bims-preonc 2024-10-20 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2024–10–20
sixteen papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Detection of Circulating Tumor DNA in Lymphoma Patients.
Applications of cerebrospinal fluid circulating tumor cells and circulating tumor-derived DNA in diagnosis, prognosis, and personalized treatment of CNS metastases.
Prospective assessment of circulating tumor DNA in patients with metastatic uveal melanoma treated with tebentafusp.
Molecular evolution of central nervous system metastasis and therapeutic implications.
Updated EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection - Update 1.
The Role of Liquid Biopsy in Gastroenteropancreatic Neuroendocrine Neoplasms.
Resectable Non-Small Cell Lung Cancer Heterogeneity and Recurrence Assessed by Tissue Next-Generation Sequencing Genotyping and Circulating Tumor Cell EZH2 Characterization.
Clinical and Technical Validation of OncoIndx® Assay-A Comprehensive Genome Profiling Assay for Pan-Cancer Investigations.
Detection of genomic alterations in liquid biopsies from patients with non-small cell lung cancer using FoundationOne Liquid CDx: a cost-effectiveness analysis.
Incidental finding of a BRCA2 variant following whole genome sequencing to molecularly diagnose bilateral congenital cataracts.
Longitudinal monitoring of circulating tumor DNA to detect relapse early and predict outcome in early breast cancer.
Circulating tumor cells in pancreatic cancer: more than liquid biopsy.
Clinical features and prognostic factors in thymoma and thymic carcinoma.
Advancing Precision Oncology: Whole-Exome Sequencing in Endometrial Cancer Liquid-Based Cytology.
Harnessing the role of aberrant cell signaling pathways in glioblastoma multiforme: a prospect towards the targeted therapy.
Tumor Mutational Burden as a Biomarker of Immunotherapy Response: An Immunogram Approach in Onco-immunology.

Methods Mol Biol. 2025 ;2865 475-490

Detection of Circulating Tumor DNA in Lymphoma Patients.

Alessio Bruscaggin, Katia Pini, Davide Rossi.

  Liquid biopsy has become an opportunity in lymphoma diagnostics, since plasma circulating tumor DNA (ctDNA) is an easily accessible source of tumor DNA, which can be complementary to tissue biopsy. Through ctDNA, lymphomas can be molecularly characterized, tumor clonal evolution can be tracked, while monitoring minimal residual diseases during and after therapy. Here, we describe the methodology of cancer personalized profiling by deep sequencing (CAPP-seq) that we use for ctDNA qualification and quantification.

Keywords:  CAPP-seq; Liquid biopsy; Lymphoma; Next-generation sequencing; Somatic mutations; cfDNA

DOI:  https://doi.org/10.1007/978-1-0716-4188-0_21
Front Oncol. 2024 ;14 1409383

Applications of cerebrospinal fluid circulating tumor cells and circulating tumor-derived DNA in diagnosis, prognosis, and personalized treatment of CNS metastases.

Elena Pentsova.

  A common feature of advanced solid tumors is their ability to metastasize and colonize distant organs, including the Central Nervous System (CNS), which encompasses brain and leptomeningeal metastases (LM). While cerebrospinal fluid cytopathological analysis remains a gold standard diagnostic tool, it only provides limited insights into the biology of tumor cells; thus, it is urgent to develop minimally invasive biomarkers that enable a comprehensive quantitative and molecular characterization of disseminated cells, therapy response assessment, and disease monitoring. Liquid biopsy methods have been swiftly developed for some readily accessible bodily fluids such as plasma and urine; circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) from these sources have been rapidly implemented into clinical trial design, disease monitoring, and treatment assignment across different tumor types. However, the filter imposed by the brain blood barrier (BBB) hampers the release of tumor-derived cells and molecules from CNS metastases. Crucially, cerebrospinal fluid (CSF) liquid biopsy methods offer a unique and unparallel source to develop liquid biopsy methodologies in patients with CNS-disseminated disease, including the characterization of CTCs and ctDNA arising specifically from brain and leptomeningeal metastasis. These technologies have enabled a deeper understanding of tumor cell and molecular dynamics, including the reconstruction of clonal evolution in the brain microenvironment through longitudinal sapling. Here, we discuss the current challenges and opportunities that CSF liquid biopsy methods face for the implementation of these approaches into clinical settings.

Keywords:  biomarkers; brain metastasis; cerebrospinal fluid; leptomeningeal metastasis; liquid biopsy

DOI:  https://doi.org/10.3389/fonc.2024.1409383
Nat Commun. 2024 Oct 14. 15(1): 8851

Prospective assessment of circulating tumor DNA in patients with metastatic uveal melanoma treated with tebentafusp.

Manuel Rodrigues, Toulsie Ramtohul, Aurore Rampanou, José Luis Sandoval, Alexandre Houy, Vincent Servois, Léah Mailly-Giacchetti, Gaelle Pierron, Anne Vincent-Salomon, Nathalie Cassoux, Pascale Mariani, Caroline Dutriaux, Marc Pracht, Thomas Ryckewaert, Jean-Emmanuel Kurtz, Sergio Roman-Roman, Sophie Piperno-Neumann, François-Clément Bidard, Marc-Henri Stern, Shufang Renault.

Tebentafusp, a bispecific immune therapy, is the only drug that demonstrated an overall survival benefit in patients with metastatic uveal melanoma (MUM). Circulating tumor DNA (ctDNA) has emerged as a potential prognostic and predictive marker in the phase 3 IMCgp100-202 trial using multiplex PCR-based next-generation sequencing (NGS). In this study (NCT02866149), ctDNA dynamics were assessed using droplet digital PCR (ddPCR) in 69 MUM patients undergoing tebentafusp treatment. Notably, 61% of patients exhibited detectable ctDNA before treatment initiation, which was associated with shorter overall survival (median 12.9 months versus 40.5 months for patients with undetectable ctDNA; p < 0.001). Patients manifesting a 90% or greater reduction in ctDNA levels at 12 weeks demonstrated markedly prolonged overall survival (median 21.2 months versus 12.9 months; p = 0.02). Our findings highlight the potential of ddPCR-based ctDNA monitoring as an economical, pragmatic and informative approach in MUM management, offering valuable insights into treatment response and prognosis.

DOI: https://doi.org/10.1038/s41467-024-53145-0
Trends Mol Med. 2024 Oct 17. pii: S1471-4914(24)00265-X. [Epub ahead of print]

Molecular evolution of central nervous system metastasis and therapeutic implications.

David Gritsch, Priscilla K Brastianos.

  The increasing prevalence and poor prognosis of central nervous system (CNS) metastases pose a significant challenge in oncology, necessitating improved therapeutic strategies. Recent research has shed light on the complex genomic landscape of brain metastases, identifying unique and potentially actionable genetic alterations. These insights offer new avenues for targeted therapy, highlighting the potential of precision medicine approaches in treating CNS metastases. However, translating these discoveries into clinical practice requires overcoming challenges such as availability of tissue for characterization, access to molecular testing, drug delivery across the blood-brain barrier (BBB) and addressing intra- and intertumoral genetic heterogeneity. This review explores novel insights into the evolution of CNS metastases, the molecular mechanisms underlying their development, and implications for therapeutic interventions.

Keywords:  actionable mutations; blood–brain barrier; brain metastasis; branched evolution; molecular profiling; targeted therapy

DOI:  https://doi.org/10.1016/j.molmed.2024.09.008
Neuro Oncol. 2024 Oct 10. pii: noae213. [Epub ahead of print]

Updated EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection - Update 1.

Martin J van den Bent, Enrico Franceschi, Mehdi Touat, Pim J French, Ahmed Idbaih, Giuseppe Lombardi, Roberta Rudaà, Leonille Schweizer, David Capper, Marc Sanson, Pieter Wesseling, Michael Weller, Marica Eoli, Elena Anghileri, Franck Bielle, Phillipp Euskirchen, Marjolein Geurts, Patrick Y Wen, Matthias Preusser.

  The standard of care for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a major part of the standard treatment, however, the predictive significance of most of the targets for treatment in systemic cancer are less well established in central nervous system (CNS) tumors . In 2023 the EANO Guideline Committee presented evidence based recommendations for rational testing of molecular targets for targeted treatments. From all targets reviewed, only testing for BRAF V600E mutations was of proven clinical benefit; despite regulatory approvals for tumor agnostic treatment of NTRK gene fusions and high Tumor Mutational Burden (TMB) for patients with adult brain tumors, the evidence of clinical benefit for patients was still limited . This guideline has a modular structure, allowing regular updating of individual sections and adding new ones. The present version (Update 1) presents a review of the rationale of testing for PTEN, H3F3A, MTAP, RET and IDH, and presents an update of the text on TMB high and mismatch repair deficiency. It also presents an overview of therapeutic yield of routine next generation sequencing for mutations and fusion detection. The supplement accompanying this version contains the in depth review of all targets, whereas in the main manuscript the final recommendations of the revised and new targets are presented. Updates will be made on a regular basis.

Keywords:  (glio)neuronal tumors; Diffuse glioma; EANO guideline; IDH; targeted treatment

DOI:  https://doi.org/10.1093/neuonc/noae213
Cancers (Basel). 2024 Sep 30. pii: 3349. [Epub ahead of print]16(19):

The Role of Liquid Biopsy in Gastroenteropancreatic Neuroendocrine Neoplasms.

Catarina Almeida, Lorenzo Gervaso, Gianmaria Frigè, Francesca Spada, Lavinia Benini, Chiara Alessandra Cella, Luca Mazzarella, Nicola Fazio.

  Neuroendocrine neoplasms incidence has been increasing, arising the need for precise and early diagnostic tools. Liquid biopsy (LB) offers a less invasive alternative to tissue biopsy, providing real-time molecular information from circulating tumour components in body fluids. The aim of this review is to analyse the current evidence concerning LB in NENs and its role in clinical practice. We conducted a systematic review in July 2024 focusing on LB applications in NENs, including circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), micro RNA (miRNA), messenger RNA (mRNA) and extracellular vesicles. Sixty-five relevant articles were analysed. The LB showed potential in diagnosing and monitoring NENs. While CTCs face limitations due to low shedding, ctDNA provides valuable information on high-grade neoplasms. MiRNA and mRNA (e.g., the NETest) offer high sensitivity and specificity for diagnosis and prognosis, outperforming traditional markers like chromogranin A. The LB has significant potential for NEN diagnosis and monitoring but lacks widespread clinical integration due to limited prospective studies and guidelines, requiring further validation. Advances in sequencing technologies may enhance the clinical utility of LB in NENs. Future research should focus on refining LB methods, standardising protocols and exploring applications in high-grade NENs.

Keywords:  circulating tumour DNA; gastroenteropancreatic tract; liquid biopsy; neuroendocrine neoplasms; precision medicine

DOI:  https://doi.org/10.3390/cancers16193349
Arch Bronconeumol. 2024 Oct 04. pii: S0300-2896(24)00360-0. [Epub ahead of print]

Resectable Non-Small Cell Lung Cancer Heterogeneity and Recurrence Assessed by Tissue Next-Generation Sequencing Genotyping and Circulating Tumor Cell EZH2 Characterization.

Abel Garcia-Diaz, María José Moyano-Rodríguez, María Del Carmen Garrido-Navas, Diego de Miguel-Perez, Jose Expósito-Hernández, Bernardino Alcázar-Navarrete, Francisco Ortuño, David Landeira, Pedro J Romero, Adrian Garcia-Moreno, Jose A Lorente, Javier Lopez-Hidalgo, Clara Bayarri-Lara, Maria Jose Serrano.

   INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common type of lung neoplasm. Despite surgical resection, it has a high relapse rate, accounting for 30-55% of all cases. Next-generation sequencing (NGS) based on a customized gene panel and the analysis of circulating tumor cells (CTCs) can help identify heterogeneity, stratify high-risk patients, and guide treatment decisions. In this descriptive study involving a small prospective cohort, we focus on the phenotypic characterization of CTCs, particularly concerning EZH2 expression (a member of the Polycomb Repression Complex 2), as well as on the mutation profiles of the tissue using a customized gene panel and their association with poor outcomes in NSCLC.
METHODS: Isolation and characterization of EZH2 on CTCs were evaluated before surgical resection (CTC1) and one month after surgery (CTC2) in resectable NSCLC patients. Targeted NGS was performed using a customized 50-gene panel on tissue samples from a subset of patients.
RESULTS: 76 patients with resectable NSCLC were recruited. The top mutated genes in the cohort included TP53, FLT1, MUC5AC, EGFR, and NLRP3. Pair of genes that had mutually exclusive mutations was TP53-RIN3, and pairs of genes with co-occurring mutations were CD163-TLR4, FGF10-FOXP2, ADAMTSL3-FLT1, ADAMTSL3-MUC5AC and MUC5AC-NLRP3. CTCs decreased significantly between the two time points CTC1 and CTC2 (p<0.0001), and CTCs+ patients with high EZH2 expression had an 87% increased risk of death (p=0.018).
CONCLUSIONS: Integrating molecular profiling of tumors and CTC characterization can provide valuable insights into tumor heterogeneity and improve patient stratification for resectable NSCLC.

Keywords:  CTCs; EZH2; Liquid biopsy; MRD; NGS; NSCLC

DOI:  https://doi.org/10.1016/j.arbres.2024.08.006
Cancers (Basel). 2024 Oct 08. pii: 3415. [Epub ahead of print]16(19):

Clinical and Technical Validation of OncoIndx® Assay-A Comprehensive Genome Profiling Assay for Pan-Cancer Investigations.

Aarthi Ramesh, Atul Bharde, Alain D'Souza, Bhagwat Jadhav, Sangeeta Prajapati, Kanchan Hariramani, Madhura Basavalingegowda, Sandhya Iyer, Sumit Halder, Mahesh Deochake, Hrishita Kothavade, Aravindan Vasudevan, Mohan Uttarwar, Jayant Khandare, Gowhar Shafi.

  Comprehensive next-generation sequencing (NGS) assays enable the identification of clinically relevant mutations, enhancing the capability for targeted therapeutic interventions. In addition, genomic alterations driving the oncogenic roadmap and leading to resistance mechanisms are reshaping precision oncology. We report the workflow and clinical and technical validation of the OncoIndx® NGS platform-a comprehensive genomic profiling (CGP)-based assay for pan-cancer investigation. We evaluated the concordance between the OncoIndx® test findings and clinically established hotspot detection using SeraSeq reference standards. OncoIndx is a hybridization capture-based NGS assay for the targeted deep sequencing of all exons and selected introns of 1080 cancer-related genes. We show the outcome in the form of tier I and tier II single nucleotide variants (SNVs), copy number alterations (CNAs), and specific gene fusions. OncoIndx® also informs genome-wide tumor mutational burden (TMB), microsatellite instability (MSI), homologous recombination deficiency (HRD), and genomic loss of heterozygosity (gLOH). A total of 63 samples were utilized for validation with reference standards, clinical samples, and orthogonal assessment for genomic alterations. In addition, 49 cross-laboratory samples were validated for microsatellite instability (MSI), and for the tumor mutation burden (TMB), 18 samples as reference standards, 6 cross-laboratory samples, and 29 TCGA samples were utilized. We show a maximum clinical sensitivity of 98% and a positive predictive value (PPV) of 100% for the clinically actionable genomic variants detected by the assay. In addition, we demonstrate analytical validation with the performance of the assay, limit of detection (LoD), precision, and orthogonal concordance for various types of SVs, CNAs, genomic rearrangements, and complex biomarkers like TMB, MSI, and HRD. The assay offers reliable genomic predictions with the high-precision detection of actionable variants, validated by established reference standards.

Keywords:  artificial intelligence; cancer genomics; comprehensive genomic profiling (CGP); next-generation sequencing (NGS); targeted gene sequencing

DOI:  https://doi.org/10.3390/cancers16193415
J Med Econ. 2024 Oct 10. 1-18

Detection of genomic alterations in liquid biopsies from patients with non-small cell lung cancer using FoundationOne Liquid CDx: a cost-effectiveness analysis.

Dolores Isla, Rosa Álvarez, María Arnal, Edurne Arriola, Aitor Azkarate, Eider Azkona, Rosario García-Campelo, Pilar Garrido, Ernest Nadal, Ana L Ortega, David Carcedo, María Crespo, Jesús Lavara, Fernando Córcoles, Reyes Bernabé.

   OBJECTIVE: Liquid biopsy (LB) is a non-invasive technique to detect genetic alterations by next-generation sequencing (NGS) when tissue biopsy is not available. This study aims to estimate in the Spanish setting, the cost-effectiveness of using FoundationOne Liquid CDx (F1L CDx), a novel blood-derived LB test based on NGS, versus non-molecular diagnosis (non-mDx) in patients with advanced non-small cell lung cancer (NSCLC) in whom tissue sampling is not feasible.
METHODS: A joint model was developed combining a decision-tree with partitioned survival models to calculate the costs and health outcomes over a lifetime horizon, comparing F1L CDx in LB versus non-mDx. Only direct costs (expressed in €of 2023) were included and a 3% discount rate for future costs and effects was considered. Health outcomes were expressed in Life Years (LYs) and Quality-Adjusted Life Years (QALYs). Utilities and treatment efficacy were obtained from the literature. An expert panel of 11 Spanish oncologists determined the treatment allocation and validated all model inputs and assumptions. Several sensitivity analyses were performed to assess the robustness of the results.
RESULTS: In a hypothetical cohort of 1,000 patients, LB using F1L CDx would detect 386 alterations, so those patients could be treated with targeted therapies or enrolled in clinical trials. Cost-effectiveness results showed that F1L CDx provides greater effectiveness than non-mDx (+383.95 LYs and +305.94 QALYs), with an additional cost of €2,898,308. The incremental cost-utility ratio was €9,473/QALY gained. The probabilistic sensitivity analysis confirmed the robustness of the cost-effectiveness results.
LIMITATIONS: Various limitations inherent to cost-effectiveness analyses were described.
CONCLUSION: LB with F1L CDx test is a cost-effective strategy in Spain for patients with advanced NSCLC without tissue sample available for molecular diagnosis, improving the personalized treatment of these patients.

Keywords:  C; C5; C52; FoundationOne Liquid CDx; I; I1; I10; cost-effectiveness analysis; liquid biopsy; molecular testing; non-small cell lung cancer

DOI:  https://doi.org/10.1080/13696998.2024.2413289
BMJ Case Rep. 2024 Oct 11. pii: e260755. [Epub ahead of print]17(10):

Incidental finding of a BRCA2 variant following whole genome sequencing to molecularly diagnose bilateral congenital cataracts.

Cara Heppell, Samantha Malka, Mariya Moosajee.

  A male patient in his 20s with a history of bilateral congenital cataracts and nystagmus presented to the genetic eye disease clinic at Moorfields Eye Hospital to enquire about genetic testing for family decision-making and access to preimplantation genetic testing. He had a history of lensectomy with best-corrected visual acuities of logMAR 0.60 and 1.00 in the right and left eye. Whole genome sequencing (WGS) was conducted, which included targeted analysis of a panel of 115 lens-related genes and incidental findings, for which patients are unable to opt-out. Genetic testing identified the causative variant c.134T>C (p.Leu45Pro) in the CRYGC gene. A pathogenic variant in BRCA2 was also identified as a secondary finding. This was unexpected given the absence of a strong family history of breast or ovarian cancer. This case illustrates the importance of genetic counselling and informing patients about the implications of incidental findings that arise from WGS.

Keywords:  Ethics; Genetic screening / counselling; Genetics; Ophthalmology

DOI:  https://doi.org/10.1136/bcr-2024-260755
Breast Cancer Res Treat. 2024 Oct 18.

Longitudinal monitoring of circulating tumor DNA to detect relapse early and predict outcome in early breast cancer.

Isaac Garcia-Murillas, Rosalind J Cutts, Giselle Walsh-Crestani, Edward Phillips, Sarah Hrebien, Kathryn Dunne, Kally Sidhu, Robert Daber, Benjamin Hubert, Chiharu Graybill, Peter M DeFord, David J Wooten, Jianhua Zhao, Rachel E Ellsworth, Stephen R D Johnston, Alistair Ring, Simon Russell, Abigail Evans, Anthony Skene, Duncan Wheatley, Ian E Smith, W Michael Korn, Nicholas C Turner.

   PURPOSE: Detection of molecular residual disease (MRD) allows for the identification of breast cancer patients at high-risk of recurrence, with the potential that early initiation of treatment at early stages of relapse could improve patient outcomes. The Invitae Personalized Cancer Monitoring™ assay (PCM) is a newly developed next-generation sequencing approach that utilizes up to 50 patient-specific, tumor-informed DNA variants, to detect circulating tumor DNA (ctDNA). The ability of the PCM assay to detect MRD before clinical relapse was evaluated.
METHODS: The cohort included 61 female patients with high-risk breast cancer who underwent neoadjuvant chemotherapy. Plasma samples were collected before and during neoadjuvant therapy, after surgery and during monitoring. PCM was used to detect ctDNA at each time point.
RESULTS: The sensitivity to detect ctDNA in plasma from patients who relapsed during the monitoring phase was 76.9% (10/13). Specificity and positive predictive values were both 100% with all (10/61, 16%) of the patients who had ctDNA detected during the monitoring phase subsequently relapsing. Detection of ctDNA during monitoring was associated with a high-risk of future relapse (HR 37.2, 95% CI 10.5-131.9, p < 0.0001), with a median lead-time from ctDNA detection to clinical relapse of 11.7 months.
CONCLUSION: PCM detected ctDNA in patients who relapsed with a long lead-time over clinical relapse, shows strong association with relapse-free survival and may be used to identify patients at high-risk for relapse, allowing for earlier intervention.

Keywords:  Breast cancer; CtDNA; Liquid biopsy; Minimal residual disease; Relapse

DOI:  https://doi.org/10.1007/s10549-024-07508-2
Ther Adv Med Oncol. 2024 ;16 17588359241284935

Circulating tumor cells in pancreatic cancer: more than liquid biopsy.

Zeru Li, Cheng Qin, Bangbo Zhao, Tianyu Li, Yutong Zhao, Xiangyu Zhang, Weibin Wang.

  Circulating tumor cells (CTCs) are tumor cells that slough off the primary lesions and extravasate into the bloodstream. By forming CTC clusters and interacting with other circulating cells (platelets, NK cells, macrophage, etc.), CTCs are able to survive in the circulatory system of tumor patients and colonize to metastatic organs. In recent years, the potential of CTCs in diagnosis, prognostic assessment, and individualized therapy of various types of tumors has been gradually explored, while advances in biotechnology have made it possible to extract CTCs from patient blood samples. These biological features of CTCs provide us with new insights into cancer vulnerabilities. With the advent of new immunotherapies and personalized medicines, disrupting the heterotypical interaction between CTCs and circulatory cells as well as direct CTCs targeting hold great promise. Pancreatic cancer (PC) is one of the most malignant cancers, in part because of early metastasis, difficult diagnosis, and limited treatment options. Although there is significant potential for CTCs as a biomarker to impact PC from diagnosis to therapy, there still remain a number of challenges to the routine implementation of CTCs in the clinical management of PC. In this review, we summed up the progress made in understanding biological characteristics and exceptional technological advances of CTCs and provided insight into exploiting these developments to design future clinical tools for improving the diagnosis and treatment of PC.

Keywords:  circulating tumor cells; diagnosis; metastasis; pancreatic cancer; personal therapy

DOI:  https://doi.org/10.1177/17588359241284935
Indian J Thorac Cardiovasc Surg. 2024 Nov;40(6): 660-668

Clinical features and prognostic factors in thymoma and thymic carcinoma.

Doğan Bayram, Serhat Sekmek, Mehmet Kayaalp, Murat Bardakçı, Emre Hafızoğlu, Gökhan Uçar, Efnan Algin, Oznur Bal, Burak Civelek, Mehmet Ali Nahit Şendur, Fahriye Tugba Kos, Dogan Uncu.

   Introduction: Thymic epithelial tumors represent the most common cause of anterior mediastinal masses in adults. Among these tumors, thymomas constitute the majority, whereas thymic carcinomas are less prevalent and associated with a poorer prognosis. This study seeks to investigate the clinical and prognostic factors of these rare entities, thymoma, and thymic carcinomas.
Materials and methods: We conducted a retrospective analysis on a cohort of 60 patients diagnosed with thymoma and thymic carcinoma, who were under follow-up at our clinic between January 1998 and February 2023. The clinical characteristics and prognostic factors of these patients were analyzed separately.
Results: Thymomas accounted for 75% of the cases. The median age at diagnosis was 46 years in both patient groups. Masaoka stage 4 was observed in 28.9% of thymoma patients and 66.7% of thymic carcinoma patients. The median overall survival (mOS) for thymoma patients was 261.4 months, while it was 9.23 months for patients with thymic carcinoma. Curative surgery emerged as a prognostic factor significantly influencing overall survival in both thymoma and thymic carcinoma patients.
Conclusion: Our study highlights the significance of Eastern Cooperative Oncology Group (ECOG) performance status and curative surgery as prognostic factors affecting overall survival in thymoma patients. In thymic carcinoma, only curative surgery was found as a prognostic factor. These findings may enhance patient care and guide personalized treatment strategies. Further investigations and prospective studies are warranted to corroborate and expand upon these results.

Keywords:  Curative surgery; Masaoka stage; Thymic carcinoma; Thymoma

DOI:  https://doi.org/10.1007/s12055-024-01741-6
Arch Pathol Lab Med. 2024 Oct 14.

Advancing Precision Oncology: Whole-Exome Sequencing in Endometrial Cancer Liquid-Based Cytology.

Reika Takamatsu, Kohei Nakamura, Tatsuyuki Chiyoda, Kosuke Tsuji, Ryutaro Kawano, Naoki Yoshimi, Wataru Yamagami, Hiroshi Nishihara.

CONTEXT.—: Diagnostic strategies for endometrial cancer have been evolving, with cytologic analysis being considered a key method in integrated oncologic diagnostics because of its less invasive nature and adaptability to various assessments. Liquid-based cytology (LBC) has emerged as a promising method for intact DNA preservation; it exhibits improved efficiency in advanced sequencing applications such as next-generation sequencing. However, despite the use of LBC in panel assays, its application in whole-exome sequencing (WES) for comprehensive genomic profiling remains underexplored.
OBJECTIVE.—: To investigate whether molecular classification is possible based on WES using DNA derived from LBC specimens.
DESIGN.—: We combined WES with targeted gene panel analysis to compare genomic findings of LBC and traditional tissue samples obtained from 7 cases of endometrial cancer. We investigated pathogenic mutations, tumor mutational burden, and microsatellite instability, and achieved molecular classification with high accuracy.
RESULTS.—: We found a substantial concordance between LBC and traditional tissue samples in terms of pathogenic mutation detection, with a 95% match in the LBC samples and 94% in the tissue samples. Notably, our results highlight the importance of combining WES with panel-based analysis in identifying the ultramutated status of a case that had been missed during panel analysis.
CONCLUSIONS.—: Our findings emphasize the potential of LBC samples in the precise and noninvasive genomic analysis of cases of endometrial cancer and offer a new avenue for developing diagnostic and therapeutic strategies in precision oncology.

DOI: https://doi.org/10.5858/arpa.2024-0137-OA
Mol Biol Rep. 2024 Oct 19. 51(1): 1069

Harnessing the role of aberrant cell signaling pathways in glioblastoma multiforme: a prospect towards the targeted therapy.

Subbrina Hasan, Zimam Mahmud, Mahmud Hossain, Sohidul Islam.

  Glioblastoma Multiforme (GBM), designated as grade IV by the World Health Organization, is the most aggressive and challenging brain tumor within the central nervous system. Around 80% of GBM patients have a poor prognosis, with a median survival of 12-15 months. Approximately 90% of GBM cases originate from normal glial cells via oncogenic processes, while the remainder arise from low-grade tumors. GBM is notorious for its heterogeneity, high recurrence rates, invasiveness, and aggressive behavior. Its malignancy is driven by increased invasive migration, proliferation, angiogenesis, and reduced apoptosis. Throughout various stages of central nervous system (CNS) development, pivotal signaling pathways, including Wnt/β-catenin, Sonic hedgehog signaling (Shh), PI3K/AKT/mTOR, Ras/Raf/MAPK/ERK, STAT3, NF-КB, TGF-β, and Notch signaling, orchestrate the growth, proliferation, differentiation, and migration of neural progenitor cells in the brain. Numerous upstream and downstream regulators within these signaling pathways have been identified as significant contributors to the development of human malignancies. Disruptions or aberrant activations in these pathways are linked to gliomagenesis, enhancing the invasiveness, progression, and aggressiveness of GBM, along with epithelial to mesenchymal transition (EMT) and the presence of glioma stem cells (GSCs). Traditional GBM treatment involves surgery, radiotherapy, and chemotherapy with Temozolomide (TMZ). However, most patients experience tumor recurrence, leading to low survival rates. This review provides an overview of the major cell signaling pathways involved in gliomagenesis. Furthermore, we explore the signaling pathways leading to therapy resistance and target key molecules within these signaling pathways, paving the way for the development of novel therapeutic approaches.

Keywords:  Cell signaling pathways; Glioblastoma Multiforme; Notch; PI3K; TGF-β; Targeted therapy; Wnt/β-catenin

DOI:  https://doi.org/10.1007/s11033-024-09996-3
Curr Mol Med. 2024 ;24(12): 1461-1469

Tumor Mutational Burden as a Biomarker of Immunotherapy Response: An Immunogram Approach in Onco-immunology.

Afzal Ansari, Suman Kumar Ray, Mukul Sharma, Rakesh Rawal, Pushpendra Singh.

  Immune checkpoint inhibitors have revolutionized cancer treatment by allowing T cells to reactivate. Tumor mutational burden (TMB) is a biomarker that has emerged as a viable diagnostic for locating patients who would benefit from immunotherapy in particular cancer types. Greater neo-antigens mean more opportunities for T cell identification, and TMB is clinically linked to better immune checkpoint inhibitors. Tumor foreignness is a cancer immunogram, and TMB can be used as a substitute for foreignness. The role of TMB analysis as an independent predictor of immunotherapy response in the context of immune checkpoint inhibitor medications is the subject of this mini-review.

Keywords:  Tumor mutational burden; biomarkers; immune checkpoint inhibitor; immunotherapies.; neo-antigens

DOI:  https://doi.org/10.2174/0115665240266906231024111920