Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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15 pages, 787 KiB  
Review
Tumor Infiltrating Lymphocytes across Breast Cancer Subtypes: Current Issues for Biomarker Assessment
by Carmine Valenza, Beatrice Taurelli Salimbeni, Celeste Santoro, Dario Trapani, Gabriele Antonarelli and Giuseppe Curigliano
Cancers 2023, 15(3), 767; https://doi.org/10.3390/cancers15030767 - 26 Jan 2023
Cited by 20 | Viewed by 3329
Abstract
Tumor-infiltrating lymphocytes (TILs) represent a surrogate biomarker of anti-tumor, lymphocyte-mediated immunity. In early, triple-negative breast cancer, TILs have level 1B of evidence to predict clinical outcomes. TILs represent a promising biomarker to select patients who can experience a better prognosis with de-intensified cancer [...] Read more.
Tumor-infiltrating lymphocytes (TILs) represent a surrogate biomarker of anti-tumor, lymphocyte-mediated immunity. In early, triple-negative breast cancer, TILs have level 1B of evidence to predict clinical outcomes. TILs represent a promising biomarker to select patients who can experience a better prognosis with de-intensified cancer treatments and derive larger benefits from immune checkpoint inhibitors. However, the assessment and the validation of TILs as a biomarker require a prospective and rigorous demonstration of its clinical validity and utility, provided reproducible analytical performance. With pending data about the prospective validation of TILs’ clinical validity to modulate treatments in early breast cancer, this review summarizes the most important current issues and future challenges related to the implementation of TILs assessments across all breast cancer subtypes and their potential integration into clinical practice. Full article
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31 pages, 974 KiB  
Review
Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy
by Marianna Sirico, Alberto D’Angelo, Caterina Gianni, Chiara Casadei, Filippo Merloni and Ugo De Giorgi
Cancers 2023, 15(3), 703; https://doi.org/10.3390/cancers15030703 - 23 Jan 2023
Cited by 15 | Viewed by 3601
Abstract
The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of the rapamycin (mTOR) axis is a key signal transduction system that links oncogenes and multiple receptor classes which are involved in many essential cellular functions. Aberrant PI3K signalling is one of the most [...] Read more.
The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of the rapamycin (mTOR) axis is a key signal transduction system that links oncogenes and multiple receptor classes which are involved in many essential cellular functions. Aberrant PI3K signalling is one of the most commonly mutated pathways in cancer. Consequently, more than 40 compounds targeting key components of this signalling network have been tested in clinical trials among various types of cancer. As the oncogenic activation of the PI3K/AKT/mTOR pathway often occurs alongside mutations in other signalling networks, combination therapy should be considered. In this review, we highlight recent advances in the knowledge of the PI3K pathway and discuss the current state and future challenges of targeting this pathway in clinical practice. Full article
(This article belongs to the Special Issue PI3K Pathway in Cancer)
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17 pages, 920 KiB  
Article
Safety and Feasibility of Radiation Therapy Combined with CDK 4/6 Inhibitors in the Management of Advanced Breast Cancer
by Marcin Kubeczko, Dorota Gabryś, Marzena Gawkowska, Anna Polakiewicz-Gilowska, Alexander J. Cortez, Aleksandra Krzywon, Grzegorz Woźniak, Tomasz Latusek, Aleksandra Leśniak, Katarzyna Świderska, Marta Mianowska-Malec, Barbara Łanoszka, Konstanty Chomik, Mateusz Gajek, Anna Michalik, Elżbieta Nowicka, Rafał Tarnawski, Tomasz Rutkowski and Michał Jarząb
Cancers 2023, 15(3), 690; https://doi.org/10.3390/cancers15030690 - 22 Jan 2023
Cited by 6 | Viewed by 3814
Abstract
The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast [...] Read more.
The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast cancer patients (pts) treated with CDK4/6i was performed, and 100 pts also received RT. Forty-six pts received 63 RT courses concurrently and fifty-four sequentially before CDK4/6i initiation (76 RT courses). Neutropenia was common (79%) and more frequent during and after concurrent RT than sequential RT (86% vs. 76%); however, CDK4/6i dose reduction rates were similar. In patients treated with CDK4/6i alone, the dose reduction rate was 42% (79 pts) versus 38% with combined therapy, and 5% discontinued treatment due to toxicity in the combined group. The risk of CDK4/6i dose reduction was correlated with neutropenia grade, RT performed within the first two CDK4/6i cycles, and more than one concurrent RT; a tendency was observed in concurrent bone irradiation. However, on multivariate regression analysis, only ECOG 1 performance status and severe neutropenia at the beginning of the second cycle were found to be associated with a higher risk of CDK4/6i dose reduction. This largest single-center experience published to date confirmed the acceptable safety profile of the CDK4/6i and RT combination without a significantly increased toxicity compared with CDK4/6i alone. However, one might delay RT for the first two CDK4/6i cycles, when myelotoxic AE are most common. Full article
(This article belongs to the Special Issue Radiation Therapy for Breast Cancer: Recent Advances and Challenges)
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25 pages, 1287 KiB  
Review
Treatment Strategies for Non-Small Cell Lung Cancer with Common EGFR Mutations: A Review of the History of EGFR TKIs Approval and Emerging Data
by Julian A. Marin-Acevedo, Bruna Pellini, ErinMarie O. Kimbrough, J. Kevin Hicks and Alberto Chiappori
Cancers 2023, 15(3), 629; https://doi.org/10.3390/cancers15030629 - 19 Jan 2023
Cited by 10 | Viewed by 5691
Abstract
The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR-mutant NSCLC [...] Read more.
The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR-mutant NSCLC in the first-line setting, therapy selection after progression on EGFR TKIs remains complex. Multiple groups are investigating novel therapies and drug combinations to determine the optimal therapy and treatment sequence for these patients. In this review, we summarize the landmark trials and history of the approval of EGFR TKIs, their efficacy and tolerability, and the role of these therapies in patients with central nervous system metastasis. We also briefly discuss the mechanisms of resistance to EGFR TKIs, ongoing attempts to overcome resistance and improve outcomes, and finalize by offering treatment sequencing recommendations. Full article
(This article belongs to the Special Issue Lung Cancer - Molecular Insights and Targeted Therapies)
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22 pages, 2233 KiB  
Review
MicroRNAs in the Pathogenesis, Prognostication and Prediction of Treatment Resistance in Soft Tissue Sarcomas
by Andrea York Tiang Teo, Vivian Yujing Lim and Valerie Shiwen Yang
Cancers 2023, 15(3), 577; https://doi.org/10.3390/cancers15030577 - 18 Jan 2023
Cited by 1 | Viewed by 4859
Abstract
Soft tissue sarcomas are highly aggressive malignant neoplasms of mesenchymal origin, accounting for less than 1% of adult cancers, but comprising over 20% of paediatric solid tumours. In locally advanced, unresectable, or metastatic disease, outcomes from even the first line of systemic treatment [...] Read more.
Soft tissue sarcomas are highly aggressive malignant neoplasms of mesenchymal origin, accounting for less than 1% of adult cancers, but comprising over 20% of paediatric solid tumours. In locally advanced, unresectable, or metastatic disease, outcomes from even the first line of systemic treatment are invariably poor. MicroRNAs (miRNAs), which are short non-coding RNA molecules, target and modulate multiple dysregulated target genes and/or signalling pathways within cancer cells. Accordingly, miRNAs demonstrate great promise for their utility in diagnosing, prognosticating and improving treatment for soft tissue sarcomas. This review aims to provide an updated discussion on the known roles of specific miRNAs in the pathogenesis of sarcomas, and their potential use in prognosticating outcomes and prediction of therapeutic resistance. Full article
(This article belongs to the Topic Soft Tissue Sarcomas: Treatment and Management)
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19 pages, 1305 KiB  
Review
Mass Spectrometry-Based Proteomics Workflows in Cancer Research: The Relevance of Choosing the Right Steps
by Paula Carrillo-Rodriguez, Frode Selheim and Maria Hernandez-Valladares
Cancers 2023, 15(2), 555; https://doi.org/10.3390/cancers15020555 - 16 Jan 2023
Cited by 12 | Viewed by 7068
Abstract
The qualitative and quantitative evaluation of proteome changes that condition cancer development can be achieved with liquid chromatography–mass spectrometry (LC-MS). LC-MS-based proteomics strategies are carried out according to predesigned workflows that comprise several steps such as sample selection, sample processing including labeling, MS [...] Read more.
The qualitative and quantitative evaluation of proteome changes that condition cancer development can be achieved with liquid chromatography–mass spectrometry (LC-MS). LC-MS-based proteomics strategies are carried out according to predesigned workflows that comprise several steps such as sample selection, sample processing including labeling, MS acquisition methods, statistical treatment, and bioinformatics to understand the biological meaning of the findings and set predictive classifiers. As the choice of best options might not be straightforward, we herein review and assess past and current proteomics approaches for the discovery of new cancer biomarkers. Moreover, we review major bioinformatics tools for interpreting and visualizing proteomics results and suggest the most popular machine learning techniques for the selection of predictive biomarkers. Finally, we consider the approximation of proteomics strategies for clinical diagnosis and prognosis by discussing current barriers and proposals to circumvent them. Full article
(This article belongs to the Special Issue Application of Proteomics in Cancers)
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18 pages, 1714 KiB  
Review
Mechanisms of Acquired Resistance and Tolerance to EGFR Targeted Therapy in Non-Small Cell Lung Cancer
by Houssein Chhouri, David Alexandre and Luca Grumolato
Cancers 2023, 15(2), 504; https://doi.org/10.3390/cancers15020504 - 13 Jan 2023
Cited by 19 | Viewed by 6616
Abstract
Non-small cell lung cancers (NSCLC) harboring activating mutations of the epidermal growth factor receptor (EGFR) are treated with specific tyrosine kinase inhibitors (EGFR-TKIs) of this receptor, resulting in clinically responses that can generally last several months. Unfortunately, EGFR-targeted therapy also favors the emergence [...] Read more.
Non-small cell lung cancers (NSCLC) harboring activating mutations of the epidermal growth factor receptor (EGFR) are treated with specific tyrosine kinase inhibitors (EGFR-TKIs) of this receptor, resulting in clinically responses that can generally last several months. Unfortunately, EGFR-targeted therapy also favors the emergence of drug tolerant or resistant cells, ultimately resulting in tumor relapse. Recently, cellular barcoding strategies have arisen as a powerful tool to investigate the clonal evolution of these subpopulations in response to anti-cancer drugs. In this review, we provide an overview of the currently available treatment options for NSCLC, focusing on EGFR targeted therapy, and discuss the common mechanisms of resistance to EGFR-TKIs. We also review the characteristics of drug-tolerant persister (DTP) cells and the mechanistic basis of drug tolerance in EGFR-mutant NSCLC. Lastly, we address how cellular barcoding can be applied to investigate the response and the behavior of DTP cells upon EGFR-TKI treatment. Full article
(This article belongs to the Special Issue Mechanisms of Acquired Resistance to Targeted Therapy)
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21 pages, 1058 KiB  
Review
Obesity and Cancer: A Current Overview of Epidemiology, Pathogenesis, Outcomes, and Management
by Sukanya Pati, Wadeed Irfan, Ahmad Jameel, Shahid Ahmed and Rabia K. Shahid
Cancers 2023, 15(2), 485; https://doi.org/10.3390/cancers15020485 - 12 Jan 2023
Cited by 113 | Viewed by 13828
Abstract
Background: Obesity or excess body fat is a major global health challenge that has not only been associated with diabetes mellitus and cardiovascular disease but is also a major risk factor for the development of and mortality related to a subgroup of cancer. [...] Read more.
Background: Obesity or excess body fat is a major global health challenge that has not only been associated with diabetes mellitus and cardiovascular disease but is also a major risk factor for the development of and mortality related to a subgroup of cancer. This review focuses on epidemiology, the relationship between obesity and the risk associated with the development and recurrence of cancer and the management of obesity. Methods: A literature search using PubMed and Google Scholar was performed and the keywords ‘obesity’ and cancer’ were used. The search was limited to research papers published in English prior to September 2022 and focused on studies that investigated epidemiology, the pathogenesis of cancer, cancer incidence and the risk of recurrence, and the management of obesity. Results: About 4–8% of all cancers are attributed to obesity. Obesity is a risk factor for several major cancers, including post-menopausal breast, colorectal, endometrial, kidney, esophageal, pancreatic, liver, and gallbladder cancer. Excess body fat results in an approximately 17% increased risk of cancer-specific mortality. The relationship between obesity and the risk associated with the development of cancer and its recurrence is not fully understood and involves altered fatty acid metabolism, extracellular matrix remodeling, the secretion of adipokines and anabolic and sex hormones, immune dysregulation, and chronic inflammation. Obesity may also increase treatment-related adverse effects and influence treatment decisions regarding specific types of cancer therapy. Structured exercise in combination with dietary support and behavior therapy are effective interventions. Treatment with glucagon-like peptide-1 analogues and bariatric surgery result in more rapid weight loss and can be considered in selected cancer survivors. Conclusions: Obesity increases cancer risk and mortality. Weight-reducing strategies in obesity-associated cancers are important interventions as a key component of cancer care. Future studies are warranted to further elucidate the complex relationship between obesity and cancer with the identification of targets for effective interventions. Full article
(This article belongs to the Special Issue Environmental Carcinogenesis)
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13 pages, 521 KiB  
Review
Metastatic Prostate Cancer—A Review of Current Treatment Options and Promising New Approaches
by Philip Posdzich, Christopher Darr, Thomas Hilser, Milan Wahl, Ken Herrmann, Boris Hadaschik and Viktor Grünwald
Cancers 2023, 15(2), 461; https://doi.org/10.3390/cancers15020461 - 11 Jan 2023
Cited by 36 | Viewed by 6835
Abstract
Androgen deprivation therapy (ADT) alone has been the standard of care for many years in men with metastatic prostate cancer. Due to the limited survival under this monotherapy, many new treatment options have been developed in the last few years. Regarding hormone-sensitive prostate [...] Read more.
Androgen deprivation therapy (ADT) alone has been the standard of care for many years in men with metastatic prostate cancer. Due to the limited survival under this monotherapy, many new treatment options have been developed in the last few years. Regarding hormone-sensitive prostate cancer, combination therapies of two or three agents of ADT, androgen receptor signaling inhibitors (ARSI) and chemotherapy have been established and led to a significant benefit in overall survival. Additionally, in patients with metastatic castration-resistant prostate cancer, there are many new therapeutic approaches. Chemotherapy alone has been the standard of care in this situation. In the last years, some new therapeutic options have been developed, which led to an improved survival after progression under chemotherapy. These therapies include ARSI, PARP inhibitors and Lu-PSMA radioligand therapy. The use of a bispecific T-cell engager (BiTE) in this setting is a new promising therapeutic approach, which has not been established as standard of care yet. The role of immunotherapy in prostate cancer is still under investigation. Overall, many new treatment options make prostate cancer therapy a challenging and promising field. Full article
(This article belongs to the Special Issue Novel Therapeutics for Genitourinary Tumors)
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44 pages, 1344 KiB  
Review
DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities
by María Ovejero-Sánchez, Rogelio González-Sarmiento and Ana Belén Herrero
Cancers 2023, 15(2), 448; https://doi.org/10.3390/cancers15020448 - 10 Jan 2023
Cited by 9 | Viewed by 4370
Abstract
The DNA damage response (DDR), a set of signaling pathways for DNA damage detection and repair, maintains genomic stability when cells are exposed to endogenous or exogenous DNA-damaging agents. Alterations in these pathways are strongly associated with cancer development, including ovarian cancer (OC), [...] Read more.
The DNA damage response (DDR), a set of signaling pathways for DNA damage detection and repair, maintains genomic stability when cells are exposed to endogenous or exogenous DNA-damaging agents. Alterations in these pathways are strongly associated with cancer development, including ovarian cancer (OC), the most lethal gynecologic malignancy. In OC, failures in the DDR have been related not only to the onset but also to progression and chemoresistance. It is known that approximately half of the most frequent subtype, high-grade serous carcinoma (HGSC), exhibit defects in DNA double-strand break (DSB) repair by homologous recombination (HR), and current evidence indicates that probably all HGSCs harbor a defect in at least one DDR pathway. These defects are not restricted to HGSCs; mutations in ARID1A, which are present in 30% of endometrioid OCs and 50% of clear cell (CC) carcinomas, have also been found to confer deficiencies in DNA repair. Moreover, DDR alterations have been described in a variable percentage of the different OC subtypes. Here, we overview the main DNA repair pathways involved in the maintenance of genome stability and their deregulation in OC. We also recapitulate the preclinical and clinical data supporting the potential of targeting the DDR to fight the disease. Full article
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25 pages, 1780 KiB  
Review
The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited
by Kevin Dzobo, Dimakatso A. Senthebane and Collet Dandara
Cancers 2023, 15(2), 376; https://doi.org/10.3390/cancers15020376 - 6 Jan 2023
Cited by 54 | Viewed by 7962
Abstract
Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, [...] Read more.
Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation. Full article
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25 pages, 7771 KiB  
Review
Risk Assessment and Pancreatic Cancer: Diagnostic Management and Artificial Intelligence
by Vincenza Granata, Roberta Fusco, Sergio Venanzio Setola, Roberta Galdiero, Nicola Maggialetti, Lucrezia Silvestro, Mario De Bellis, Elena Di Girolamo, Giulia Grazzini, Giuditta Chiti, Maria Chiara Brunese, Andrea Belli, Renato Patrone, Raffaele Palaia, Antonio Avallone, Antonella Petrillo and Francesco Izzo
Cancers 2023, 15(2), 351; https://doi.org/10.3390/cancers15020351 - 5 Jan 2023
Cited by 7 | Viewed by 3416
Abstract
Pancreatic cancer (PC) is one of the deadliest cancers, and it is responsible for a number of deaths almost equal to its incidence. The high mortality rate is correlated with several explanations; the main one is the late disease stage at which the [...] Read more.
Pancreatic cancer (PC) is one of the deadliest cancers, and it is responsible for a number of deaths almost equal to its incidence. The high mortality rate is correlated with several explanations; the main one is the late disease stage at which the majority of patients are diagnosed. Since surgical resection has been recognised as the only curative treatment, a PC diagnosis at the initial stage is believed the main tool to improve survival. Therefore, patient stratification according to familial and genetic risk and the creation of screening protocol by using minimally invasive diagnostic tools would be appropriate. Pancreatic cystic neoplasms (PCNs) are subsets of lesions which deserve special management to avoid overtreatment. The current PC screening programs are based on the annual employment of magnetic resonance imaging with cholangiopancreatography sequences (MR/MRCP) and/or endoscopic ultrasonography (EUS). For patients unfit for MRI, computed tomography (CT) could be proposed, although CT results in lower detection rates, compared to MRI, for small lesions. The actual major limit is the incapacity to detect and characterize the pancreatic intraepithelial neoplasia (PanIN) by EUS and MR/MRCP. The possibility of utilizing artificial intelligence models to evaluate higher-risk patients could favour the diagnosis of these entities, although more data are needed to support the real utility of these applications in the field of screening. For these motives, it would be appropriate to realize screening programs in research settings. Full article
(This article belongs to the Special Issue Diagnostics and Therapeutics Advances in Pancreatic Cancer)
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25 pages, 3043 KiB  
Review
Physical Exercise and the Hallmarks of Breast Cancer: A Narrative Review
by Celia García-Chico, Susana López-Ortiz, Saúl Peñín-Grandes, José Pinto-Fraga, Pedro L. Valenzuela, Enzo Emanuele, Claudia Ceci, Grazia Graziani, Carmen Fiuza-Luces, Simone Lista, Alejandro Lucia and Alejandro Santos-Lozano
Cancers 2023, 15(1), 324; https://doi.org/10.3390/cancers15010324 - 3 Jan 2023
Cited by 14 | Viewed by 8191
Abstract
Growing evidence suggests that, among the different molecular/cellular pathophysiological mechanisms associated with cancer, there are 14 hallmarks that play a major role, including: (i) sustaining proliferative signaling, (ii) evading growth suppressors, (iii) activating invasion and metastasis, (iv) enabling replicative immortality, (v) inducing angiogenesis, [...] Read more.
Growing evidence suggests that, among the different molecular/cellular pathophysiological mechanisms associated with cancer, there are 14 hallmarks that play a major role, including: (i) sustaining proliferative signaling, (ii) evading growth suppressors, (iii) activating invasion and metastasis, (iv) enabling replicative immortality, (v) inducing angiogenesis, (vi) resisting cell death, (vii) reprogramming energy metabolism, (viii) evading immune destruction, (ix) genome instability and mutations, (x) tumor-promoting inflammation, (xi) unlocking phenotypic plasticity, (xii) nonmutational epigenetic reprogramming, (xiii) polymorphic microbiomes, and (xiv) senescent cells. These hallmarks are also associated with the development of breast cancer, which represents the most prevalent tumor type in the world. The present narrative review aims to describe, for the first time, the effects of physical activity/exercise on these hallmarks. In summary, an active lifestyle, and particularly regular physical exercise, provides beneficial effects on all major hallmarks associated with breast cancer, and might therefore help to counteract the progression of the disease or its associated burden. Full article
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28 pages, 1054 KiB  
Review
Immunotherapy for Triple-Negative Breast Cancer: Combination Strategies to Improve Outcome
by Liying Li, Fan Zhang, Zhenyu Liu and Zhimin Fan
Cancers 2023, 15(1), 321; https://doi.org/10.3390/cancers15010321 - 3 Jan 2023
Cited by 26 | Viewed by 6655
Abstract
Due to the absence of hormone receptor (both estrogen receptors and progesterone receptors) along with human epidermal growth factor receptor 2 (HER-2) amplification, the treatment of triple-negative breast cancer (TNBC) cannot benefit from endocrine or anti-HER-2 therapy. For a long time, [...] Read more.
Due to the absence of hormone receptor (both estrogen receptors and progesterone receptors) along with human epidermal growth factor receptor 2 (HER-2) amplification, the treatment of triple-negative breast cancer (TNBC) cannot benefit from endocrine or anti-HER-2 therapy. For a long time, chemotherapy was the only systemic treatment for TNBC. Due to the lack of effective treatment options, the prognosis for TNBC is extremely poor. The successful application of immune checkpoint inhibitors (ICIs) launched the era of immunotherapy in TNBC. However, the current findings show modest efficacy of programmed cell death- (ligand) 1 (PD-(L)1) inhibitors monotherapy and only a small proportion of patients can benefit from this approach. Based on the basic principles of immunotherapy and the characteristics of the tumor immune microenvironment (TIME) in TNBC, immune combination therapy is expected to further enhance the efficacy and expand the beneficiary population of patients. Given the diversity of drugs that can be combined, it is important to select effective biomarkers to identify the target population. Moreover, the side effects associated with the combination of multiple drugs should also be considered. Full article
(This article belongs to the Special Issue Immunotherapy of Triple-Negative Breast Cancer)
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18 pages, 13914 KiB  
Review
Emerging Indications for Interventional Oncology: Expert Discussion on New Locoregional Treatments
by Roberto Iezzi, Afshin Gangi, Alessandro Posa, Uei Pua, Ping Liang, Ernesto Santos, Anil N. Kurup, Alessandro Tanzilli, Lorenzo Tenore, Davide De Leoni, Dimitrios Filippiadis, Felice Giuliante, Vincenzo Valentini, Antonio Gasbarrini, Shraga N. Goldberg, Martijn Meijerink, Riccardo Manfredi, Alexis Kelekis, Cesare Colosimo and David C. Madoff
Cancers 2023, 15(1), 308; https://doi.org/10.3390/cancers15010308 - 2 Jan 2023
Cited by 2 | Viewed by 4188
Abstract
Interventional oncology (IO) employs image-guided techniques to perform minimally invasive procedures, providing lower-risk alternatives to many traditional medical and surgical therapies for cancer patients. Since its advent, due to rapidly evolving research development, its role has expanded to encompass the diagnosis and treatment [...] Read more.
Interventional oncology (IO) employs image-guided techniques to perform minimally invasive procedures, providing lower-risk alternatives to many traditional medical and surgical therapies for cancer patients. Since its advent, due to rapidly evolving research development, its role has expanded to encompass the diagnosis and treatment of diseases across multiple body systems. In detail, interventional oncology is expanding its role across a wide spectrum of disease sites, offering a potential cure, control, or palliative care for many types of cancer patients. Due to its widespread use, a comprehensive review of the new indications for locoregional procedures is mandatory. This article summarizes the expert discussion and report from the “MIOLive Meet SIO” (Society of Interventional Oncology) session during the last MIOLive 2022 (Mediterranean Interventional Oncology Live) congress held in Rome, Italy, integrating evidence-reported literature and experience-based perceptions. The aim of this paper is to provide an updated review of the new techniques and devices available for innovative indications not only to residents and fellows but also to colleagues approaching locoregional treatments. Full article
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20 pages, 1149 KiB  
Review
Current State of Immunotherapy and Mechanisms of Immune Evasion in Ewing Sarcoma and Osteosarcoma
by Valentina Evdokimova, Hendrik Gassmann, Laszlo Radvanyi and Stefan E. G. Burdach
Cancers 2023, 15(1), 272; https://doi.org/10.3390/cancers15010272 - 30 Dec 2022
Cited by 17 | Viewed by 3510
Abstract
We argue here that in many ways, Ewing sarcoma (EwS) is a unique tumor entity and yet, it shares many commonalities with other immunologically cold solid malignancies. From the historical perspective, EwS, osteosarcoma (OS) and other bone and soft-tissue sarcomas were the first [...] Read more.
We argue here that in many ways, Ewing sarcoma (EwS) is a unique tumor entity and yet, it shares many commonalities with other immunologically cold solid malignancies. From the historical perspective, EwS, osteosarcoma (OS) and other bone and soft-tissue sarcomas were the first types of tumors treated with the immunotherapy approach: more than 100 years ago American surgeon William B. Coley injected his patients with a mixture of heat-inactivated bacteria, achieving survival rates apparently higher than with surgery alone. In contrast to OS which exhibits recurrent somatic copy-number alterations, EwS possesses one of the lowest mutation rates among cancers, being driven by a single oncogenic fusion protein, most frequently EWS-FLI1. In spite these differences, both EwS and OS are allied with immune tolerance and low immunogenicity. We discuss here the potential mechanisms of immune escape in these tumors, including low representation of tumor-specific antigens, low expression levels of MHC-I antigen-presenting molecules, accumulation of immunosuppressive M2 macrophages and myeloid proinflammatory cells, and release of extracellular vesicles (EVs) which are capable of reprogramming host cells in the tumor microenvironment and systemic circulation. We also discuss the vulnerabilities of EwS and OS and potential novel strategies for their targeting. Full article
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14 pages, 1645 KiB  
Review
Exploring the Dynamic Crosstalk between the Immune System and Genetics in Gastrointestinal Stromal Tumors
by Alessandra Dimino, Chiara Brando, Laura Algeri, Valerio Gristina, Erika Pedone, Marta Peri, Alessandro Perez, Ida De Luca, Roberta Sciacchitano, Luigi Magrin, Tancredi Didier Bazan Russo, Marco Bono, Nadia Barraco, Silvia Contino, Maria La Mantia, Antonio Galvano, Giuseppe Badalamenti, Antonio Russo, Viviana Bazan and Lorena Incorvaia
Cancers 2023, 15(1), 216; https://doi.org/10.3390/cancers15010216 - 29 Dec 2022
Cited by 7 | Viewed by 1753
Abstract
Gastrointestinal Stromal Tumors (GISTs) represent a paradigmatic model of oncogene addiction. Despite the well-known impact of the mutational status on clinical outcomes, we need to expand our knowledge to other factors that influence behavior heterogeneity in GIST patients. A growing body of studies [...] Read more.
Gastrointestinal Stromal Tumors (GISTs) represent a paradigmatic model of oncogene addiction. Despite the well-known impact of the mutational status on clinical outcomes, we need to expand our knowledge to other factors that influence behavior heterogeneity in GIST patients. A growing body of studies has revealed that the tumor microenvironment (TME), mostly populated by tumor-associated macrophages (TAMs) and lymphocytes (TILs), and stromal differentiation (SD) have a significant impact on prognosis and response to treatment. Interestingly, even though the current knowledge of the role of immune response in this setting is still limited, recent pre-clinical and clinical data have highlighted the relevance of the TME in GISTs, with possible implications for clinical practice in the near future. Moreover, the expression of immune checkpoints, such as PD-L1, PD-1, and CTLA-4, and their relationship to the clinical phenotype in GIST are emerging as potential prognostic biomarkers. Looking forward, these variables related to the underlying tumoral microenvironment in GIST, though limited to still-ongoing trials, might lead to the potential use of immunotherapy, alone or in combination with targeted therapy, in advanced TKI-refractory GISTs. This review aims to deepen understanding of the potential link between mutational status and the immune microenvironment in GIST. Full article
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21 pages, 5981 KiB  
Article
Single-Cell Transcriptomic Profiles of Lung Pre-Metastatic Niche Reveal Neutrophil and Lymphatic Endothelial Cell Roles in Breast Cancer
by Yung-Chi Huang, Chao-Yuan Chang, Yu-Yuan Wu, Kuan-Li Wu, Ying-Ming Tsai, Hsiao-Chen Lee, Eing-Mei Tsai and Ya-Ling Hsu
Cancers 2023, 15(1), 176; https://doi.org/10.3390/cancers15010176 - 28 Dec 2022
Cited by 3 | Viewed by 4307
Abstract
The establishment of a pre-metastatic niche (PMN) is critical for cancer metastasis. However, it remains unclear as to which phenotypes induce changes in the PMN. Single-cell transcriptomic profiling of all cells of the lung in cancer-bearing MMTV-PyVT mice revealed an increased infiltration of [...] Read more.
The establishment of a pre-metastatic niche (PMN) is critical for cancer metastasis. However, it remains unclear as to which phenotypes induce changes in the PMN. Single-cell transcriptomic profiling of all cells of the lung in cancer-bearing MMTV-PyVT mice revealed an increased infiltration of N2-type neutrophils and classical monocytes associated with chronic inflammation; notably, lung neutrophils isolated from mice with primary cancer exhibited similar N2-type phenotypes and expressed high levels of inflammatory and angiogenic factors. We also discovered a new cluster of Ki67-upregulated lymphatic endothelial cells (ECs) that activated several cell division-related pathways. Receptor–ligand interactions within the lung potentially mediated PMN formation; these were exemplified by the cross talk of lymphatic EC–N2-type neutrophil via S100A6. In vitro study revealed S100A6 impaired EC tight junction and increased the transendothelial migration of neutrophils. Our results highlight the molecular mechanisms that shape lung PMN and inspire preventive strategies for lung metastasis in breast cancer. Full article
(This article belongs to the Section Molecular Cancer Biology)
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19 pages, 3444 KiB  
Article
BRAF and MEK Inhibitors and Their Toxicities: A Meta-Analysis
by Mattia Garutti, Melissa Bergnach, Jerry Polesel, Lorenza Palmero, Maria Antonietta Pizzichetta and Fabio Puglisi
Cancers 2023, 15(1), 141; https://doi.org/10.3390/cancers15010141 - 26 Dec 2022
Cited by 23 | Viewed by 3712
Abstract
Purpose: This meta-analysis summarizes the incidence of treatment-related adverse events (AE) of BRAFi and MEKi. Methods: A systematic search of Medline/PubMed was conducted to identify suitable articles published in English up to 31 December 2021. The primary outcomes were profiles for all-grade and [...] Read more.
Purpose: This meta-analysis summarizes the incidence of treatment-related adverse events (AE) of BRAFi and MEKi. Methods: A systematic search of Medline/PubMed was conducted to identify suitable articles published in English up to 31 December 2021. The primary outcomes were profiles for all-grade and grade 3 or higher treatment-related AEs, and the analysis of single side effects belonging to both categories. Results: The overall incidence of treatment-related all-grade Aes was 99% for Encorafenib (95% CI: 0.97–1.00) and 97% for Trametinib (95% CI: 0.92–0.99; I2 = 66%) and Binimetinib (95% CI: 0.94–0.99; I2 = 0%). In combined therapies, the rate was 98% for both Vemurafenib + Cobimetinib (95% CI: 0.96–0.99; I2 = 77%) and Encorafenib + Binimetinib (95% CI: 0.96–1.00). Grade 3 or higher adverse events were reported in 69% of cases for Binimetinib (95% CI: 0.50–0.84; I2 = 71%), 68% for Encorafenib (95% CI: 0.61–0.74), and 72% for Vemurafenib + Cobimetinib (95% CI: 0.65–0.79; I2 = 84%). The most common grade 1–2 AEs were pyrexia (43%) and fatigue (28%) for Dabrafenib + Trametinib and diarrhea for both Vemurafenib + Cobimetinib (52%) and Encorafenib + Binimetinib (34%). The most common AEs of grade 3 or higher were pyrexia, rash, and hypertension for Dabrafenib + Trametinib (6%), rash and hypertension for Encorafenib + Binimetinib (6%), and increased AST and ALT for Vemurafenib + Cobimetinib (10%). Conclusions: Our study provides comprehensive data on treatment-related adverse events of BRAFi and MEKi combination therapies, showing related toxicity profiles to offer a helpful tool for clinicians in the choice of therapy. Full article
(This article belongs to the Special Issue Side Effects of Anticancer Therapy: Prevention and Management)
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27 pages, 1386 KiB  
Review
CAR-NK as a Rapidly Developed and Efficient Immunotherapeutic Strategy against Cancer
by Marta Włodarczyk and Beata Pyrzynska
Cancers 2023, 15(1), 117; https://doi.org/10.3390/cancers15010117 - 24 Dec 2022
Cited by 11 | Viewed by 7126
Abstract
Chimeric antigen receptor (CAR)-modified T cell therapy has been rapidly developing in recent years, ultimately revolutionizing immunotherapeutic strategies and providing significant anti-tumor potency, mainly in treating hematological neoplasms. However, graft-versus-host disease (GVHD) and other adverse effects, such as cytokine release syndromes (CRS) and [...] Read more.
Chimeric antigen receptor (CAR)-modified T cell therapy has been rapidly developing in recent years, ultimately revolutionizing immunotherapeutic strategies and providing significant anti-tumor potency, mainly in treating hematological neoplasms. However, graft-versus-host disease (GVHD) and other adverse effects, such as cytokine release syndromes (CRS) and neurotoxicity associated with CAR-T cell infusion, have raised some concerns about the broad application of this therapy. Natural killer (NK) cells have been identified as promising alternative platforms for CAR-based therapies because of their unique features, such as a lack of human leukocyte antigen (HLA)-matching restriction, superior safety, and better anti-tumor activity when compared with CAR-T cells. The lack of CRS, neurotoxicity, or GVHD, in the case of CAR-NK therapy, in addition to the possibility of using allogeneic NK cells as a CAR platform for “off-the-shelf” therapy, opens new windows for strategic opportunities. This review underlines recent design achievements in CAR constructs and summarizes preclinical studies’ results regarding CAR-NK therapies’ safety and anti-tumor potency. Additionally, new approaches in CAR-NK technology are briefly described, and currently registered clinical trials are listed. Full article
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32 pages, 3691 KiB  
Article
Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand
by M. Isabel Acuña, Ana R. Rubio, Marta Martínez-Alonso, Natalia Busto, Ana María Rodríguez, Nerea Davila-Ferreira, Carl Smythe, Gustavo Espino, Begoña García and Fernando Domínguez
Cancers 2023, 15(1), 107; https://doi.org/10.3390/cancers15010107 - 24 Dec 2022
Cited by 4 | Viewed by 3750
Abstract
Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular [...] Read more.
Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III) complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes, especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new compounds to exploit this vulnerability. Full article
(This article belongs to the Special Issue Advances in Anticancer Drugs and Pharmacotherapy of Cancer)
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19 pages, 801 KiB  
Review
Role of Machine Learning in Precision Oncology: Applications in Gastrointestinal Cancers
by Azadeh Tabari, Shin Mei Chan, Omar Mustafa Fathy Omar, Shams I. Iqbal, Michael S. Gee and Dania Daye
Cancers 2023, 15(1), 63; https://doi.org/10.3390/cancers15010063 - 22 Dec 2022
Cited by 16 | Viewed by 5459
Abstract
Gastrointestinal (GI) cancers, consisting of a wide spectrum of pathologies, have become a prominent health issue globally. Despite medical imaging playing a crucial role in the clinical workflow of cancers, standard evaluation of different imaging modalities may provide limited information. Accurate tumor detection, [...] Read more.
Gastrointestinal (GI) cancers, consisting of a wide spectrum of pathologies, have become a prominent health issue globally. Despite medical imaging playing a crucial role in the clinical workflow of cancers, standard evaluation of different imaging modalities may provide limited information. Accurate tumor detection, characterization, and monitoring remain a challenge. Progress in quantitative imaging analysis techniques resulted in ”radiomics”, a promising methodical tool that helps to personalize diagnosis and treatment optimization. Radiomics, a sub-field of computer vision analysis, is a bourgeoning area of interest, especially in this era of precision medicine. In the field of oncology, radiomics has been described as a tool to aid in the diagnosis, classification, and categorization of malignancies and to predict outcomes using various endpoints. In addition, machine learning is a technique for analyzing and predicting by learning from sample data, finding patterns in it, and applying it to new data. Machine learning has been increasingly applied in this field, where it is being studied in image diagnosis. This review assesses the current landscape of radiomics and methodological processes in GI cancers (including gastric, colorectal, liver, pancreatic, neuroendocrine, GI stromal, and rectal cancers). We explain in a stepwise fashion the process from data acquisition and curation to segmentation and feature extraction. Furthermore, the applications of radiomics for diagnosis, staging, assessment of tumor prognosis and treatment response according to different GI cancer types are explored. Finally, we discussed the existing challenges and limitations of radiomics in abdominal cancers and investigate future opportunities. Full article
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12 pages, 1091 KiB  
Article
Low-Energy X-Ray Intraoperative Radiation Therapy (Lex-IORT) for Resected Brain Metastases: A Single-Institution Experience
by Christian D. Diehl, Steffi U. Pigorsch, Jens Gempt, Sandro M. Krieg, Silvia Reitz, Maria Waltenberger, Melanie Barz, Hanno S. Meyer, Arthur Wagner, Jan Wilkens, Benedikt Wiestler, Claus Zimmer, Bernhard Meyer and Stephanie E. Combs
Cancers 2023, 15(1), 14; https://doi.org/10.3390/cancers15010014 - 20 Dec 2022
Cited by 11 | Viewed by 1793
Abstract
Background: Resection followed by local radiation therapy (RT) is the standard of care for symptomatic brain metastases. However, the optimal technique, fractionation scheme and dose are still being debated. Lately, low-energy X-ray intraoperative RT (lex-IORT) has been of increasing interest. Method: Eighteen consecutive [...] Read more.
Background: Resection followed by local radiation therapy (RT) is the standard of care for symptomatic brain metastases. However, the optimal technique, fractionation scheme and dose are still being debated. Lately, low-energy X-ray intraoperative RT (lex-IORT) has been of increasing interest. Method: Eighteen consecutive patients undergoing BM resection followed by immediate lex-IORT with 16–30 Gy applied to the spherical applicator were retrospectively analyzed. Demographic, RT-specific, radiographic and clinical data were reviewed to evaluate the effectiveness and safety of IORT for BM. Descriptive statistics and Kaplan–Meyer analysis were applied. Results: The mean follow-up time was 10.8 months (range, 0–39 months). The estimated local control (LC), distant brain control (DBC) and overall survival (OS) at 12 months post IORT were 92.9% (95%-CI 79.3–100%), 71.4% (95%-CI 50.2–92.6%) and 58.0% (95%-CI 34.1–81.9%), respectively. Two patients developed radiation necrosis (11.1%) and wound infection (CTCAE grade III); both had additional adjuvant treatment after IORT. For five patients (27.8%), the time to the start or continuation of systemic treatment was ≤15 days and hence shorter than wound healing and adjuvant RT would have required. Conclusion: In accordance with previous series, this study demonstrates the effectiveness and safety of IORT in the management of brain metastases despite the small cohort and the retrospective characteristic of this analysis. Full article
(This article belongs to the Special Issue Advances in Modern Radiation Oncology)
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18 pages, 2854 KiB  
Review
Liver Microenvironment Response to Prostate Cancer Metastasis and Hormonal Therapy
by Alison K. Buxton, Salma Abbasova, Charlotte L. Bevan and Damien A. Leach
Cancers 2022, 14(24), 6189; https://doi.org/10.3390/cancers14246189 - 15 Dec 2022
Cited by 6 | Viewed by 3492
Abstract
Prostate cancer-associated deaths arise from disease progression and metastasis. Metastasis to the liver is associated with the worst clinical outcomes for prostate cancer patients, and these metastatic tumors can be particularly resistant to the currently widely used chemotherapy and hormonal therapies, such as [...] Read more.
Prostate cancer-associated deaths arise from disease progression and metastasis. Metastasis to the liver is associated with the worst clinical outcomes for prostate cancer patients, and these metastatic tumors can be particularly resistant to the currently widely used chemotherapy and hormonal therapies, such as anti-androgens which block androgen synthesis or directly target the androgen receptor. The incidence of liver metastases is reportedly increasing, with a potential correlation with use of anti-androgen therapies. A key player in prostate cancer progression and therapeutic response is the microenvironment of the tumor(s). This is a dynamic and adaptive collection of cells and proteins, which impart signals and stimuli that can alter biological processes within prostate cancer cells. Investigation in the prostate primary site has demonstrated that cells of the microenvironment are also responsive to hormones and hormonal therapies. In this review, we collate information about what happens when cancer moves to the liver: the types of prostate cancer cells that metastasize there, the response of resident mesenchymal cells of the liver, and how the interactions between the cancer cells and the microenvironment may be altered by hormonal therapy. Full article
(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)
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17 pages, 2313 KiB  
Article
TP53 Co-Mutation Status Association with Clinical Outcomes in Patients with EGFR-Mutant Non-Small Cell Lung Cancer
by Xiuning Le, Cliff Molife, Mark S. Leusch, Maria Teresa Rizzo, Patrick M. Peterson, Nicola Caria, Yongmei Chen, Elena Gonzalez Gugel and Carla Visseren-Grul
Cancers 2022, 14(24), 6127; https://doi.org/10.3390/cancers14246127 - 12 Dec 2022
Cited by 8 | Viewed by 2161
Abstract
TP53 co-mutations have shown association with poor prognosis in various solid tumors. For EGFR-mutated advanced non-small cell lung cancer (aNSCLC), conflicting results exist regarding its impact on survival. Clinical outcomes and genomic data were obtained retrospectively from the real-world (rw) de-identified clinicogenomic [...] Read more.
TP53 co-mutations have shown association with poor prognosis in various solid tumors. For EGFR-mutated advanced non-small cell lung cancer (aNSCLC), conflicting results exist regarding its impact on survival. Clinical outcomes and genomic data were obtained retrospectively from the real-world (rw) de-identified clinicogenomic database. Patients who initiated therapy for EGFR-mutated aNSCLC between January 2014 and December 2020 were identified. Clinical outcomes were evaluated by TP53-mutational status. In 356 eligible EGFR-mutated aNSCLC patients (median age 68 years), 210 (59.0%) had TP53 co-mutation and 146 (41.0%) had TP53 wild-type tumor. Unadjusted analysis showed significantly shorter survival in patients with TP53 co-mutation versus TP53 wild-type (rw progression-free survival [rwPFS]: HR = 1.4, 95% CI 1.1–1.9, p = 0.0196; overall survival [OS]: HR = 1.6, 95% CI 1.1–2.2, p = 0.0088). Multivariable analysis confirmed independent association between TP53 co-mutation and worse rwPFS (HR = 1.4, 95% CI 1.0–0.9, p = 0.0280) and OS (HR = 1.4, 95% CI 1.0–2.0, p = 0.0345). Directionally consistent findings were observed for response rates, and subgroups by EGFR-activating mutation and first-line (1 L) therapy, with more pronounced negative effect in 1 L EGFR-TKI subgroup. TP53 co-mutations negatively affected survival in patients with EGFR-mutated aNSCLC receiving standard 1 L therapy in real-world practice. Full article
(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)
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16 pages, 1610 KiB  
Article
Dual NGS Comparative Analysis of Liquid Biopsy (LB) and Formalin-Fixed Paraffin-Embedded (FFPE) Samples of Non-Small Cell Lung Carcinoma (NSCLC)
by Laura Buburuzan, Maria-Anca Zamfir (Irofei), Carmen Maria Ardeleanu, Alin Horatiu Muresan, Florina Vasilescu, Ariana Hudita, Marieta Costache, Bianca Galateanu, Alexandra Puscasu, Alexandru Filippi and Natalia Motas
Cancers 2022, 14(24), 6084; https://doi.org/10.3390/cancers14246084 - 10 Dec 2022
Viewed by 3199
Abstract
Lung cancer ranks second worldwide after breast cancer and third in Europe after breast and colorectal cancers when both sexes and all ages are considered. In this context, the aim of this study was to emphasize the power of dual analysis of the [...] Read more.
Lung cancer ranks second worldwide after breast cancer and third in Europe after breast and colorectal cancers when both sexes and all ages are considered. In this context, the aim of this study was to emphasize the power of dual analysis of the molecular profile both in tumor tissue and plasma by NGS assay as a liquid biopsy approach with impact on prognosis and therapy modulation in NSCLC patients. NGS analysis was performed both from tissue biopsies and from cfNAs isolated from peripheral blood samples. Out of all 29 different mutations detectable by both NGS panels (plasma and tumor tissue), seven different variants (24.13%; EGFR L858R in two patients, KRAS G13D and Q61H and TP53 G244D, V197M, R213P, and R273H) were detected only in plasma and not in the tumor itself. These mutations were detected in seven different patients, two of them having known distant organ metastasis. Our data show that NGS analysis of cfDNA could identify actionable mutations in advanced NSCLC and, therefore, this analysis could be used to monitor the disease progression and the treatment response and even to modulate the therapy in real time. Full article
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56 pages, 2099 KiB  
Review
Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?
by Mariana Tannoury, Delphine Garnier, Santos A. Susin and Brigitte Bauvois
Cancers 2022, 14(24), 6026; https://doi.org/10.3390/cancers14246026 - 7 Dec 2022
Cited by 4 | Viewed by 4141
Abstract
Resistance to death is one of the hallmarks of human B cell malignancies and often contributes to the lack of a lasting response to today’s commonly used treatments. Drug discovery approaches designed to activate the death machinery have generated a large number of [...] Read more.
Resistance to death is one of the hallmarks of human B cell malignancies and often contributes to the lack of a lasting response to today’s commonly used treatments. Drug discovery approaches designed to activate the death machinery have generated a large number of inhibitors of anti-apoptotic proteins from the B-cell lymphoma/leukemia 2 family and the B-cell receptor (BCR) signaling pathway. Orally administered small-molecule inhibitors of Bcl-2 protein and BCR partners (e.g., Bruton’s tyrosine kinase and phosphatidylinositol-3 kinase) have already been included (as monotherapies or combination therapies) in the standard of care for selected B cell malignancies. Agonistic monoclonal antibodies and their derivatives (antibody–drug conjugates, antibody–radioisotope conjugates, bispecific T cell engagers, and chimeric antigen receptor-modified T cells) targeting tumor-associated antigens (TAAs, such as CD19, CD20, CD22, and CD38) are indicated for treatment (as monotherapies or combination therapies) of patients with B cell tumors. However, given that some patients are either refractory to current therapies or relapse after treatment, novel therapeutic strategies are needed. Here, we review current strategies for managing B cell malignancies, with a focus on the ongoing clinical development of more effective, selective drugs targeting these molecules, as well as other TAAs and signaling proteins. The observed impact of metabolic reprogramming on B cell pathophysiology highlights the promise of targeting metabolic checkpoints in the treatment of these disorders. Full article
(This article belongs to the Section Cancer Biomarkers)
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39 pages, 8167 KiB  
Article
Integrating Pharmacogenomics Data-Driven Computational Drug Prediction with Single-Cell RNAseq to Demonstrate the Efficacy of a NAMPT Inhibitor against Aggressive, Taxane-Resistant, and Stem-like Cells in Lethal Prostate Cancer
by Suman Mazumder, Taraswi Mitra Ghosh, Ujjal K. Mukherjee, Sayak Chakravarti, Farshad Amiri, Razan S. Waliagha, Farnaz Hemmati, Panagiotis Mistriotis, Salsabil Ahmed, Isra Elhussin, Ahmad-Bin Salam, Windy Dean-Colomb, Clayton Yates, Robert D. Arnold and Amit K. Mitra
Cancers 2022, 14(23), 6009; https://doi.org/10.3390/cancers14236009 - 6 Dec 2022
Cited by 4 | Viewed by 3778
Abstract
Metastatic prostate cancer/PCa is the second leading cause of cancer deaths in US men. Most early-stage PCa are dependent on overexpression of the androgen receptor (AR) and, therefore, androgen deprivation therapies/ADT-sensitive. However, eventual resistance to standard medical castration (AR-inhibitors) and secondary chemotherapies (taxanes) [...] Read more.
Metastatic prostate cancer/PCa is the second leading cause of cancer deaths in US men. Most early-stage PCa are dependent on overexpression of the androgen receptor (AR) and, therefore, androgen deprivation therapies/ADT-sensitive. However, eventual resistance to standard medical castration (AR-inhibitors) and secondary chemotherapies (taxanes) is nearly universal. Further, the presence of cancer stem-like cells (EMT/epithelial-to-mesenchymal transdifferentiation) and neuroendocrine PCa (NEPC) subtypes significantly contribute to aggressive/lethal/advanced variants of PCa (AVPC). In this study, we introduced a pharmacogenomics data-driven optimization-regularization-based computational prediction algorithm (“secDrugs”) to predict novel drugs against lethal PCa. Integrating secDrug with single-cell RNA-sequencing/scRNAseq as a ‘Double-Hit’ drug screening tool, we demonstrated that single-cells representing drug-resistant and stem-cell-like cells showed high expression of the NAMPT pathway genes, indicating potential efficacy of the secDrug FK866 which targets NAMPT. Next, using several cell-based assays, we showed substantial impact of FK866 on clinically advanced PCa as a single agent and in combination with taxanes or AR-inhibitors. Bulk-RNAseq and scRNAseq revealed that, in addition to NAMPT inhibition, FK866 regulates tumor metastasis, cell migration, invasion, DNA repair machinery, redox homeostasis, autophagy, as well as cancer stemness–related genes, HES1 and CD44. Further, we combined a microfluidic chip-based cell migration assay with a traditional cell migration/‘scratch’ assay and demonstrated that FK866 reduces cancer cell invasion and motility, indicating abrogation of metastasis. Finally, using PCa patient datasets, we showed that FK866 is potentially capable of reversing the expression of several genes associated with biochemical recurrence, including IFITM3 and LTB4R. Thus, using FK866 as a proof-of-concept candidate for drug repurposing, we introduced a novel, universally applicable preclinical drug development pipeline to circumvent subclonal aggressiveness, drug resistance, and stemness in lethal PCa. Full article
(This article belongs to the Special Issue Prostate Cancer: Pathophysiology, Pathology and Therapy)
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30 pages, 1375 KiB  
Review
Efficacy, Safety, and Challenges of CAR T-Cells in the Treatment of Solid Tumors
by Qiuqiang Chen, Lingeng Lu and Wenxue Ma
Cancers 2022, 14(23), 5983; https://doi.org/10.3390/cancers14235983 - 3 Dec 2022
Cited by 8 | Viewed by 3591
Abstract
Immunotherapy has been the fifth pillar of cancer treatment in the past decade. Chimeric antigen receptor (CAR) T-cell therapy is a newly designed adoptive immunotherapy that is able to target and further eliminate cancer cells by engaging with MHC-independent tumor-antigens. CAR T-cell therapy [...] Read more.
Immunotherapy has been the fifth pillar of cancer treatment in the past decade. Chimeric antigen receptor (CAR) T-cell therapy is a newly designed adoptive immunotherapy that is able to target and further eliminate cancer cells by engaging with MHC-independent tumor-antigens. CAR T-cell therapy has exhibited conspicuous clinical efficacy in hematological malignancies, but more than half of patients will relapse. Of note, the efficacy of CAR T-cell therapy has been even more disappointing in solid tumors. These challenges mainly include (1) the failures of CAR T-cells to treat highly heterogeneous solid tumors due to the difficulty in identifying unique tumor antigen targets, (2) the expression of target antigens in non-cancer cells, (3) the inability of CAR T-cells to effectively infiltrate solid tumors, (4) the short lifespan and lack of persistence of CAR T-cells, and (5) cytokine release syndrome and neurotoxicity. In combination with these characteristics, the ideal CAR T-cell therapy for solid tumors should maintain adequate T-cell response over a long term while sparing healthy tissues. This article reviewed the status, clinical application, efficacy, safety, and challenges of CAR T-cell therapies, as well as the latest progress of CAR T-cell therapies for solid tumors. In addition, the potential strategies to improve the efficacy of CAR T-cells and prevent side effects in solid tumors were also explored. Full article
(This article belongs to the Special Issue Cytokines in Clinical Cancer Immunotherapy)
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9 pages, 246 KiB  
Review
Circulating Human Papillomavirus DNA in Head and Neck Squamous Cell Carcinoma: Possible Applications and Future Directions
by Dauren Adilbay, Saudamini Lele, John Pang, Ameya Asarkar, Jason Calligas and Cherie-Ann Nathan
Cancers 2022, 14(23), 5946; https://doi.org/10.3390/cancers14235946 - 1 Dec 2022
Cited by 11 | Viewed by 1786
Abstract
There has been a rising trend in HPV-induced head and neck cancers in the last several decades. This subgroup of squamous cell carcinoma is mostly located in the oropharynx and comprises a subset of patients who are typically younger and without the usual [...] Read more.
There has been a rising trend in HPV-induced head and neck cancers in the last several decades. This subgroup of squamous cell carcinoma is mostly located in the oropharynx and comprises a subset of patients who are typically younger and without the usual risk factors of smoking and alcohol use. As the prognosis of HPV-induced OPC is more favorable, there is a desire to properly select these patients for de-intensification protocols while identifying individuals who may suffer treatment failure. Here, we describe recent developments in circulating tumor HPV DNA as a marker of HPV-positive oropharyngeal cancer that can potentially be used as a diagnostic tool to stratify patients for de-escalation strategies and to survey for recurrence. Full article
(This article belongs to the Special Issue Epidemiology of HPV-Associated Oropharyngeal Squamous Cell Carcinoma)
15 pages, 4023 KiB  
Article
Regression of Lung Cancer in Mice by Intranasal Administration of SARS-CoV-2 Spike S1
by Monica Sheinin, Brian Jeong, Ramesh K. Paidi and Kalipada Pahan
Cancers 2022, 14(22), 5648; https://doi.org/10.3390/cancers14225648 - 17 Nov 2022
Cited by 12 | Viewed by 8128
Abstract
This study underlines the importance of SARS-CoV-2 spike S1 in prompting death in cultured non-small cell lung cancer (NSCLC) cells and in vivo in lung tumors in mice. Interestingly, we found that recombinant spike S1 treatment at very low doses led to death [...] Read more.
This study underlines the importance of SARS-CoV-2 spike S1 in prompting death in cultured non-small cell lung cancer (NSCLC) cells and in vivo in lung tumors in mice. Interestingly, we found that recombinant spike S1 treatment at very low doses led to death of human A549 NSCLC cells. On the other hand, boiled recombinant SARS-CoV-2 spike S1 remained unable to induce death, suggesting that the induction of cell death in A549 cells was due to native SARS-CoV-2 spike S1 protein. SARS-CoV-2 spike S1-induced A549 cell death was also inhibited by neutralizing antibodies against spike S1 and ACE2. Moreover, our newly designed wild type ACE2-interacting domain of SARS-CoV-2 (wtAIDS), but not mAIDS, peptide also attenuated SARS-CoV-2 spike S1-induced cell death, suggesting that SARS-CoV-2 spike S1-induced death in A549 NSCLC cells depends on its interaction with ACE2 receptor. Similarly, recombinant spike S1 treatment also led to death of human H1299 and H358 NSCLC cells. Finally, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) intoxication led to the formation tumors in lungs of A/J mice and alternate day intranasal treatment with low dose of recombinant SARS-CoV-2 spike S1 from 22-weeks of NNK insult (late stage) induced apoptosis and tumor regression in the lungs. These studies indicate that SARS-CoV-2 spike S1 may have implications for lung cancer treatment. Full article
(This article belongs to the Section Cancer Therapy)
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19 pages, 4696 KiB  
Article
Gambogic Acid Induces Pyroptosis of Colorectal Cancer Cells through the GSDME-Dependent Pathway and Elicits an Antitumor Immune Response
by Hanjie Xu, Danya Zhang, Rui Wei, Ying Zhou, Geyang Dai, Jie Li, Yue Sun, Fei Li and Ling Xi
Cancers 2022, 14(22), 5505; https://doi.org/10.3390/cancers14225505 - 9 Nov 2022
Cited by 15 | Viewed by 2543
Abstract
Pyroptosis is a recently identified form of programmed cell death (PCD) that exerts a vital influence on the antitumor immune response. GA, a xanthone structure isolated from gamboge resin, is a naturally occurring bioactive ingredient with several anticancer activities, such as activities that [...] Read more.
Pyroptosis is a recently identified form of programmed cell death (PCD) that exerts a vital influence on the antitumor immune response. GA, a xanthone structure isolated from gamboge resin, is a naturally occurring bioactive ingredient with several anticancer activities, such as activities that affect cell cycle arrest, apoptosis, and autophagy. Here, we found that GA decreased the viability of the CRC cell lines, HCT116 and CT26, in a dose- and time-dependent manner, and multiple pores and large bubbles in the membranes, which are morphological characteristics of pyroptosis, were observed by light microscopy and transmission electron microscopy (TEM). Furthermore, the cleavage of gasdermin E (GSDME) was observed after exposure to GA, along with concomitant activation of caspase-3. Additionally, GSDME-dependent pyroptosis triggered by GA could be attenuated by siRNA-mediated knockdown of GSDME and treatment with the caspase-3 inhibitor. Moreover, we found that GA induced pyroptosis and significantly inhibited tumor growth in CT26 tumor-bearing mice. Strikingly, significantly increased proportions of CD3+ T cells, cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs) were observed in the tumor microenvironment in the GA-treated groups. Moreover, significantly increased proportions of CTLs and effector memory T cells (TEM) (CD8+ CD44+ CD62L) were also detected in the spleens of the GA-treated groups, suggesting that the pyroptosis-induced immune response generated a robust memory response that mediated protective immunity. In this study, we revealed a previously unrecognized mechanism by which GA induces GSDME-dependent pyroptosis and enhances the anticancer immune response. Based on this mechanism, GA is a promising antitumor drug for CRC treatment that induces caspase-3-GSDME-dependent pyroptosis. This study provides novel insight into cancer chemoimmunotherapy. Full article
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10 pages, 514 KiB  
Article
Global Association of COVID-19 Pandemic Measures with Cancer Treatment: A Systematic Review and Meta-Analysis
by Federica Teglia, Marco Angelini, Giulia Casolari, Laura Astolfi and Paolo Boffetta
Cancers 2022, 14(22), 5490; https://doi.org/10.3390/cancers14225490 - 8 Nov 2022
Cited by 11 | Viewed by 1567
Abstract
Importance: The COVID-19 pandemic has put a serious strain on health services, including cancer treatment. Objective: This study aimed to investigate the changes in cancer treatment worldwide during the first phase of the SARS-CoV-2 outbreak. Data Sources: Pubmed, Proquest, and Scopus databases were [...] Read more.
Importance: The COVID-19 pandemic has put a serious strain on health services, including cancer treatment. Objective: This study aimed to investigate the changes in cancer treatment worldwide during the first phase of the SARS-CoV-2 outbreak. Data Sources: Pubmed, Proquest, and Scopus databases were searched comprehensively for articles published between 1 January 2020 and 12 December 2021, in order to perform a systematic review and meta-analysis conducted following the PRISMA statement. Study Selection: Studies and articles that reported data on the number of or variation in cancer treatments between the pandemic and pre-pandemic periods, comprising oncological surgery, radiotherapy, and systemic therapies, were included. Data Extraction and Synthesis: Data were extracted from two pairs of independent reviewers. The weighted average of the percentage variation was calculated between the two periods to assess the change in the number of cancer treatments performed during the pandemic. Stratified analyses were performed by type of treatment, geographic area, time period, study setting, and type of cancer. Results: Among the 47 articles retained, we found an overall reduction of −18.7% (95% CI, −24.1 to −13.3) in the total number of cancer treatments administered during the COVID-19 pandemic compared to the previous periods. Surgical treatment had a larger decrease compared to medical treatment (−33.9% versus −12.6%). For all three types of treatments, we identified a U-shaped temporal trend during the entire period January–October 2020. Significant decreases were also identified for different types of cancer, in particular for skin cancer (−34.7% [95% CI, −46.8 to −22.5]) and for all geographic areas, in particular, Asia (−42.1% [95% CI, −49.6 to −34.7]). Conclusions and Relevance: The interruption, delay, and modifications to cancer treatment due to the COVID-19 pandemic are expected to alter the quality of care and patient outcomes. Full article
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18 pages, 1880 KiB  
Article
An Effective Method for Lung Cancer Diagnosis from CT Scan Using Deep Learning-Based Support Vector Network
by Imran Shafi, Sadia Din, Asim Khan, Isabel De La Torre Díez, Ramón del Jesús Palí Casanova, Kilian Tutusaus Pifarre and Imran Ashraf
Cancers 2022, 14(21), 5457; https://doi.org/10.3390/cancers14215457 - 6 Nov 2022
Cited by 35 | Viewed by 8899
Abstract
The diagnosis of early-stage lung cancer is challenging due to its asymptomatic nature, especially given the repeated radiation exposure and high cost of computed tomography(CT). Examining the lung CT images to detect pulmonary nodules, especially the cell lung cancer lesions, is also tedious [...] Read more.
The diagnosis of early-stage lung cancer is challenging due to its asymptomatic nature, especially given the repeated radiation exposure and high cost of computed tomography(CT). Examining the lung CT images to detect pulmonary nodules, especially the cell lung cancer lesions, is also tedious and prone to errors even by a specialist. This study proposes a cancer diagnostic model based on a deep learning-enabled support vector machine (SVM). The proposed computer-aided design (CAD) model identifies the physiological and pathological changes in the soft tissues of the cross-section in lung cancer lesions. The model is first trained to recognize lung cancer by measuring and comparing the selected profile values in CT images obtained from patients and control patients at their diagnosis. Then, the model is tested and validated using the CT scans of both patients and control patients that are not shown in the training phase. The study investigates 888 annotated CT scans from the publicly available LIDC/IDRI database. The proposed deep learning-assisted SVM-based model yields 94% accuracy for pulmonary nodule detection representing early-stage lung cancer. It is found superior to other existing methods including complex deep learning, simple machine learning, and the hybrid techniques used on lung CT images for nodule detection. Experimental results demonstrate that the proposed approach can greatly assist radiologists in detecting early lung cancer and facilitating the timely management of patients. Full article
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43 pages, 2814 KiB  
Review
Physical Activity as the Best Supportive Care in Cancer: The Clinician’s and the Researcher’s Perspectives
by Cécile Torregrosa, Frédéric Chorin, Eva Ester Molina Beltran, Cindy Neuzillet and Victoire Cardot-Ruffino
Cancers 2022, 14(21), 5402; https://doi.org/10.3390/cancers14215402 - 2 Nov 2022
Cited by 13 | Viewed by 7477
Abstract
Multidisciplinary supportive care, integrating the dimensions of exercise alongside oncological treatments, is now regarded as a new paradigm to improve patient survival and quality of life. Its impact is important on the factors that control tumor development, such as the immune system, inflammation, [...] Read more.
Multidisciplinary supportive care, integrating the dimensions of exercise alongside oncological treatments, is now regarded as a new paradigm to improve patient survival and quality of life. Its impact is important on the factors that control tumor development, such as the immune system, inflammation, tissue perfusion, hypoxia, insulin resistance, metabolism, glucocorticoid levels, and cachexia. An increasing amount of research has been published in the last years on the effects of physical activity within the framework of oncology, marking the appearance of a new medical field, commonly known as “exercise oncology”. This emerging research field is trying to determine the biological mechanisms by which, aerobic exercise affects the incidence of cancer, the progression and/or the appearance of metastases. We propose an overview of the current state of the art physical exercise interventions in the management of cancer patients, including a pragmatic perspective with tips for routine practice. We then develop the emerging mechanistic views about physical exercise and their potential clinical applications. Moving toward a more personalized, integrated, patient-centered, and multidisciplinary management, by trying to understand the different interactions between the cancer and the host, as well as the impact of the disease and the treatments on the different organs, this seems to be the most promising method to improve the care of cancer patients. Full article
(This article belongs to the Special Issue Physical Activity and Cancer Care)
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12 pages, 2080 KiB  
Article
Predicting Malignant Lymph Nodes Using a Novel Scoring System Based on Multi-Endobronchial Ultrasound Features
by Momoko Morishita, Keigo Uchimura, Hideaki Furuse, Tatsuya Imabayashi, Takaaki Tsuchida and Yuji Matsumoto
Cancers 2022, 14(21), 5355; https://doi.org/10.3390/cancers14215355 - 30 Oct 2022
Cited by 3 | Viewed by 10515
Abstract
Endobronchial ultrasound (EBUS) features with B-, power/color Doppler, and elastography modes help differentiate between benign and malignant lymph nodes (MLNs) during transbronchial needle aspiration (TBNA); however, only few studies have assessed them simultaneously. We evaluated the diagnostic accuracy of each EBUS feature and [...] Read more.
Endobronchial ultrasound (EBUS) features with B-, power/color Doppler, and elastography modes help differentiate between benign and malignant lymph nodes (MLNs) during transbronchial needle aspiration (TBNA); however, only few studies have assessed them simultaneously. We evaluated the diagnostic accuracy of each EBUS feature and aimed to establish a scoring system to predict MLNs. EBUS features of consecutive patients and final diagnosis per lymph node (LN) were examined retrospectively. In total, 594 LNs from 301 patients were analyzed. Univariable analyses revealed that EBUS features, except for round shape, could differentiate MLNs from benign LNs. Multivariable analysis revealed that short axis (>1 cm), heterogeneous echogenicity, absence of central hilar structure, presence of coagulation necrosis sign, and blue-dominant elastographic images were independent predictors of MLNs. At three or more EBUS features predicting MLNs, our scoring system had high sensitivity (77.9%) and specificity (91.8%). The area under the receiver operating curve (AUC) was 0.894 (95% confidence interval (CI): 0.868–0.920), which was higher than that of B-mode features alone (AUC: 0.840 (95% CI: 0.807–0.873)). The novel scoring system could predict MLNs more accurately than B-mode features alone. Multi-EBUS features may increase EBUS-TBNA efficiency for LN evaluation. Full article
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27 pages, 3015 KiB  
Review
In Vivo Models for Prostate Cancer Research
by Robert Adamiecki, Anita Hryniewicz-Jankowska, Maria A. Ortiz, Xiang Li, Baylee A. Porter-Hansen, Imad Nsouli, Gennady Bratslavsky and Leszek Kotula
Cancers 2022, 14(21), 5321; https://doi.org/10.3390/cancers14215321 - 28 Oct 2022
Cited by 6 | Viewed by 3440
Abstract
In 2022, prostate cancer (PCa) is estimated to be the most commonly diagnosed cancer in men in the United States—almost 270,000 American men are estimated to be diagnosed with PCa in 2022. This review compares and contrasts in vivo models of PCa with [...] Read more.
In 2022, prostate cancer (PCa) is estimated to be the most commonly diagnosed cancer in men in the United States—almost 270,000 American men are estimated to be diagnosed with PCa in 2022. This review compares and contrasts in vivo models of PCa with regards to the altered genes, signaling pathways, and stages of tumor progression associated with each model. The main type of model included in this review are genetically engineered mouse models, which include conditional and constitutive knockout model. 2D cell lines, 3D organoids and spheroids, xenografts and allografts, and patient derived models are also included. The major applications, advantages and disadvantages, and ease of use and cost are unique to each type of model, but they all make it easier to translate the tumor progression that is seen in the mouse prostate to the human prostate. Although both human and mouse prostates are androgen-dependent, the fact that the native, genetically unaltered prostate in mice cannot give rise to carcinoma is an especially critical component of PCa models. Thanks to the similarities between the mouse and human genome, our knowledge of PCa has been expanded, and will continue to do so, through models of PCa. Full article
(This article belongs to the Topic Animal Model in Biomedical Research, 2nd Volume)
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30 pages, 36396 KiB  
Article
A Soft Label Deep Learning to Assist Breast Cancer Target Therapy and Thyroid Cancer Diagnosis
by Ching-Wei Wang, Kuan-Yu Lin, Yi-Jia Lin, Muhammad-Adil Khalil, Kai-Lin Chu and Tai-Kuang Chao
Cancers 2022, 14(21), 5312; https://doi.org/10.3390/cancers14215312 - 28 Oct 2022
Cited by 9 | Viewed by 2330
Abstract
According to the World Health Organization Report 2022, cancer is the most common cause of death contributing to nearly one out of six deaths worldwide. Early cancer diagnosis and prognosis have become essential in reducing the mortality rate. On the other hand, cancer [...] Read more.
According to the World Health Organization Report 2022, cancer is the most common cause of death contributing to nearly one out of six deaths worldwide. Early cancer diagnosis and prognosis have become essential in reducing the mortality rate. On the other hand, cancer detection is a challenging task in cancer pathology. Trained pathologists can detect cancer, but their decisions are subjective to high intra- and inter-observer variability, which can lead to poor patient care owing to false-positive and false-negative results. In this study, we present a soft label fully convolutional network (SL-FCN) to assist in breast cancer target therapy and thyroid cancer diagnosis, using four datasets. To aid in breast cancer target therapy, the proposed method automatically segments human epidermal growth factor receptor 2 (HER2) amplification in fluorescence in situ hybridization (FISH) and dual in situ hybridization (DISH) images. To help in thyroid cancer diagnosis, the proposed method automatically segments papillary thyroid carcinoma (PTC) on Papanicolaou-stained fine needle aspiration and thin prep whole slide images (WSIs). In the evaluation of segmentation of HER2 amplification in FISH and DISH images, we compare the proposed method with thirteen deep learning approaches, including U-Net, U-Net with InceptionV5, Ensemble of U-Net with Inception-v4, Inception-Resnet-v2 encoder, and ResNet-34 encoder, SegNet, FCN, modified FCN, YOLOv5, CPN, SOLOv2, BCNet, and DeepLabv3+ with three different backbones, including MobileNet, ResNet, and Xception, on three clinical datasets, including two DISH datasets on two different magnification levels and a FISH dataset. The result on DISH breast dataset 1 shows that the proposed method achieves high accuracy of 87.77 ± 14.97%, recall of 91.20 ± 7.72%, and F1-score of 81.67 ± 17.76%, while, on DISH breast dataset 2, the proposed method achieves high accuracy of 94.64 ± 2.23%, recall of 83.78 ± 6.42%, and F1-score of 85.14 ± 6.61% and, on the FISH breast dataset, the proposed method achieves high accuracy of 93.54 ± 5.24%, recall of 83.52 ± 13.15%, and F1-score of 86.98 ± 9.85%, respectively. Furthermore, the proposed method outperforms most of the benchmark approaches by a significant margin (p <0.001). In evaluation of segmentation of PTC on Papanicolaou-stained WSIs, the proposed method is compared with three deep learning methods, including Modified FCN, U-Net, and SegNet. The experimental result demonstrates that the proposed method achieves high accuracy of 99.99 ± 0.01%, precision of 92.02 ± 16.6%, recall of 90.90 ± 14.25%, and F1-score of 89.82 ± 14.92% and significantly outperforms the baseline methods, including U-Net and FCN (p <0.001). With the high degree of accuracy, precision, and recall, the results show that the proposed method could be used in assisting breast cancer target therapy and thyroid cancer diagnosis with faster evaluation and minimizing human judgment errors. Full article
(This article belongs to the Special Issue Clinical Perspective and Translational Oncology of Liquid Biopsy)
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30 pages, 1177 KiB  
Review
Dietary Interventions in Cancer Treatment and Response: A Comprehensive Review
by Benjamin D. Mercier, Eemon Tizpa, Errol J. Philip, Qianhua Feng, Ziyi Huang, Reeny M. Thomas, Sumanta K. Pal, Tanya B. Dorff and Yun R. Li
Cancers 2022, 14(20), 5149; https://doi.org/10.3390/cancers14205149 - 20 Oct 2022
Cited by 11 | Viewed by 6874
Abstract
Chemotherapy and radiotherapy are first-line treatments in the management of advanced solid tumors. Whereas these treatments are directed at eliminating cancer cells, they cause significant adverse effects that can be detrimental to a patient’s quality of life and even life-threatening. Diet is a [...] Read more.
Chemotherapy and radiotherapy are first-line treatments in the management of advanced solid tumors. Whereas these treatments are directed at eliminating cancer cells, they cause significant adverse effects that can be detrimental to a patient’s quality of life and even life-threatening. Diet is a modifiable risk factor that has been shown to affect cancer risk, recurrence, and treatment toxicity, but little information is known how diet interacts with cancer treatment modalities. Although dietary interventions, such as intermittent fasting and ketogenic diets, have shown promise in pre-clinical studies by reducing the toxicity and increasing the efficacy of chemotherapeutics, there remains a limited number of clinical studies in this space. This review surveys the impact of dietary interventions (caloric restriction, intermittent and short-term fasting, and ketogenic diet) on cancer treatment outcomes in both pre-clinical and clinical studies. Early studies support a complementary role for these dietary interventions in improving patient quality of life across multiple cancer types by reducing toxicity and perhaps a benefit in treatment efficacy. Larger, phase III, randomized clinical trials are ultimately necessary to evaluate the efficacy of these dietary interventions in improving oncologic or quality of life outcomes for patients that are undergoing chemotherapy or radiotherapy. Full article
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34 pages, 4145 KiB  
Article
Involvement of HHV-4 (Epstein–Barr Virus) and HHV-5 (Cytomegalovirus) in Inflammatory Bowel Disease and Colorectal Cancer: A Meta-Analysis
by Luigi Marongiu, Sascha Venturelli and Heike Allgayer
Cancers 2022, 14(20), 5085; https://doi.org/10.3390/cancers14205085 - 17 Oct 2022
Cited by 4 | Viewed by 2591
Abstract
Gastrointestinal diseases (GDs) include colorectal cancer (CRC), gastric cancer (GC), and inflammatory bowel disease (IBD). CRC and GC are typically diagnosed at later stages of development, reducing patients’ chances of survival. IBD is characterized by chronic intestinal inflammation and is a significant risk [...] Read more.
Gastrointestinal diseases (GDs) include colorectal cancer (CRC), gastric cancer (GC), and inflammatory bowel disease (IBD). CRC and GC are typically diagnosed at later stages of development, reducing patients’ chances of survival. IBD is characterized by chronic intestinal inflammation and is a significant risk factor for the development of CRC. Chronic bacterial infections have been shown to promote some GDs, but the role of viruses in the etiology of these diseases is less clear. The present meta-analysis retrieved literature on the viral prevalence in GD patients, measuring the GD risk in odd ratios. By quantifying the study heterogeneity, the literature bias was fundamentally included in the analysis. The analysis also included 11 metagenomic studies. Our meta-analysis retrieved 11,413 studies, with 196 suitable for analysis. HHV-4 (Epstein–Barr virus) was identified as a significant risk factor for the development of IBD, and HHV-5 (cytomegalovirus) as a risk factor for both CRC and IBD. Polyomaviruses and the Hepatitis B virus were also, less strongly, involved in the risk of CRC and IBD. No relations withstanding the literature bias were identified for GC. The study discusses these findings, as well as the role of other viruses in the etiology of CRC and IBD. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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21 pages, 2437 KiB  
Review
Chronotherapy: Circadian Rhythms and Their Influence in Cancer Therapy
by Ana Amiama-Roig, Eva M. Verdugo-Sivianes, Amancio Carnero and José-Ramón Blanco
Cancers 2022, 14(20), 5071; https://doi.org/10.3390/cancers14205071 - 17 Oct 2022
Cited by 24 | Viewed by 7409
Abstract
Living organisms present rhythmic fluctuations every 24 h in their behavior and metabolism to anticipate changes in the environment. These fluctuations are controlled by a very complex molecular mechanism, the circadian clock, that regulates the expression of multiple genes to ensure the right [...] Read more.
Living organisms present rhythmic fluctuations every 24 h in their behavior and metabolism to anticipate changes in the environment. These fluctuations are controlled by a very complex molecular mechanism, the circadian clock, that regulates the expression of multiple genes to ensure the right functioning of the body. An individual’s circadian system is altered during aging, and this is related to numerous age-associated pathologies and other alterations that could contribute to the development of cancer. Nowadays, there is an increasing interest in understanding how circadian rhythms could be used in the treatment of cancer. Chronotherapy aims to understand the impact that biological rhythms have on the response to a therapy to optimize its action, maximize health benefits and minimize possible adverse effects. Clinical trials so far have confirmed that optimal timing of treatment with chemo or immunotherapies could decrease drug toxicity and increase efficacy. Instead, chronoradiotherapy seems to minimize treatment-related symptoms rather than tumor progression or patient survival. In addition, potential therapeutic targets within the molecular clock have also been identified. Therefore, results of the application of chronotherapy in cancer therapy until now are challenging, feasible, and could be applied to clinical practice to improve cancer treatment without additional costs. However, different limitations and variables such as age, sex, or chronotypes, among others, should be overcome before chronotherapy can really be put into clinical practice. Full article
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24 pages, 11851 KiB  
Article
Development of a High-Affinity Antibody against the Tumor-Specific and Hyperactive 611-p95HER2 Isoform
by Esmaeil Dorraji, Elin Borgen, Dario Segura-Peña, Puneet Rawat, Eva Smorodina, Claire Dunn, Victor Greiff, Nikolina Sekulić, Hege Russnes and Jon Amund Kyte
Cancers 2022, 14(19), 4859; https://doi.org/10.3390/cancers14194859 - 5 Oct 2022
Viewed by 3586
Abstract
The expression of human epidermal growth factor receptor 2 (HER2) is a key classification factor in breast cancer. Many breast cancers express isoforms of HER2 with truncated carboxy-terminal fragments (CTF), collectively known as p95HER2. A common p95HER2 isoform, 611-CTF, is a biomarker for [...] Read more.
The expression of human epidermal growth factor receptor 2 (HER2) is a key classification factor in breast cancer. Many breast cancers express isoforms of HER2 with truncated carboxy-terminal fragments (CTF), collectively known as p95HER2. A common p95HER2 isoform, 611-CTF, is a biomarker for aggressive disease and confers resistance to therapy. Contrary to full-length HER2, 611-p95HER2 has negligible normal tissue expression. There is currently no approved diagnostic assay to identify this subgroup and no therapy targeting this mechanism of tumor escape. The purpose of this study was to develop a monoclonal antibody (mAb) against 611-CTF-p95HER2. Hybridomas were generated from rats immunized with cells expressing 611-CTF. A hybridoma producing a highly specific Ab was identified and cloned further as a mAb. This mAb, called Oslo-2, gave strong staining for 611-CTF and no binding to full-length HER2, as assessed in cell lines and tissues by flow cytometry, immunohistochemistry and immunofluorescence. No cross-reactivity against HER2 negative controls was detected. Surface plasmon resonance analysis demonstrated a high binding affinity (equilibrium dissociation constant 2 nM). The target epitope was identified at the N-terminal end, using experimental alanine scanning. Further, the mAb paratope was identified and characterized with hydrogen-deuterium-exchange, and a molecular model for the (Oslo-2 mAb:611-CTF-p95HER2) complex was generated by an experimental-information-driven docking approach. We conclude that the Oslo-2 mAb has a high affinity and is highly specific for 611-CTF-p95HER2. The Ab may be used to develop potent and safe therapies, overcoming p95HER2-mediated tumor escape, as well as for developing diagnostic assays. Full article
(This article belongs to the Section Methods and Technologies Development)
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15 pages, 1932 KiB  
Review
Challenges for Triple Negative Breast Cancer Treatment: Defeating Heterogeneity and Cancer Stemness
by Rinad Mahmoud, Paloma Ordóñez-Morán and Cinzia Allegrucci
Cancers 2022, 14(17), 4280; https://doi.org/10.3390/cancers14174280 - 1 Sep 2022
Cited by 20 | Viewed by 9582
Abstract
The Triple Negative Breast Cancer (TNBC) subtype is known to have a more aggressive clinical course compared to other breast cancer subtypes. Targeted therapies for this type of breast cancer are limited and patients are mostly treated with conventional chemo- and radio-therapies which [...] Read more.
The Triple Negative Breast Cancer (TNBC) subtype is known to have a more aggressive clinical course compared to other breast cancer subtypes. Targeted therapies for this type of breast cancer are limited and patients are mostly treated with conventional chemo- and radio-therapies which are not specific and do not target resistant cells. Therefore, one of the major clinical challenges is to find compounds that target the drug-resistant cell populations which are responsible for reforming secondary tumours. The molecular profiling of the different TNBC subtypes holds a promise for better defining these resistant cells specific to each tumour. To this end, a better understanding of TNBC heterogeneity and cancer stemness is required, and extensive genomic analysis can help to understand the disease complexity and distinguish new molecular drivers that can be targeted in the clinics. The use of persister cancer cell-targeting therapies combined with other therapies may provide a big advance to improve TNBC patients’ survival. Full article
(This article belongs to the Collection Stemness and Drug-Persistence in Cancer)
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14 pages, 1022 KiB  
Review
Heterogeneity of Cancer-Associated Fibroblasts and the Tumor Immune Microenvironment in Pancreatic Cancer
by Tomohiko Shinkawa, Kenoki Ohuchida and Masafumi Nakamura
Cancers 2022, 14(16), 3994; https://doi.org/10.3390/cancers14163994 - 18 Aug 2022
Cited by 17 | Viewed by 4721
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a 5-year survival rate of 9%. Cancer-associated fibroblasts (CAFs) have historically been considered tumor-promoting. However, multiple studies reporting that suppression of CAFs in PDAC mouse models resulted in more aggressive tumors [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a 5-year survival rate of 9%. Cancer-associated fibroblasts (CAFs) have historically been considered tumor-promoting. However, multiple studies reporting that suppression of CAFs in PDAC mouse models resulted in more aggressive tumors and worse prognosis have suggested the existence of a tumor-suppressive population within CAFs, leading to further research on heterogeneity within CAFs. In recent years, the benefits of cancer immunotherapy have been reported in various carcinomas. Unfortunately, the efficacy of immunotherapies in PDAC has been limited, and the CAF-driven cancer immunosuppressive microenvironment has been suggested as the cause. Thus, clarification of heterogeneity within the tumor microenvironment, including CAFs and tumor immunity, is urgently needed to establish effective therapeutic strategies for PDAC. In this review, we report the latest findings on the heterogeneity of CAFs and the functions of each major CAF subtype, which have been revealed by single-cell RNA sequencing in recent years. We also describe reports of tumor-suppressive CAF subtypes and the existence of CAFs that maintain a differentiated PDAC phenotype and review the potential for targeted therapy. Full article
(This article belongs to the Special Issue Tumor Microenvironment and Pancreatic Cancer)
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13 pages, 696 KiB  
Review
New Therapeutic Interventions for Kidney Carcinoma: Looking to the Future
by Lucio Dell’Atti, Nicoletta Bianchi and Gianluca Aguiari
Cancers 2022, 14(15), 3616; https://doi.org/10.3390/cancers14153616 - 25 Jul 2022
Cited by 19 | Viewed by 5092
Abstract
Patients suffering from metastatic renal cell carcinoma (mRCC) show an overall survival rate of lower than 10% after 5 years from diagnosis. Currently, the first-line treatment for mRCC patients is based on antiangiogenic drugs that are able to inhibit tyrosine kinase receptors (TKI) [...] Read more.
Patients suffering from metastatic renal cell carcinoma (mRCC) show an overall survival rate of lower than 10% after 5 years from diagnosis. Currently, the first-line treatment for mRCC patients is based on antiangiogenic drugs that are able to inhibit tyrosine kinase receptors (TKI) in combination with immuno-oncology (IO) therapy or IO-IO treatments. Second-line therapy involves the use of other TKIs, immunotherapeutic drugs, and mTOR inhibitors. Nevertheless, many patients treated with mTOR and TK inhibitors acquire drug resistance, making the therapy ineffective. Therefore, the research of new therapeutic targets is crucial for improving the overall survival and quality of life of mRCC patients. The investigation of the molecular basis of RCC, especially in clear cell renal cell carcinoma (ccRCC), has led to the identification of different signaling pathways that are involved in renal carcinogenesis. Most of ccRCCs are associated with mutation in VHL gene, which mediates the degradation of hypoxia-inducible factors (HIFs), that, in turn, regulate the pathways related to tumorigenesis, including angiogenesis and invasion. Renal tumorigenesis is also associated with the activation of tyrosine kinases that modulate the PI3K-Akt-mTOR pathway, promoting cell proliferation and survival. In ccRCC, the abnormal activity of mTOR activates the MDM2 protein, which leads to the degradation of tumor suppressor p53 via proteasome machinery. In addition, p53 may be degraded by autophagy in a mechanism involving the enzyme transglutaminase 2 (TG2). Suppression of wild-type p53 promotes cell growth, invasion, and drug resistance. Finally, the activation of ferroptosis appears to inhibit cancer progression in RCC. In conclusion, these pathways might represent new therapeutic targets for mRCC. Full article
(This article belongs to the Special Issue Advances in the Treatment of Renal Cell Carcinoma)
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15 pages, 918 KiB  
Review
The Emerging Impact of Tumor Budding in Oral Squamous Cell Carcinoma: Main Issues and Clinical Relevance of a New Prognostic Marker
by Lucrezia Togni, Vito Carlo Alberto Caponio, Nicoletta Zerman, Giuseppe Troiano, Khrystyna Zhurakivska, Lorenzo Lo Muzio, Andrea Balercia, Marco Mascitti and Andrea Santarelli
Cancers 2022, 14(15), 3571; https://doi.org/10.3390/cancers14153571 - 22 Jul 2022
Cited by 22 | Viewed by 4174
Abstract
Tumor Budding (TB) represents a single cancer cell or a small cluster of less than five cancer cells on the infiltrative tumor front. Accumulating evidence suggests TB is an independent prognostic factor in oral squamous cell carcinoma (OSCC). However, its exact role is [...] Read more.
Tumor Budding (TB) represents a single cancer cell or a small cluster of less than five cancer cells on the infiltrative tumor front. Accumulating evidence suggests TB is an independent prognostic factor in oral squamous cell carcinoma (OSCC). However, its exact role is not yet elucidated, and a standardized scoring system is still necessary. The study aims to extensively review the literature data regarding the prognostic role of TB in OSCC. The results of TB are an independent prognostic factor of poor survival outcomes in OSCC. To date, the manual detection of hematoxylin and eosin-staining or pancytokeratin-immunostaining sections are the most commonly used methods. Between the several cut-offs, the two-tier system with five buds/field cut-offs provides better risk stratification. The prognostic role of the BD model in predicting survival outcomes was extensively validated; however, the inclusion of DOI, which is already a staging parameter, encouraged other authors to propose other models, integrating TB count with other adverse risk factors, such as the tumor–stroma ratio and tumor-infiltrated lymphocytes. The prognostic relevance of TB in OSCC highlights its evaluation in daily pathological practice. Therefore, the TB detection method and the TB scoring system should be validated based on tumor stage and site. Full article
(This article belongs to the Special Issue Advances in Oral Cancer: From Pathology to Treatment)
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28 pages, 724 KiB  
Review
Origin and Therapies of Osteosarcoma
by Brice Moukengue, Morgane Lallier, Louise Marchandet, Marc Baud’huin, Franck Verrecchia, Benjamin Ory and Francois Lamoureux
Cancers 2022, 14(14), 3503; https://doi.org/10.3390/cancers14143503 - 19 Jul 2022
Cited by 32 | Viewed by 4445
Abstract
Osteosarcoma (OS) is the most frequent primary bone tumor, mainly affecting children and young adults. Despite therapeutic advances, the 5-year survival rate is 70% but drastically decreases to 20–30% for poor responders to therapies or for patients with metastasis. No real evolution of [...] Read more.
Osteosarcoma (OS) is the most frequent primary bone tumor, mainly affecting children and young adults. Despite therapeutic advances, the 5-year survival rate is 70% but drastically decreases to 20–30% for poor responders to therapies or for patients with metastasis. No real evolution of the survival rates has been observed for four decades, explained by poor knowledge of the origin, difficulties related to diagnosis and the lack of targeted therapies for this pediatric tumor. This review will describe a non-exhaustive overview of osteosarcoma disease from a clinical and biological point of view, describing the origin, diagnosis and therapies. Full article
(This article belongs to the Special Issue Diagnosis and Treatment for Bone Tumor and Sarcoma)
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22 pages, 2945 KiB  
Article
Factors Predicting Surgical Effort Using Explainable Artificial Intelligence in Advanced Stage Epithelial Ovarian Cancer
by Alexandros Laios, Evangelos Kalampokis, Racheal Johnson, Sarika Munot, Amudha Thangavelu, Richard Hutson, Tim Broadhead, Georgios Theophilou, Chris Leach, David Nugent and Diederick De Jong
Cancers 2022, 14(14), 3447; https://doi.org/10.3390/cancers14143447 - 15 Jul 2022
Cited by 16 | Viewed by 4100
Abstract
(1) Background: Surgical cytoreduction for epithelial ovarian cancer (EOC) is a complex procedure. Encompassed within the performance skills to achieve surgical precision, intra-operative surgical decision-making remains a core feature. The use of eXplainable Artificial Intelligence (XAI) could potentially interpret the influence of human [...] Read more.
(1) Background: Surgical cytoreduction for epithelial ovarian cancer (EOC) is a complex procedure. Encompassed within the performance skills to achieve surgical precision, intra-operative surgical decision-making remains a core feature. The use of eXplainable Artificial Intelligence (XAI) could potentially interpret the influence of human factors on the surgical effort for the cytoreductive outcome in question; (2) Methods: The retrospective cohort study evaluated 560 consecutive EOC patients who underwent cytoreductive surgery between January 2014 and December 2019 in a single public institution. The eXtreme Gradient Boosting (XGBoost) and Deep Neural Network (DNN) algorithms were employed to develop the predictive model, including patient- and operation-specific features, and novel features reflecting human factors in surgical heuristics. The precision, recall, F1 score, and area under curve (AUC) were compared between both training algorithms. The SHapley Additive exPlanations (SHAP) framework was used to provide global and local explainability for the predictive model; (3) Results: A surgical complexity score (SCS) cut-off value of five was calculated using a Receiver Operator Characteristic (ROC) curve, above which the probability of incomplete cytoreduction was more likely (area under the curve [AUC] = 0.644; 95% confidence interval [CI] = 0.598–0.69; sensitivity and specificity 34.1%, 86.5%, respectively; p = 0.000). The XGBoost outperformed the DNN assessment for the prediction of the above threshold surgical effort outcome (AUC = 0.77; 95% [CI] 0.69–0.85; p < 0.05 vs. AUC 0.739; 95% [CI] 0.655–0.823; p < 0.95). We identified “turning points” that demonstrated a clear preference towards above the given cut-off level of surgical effort; in consultant surgeons with <12 years of experience, age <53 years old, who, when attempting primary cytoreductive surgery, recorded the presence of ascites, an Intraoperative Mapping of Ovarian Cancer score >4, and a Peritoneal Carcinomatosis Index >7, in a surgical environment with the optimization of infrastructural support. (4) Conclusions: Using XAI, we explain how intra-operative decisions may consider human factors during EOC cytoreduction alongside factual knowledge, to maximize the magnitude of the selected trade-off in effort. XAI techniques are critical for a better understanding of Artificial Intelligence frameworks, and to enhance their incorporation in medical applications. Full article
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14 pages, 900 KiB  
Article
Accurate Screening for Early-Stage Breast Cancer by Detection and Profiling of Circulating Tumor Cells
by Timothy Crook, Robert Leonard, Kefah Mokbel, Alastair Thompson, Michael Michell, Raymond Page, Ashok Vaid, Ravi Mehrotra, Anantbhushan Ranade, Sewanti Limaye, Darshana Patil, Dadasaheb Akolkar, Vineet Datta, Pradip Fulmali, Sachin Apurwa, Stefan Schuster, Ajay Srinivasan and Rajan Datar
Cancers 2022, 14(14), 3341; https://doi.org/10.3390/cancers14143341 - 9 Jul 2022
Cited by 23 | Viewed by 9462
Abstract
Background: The early detection of breast cancer (BrC) is associated with improved survival. We describe a blood-based breast cancer detection test based on functional enrichment of breast-adenocarcinoma-associated circulating tumor cells (BrAD-CTCs) and their identification via multiplexed fluorescence immunocytochemistry (ICC) profiling for GCDFP15, GATA3, [...] Read more.
Background: The early detection of breast cancer (BrC) is associated with improved survival. We describe a blood-based breast cancer detection test based on functional enrichment of breast-adenocarcinoma-associated circulating tumor cells (BrAD-CTCs) and their identification via multiplexed fluorescence immunocytochemistry (ICC) profiling for GCDFP15, GATA3, EpCAM, PanCK, and CD45 status. Methods: The ability of the test to differentiate BrC cases (N = 548) from healthy women (N = 9632) was evaluated in a case–control clinical study. The ability of the test to differentiate BrC cases from those with benign breast conditions was evaluated in a prospective clinical study of women (N = 141) suspected of BrC. Results: The test accurately detects BrAD-CTCs in breast cancers, irrespective of age, ethnicity, disease stage, grade, or hormone receptor status. Analytical validation established the high accuracy and reliability of the test under intended use conditions. The test detects and differentiates BrC cases from healthy women with 100% specificity and 92.07% overall sensitivity in a case–control study. In a prospective clinical study, the test shows 93.1% specificity and 94.64% overall sensitivity in differentiating breast cancer cases (N = 112) from benign breast conditions (N = 29). Conclusion: The findings reported in this manuscript support the clinical potential of this test for blood-based BrC detection. Full article
(This article belongs to the Special Issue Breast Development and Cancer)
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31 pages, 1368 KiB  
Review
Resistance to TKIs in EGFR-Mutated Non-Small Cell Lung Cancer: From Mechanisms to New Therapeutic Strategies
by Andreas Koulouris, Christos Tsagkaris, Anna Chiara Corriero, Giulio Metro and Giannis Mountzios
Cancers 2022, 14(14), 3337; https://doi.org/10.3390/cancers14143337 - 8 Jul 2022
Cited by 22 | Viewed by 5544
Abstract
Resistance to tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in advanced mutant Non-Small Cell Lung Cancer (NSCLC) constitutes a therapeutic challenge. This review intends to summarize the existing knowledge about the mechanisms of resistance to TKIs in the context [...] Read more.
Resistance to tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in advanced mutant Non-Small Cell Lung Cancer (NSCLC) constitutes a therapeutic challenge. This review intends to summarize the existing knowledge about the mechanisms of resistance to TKIs in the context of EGFR mutant NSCLC and discuss its clinical and therapeutic implications. EGFR-dependent and independent molecular pathways have the potential to overcome or circumvent the activity of EGFR-targeted agents including the third-generation TKI, osimertinib, negatively impacting clinical outcomes. CNS metastases occur frequently in patients on EGFR-TKIs, due to the inability of first and second-generation agents to overcome both the BBB and the acquired resistance of cancer cells in the CNS. Newer-generation TKIs, TKIs targeting EGFR-independent resistance mechanisms, bispecific antibodies and antibody-drug conjugates or combinations of TKIs with other TKIs or chemotherapy, immunotherapy and Anti-Vascular Endothelial Growth Factors (anti-VEGFs) are currently in use or under investigation in EGFR mutant NSCLC. Liquid biopsies detecting mutant cell-free DNA (cfDNA) provide a window of opportunity to attack mutant clones before they become clinically apparent. Overall, EGFR TKIs-resistant NSCLC constitutes a multifaceted therapeutic challenge. Mapping its underlying mutational landscape, accelerating the detection of resistance mechanisms and diversifying treatment strategies are essential for the management of the disease. Full article
(This article belongs to the Special Issue Mechanisms of Resistance in EGFR-Mutated Non-Small Cell Lung Cancer)
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