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Cancers, Volume 15, Issue 7 (April-1 2023) – 271 articles

Cover Story (view full-size image): Treatment options after progression on CDK4/6 inhibitors are limited. Recent trials have reported encouraging efficacy of novel drugs such as the AKT inhibitors (Capivasertib), oral selective estrogen receptor degraders such as Elacestrant, proteolysis targeting chimeras (PROTACs) and PARP inhibitors. Some patients may benefit from the continuation of CDK4/6 inhibitors beyond progression. However, the efficacy of these treatments remains modest. In this narrative review, we take a deep dive into the data supporting these new treatments and discuss existing evidence gaps, limitations, and ongoing clinical trials. View this paper
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14 pages, 3283 KiB  
Article
Arginase Inhibition Mitigates Bortezomib-Exacerbated Cardiotoxicity in Multiple Myeloma
by Aleksandra Paterek, Marta Oknińska, Zofia Pilch, Anna Sosnowska, Kavita Ramji, Urszula Mackiewicz, Jakub Golab, Dominika Nowis and Michał Mączewski
Cancers 2023, 15(7), 2191; https://doi.org/10.3390/cancers15072191 - 06 Apr 2023
Viewed by 1638
Abstract
Background: Multiple myeloma (MM) is associated with increased cardiovascular morbidity and mortality, while MM therapies also result in adverse cardiac effects. Endothelial dysfunction and impaired nitric oxide (NO) pathway is their possible mediator. Objective: Since MM is associated with increased arginase expression, resulting [...] Read more.
Background: Multiple myeloma (MM) is associated with increased cardiovascular morbidity and mortality, while MM therapies also result in adverse cardiac effects. Endothelial dysfunction and impaired nitric oxide (NO) pathway is their possible mediator. Objective: Since MM is associated with increased arginase expression, resulting in the consumption of ʟ-arginine, precursor for NO synthesis, our aim was to test if cardiotoxicity mediated by MM and MM therapeutic, bortezomib (a proteasome inhibitor), can be ameliorated by an arginase inhibitor through improved endothelial function. Methods: We used a mouse Vĸ*MYC model of non-light chain MM. Cardiac function was assessed by echocardiography. Results: MM resulted in progressive left ventricular (LV) systolic dysfunction, and bortezomib exacerbated this effect, leading to significant impairment of LV performance. An arginase inhibitor, OAT-1746, protected the heart against bortezomib- or MM-induced toxicity but did not completely prevent the effects of the MM+bortezomib combination. MM was associated with improved endothelial function (assessed as NO production) vs. healthy controls, while bortezomib did not affect it. OAT-1746 improved endothelial function only in healthy mice. NO plasma concentration was increased by OAT-1746 but was not affected by MM or bortezomib. Conclusions: Bortezomib exacerbates MM-mediated LV systolic dysfunction in a mouse model of MM, while an arginase inhibitor partially prevents it. Endothelium does not mediate either these adverse or beneficial effects. This suggests that proteasome inhibitors should be used with caution in patients with advanced myeloma, where the summation of cardiotoxicity could be expected. Therapies aimed at the NO pathway, in particular arginase inhibitors, could offer promise in the prevention/treatment of cardiotoxicity in MM. Full article
(This article belongs to the Collection Advances in Multiple Myeloma Research and Treatment)
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22 pages, 5283 KiB  
Article
PATZ1 in Non-Small Cell Lung Cancer: A New Biomarker That Negatively Correlates with PD-L1 Expression and Suppresses the Malignant Phenotype
by Stefano Lucà, Renato Franco, Antonella Napolitano, Valeria Soria, Andrea Ronchi, Federica Zito Marino, Carminia Maria Della Corte, Floriana Morgillo, Alfonso Fiorelli, Antonio Luciano, Giuseppe Palma, Claudio Arra, Sabrina Battista, Laura Cerchia and Monica Fedele
Cancers 2023, 15(7), 2190; https://doi.org/10.3390/cancers15072190 - 06 Apr 2023
Cited by 4 | Viewed by 2094
Abstract
Non-small cell lung cancer (NSCLC), the leading cause of cancer death worldwide, is still an unmet medical problem due to the lack of both effective therapies against advanced stages and markers to allow a diagnosis of the disease at early stages before its [...] Read more.
Non-small cell lung cancer (NSCLC), the leading cause of cancer death worldwide, is still an unmet medical problem due to the lack of both effective therapies against advanced stages and markers to allow a diagnosis of the disease at early stages before its progression. Immunotherapy targeting the PD-1/PD-L1 checkpoint is promising for many cancers, including NSCLC, but its success depends on the tumor expression of PD-L1. PATZ1 is an emerging cancer-related transcriptional regulator and diagnostic/prognostic biomarker in different malignant tumors, but its role in lung cancer is still obscure. Here we investigated expression and role of PATZ1 in NSCLC, in correlation with NSCLC subtypes and PD-L1 expression. A cohort of 104 NSCLCs, including lung squamous cell carcinomas (LUSCs) and adenocarcinomas (LUADs), was retrospectively analyzed by immunohistochemistry for the expression of PATZ1 and PD-L1. The results were correlated with each other and with the clinical characteristics, showing on the one hand a positive correlation between the high expression of PATZ1 and the LUSC subtype and, on the other hand, a negative correlation between PATZ1 and PD-L1, validated at the mRNA level in independent NSCLC datasets. Consistently, two NSCLC cell lines transfected with a PATZ1-overexpressing plasmid showed PD-L1 downregulation, suggesting a role for PATZ1 in the negative regulation of PD-L1. We also showed that PATZ1 overexpression inhibits NSCLC cell proliferation, migration, and invasion, and that Patz1-knockout mice develop LUAD. Overall, this suggests that PATZ1 may act as a tumor suppressor in NSCLC. Full article
(This article belongs to the Special Issue New Insight of Non-small Cell Lung Cancer)
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17 pages, 5186 KiB  
Article
THY1 (CD90) Maintains the Adherens Junctions in Nasopharyngeal Carcinoma via Inhibition of SRC Activation
by Luo Chen, Wai Yin Chau, Hei Tung Yuen, Xiao Han Liu, Robert Zhong Qi, Maria Li Lung and Hong Lok Lung
Cancers 2023, 15(7), 2189; https://doi.org/10.3390/cancers15072189 - 06 Apr 2023
Cited by 1 | Viewed by 1765
Abstract
We had previously shown that THY1 (CD90) is a tumor suppressor in nasopharyngeal carcinoma (NPC) and that its down-regulation and loss of expression are associated with tumor metastasis, yet the mechanism leading to such effects remains unknown. In this study we show that [...] Read more.
We had previously shown that THY1 (CD90) is a tumor suppressor in nasopharyngeal carcinoma (NPC) and that its down-regulation and loss of expression are associated with tumor metastasis, yet the mechanism leading to such effects remains unknown. In this study we show that tumor invasion could be suppressed by THY1 via adherens junction formation in a few NPC cell lines, and knockdown of THY1 would disrupt this cell-cell adhesion phenotype. Mechanistically, the activity of the SRC family kinase (SFK) member, SRC, and canonical Wnt signaling were dramatically reduced when THY1 was constitutively expressed. Previous studies by others have found that high levels of SRC activity in NPCs are associated with EMT and a poor prognosis. We hypothesized that THY1 can suppress tumor invasion in NPC via inhibition of SRC. By gene silencing of SRC, we found that the in vitro NPC cell invasion was significantly reduced and adherens junctions were restored. Through proteomic analysis, we identified that platelet-derived growth factor receptor β (PDGF-Rβ) and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) are novel and potential binding partners of THY1, which were subsequently verified by co-immunoprecipitation (co-IP) analysis. The ligand of PDGF-Rβ (PDGF-BB) could highly induce SRC activation and NPC cell invasion, which could be almost completely suppressed by THY1 expression. On the other hand, the PTPN22 siRNA could enhance both the SRC activities and the cell invasion and could also disrupt the adherens junctions in the THY1-expressing NPC cells; the original THY1-induced phenotypes were reverted when the PTPN22 expression was reduced. Together, our results identified that PTPN22 is essential for THY1 to suppress cell invasion and SRC activity, maintain tight adherens junctions, and prevent NPC metastasis. These results suggested that PDGF-Rβ and SRC can be used as drug targets for suppressing NPC metastasis. Indeed, our in vivo assay using the SRC inhibitor KX2-391, clearly showed that inhibition of SRC signaling can prevent the metastasis of NPC, indicating that targeting SRC can be a promising approach to control the NPC progression. Full article
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14 pages, 1591 KiB  
Article
Perioperative Cetuximab with Cisplatin and 5-Fluorouracil in Esogastric Adenocarcinoma: A Phase II Study
by Caroline Gronnier, Christophe Mariette, Come Lepage, Carole Monterymard, Marine Jary, Aurélie Ferru, Mathieu Baconnier, Xavier Adhoute, David Tavan, Hervé Perrier, Véronique Guerin-Meyer, Cédric Lecaille, Nathalie Bonichon-Lamichhane, Didier Pillon, Oana Cojocarasu, Joëlle Egreteau, Xavier Benoit D’journo, Laétitia Dahan, Christophe Locher, Patrick Texereau, Denis Collet, Pierre Michel, Meher Ben Abdelghani, Rosine Guimbaud, Marie Muller, Olivier Bouché and Guillaume Piessenadd Show full author list remove Hide full author list
Cancers 2023, 15(7), 2188; https://doi.org/10.3390/cancers15072188 - 06 Apr 2023
Cited by 2 | Viewed by 1294
Abstract
Purpose: While perioperative chemotherapy provides a survival benefit over surgery alone in gastric and gastroesophageal junction (G/GEJ) adenocarcinomas, the results need to be improved. This study aimed to evaluate the efficacy and safety of perioperative cetuximab combined with 5-fluorouracil and cisplatin. Patients and [...] Read more.
Purpose: While perioperative chemotherapy provides a survival benefit over surgery alone in gastric and gastroesophageal junction (G/GEJ) adenocarcinomas, the results need to be improved. This study aimed to evaluate the efficacy and safety of perioperative cetuximab combined with 5-fluorouracil and cisplatin. Patients and Methods: Patients received six cycles of cetuximab, cisplatin, and simplified LV5FU2 before and after surgery. The primary objective was a combined evaluation of the tumor objective response (TOR), assessed by computed tomography, and the absence of major toxicities resulting in discontinuation of neoadjuvant chemotherapy (NCT) (45% and 90%, respectively). Results: From 2011 to 2013, 65 patients were enrolled. From 64 patients evaluable for the primary endpoint, 19 (29.7%) had a morphological TOR and 61 (95.3%) did not stop NCT prematurely due to major toxicity. Sixty patients (92.3%) underwent resection. Sixteen patients (/56 available, 28.5%) had histological responses (Mandard tumor regression grade ≤3). After a median follow-up of 44.5 months, median disease-free and overall survival were 24.4 [95% CI: 16.4-39.4] and 40.3 months [95% CI: 27.5-NA], respectively. Conclusion: Adding cetuximab to the NCT regimen in operable G/GEJ adenocarcinomas is safe, but did not show enough efficacy in the present study to meet the primary endpoint (NCT01360086). Full article
(This article belongs to the Special Issue New Trends in Esophageal Cancer Management)
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19 pages, 1550 KiB  
Article
The Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio for Small Renal Cell Carcinomas after Image-Guided Cryoablation or Radio-Frequency Ablation
by Aqua Asif, Vinson Wai-Shun Chan, Filzah Hanis Osman, Jasmine Sze-Ern Koe, Alexander Ng, Oliver Edward Burton, Jon Cartledge, Michael Kimuli, Naveen Vasudev, Christy Ralph, Satinder Jagdev, Selina Bhattarai, Jonathan Smith, James Lenton and Tze Min Wah
Cancers 2023, 15(7), 2187; https://doi.org/10.3390/cancers15072187 - 06 Apr 2023
Viewed by 1489
Abstract
There is a lack of cheap and effective biomarkers for the prediction of renal cancer outcomes post-image-guided ablation. This is a retrospective study of patients with localised small renal cell cancer (T1a or T1b) undergoing cryoablation or radiofrequency ablation (RFA) at our institution [...] Read more.
There is a lack of cheap and effective biomarkers for the prediction of renal cancer outcomes post-image-guided ablation. This is a retrospective study of patients with localised small renal cell cancer (T1a or T1b) undergoing cryoablation or radiofrequency ablation (RFA) at our institution from 2003 to 2016. A total of 203 patients were included in the analysis. In the multivariable analysis, patients with raised neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) pre-operatively, post-operatively and peri-operatively are associated with significantly worsened cancer-specific survival, overall survival and metastasis-free survival. Furthermore, an increased PLR pre-operatively is also associated with increased odds of a larger than 25% drop in renal function post-operatively. In conclusion, NLR and PLR are effective prognostic factors in predicting oncological outcomes and peri-operative outcomes; however, larger external datasets should be used to validate the findings prior to clinical application. Full article
(This article belongs to the Special Issue Biomarkers in Interventional Oncology)
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22 pages, 2680 KiB  
Review
Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases
by Christian Bailly and Xavier Thuru
Cancers 2023, 15(7), 2186; https://doi.org/10.3390/cancers15072186 - 06 Apr 2023
Cited by 8 | Viewed by 3745
Abstract
Tetraspanin CD81 plays major roles in cell-cell interactions and the regulation of cellular trafficking. This cholesterol-embarking transmembrane protein is a co-receptor for several viruses, including HCV, HIV-1 and Chikungunya virus, which exploits the large extracellular loop EC2 for cell entry. CD81 is also [...] Read more.
Tetraspanin CD81 plays major roles in cell-cell interactions and the regulation of cellular trafficking. This cholesterol-embarking transmembrane protein is a co-receptor for several viruses, including HCV, HIV-1 and Chikungunya virus, which exploits the large extracellular loop EC2 for cell entry. CD81 is also an anticancer target implicated in cancer cell proliferation and mobility, and in tumor metastasis. CD81 signaling contributes to the development of solid tumors (notably colorectal, liver and gastric cancers) and has been implicated in the aggressivity of B-cell lymphomas. A variety of protein partners can interact with CD81, either to regulate attachment and uptake of viruses (HCV E2, claudin-1, IFIM1) or to contribute to tumor growth and dissemination (CD19, CD44, EWI-2). CD81-protein interactions can be modulated with molecules targeting the extracellular domain of CD81, investigated as antiviral and/or anticancer agents. Several monoclonal antibodies anti-CD81 have been developed, notably mAb 5A6 active against invasion and metastasis of triple-negative breast cancer cells. CD81-EC2 can also be targeted with natural products (trachelogenin and harzianoic acids A-B) and synthetic compounds (such as benzothiazole-quinoline derivatives). They are weak CD81 binders but offer templates for the design of new compounds targeting the open EC2 loop. There is no anti-CD81 compound in clinical development at present, but this structurally well-characterized tetraspanin warrants more substantial considerations as a drug target. Full article
(This article belongs to the Section Cancer Drug Development)
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20 pages, 1020 KiB  
Review
Detection and Molecular Characterization of Circulating Tumour Cells: Challenges for the Clinical Setting
by Areti Strati, Athina Markou, Evgenia Kyriakopoulou and Evi Lianidou
Cancers 2023, 15(7), 2185; https://doi.org/10.3390/cancers15072185 - 06 Apr 2023
Cited by 7 | Viewed by 2807
Abstract
Over the last decade, liquid biopsy has gained much attention as a powerful tool in personalized medicine since it enables monitoring cancer evolution and follow-up of cancer patients in real time. Through minimally invasive procedures, liquid biopsy provides important information through the analysis [...] Read more.
Over the last decade, liquid biopsy has gained much attention as a powerful tool in personalized medicine since it enables monitoring cancer evolution and follow-up of cancer patients in real time. Through minimally invasive procedures, liquid biopsy provides important information through the analysis of circulating tumour cells (CTCs) and circulating tumour-derived material, such as circulating tumour DNA (ctDNA), circulating miRNAs (cfmiRNAs) and extracellular vehicles (EVs). CTC analysis has already had an important impact on the prognosis, detection of minimal residual disease (MRD), treatment selection and monitoring of cancer patients. Numerous clinical trials nowadays include a liquid biopsy arm. CTC analysis is now an exponentially expanding field in almost all types of solid cancers. Functional studies, mainly based on CTC-derived cell-lines and CTC-derived explants (CDx), provide important insights into the metastatic process. The purpose of this review is to summarize the latest findings on the clinical significance of CTCs for the management of cancer patients, covering the last four years. This review focuses on providing a comprehensive overview of CTC analysis in breast, prostate and non-small-cell lung cancer. The unique potential of CTC single-cell analysis for understanding metastasis biology, and the importance of quality control and standardization of methodologies used in this field, is also discussed. Full article
(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)
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18 pages, 970 KiB  
Review
The Role of Molecular Imaging in Patients with Brain Metastases: A Literature Review
by Luca Urso, Elena Bonatto, Alberto Nieri, Angelo Castello, Anna Margherita Maffione, Maria Cristina Marzola, Corrado Cittanti, Mirco Bartolomei, Stefano Panareo, Luigi Mansi, Egesta Lopci, Luigia Florimonte and Massimo Castellani
Cancers 2023, 15(7), 2184; https://doi.org/10.3390/cancers15072184 - 06 Apr 2023
Cited by 2 | Viewed by 1601
Abstract
Over the last several years, molecular imaging has gained a primary role in the evaluation of patients with brain metastases (BM). Therefore, the “Response Assessment in Neuro-Oncology” (RANO) group recommends amino acid radiotracers for the assessment of BM. Our review summarizes the current [...] Read more.
Over the last several years, molecular imaging has gained a primary role in the evaluation of patients with brain metastases (BM). Therefore, the “Response Assessment in Neuro-Oncology” (RANO) group recommends amino acid radiotracers for the assessment of BM. Our review summarizes the current use of positron emission tomography (PET) radiotracers in patients with BM, ranging from present to future perspectives with new PET radiotracers, including the role of radiomics and potential theranostics approaches. A comprehensive search of PubMed results was conducted. All studies published in English up to and including December 2022 were reviewed. Current evidence confirms the important role of amino acid PET radiotracers for the delineation of BM extension, for the assessment of response to therapy, and particularly for the differentiation between tumor progression and radionecrosis. The newer radiotracers explore non-invasively different biological tumor processes, although more consistent findings in larger clinical trials are necessary to confirm preliminary results. Our review illustrates the role of molecular imaging in patients with BM. Along with magnetic resonance imaging (MRI), the gold standard for diagnosis of BM, PET is a useful complementary technique for processes that otherwise cannot be obtained from anatomical MRI alone. Full article
(This article belongs to the Special Issue Advanced Research in Metastatic Brain Tumors)
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37 pages, 4133 KiB  
Review
Biosynthesis and Significance of Fatty Acids, Glycerophospholipids, and Triacylglycerol in the Processes of Glioblastoma Tumorigenesis
by Jan Korbecki, Mateusz Bosiacki, Izabela Gutowska, Dariusz Chlubek and Irena Baranowska-Bosiacka
Cancers 2023, 15(7), 2183; https://doi.org/10.3390/cancers15072183 - 06 Apr 2023
Cited by 4 | Viewed by 2586
Abstract
One area of glioblastoma research is the metabolism of tumor cells and detecting differences between tumor and healthy brain tissue metabolism. Here, we review differences in fatty acid metabolism, with a particular focus on the biosynthesis of saturated fatty acids (SFA), monounsaturated fatty [...] Read more.
One area of glioblastoma research is the metabolism of tumor cells and detecting differences between tumor and healthy brain tissue metabolism. Here, we review differences in fatty acid metabolism, with a particular focus on the biosynthesis of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA) by fatty acid synthase (FASN), elongases, and desaturases. We also describe the significance of individual fatty acids in glioblastoma tumorigenesis, as well as the importance of glycerophospholipid and triacylglycerol synthesis in this process. Specifically, we show the significance and function of various isoforms of glycerol-3-phosphate acyltransferases (GPAT), 1-acylglycerol-3-phosphate O-acyltransferases (AGPAT), lipins, as well as enzymes involved in the synthesis of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), and cardiolipin (CL). This review also highlights the involvement of diacylglycerol O-acyltransferase (DGAT) in triacylglycerol biosynthesis. Due to significant gaps in knowledge, the GEPIA database was utilized to demonstrate the significance of individual enzymes in glioblastoma tumorigenesis. Finally, we also describe the significance of lipid droplets in glioblastoma and the impact of fatty acid synthesis, particularly docosahexaenoic acid (DHA), on cell membrane fluidity and signal transduction from the epidermal growth factor receptor (EGFR). Full article
(This article belongs to the Special Issue Lipids and Small Metabolites in Cancer)
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22 pages, 1927 KiB  
Review
Tumor-Infiltrating B Lymphocytes: Promising Immunotherapeutic Targets for Primary Liver Cancer Treatment
by Giulia Milardi and Ana Lleo
Cancers 2023, 15(7), 2182; https://doi.org/10.3390/cancers15072182 - 06 Apr 2023
Cited by 3 | Viewed by 2097
Abstract
Hepatocellular carcinoma and cholangiocarcinoma are the fourth most lethal primary cancers worldwide. Therefore, there is an urgent need for therapeutic strategies, including immune cell targeting therapies. The heterogeneity of liver cancer is partially explained by the characteristics of the tumor microenvironment (TME), where [...] Read more.
Hepatocellular carcinoma and cholangiocarcinoma are the fourth most lethal primary cancers worldwide. Therefore, there is an urgent need for therapeutic strategies, including immune cell targeting therapies. The heterogeneity of liver cancer is partially explained by the characteristics of the tumor microenvironment (TME), where adaptive and innate immune system cells are the main components. Pioneering studies of primary liver cancers revealed that tumor-infiltrating immune cells and their dynamic interaction with cancer cells significantly impacted carcinogenesis, playing an important role in cancer immune evasion and responses to immunotherapy treatment. In particular, B cells may play a prominent role and have a controversial function in the TME. In this work, we highlight the effect of B lymphocytes as tumor infiltrates in relation to primary liver cancers and their potential prognostic value. We also present the key pathways underlying B-cell interactions within the TME, as well as the way that a comprehensive characterization of B-cell biology can be exploited to develop novel immune-based therapeutic approaches. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Primary Liver Cancer)
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13 pages, 634 KiB  
Article
Characteristics of Cancer-Related Fatigue and an Efficient Model to Identify Patients with Gynecological Cancer Seeking Fatigue-Related Management
by Ying-Wen Wang, Yu-Che Ou, Hao Lin, Kun-Siang Huang, Hung-Chun Fu, Chen-Hsuan Wu, Ying-Yi Chen, Szu-Wei Huang, Hung-Pin Tu and Ching-Chou Tsai
Cancers 2023, 15(7), 2181; https://doi.org/10.3390/cancers15072181 - 06 Apr 2023
Cited by 2 | Viewed by 1758
Abstract
Cancer-related fatigue (CRF) is the most common somatic discomfort in patients with gynecological cancers. CRF is often overlooked; however, it can impair the patients’ quality of life considerably. This cross-sectional study aimed to identify the clinical characteristics of CRF in gynecological cancer patients. [...] Read more.
Cancer-related fatigue (CRF) is the most common somatic discomfort in patients with gynecological cancers. CRF is often overlooked; however, it can impair the patients’ quality of life considerably. This cross-sectional study aimed to identify the clinical characteristics of CRF in gynecological cancer patients. Questionnaires and the International Classification of Diseases 10th Revision (ICD-10) criteria were used to identify CRF. The enrolled patients were further categorized according to the amount of fatigue-related management received. Of the enrolled 190 patients, 40.0% had endometrial cancer, 28.9% had cervical cancer, and 31.1% had ovarian cancer. On the basis of the ICD-10 diagnostic criteria, 42.6% had non-cancer-related fatigue, 10% had CRF, and 51% had BFI-T questionnaire-based fatigue. Moreover, 77.9% of the study cohort had ever received fatigue-related management. Further analysis showed that patients with endometrial/cervical cancer, International Federation of Gynecology and Obstetrics stage >1, Eastern Cooperative Oncology Group performance status score ≥1, inadequate cancer treatment response, and receiving cancer treatment in the past week had a higher probability of receiving more fatigue-related management. The five-item predictive model developed from these factors may help physicians recognize patients seeking more fatigue-related management more efficiently. This is important as they may suffer from a more profound CRF. Full article
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14 pages, 5720 KiB  
Article
MR Vascular Fingerprinting with Hybrid Gradient–Spin Echo Dynamic Susceptibility Contrast MRI for Characterization of Microvasculature in Gliomas
by Krishnapriya Venugopal, Fatemeh Arzanforoosh, Daniëlle van Dorth, Marion Smits, Matthias J. P. van Osch, Juan A. Hernandez-Tamames, Esther A. H. Warnert and Dirk H. J. Poot
Cancers 2023, 15(7), 2180; https://doi.org/10.3390/cancers15072180 - 06 Apr 2023
Cited by 1 | Viewed by 1476
Abstract
Characterization of tumor microvasculature is important in tumor assessment and studying treatment response. This is possible by acquiring vascular biomarkers with magnetic resonance imaging (MRI) based on dynamic susceptibility contrast (DSC). We propose magnetic resonance vascular fingerprinting (MRVF) for hybrid echo planar imaging [...] Read more.
Characterization of tumor microvasculature is important in tumor assessment and studying treatment response. This is possible by acquiring vascular biomarkers with magnetic resonance imaging (MRI) based on dynamic susceptibility contrast (DSC). We propose magnetic resonance vascular fingerprinting (MRVF) for hybrid echo planar imaging (HEPI) acquired during the first passage of the contrast agent (CA). The proposed approach was evaluated in patients with gliomas, and we simultaneously estimated vessel radius and relative cerebral blood volume. These parameters were also compared to the respective values estimated using the previously introduced vessel size imaging (VSI) technique. The results of both methods were found to be consistent. MRVF was also found to be robust to noise in the estimation of the parameters. DSC-HEPI-based MRVF provides characterization of microvasculature in gliomas with a short acquisition time and can be further improved in several ways to increase our understanding of tumor physiology. Full article
(This article belongs to the Special Issue Advances in Neuro-Oncological Imaging)
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28 pages, 7398 KiB  
Article
DSCC_Net: Multi-Classification Deep Learning Models for Diagnosing of Skin Cancer Using Dermoscopic Images
by Maryam Tahir, Ahmad Naeem, Hassaan Malik, Jawad Tanveer, Rizwan Ali Naqvi and Seung-Won Lee
Cancers 2023, 15(7), 2179; https://doi.org/10.3390/cancers15072179 - 06 Apr 2023
Cited by 33 | Viewed by 5989
Abstract
Skin cancer is one of the most lethal kinds of human illness. In the present state of the health care system, skin cancer identification is a time-consuming procedure and if it is not diagnosed initially then it can be threatening to human life. [...] Read more.
Skin cancer is one of the most lethal kinds of human illness. In the present state of the health care system, skin cancer identification is a time-consuming procedure and if it is not diagnosed initially then it can be threatening to human life. To attain a high prospect of complete recovery, early detection of skin cancer is crucial. In the last several years, the application of deep learning (DL) algorithms for the detection of skin cancer has grown in popularity. Based on a DL model, this work intended to build a multi-classification technique for diagnosing skin cancers such as melanoma (MEL), basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanocytic nevi (MN). In this paper, we have proposed a novel model, a deep learning-based skin cancer classification network (DSCC_Net) that is based on a convolutional neural network (CNN), and evaluated it on three publicly available benchmark datasets (i.e., ISIC 2020, HAM10000, and DermIS). For the skin cancer diagnosis, the classification performance of the proposed DSCC_Net model is compared with six baseline deep networks, including ResNet-152, Vgg-16, Vgg-19, Inception-V3, EfficientNet-B0, and MobileNet. In addition, we used SMOTE Tomek to handle the minority classes issue that exists in this dataset. The proposed DSCC_Net obtained a 99.43% AUC, along with a 94.17%, accuracy, a recall of 93.76%, a precision of 94.28%, and an F1-score of 93.93% in categorizing the four distinct types of skin cancer diseases. The rates of accuracy for ResNet-152, Vgg-19, MobileNet, Vgg-16, EfficientNet-B0, and Inception-V3 are 89.32%, 91.68%, 92.51%, 91.12%, 89.46% and 91.82%, respectively. The results showed that our proposed DSCC_Net model performs better as compared to baseline models, thus offering significant support to dermatologists and health experts to diagnose skin cancer. Full article
(This article belongs to the Special Issue Artificial Intelligence in Cancer Screening)
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18 pages, 1149 KiB  
Review
R-Loops at Chromosome Ends: From Formation, Regulation, and Cellular Consequence
by Yi Gong and Yie Liu
Cancers 2023, 15(7), 2178; https://doi.org/10.3390/cancers15072178 - 06 Apr 2023
Cited by 9 | Viewed by 2399
Abstract
Telomeric repeat containing RNA (TERRA) is transcribed from subtelomeric regions to telomeres. TERRA RNA can invade telomeric dsDNA and form telomeric R-loop structures. A growing body of evidence suggests that TERRA-mediated R-loops are critical players in telomere length homeostasis. Here, we will review [...] Read more.
Telomeric repeat containing RNA (TERRA) is transcribed from subtelomeric regions to telomeres. TERRA RNA can invade telomeric dsDNA and form telomeric R-loop structures. A growing body of evidence suggests that TERRA-mediated R-loops are critical players in telomere length homeostasis. Here, we will review current knowledge on the regulation of R-loop levels at telomeres. In particular, we will discuss how the central player TERRA and its binding proteins modulate R-loop levels through various mechanisms. We will further provide an overview of the consequences of TERRA-mediated persistent or unscheduled R-loops at telomeres in human ALT cancers and other organisms, with a focus on telomere length regulation after replication interference-induced damage and DNA homologous recombination-mediated repair. Full article
(This article belongs to the Special Issue Alternative Lengthening of Telomeres in Neoplasia)
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9 pages, 1166 KiB  
Opinion
Staged or Simultaneous Surgery for Colon or Rectal Cancer with Synchronous Liver Metastases: Implications for Study Design and Clinical Endpoints
by Sheraz Yaqub, Georgios Antonios Margonis and Kjetil Søreide
Cancers 2023, 15(7), 2177; https://doi.org/10.3390/cancers15072177 - 06 Apr 2023
Cited by 1 | Viewed by 1550
Abstract
In patients presenting with colorectal cancer and synchronous liver metastases, the disease burden related to the liver metastasis is the driving cause of limited longevity and, eventually, risk of death. Surgical resection is the potentially curative treatment for colorectal cancer liver metastases. In [...] Read more.
In patients presenting with colorectal cancer and synchronous liver metastases, the disease burden related to the liver metastasis is the driving cause of limited longevity and, eventually, risk of death. Surgical resection is the potentially curative treatment for colorectal cancer liver metastases. In the synchronous setting where both the liver metastases and the primary tumor are resectable with a relative low risk, the oncological surgeon and the patient may consider three potential treatment strategies. Firstly, a “staged” or a “simultaneous” surgical approach. Secondly, for a staged strategy, a ‘conventional approach’ will suggest removal of the primary tumor first (either colon or rectal cancer) and plan for liver surgery after recovery from the first operation. A “Liver first” strategy is prioritizing the liver resection before resection of the primary tumor. Planning a surgical trial investigating a two-organ oncological resection with highly variable extent and complexity of resection as well as the potential impact of perioperative chemo(radio)therapy makes it difficult to find the optimal primary endpoint. Here, we suggest running investigational trials with carefully chosen composite endpoints as well as embedded risk-stratification strategies to identify subgroups of patients who may benefit from simultaneous surgery. Full article
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17 pages, 2346 KiB  
Article
Disequilibrium between BRCA1 and BRCA2 Circular and Messenger RNAs Plays a Role in Breast Cancer
by Corentin Levacher, Mathieu Viennot, Aurélie Drouet, Ludivine Beaussire, Sophie Coutant, Jean-Christophe Théry, Stéphanie Baert-Desurmont, Marick Laé, Philippe Ruminy and Claude Houdayer
Cancers 2023, 15(7), 2176; https://doi.org/10.3390/cancers15072176 - 06 Apr 2023
Viewed by 1240
Abstract
Breast cancer is a frequent disease for which the discovery of markers that enable early detection or prognostic assessment remains challenging. Circular RNAs (circRNAs) are single-stranded structures in closed loops that are produced by backsplicing. CircRNA and messenger RNA (mRNA) are generated co-transcriptionally, [...] Read more.
Breast cancer is a frequent disease for which the discovery of markers that enable early detection or prognostic assessment remains challenging. Circular RNAs (circRNAs) are single-stranded structures in closed loops that are produced by backsplicing. CircRNA and messenger RNA (mRNA) are generated co-transcriptionally, and backsplicing and linear splicing compete against each other. As mRNAs are key players in tumorigenesis, we hypothesize that a disruption of the balance between circRNAs and mRNAs could promote breast cancer. Hence, we developed an assay for a simultaneous study of circRNAs and mRNAs, which we have called splice and expression analyses by exon ligation and high-throughput sequencing (SEALigHTS). Following SEALigHTS validation for BRCA1 and BRCA2, our hypothesis was tested using an independent research set of 95 pairs from tumor and adjacent normal breast tissues. In this research set, ratios of BRCA1 and BRCA2 circRNAs/mRNAs were significantly lower in the tumor breast tissue compared to normal tissue (p = 1.6 × 10−9 and p = 4.4 × 10−5 for BRCA1 and BRCA2, respectively). Overall, we developed an innovative method to study linear splicing and backsplicing, described the repertoire of BRCA1 and BRCA2 circRNAs, including 15 novel ones, and showed for the first time that a disequilibrium between BRCA1 and BRCA2 circRNAs and mRNAs plays a role in breast cancer. Full article
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14 pages, 1182 KiB  
Article
Epidemiology of Oral Cancer in Taiwan: A Population-Based Cancer Registry Study
by Chao-Wei Chou, Chun-Ru Lin, Yi-Ting Chung and Chin-Sheng Tang
Cancers 2023, 15(7), 2175; https://doi.org/10.3390/cancers15072175 - 06 Apr 2023
Cited by 8 | Viewed by 1891
Abstract
Oral cancer (OC) is one of the most common cancers worldwide, and its incidence has regional differences. In this study, the cancer registry database obtained from 1980 to 2019 was used to analyze the characteristic of incidence of OC by average annual percentage [...] Read more.
Oral cancer (OC) is one of the most common cancers worldwide, and its incidence has regional differences. In this study, the cancer registry database obtained from 1980 to 2019 was used to analyze the characteristic of incidence of OC by average annual percentage change (AAPC) and an age–period–cohort model. Spearman’s correlation was used to analyze the relationship between the age-standard incidence rates (ASR) of OC and related risk factors. Our results showed that the ASR of OC increased from 4.19 to 27.19 per 100,000 population with an AAPC of 5.1% (95% CI = 3.9–6.3, p value < 0.001) in men and from 1.16 to 2.8 per 100,000 population with an AAPC of 3.1% (95% CI = 2.6–3.6, p value < 0.001) in women between 1980–1984 and 2015–2019. The age–period–cohort model reported a trend of rising then declining for the rate ratio in men, with peaks occurring in the 1975 cohort, with a rate ratio of 6.80. The trend of incidence of oral cancer was related to changes in the consumption of cigarettes and alcohol and production of betel quid, with r values of 0.952, 0.979 and 0.963, respectively (all p values < 0.001). We strongly suggest avoiding these risk factors in order to prevent OC. Full article
(This article belongs to the Section Cancer Epidemiology and Prevention)
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16 pages, 2557 KiB  
Article
Melanoma Clinical Decision Support System: An Artificial Intelligence-Based Tool to Diagnose and Predict Disease Outcome in Early-Stage Melanoma Patients
by Jose Luis Diaz-Ramón, Jesus Gardeazabal, Rosa Maria Izu, Estibaliz Garrote, Javier Rasero, Aintzane Apraiz, Cristina Penas, Sandra Seijo, Cristina Lopez-Saratxaga, Pedro Maria De la Peña, Ana Sanchez-Diaz, Goikoane Cancho-Galan, Veronica Velasco, Arrate Sevilla, David Fernandez, Iciar Cuenca, Jesus María Cortes, Santos Alonso, Aintzane Asumendi and María Dolores Boyano
Cancers 2023, 15(7), 2174; https://doi.org/10.3390/cancers15072174 - 06 Apr 2023
Cited by 4 | Viewed by 2234
Abstract
This study set out to assess the performance of an artificial intelligence (AI) algorithm based on clinical data and dermatoscopic imaging for the early diagnosis of melanoma, and its capacity to define the metastatic progression of melanoma through serological and histopathological biomarkers, enabling [...] Read more.
This study set out to assess the performance of an artificial intelligence (AI) algorithm based on clinical data and dermatoscopic imaging for the early diagnosis of melanoma, and its capacity to define the metastatic progression of melanoma through serological and histopathological biomarkers, enabling dermatologists to make more informed decisions about patient management. Integrated analysis of demographic data, images of the skin lesions, and serum and histopathological markers were analyzed in a group of 196 patients with melanoma. The interleukins (ILs) IL-4, IL-6, IL-10, and IL-17A as well as IFNγ (interferon), GM-CSF (granulocyte and macrophage colony-stimulating factor), TGFβ (transforming growth factor), and the protein DCD (dermcidin) were quantified in the serum of melanoma patients at the time of diagnosis, and the expression of the RKIP, PIRIN, BCL2, BCL3, MITF, and ANXA5 proteins was detected by immunohistochemistry (IHC) in melanoma biopsies. An AI algorithm was used to improve the early diagnosis of melanoma and to predict the risk of metastasis and of disease-free survival. Two models were obtained to predict metastasis (including “all patients” or only patients “at early stages of melanoma”), and a series of attributes were seen to predict the progression of metastasis: Breslow thickness, infiltrating BCL-2 expressing lymphocytes, and IL-4 and IL-6 serum levels. Importantly, a decrease in serum GM-CSF seems to be a marker of poor prognosis in patients with early-stage melanomas. Full article
(This article belongs to the Collection Artificial Intelligence in Oncology)
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17 pages, 370 KiB  
Review
Technical Aspects of Motor and Language Mapping in Glioma Patients
by Nadeem N. Al-Adli, Jacob S. Young, Youssef E. Sibih and Mitchel S. Berger
Cancers 2023, 15(7), 2173; https://doi.org/10.3390/cancers15072173 - 06 Apr 2023
Cited by 4 | Viewed by 1844
Abstract
Gliomas are infiltrative primary brain tumors that often invade functional cortical and subcortical regions, and they mandate individualized brain mapping strategies to avoid postoperative neurological deficits. It is well known that maximal safe resection significantly improves survival, while postoperative deficits minimize the benefits [...] Read more.
Gliomas are infiltrative primary brain tumors that often invade functional cortical and subcortical regions, and they mandate individualized brain mapping strategies to avoid postoperative neurological deficits. It is well known that maximal safe resection significantly improves survival, while postoperative deficits minimize the benefits associated with aggressive resections and diminish patients’ quality of life. Although non-invasive imaging tools serve as useful adjuncts, intraoperative stimulation mapping (ISM) is the gold standard for identifying functional cortical and subcortical regions and minimizing morbidity during these challenging resections. Current mapping methods rely on the use of low-frequency and high-frequency stimulation, delivered with monopolar or bipolar probes either directly to the cortical surface or to the subcortical white matter structures. Stimulation effects can be monitored through patient responses during awake mapping procedures and/or with motor-evoked and somatosensory-evoked potentials in patients who are asleep. Depending on the patient’s preoperative status and tumor location and size, neurosurgeons may choose to employ these mapping methods during awake or asleep craniotomies, both of which have their own benefits and challenges. Regardless of which method is used, the goal of intraoperative stimulation is to identify areas of non-functional tissue that can be safely removed to facilitate an approach trajectory to the equator, or center, of the tumor. Recent technological advances have improved ISM’s utility in identifying subcortical structures and minimized the seizure risk associated with cortical stimulation. In this review, we summarize the salient technical aspects of which neurosurgeons should be aware in order to implement intraoperative stimulation mapping effectively and safely during glioma surgery. Full article
(This article belongs to the Special Issue Advances of Brain Mapping in Cancer Research)
14 pages, 2906 KiB  
Article
Label-Free Quantification Mass Spectrometry Identifies Protein Markers of Chemotherapy Response in High-Grade Serous Ovarian Cancer
by Georgia Arentz, Parul Mittal, Manuela Klingler-Hoffmann, Mark R. Condina, Carmela Ricciardelli, Noor A. Lokman, Gurjeet Kaur, Martin K. Oehler and Peter Hoffmann
Cancers 2023, 15(7), 2172; https://doi.org/10.3390/cancers15072172 - 06 Apr 2023
Cited by 2 | Viewed by 1837
Abstract
Eighty percent of ovarian cancer patients initially respond to chemotherapy, but the majority eventually experience a relapse and die from the disease with acquired chemoresistance. In addition, 20% of patients do not respond to treatment at all, as their disease is intrinsically chemotherapy [...] Read more.
Eighty percent of ovarian cancer patients initially respond to chemotherapy, but the majority eventually experience a relapse and die from the disease with acquired chemoresistance. In addition, 20% of patients do not respond to treatment at all, as their disease is intrinsically chemotherapy resistant. Data-independent acquisition nano-flow liquid chromatography–mass spectrometry (DIA LC-MS) identified the three protein markers: gelsolin (GSN), calmodulin (CALM1), and thioredoxin (TXN), to be elevated in high-grade serous ovarian cancer (HGSOC) tissues from patients that responded to chemotherapy compared to those who did not; the differential expression of the three protein markers was confirmed by immunohistochemistry. Analysis of the online GENT2 database showed that mRNA levels of GSN, CALM1, and TXN were decreased in HGSOC compared to fallopian tube epithelium. Elevated levels of GSN and TXN mRNA expression correlated with increased overall and progression-free survival, respectively, in a Kaplan–Meier analysis of a large online repository of HGSOC patient data. Importantly, differential expression of the three protein markers was further confirmed when comparing parental OVCAR-5 cells to carboplatin-resistant OVCAR-5 cells using DIA LC-MS analysis. Our findings suggest that GSN, CALM1, and TXN may be useful biomarkers for predicting chemotherapy response and understanding the mechanisms of chemotherapy resistance. Proteomic data are available via ProteomeXchange with identifier PXD033785. Full article
(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)
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16 pages, 3491 KiB  
Article
Upregulation of Cell Surface Glycoproteins in Correlation with KSHV LANA in the Kaposi Sarcoma Tumor Microenvironment
by Sara R. Privatt, Owen Ngalamika, Jianshui Zhang, Qinsheng Li, Charles Wood and John T. West
Cancers 2023, 15(7), 2171; https://doi.org/10.3390/cancers15072171 - 06 Apr 2023
Viewed by 1494
Abstract
HIV-associated epidemic Kaposi sarcoma (EpKS) remains one of the most prevalent cancers in sub-Saharan Africa despite the widespread uptake of anti-retroviral therapy and HIV-1 suppression. In an effort to define potential therapeutic targets against KS tumors, we analyzed previously published KS bulk tumor [...] Read more.
HIV-associated epidemic Kaposi sarcoma (EpKS) remains one of the most prevalent cancers in sub-Saharan Africa despite the widespread uptake of anti-retroviral therapy and HIV-1 suppression. In an effort to define potential therapeutic targets against KS tumors, we analyzed previously published KS bulk tumor transcriptomics to identify cell surface biomarkers. In addition to upregulated gene expression (>6-fold) in the EpKS tumor microenvironment, biomarkers were selected for correlation with KSHV latency-associated nuclear antigen (LANA) expression. The cell surface glycoprotein genes identified were KDR, FLT4, ADAM12, UNC5A, ZP2, and OX40, as well as the endothelial lineage determinants Prox-1 and CD34. Each protein was evaluated for its expression and co-localization with KSHV LANA using multi-color immunofluorescence in KS tissues, KSHV-infected L1T2 cells, uninfected TIVE cells, and murine L1T2 tumor xenografts. Five surface glycoproteins (KDR, FLT4, UNC5A, ADAM12, and CD34) were associated with LANA-positive cells but were also detected in uninfected cells in the KS microenvironment. In vitro L1T2 cultures showed evidence of only FLT4, KDR, and UNC5A, whereas mouse L1T2 xenografts recapitulated human KS cell surface expression profiles, with the exception of CD34 and Prox-1. In KS tumors, most LANA-positive cells co-expressed markers of vascular as well as lymphatic endothelial lineages, suggesting KS-associated dedifferentiation to a more mesenchymal/progenitor phenotype. Full article
(This article belongs to the Section Infectious Agents and Cancer)
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10 pages, 2111 KiB  
Communication
Cardiovascular Immunotoxicity Associated with Immune Checkpoint Inhibitors in Metastatic Melanoma
by Jean-Matthieu L’Orphelin, Charles Dollalille, Julia Akroun, Joachim Alexandre and Anne Dompmartin
Cancers 2023, 15(7), 2170; https://doi.org/10.3390/cancers15072170 - 06 Apr 2023
Viewed by 1752
Abstract
Background: Checkpoint inhibitors, such as PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab), are widely used in metastatic melanoma, and most immune-related adverse events are known. Several cardiovascular AEs (CVAEs) associated with immune checkpoint inhibitor exposure have been reported in post-marketing surveillance studies [...] Read more.
Background: Checkpoint inhibitors, such as PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab), are widely used in metastatic melanoma, and most immune-related adverse events are known. Several cardiovascular AEs (CVAEs) associated with immune checkpoint inhibitor exposure have been reported in post-marketing surveillance studies and represent major issues for patients with melanoma during and after cancer treatment. Data on CVAES induced by immune checkpoint inhibitors in melanoma, especially incidence and risk factors, are lacking. Methods: A systematic review of the literature up to 31 August 2020 was performed in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and the ClinicalTrials.gov register according to prespecified selection criteria from inception to 7 April 2020. Statistics were performed on 3289 patients from five randomized clinical trials on melanoma. Results: Patients with melanoma treated with immune checkpoint inhibitors had a significant risk of presenting dyslipidemia (Peto OR: 4.74, 95% CI: 2.16–10.41, p < 0.01, I2 = 0%, p = 0.94). The Peto OR was numerically significant for pericarditis, myocarditis, heart failure, myocardial infarction, cerebral ischemia, high pulmonary pressure, blood high pressure, arrhythmias, endocarditis, and conduction disturbances, but the confidence interval was not significant. The risk of CVAEs was not statistically different between melanoma treated with immune checkpoint inhibitors and other tumors treated with immune checkpoint inhibitors (range of p-value from 0.13 to 0.95). No interaction between follow-up length and CVAE reporting was found. Conclusions: Our study underlines that checkpoint inhibitors used for melanoma increase CVAEs, especially dyslipidemia, which could pave the way to chronic inflammatory processes, atherosclerosis, and, finally, ischemic cardiopathy. These cardiovascular adverse events could be acute or delayed, justifying the monitoring of lipidic biology and a baseline cardiology consultation. Full article
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25 pages, 1410 KiB  
Review
The Cell Biology of Metastatic Invasion in Pancreatic Cancer: Updates and Mechanistic Insights
by Vidhu B. Joshi, Omar L. Gutierrez Ruiz and Gina L. Razidlo
Cancers 2023, 15(7), 2169; https://doi.org/10.3390/cancers15072169 - 06 Apr 2023
Cited by 4 | Viewed by 3029
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality worldwide. This is largely due to the lack of routine screening protocols, an absence of symptoms in early-stage disease leading to late detection, and a paucity of effective treatment options. [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality worldwide. This is largely due to the lack of routine screening protocols, an absence of symptoms in early-stage disease leading to late detection, and a paucity of effective treatment options. Critically, the majority of patients either present with metastatic disease or rapidly develop metastatic disease. Thus, there is an urgent need to deepen our understanding of metastasis in PDAC. During metastasis, tumor cells escape from the primary tumor, enter the circulation, and travel to a distant site to form a secondary tumor. In order to accomplish this relatively rare event, tumor cells develop an enhanced ability to detach from the primary tumor, migrate into the surrounding matrix, and invade across the basement membrane. In addition, cancer cells interact with the various cell types and matrix proteins that comprise the tumor microenvironment, with some of these factors working to promote metastasis and others working to suppress it. In PDAC, many of these processes are not well understood. The purpose of this review is to highlight recent advances in the cell biology of the early steps of the metastatic cascade in pancreatic cancer. Specifically, we will examine the regulation of epithelial-to-mesenchymal transition (EMT) in PDAC and its requirement for metastasis, summarize our understanding of how PDAC cells invade and degrade the surrounding matrix, and discuss how migration and adhesion dynamics are regulated in PDAC to optimize cancer cell motility. In addition, the role of the tumor microenvironment in PDAC will also be discussed for each of these invasive processes. Full article
(This article belongs to the Collection Recent Advances in Pancreatic Ductal Adenocarcinoma)
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31 pages, 904 KiB  
Systematic Review
Functional Alteration in the Brain Due to Tumour Invasion in Paediatric Patients: A Systematic Review
by Nur Shaheera Aidilla Sahrizan, Hanani Abdul Manan, Hamzaini Abdul Hamid, Jafri Malin Abdullah and Noorazrul Yahya
Cancers 2023, 15(7), 2168; https://doi.org/10.3390/cancers15072168 - 06 Apr 2023
Cited by 1 | Viewed by 1715
Abstract
Working memory, language and speech abilities, motor skills, and visual abilities are often impaired in children with brain tumours. This is because tumours can invade the brain’s functional areas and cause alterations to the neuronal networks. However, it is unclear what the mechanism [...] Read more.
Working memory, language and speech abilities, motor skills, and visual abilities are often impaired in children with brain tumours. This is because tumours can invade the brain’s functional areas and cause alterations to the neuronal networks. However, it is unclear what the mechanism of tumour invasion is and how various treatments can cause cognitive impairment. Therefore, this study aims to systematically evaluate the effects of tumour invasion on the cognitive, language, motor, and visual abilities of paediatric patients, as well as discuss the alterations and modifications in neuronal networks and anatomy. The electronic database, PubMed, was used to find relevant studies. The studies were systematically reviewed based on the type and location of brain tumours, cognitive assessment, and pre- and post-operative deficits experienced by patients. Sixteen studies were selected based on the inclusion and exclusion criteria following the guidelines from PRISMA. Most studies agree that tumour invasion in the brain causes cognitive dysfunction and alteration in patients. The effects of a tumour on cognition, language, motor, and visual abilities depend on the type of tumour and its location in the brain. The alteration to the neuronal networks is also dependent on the type and location of the tumour. However, the default mode network (DMN) is the most affected network, regardless of the tumour type and location.Furthermore, our findings suggest that different treatment types can also contribute to patients’ cognitive function to improve or deteriorate. Deficits that persisted or were acquired after surgery could result from surgical manipulation or the progression of the tumour’s growth. Meanwhile, recovery from the deficits indicated that the brain has the ability to recover and reorganise itself. Full article
(This article belongs to the Special Issue Pediatric Brain Tumors: From Diagnosis to Treatment)
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13 pages, 1438 KiB  
Article
Predictors for Survival of Patients with Squamous Cell Carcinoma of Unknown Primary in the Head and Neck Region
by Steffen Wagner, Christine Langer, Nora Wuerdemann, Susanne Reiser, Helen Abing, Jörn Pons-Kühnemann, Elena-Sophie Prigge, Magnus von Knebel Doeberitz, Stefan Gattenlöhner, Tim Waterboer, Lea Schroeder, Christoph Arens, Jens Peter Klussmann and Claus Wittekindt
Cancers 2023, 15(7), 2167; https://doi.org/10.3390/cancers15072167 - 06 Apr 2023
Cited by 1 | Viewed by 1422
Abstract
Background: Human papillomavirus (HPV) status is the most important predictor of survival in oropharyngeal squamous cell carcinoma (OPSCC). In patients with cervical lymph node metastases of squamous cell carcinoma of unknown origin (CUPHNSCC), much less is known. Methods: We assessed a [...] Read more.
Background: Human papillomavirus (HPV) status is the most important predictor of survival in oropharyngeal squamous cell carcinoma (OPSCC). In patients with cervical lymph node metastases of squamous cell carcinoma of unknown origin (CUPHNSCC), much less is known. Methods: We assessed a consecutive cohort of CUPHNSCC diagnosed from 2000–2018 for HPV DNA, mRNA, p16INK4a (p16) expression, and risk factors to identify prognostic classification markers. Results: In 32/103 (31%) CUPHNSCC, p16 was overexpressed, and high-risk HPV DNA was detected in 18/32 (56.3%). This was mostly consistent with mRNA detection. In recursive partitioning analysis, CUPHNSCC patients were classified into three risk groups according to performance status (ECOG) and p16. Principal component analysis suggests a negative correlation of p16, HPV DNA, and gender in relation to ECOG, as well as a correlation between N stage, extranodal extension, and tobacco/alcohol consumption. Conclusions: Despite obvious differences, CUPHNSCC shares similarities in risk profile with OPSCC. However, the detection of p16 alone appears to be more suitable for the classification of CUPHNSCC than for OPSCC and, in combination with ECOG, allows stratification into three risk groups. In the future, additional factors besides p16 and ECOG may become important in larger studies or cases with special risk profiles. Full article
(This article belongs to the Special Issue Advances in HPV-Associated Cancers of Different Organs)
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10 pages, 1322 KiB  
Article
New Automated Method for Lung Functional Volumes Delineation with Lung Perfusion PET/CT Imaging
by Fanny Pinot, David Bourhis, Vincent Bourbonne, Romain Floch, Maelle Mauguen, Frédérique Blanc-Béguin, Ulrike Schick, Mohamed Hamya, Ronan Abgral, Grégoire Le Gal, Pierre-Yves Salaün, François Lucia and Pierre-Yves Le Roux
Cancers 2023, 15(7), 2166; https://doi.org/10.3390/cancers15072166 - 06 Apr 2023
Cited by 2 | Viewed by 1117
Abstract
Background: Gallium-68 lung perfusion PET/CT is an emerging imaging modality for the assessment of regional lung function, especially to optimise radiotherapy (RT) planning. A key step of lung functional avoidance RT is the delineation of lung functional volumes (LFVs) to be integrated into [...] Read more.
Background: Gallium-68 lung perfusion PET/CT is an emerging imaging modality for the assessment of regional lung function, especially to optimise radiotherapy (RT) planning. A key step of lung functional avoidance RT is the delineation of lung functional volumes (LFVs) to be integrated into radiation plans. However, there is currently no consistent and reproducible delineation method for LFVs. The aim of this study was to develop and evaluate an automated delineation threshold method based on total lung function for LFVs delineation with Gallium-68 MAA lung PET/CT imaging. Material and Method: Patients prospectively enrolled in the PEGASUS trial—a pilot study assessing the feasibility of lung functional avoidance using perfusion PET/CT imaging for lung stereotactic body radiotherapy (SBRT) of primary or secondary lesion—were analysed. Patients underwent lung perfusion MAA-68Ga PET/CT imaging and pulmonary function tests (PFTs) as part of pre-treatment evaluation. LFVs were delineated using two methods: the commonly used relative to the maximal pixel value threshold method (pmax threshold method, X%pmax volumes) and a new approach based on a relative to whole lung function threshold method (WLF threshold method, FVX% volumes) using a dedicated iterative algorithm. For both methods, LFVs were expressed in terms of % of the anatomical lung volume (AV) and of % of the total lung activity. Functional volumes were compared for patients with normal PFTs and pre-existing airway disease. Results: 60 patients were analysed. Among the 48 patients who had PFTs, 31 (65%) had pre-existing lung disease. The pmax and WLF threshold methods clearly provided different functional volumes with a wide range of relative lung function for a given pmax volume, and conversely, a wide range of corresponding pmax values for a given WLF volume. The WLF threshold method provided more reliable and consistent volumes with much lower dispersion of LFVs as compared to the pmax method, especially in patients with normal PFTs. Conclusions: We developed a relative to whole lung function threshold segmentation method to delineate lung functional volumes on perfusion PET/CT imaging. The automated algorithm allows for reproducible contouring. This new approach, relatively unaffected by the presence of hot spots, provides reliable and consistent functional volumes, and is clinically meaningful for clinicians. Full article
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15 pages, 3365 KiB  
Article
Exploring Spatial Heterogeneity of Immune Cells in Nasopharyngeal Cancer
by Aastha Sobti, Christina Sakellariou, Johan S. Nilsson, David Askmyr, Lennart Greiff and Malin Lindstedt
Cancers 2023, 15(7), 2165; https://doi.org/10.3390/cancers15072165 - 05 Apr 2023
Cited by 2 | Viewed by 2180
Abstract
Nasopharyngeal cancer (NPC) is a malignant tumor. In a recent publication, we described the presence and distribution of CD8+ T cells in NPC and used the information to identify ‘inflamed’, ‘immune-excluded’, and ‘desert’ immune phenotypes, where ‘inflamed’ and ‘immune-excluded’ NPCs were correlated [...] Read more.
Nasopharyngeal cancer (NPC) is a malignant tumor. In a recent publication, we described the presence and distribution of CD8+ T cells in NPC and used the information to identify ‘inflamed’, ‘immune-excluded’, and ‘desert’ immune phenotypes, where ‘inflamed’ and ‘immune-excluded’ NPCs were correlated with CD8 T cell infiltration and survival. Arguably, more detailed and, in particular, spatially resolved data are required for patient stratification and for the identification of new treatment targets. In this study, we investigate the phenotype of CD45+ leukocytes in the previously analyzed NPC samples by applying multiplexed tissue analysis to assess the spatial distribution of cell types and to quantify selected biomarkers. A total of 47 specified regions-of-interest (ROIs) were generated based on CD45, CD8, and PanCK morphological staining. Using the GeoMx® Digital Spatial Profiler (DSP), 49 target proteins were digitally quantified from the selected ROIs of a tissue microarray consisting of 30 unique NPC biopsies. Protein targets associated with B cells (CD20), NK cells (CD56), macrophages (CD68), and regulatory T cells (PD-1, FOXP3) were most differentially expressed in CD45+ segments within ‘immune-rich cancer cell islet’ regions of the tumor (cf. ‘surrounding stromal leukocyte’ regions). In contrast, markers associated with suppressive populations of myeloid cells (CD163, B7-H3, VISTA) and T cells (CD4, LAG3, Tim-3) were expressed at a higher level in CD45+ segments in the ‘surrounding stromal leukocyte’ regions (cf. ‘immune-rich cancer cell islet’ regions). When comparing the three phenotypes, the ‘inflamed’ profile (cf. ‘immune-excluded’ and ‘desert’) exhibited higher expression of markers associated with B cells, NK cells, macrophages, and myeloid cells. Myeloid markers were highly expressed in the ‘immune-excluded’ phenotype. Granulocyte markers and immune-regulatory markers were higher in the ‘desert‘ profile (cf. ‘inflamed’ and ‘immune-excluded’). In conclusion, this study describes the spatial heterogeneity of the immune microenvironment in NPC and highlights immune-related biomarkers in immune phenotypes, which may aid in the stratification of patients for therapeutic purposes. Full article
(This article belongs to the Special Issue Epstein-Barr Virus-Associated Cancers: From Pathogenesis to Treatment)
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13 pages, 288 KiB  
Article
Lung Cancer Incidence by Detailed Race–Ethnicity
by Hannah M. Cranford, Tulay Koru-Sengul, Gilberto Lopes and Paulo S. Pinheiro
Cancers 2023, 15(7), 2164; https://doi.org/10.3390/cancers15072164 - 05 Apr 2023
Cited by 1 | Viewed by 1576
Abstract
Lung cancer (LC) incidence rates and tumor characteristics among (non-Hispanic) Black and Hispanic detailed groups, normally characterized in aggregate, have been overlooked in the US. We used LC data from the Florida state cancer registry, 2012–2018, to compute LC age-adjusted incidence rates (AAIR) [...] Read more.
Lung cancer (LC) incidence rates and tumor characteristics among (non-Hispanic) Black and Hispanic detailed groups, normally characterized in aggregate, have been overlooked in the US. We used LC data from the Florida state cancer registry, 2012–2018, to compute LC age-adjusted incidence rates (AAIR) for US-born Black, Caribbean-born Black, Mexican, Puerto Rican, Cuban, Dominican, and Central and South American populations. We analyzed 120,550 total LC cases. Among Hispanics, Cuban males had the highest AAIR (65.6 per 100,000; 95%CI: 63.6–67.6), only 8% [Incidence Rate Ratio (IRR): 0.92; 95%CI: 0.89–0.95] lower than Whites, but 2.7 (IRR 95%CI: 2.31-3.19) times higher than Central Americans. Among Blacks, the AAIR for US-born Black males was over three times that of those Caribbean-born (IRR: 3.12; 95%CI: 2.80–3.40) and 14% higher than White males (IRR: 1.14; 95%CI: 1.11–1.18). Among women, US-born Blacks (46.4 per 100,000) and foreign-born Mexicans (12.2 per 100,000) had the highest and lowest rates. Aggregation of non-Hispanic Blacks or Hispanics obscures inherent disparities within groups. Understanding the distinct LC rates in US populations is crucial for targeting public health measures for LC diagnosis, prevention, and treatment. Further LC research exploring detailed race–ethnicity regarding LC in never-smokers is necessary, particularly among females and considering pertinent environmental factors. Full article
(This article belongs to the Section Cancer Epidemiology and Prevention)
23 pages, 8623 KiB  
Article
Adefovir Dipivoxil as a Therapeutic Candidate for Medullary Thyroid Carcinoma: Targeting RET and STAT3 Proto-Oncogenes
by Tariq Alqahtani, Vishnu Kumarasamy, Sahar Saleh Alghamdi, Rasha Saad Suliman, Khalid Bin Saleh, Mohammed A. Alrashed, Mohammed Aldhaeefi and Daekyu Sun
Cancers 2023, 15(7), 2163; https://doi.org/10.3390/cancers15072163 - 05 Apr 2023
Viewed by 1687
Abstract
Aberrant gene expression is often linked to the progression of various cancers, making the targeting of oncogene transcriptional activation a potential strategy to control tumor growth and development. The RET proto-oncogene’s gain-of-function mutation is a major cause of medullary thyroid carcinoma (MTC), which [...] Read more.
Aberrant gene expression is often linked to the progression of various cancers, making the targeting of oncogene transcriptional activation a potential strategy to control tumor growth and development. The RET proto-oncogene’s gain-of-function mutation is a major cause of medullary thyroid carcinoma (MTC), which is part of multiple endocrine neoplasia type 2 (MEN2) syndrome. In this study, we used a cell-based bioluminescence reporter system driven by the RET promoter to screen for small molecules that potentially suppress the RET gene transcription. We identified adefovir dipivoxil as a transcriptional inhibitor of the RET gene, which suppressed endogenous RET protein expression in MTC TT cells. Adefovir dipivoxil also interfered with STAT3 phosphorylation and showed high affinity to bind to STAT3. Additionally, it inhibited RET-dependent TT cell proliferation and increased apoptosis. These results demonstrate the potential of cell-based screening assays in identifying transcriptional inhibitors for other oncogenes. Full article
(This article belongs to the Section Cancer Therapy)
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14 pages, 4494 KiB  
Article
Raman Spectroscopic Imaging of Human Bladder Resectates towards Intraoperative Cancer Assessment
by Christoph Krafft, Jürgen Popp, Peter Bronsert and Arkadiusz Miernik
Cancers 2023, 15(7), 2162; https://doi.org/10.3390/cancers15072162 - 05 Apr 2023
Cited by 3 | Viewed by 1990
Abstract
Raman spectroscopy offers label-free assessment of bladder tissue for in vivo and ex vivo intraoperative applications. In a retrospective study, control and cancer specimens were prepared from ten human bladder resectates. Raman microspectroscopic images were collected from whole tissue samples in a closed [...] Read more.
Raman spectroscopy offers label-free assessment of bladder tissue for in vivo and ex vivo intraoperative applications. In a retrospective study, control and cancer specimens were prepared from ten human bladder resectates. Raman microspectroscopic images were collected from whole tissue samples in a closed chamber at 785 nm laser excitation using a 20× objective lens and 250 µm step size. Without further preprocessing, Raman images were decomposed by the hyperspectral unmixing algorithm vertex component analysis into endmember spectra and their abundancies. Hierarchical cluster analysis distinguished endmember Raman spectra that were assigned to normal bladder, bladder cancer, necrosis, epithelium and lipid inclusions. Interestingly, Raman spectra of microplastic particles, pigments or carotenoids were detected in 13 out of 20 specimens inside tissue and near tissue margins and their identity was confirmed by spectral library surveys. Hypotheses about the origin of these foreign materials are discussed. In conclusion, our Raman workflow and data processing protocol with minimal user interference offers advantages for future clinical translation such as intraoperative tumor detection and label-free material identification in complex matrices. Full article
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