Aakash Desai, Neha K Reddy, Vivek Subbiah
The advent of precision medicine has changed the landscape of oncologic biomarkers, drug discovery, drug development, and, more importantly, outcomes for patients with cancer. Precision oncology entails the genomic profiling of tumors to detect actionable aberrations. The advances in clinical next-generation sequencing from both tumor tissue and liquid biopsy and availability of targeted therapies has rapidly entered mainstream clinical practice. In this review, recent major developments in precision oncology that have affected outcomes for patients with cancer are discussed...
March 22, 2023: Cancer
Qiang Li, Tienan Feng, Tengteng Zhu, Weituo Zhang, Ying Qian, Huan Zhang, Xiangqian Zheng, Dapeng Li, Xinwei Yun, Jingzhu Zhao, Yangyang Li, Herbert Yu, Ming Gao, Biyun Qian
BACKGROUND: Papillary thyroid microcarcinoma (PTMC) incidence has significantly increased, and some cases still exhibit invasive traits. The entire molecular landscape of PTMC, which can offer hints for the etiology of cancer, is currently absent. METHODS: We compared our findings with those for PTMC in the TCGA by analyzing the largest study at the current stage of whole exome sequencing and RNA-sequencing data from 64 patients with PTMC. Then, we systematically demonstrated the differences between the two PTMC subtypes based on multi-omics analyses...
March 20, 2023: Journal of Translational Medicine
Boulos Mansour, Tomas Vanecek, Liubov Kastnerova, Daniel Nosek, Dmitry V Kazakov, Michele Donati
Spitz tumors are melanocytic neoplasms characterized by specific, mutually exclusive driver molecular events, namely genomic rearrangements involving the threonine kinase BRAF and the tyrosine kinase receptors ALK, NTRK1, NTRK2, NTRK3, MET, RET, ROS1, and MAP3K8 or less commonly, mutations in HRAS or MAP2K1. We hereby report 5 Spitz tumors with a SQSTM1::NTRK2 fusion. All patients were woman with the ages at diagnosis ranging from 30 to 50 years. Locations included the lower extremity (n = 3), forearm, and back (one each)...
March 20, 2023: American Journal of Dermatopathology
Juan A Santamaria-Barria, Chikako Matsuba, Adam Khader, Anthony J Scholar, Mary Garland-Kledzik, Trevan D Fischer, Richard Essner, Matthew P Salomon, Joshua M V Mammen, Melanie Goldfarb
BACKGROUND AND OBJECTIVES: Melanoma mutational burden is high and approximately 50% have oncogenic mutations in BRAF. We sought to evaluate age-related mutational differences in melanoma. METHODS: We analyzed melanoma samples in the Genomics Evidence Neoplasia Information Exchange database. Targetable mutations were identified using the Precision Oncology Knowledge Base (OncoKB). RESULTS: We found 1194 patients with a common set of 30 genes...
March 20, 2023: Journal of Surgical Oncology
Francesco Quaglino, Alex Bruno Bellocchia, Gerdi Tuli, Jessica Munarin, Patrizia Matarazzo, Luca Cestino, Federico Festa, Giulia Carbonaro, Salvatore Oleandri, Claudia Manini, Riccardo Vergano, Luisa De Sanctis
INTRODUCTION: Pediatric thyroid carcinoma represents about 4-5% of all pediatric carcinoma with an incidence of 0.5 cases/100,000, compared to 2-10/100000 cases in the adult population. The aim of this study is to present the experience of a reference adult endocrine surgery unit in charge of the treatment of pediatric thyroid diseases. MATERIALS AND METHODS: From January 2019 to September 2022, 25 patients, aged 5-17, underwent thyroid surgery. We analysed indications for surgery, use of intraoperative nerve monitoring (IONM), definitive histological examination, postoperative outcomes and risk factors related...
2023: Frontiers in Endocrinology
Tongzhou Xu, LaurieL Molday, RobertS Molday
N-retinylidene-phosphatidylethanolamine (N-Ret-PE), the Schiff-base conjugate formed through the reversible reaction of retinal (Vitamin A-aldehyde) and phosphatidylethanolamine, plays a crucial role in the visual cycle and visual pigment photoregeneration. However, N-Ret-PE can react with another molecule of retinal to form toxic di-retinoids if not removed from photoreceptors through its transport across photoreceptor membranes by the ATP-binding-cassette transporter ABCA4. Loss-of-function mutations in ABCA4 are known to cause Stargardt disease (STGD1), an inherited retinal degenerative disease associated with the accumulation of fluorescent di-retinoids and severe loss in vision...
March 15, 2023: Journal of Biological Chemistry
Andreas Machens, Kerstin Lorenz, Tim Brandenburg, Dagmar Führer-Sakel, Frank Weber, Henning Dralle
CONTEXT: Early genetic association studies yielded too high risk estimates for multiple endocrine neoplasia (MEN2A), suggesting a need for extended surgery. OBJECTIVE: The objective was to delineate temporal changes in MEN2A presentation by birth cohort analyses. METHODS: Birth cohort analyses (10-year increments; ≤1950 to 2011-2020) of carriers of rearranged during transfection (RET) mutations who underwent surgery for MEN2A. RESULTS: Included in this study were 604 carriers (155 index, 445 nonindex, 4 additional patients), with 237 carriers harboring high risk mutations, 165 carriers moderate-high risk mutations, and 202 carriers low-moderate risk mutations...
March 17, 2023: Journal of Clinical Endocrinology and Metabolism
Carolyn D Seib, Thomas C Beck, Electron Kebebew
Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor that can be sporadic or inherited and is often associated with mutations in the RET (Rearranged during Transfection) oncogene. The primary treatment for MTC is surgical resection of all suspected disease, but recent advances in targeted therapies for MTC, including the selective RET inhibitors selpercatinib and pralsetinib, have led to changes in the management of patients with locally advanced, metastatic, or recurrent MTC. In this article, we review updates on the evaluation and management of patients with MTC, focusing on new and emerging therapies that are likely to improve patient outcomes...
April 2023: Surgical Oncology Clinics of North America
Matti L Gild, Martyn Bullock, Venessa Tsang, Roderick Clifton-Bligh, Bruce Robinson, Lori J Wirth
BACKGROUND: BRAF V600E and K/N/H RAS mutations and oncogenic kinase fusions involving NTRK, RET, ALK and ROS1 have been identified as actionable targets in thyroid cancer. These driver alterations lead to onocogene addiction which has been successfully exploited through tyrosine kinase inhibitors. Acquired resistance may develop following an initial response requiring a therapeutic pivot to new therapies. SUMMARY: Several pathways for development of acquired resistance have been identified...
March 16, 2023: Thyroid: Official Journal of the American Thyroid Association
Kaifu Wu, Rui He, Zongyang Li, Kongxi Qiu, Guorong Xiao, Lijie Peng, Xiangbao Meng, Canhui Zheng, Zhang Zhang, Qian Cai
Rearranged during transfection (RET) is a promising target for antitumor drug development. Multikinase inhibitors (MKI) have been developed for RET-driven cancers but displayed limited efficacy in disease control. Two selective RET inhibitors were approved by FDA in 2020 and proved potent clinical efficacy. However, the discovery of novel RET inhibitors with high target selectivity and improved safety is still highly desirable. Herein, we reported a class of 3,5-diaryl-1H-pyrazol-based ureas as new RET inhibitors...
March 3, 2023: European Journal of Medicinal Chemistry
Amol Gupta, Razelle Kurzrock, Jacob J Adashek
In the past two decades, molecular targeted therapy has revolutionized the treatment landscape of several malignancies. Lethal malignancies such as non-small cell lung cancer (NSCLC) have become a model for precision-matched immune- and gene-targeted therapies. Multiple small subgroups of NSCLC defined by their genomic aberrations are now recognized; remarkably, taken together, almost 70% of NSCLCs now have a druggable anomaly. Cholangiocarcinoma (CCA) is a rare tumor with a poor prognosis. Novel molecular alterations have been recently identified in patients with CCA, and the potential for targeted therapy is being realized...
March 3, 2023: Cancers
Lan Chen, Jing-Xin Zhang, Dong-Ge Liu, Hong-Gang Liu
This paper illustrates a rare syndrome of multiple endocrine neoplasia type 2A (MEN2A) in a family of three generations. In our case, the father, son and one daughter developed phaeochromocytoma (PHEO) and medullary thyroid carcinoma (MTC) over a period of 35 years. Because of the metachronous onset of the disease and lack of digital medical records in the past, the syndrome was not found until a recent fine needle aspiration of an MTC-metastasized lymph node from the son. All resected tumors from the family members were then reviewed and supplemented with immunohistochemical studies, previously wrong diagnoses were then corrected...
March 2, 2023: Diagnostics
Thomas Hofmarcher, Chiara Malmberg, Peter Lindgren
OBJECTIVES: Biomarker testing is indispensable for the implementation of precision medicine (PM) in oncology. The aim of this study was to assess the value of biomarker testing from a holistic perspective based on the example of advanced non-small cell lung cancer (aNSCLC). MATERIALS AND METHODS: A partitioned survival model was populated with data from pivotal clinical trials of first-line treatments in aNSCLC. Three testing scenarios were considered; "no biomarker testing" encompassing chemotherapy treatment, "sequential testing" for EGFR and ALK encompassing treatment with targeted- or chemotherapy, and "multigene testing" covering EGFR, ALK, ROS1, BRAF, NTRK, MET, RET and encompassing treatment with targeted- or immuno(chemo)therapy...
2023: Frontiers in Medicine
Cesare Miani, Luca Giovanni Locatello, Maria Gabriella Rugiu, Jamile Karina Antonio, Carla Di Loreto, Enrico Pegolo
BACKGROUND: Val804Met RET is one of the most common genetic alterations in Multiple Endocrine Neoplasia 2 and is considered to confer only a moderate risk for familial medullary thyroid carcinoma (MTC). The associated phenotype can however be much more complex in some cases. METHODS: A clinical, genetic, and pathological analysis was conducted on a family cluster of thyroid neoplasms associated with Val804Met RET mutation. RESULTS: All the kindreds who are carriers of the mutated RET received total thyroidectomy + /- VI level dissection...
February 24, 2023: Pathology, Research and Practice
Lu Zhao, Na Wang, Dou Zhang, Yingjie Jia, Fanming Kong
RET gene plays significant roles in the nervous system and many other tissues. Rearranged during transfection (RET) mutation is related to cell proliferation, invasion, and migration. Many invasive tumors (e.g., non-small cell lung cancer, thyroid cancer, and breast cancer) were found to have changes in RET. Recently, great efforts have been made against RET. Selpercatinib and pralsetinib, with encouraging efficacy, intracranial activity, and tolerability, were approved by the Food and Drug Administration (FDA) in 2020...
2023: Frontiers in Oncology
Qiang Zheng, Likun Hou, Guoguo Shang, Xiaowei Qi, Mengmeng Zhang, Yan Jin, Yue Wang, Qianqian Xue, Chunyan Wu, Yuan Li
INTRODUCTION: Herein we describe a series of rare peripheral pulmonary neoplasms temporarily termed "peripheral type squamous cell neoplasm of uncertain malignant potential (PSCN-UMP)" and investigate their relationship to bronchiolar adenoma (BA) and squamous cell carcinoma (SCC). MATERIALS AND METHODS: The histologic and immunohistochemical features of 10 PSCN-UMPs and six BAs were compared. Whole exome sequencing (WES) and bioinformatics analysis were performed to further compare the genetic features of PSCN-UMPs, BAs, and NSCLCs...
February 18, 2023: Histopathology
Jun Xiao, Lu-Wen Hao, Jing Wang, Xiao-Si Yu, Jing-Yi You, Ze-Jian Li, Han-Dan Mao, Xin-Yao Meng, Jie-Xiong Feng
BACKGROUND: Hirschsprung's disease (HSCR) is one of the most common congenital digestive tract malformations and can cause stubborn constipation or gastrointestinal obstruction after birth, causing great physical and mental pain to patients and their families. Studies have shown that more than 20 genes are involved in HSCR, and most cases of HSCR are sporadic. However, the overall rate of familial recurrence in 4331 cases of HSCR is about 7.6%. Furthermore, familial HSCR patients show incomplete dominance...
March 1, 2023: World Journal of Pediatrics: WJP
Deepak Gulwani, Priyanka Upadhyay, Ridhima Goel, Vijaya Sarangthem, Thoudam Debraj Singh
Thyroid cancer's incidence has increased by leaps and bounds over the last years and accounts for 2.8% of new cases of cancers. This increasing bar is partially assisted by enormous screening to understand the sub-clinical status. Advanced tumor growth is the leading cause of thyroid cancer-associated death. However, the complete understanding of the underlying cause is still to be disclosed. The updated clinical assessment evidenced a few major oncogenes viz. RAS, BRAF, and RET as key drivers in the development and progression of thyroid cancer...
February 1, 2023: Asian Pacific Journal of Cancer Prevention: APJCP
Dorothea K Torous, Svetlana Avlasevich, Jeffrey C Bemis, Thad Howard, Russell E Ware, Chunkit Fung, Yuhchyau Chen, Deepak Sahsrabudhe, James T MacGregor, Stephen D Dertinger
Hydroxyurea is approved for treating children and adults with sickle cell anemia (SCA). Despite its proven efficacy, concerns remain about its mutagenic and carcinogenic potential that hamper its widespread use. Cell culture- and animal-based investigations indicate that hydroxyurea's genotoxic effects are due to indirect clastogenicity in select cell types when high dose and time thresholds are exceeded [reviewed by Ware and Dertinger, 2021]. The current study extends these preclinical observations to pediatric patients receiving hydroxyurea for treatment of SCA...
February 26, 2023: Environmental and Molecular Mutagenesis
Archana M Agarwal, Valarie McMurty, Adam L Clayton, Ashini Bolia, N Scott Reading, Coumarane Mani, Jay L Patel, Anton Rets
INTRODUCTION: Hereditary hemolytic anemias (HHA) comprise a heterogeneous group of disorders resulting from defective red blood cell (RBC) cytoskeleton, RBC enzyme deficiencies, and hemoglobin (Hb) synthesis disorders such as thalassemia or sideroblastic anemia. MATERIALS AND METHODS: Our hemolytic anemia diagnostic next-generation sequencing (NGS) panel includes 28 genes encoding RBC cytoskeletal proteins, membrane transporter, RBC enzymes, and certain bilirubin metabolism genes...
February 24, 2023: European Journal of Haematology
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