scholarly journals De-differentiation in thyroid cancer- an increasingly appreciated concept

2021 ◽  
Vol 8 (2) ◽  
pp. 757
Author(s):  
Prasanth Poolakkil ◽  
Sajith Babu Thavarool ◽  
Satheesan Balasubramanyam ◽  
Kandathil Joseph Philip
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Rare Case ◽  
Treatment Strategies ◽  
Good Prognosis ◽  
Genetic Changes ◽  
Molecular Changes ◽  
Clinical Behaviour ◽  
Differentiation Theory ◽  
Differentiation Pattern

Thyroid cancer is the most common endocrine malignancy. In general, they are said to be of good prognosis, still there are a few aggressive variants. Differentiated carcinomas like papillary and follicular comprise of major proportion and have a less aggressive clinical behaviour, even though some of them tend to be otherwise. De-differentiated and undifferentiated cancers are more aggressive. There has been an already existing theory that these de-differentiated cancers arise from differentiated ones by a process of stepwise molecular changes. There are already reported cases of coexistence of multiple histologies. Appreciation of dedifferentiation and identification of the genetic changes may be of help in forming improved treatment strategies, including targeted therapy. This article is to report a rare case we came across, in which three different histologies coexisted and may be pointing towards graded de-differentiation pattern. This is a further support to the stepwise de-differentiation theory.

Preoperative neoadjuvant targeted therapy for inoperable differentiated thyroid cancer: a case report

2020 ◽  
Author(s):  
Yingchao Zhang ◽  
Xianzhao Deng ◽  
Zheng Ding ◽  
Yiqi Niu ◽  
Jianzhong Hou ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Neoadjuvant Therapy ◽  
Differentiated Thyroid Cancer ◽  
Clinical Stage ◽  
Locally Advanced ◽  
Complete Removal ◽  
Good Prognosis ◽  
Unresectable Tumor ◽  
One Year

Abstract Background: The majority of differentiated thyroid cancer (DTC) has good prognosis after a careful standardized therapy according to the current guidelines. However, approximately 13% to 15% of DTC shows surprisingly aggressive behavior and invades the surrounding structures, and then a few is very difficult to remove. In that specific context, preoperative neoadjuvant targeted therapy may improve the clinical stage and create an opportunity for operation.Case presentation: We reported a case of 64-year-old woman with locally advanced papillary thyroid cancer (PTC) who presented with dysphagia due to seemingly unresectable tumor, which severely invaded the left esophagus at the junction of neck and thorax, difficult to undergo a safe and complete removal. With an approvement of institution ethics committee, this patient was treated with neoadjuvant therapy (apatinib 500mg orally qd).Six weeks later, the tumor dramatically shrunk from 56*37mm to 29*26mm with well-controlled mild hypertension. After 10 days interval of apatinib withdrawal, complete tumor excision was accomplished without esophagus fistula. Postoperative inhibition and radioiodine 131I ablation were performed. At one-year follow-up evaluation, no tumor recurrence or metastasis was observed.Conclusion: Preoperative short-termed targeted treatment for locally advanced inoperable DTC may become a promising neoadjuvant therapy, which can reduce the tumor size and decrease stage, thus being convenient for complete and safe removal.

scholarly journals Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor–Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial

2017 ◽  
Vol 35 (29) ◽  
pp. 3315-3321 ◽  
Author(s):  
Maria E. Cabanillas ◽  
Jonas A. de Souza ◽  
Susan Geyer ◽  
Lori J. Wirth ◽  
Michael E. Menefee ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Phase Ii ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Multikinase Inhibitor

Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.

scholarly journals Chronic Alcohol Use Induces Molecular Genetic Changes in the Dorsomedial Thalamus of People with Alcohol-Related Disorders

2021 ◽  
Vol 11 (4) ◽  
pp. 435
Author(s):  
Andreas-Christian Hade ◽  
Mari-Anne Philips ◽  
Ene Reimann ◽  
Toomas Jagomäe ◽  
Kattri-Liis Eskla ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Molecular Genetic ◽  
Brain Structures ◽  
Thalamic Nuclei ◽  
Genetic Changes ◽  
Molecular Changes ◽  
Gabaergic Neurotransmission ◽  
And Control ◽  
Upregulated Genes

The Mediodorsal (MD) thalamus that represents a fundamental subcortical relay has been underrepresented in the studies focusing on the molecular changes in the brains of subjects with alcohol use disorder (AUD). In the current study, MD thalamic regions from AUD subjects and controls were analyzed with Affymetrix Clariom S human microarray. Long-term alcohol use induced a significant (FDR ≤ 0.05) upregulation of 2802 transcripts and downregulation of 1893 genes in the MD thalamus of AUD subjects. A significant upregulation of GRIN1 (glutamate receptor NMDA type 1) and FTO (alpha-ketoglutarate dependent dioxygenase) was confirmed in western blot analysis. Immunohistochemical staining revealed similar heterogenous distribution of GRIN1 in the thalamic nuclei of both AUD and control subjects. The most prevalent functional categories of upregulated genes were related to glutamatergic and GABAergic neurotransmission, cellular metabolism, and neurodevelopment. The prevalent gene cluster among down-regulated genes was immune system mediators. Forty-two differentially expressed genes, including FTO, ADH1B, DRD2, CADM2, TCF4, GCKR, DPP6, MAPT and CHRH1, have been shown to have strong associations (FDR p < 10−8) with AUD or/and alcohol use phenotypes in recent GWA studies. Despite a small number of subjects, we were able to detect robust molecular changes in the mediodorsal thalamus caused by alcohol emphasizing the importance of deeper brain structures such as diencephalon, in the development of AUD-related dysregulation of neurocircuitry.

Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer who have progressed after prior VEGFR-targeted therapy: Results from the phase 3 COSMIC-311 trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6001-6001
Author(s):  
Marcia S. Brose ◽  
Bruce Robinson ◽  
Steven I. Sherman ◽  
Barbara Jarzab ◽  
Chia-Chi Lin ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Disease Progression ◽  
Differentiated Thyroid Cancer ◽  
Statistical Significance ◽  
Phase 1 ◽  
Objective Response ◽  
Standard Of Care ◽  
Clinical Activity ◽  
Phase 3

6001 Background: Cabozantinib (C), an inhibitor of VEGFR2, MET, AXL, and RET, showed clinical activity in patients (pts) with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) in phase 1/2 studies (Cabanillas 2017; Brose 2018). This phase 3 study (NCT03690388) evaluated the efficacy and safety of C vs placebo (P) in pts with RAI-refractory DTC who had progressed during/after prior VEGFR-targeted therapy for whom there is no standard of care. Methods: In this double-blind, phase 3 trial, pts were randomized 2:1 to receive C (60 mg QD) or P, stratified by prior lenvatinib treatment (L; yes, no) and age (≤65, > 65 yr). Pts with RAI-refractory DTC must have received L or sorafenib for DTC and progressed during or following treatment with ≤ 2 prior VEGFR inhibitors. Pts randomized to P could cross over to open-label C upon disease progression per blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (ORR) in the first 100 randomized pts and progression-free survival (PFS) in all randomized pts. PFS and ORR were assessed by BIRC per RECIST v1.1. The study was designed to detect an ORR for C vs P (2-sided α = 0.01) and a hazard ratio (HR) for PFS of 0.61 (90% power, 2-sided α = 0.04). A prespecified interim PFS analysis was planned for the ITT population at the time of the primary ORR analysis. Results: As of 19 Aug 2020,125 vs 62 pts had been randomized to the C and P arms, respectively; median age was 66 yr, 55% were female and 63% received prior L. Median (m) follow-up was 6.2 months (mo). At the planned interim analysis, the trial met the primary endpoint of PFS with C demonstrating significant improvement over P (HR 0.22, 96% CI 0.13–0.36; p < 0.0001). mPFS was not reached for C vs 1.9 mo for P; PFS benefit was observed in all prespecified subgroups including prior L (yes, HR 0.26; no, HR 0.11) and age (≤65 yr, HR 0.16; > 65 yr, HR 0.31). ORR was 15% for C vs 0% for P (p = 0.0281) but did not meet the prespecified criteria for statistical significance (p < 0.01). A favorable OS trend was observed for C vs P (HR 0.54, 95% CI 0.27–1.11). Treatment-emergent adverse events (AEs) of any grade with higher occurrences in the C vs P arm included diarrhea (51% vs 3%), hand-foot skin reaction (46% vs 0%), hypertension (28% vs 5%), fatigue (27% vs 8%), and nausea (24% vs 2%); grade 3/4 AEs were experienced by 57% of pts with C vs 26% with P. Dose reductions due to any grade AEs occurred in 57% of pts with C vs 5% with P. Treatment discontinuations due to AEs not related to disease progression occurred in 5% of pts with C vs 0% with P. No treatment-related deaths occurred in either arm. Conclusions: C showed a clinically and statistically significant improvement in PFS over P in pts with RAI-refractory DTC after prior VEGFR-targeted therapy with no unexpected toxicities. C may represent a new standard of care in pts with previously treated DTC. Clinical trial information: NCT03690388.

Novel Recurrent Altered Genes in Chinese Patients With Anaplastic Thyroid Cancer

2021 ◽  
Author(s):  
Lingyun Zhang ◽  
Zhixiang Ren ◽  
Zhengzheng Su ◽  
Yang Liu ◽  
Tian Yang ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Copy Number ◽  
Treatment Strategies ◽  
Gene Mutations ◽  
Anaplastic Thyroid Cancer ◽  
Chinese Patients ◽  
Driver Gene ◽  
Phosphatidylinositol 3 Kinase ◽  
Entire Cohort ◽  
Whole Exome

Abstract Background Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy, and few systematic investigations on genomic profiles of ATC have been performed in Chinese patients. Methods Fifty-four ATC patients in West China Hospital between 2010 to 2020 were retrospectively analyzed, while 29 patients with available samples were sequenced by whole-exome sequencing (WES). The associations between genomic alterations and clinical characteristics were statistically evaluated. Results The median overall survival was 3.0 months in the entire cohort, which was impacted by multiple clinical features, including age, tumor size, and different treatment strategies. In the WES cohort, totally 797 nonsilent mutations were detected; the most frequently altered genes were TP53 (48%), BRAF (24%), PIK3CA (24%), and TERT promoter (21%). Although these mutations have been well-reported in previous studies, ethnic specificity was exhibited in terms of mutation frequency. Moreover, several novel significantly mutated genes were identified including RBM15 (17%), NOTCH2NL (14%), CTNNA3 (10%), and KATNAL2 (10%). WES-based copy number alteration analysis also revealed a high frequent gain of NOTCH2NL (41%), which induced its increased expression. Gene mutations and copy number alterations were enriched in phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin (mTOR), NOTCH, and WNT pathways. Conclusions This study reveals shared and ethnicity-specific genomic profiles of ATC in Chinese patients and suggests NOTCH2NL may act as a novel candidate driver gene for ATC tumorigenesis.

scholarly journals Primary maxillofacial chordoma: a rare case report and literature review

2019 ◽  
Vol 47 (9) ◽  
pp. 4575-4579
Author(s):  
Yu Cui ◽  
Xiang-yan Cui ◽  
Tingting Yu ◽  
Zhan-peng Zhu ◽  
Xin Wang
Keyword(s):  
Adjuvant Radiotherapy ◽  
Rare Case ◽  
Postoperative Radiotherapy ◽  
Eastern Cooperative Oncology Group ◽  
Treatment Strategies ◽  
Comprehensive Treatment ◽  
Neck Lymph Node ◽  
Group Score ◽  
Rare Case Report

Primary maxillofacial chordoma is extremely rare. We herein report a very rare case of a recurrent maxillofacial chordate tumor that was diagnosed in a 56-year-old woman who underwent three tumor resections. After surgical treatment, the patient healed well with an Eastern Cooperative Oncology Group score of 1. She was discharged to a local hospital for adjuvant radiotherapy. Close follow-up was ongoing at the time of this writing. Radical surgery and adjuvant radiotherapy remain the main treatment strategies for chordoma. Postoperative radiotherapy is particularly important. Our experience is to administer a total dose of 50 Gy to a clearly delineated target. If appropriate comprehensive treatment is available, distant metastasis of primary chordoma is rare, and neck dissection is therefore not generally recommended. Neck lymph node dissection is generally not recommended.

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