Chiara Catania, Andrea Riccardo Filippi, Claudia Sangalli, Gaia Piperno, Marco Russano, Carlo Greco, Vieri Scotti, Claudia Proto, Chiara Bennati, Marzia Di Pietro Paolo, Angelo Platania, Emanuela Olmetto, Francesco Agustoni, Nazario Teodorani, Vincenzo Agbaje, Alessandro Russo
IMPORTANCE: After the PACIFIC trial, concurrent chemo-radiotherapy followed by consolidation therapy with durvalumab for 1 year (limited to PD-L1 tumour proportion score ≥ 1% in the EMA region) is the firmly established standard of care treatment for unresectable NSCLC patients. Several relevant questions are emerging with the growing use of this approach, posing novel challenges in clinical practice. Treatment of oncogene-addicted NSCLCs, management of mediastinal disease recurrence after surgery and the optimal management of patients progressing during or after durvalumab are now some of the most clinically relevant issues...
August 24, 2023: Critical Reviews in Oncology/hematology
Antoine Desilets, Matteo Repetto, Soo-Ryum Yang, Eric J Sherman, Alexander Drilon
RET alterations, such as fusions or mutations, drive the growth of multiple tumor types. These alterations are found in canonical (lung and thyroid) and non-canonical (e.g., gastrointestinal, breast, gynecological, genitourinary, histiocytic) cancers. RET alterations are best identified via comprehensive next-generation sequencing, preferably with DNA and RNA interrogation for fusions. Targeted therapies for RET -dependent cancers have evolved from older multikinase inhibitors to selective inhibitors of RET such as selpercatinib and pralsetinib...
August 17, 2023: Cancers
Airat Bilyalov, Sergey Nikolaev, Anastasiia Danishevich, Igor Khatkov, Komron Makhmudov, Zhainagul Isakova, Nurbek Bakirov, Ernis Omurbaev, Alena Osipova, Ramaldan Ramaldanov, Elena Shagimardanova, Andrey Kiyasov, Oleg Gusev, Natalia Bodunova
Gastric cancer is a major challenge in modern oncology due to its high detection rate and prevalence. While sporadic cases make up the majority of gastric cancer, hereditary gastric cancer is caused by germline mutations in several genes linked to different syndromes. Thus, identifying hereditary forms of gastric cancer is considered crucial globally. A survey study using NGS-based analysis was conducted to determine the frequency of different types of hereditary gastric cancer in the yet-unstudied Kyrgyz population...
July 31, 2023: Current Issues in Molecular Biology
Gaoda Ju, Yuqing Sun, Hao Wang, Xin Zhang, Zhuanzhuan Mu, Di Sun, Lisha Huang, Ruijue Lin, Tao Xing, Wuying Cheng, Jun Liang, Yan-Song Lin
BACKGROUND: Fusion oncogenes are involved in the underlying pathology of advanced differentiated thyroid cancer (DTC), and even the cause of radioactive iodine (RAI)-refractoriness. However, there is still lacking in investigation between fusion oncogenes and the clinicopathological characteristics involving a large-scale cohort of advanced DTC patients. METHODS: We collected 278 tumor samples from patients with locally advanced (N1b or T4) or distant metastatic DTC...
August 25, 2023: Journal of Clinical Endocrinology and Metabolism
Jun-Yi Ke, Shu Huang, Zhi-Tao Jing, Min-Chao Duan
Rearranged during transfection (RET) fusion-positive occurs in approximately 2% of non-small cell lung cancer (NSCLC). This mutation often predicts metastasis risk and poor prognosis, and current mainstream therapies provide limited patient benefit. Selective RET inhibitors Pralsetinib and Selpercatinib are targeted drugs approved by the US Food and Drug Administration for treating RET-mutated tumors. The phase I/II clinical trial results of their treatment of NSCLC have been published. However, the clinical effect of selective RET inhibitors on RET fusion-positive NSCLC remains controversial...
August 21, 2023: Investigational New Drugs
Yinghui Bi, Chaoran Xia, Xinglin Zhang, Haixin Liu
Ongoing investigations of targeted therapeutic agents and their increased clinical applications, together with research in genomics and proteomics, have explored a variety of novel approaches for treatment of lung cancer, and 'molecular subtypes' have been defined based on specific actionable genetic aberrations. Liquid biopsies, including circulating tumor DNA (ctDNA) testing, are of value for cancer diagnosis and comprehensive genomic profiling, such as the identification of cancer subtypes and major genetic alterations in cancer cells...
September 2023: Oncology Letters
Shannon S Wu, Eric D Lamarre, Joseph Scharpf, Brandon Prendes, Jamie A Ku, Natalie Silver, Brian Burkey, Neil Woody, Shauna R Campbell, Emrullah Yilmaz, Shlomo A Koyfman, Jessica Geiger
BACKGROUND: Small molecule inhibitors (SMI) are targeted therapies increasingly used in advanced thyroid carcinomas. This study aimed to evaluate survival outcomes of thyroid cancer on SMI treatment, including in patients with brain metastases. METHODS: This retrospective study included patients with thyroid carcinomas who received at least one SMI between 2008-2022 at a tertiary-level, academic institution. SMI included lenvatinib, sorafenib, dabrafenib-trametinib, selpercatinib, and cabozantinib...
August 17, 2023: Endocrine Practice
Erica Steen, Mariam Basilaia, William Kim, Taelor Getz, Jeffrey Gustafson, Peter E Zage
The RET (REarranged during Transfection) gene, which encodes for a transmembrane receptor tyrosine kinase, is an established oncogene associated with the etiology and progression of multiple types of cancer. Oncogenic RET mutations and rearrangements resulting in gene fusions have been identified in many adult cancers, including medullary and papillary thyroid cancers, lung adenocarcinomas, colon and breast cancers, and many others. While genetic RET aberrations are much less common in pediatric solid tumors, increased RET expression has been shown to be associated with poor prognosis in children with solid tumors such as neuroblastoma, prompting an interest in RET inhibition as a form of therapy for these children...
August 16, 2023: Biochemical Pharmacology
Huriye Seker-Cin, Timothy Kwang Yong Tay, Daniel Kazdal, Klaus Kluck, Markus Ball, Olaf Neumann, Hauke Winter, Felix Herth, Claus-Peter Heußel, Rajkumar Savai, Peter Schirmacher, Michael Thomas, Jan Budczies, Michael Allgäuer, Petros Christopoulos, Albrecht Stenzinger, Anna-Lena Volckmar
OBJECTIVES: Molecular diagnosis for targeted therapies has been improved significantly in non-small-cell lung cancer (NSCLC) patients in recent years. Here we report on the prevalence of rare fusions in NSCLC and dissect their genomic architecture and potential clinical implications. MATERIALS AND METHODS: Overall, n = 5554 NSCLC patients underwent next-generation sequencing (NGS) for combined detection of oncogenic mutations and fusions either at primary diagnosis (n = 5246) or after therapy resistance (n = 308)...
July 27, 2023: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Suzanne Murray, Vivek Subbiah, Steven I Sherman, Sophie Péloquin, Anthony Sireci, Christian Grohé, Patrick Bubach, Patrice Lazure
BACKGROUND: The discovery of driver oncogenes for thyroid carcinomas and the identification of genomically targeted therapies to inhibit those oncogenes have altered the treatment algorithm in thyroid cancer (TC), while germline testing for RET mutations has become indicated for patients with a family history of RET gene mutations or hereditary medullary TC (MTC). In the context of an increasing number of selective RET inhibitors approved for use, this paper aims to describe challenges and barriers affecting providers' ability to deliver optimal care for patients with RET-altered TC across the patient healthcare journey...
August 14, 2023: Thyroid Research
Claudia Ricci, Antonia Salvemini, Cristina Dalmiglio, Maria Grazia Castagna, Silvia Cantara
Medullary thyroid carcinoma (MTC) is a malignant tumor that arises from parafollicular C cells, which are responsible for producing calcitonin. The majority (75%) of MTC cases are sporadic forms, while the remaining (25%) have a hereditary component. In these hereditary cases, MTC can occur in conjunction with other endocrine disorders (i.e., pheochromocytoma) or as an isolated condition known as familial medullary thyroid carcinoma. The primary genetic mutation associated with the development of MTC, regardless of its hereditary or sporadic nature, is a point mutation in the RET gene...
August 7, 2023: Cancers
Damian Mielecki, Ewa Gajda, Justyna Sikorska, Anna Betkowska, Marcin Rozwadowski, Agata M Gawel, Maria Kulecka, Natalia Zeber-Lubecka, Marlena Godlewska, Damian Gawel
The intracellular level of podoplanin (PDPN), a transmembrane protein of still unclear function, is frequently altered in metastatic tumors. High expression of PDPN is frequently observed in papillary thyroid cancer (PTC) specimens. Similarly, PTC-derived cell lines (BCPAP and TPC1, harboring the BRAF V600E mutation and RET /PTC1 fusion, respectively), also present enhanced PDPN yield. We previously reported that depletion of PDPN impairs migration of TPC1 cells, but augments metastasis of BCPAP cells. Interestingly, this phenomenon stays in contrast to the migratory pattern observed for wild-type cells, where TPC1 exhibited higher motility than BCPAP cells...
2023: Computational and Structural Biotechnology Journal
Jeffrey A Scott, Jochen Lennerz, Melissa Lynne Johnson, Lucio N Gordan, Robert H Dumanois, Luca Quagliata, Lauren L Ritterhouse, Federico Cappuzzo, Brandon Wang, Mei Xue, Anupama Vasudevan, Prateesh Varughese, Varun Vaidya, Mike Gart, Natalie Dorrow, Hinco J Gierman, Rushir J Choksi
PURPOSE: Identification and targeting of actionable oncogenic drivers (AODs) in advanced non-small-cell lung cancer (NSCLC) has dramatically improved outcomes. However, genomic testing uptake is variable and hampered by factors including slow turnaround time, frequently resulting in initial non-tyrosine kinase inhibitor (TKI) treatment. We investigate how this behavior affects outcomes. METHODS: This retrospective analysis of real-world, deidentified data from the Integra Connect Database included adults with stage IV NSCLC newly diagnosed from January 1, 2018, to December 31, 2020, with mutations of EGFR , ALK , ROS1 , BRAF , MET , RET , ERBB2 , or NTRK ...
August 9, 2023: JCO oncology practice
Tommaso Porcelli, Marialuisa Moccia, Maria Angela De Stefano, Raffaele Ambrosio, Ettore Capoluongo, Massimo Santoro, Julien Hadoux, Martin Schlumberger, Francesca Carlomagno, Domenico Salvatore
PURPOSE: We analyzed the oncogenic potential of RET Δ898-901 mutant and its response to selpercatinib, vandetanib, and cabozantinib in vitro and in a clinical case. MATERIALS AND METHODS: A 35-year-old man with a medullary thyroid cancer (MTC) harboring a somatic D898_E901 RET deletion was sequentially treated with vandetanib, selpercatinib, cabozantinib, and fluorouracil (5-FU)-dacarbazine. Functional study of RET Δ898-901 mutant was performed in HEK-293T, NIH-3T3, and Ba/F3 cells...
August 2023: JCO Precision Oncology
Zeynep Şıklar, Tuğba Kontbay, Handan Dincaslan, Emel Ünal, Merih Berberoglu
Inherited forms of medullary thyroid carcinoma (MTC) can cause serious problems in diagnosis and follow-up. Family screening is performed, and prophylactic thyroidectomy at an appropriate age can be life-saving. This study aimed to investigate the diagnostic, clinical, laboratory characteristics, and treatment methods of cases with rearranged during transfection (RET) mutation in the childhood age group. Patients diagnosed with hereditary MTC and patients who were evaluated by detecting MTC and/or RET mutations in their families were included in this study...
July 24, 2023: Journal of Pediatric Hematology/oncology
Rui Sousa Martins, Tito Teles Jesus, Luís Cardoso, Paula Soares, João Vinagre
Medullary thyroid carcinoma (MTC) arises from parafollicular cells in the thyroid gland, and although rare, it represents an aggressive type of thyroid cancer. MTC is recognized for its low mutational burden, with point mutations in RET or RAS genes being the most common oncogenic events. MTC can be resistant to cytotoxic chemotherapy, and multitarget kinase inhibitors (MKIs) have been considered a treatment option. They act by inhibiting the activities of specific tyrosine kinase receptors involved in tumor growth and angiogenesis...
July 13, 2023: Journal of Personalized Medicine
Shalini G Hegde, Sarita Devi, Ambily Sivadas, Attibele Mahadevaiah Shubha, Annamma Thomas, Arpita Mukhopadhyay, Anura V Kurpad
BACKGROUND AND AIMS: The gene-environment interaction of the RET gene with vitamin A in the etiopathogenesis of Hirschsprung disease (HSCR) has been suggested in rodents. The aim of this study was to evaluate vitamin A status in mothers of children with HSCR and to assess its association with pathogenic variants of the RET gene in affected children. METHODS: Case-control study of stable-isotope based vitamin A measurement stores of mothers of children diagnosed with HSCR (within 8 months from birth, n=7) and age-matched mothers of normal children (n=6)...
July 26, 2023: Clinical and Translational Gastroenterology
Andreas Machens, Kerstin Lorenz, Frank Weber, Tim Brandenburg, Dagmar Führer-Sakel, Henning Dralle
PURPOSE: Differences in syndromic manifestations of multiple endocrine neoplasia 2 A (MEN2A) between index and non-index patients are ill-defined. METHODS: Cross-sectional analysis of 602 REarranged during Transfection (RET) carriers (156 index and 446 non-index patients) who underwent thyroidectomy, adrenalectomy, and/or parathyroidectomy between 1985 and 2022, stratified by mutational risk. RESULTS: Index patients were 5.8-13.9 years older at thyroidectomy than non-index patients, at which point they had developed 10...
July 21, 2023: Endocrine
Tong Sun, Syed Gilani, Dhanpat Jain, Guoping Cai
OBJECTIVES: As a rare tumor in pancreas, pancreatic acinar cell carcinoma (PACC) possesses a distinct molecular feature from pancreatic ductal carcinoma (PDAC). Though the diagnosis of PACC is often established based on cytology specimens, its cytologic diagnosis can be challenging. Furthermore, the correlation between PACC cytomorphology and its unique different molecular alterations have not been fully explored. METHODS: Cytology features were analyzed in 8 histologically proven PACC and cytohistological correlation was performed...
July 19, 2023: Diagnostic Cytopathology
Yaying Du, Shu Zhang, Gang Zhang, Jiaying Hu, Lianhua Zhao, Yuanyuan Xiong, Lu Shen, Rongrong Chen, Ke Ye, Yan Xu
BACKGROUND: The incidence of thyroid cancer in China has rapidly increased in recent decades. As the genetic profiles of thyroid cancer vary dramatically between different geographical regions, a comprehensive genetic landscape of thyroid cancer in the Chinese population is urgently needed. METHODS: We retrospectively included thyroid cancer patients from three Chinese medical centers between February 2015 and August 2020. To dissect the genomic profiling of these patients, we performed targeted next-generation sequencing on their tumor tissues using a 1,021-gene panel...
2023: Frontiers in Endocrinology
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