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R Michael Tuttle, Duan Li, and Fourat Ridouani

Graphical abstract


Minimalistic management options such as active surveillance and thyroid lobectomy are increasingly being accepted as reasonable management options for properly selected patients with low-risk papillary thyroid cancer. Leveraging technologies developed for the treatment of benign thyroid nodules, ultrasound-guided percutaneous thermal ablation is now being evaluated as a potential additional minimalistic management option for small, intrathyroidal, low-risk papillary thyroid cancer. Published retrospective data on more than 5000 low-risk papillary thyroid cancer patients treated with thermal ablation indicate that with appropriate training and proper patient selection, these technologies can be safely and effectively applied to papillary microcarcinomas. When compared to immediate surgery, thermal ablation appears to have lower complication rates with similar short-term rates of recurrence. Proper patient selection is facilitated by the use of a clinical framework which integrates imaging characteristics, patient characteristics, and medical team characteristics to classify a patient as ideal, appropriate, or inappropriate for minimalistic management options (active surveillance, thyroid lobectomy, or thermal ablation). While retrospective in nature and lacking randomized prospective clinical trial data, currently available data do support the proposition that thermal ablation technologies reliably destroy papillary thyroid microcarcinoma lesions and are associated with clinically acceptable oncologic outcomes when done by experienced teams in properly selected patients.

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Sonia Kaniuka-Jakubowska, Miles J Levy, Aparna Pal, Dayakshi Abeyaratne, William M Drake, Nikolaos Kyriakakis, Robert D Murray, Steve M Orme, Shailesh Gohil, Antonia Brooke, Graham P Leese, Márta Korbonits, and John AH Wass

The aim of this study is to characterise somatostatin analogue-responsive headache in acromegaly, hitherto not systematically documented in a significant cohort. Using the UK pituitary network, we have clinically characterised a cohort of 18 patients suffering from acromegaly-related headache with a clear response to somatostatin analogues. The majority of patients had chronic migraine (78%) as defined by the International Headache Society diagnostic criteria. Headache was present at the time of acromegaly presentation and clearly associated temporally with disease activity in all cases. Short-acting somatostatin analogues uniquely resolved pain within minutes and the mean duration of analgesia was 1–6 h. Patients on long-acting analogues required less short-acting injections (mean: 3.7 vs 10.4 injections per day, P = 0.005). 94% used somatostatin analogues to control ongoing headache pain. All patients presented with macroadenoma, most had incomplete resection (94%) and headache was ipsilateral to remnant tissue (94%). Although biochemical control was achieved in 78% of patients, headache remained in 71% of them. Patients selected for this study had ongoing headache post-treatment (mean duration: 16 years after diagnosis); only four patients reached headache remission 26 years (mean range: 14–33) after the diagnosis. Headache in acromegaly patients can be persistent, severe, unrelieved by surgery, long-lasting and uncoupled from biochemical control. We show here that long-acting analogues allow a decrease in the number of short-acting analogue injections for headache relief. Further studies are needed to understand the mechanisms, markers and tumour tissue characteristics of acromegaly-related headache. Until then, this publication serves to provide the clinical characteristics as a reference point for further study.

Open access

Dimitrios Papantoniou, Malin Grönberg, Espen Thiis-Evensen, Halfdan Sorbye, Kalle Landerholm, Staffan Welin, and Eva Tiensuu Janson

Small intestinal neuroendocrine tumours (Si-NET) are often studied as a uniform group. Proliferation index Ki-67 influences prognosis and determines tumour grade. We hypothesized that Si-NET grade 2 (G2) tumours, which have a higher Ki-67 than G1 tumours, might benefit less from established treatments for metastatic disease. We conducted a retrospective cohort study of 212 patients with metastatic Si-NET G2 treated in two Swedish hospitals during 20 years (2000–2019). Median cancer-specific survival on first-line somatostatin analogues (SSA) was 77 months. Median progression-free survival (PFS) was 12.4 months when SSA was given as monotherapy and 19 months for all patients receiving first-line SSA. PFS after SSA dose escalation was 6 months in patients with radiological progression. Treatment efficacies of SSA and peptide receptor radionuclide treatment (PRRT) were studied separately in patients with Ki-67 of 3–5%, 5–10% and 10–20%. For SSA, PFS was significantly shorter at higher Ki-67 levels (31, 18 and 10 months, respectively), while there was only a minor difference in PFS for PRRT (29, 25 and 25 months). Median PFS for sequential treatment with interferon-alpha (IFNα), everolimus and chemotherapy was 6, 5 and 9 months. IFNα seemed to be effective in tumours with low somatostatin–receptor expression. In conclusion, established treatments appeared effective in Si-NET G2, despite their higher proliferation index compared to G1 tumours. However, efficacy of SSA but not PRRT was reduced at higher Ki-67 levels. SSA dose escalation provided limited disease stabilization.

Free access

C Christofer Juhlin, Ozgur Mete, and Zubair W Baloch

The fifth edition of the Classification of Endocrine and Neuroendocrine Tumors has been released by the World Health Organization. This timely publication integrates several changes to the nomenclature of non-neoplastic and neoplastic thyroid diseases, as well as novel concepts that are essential for patient management. The heterogeneous group of non-neoplastic and benign neoplastic lesions are now collectively termed as ‘thyroid follicular nodular disease’ to better reflect the clonal and non-clonal proliferations that clinically present as multinodular goiter. Thyroid neoplasms originating from follicular cells are distinctly divided into benign, low-risk and malignant neoplasms. The new classification scheme stresses that papillary thyroid carcinoma (PTC) should be subtyped based on histomorphologic features irrespective of tumor size to avoid treating all sub-centimeter/small lesions as low-risk disease. Formerly known as the cribriform-morular variant of PTC is redefined as cribriform-morular thyroid carcinoma since this tumor is now considered a distinct malignant thyroid neoplasm of uncertain histogenesis. The ‘differentiated high-grade thyroid carcinoma’ is a new diagnostic category including PTCs, follicular thyroid carcinomas and oncocytic carcinomas with high-grade features associated with poorer prognosis similar to the traditionally defined poorly differentiated thyroid carcinoma as per Turin criteria. In addition, squamous cell carcinoma of the thyroid is now considered a morphologic pattern/subtype of anaplastic thyroid carcinoma. In this review, we will highlight the key changes in the newly devised fifth edition of the WHO classification scheme of thyroid tumors with reflections on its applicability in patient management and future directions in this field.

Open access

Camilo Jimenez, Bennett B Chin, Richard B Noto, Joseph S Dillon, Lilja Solnes, Nancy Stambler, Vincent A DiPippo, and Daniel A Pryma

The objective of this study is to present the complete biomarker response dataset from a pivotal trial evaluating the efficacy and safety of high-specific-activity I-131 meta-iodobenzylguanidine in patients with advanced pheochromocytoma or paraganglioma. Biomarker status was assessed and post-treatment responses were analyzed for catecholamines, metanephrines, and serum chromogranin A. Complete biomarker response (normalization) or partial response, defined as at least 50% reduction from baseline if above the normal range, was evaluated at specified time points over a 12-month period. These results were correlated with two other study objectives: blood pressure control and objective tumor response as per RECIST 1.0. In this open-label, single-arm study, 68 patients received at least one therapeutic dose (~18.5 GBq (~500 mCi)) of high-specific-activity I-131 meta-iodobenzylguanidine. Of the patients, 79% and 72% had tumors associated with elevated total plasma free metanephrines and serum chromogranin A levels, respectively. Best overall biomarker responses (complete or partial response) for total plasma free metanephrines and chromogranin A were observed in 69% (37/54) and 80% (39/49) of patients, respectively. The best response for individual biomarkers was observed 6–12 months following the first administration of high-specific-activity I-131 meta-iodobenzylguanidine. Biochemical tumor marker response was significantly associated with both reduction in antihypertensive medication use (correlation coefficient 0.35; P = 0.006) as well as objective tumor response (correlation coefficient 0.36; P = 0.007). Treatment with high-specific-activity I-131 meta-iodobenzylguanidine resulted in long-lasting biomarker responses in patients with advanced pheochromocytoma or paraganglioma that correlated with blood pressure control and objective response rate. number: NCT00874614.

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Chunyan Hu, Manli Wang, Miao Hu, Shanshan Ma, Bingmo Yang, Wei Xiao, Qian Zhou, Ming Zhou, and Zhong Li

Genistein (GE), the most important phytoestrogen in diet, is known to behave as a partial agonist of estrogen receptor α and shows a proliferative effect on the growth of breast cancer cell lines. Recent research has reported that long-term consumption of low doses of GE results in hormone-independent growth phenotypes of MCF-7 tumors, with increased HER2. Overexpression of HER2 has been associated with endocrine resistance in human breast cancer, but whether long-term low-level GE-induced HER2 expression is the cause of endocrine resistance remains to be determined. Short-term and long-term treatments with GE may have different effects on HER2 expression. We found that low doses of GE had estrogen-like effects and inhibited HER2 expression after short-term exposure in estrogen receptor-positive breast cancers cells. However, in contrast to short-term exposure, long-term exposure induced an increase in HER2 expression, which led to endocrine resistance. During long-term low-level exposure, the continuous activation of ERK1/2-phosphorylated EZH2 at Ser21 resulted in a decrease of lysine 27 trimethylation. As H3K27me3 levels decreased, the expression of interleukin-6 (IL-6) and IL-8 increased, and HER2 levels gradually increased, forming a feedback loop of ERK1/2/EZH2/IL-6 and IL-8/HER2. We identified a novel pathway by which EZH2 phosphorylation contributed to long-term low-level GE-induced HER2 overexpression and provided new insight for long-term low-level GE-induced acquired endocrine resistance. For breast cancer patients, long-term low-level use of soy supplements has potential health risks, and monitoring dietary exposure to GE is advisable when patients are treated with tamoxifen.

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Francesca Branzoli, Betty Salgues, Małgorzata Marjańska, Marie Laloi-Michelin, Philippe Herman, Lauriane Le Collen, Brigitte Delemer, Julien Riancho, Emmanuelle Kuhn, Christel Jublanc, Nelly Burnichon, Laurence Amar, Judith Favier, Anne-Paule Gimenez-Roqueplo, Alexandre Buffet, and Charlotte Lussey-Lepoutre

Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequently involved in pheochromocytoma/paraganglioma (PPGL) development and were implicated in patients with the ‘3PAs’ syndrome (associating pituitary adenoma (PA) and PPGL) or isolated PA. However, the causality link between SDHx mutation and PA remains difficult to establish, and in vivo tools for detecting hallmarks of SDH deficiency are scarce. Proton magnetic resonance spectroscopy (1H-MRS) can detect succinate in vivo as a biomarker of SDHx mutations in PGL. The objective of this study was to demonstrate the causality link between PA and SDH deficiency in vivo using 1H-MRS as a novel noninvasive tool for succinate detection in PA. Three SDHx-mutated patients suffering from a PPGL and a macroprolactinoma and one patient with an apparently sporadic non-functioning pituitary macroadenoma underwent MRI examination at 3 T. An optimized 1H-MRS semi-LASER sequence (TR = 2500 ms, TE = 144 ms) was employed for the detection of succinate in vivo. Succinate and choline-containing compounds were identified in the MR spectra as single resonances at 2.44 and 3.2 ppm, respectively. Choline compounds were detected in all the tumors (three PGL and four PAs), while a succinate peak was only observed in the three macroprolactinomas and the three PGL of SDHx-mutated patients, demonstrating SDH deficiency in these tumors. In conclusion, the detection of succinate by 1H-MRS as a hallmark of SDH deficiency in vivo is feasible in PA, laying the groundwork for a better understanding of the biological link between SDHx mutations and the development of these tumors.

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Andrea Abate, Mariangela Tamburello, Elisa Rossini, Ram Manohar Basnet, Giovanni Ribaudo, Alessandra Gianoncelli, Constanze Hantel, Deborah Cosentini, Marta Laganà, Salvatore Grisanti, Guido Alberto Massimo Tiberio, Maurizio Memo, Alfredo Berruti, and Sandra Sigala

The pharmacological approach to adrenocortical carcinoma (ACC) is based on mitotane with/without etoposide, doxorubicin, and cisplatin, according to the disease stage. Considering the limited efficacy and toxicity of this treatment, new strategies are required. Trabectedin is a marine-derivated antitumoral agent that inhibits oncogenic transcription. We have already demonstrated trabectedin cytotoxic activity at sub-nanomolar concentrations in ACC cells. Here, we expanded the investigation of trabectedin effect on ACC preclinical models, evaluating whether trabectedin could affect ACC cells’ invasiveness and metastasis formation. NCI-H295R, MUC-1, and TVBF-7 cell lines were used. Cell tumor xenografts in Danio rerio embryos were performed. The tumor mass areas and the number of embryos with metastasis were evaluated. The in vitro invasiveness of cells was evaluated. Effects of trabectedin of MMP2, TIMP1, and TIMP2 were evaluated at gene level qRT-PCR. MMP2 secreted in the cell medium was evaluated by Western blot and by zymography. Xenograft experiments demonstrated that trabectedin significantly reduced the tumor area in each ACC cell model and metastasis formation in embryos injected with metastasis-derived cell lines. Trabectedin treatment reduced the invasiveness of ACC cells across the matrix, which was greater at baseline for the metastatic models. In metastatic cell models, protein analysis demonstrated a reduction of MMP2 secretion and activity in the culture medium after treatment. Our results indicate that trabectedin interferes with invasiveness and metastasis processes, both dramatic features of ACC. Furthermore, these results support those previously published in providing the rationale for a clinical evaluation of the efficacy of trabectedin in ACC patients.

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Wenwen Li, Teng Wang, Guobin Fu, Yuan Xu, Nasha Zhang, Linyu Han, and Ming Yang

Papillary thyroid cancer (PTC) is one of the histological subtypes of thyroid cancer which is the most common endocrine malignancy in the world. The disrupted balance of the adenosine-to-inosine (A-to-I) RNA editing due to dysregulation of the editing genes exists in thyroid cancer. However, it is still largely unknown how functional single-nucleotide polymorphisms (SNPs) in the A-to-I RNA editing genes contribute to PTC genetic susceptibility. In this study, we systematically annotated and investigated the role of 28 potential functional SNPs of ADAR, ADARB1, ADARB2 and AIMP2 in PTC. We identified ADARB2 rs904957 and rs1007147 genetic variants which are associated with significantly elevated PTC risk in two case–control sets consisting of 2020 PTC cases and 2021 controls. Further investigations disclosed that ADARB2 could inhibit cell viability and invasion capabilities of PTC cells as a novel tumor suppressor. The ADARB2 rs904957 thymine-to-cytosine (T-to-C) polymorphism in gene 3'-untranslated region enhances miR-1180-3p-binding affinity and represses ADARB2 expression through an allele-specific manner. In line with this, carriers with the rs904957 C allele correlated with decreased tumor suppressor ADARB2 expression in tissue specimens showed notably increased risk of developing PTC compared to the T allele carriers. Our findings highlight that the A-to-I RNA editing gene ADARB2 SNPs confer PTC risk. Importantly, these insights would improve our understanding for the general roles of RNA editing and editing genes during cancer development.