significant correlation was found between the type and location of MEN1 mutations and the clinical phenotype. Since all MEN1 mutation-positive sporadic patients had a phenotype resembling that of familial MEN1 (multiglandular parathyroid hyperplasia, a prevalence of gastro-entero-pancreatic tumors and/or the classic triad) we might hypothesize that a subset of the sporadic MEN1 mutation-negative patients could represent an incidental coexistence of sporadic primary hyperparathyroidism and pituitary tumors or a MEN1 phenocopy, in our cohort, as in most cases described in the literature

Aggressive differentiated thyroid cancer with multiple metastases and NRAS and TERT promoter mutations: A case report

Sorafenib, a tyrosine kinase inhibitor, is approved for the treatment of advanced differentiated thyroid carcinoma (DTC). Resistance to sorafenib may appear under treatment and may be associated with increased aggressiveness of the neoplasia. The present study reports the case of a 65-year-old male who underwent total thyroidectomy for a follicular thyroid carcinoma, Hürthle cell variant, in February 2005. Until January 2010, the patient received four consecutive 131I doses (total dose, 612 mCi) for increased serum thyroglobulin (Tg) and initial faint lung uptake (which eventually became undetectable). Subsequently, the patient developed several sequential bone (humerus, rib and skull), adrenal and lung metastases, the majority of which were surgically removed. Histological examination in all cases revealed evidence of DTC metastases that were strongly positive for Tg, as revealed by immunohistochemistry. In March 2014, sorafenib therapy was initiated, but it was discontinued 10 months later to allow an undelayable prostatectomy. Immediately upon surgery, the patient developed a large metastatic lesion in the right gluteal muscle, whose biopsy revealed undifferentiated neoplasia of epithelial origin, and the patient succumbed shortly afterwards. An extensive comparative search for biochemical and molecular markers was performed on all available tissues (primary tumor, and differentiated and undifferentiated metastases). The primary tumor and all the available metastases exhibited the same molecular oncogenic markers (namely, the RAS mutation p.Q61R and the telomerase promoter mutation C228T). In addition, the undifferentiated metastasis exhibited a p53 mutation. The present study reports a case of a sudden acceleration of DTC metastatic progression following sorafenib discontinuation, which could have been due to the emergence of sorafenib-resistant undifferentiated p53-positive tumor cell clones

High prevalence of papillary thyroid carcinoma in nodular Hashimoto's thyroiditis at the first diagnosis and during the follow-up

Background: The association between Hashimoto’s thyroiditis (HT) and papillary thyroid carcinoma (PTC) remains to be elucidated. Materials and methods: A total of 484 HT patients were retrospectively subdivided into two groups: 243 without thyroid nodules, TNs (HTN−) and 241 with TNs (HTN+). Fine-needle aspiration cytology was available in 152 HTN+ patients. This group was compared to a group of 161 patients with nodular goiter (NG) without HT. Finally, 70 HTN+ and 37 NG patients underwent surgery. Results: A very high prevalence of suspicious/malignant cytology (Thy 4–5) at the first diagnosis (38/124; 31%) and during the follow-up (6/28; 22%) was found in HTN+ group. In HTN- group, 22/130 (17%) patients developed TN, but none showed malignant features during the follow-up. HTN+ patients had higher prevalence of Thy 4–5 (44/152 = 28.9%) compared to NG patients (12/161 = 7.4%, p 1.0 μUI/ml, [OR 1.93, 95% confidence interval (CI) 1.41–2.64, p < 0.0001], male sex (OR 3.44, CI 1.48–8.02, p = 0.004) and HT (OR 3.14; CI 1.08–9.31, p < 0.05). Malignant histology (mostly PTC) was confirmed higher in HTN+ (48/70, 68.6%) compared to NG (15/37, 40.5%; p < 0.05). Higher prevalence of extrathyroidal infiltration (24/48, 50%) and vascular invasion (25/48, 52%) was found in HTN+ vs NG (2/15, 1.3% p < 0.01), (3/16, 1.8% p < 0.05), respectively. Conclusions: This study confirms higher prevalence of suspicious/malignant cytology and PTC at histology in nodular HT compared to NG, without evidence of malignancy in non-nodular HT patients during the follow-up

The role of “closed abdomen” hyperthermic intraperitoneal chemotherapy (HIPEC) in the palliative treatment of neoplastic ascites from peritoneal carcinomatosis: report of a single-center experience

Purpose: The purpose of this study was to review the results of a single-center experience in the management of “closed abdomen” hyperthermic intraperitoneal chemotherapy (HIPEC) using a sophisticated technical device (EXIPER®) in the palliative setting of neoplastic ascites from peritoneal carcinomatosis in patients with advanced cancer of different primary sites. Patients and methods: The study was an open, prospective, single-center, non-randomized study conducted at the Department of Medical Oncology 1, University of Cagliari, Italy, from May 2006 to October 2012. Fifteen patients with peritoneal carcinomatosis were treated with HIPEC: 5 males and 10 females (age range 51–82, median 62 years), for a total of 30 procedures (5 patients were treated more than once). Malignant ascites were from ovarian, uterine cervical, colorectal, gastric, malignant pleural mesothelioma, and unknown primary cancer. Main endpoints were increase of free interval between two consecutive procedures, progressive reduction of ascites volumes and improvement of quality of life assessed with ECOG performance status and EORTC QLQ-C30 questionnaire, and improvement of immunologic function. Results: Twelve patients were completely evaluable while three patients were “lost” to follow-up. The treatment was well tolerated. The mean free interval between two consecutive drainages increased from 11.2 to 39.5 days. The mean ascites volume drained decreased from 7.8 to 1.8 l. ECOG PS improved in the majority of patients and EORTC QLQ-C30 scores in all patients as well as immunologic function. In September 2015, only one patient was still alive. Conclusions: Our study shows that good results may be achieved in terms of symptom palliation and improvement of quality of life in very advanced cancer patients with MA from PC. The treatment was generally well tolerated considering the limited treatment options available for these patients

Regorafenib-induced hypothyroidism and cancer-related fatigue: is there a potential link?

Objective: Thyroid dysfunction has been reported during Regorafenib (Reg) administration, but no detailed study is presently available. Design: Prospective, observational cohort study. Patients with documented metastatic colorectal cancer and progression of disease during or within 3 months after the last standard therapy, with no evidence and history of previous thyroid disease were enrolled. Methods: Twenty-five consecutive patients were evaluated before and 8–50 weeks after initiating Reg therapy by monthly clinical, ultrasound and laboratory (thyrotropin (TSH), free thyroxine (fT4), antithyroglobulin (TgAb) and antithyroid peroxidase (TPOAb)) evaluation. Results: Thirteen/25 patients (52%) became hypothyroid (TSH: 12.5 ± 4.01 IU/L, range: 4.6–22.0) within 5 months of therapy. TPOAb became detectable (99–155 IU/mL) in 2/25 (8%) patients. Thyroid volume progressively decreased (from 8.6 ± 2.2 mL to 4.9 ± 2.4 mL after 5 months of Reg therapy, P < 0.0001). The progression-free survival (PFS) was longer in patients developing hypothyroidism (43 weeks) than in those remaining euthyroid (17 weeks, P < 0.01). Fatigue (the most common general serious Reg adverse event) was associated with hypothyroidism severity and reversed after levothyroxine therapy (L-T4). Conclusions: Reg rapidly causes hypothyroidism in about 50% of patients and in a minority of them also triggers thyroid autoimmunity. Reg-induced hypothyroidism was strictly related to fatigue, easily reversed by L-T4 administration and associated to longer survival. These results suggest that prompt recognition of hypothyroidism in patients with severe fatigue may prevent unnecessary Reg dose reduction or withdrawal

Thyroid dysfunction and ultrasonography features in patients with metastatic colorectal cancer treated with Regorafenib. Results from a single centre prospective cohort study.

INTRODUCTION: Regorafenib (Reg) a Tyrosine kinase inhibitor (TKI) recently approved for the treatment of metastatic colorectal cancer patients could be responsible, like others TKIs of potential endocrine side effects, but scanty data are presently available on this specific drug. METHODS: Prospective evaluation of thyroid function, autoimmunity and morphology during treatment with Regorafenib. From November 2015, 17 consecutive patients (7 males and 10 females; mean age 64.2 ± 7.8) with metastatic colorectal cancer with comparable tumor staging, normal thyroid function and no evidence of associated thyroid autoimmunity, were studied before and at monthly intervals after beginning Regorafenib at scheduled dose of 160 mg oral daily according to standard protocols. In all cases FT3, FT4, TSH and thyroid antibodies (TgAb and TPOAb) were measured together with clinical assessment and thyroid ultrasonography up to five months. RESULTS: 8/17 patients (66%) became hypothyroid (TSH 7.9 ± 4.9 mIU/l, range 7.0–18.5) within 30 days of therapy. Interestingly, in 4 of those who developed higher degree of hypothyroidism, we observed highest score of fatigue (G3), the most common general serious adverse event during Reg administration. TPOAb became detectable in 2 (12%) patients 1 month after therapy. Thyroid volume significantly decreased in 9 (52%) patients (from 8.6 ± 2.2 ml before to 4.8 ± 1.6 ml 5 months after Reg, p < 0.01 by paired Student t test), together with the appearance of mild hypoechogenicity and a significant reduction of parenchymal thyroid vascularity (p < 0.05). RESULTS: These data indicate that Reg, similarly to other TKIs inhibitors, may rapidly cause hypothyroidism in about one half of patients, and probably trigger thyroid autoimmunity. An early diagnosis and management of hypothyroidism is therefore mandatory for an effective clinical control of fatigue in most of the cases, in order to prevent unnecessary Reg dose reductions and modifications. Further studies are needed to characterize longer-term effects on thyroid function/autoimmunity and to assess whether hypothyroidism may have a prognostic value as a potential biomarker of clinical response