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Cancers
Volume 14
Issue 18
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Cancers, Volume 14, Issue 18 (September-2 2022) – 201 articles

Cover Story (view full-size image): Ovarian cancer is treated with cytoreductive surgery to remove all visible cancer, in addition to platinum chemotherapy. Ultra-radical surgery, i.e., surgery involving upper abdominal organs, e.g., splenectomy, diaphragm resection, and bowel surgery, achieves this goal even when cancer has spread widely across the abdominal cavity. We analyzed cancer registry data to identify whether cancer centres practicing ultra-radical surgery have better survival than those who practice less radical surgery, including every patient with advanced ovarian cancer in the catchment of 11 UK cancer centres. We found that centres practicing ultra-radical surgery have better median survival than those who do not, even after adjusting for age and deprivation. The strength of the study is the population-based nature of the data. View this paper
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25 pages, 1539 KiB  
Review
Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs
by Manuel Gámez-Chiachio, David Sarrió and Gema Moreno-Bueno
Cancers 2022, 14(18), 4543; https://doi.org/10.3390/cancers14184543 - 19 Sep 2022
Cited by 13 | Viewed by 4396
Abstract
The prognosis and quality of life of HER2 breast cancer patients have significantly improved due to the crucial clinical benefit of various anti-HER2 targeted therapies. However, HER2 tumors can possess or develop several resistance mechanisms to these treatments, thus leaving patients with a [...] Read more.
The prognosis and quality of life of HER2 breast cancer patients have significantly improved due to the crucial clinical benefit of various anti-HER2 targeted therapies. However, HER2 tumors can possess or develop several resistance mechanisms to these treatments, thus leaving patients with a limited set of additional therapeutic options. Fortunately, to overcome this problem, in recent years, multiple different and complementary approaches have been developed (such as antibody–drug conjugates (ADCs)) that are in clinical or preclinical stages. In this review, we focus on emerging strategies other than on ADCs that are either aimed at directly target the HER2 receptor (i.e., novel tyrosine kinase inhibitors) or subsequent intracellular signaling (e.g., PI3K/AKT/mTOR, CDK4/6 inhibitors, etc.), as well as on innovative approaches designed to attack other potential tumor weaknesses (such as immunotherapy, autophagy blockade, or targeting of other genes within the HER2 amplicon). Moreover, relevant technical advances such as anti-HER2 nanotherapies and immunotoxins are also discussed. In brief, this review summarizes the impact of novel therapeutic approaches on current and future clinical management of aggressive HER2 breast tumors. Full article
(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)
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18 pages, 4851 KiB  
Article
Protein Profiling of Breast Carcinomas Reveals Expression of Immune-Suppressive Factors and Signatures Relevant for Patient Outcome
by Felix Ruoff, Nicolas Kersten, Nicole Anderle, Sandra Jerbi, Aaron Stahl, André Koch, Annette Staebler, Andreas Hartkopf, Sara Y. Brucker, Markus Hahn, Katja Schenke-Layland, Christian Schmees and Markus F. Templin
Cancers 2022, 14(18), 4542; https://doi.org/10.3390/cancers14184542 - 19 Sep 2022
Viewed by 2538
Abstract
In cancer, the complex interplay between tumor cells and the tumor microenvironment results in the modulation of signaling processes. By assessing the expression of a multitude of proteins and protein variants in cancer tissue, wide-ranging information on signaling pathway activation and the status [...] Read more.
In cancer, the complex interplay between tumor cells and the tumor microenvironment results in the modulation of signaling processes. By assessing the expression of a multitude of proteins and protein variants in cancer tissue, wide-ranging information on signaling pathway activation and the status of the immunological landscape is obtainable and may provide viable information on the treatment response. Archived breast cancer tissues from a cohort of 84 patients (no adjuvant therapy) were analyzed by high-throughput Western blotting, and the expression of 150 proteins covering central cancer pathways and immune cell markers was examined. By assessing CD8α, CD11c, CD16 and CD68 expression, immune cell infiltration was determined and revealed a strong correlation between event-free patient survival and the infiltration of immune cells. The presence of tumor-infiltrating lymphocytes was linked to the pronounced activation of the Jak/Stat signaling pathway and apoptotic processes. The elevated phosphorylation of PPARγ (pS112) in non-immune-infiltrated tumors suggests a novel immune evasion mechanism in breast cancer characterized by increased PPARγ phosphorylation. Multiplexed immune cell marker assessment and the protein profiling of tumor tissue provide functional signaling data facilitating breast cancer patient stratification. Full article
(This article belongs to the Section Cancer Causes, Screening and Diagnosis)
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18 pages, 1282 KiB  
Article
Splicing Analysis of 16 PALB2 ClinVar Variants by Minigene Assays: Identification of Six Likely Pathogenic Variants
by Alberto Valenzuela-Palomo, Lara Sanoguera-Miralles, Elena Bueno-Martínez, Ada Esteban-Sánchez, Inés Llinares-Burguet, Alicia García-Álvarez, Pedro Pérez-Segura, Susana Gómez-Barrero, Miguel de la Hoya and Eladio A. Velasco-Sampedro
Cancers 2022, 14(18), 4541; https://doi.org/10.3390/cancers14184541 - 19 Sep 2022
Cited by 2 | Viewed by 2808
Abstract
PALB2 loss-of-function variants are associated with significant increased risk of breast cancer as well as other types of tumors. Likewise, splicing disruptions are a common mechanism of disease susceptibility. Indeed, we previously showed, by minigene assays, that 35 out of 42 PALB2 variants [...] Read more.
PALB2 loss-of-function variants are associated with significant increased risk of breast cancer as well as other types of tumors. Likewise, splicing disruptions are a common mechanism of disease susceptibility. Indeed, we previously showed, by minigene assays, that 35 out of 42 PALB2 variants impaired splicing. Taking advantage of one of these constructs (mgPALB2_ex1-3), we proceeded to analyze other variants at exons 1 to 3 reported at the ClinVar database. Thirty-one variants were bioinformatically analyzed with MaxEntScan and SpliceAI. Then, 16 variants were selected for subsequent RNA assays. We identified a total of 12 spliceogenic variants, 11 of which did not produce any trace of the expected minigene full-length transcript. Interestingly, variant c.49-1G > A mimicked previous outcomes in patient RNA (transcript ∆(E2p6)), supporting the reproducibility of the minigene approach. A total of eight variant-induced transcripts were characterized, three of which (∆(E1q17), ∆(E3p11), and ∆(E3)) were predicted to introduce a premature termination codon and to undergo nonsense-mediated decay, and five (▼(E1q9), ∆(E2p6), ∆(E2), ▼(E3q48)-a, and ▼(E3q48)-b) maintained the reading frame. According to an ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme, which integrates mgPALB2 data, six PALB2 variants were classified as pathogenic/likely pathogenic, five as VUS, and five as likely benign. Furthermore, five ±1,2 variants were catalogued as VUS because they produced significant proportions of in-frame transcripts of unknown impact on protein function. Full article
(This article belongs to the Special Issue Updates on Breast Cancer)
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20 pages, 9617 KiB  
Article
RNA-seq and ChIP-seq Identification of Unique and Overlapping Targets of GLI Transcription Factors in Melanoma Cell Lines
by Matea Kurtović, Nikolina Piteša, Nenad Bartoniček, Petar Ozretić, Vesna Musani, Josipa Čonkaš, Tina Petrić, Cecile King and Maja Sabol
Cancers 2022, 14(18), 4540; https://doi.org/10.3390/cancers14184540 - 19 Sep 2022
Cited by 7 | Viewed by 3993
Abstract
Background: Despite significant progress in therapy, melanoma still has a rising incidence worldwide, and novel treatment strategies are needed. Recently, researchers have recognized the involvement of the Hedgehog-GLI (HH-GLI) signaling pathway in melanoma and its consistent crosstalk with the MAPK pathway. In order [...] Read more.
Background: Despite significant progress in therapy, melanoma still has a rising incidence worldwide, and novel treatment strategies are needed. Recently, researchers have recognized the involvement of the Hedgehog-GLI (HH-GLI) signaling pathway in melanoma and its consistent crosstalk with the MAPK pathway. In order to further investigate the link between the two pathways and to find new target genes that could be considered for combination therapy, we set out to find transcriptional targets of all three GLI proteins in melanoma. Methods: We performed RNA sequencing on three melanoma cell lines (CHL-1, A375, and MEL224) with overexpressed GLI1, GLI2, and GLI3 and combined them with the results of ChIP-sequencing on endogenous GLI1, GLI2, and GLI3 proteins. After combining these results, 21 targets were selected for validation by qPCR. Results: RNA-seq revealed a total of 808 differentially expressed genes (DEGs) for GLI1, 941 DEGs for GLI2, and 58 DEGs for GLI3. ChIP-seq identified 527 genes that contained GLI1 binding sites in their promoters, 1103 for GLI2 and 553 for GLI3. A total of 15 of these targets were validated in the tested cell lines, 6 of which were detected by both RNA-seq and ChIP-seq. Conclusions: Our study provides insight into the unique and overlapping transcriptional output of the GLI proteins in melanoma. We suggest that our findings could provide new potential targets to consider while designing melanoma-targeted therapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Signaling Pathways in Melanoma)
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31 pages, 3545 KiB  
Review
A Review on Annona muricata and Its Anticancer Activity
by Suganya Ilango, Dipak Kumar Sahoo, Biswaranjan Paital, Kavibharathi Kathirvel, Jerrina Issac Gabriel, Kalyani Subramaniam, Priyanka Jayachandran, Rajendra Kumar Dash, Akshaya Kumar Hati, Tapas Ranjan Behera, Pragnyashree Mishra and Ramalingam Nirmaladevi
Cancers 2022, 14(18), 4539; https://doi.org/10.3390/cancers14184539 - 19 Sep 2022
Cited by 31 | Viewed by 11228
Abstract
The ongoing rise in the number of cancer cases raises concerns regarding the efficacy of the various treatment methods that are currently available. Consequently, patients are looking for alternatives to traditional cancer treatments such as surgery, chemotherapy, and radiotherapy as a replacement. Medicinal [...] Read more.
The ongoing rise in the number of cancer cases raises concerns regarding the efficacy of the various treatment methods that are currently available. Consequently, patients are looking for alternatives to traditional cancer treatments such as surgery, chemotherapy, and radiotherapy as a replacement. Medicinal plants are universally acknowledged as the cornerstone of preventative medicine and therapeutic practices. Annona muricata is a member of the family Annonaceae and is familiar for its medicinal properties. A. muricata has been identified to have promising compounds that could potentially be utilized for the treatment of cancer. The most prevalent phytochemical components identified and isolated from this plant are alkaloids, phenols, and acetogenins. This review focuses on the role of A. muricata extract against various types of cancer, modulation of cellular proliferation and necrosis, and bioactive metabolites responsible for various pharmacological activities along with their ethnomedicinal uses. Additionally, this review highlights the molecular mechanism of the role of A. muricata extract in downregulating anti-apoptotic and several genes involved in the pro-cancer metabolic pathways and decreasing the expression of proteins involved in cell invasion and metastasis while upregulating proapoptotic genes and genes involved in the destruction of cancer cells. Therefore, the active phytochemicals identified in A. muricata have the potential to be employed as a promising anti-cancer agent. Full article
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20 pages, 2976 KiB  
Review
MicroRNA-34a, Prostate Cancer Stem Cells, and Therapeutic Development
by Wen (Jess) Li, Xiaozhuo Liu, Emily M. Dougherty and Dean G. Tang
Cancers 2022, 14(18), 4538; https://doi.org/10.3390/cancers14184538 - 19 Sep 2022
Cited by 12 | Viewed by 3224
Abstract
Prostate cancer (PCa) is a highly heterogeneous disease and typically presents with multiple distinct cancer foci. Heterogeneity in androgen receptor (AR) expression levels in PCa has been observed for decades, from untreated tumors to castration-resistant prostate cancer (CRPC) to disseminated metastases. Current standard-of-care [...] Read more.
Prostate cancer (PCa) is a highly heterogeneous disease and typically presents with multiple distinct cancer foci. Heterogeneity in androgen receptor (AR) expression levels in PCa has been observed for decades, from untreated tumors to castration-resistant prostate cancer (CRPC) to disseminated metastases. Current standard-of-care therapies for metastatic CRPC can only extend life by a few months. Cancer stem cells (CSCs) are defined as a subpopulation of cancer cells that exists in almost all treatment-naive tumors. Additionally, non-CSCs may undergo cellular plasticity to be reprogrammed to prostate cancer stem cells (PCSCs) during spontaneous tumor progression or upon therapeutic treatments. Consequently, PCSCs may become the predominant population in treatment-resistant tumors, and the “root cause” for drug resistance. microRNA-34a (miR-34a) is a bona fide tumor-suppressive miRNA, and its expression is dysregulated in PCa. Importantly, miR-34a functions as a potent CSC suppressor by targeting many molecules essential for CSC survival and functions, which makes it a promising anti-PCSC therapeutic. Here, we conducted a comprehensive literature survey of miR-34a in the context of PCa and especially PCSCs. We provided an updated overview on the mechanisms of miR-34a regulation followed by discussing its tumor suppressive functions in PCa. Finally, based on current advances in miR-34a preclinical studies in PCa, we offered potential delivery strategies for miR-34a-based therapeutics for treating advanced PCa. Full article
(This article belongs to the Special Issue Research in MicroRNA Profiling of Prostate Cancer)
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17 pages, 3514 KiB  
Article
A Selective Histone Deacetylase Inhibitor Induces Autophagy and Cell Death via SCNN1A Downregulation in Glioblastoma Cells
by Hui Hua Chang, Yao-Yuan Chang, Bing-Chen Tsai, Li-Jyun Chen, An-Chi Chang, Jian-Ying Chuang, Po-Wu Gean and Yuan-Shuo Hsueh
Cancers 2022, 14(18), 4537; https://doi.org/10.3390/cancers14184537 - 19 Sep 2022
Cited by 8 | Viewed by 2453
Abstract
Glioblastoma multiforme (GBM) is a grade IV, highly malignant brain tumor. Because of the heterogeneity of GBM, a multitarget drug is a rational strategy for GBM treatment. Histone deacetylase inhibitors (HDACis) regulate the expression of numerous genes involved in cell death, apoptosis, and [...] Read more.
Glioblastoma multiforme (GBM) is a grade IV, highly malignant brain tumor. Because of the heterogeneity of GBM, a multitarget drug is a rational strategy for GBM treatment. Histone deacetylase inhibitors (HDACis) regulate the expression of numerous genes involved in cell death, apoptosis, and tumorigenesis. We found that the HDAC4/HDAC5 inhibitor LMK235 at 0.5 µM significantly reduced the cell viability and colony formation of patient-derived, temozolomide-resistant GBM P#5 TMZ-R, U-87 MG, and T98G cells. Moreover, LMK235 also significantly increased TUBA acetylation, which is an indicator of HDAC inhibition. Interestingly, LMK235 induced MAP1LC3 robust readout and puncta accumulation but did not enhance PARP1 cleavage or the proportion of annexin V-positive cells, suggesting that LMK235-induced cell death occurred via autophagy activation. Further RNA-seq analysis after LMK235 treatment showed that 597 different expression genes compared to control. After bioinformatic analysis by KEGG and STRING, we focused on 34 genes and validated their mRNA expression by qPCR. Further validation showed that 2 µM LMK235 significantly reduced the mRNA and protein expression of SCNN1A. Cell viability of SCNN1A-silenced cells were reduced, but cells were rescued while treated with an autophagy inhibitor bafilomycin A1. Conclusively, SCNN1A plays a role in LMK235-induced autophagy and cell death in GBM cells. Full article
(This article belongs to the Special Issue The Role of Autophagy in Brain Tumors)
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25 pages, 2083 KiB  
Review
Emerging Roles of TRIM Family Proteins in Gliomas Pathogenesis
by Angeliki-Ioanna Giannopoulou, Charalampos Xanthopoulos, Christina Piperi and Efterpi Kostareli
Cancers 2022, 14(18), 4536; https://doi.org/10.3390/cancers14184536 - 19 Sep 2022
Cited by 4 | Viewed by 2921
Abstract
Gliomas encompass a vast category of CNS tumors affecting both adults and children. Treatment and diagnosis are often impeded due to intratumor heterogeneity and the aggressive nature of the more malignant forms. It is therefore essential to elucidate the molecular mechanisms and explore [...] Read more.
Gliomas encompass a vast category of CNS tumors affecting both adults and children. Treatment and diagnosis are often impeded due to intratumor heterogeneity and the aggressive nature of the more malignant forms. It is therefore essential to elucidate the molecular mechanisms and explore the intracellular signaling pathways underlying tumor pathology to provide more promising diagnostic, prognostic, and therapeutic tools for gliomas. The tripartite motif-containing (TRIM) superfamily of proteins plays a key role in many physiological cellular processes, including brain development and function. Emerging evidence supports the association of TRIMs with a wide variety of cancers, exhibiting both an oncogenic as well as a tumor suppressive role depending on cancer type. In this review, we provide evidence of the pivotal role of TRIM proteins in gliomagenesis and exploit their potential as prognostic biomarkers and therapeutic targets. Full article
(This article belongs to the Special Issue Interplay between Signaling Pathways and Metabolism in Brain Tumors)
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24 pages, 3797 KiB  
Article
Targeting Microtubule-Associated Protein Tau in Chemotherapy-Resistant Models of High-Grade Serous Ovarian Carcinoma
by Maria V. Barbolina
Cancers 2022, 14(18), 4535; https://doi.org/10.3390/cancers14184535 - 19 Sep 2022
Cited by 5 | Viewed by 2177
Abstract
Relapsed, recurrent, chemotherapy-resistant high-grade serous ovarian carcinoma is the deadliest stage of this disease. Expression of microtubule-associated protein tau (tau) has been linked to resistance to paclitaxel treatment. Here, I used models of platinum-resistant and created models of platinum/paclitaxel-resistant high-grade serous ovarian carcinoma [...] Read more.
Relapsed, recurrent, chemotherapy-resistant high-grade serous ovarian carcinoma is the deadliest stage of this disease. Expression of microtubule-associated protein tau (tau) has been linked to resistance to paclitaxel treatment. Here, I used models of platinum-resistant and created models of platinum/paclitaxel-resistant high-grade serous ovarian carcinoma to examine the impact of reducing tau expression on cell survival and tumor burden in cell culture and xenograft and syngeneic models of the disease. Tau was overexpressed in platinum/paclitaxel-resistant models; expression of phosphoSer396 and phosphoThr181 species was also found. A treatment with leucomethylene blue reduced the levels of tau in treated cells, was cytotoxic in cell cultures, and efficiently reduced the tumor burden in xenograft models. Furthermore, a combination of leucomethylene blue and paclitaxel synergized in eliminating cancer cells in cell culture and xenograft models. These findings underscore the feasibility of targeting tau as a treatment option in terminal-stage high-grade serous ovarian cancer. Full article
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12 pages, 2454 KiB  
Article
Generation and Evaluation of Synthetic Computed Tomography (CT) from Cone-Beam CT (CBCT) by Incorporating Feature-Driven Loss into Intensity-Based Loss Functions in Deep Convolutional Neural Network
by Sang Kyun Yoo, Hojin Kim, Byoung Su Choi, Inkyung Park and Jin Sung Kim
Cancers 2022, 14(18), 4534; https://doi.org/10.3390/cancers14184534 - 19 Sep 2022
Cited by 6 | Viewed by 2808
Abstract
Deep convolutional neural network (CNN) helped enhance image quality of cone-beam computed tomography (CBCT) by generating synthetic CT. Most of the previous works, however, trained network by intensity-based loss functions, possibly undermining to promote image feature similarity. The verifications were not sufficient to [...] Read more.
Deep convolutional neural network (CNN) helped enhance image quality of cone-beam computed tomography (CBCT) by generating synthetic CT. Most of the previous works, however, trained network by intensity-based loss functions, possibly undermining to promote image feature similarity. The verifications were not sufficient to demonstrate clinical applicability, either. This work investigated the effect of variable loss functions combining feature- and intensity-driven losses in synthetic CT generation, followed by strengthening the verification of generated images in both image similarity and dosimetry accuracy. The proposed strategy highlighted the feature-driven quantification in (1) training the network by perceptual loss, besides L1 and structural similarity (SSIM) losses regarding anatomical similarity, and (2) evaluating image similarity by feature mapping ratio (FMR), besides conventional metrics. In addition, the synthetic CT images were assessed in terms of dose calculating accuracy by a commercial Monte-Carlo algorithm. The network was trained with 50 paired CBCT-CT scans acquired at the same CT simulator and treatment unit to constrain environmental factors any other than loss functions. For 10 independent cases, incorporating perceptual loss into L1 and SSIM losses outperformed the other combinations, which enhanced FMR of image similarity by 10%, and the dose calculating accuracy by 1–2% of gamma passing rate in 1%/1mm criterion. Full article
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19 pages, 1931 KiB  
Article
Comparison of Selected Non-Coding RNAs and Gene Expression Profiles between Common Osteosarcoma Cell Lines
by Mateusz Sikora, Katarzyna Krajewska, Klaudia Marcinkowska, Anna Raciborska, Rafał Jakub Wiglusz and Agnieszka Śmieszek
Cancers 2022, 14(18), 4533; https://doi.org/10.3390/cancers14184533 - 19 Sep 2022
Cited by 5 | Viewed by 2283
Abstract
Osteosarcoma (OS) is a bone tumour affecting adolescents and elderly people. Unfortunately, basic treatment methods are still underdeveloped, which has a high impact on the poor survivability of the patients. Studies designed to understand the underlying mechanisms of osteosarcoma development, as well as [...] Read more.
Osteosarcoma (OS) is a bone tumour affecting adolescents and elderly people. Unfortunately, basic treatment methods are still underdeveloped, which has a high impact on the poor survivability of the patients. Studies designed to understand the underlying mechanisms of osteosarcoma development, as well as preclinical investigations aimed at establishing novel therapeutic strategies, rely significantly upon in vitro models, which apply well-established cell lines such as U-2 OS, Saos-2 and MG-63. In this study, the expression of chosen markers associated with tumour progression, metastasis and survival were identified using RT-qPCR. Levels of several onco-miRs (miR-21-5p, miR-124-3p, miR-223-3p and miR-320a-3p) and long non-coding RNA MEG3 were established. The mRNA expression of bone morphogenetic proteins (BMPs), including BMP-2, BMP-3, BMP-4, BMP-6, BMP-7, as well as their receptors: BMPR-IA, BMPR-IB and BMPR-II was also determined. Other tested markers included metalloproteinases, i.e., MMP-7 and MMP-14 and survivin (BIRC5), C-MYC, as well as CYCLIN D (CCND1). The analysis included comparing obtained profiles with transcript levels established for the osteogenic HeLa cell line and human adipose-derived stromal cells (hASCs). The tested OS cell lines were characterised by a cancer-related phenotype, such as increased expression of mRNA for BMP-7, as well as MMP-7 and MMP-14. Osteosarcoma cells differ considerably in miR-21-5p and miR-124-3p levels, which can be related to uncontrolled tumour growth. The comprehensive examination of osteosarcoma transcriptome profiles may facilitate the selection of appropriate cell models for preclinical investigations aimed at the development of new strategies for OS treatment. Full article
(This article belongs to the Special Issue Rare Tumors Involving Bone–Insight into Their Biology, Novel Diagnostic and Therapeutic Tools, including Targeted Therapies)
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21 pages, 5736 KiB  
Article
Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE)
by Pallavi Sachdev, Roy Ronen, Janusz Dutkowski and Bruce A. Littlefield
Cancers 2022, 14(18), 4532; https://doi.org/10.3390/cancers14184532 - 19 Sep 2022
Cited by 3 | Viewed by 2440
Abstract
Eribulin, a natural product-based microtubule targeting agent with cytotoxic and noncytotoxic mechanisms, is FDA approved for certain patients with advanced breast cancer and liposarcoma. To investigate the feasibility of developing drug-specific predictive biomarkers, we quantified antiproliferative activities of eribulin versus paclitaxel and vinorelbine [...] Read more.
Eribulin, a natural product-based microtubule targeting agent with cytotoxic and noncytotoxic mechanisms, is FDA approved for certain patients with advanced breast cancer and liposarcoma. To investigate the feasibility of developing drug-specific predictive biomarkers, we quantified antiproliferative activities of eribulin versus paclitaxel and vinorelbine against 100 human cancer cell lines from the Cancer Cell Line Encyclopedia, and correlated results with publicly available databases to identify genes and pathways associated with eribulin response, either uniquely or shared with paclitaxel or vinorelbine. Mean expression ratios of 11,985 genes between the most and least sensitive cell line quartiles were sorted by p-values and drug overlaps, yielding 52, 29 and 80 genes uniquely associated with eribulin, paclitaxel and vinorelbine, respectively. Further restriction to minimum 2-fold ratios followed by reintroducing data from the middle two quartiles identified 9 and 13 drug-specific unique fingerprint genes for eribulin and vinorelbine, respectively; surprisingly, no gene met all criteria for paclitaxel. Interactome and Reactome pathway analyses showed that unique fingerprint genes of both drugs were primarily associated with cellular signaling, not microtubule-related pathways, although considerable differences existed in individual pathways identified. Finally, four-gene (C5ORF38, DAAM1, IRX2, CD70) and five-gene (EPHA2, NGEF, SEPTIN10, TRIP10, VSIG10) multivariate regression models for eribulin and vinorelbine showed high statistical correlation with drug-specific responses across the 100 cell lines and accurately calculated predicted mean IC50s for the most and least sensitive cell line quartiles as surrogates for responders and nonresponders, respectively. Collectively, these results provide a foundation for developing drug-specific predictive biomarkers for eribulin and vinorelbine. Full article
(This article belongs to the Collection Cancer Biomarkers)
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12 pages, 1269 KiB  
Article
Primary Chemoradiotherapy Treatment (PCRT) for HER2+ and Triple Negative Breast Cancer Patients: A Feasible Combination
by Raquel Ciérvide, Ángel Montero, Eduardo García-Rico, Mariola García-Aranda, Mercedes Herrero, Jessica Skaarup, Leticia Benassi, Maria José Barrera, Estela Vega, Beatriz Rojas, Raquel Bratos, Ana Luna, Manuela Parras, María López, Ana Delgado, Paloma Quevedo, Silvia Castilla, Margarita Feyjoo, Ana Higueras, Mario Prieto, Ana Suarez-Gauthier, Lina Garcia-Cañamaque, Nieves Escolán, Beatriz Álvarez, Xin Chen, Rosa Alonso, Mercedes López, Ovidio Hernando, Jeannette Valero, Emilio Sánchez, Eva Ciruelos and Carmen Rubioadd Show full author list remove Hide full author list
Cancers 2022, 14(18), 4531; https://doi.org/10.3390/cancers14184531 - 19 Sep 2022
Cited by 5 | Viewed by 3940
Abstract
Primary systemic treatment (PST) downsizes the tumor and improves pathological response. The aim of this study is to analyze the feasibility and tolerance of primary concurrent radio–chemotherapy (PCRT) in breast cancer patients. Patients with localized TN/HER2+ tumors were enrolled in this prospective study. [...] Read more.
Primary systemic treatment (PST) downsizes the tumor and improves pathological response. The aim of this study is to analyze the feasibility and tolerance of primary concurrent radio–chemotherapy (PCRT) in breast cancer patients. Patients with localized TN/HER2+ tumors were enrolled in this prospective study. Radiation was delivered concomitantly during the first 3 weeks of chemotherapy, and it was based on a 15 fractions scheme, 40.5 Gy/2.7 Gy per fraction to whole breast and nodal levels I-IV. Chemotherapy (CT) was based on Pertuzumab–Trastuzumab–Paclitaxel followed by anthracyclines in HER2+ and CBDCA-Paclitaxel followed by anthracyclines in TN breast cancers patients. A total of 58 patients were enrolled; 25 patients (43%) were TN and 33 patients HER2+ (57%). With a median follow-up of 24.2 months, 56 patients completed PCRT and surgery. A total of 35 patients (87.5%) achieved >90% loss of invasive carcinoma cells in the surgical specimen. The 70.8% and the 53.1% of patients with TN and HER-2+ subtype, respectively, achieved complete pathological response (pCR). This is the first study of concurrent neoadjuvant treatment in breast cancer in which three strategies were applied simultaneously: fractionation of RT (radiotherapy) in 15 sessions, adjustment of CT to tumor phenotype and local planning by PET. The pCR rates are encouraging. Full article
(This article belongs to the Section Cancer Therapy)
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10 pages, 1144 KiB  
Commentary
The Evolving Interplay of SBRT and the Immune System, along with Future Directions in the Field
by Mihailo Miljanic, Steven Montalvo, Maureen Aliru, Tidie Song, Maria Leon-Camarena, Kevin Innella, Dragan Vujovic, Ritsuko Komaki and Puneeth Iyengar
Cancers 2022, 14(18), 4530; https://doi.org/10.3390/cancers14184530 - 19 Sep 2022
Cited by 10 | Viewed by 2421
Abstract
In this commentary, we describe the potential of highly ablative doses utilizing Stereotactic Body Radiation Therapy (SBRT) in single or few fractions to enhance immune-responsiveness, how timing of this approach in combination with immune-checkpoint inhibitors may augment treatment-effect, and whether Personalized Ultrafractionated Stereotactic [...] Read more.
In this commentary, we describe the potential of highly ablative doses utilizing Stereotactic Body Radiation Therapy (SBRT) in single or few fractions to enhance immune-responsiveness, how timing of this approach in combination with immune-checkpoint inhibitors may augment treatment-effect, and whether Personalized Ultrafractionated Stereotactic Adaptive Radiation Therapy (PULSAR) is an avenue for future advancement in the continued endeavor to foster a systemic effect of therapy beyond the radiation treatment field. The ablative potential of SBRT may support an increase in tumor-antigen presentation, enhancement of immune-stimulatory components, and an improvement in tumor-microenvironment immune cell infiltration. Furthermore, the latest advancement of ablative radiation delivery is PULSAR-based therapy, whereby ablative doses are delivered in pulses of treatment that may be several weeks apart, combined with adaptive treatment to tumor changes across time. The benefits of this novel approach include the ability to optimize direct tumor control by assessment of tumor size and location via dedicated imaging acquired prior to each delivered pulse, and further potentiation of immune recognition through combination with concurrent immune-checkpoint blockade. Full article
(This article belongs to the Special Issue Stereotactic Body Radiotherapy for Various Cancers: Recent Advances and Future)
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1 pages, 468 KiB  
Correction
Correction: Pandey et al. ROR1 Potentiates FGFR Signaling in Basal-Like Breast Cancer. Cancers 2019, 11, 718
by Gaurav Pandey, Nicholas Borcherding, Ryan Kolb, Paige Kluz, Wei Li, Sonia Sugg, Jun Zhang, Dazhi A. Lai and Weizhou Zhang
Cancers 2022, 14(18), 4529; https://doi.org/10.3390/cancers14184529 - 19 Sep 2022
Viewed by 1140
Abstract
In the original publication [...] Full article
16 pages, 2159 KiB  
Review
LincRNAs and snoRNAs in Breast Cancer Cell Metastasis: The Unknown Players
by Maria Louca and Vasiliki Gkretsi
Cancers 2022, 14(18), 4528; https://doi.org/10.3390/cancers14184528 - 19 Sep 2022
Cited by 9 | Viewed by 2395
Abstract
Recent advances in research have led to earlier diagnosis and targeted therapies against breast cancer, which has resulted in reduced breast cancer-related mortality. However, the majority of breast cancer-related deaths are due to metastasis of cancer cells to other organs, a process that [...] Read more.
Recent advances in research have led to earlier diagnosis and targeted therapies against breast cancer, which has resulted in reduced breast cancer-related mortality. However, the majority of breast cancer-related deaths are due to metastasis of cancer cells to other organs, a process that has not been fully elucidated. Among the factors and genes implicated in the metastatic process regulation, non-coding RNAs have emerged as crucial players. This review focuses on the role of long intergenic noncoding RNAs (lincRNAs) and small nucleolar RNAs (snoRNAs) in breast cancer cell metastasis. LincRNAs are transcribed between two protein-coding genes and are longer than 200 nucleotides, they do not code for a specific protein but function as regulatory molecules in processes such as cell proliferation, apoptosis, epithelial-to-mesenchymal transition, migration, and invasion while most of them are highly elevated in breast cancer tissues and seem to function as competing endogenous RNAs (ceRNAs) inhibiting relevant miRNAs that specifically target vital metastasis-related genes. Similarly, snoRNAs are 60–300 nucleotides long and are found in the nucleolus being responsible for the post-transcriptional modification of ribosomal and spliceosomal RNAs. Most snoRNAs are hosted inside intron sequences of protein-coding and non-protein-coding genes, and they also regulate metastasis-related genes affecting related cellular properties. Full article
(This article belongs to the Collection Molecular Function and Clinical Value of Non-coding RNAs (ncRNAs) in Cancer Regulation)
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12 pages, 308 KiB  
Review
Surgical Site Infection after Bone Tumor Surgery: Risk Factors and New Preventive Techniques
by Shinji Miwa, Norio Yamamoto, Katsuhiro Hayashi, Akihiko Takeuchi, Kentaro Igarashi and Hiroyuki Tsuchiya
Cancers 2022, 14(18), 4527; https://doi.org/10.3390/cancers14184527 - 19 Sep 2022
Cited by 11 | Viewed by 2257
Abstract
The management of malignant bone tumors requires multidisciplinary interventions including chemotherapy, radiation therapy, and surgical tumor resection and reconstruction. Surgical site infection (SSI) is a serious complication in the treatment of malignant bone tumors. Compared to other orthopedic surgeries, the surgical treatment of [...] Read more.
The management of malignant bone tumors requires multidisciplinary interventions including chemotherapy, radiation therapy, and surgical tumor resection and reconstruction. Surgical site infection (SSI) is a serious complication in the treatment of malignant bone tumors. Compared to other orthopedic surgeries, the surgical treatment of malignant bone tumors is associated with higher rates of SSIs. In patients with SSIs, additional surgeries, long-term administrations of antibiotics, extended hospital stays, and the postponement of scheduled adjuvant treatments are required. Therefore, SSI may adversely affect functional and oncological outcomes. To improve surgical outcomes in patients with malignant bone tumors, preoperative risk assessments for SSIs, new preventive techniques against SSIs, and the optimal use of prophylactic antibiotics are often required. Previous reports have demonstrated that age, tumor site (pelvis and tibia), extended operative time, implant use, body mass index, leukocytopenia, and reconstruction procedures are associated with an increased risk for SSIs. Furthermore, prophylactic techniques, such as silver and iodine coatings on implants, have been developed and proven to be efficacious and safe in clinical studies. In this review, predictive factors of SSIs and new prophylactic techniques are discussed. Full article
(This article belongs to the Special Issue Sarcoma and Bone Cancer Awareness Month)
16 pages, 3029 KiB  
Review
Emerging Roles of Lipophagy in Cancer Metastasis
by Haimeng Yin, Ying Shan, Tian Xia, Yan Ji, Ling Yuan, Yiwen You and Bo You
Cancers 2022, 14(18), 4526; https://doi.org/10.3390/cancers14184526 - 19 Sep 2022
Cited by 3 | Viewed by 3728
Abstract
Obesity is a prominent risk factor for certain types of tumor progression. Adipocytes within tumor stroma contribute to reshaping tumor microenvironment (TME) and the metabolism and metastasis of tumors through the production of cytokines and adipokines. However, the crosstalk between adipocytes and tumor [...] Read more.
Obesity is a prominent risk factor for certain types of tumor progression. Adipocytes within tumor stroma contribute to reshaping tumor microenvironment (TME) and the metabolism and metastasis of tumors through the production of cytokines and adipokines. However, the crosstalk between adipocytes and tumor cells remains a major gap in this field. Known as a subtype of selective autophagy, lipophagy is thought to contribute to lipid metabolism by breaking down intracellular lipid droplets (LDs) and generating free fatty acids (FAs). The metastatic potential of cancer cells closely correlates with the lipid degradation mechanisms, which are required for energy generation, signal transduction, and biosynthesis of membranes. Here, we discuss the recent advance in the understanding of lipophagy with tumor lipid metabolism and review current studies on the roles of lipoghagy in the metastasis of certain human malignancies. Additionally, the novel candidate drugs targeting lipophagy are integrated for effective treatment strategies. Full article
(This article belongs to the Special Issue The Role of Adipocyte Crosstalk in the Tumor Microenvironment)
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2 pages, 170 KiB  
Correction
Correction: Zhang et al. Association between Body Mass Index and Immune-Related Adverse Events (irAEs) among Advanced-Stage Cancer Patients Receiving Immune Checkpoint Inhibitors: A Pan-Cancer Analysis. Cancers 2021, 13, 6109
by Dongyu Zhang, Neil J. Shah, Michael Cook, Matthew Blackburn, Michael T. Serzan, Shailesh Advani, Arnold L. Potosky, Subha Madhavan, Anas Belouali, Michael B. Atkins and Dejana Braithwaite
Cancers 2022, 14(18), 4525; https://doi.org/10.3390/cancers14184525 - 19 Sep 2022
Cited by 2 | Viewed by 1600
Abstract
Subha Madhavan (S.M.) and Anas Belouali (A.B.) were not included as authors in the published article [...] Full article
(This article belongs to the Special Issue Cancer Immunotherapy and Immune-Related Adverse Events)
25 pages, 5464 KiB  
Article
Circular RNA hsa_circ_0062682 Binds to YBX1 and Promotes Oncogenesis in Hepatocellular Carcinoma
by Rok Razpotnik, Robert Vidmar, Marko Fonović, Damjana Rozman and Tadeja Režen
Cancers 2022, 14(18), 4524; https://doi.org/10.3390/cancers14184524 - 19 Sep 2022
Cited by 9 | Viewed by 2971
Abstract
Circular RNAs (circRNAs) have been shown to play an important role in the pathogenesis of hepatocellular carcinoma (HCC). By implementing available transcriptomic analyses of HCC patients, we identified an upregulated circRNA hsa_circ_0062682. Stable perturbations of hsa_circ_0062682 in Huh-7 and SNU-449 cell lines influenced [...] Read more.
Circular RNAs (circRNAs) have been shown to play an important role in the pathogenesis of hepatocellular carcinoma (HCC). By implementing available transcriptomic analyses of HCC patients, we identified an upregulated circRNA hsa_circ_0062682. Stable perturbations of hsa_circ_0062682 in Huh-7 and SNU-449 cell lines influenced colony formation, migration, cell proliferation, sorafenib sensitivity, and additionally induced morphological changes in cell lines, indicating an important role of hsa_circ_0062682 in oncogenesis. Pathway enrichment analysis and gene set enrichment analysis of the transcriptome data from hsa_circ_0062682 knockdown explained the observed phenotypes and exposed transcription factors E2F1, Sp1, HIF-1α, and NFκB1 as potential downstream targets. Biotinylated oligonucleotide pulldown combined with proteomic analyses identified protein interaction partners of which YBX1, a known oncogene, was confirmed by RNA immunoprecipitation. Furthermore, we discovered a complex cell-type-specific phenotype in response to the oncogenic potential of hsa_circ_0062682. This finding is in line with different classes of HCC tumours, and more studies are needed to shed a light on the molecular complexity of liver cancer. Full article
(This article belongs to the Special Issue Circular RNAs: New Insights into the Molecular Biology of Cancer)
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16 pages, 343 KiB  
Review
Immunotherapy and Hepatocellular Cancer: Where Are We Now?
by Marine Valery, Baptiste Cervantes, Ramy Samaha, Maximiliano Gelli, Cristina Smolenschi, Alina Fuerea, Lambros Tselikas, Caroline Klotz-Prieux, Antoine Hollebecque, Valérie Boige and Michel Ducreux
Cancers 2022, 14(18), 4523; https://doi.org/10.3390/cancers14184523 - 19 Sep 2022
Cited by 8 | Viewed by 3820
Abstract
Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies [...] Read more.
Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as “adjuvants” to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner. Full article
(This article belongs to the Special Issue Immune Checkpoint and Novel Perspectives in the Management of Hepatocellular Carcinoma)
19 pages, 26827 KiB  
Article
Pan-Cancer Analysis and Experimental Validation Identify ACOT7 as a Novel Oncogene and Potential Therapeutic Target in Lung Adenocarcinoma
by Chao Zheng, Guochao Zhang, Kai Xie, Yifei Diao, Chao Luo, Yanqing Wang, Yi Shen and Qi Xue
Cancers 2022, 14(18), 4522; https://doi.org/10.3390/cancers14184522 - 18 Sep 2022
Cited by 2 | Viewed by 3331
Abstract
Background: Acyl-CoA thioesterase 7 (ACOT7) is of great significance in regulating cell cycle, cell proliferation, and glucose metabolism. The function of ACOT7 in pan-cancer and its capacity as a prognostic indicator in lung adenocarcinoma (LUAD) remains unknown. We intended to perform a comprehensive [...] Read more.
Background: Acyl-CoA thioesterase 7 (ACOT7) is of great significance in regulating cell cycle, cell proliferation, and glucose metabolism. The function of ACOT7 in pan-cancer and its capacity as a prognostic indicator in lung adenocarcinoma (LUAD) remains unknown. We intended to perform a comprehensive pan-cancer analysis of ACOT7 and to validate its value in LUAD. Methods: The expression levels, prognostic significance, molecular function, signaling pathways, and immune infiltration pattern of ACOT7 in 33 cancers were explored via systematic bioinformatics analysis. Multivariate Cox regression was applied to construct nomograms to predict patients’ prognoses. Moreover, we conducted in vitro experiments including CCK8, scratch, Transwell, and Matrigel assays to further explore the function of ACOT7 in LUAD. Results: Patients with high ACOT7 expression have notably poorer long-term survival in many cancer types, including LUAD. Further enrichment analyses reveal that ACOT7 is involved in immune cells’ infiltration and is substantially related to the cancer–immune microenvironment. ACOT7 could influence drug sensitivities, including afatinib, gefitinib, ibrutinib, lapatinib, osimertinib, sapitinib, taselisib, and PLX-4720 (all p < 0.01). A nomogram demonstrated a fair predictive value of ACOT7 in LUAD (C-index: 0.613, 95% CI: 0.568–0.658). The proliferation and migration of PC9 cells were significantly repressed when ACOT7 expression was downregulated. Conclusion: As an oncogene, ACOT7 is critical in the tumor microenvironment of pan-cancer and might be a novel therapeutic target for LUAD. Full article
(This article belongs to the Collection Application of Bioinformatics in Cancers)
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12 pages, 1815 KiB  
Article
Body Composition as a Predictor of the Survival in Anal Cancer
by Ahmed Allam Mohamed, Kathrin Risse, Jennifer Stock, Alexander Heinzel, Felix M. Mottaghy, Philipp Bruners and Michael J. Eble
Cancers 2022, 14(18), 4521; https://doi.org/10.3390/cancers14184521 - 18 Sep 2022
Cited by 3 | Viewed by 2045
Abstract
Background and aim: Sarcopenia and body composition parameters such as visceral and subcutaneous adipose tissue and visceral-to-subcutaneous adipose tissue ratio have been shown to be relevant biomarkers for prognosis in patients with different types of cancer. However, these findings have not been well [...] Read more.
Background and aim: Sarcopenia and body composition parameters such as visceral and subcutaneous adipose tissue and visceral-to-subcutaneous adipose tissue ratio have been shown to be relevant biomarkers for prognosis in patients with different types of cancer. However, these findings have not been well studied in anal cancer to date. Therefore, the aim of this study was to evaluate the prognostic value of different body composition parameters in patients undergoing radiation therapy for the treatment of anal cancer with curative intent. Material and Methods: After approval by the institutional ethical committee, we retrospectively identified 81 patients in our local registry, who received radical intensity-modulated radiotherapy for the management of anal squamous cell cancer (ASCC). Clinical information, including body mass index (BMI), survival, and toxicities outcome, were retrieved from the local hospital registry. Based on the pre-therapeutic computer tomography (CT), we measured the total psoas muscle area, visceral adipose tissue area (VAT), subcutaneous adipose tissue area (SAT), and visceral-to-subcutaneous adipose tissue area ratio (VSR). In addition to the classical prognostic factors as T-stage, N-stage, gender, and treatment duration, we analyzed the impact of body composition on the prognosis in univariate and multivariate analyses. Results: Sarcopenia was not associated with increased mortality in anal cancer patients, whereas increased BMI (≥27 kg/m2) and VSR (≥0.45) were significantly associated with worsened overall survival and cancer-specific survival in both univariate and multivariate analyses. VSR—not BMI—was statistically higher in males. Sarcopenia and VSR ≥ 0.45 were associated with advanced T-stages. None of the body composition parameters resulted in a significant increase in treatment-related toxicities. Conclusion: BMI and visceral adiposity are independent prognostic factors for the survival of patients with anal cancer. Measurements to treat adiposity at the time of diagnosis may be needed to improve the survival outcomes for the affected patients. Full article
(This article belongs to the Collection Imaging Biomarker in Oncology)
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16 pages, 2501 KiB  
Article
Biomimetic Red Blood Cell Membrane-Mediated Nanodrugs Loading Ursolic Acid for Targeting NSCLC Therapy
by Ting Wu, Dan Yan, Wenjun Hou, Hui Jiang, Min Wu, Yanling Wang, Gang Chen, Chunming Tang, Yijun Wang and Huae Xu
Cancers 2022, 14(18), 4520; https://doi.org/10.3390/cancers14184520 - 18 Sep 2022
Cited by 4 | Viewed by 2189
Abstract
As one of the most common cancers worldwide, non-small-cell lung cancer (NSCLC) treatment always fails owing to the tumor microenvironment and resistance. UA, a traditional Chinese medicine, was reported to have antitumor potential in tumor models in vitro and in vivo, but showed [...] Read more.
As one of the most common cancers worldwide, non-small-cell lung cancer (NSCLC) treatment always fails owing to the tumor microenvironment and resistance. UA, a traditional Chinese medicine, was reported to have antitumor potential in tumor models in vitro and in vivo, but showed impressive results in its potential application for poor water solubility. In this study, a novel biomimetic drug-delivery system based on UA-loaded nanoparticles (UaNPs) with a red blood cell membrane (RBCM) coating was developed. The RBCM-coated UANPs (UMNPs) exhibited improved water solubility, high stability, good biosafety, and efficient tumor accumulation. Importantly, the excellent antitumor efficiency of the UMNPs was confirmed both in vitro and in vivo in cancer models. In addition, we further investigated the antitumor mechanism of UMNPs. The results of Western blotting showed that UMNPs exerted an anticancer effect by inducing the apoptosis and autophagy of NSCLC cells, which makes it superior to free UA. In addition, body weight monitoring, hematoxylin and eosin (HE) analysis, and immunohistochemical (IHC) analysis showed no significant difference between UMNPs and the control group, indicating the safety of UMNPs. Altogether, the preparation of biomimetic UMNPs provides a promising strategy to improve outcomes in NSCLC. Full article
(This article belongs to the Collection Cancer Nanomedicine)
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12 pages, 303 KiB  
Review
How I Treat TP53-Mutated Acute Myeloid Leukemia and Myelodysplastic Syndromes
by Michael Loschi, Pierre Fenaux and Thomas Cluzeau
Cancers 2022, 14(18), 4519; https://doi.org/10.3390/cancers14184519 - 18 Sep 2022
Cited by 11 | Viewed by 5427
Abstract
TP53-mutated acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are among the myeloid malignancies with the poorest prognosis. In this review, we analyze the prognosis of these two diseases, focussing particularly on the extent of the mono or biallelic mutation status of [...] Read more.
TP53-mutated acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are among the myeloid malignancies with the poorest prognosis. In this review, we analyze the prognosis of these two diseases, focussing particularly on the extent of the mono or biallelic mutation status of TP53 mutation, which is largely correlated with cytogenetic complexity. We discuss the possible/potential improvement in outcome based on recent results obtained with new drugs (especially eprenetapopt and magrolimab). We also focus on the impact of allogeneic hematopoietic stem cell transplantation (aHSCT) including post aHSCT treatment. Full article
(This article belongs to the Collection Acute Myeloid Leukemia (AML))
20 pages, 1286 KiB  
Review
The Role of Hypoxia-Inducible Factor Isoforms in Breast Cancer and Perspectives on Their Inhibition in Therapy
by Karolina Kozal and Anna Krześlak
Cancers 2022, 14(18), 4518; https://doi.org/10.3390/cancers14184518 - 17 Sep 2022
Cited by 11 | Viewed by 2748
Abstract
Hypoxia is a common feature associated with many types of cancer. The activity of the hypoxia-inducible factors (HIFs), the critical element of response and adaptation to hypoxia, enhances cancer hallmarks such as suppression of the immune response, altered metabolism, angiogenesis, invasion, metastasis, and [...] Read more.
Hypoxia is a common feature associated with many types of cancer. The activity of the hypoxia-inducible factors (HIFs), the critical element of response and adaptation to hypoxia, enhances cancer hallmarks such as suppression of the immune response, altered metabolism, angiogenesis, invasion, metastasis, and more. The HIF-1α and HIF-2α isoforms show similar regulation characteristics, although they are active in different types of hypoxia and can show different or even opposite effects. Breast cancers present several unique ways of non-canonical hypoxia-inducible factors activity induction, not limited to the hypoxia itself. This review summarizes different effects of HIFs activation in breast cancer, where areas such as metabolism, evasion of the immune response, cell survival and death, angiogenesis, invasion, metastasis, cancer stem cells, and hormone receptors status have been covered. The differences between HIF-1α and HIF-2α activity and their impacts are given special attention. The paper also discusses perspectives on using hypoxia-inducible factors as targets in anticancer therapy, given current knowledge acquired in molecular studies. Full article
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15 pages, 2373 KiB  
Article
Surgical and Functional Outcome after Resection of 64 Petroclival Meningiomas
by Arthur Wagner, Marie Alraun, Victoria Kahlig, Anne-Sophie Dorier, Amir Kaywan Aftahy, Denise Bernhardt, Stephanie E. Combs, Jens Gempt, Ehab Shiban, Bernhard Meyer and Chiara Negwer
Cancers 2022, 14(18), 4517; https://doi.org/10.3390/cancers14184517 - 17 Sep 2022
Cited by 8 | Viewed by 3190
Abstract
Objective: The management of petroclival meningiomas (PCMs) remains notoriously difficult due to their close association with neurovascular structures and their complex anatomy, hence the surgical paradigm change from radical to functional resection in the past. With this study, we aimed to analyze surgical [...] Read more.
Objective: The management of petroclival meningiomas (PCMs) remains notoriously difficult due to their close association with neurovascular structures and their complex anatomy, hence the surgical paradigm change from radical to functional resection in the past. With this study, we aimed to analyze surgical and functional outcomes of a modern consecutive series of patients with PCMs. Methods: We reviewed patient charts and imaging data of 64 consecutive patients from 2006 to 2018 with a PCM resected at our institution and compared surgical and functional outcomes between subgroups stratified by surgical approach. Results: Females comprised 67.2% of patients (n = 43), with a mean age of 55 years (median 56; range 21–84). Follow-up data were available for 68.8% and reached a mean of 42.3 months (range 1–129) with a median of 28.5 months. The mean tumor diameter was 37.3 mm (standard deviation (SD) 15.4; median 37.0). Infiltration of the cavernous sinus was observed in 34 cases (53.1%), and the lesions affected the brain stem in 28 cases (43.8%). Preoperative cranial nerve palsy was observed in 73.4% of cases; trigeminal neuropathy (42.2%), hearing loss (32.8%), and impairment of vision (18.8%) were the most common. A retrosigmoid approach was employed in 47 cases (78.1%), pterional in 10 (15.6%), combined petrosal in 2 (3.1%), and transnasal and subtemporal in 1 (1.6%). Fifteen cases (23.4%) were resected in a two-staged fashion. Gross total resection (GTR) was attempted in 30 (46.9%) cases without cavernous sinus infiltration and was achieved in 21 (70.0%) of these cases. Surgical complications occurred in 13 cases (20.3%), most commonly meningitis (n = 4; 6.3%). Postoperatively, 56 patients (87.5%) developed new cranial nerve palsy, of which 36 (63.6%) had improved or resolved on last follow up. Achieving GTR was not significantly associated with higher rates of surgical complications (chi-square; p = 0.288) or postoperative cranial nerve palsy (chi-square; p = 0.842). Of all cases, 20 (31.3%) underwent postoperative radiation. Tumor progression was observed in 10 patients (15.9%) after a mean 102 months (median 124). Conclusions: Surgical resection remains the mainstay of treatment for PCMs, with perioperative cranial neuropathies exhibiting favorable recovery rates. Most essentially, the preselection of patients with hallmarks of brain stem affection and cavernous sinus infiltration should dictate whether to strive for a functionally oriented strategy in favor of radical resection. Full article
(This article belongs to the Special Issue Meningioma: From Bench to Bedside)
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19 pages, 768 KiB  
Review
Therapeutic Benefit of Systematic Lymphadenectomy in Node-Negative Uterine-Confined Endometrioid Endometrial Carcinoma: Omission of Adjuvant Therapy
by Isao Otsuka
Cancers 2022, 14(18), 4516; https://doi.org/10.3390/cancers14184516 - 17 Sep 2022
Cited by 1 | Viewed by 4003
Abstract
Endometrial cancer is the most common gynecological tract malignancy in developed countries, and its incidence has been increasing globally with rising obesity rates and longer life expectancy. In endometrial cancer, extrauterine disease, in particular lymph node metastasis, is an important prognostic factor. Nevertheless, [...] Read more.
Endometrial cancer is the most common gynecological tract malignancy in developed countries, and its incidence has been increasing globally with rising obesity rates and longer life expectancy. In endometrial cancer, extrauterine disease, in particular lymph node metastasis, is an important prognostic factor. Nevertheless, pelvic lymphadenectomy is not considered to have a therapeutic benefit, as it did not improve survival in randomized studies. However, lymphadenectomy may have a therapeutic benefit if adjuvant therapy can be omitted without decreasing oncological outcomes, as the long-term quality of life is maintained by avoiding morbidities associated with adjuvant therapy. In intermediate- and high-risk endometrioid endometrial carcinomas, adjuvant therapy may be safely omitted without decreasing long-term survival by open surgery including systematic pelvic and para-aortic lymphadenectomy when patients are node-negative. Systematic lymphadenectomy may remove undetectable low-volume lymph node metastasis in both pelvic and para-aortic regions, and open surgery may reduce vaginal recurrence even without vaginal brachytherapy. However, lymphadenectomy may not improve survival in elderly patients and patients with p53-mutant tumors. In this review, I discuss the characteristics of lymph node metastasis, the methods of lymph node assessment, and the therapeutic benefits of systematic lymphadenectomy in patients with intermediate- and high-risk endometrioid endometrial carcinoma. Full article
(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives)
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16 pages, 875 KiB  
Article
Adjuvant Radiotherapy in Surgically Treated HPV-Positive Oropharyngeal Carcinoma with Adverse Pathological Features
by Shady I. Soliman, Farhoud Faraji, John Pang, Loren K. Mell, Joseph A. Califano and Ryan K. Orosco
Cancers 2022, 14(18), 4515; https://doi.org/10.3390/cancers14184515 - 17 Sep 2022
Cited by 4 | Viewed by 2873
Abstract
Purpose: HPV-positive oropharyngeal carcinoma (HPV-OPC) is increasingly treated with primary surgery. The National Comprehensive Cancer Network (NCCN) recommends adjuvant therapy for surgically treated HPV-OPC displaying adverse pathological features (AF). We evaluated adjuvant radiotherapy patterns and outcomes in surgically treated AF-positive HPV-OPC (AF-HPV-OPC). Methods: [...] Read more.
Purpose: HPV-positive oropharyngeal carcinoma (HPV-OPC) is increasingly treated with primary surgery. The National Comprehensive Cancer Network (NCCN) recommends adjuvant therapy for surgically treated HPV-OPC displaying adverse pathological features (AF). We evaluated adjuvant radiotherapy patterns and outcomes in surgically treated AF-positive HPV-OPC (AF-HPV-OPC). Methods: The National Cancer Database was interrogated for patients ≥ 18 years with early-stage HPV-OPC from 2010 to 2017 who underwent definitive resection. Patients that had an NCCN-defined AF indication for adjuvant radiotherapy were assessed, including positive surgical margins (PSM), extranodal extension (ENE), lymphovascular invasion, and level 4/5 cervical lymph nodes. Overall survival (OS) was evaluated using Cox proportional hazards models and Kaplan–Meier analysis in whole and propensity score matched (PM) cohorts. Results: Of 15,036 patients meeting inclusion criteria, 55.7% were positive for at least one AF. Presence of any AF was associated with worse OS (hazard ratio (HR) = 1.56, p < 0.001). In isolation, each AF was associated with worse OS. On PM analysis, insurance status, T2 category, Charlson-Deyo comorbidity score, ENE (HR = 1.81, p < 0.001), and PSM (HR = 1.58, p = 0.002) were associated with worse OS. Median 3-year OS was 92.0% among AF-HPV-OPC patients undergoing adjuvant radiotherapy and 84.2% for those who did not receive adjuvant radiotherapy (p < 0.001, n = 1678). The overall rate of patients with AF-HPV-OPC who did not receive adjuvant radiotherapy was 13% and increased from 10% in 2010 to 17% in 2017 (ptrend = 0.007). Conclusions: In patients with AF-HPV-OPC, adjuvant radiotherapy is associated with improved survival. In the era of de-escalation therapy for HPV-OPC, our findings demonstrate the persistent prognostic benefit of post-operative radiotherapy in the setting of commonly identified adverse features. Ongoing clinical trials will better elucidate optimized patient selection for de-escalated therapy. Full article
(This article belongs to the Special Issue Epidemiology of HPV-Associated Oropharyngeal Squamous Cell Carcinoma)
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11 pages, 1374 KiB  
Article
Pure Solid Pattern of Non-Small Cell Lung Cancer and Clustered Circulating Tumor Cells
by Noriyoshi Sawabata, Takeshi Kawaguchi, Takashi Watanabe, Daiki Yohikawa, Noriko Ouji-Sageshima and Toshihiro Ito
Cancers 2022, 14(18), 4514; https://doi.org/10.3390/cancers14184514 - 17 Sep 2022
Cited by 4 | Viewed by 2107
Abstract
There are two solid patterns of non-small cell lung cancer (NSCLC) on computed tomography (CT): pure or mixed with ground-glass opacities (GGOs). They predict the degree of invasiveness, which may suggest the presence of clustered circulating tumor cells (CTCs), a predictor of poor [...] Read more.
There are two solid patterns of non-small cell lung cancer (NSCLC) on computed tomography (CT): pure or mixed with ground-glass opacities (GGOs). They predict the degree of invasiveness, which may suggest the presence of clustered circulating tumor cells (CTCs), a predictor of poor prognosis. In this study, we assessed the implications of the solid patterns on CT and the preoperative clustered CTCs in surgically resected NSCLC. CTCs were detected using a size selection method. The correlation between the presence of preoperative clustered CTCs and the solid pattern and the prognostic implications were evaluated using co-variables from the clinical-pathological findings. Of the 142 cases, pure solid lesions (Group PS) and mixed GGOs (Group G) were observed in 92 (64.8%) and 50 (35.2%) patients, respectively. In Groups PS and G, clustered CTCs were detected in 29 (31.5%) and 1 (2.0%) patient (p < 0.01), respectively. The PS appearance was an independent predictor of preoperative clustered CTCs in the multivariable analysis, and preoperative clustered CTCs were an independent predictor of poor recurrence-free survival; the solid pattern was not an independent variable. Thus, the PS pattern of NSCLC on CT is an indicator of preoperative clustered CTCs, which is an independent poor prognosis predictor. Full article
(This article belongs to the Special Issue Circulating Tumor Cells: From the Laboratory to the Cancer Clinic)
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