Papillary Thyroid Research Articles

Presumed Pathogenic Germ Line and Somatic Variants in African American Thyroid Cancer.

Background: African American (AA) thyroid cancer patients have worse prognoses than European Americans (EA), which has been attributed to both health care disparities and possible genetic differences. We investigated the impact of both germ line and somatic variants on clinical outcome in a cohort of AA nonmedullary thyroid cancer (NMTC) patients who had received therapeutic intervention from cancer centers. Methods: Whole-exome sequencing was performed on DNA from available blood/normal tissues (N = 37) and paired tumor samples (N = 32) collected from 37 and 29 AA NMTC patients, respectively. Variants with Combined Annotation Depletion Dependent (CADD) score of ≥20 and VarSome Clinical classification of likely pathogenic or pathogenic were classified as presumed pathogenic germ line or somatic variants (PPGVs/PPSVs). PPGVs/PPSVs in cancer-related genes and PPGVs in cardiovascular risk genes were further investigated, and PPGVs/PPSVs associated with African (AFR) ancestry were identified. Results: Among 17 PPGVs identified in 16 cancer predisposition or known cancer-related genes, only WRN was previously known to associate with NMTC predisposition. Among PPSVs, BRAFV600E was most the prevalent and detected in 12 of the 29 (41%) tumors. Examining PPGVs/PPSVs among three patients who died from NMTC, one patient who died from papillary thyroid carcinoma/anaplastic thyroid carcinoma (PTC/ATC) led us to speculate that the PPGV ERCC4R799W may have increased the risk of PPSV TP53R273H acquisition. Among PPGVs identified in 18 cardiovascular risk genes, PPGVs in SC5NA, GYG1, CBS, CFTR, and SI are known to have causal and pathogenic implications in cardiovascular disease. Conclusion: In this cohort, most AA-NMTC patients exhibit favorable outcomes after therapeutic intervention given at cancer centers, suggesting that health care disparity is the major contributor for worse prognoses among AA-NMTC patients. Nevertheless, the clinical impact of PPGVs that might facilitate the acquisition of TP53 tumor mutations, and/or PPGVs that predispose individuals to adverse cardiovascular events, which could be exacerbated by therapy-induced cardiotoxicity, needs to be further explored. Integrated analysis of PPGV/PPSV profiles among NMTC patients with different stages of disease may help to identify NMTC patients who require close monitoring or proactive intervention.

Safety and efficacy of the novel BRAF inhibitor FORE8394 in patients with advanced solid and CNS tumors: Results from a phase 1/2a study.

3006 Background: FORE8394 is an investigational inhibitor (i) of class 1 (V600) and 2 (activating non-V600) BRAF-altered tumors. FORE8394 did not have paradoxical activation of the MAPK pathway in nonclinical studies. Methods: In a phase 1/2a study, patients (pts) aged ≥3 years with BRAF-altered, advanced solid or CNS tumors received FORE8394 (900-3600 mg/day or mg/m2 dosing) with or without a pharmacokinetic booster (cobicistat 150 mg/day). CNS metastases and prior treatment with other BRAFi were allowed. Besides standard safety assessments, skin and eye exams were required. Objective response was assessed by RECIST v1.1 or RANO criteria. Efficacy was evaluated in pts with class 1/2 BRAF alterations and ≥1 post-baseline assessment, with mg/m2 dosing (n=4) reported separately. Results: On 21Nov2022, 110 pts had received ≥1 dose of FORE8394. 85% completed ≥1 4-week cycle. 10 (9%) and 3 (3%) received FORE8394 ≥2 and ≥6 years, respectively; 14 (13%) are ongoing. Pts included 61 (55%) class 1 mutations, 19 (17%) class 2 mutations (excluding fusions), and 17 (15%) BRAF fusions. 64 pts (58%) had ≥2 prior lines of systemic therapy; 28 (25%) received prior MAPKi. Increased ALT (39%), increased AST (35%), fatigue (34%), nausea (27%), diarrhea (22%), and vomiting (20%) were the most frequently reported treatment-emergent adverse events (TEAEs); most were grade (G) 1/2. G3+ TEAEs were reported in 49% (54/110), the most common being increased ALT (9%), increased blood bilirubin (6%), and hyponatremia (5%). Transient G1 pyrexia was observed in 8 (7%) pts. All rashes were G1; none required a dose change. No TEAE of hyperkeratosis, papilloma, uveitis, retinal detachment, or LVEF reduction were reported. 1 pt discontinued due to FORE8394-related TEAE. Antitumor activity was observed in pts with MAPKi-naïve, V600 mutant tumors (excluding colorectal cancer [CRC]), 39% (9/23) having a PR (median duration of response [DoR]: 32 months). In 17 pts with V600 mutated tumors (excluding CRC) treated with prior MAPKi, 3 (18%) had PR and 5 (29%) had SD. In V600 mutated tumors, PRs occurred in 6 (55%) gliomas, 3 (100%) ovarian cancers, and 1 each in CRC (7%), small bowel (50%), papillary thyroid (13%) and anaplastic thyroid (25%) cancers. Of pts with BRAF-fusions, a pt with AGK-BRAF-fused melanoma had CR (DoR 51.8+ months); 46% (6/13) had SD. Of note, 1 child with V600E mutated Langerhans cell histiocytosis had SD with improvement in neurodegenerative changes and a progression-free survival of 55.8+ months. Conclusions: As single agent anticancer therapy, FORE8394 had antitumor activity in various tumors with BRAF alterations, including pts previously treated with MAPKi and pts with BRAF fusions. Durable tolerability was observed, and TEAEs indicative of paradoxical MAPK activation were not observed, consistent with the novel mechanism of action of FORE8394. These results support further evaluation of FORE8394. Clinical trial information: NCT02428712 .

Greetings From the Editor of Clinical Thyroidology

Clinical ThyroidologyVol. 35, No. 5 Greetings from the EditorFree AccessGreetings From the Editor of Clinical ThyroidologyPublished Online:12 May 2023https://doi.org/10.1089/ct.2023;35.176-177AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Welcome to another issue of Clinical Thyroidology. The month's issue begins with a review by Dr. Elizabeth McAninch on the intersection between thyroid and renal function. Dr. Kenneth Burman summarizes a recent literature review on the topic of levothyroxine absorption tests in patients with hypothyroidism. Drs. Erivelto Volpi and Leonardo Volpi examine a study comparing the cost effectiveness between total thyroidectomy and radioactive iodine therapy in patients who relapse after a course of anti-thyroid drugs. Drs. Trisha Cubb and Natalia Genere review a study on the risk of hyperglycemia associated with teprotumumab use in patients with thyroid eye disease.On the topic of thyroid nodules and thyroid cancer, Dr. Jie Liu discusses a study examining variation in the extent of thyroid surgery performed between types of geographical settings in the United States. Dr. Giorgio Grani examines a study that analyzed the association of delayed thyroid surgery and oncologic outcomes in patients with papillary thyroid cancers.There are also reviews of several studies in this issue related to follicular thyroid cancers. Dr. Sara Ahmadi discusses a study on the genomics of follicular thyroid lesions, while Dr. Theodora Pappa reviews the prognosis of patients with large encapsulated follicular cell–derived carcinomas without vascular invasion. Drs. Yasuhiro Ito and Takashi Akamizu look at a study that examines the TERT promoter mutation in patients with follicular thyroid cancers.The issue also includes a review by Dr. Giuseppe Barbesino on a phase 2 study of MAPK inhibitory agents in radioiodine-refractory thyroid cancers. Finally, Drs. Shejil Kumar, Matti Gild, and Venessa Tsang summarize a study of neoadjuvant therapy that might be lend hope to some patients with BRAF-mutated anaplastic thyroid cancers.We remain active on our various social media channels, and I invite our readers to further engage with us there. In these channels, we recap the featured highlights from each month's issue and discuss other topics related to the latest clinical thyroid literature. All are welcome to join us at:Twitter:https://twitter.com/clinicalthyroid(@clinicalthyroid)Facebook:https://www.facebook.com/ThyroidAssociationLinkedIn:https://www.linkedin.com/company/american-thyroid-associationYoutube:https://www.youtube.com/user/thyroidorgI also thank the editorial board of Clinical Thyroidology for the Public [CTFP] (https://www.thyroid.org/patient-thyroid-information/ct-for-patients), as led by Dr. Alan Farwell, for their work in providing short summaries of our Clinical Thyroidology articles each month. These quicker reads are helpful to patients and to the general public who are interested in learning more about recently published studies in the clinical thyroid literature.We will continue to provide reviews, commentaries, editorials, and perspectives of the most relevant clinical thyroid studies from the published literature. Guidelines for submitting Letters to the Editor and select Guest Editorials that cover timely and innovative aspects of clinical thyroid disease management may be found at https://home.liebertpub.com/publications/clinical-thyroidologyand174/623/for-authors.Thank you again for your interest in Clinical Thyroidology. Please feel free to send me any questions or comments at clinicalthyroidology@thyroid.org.Warmest regards,Angela M. Leung, MD, MScEditor-in-Chief, Clinical ThyroidologyFiguresReferencesRelatedDetails Volume 35Issue 5May 2023 Information© Copyright 2023, Mary Ann Liebert, Inc.To cite this article:Greetings From the Editor of Clinical Thyroidology.Clinical Thyroidology.May 2023.176-177.http://doi.org/10.1089/ct.2023;35.176-177Published in Volume: 35 Issue 5: May 12, 2023PDF download

Concomitant clear cell renal cell carcinoma with osseous metaplasia and papillary thyroid microcarcinoma: a case report with literature review

BackgroundsAlthough calcifications have been observed in various renal masses, osseous metaplasia has very rarely been reported. Here, we present a case of concomitant clear cell renal cell carcinoma with osseous metaplasia and papillary thyroid microcarcinoma.Case presentationA 52-year-old male was being investigated for having post-prandial gaseous abdominal distention. Computed tomography of the abdomen showed a heterogeneous mass lesion measuring 27 × 24 mm at the upper/mid pole of the right kidney. It also revealed two small (10 and 11 mm) benign bone islands in the body of the D4 and L4 vertebrae. The patient underwent a metastatic workup by computed tomography, which revealed a 93 × 35 mm mass in the left thyroid lobe with coarse calcification. A partial nephrectomy was planned for the renal mass, but the site of the mass deemed this impossible. Six months after the operation, the patient underwent total thyroidectomy. Histopathology of both tissue samples revealed concomitant clear cell renal cell carcinoma with heterotopic bone formation and papillary thyroid microcarcinoma.ConclusionAlthough rare, osseous metaplasia in renal cell carcinoma can occur and may indicate an early-stage carcinoma with a favorable prognosis.

The role of lncRNA CERS6-AS1 in cancer and its molecular mechanisms: A systematic review and meta-analysis

LncRNAs have the potential to play a regulatory role in different processes of cancer development and progression. We conducted a systematic review and meta-analysis of evidence on the clinical significance and prognostic value of lncRNA CERS6-AS1 in cancer. This systematic review was conducted following PRISMA guidelines. Medline and Embase databases were searched using the relevant key terms covering lncRNA CERS6-AS1 and cancer. We pooled the estimated effect sizes and their 95% confidence interval (CI) using random-effects models in STATA 16.0 (StataCorp, College Station, TX, USA). Eleven articles on pancreatic, colorectal, gastric, papillary thyroid, breast, and hepatocellular cancers fulfilled our eligibility criteria. Studies consistently found that lncRNA CERS6-AS1 expression is upregulated in all assessed cancers. Based on our meta-analysis, its aberrant expression was directly associated with unfavorable clinical outcomes, including higher stage (pooled Odds ratios (95% CI): 3.15 (2.01-4.93; I2 = 0.0%), tumor size (1.97 (1.27-3.05; I2 = 37.8%), lymph node metastasis (6.48 (4.01-10.45; I2 = 0.40%), and poor survival (Pooled log-rank test P-value < 0.001) in patients. Regarding potential mechanisms, functional studies revealed that LncRNA CERS6-AS1 is involved in cancer growth mainly by sponging miRNAs and regulating their downstream targets. Available evidence suggests that LncRNA CERS6-AS1 is upregulated in different cancers and has an oncogenic role. LncRNA CERS6-AS1 expression level might predict cancer prognosis, highlighting its potential application as a prognostic biomarker for cancer.

Comparative evaluation of somatostatin and CXCR4 receptor expression in different types of thyroid carcinoma using well-characterised monoclonal antibodies

BackgroundPapillary and follicular thyroid carcinomas can be treated surgically and with radioiodine therapy, whereas therapeutic options for advanced stage IV medullary and for anaplastic tumours are limited. Recently, somatostatin receptors (SSTs) and the chemokine receptor CXCR4 have been evaluated for the treatment of thyroid carcinomas, however, with contradictory results.MethodsThe expression of the five SSTs and of CXCR4 was assessed in 90 samples from 56 patients with follicular, papillary, medullary, or anaplastic thyroid carcinoma by means of immunohistochemistry using well-characterised monoclonal antibodies. The stainings were evaluated using the Immunoreactivity Score (IRS) and correlated to clinical data. In order to further substantiate the immunohistochemistry results, in serial sections of a subset of the samples receptor expression was additionally examined at the mRNA level using qRT-PCR.ResultsOverall, SST and CXCR4 protein expression was low in all four entities. In single cases, however, very high IRS values for SST2 and CXCR4 were observed. SST2 was the most frequently expressed receptor, found in 38% of cases, followed by SST5 and SST4, found in 14 and 9% of tumours, respectively. SST1 and SST3 could not be detected to any significant extent. CXCR4 was present in 12.5% of medullary and 25% of anaplastic carcinomas. Expression SST3, SST4, SST5 and CXCR4 was positively correlated with expression of the proliferation marker Ki-67. Additionally, a negative interrelationship between SST4 or SST5 expression and patient survival and a positive association between SST3 expression and tumour diameter were observed. qRT-PCR revealed a similar receptor expression pattern to that seen at the protein level. However, probably due to the low overall expression, no correlation was found for the SSTs or the CXCR4 between the IRS and the mRNA values.ConclusionsSST- or CXCR4-based diagnostics or therapy in thyroid carcinomas should not be considered in general but may be feasible in single cases with high levels of expression of these receptors.

Abstract 1162: A systematic analysis of RET mutations and their sensitivity to different RET inhibitors

Abstract The RET oncogene is a receptor tyrosine kinase, mainly expressed in neural crest-derived tissues, that plays a role in cell growth and differentiation. Since the first identification of inherited mutations in RET as the cause of Multiple endocrine neoplasia type 2 (MEN2), somatic RET alterations have been identified as actionable drivers in subtypes of lung and thyroid, among other cancer types. This enabled the development of several RET targeted treatments, such as pralsetinib and selpercatinib, showing meaningful clinical benefit. To understand the full scope of RET alteration frequency and heterogeneity we used the AACR-GENIE database. We found that the frequency of RET alterations pan-cancer is 3%, of which two-thirds are missense mutations. The major cancer types with RET alterations are medullary thyroid, papillary thyroid and NSCLC, as expected, but also breast, colorectal and melanoma. An important distinction between NSCLC and thyroid cancer compared to colorectal, breast and melanoma is the fraction of missense vs. fusion events, with 30%-40% of samples in the former group containing RET fusions. This is in contrast with &amp;gt;80% of samples in the latter group containing RET missense mutations. Moreover, the heterogeneity of RET alterations is large, with over 1,000 unique types of missense mutations identified. The vast majority of mutations are classified as variants of uncertain significance (VUS). To better understand the potential activity of these mutations, we assayed over 200 different missense mutations and fusions using a high-throughput cell-based functional assay. Results were analyzed using a novel machine learning model consisting of a multi-scale deep convolutional neural net, followed by a tree-based regressor. Our results show that the assay correctly predicted the activity of both known activating alterations as well as of loss of function mutations. Interestingly, only ~3% of over 150 VUS tested were found to be activating. Furthermore, we show that the active alterations are sensitive to the FDA-approved targeted agents pralsetinib and selpercatinib, with varying IC50 values. Taken together, these results uncover the full extent of actionable RET alterations, differentiating between active and non-active variants, as well as the effectiveness of RET inhibitors. Citation Format: Shay Rotkopf, DIkla Haham, Natalie Fillipov-Levy, Lea Birnbaum, Elinor Dehan, Ilona Kifer, Zohar Barbash, Gabi Tarcic. A systematic analysis of RET mutations and their sensitivity to different RET inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1162.

P-267 The controversial association of CHEK2 pathogenic variants and colorectal cancer susceptibility

Colorectal cancer (CRC) is the third most common cancer worldwide, with an estimated worldwide incidence of approximately 1 100 000 cases and 550 000 CCR associated deaths. Hereditary factors play an important role in CCR risk. Scientific knowledge of genetic susceptibility to gastrointestinal cancers is constantly evolving with identification of new susceptibility genes. Germ line mutations of the cell cycle checkpoint kinase 2 (CHEK2) gene have been associated with a range of cancer types including CCR. CHEK2 gene 1100 delC variant in particular has been implicated as a risk factor for CRC. Considering this association various institutional surveillance guidelines have included periodic colorectal cancer screening strategies for CHEK2 mutation carriers. At our familial cancer risk clinic, all carriers of pathogenic variants are invited to a program of prospective follow up. For the CHEK2 cohort our follow up protocols include colonoscopy surveillance starting at 40 years, or 10 years before first familiar diagnosis, repeated every 3-5 years. Familial data on CCR is critical to decide on individual surveillance programs. The aim of this study was to review CCR incidence in our cohort and to establish the increased risk for CCR in CHEK2 mutation carriers. Review of clinical records of patients with CHEK2 pathogenic mutations followed in our familial cancer risk clinic between January 1994 and December 2021. The CHECK2 cohort includes 81 patients (16 with CHEK2 1100 delC (19.8%). Of these, 76 were females (93.8%), with a mean age of 47 years and the average follow up time was 111 months. Six patients died during follow 4 from cancer related causes and 2 from unrelated causes. In this period, the following cancers were observed: 64 breast cancers, 5 ovarian cancers, 5 papillary thyroid, and 1 each of: CRC, lung cancer, cervical cancer, prostate cancer, pancreatic cancer, chronic myeloid leukaemia and non-Hodgkin lymphoma. The patient with CRC was a 72-year old female with a c.319+2T>A missense CHEK2 variant without a previous diagnosis of cancer. Although previous studies suggested an increased risk of CRC cancer in CHEK2 mutation carriers, that was not confirmed in our cohort, even after a long follow up. Reasons for this observation may be related with the mean young age of our population (less than 50) and a high prevalence of non CHEK2 gene 1100 delC variants. Prospective follow up is ongoing and a phenotype/ genotype is being explored. Familial data on CCR is critical to decide on individual surveillance programs for individuals diagnosed with a CHEK2 mutation.

Interim safety and efficacy results from a phase 1 study of NT219 in adults with advanced solid tumors.

3096 Background: NT219 is a small molecule, effecting IRS1/2 degradation and inhibiting STAT3 phosphorylation. IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, altered during epithelial to mesenchymal transition (EMT) and drug resistance, and play an important role in the tumor and its microenvironment. A Phase 1/2 study (NCT04474470) includes a dose escalation of NT219 administered weekly for the treatment of relapsed and/or refractory cancer patients. Methods: In the dose escalation part of the study involving a conventional 3+3 design, patients with recurrent and/or metastatic solid tumors were administered intravenously with NT219 at 3, 6, 12 and 24mg/kg. Safety was assessed according to CTCAE v5 and anti-tumor activity was assessed by the investigators according to RECISTv1.1 using CT/MRI. The primary objectives of this part of the study are to evaluate safety, tolerability, PK and determine the recommended Phase 2 dose (RP2D). The study includes evaluation of potential biomarkers including measurements of STAT3, IRS1/2 phosphorylation, and TILs in biopsy specimens. Results: As of data cutoff date of February 8, 2022, a total of 13 patients were enrolled to 4 NT219 dose levels (3 - 24mg/kg) in the dose escalation phase, of which 11 were evaluable for dose limiting toxicity (DLT) determination, including 4 with colorectal cancer (CRC), 2 with pancreatic cancer, 2 with breast cancer, and one of each of the following cancers: gastroesophageal junction (GEJ), esophageal, appendiceal, papillary thyroid, and mesothelioma. Median number of prior treatment regimens for metastatic disease was 4 (2-11). Six Grade 3 adverse events (AEs) were observed, including alkaline phosphatase increase, aspartate aminotransferase increase, toxic encephalopathy, worsening back pain, abdominopelvic ascites, closed displaced fracture of right femoral neck, with the first 2 considered as possibly related to NT219. No Grade 4 AEs or treatment related deaths were reported. For the 11 evaluable patients, best overall response included one confirmed PR (GEJ patient, 5.5 months duration of response), and 3 SD (3 of 4 CRC patients; duration of 5.2, 4, and 2 months with ongoing follow up) with two patients awaiting follow up MRI/CT scans. As of the cutoff date, 9/11 patients that completed the DLT period are either on treatment or in follow up (range 1.1 to 14.7 months). Conclusions: Interim analysis of safety results obtained in 4 NT219 dose levels found NT219 to be well tolerated without DLTs in advanced cancer patients. The observed durable PR in a GEJ patient and SDs in 3 CRC patients are an encouraging initial signal of efficacy. Combination treatment of cetuximab with escalating NT219 doses in patients with recurrent/metastatic CRC and squamous cell carcinoma of the head and neck (SCCHN) has begun. An expansion cohort in patients with recurrent/metastatic SCCHN will be initiated at the conclusion of this part. Clinical trial information: NCT04474470.

Education and Income Do Not Impact Temporal Trends of Papillary and Follicular Thyroid Cancer Incidence in Denmark—But What Does?

Education and Income Do Not Impact Temporal Trends of Papillary and Follicular Thyroid Cancer Incidence in Denmark—But What Does?

Long-Term Follow-Up of Multiple Myeloma Patients Treated with Tandem Autologous Transplantation Following Melphalan and Upon Recovery, Total Marrow Irradiation

Total body irradiation in combination with melphalan for multiple myeloma (MM) has been shown to be prohibitively toxic. To ameliorate toxicity, total marrow irradiation (TMI) has been administered as the sole ablative modality during the second cycle of tandem autologous stem cell transplantation (TASCT) for MM patients on a phase I-II trial. Patients with MM in response or with stable disease and ≤18 months from diagnosis received melphalan 200 mg/m2 and autologous stem cell transplantation (ASCT) (cycle 1) and then, after recovery, TMI and another ASCT (cycle 2), followed by maintenance with an immunomodulatory drug (ImiD) and dexamethasone for up to 12 months. TMI doses were escalated from 1000 cGy to 1800 cGy in 200-cGy increments. Fifty-four patients were to receive TASCT between 2004 and 2011; 8 patients received single ASCT because of patient or physician preference. The median time between melphalan and TMI was 65 days (range, 47 to 125 days). Thirty patients (55.6%) underwent TASCT at the maximum tolerated dose of 1600 cGy. The complete response and very good partial response rates were 48.1% and 22.2%, respectively, following ASCT and maintenance. The median follow-up among survivors was 12.3 years (range, 9.2 to 15.5+ years). Progression-free survival (PFS) and overall survival at 10 years were 20.4% (95% confidence interval [CI], 10.9% to 31.9%) and 38.8% (95% CI, 25.9% to 51.5%), respectively. Secondary neoplasms included (1 each) acute myelogenous leukemia, papillary thyroid and prostate carcinoma, and melanoma, and there was 1 case of ductal carcinoma in situ and 4 cases of nonmelanoma skin cancers. TMI as part of TASCT was well tolerated, and TASCT was associated with a 20.4% PFS plateau. The inclusion of TMI as a conditioning regiment for MM before ASCT warrants further study in the context of modern induction and maintenance therapies.

Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids.

Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-coenzyme A (CoA). Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.

Thyroid Diseases

The thyroid plays a key role in normal metabolic and homeostatic processes, including thermomodulation, protein synthesis, carbohydrate and lipid metabolism, and modulation of adrenergic regulation. Surgical consultations are most often requested for control of hyperthyroidism or for treatment of euthyroid nodular disease. This review describes the approach to the patient with hyperthyroidism and with euthyroid nodular disease, including papillary, follicular, anaplastic, medullary, and primary thyroid cancer, and oncocytic (Hürthle cell) carcinoma. Operative techniques of thyroidectomy are described and include positioning, incisions-making, and troubleshooting. Postoperative care, including thyroid hormone management, is described. Complications and outcome evaluation are discussed. Tables list the etiologies of hyperthyroidism, benign and malignant etiologies of euthyroid nodular disease, familial syndromes of thyroid disease, the Bethesda classification of fine needle aspiration cytology and associated malignancy risk, the elements of common prognostic schemes for well-differentiated thyroid cancer, and the staging of differentiated, medullary, and anaplastic thyroid cancer. Figures show the six levels of cervical lymph nodes, the initial incision in a thyroidectomy, a midline incision, the superior pole vessels, the upper and lower parathyroid glands, the recurrent laryngeal nerve, and Delphian lymph nodes. An algorithm shows the approach to the patient with thyroid disease This review contains 7 figures, 8 tables, and 64 references.

Abstract P148: Glycogen phosphorylase and synthase inhibitors: Novel therapeutic approaches in anaplastic thyroid cancer

Abstract Thyroid cancer (TC) is the most common endocrine cancer. Effective treatment options for papillary (PTC) and follicular (FTC) thyroid cancers afford positive patient prognoses. However, there are no effective, long-lasting treatments for anaplastic thyroid cancer (ATC), which has a median survival of five to six months. While the receptor tyrosine kinase inhibitor sorafenib can extend ATC patient survival to eleven months, tumor reoccurrence and drug resistance often develop. Therefore, there is a need for more effective targeted therapies for ATC. While the cell signaling landscape is well described in ATC, little is known about tumorigenic adaptations in ATC metabolism. Tumors exhibit an increased consumption of glucose compared to normal tissues to fuel tumor progression. Some cancers meet this high glucose requirement by storing and breaking down glycogen. While glycogen has been detected in bovine and canine thyroids, no report thus far has investigated glycogen in normal human thyroids or thyroid cancer. Therefore, our objective was to determine if normal thyroid and TC cells metabolize glycogen and to evaluate pharmacological inhibition of glycogen metabolism in ATC cells. We show for the first time that normal thyroid, PTC, FTC, and ATC cells express glycogen synthase and glycogen phosphorylase brain and liver (PYGB, PYGL) isoforms. We confirmed these observations in patient samples of normal thyroid and TC tissues via immunofluorescence. We revealed that the TC samples expressed high levels of PYGB compared to normal thyroid tissue. Electron microscopy revealed that normal thyroid cells organized glycogen in discrete glycosomes, while ATC cells exhibited smaller, dispersed glycogen packets. Importantly, we demonstrated that the glycogen synthase inhibitor guaiacol depleted glycogen content and reduced ATC cell viability. Conversely, the glycogen phosphorylase inhibitor CP-91,149 (CP) increased glycogen levels and induced apoptosis. Importantly, CP also reduced the number of stem cells in the ATC cell population. We further showed that CP synergized with sorafenib to more effectively inhibit ATC proliferation. CP enhanced glycolysis but inhibited oxidative phosphorylation as revealed using Seahorse. We confirmed an increase in glucose transporter expression using RT-qPCR and glucose import following CP treatment. This possibly represents a futile response to PYGB inhibition. We reasoned that glycogen was preferentially metabolized in ATC to fuel the pentose phosphate pathway to protect against reactive oxygen species (ROS). Indeed, we detected significantly higher levels of ROS in ATC cells treated with CP. We demonstrated that thyroid cells are able to metabolize glycogen and identified a potential biomarker for thyroid cancer (PYGB), which was targeted with CP-91,149. Our work establishes glycogen metabolism as a novel metabolic process in thyroid cells that is associated with TC dedifferentiation and provides insight to the effectiveness of inhibiting glycogen metabolism as a novel therapeutic strategy in ATC. Citation Format: Cole Davidson, Jennifer Tomczak, Eyal Amiel, Frances Carr. Glycogen phosphorylase and synthase inhibitors: Novel therapeutic approaches in anaplastic thyroid cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P148.

Identification of RET fusions in a Chinese multicancer retrospective analysis by next-generation sequencing.

Fusion of RET with different partner genes has been detected in papillary thyroid, lung, colorectal, pancreatic, and breast cancer. Approval of selpercatinib for treatment of lung and thyroid cancer with RET gene mutations or fusions calls for studies to explore RET fusion partners and their eligibility for RET‐based targeted therapy. In this study, RET fusion patterns in a large group of Chinese cancer patients covering several cancer types were identified using next‑generation sequencing. A total of 44 fusion patterns were identified in the study cohort with KIF5B, CCDC6, and ERC1 being the most common RET fusion partners. Notably, 17 novel fusions were first reported in this study. Prevalence of functional RET fusions was 1.05% in lung cancer, 6.03% in thyroid cancer, 0.39% in colorectal cancer, and less than 0.1% in gastric cancer and hepatocellular carcinoma. Analysis showed a preference for fusion partners in different tumor types, with KIF5B being the common type in lung cancer, CCDC6 in thyroid cancer, and NCOA4 in colorectal cancer. Co‐occurrence of EGFR mutations and RET fusions with rare partner genes (rather than KIF5B) in lung cancer patients was correlated with epidermal growth factor receptor‐tyrosine kinase inhibitor resistance and could predict response to targeted therapies. Findings from this study provide a guide to clinicians in determining tumors with specific fusion patterns as candidates for RET targeted therapies.

A study of association between serum thyroid stimulating hormone concentration and thyroid cancer and also to assess whether serum thyroid stimulating hormone levels are of value in predicting malignancy in patients with thyroid swelling

Background: Thyroid neoplasm includes both benign and malignant tumors arising in the thyroid gland. Although thyroid cancer accounts for less than 1% of all cancers, the challenge to clinicians is to identify the minority of thyroid nodules that harbor malignancy. There are a number of well-established predictors of malignancy in thyroid nodules. More recently a few studies have suggested that higher concentration of thyroid stimulating hormone (TSH), even within the normal range are associated with subsequent diagnosis of thyroid cancer in patients with thyroid nodules and even higher serum TSH levels have been found associated with advanced stages of thyroid cancer. Methods: A prospective study was conducted on 220 cases without overt thyroid dysfunction attending Department of general surgery, Pushpagiri institute of medical science, Thiruvalla. Results: In our study incidence of malignancy of thyroid carcinoma was highest in patients with serum TSH concentrations, in range of 3.5 mIU/l-5.25 mIU/l, 55 patients out of 220 patients. Individually, incidence of papillary carcinoma (PC) (36/55 patients), follicular carcinoma (FC) (17/55 patients) and Hurthle cell carcinoma (HCC) (2/55 patients) were more in patients with higher TSH. So, from the study it can be clearly state that elevated TSH can be used as an independent predictor of thyroid malignancy. Higher TSH values are associated with papillary thyroid carcinoma.Conclusions: An elevated TSH can be used as an independent predictor of thyroid malignancy, especially for anticipating a probability of papillary carcinoma of thyroid.

Suboptimal clinician awareness of appropriate NTRK fusion testing and TRK inhibitor use in solid tumors.

229 Background: Since late 2018, 2 TRK inhibitors—larotrectinib and entrectinib—have been approved by the EMA and FDA for treating patients with advanced solid tumors harboring an NTRK fusion and progressive disease or no therapeutic alternatives. It is recommended that testing for NTRK fusions occur as early as possible after a diagnosis of advanced disease in patients with solid tumors to inform potential use of TRK inhibitors. Methods: Between April 2018 and April 2021, we conducted multiple live and online educational activities for oncology healthcare professionals (HCPs) on NTRK fusion testing and/or TRK inhibitor treatment for varied solid tumors. Each activity included polling questions designed to assess HCP knowledge and practice patterns. In this analysis, we assessed HCP responses to these questions to evaluate awareness of expert recommendations on NTRK fusion testing and the selection of TRK inhibitor therapy for appropriate patients. Results: In 6 live and online activities with data from April 2018 to April 2021, 29% of HCPs (n = 844) indicated that they ordered molecular profiling to test for NTRK fusions in all solid tumors in their current practice. Of note, low rates of testing were reported in TRK inhibitor/ NTRK testing-focused activities throughout this time period, with no significant increase over time. In assessing different patient cases across 8 activities where experts recommended TRK inhibitor therapy as optimal, many HCPs did not select a TRK inhibitor, with considerable variance by tumor type (Table). *For all cases, experts selected larotrectinib and/or entrectinib as optimal treatment. †HCP respondents. GBM, glioblastoma; GI, gastrointestinal; MSI-H, microsatellite instability-high; PD, progressive disease; PTC, papillary thyroid cancer.Conclusions: The rate of broad testing for NTRK fusions across patients with solid tumors remains low, and many HCPs lack awareness of when to consider a TRK inhibitor. Educational activities designed to address these deficiencies would be of clear benefit to HCPs treating patients with advanced solid tumors. A detailed analysis of HCP trends will be presented.[Table: see text]

DNA Methylation Age Drift Is Associated with Poor Outcomes and De-Differentiation in Papillary and Follicular Thyroid Carcinomas.

Simple SummaryNormal human tissues contain an epigenetic clock resulting from the age-dependent DNA methylation signature, which is the so-called DNA methylation (DNAm) age and can be used to precisely predict chronological age of healthy individuals. Abnormal DNAm age drift has been implicated in cancer risk and pathogenesis. Here, we observed that highly drifted DNAm age (HDDA) occurred in approximately 1/3 tumors derived from patients with papillary and follicular thyroid carcinomas. HDDA is significantly associated with dedifferentiation of tumor cells and poor patient outcomes. Thus, HDDA may serve as a new prognostic factor for thyroid carcinoma.Alterations in global DNA methylation play a critical role in both aging and cancer, and DNA methylation (DNAm) age drift has been implicated in cancer risk and pathogenesis. In the present study, we analyzed the TCGA cohort of papillary and follicular thyroid carcinoma (PTC and FTC) for their DNAm age and association with clinic-pathological features. In 54 noncancerous thyroid (NT) samples, DNAm age was highly correlated with patient chronological age (R2 = 0.928, p = 2.6 × 10−31), but drifted to younger than chronological age in most specimens, especially those from patients >50 years old. DNAm age in 502 tumors was also correlated with patient chronological age, but to a much lesser extent (R2 = 0.403). Highly drifted DNAm age (HDDA) was identified in 161 tumors, among which were 101 with DNAm age acceleration while 60 with DNAm age deceleration. Tumors with HDDA were characterized by the robust aberrations in metabolic activities, extracellular microenvironment components and inflammation/immunology responses, and dedifferentiation. Importantly, HDDA in tumors independently predicted shorter disease-free survival of patients. Collectively, NT thyroids from TC patients have younger DNAm age, while HDDA frequently occurs in TCs, and contributes to the TC progression and poor patient outcomes. HDDA may serve as a new prognostic factor for TCs.

PRKAR1A and Thyroid Tumors.

Simple SummaryIn 2021 it is estimated that there will be 44,280 new cases of thyroid cancer in the United States and the incidence rate is higher in women than in men by almost 3 times. Well-differentiated thyroid cancer is the most common subtype of thyroid cancer and includes follicular (FTC) and papillary (PTC) carcinomas. Over the last decade, researchers have been able to better understand the molecular mechanisms involved in thyroid carcinogenesis, identifying genes including but not limited to RAS, BRAF, PAX8/PPARγ chromosomal rearrangements and others, as well as several tumor genes involved in major signaling pathways regulating cell cycle, differentiation, growth, or proliferation. Patients with Carney complex (CNC) have increased incidence of thyroid tumors, including cancer, yet little is known about this association. CNC is a familial multiple neoplasia and lentiginosis syndrome cause by inactivating mutations in the PRKAR1A gene which encodes the regulatory subunit type 1α of protein kinase A. This work summarizes what we know today about PRKAR1A defects in humans and mice and their role in thyroid tumor development, as the first such review on this issue.Thyroid cancer is the most common type of endocrine malignancy and the incidence is rapidly increasing. Follicular (FTC) and papillary thyroid (PTC) carcinomas comprise the well-differentiated subtype and they are the two most common thyroid carcinomas. Multiple molecular genetic and epigenetic alterations have been identified in various types of thyroid tumors over the years. Point mutations in BRAF, RAS as well as RET/PTC and PAX8/PPARγ chromosomal rearrangements are common. Thyroid cancer, including both FTC and PTC, has been observed in patients with Carney Complex (CNC), a syndrome that is inherited in an autosomal dominant manner and predisposes to various tumors. CNC is caused by inactivating mutations in the tumor-suppressor gene encoding the cyclic AMP (cAMP)-dependent protein kinase A (PKA) type 1α regulatory subunit (PRKAR1A) mapped in chromosome 17 (17q22–24). Growth of the thyroid is driven by the TSH/cAMP/PKA signaling pathway and it has been shown in mouse models that PKA activation through genetic ablation of the regulatory subunit Prkar1a can cause FTC. In this review, we provide an overview of the molecular mechanisms contributing to thyroid tumorigenesis associated with inactivation of the RRKAR1A gene.

Identification of ferroptosis genes in immune infiltration and prognosis in thyroid papillary carcinoma using network analysis

BackgroundPapillary thyroid carcinoma (PTC) is the most common thyroid cancer. While many patients survive, a portion of PTC cases display high aggressiveness and even develop into refractory differentiated thyroid carcinoma. This may be alleviated by developing a novel model to predict the risk of recurrence. Ferroptosis is an iron-dependent form of regulated cell death (RCD) driven by lethal accumulation of lipid peroxides, is regulated by a set of genes and shows a variety of metabolic changes. To elucidate whether ferroptosis occurs in PTC, we analyse the gene expression profiles of the disease and established a new model for the correlation.MethodsThe thyroid carcinoma (THCA) datasets were downloaded from The Cancer Genome Atlas (TCGA), UCSC Xena and MisgDB, and included 502 tumour samples and 56 normal samples. A total of 60 ferroptosis related genes were summarised from MisgDB database. Gene set enrichment analysis (GSEA) and Gene set variation analysis (GSVA) were used to analyse pathways potentially involving PTC subtypes. Single sample GSEA (ssGSEA) algorithm was used to analyse the proportion of 28 types of immune cells in the tumour immune infiltration microenvironment in THCA and the hclust algorithm was used to conduct immune typing according to the proportion of immune cells. Spearman correlation analysis was performed on the ferroptosis gene expression and the correlation between immune infiltrating cells proportion. We established the WGCNA to identify genes modules that are highly correlated with the microenvironment of immune invasion. DEseq2 algorithm was further used for differential analysis of sequencing data to analyse the functions and pathways potentially involving hub genes. GO and KEGG enrichment analysis was performed using Clusterprofiler to explore the clinical efficacy of hub genes. Univariate Cox analysis was performed for hub genes combined with clinical prognostic data, and the results was included for lasso regression and constructed the risk regression model. ROC curve and survival curve were used for evaluating the model. Univariate Cox analysis and multivariate Cox analysis were performed in combination with the clinical data of THCA and the risk score value, the clinical efficacy of the model was further evaluated.ResultsWe identify two subtypes in PTC based on the expression of ferroptosis related genes, with the proportion of cluster 1 significantly higher than cluster 2 in ferroptosis signature genes that are positively associated. The mutations of Braf and Nras are detected as the major mutations of cluster 1 and 2, respectively. Subsequent analyses of TME immune cells infiltration indicated cluster 1 is remarkably richer than cluster 2. The risk score of THCA is in good performance evaluated by ROC curve and survival curve, in conjunction with univariate Cox analysis and multivariate Cox analysis results based on the clinical data shows that the risk score of the proposed model could be used as an independent prognostic indicator to predict the prognosis of patients with papillary thyroid cancer.ConclusionsOur study finds seven crucial genes, including Ac008063.2, Apoe, Bcl3, Acap3, Alox5ap, Atxn2l and B2m, and regulation of apoptosis by parathyroid hormone-related proteins significantly associated with ferroptosis and immune cells in PTC, and we construct the risk score model which can be used as an independent prognostic index to predict the prognosis of patients with PTC.