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Cancers, Volume 13, Issue 4 (February-2 2021) – 346 articles

Cover Story (view full-size image): Non-steroidal anti-inflammatory drugs (NSAIDs) are a widely used medication to relieve pain, reduce inflammation and fever. NSAIDs bind to the COX active site instead of arachidonic acid and are competitive binding inhibitors of this enzyme. They have been also one of the most promising agents in the chemoprevention of colorectal cancer. The main anticancer activity of NSAIDs is thought to be a suppression of prostaglandin E2 synthesis via COX-2 inhibition, which causes a decrease in tumor cell proliferation, angiogenesis, and increases apoptosis. Maniewska et al. provide a review of the efficacy of NSAIDs in the chemoprevention of colorectal cancer conducted by searching the MEDLINE/PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) databases. The study confirmed that there is a link between long-term use of the NSAIDs and a decrease in the risk of colorectal cancer. [...] Read more.
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Open AccessReview
The Revolutionary Roads to Study Cell–Cell Interactions in 3D In Vitro Pancreatic Cancer Models
Cancers 2021, 13(4), 930; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040930 - 23 Feb 2021
Viewed by 533
Abstract
Pancreatic cancer, the fourth most common cancer worldwide, shows a highly unsuccessful therapeutic response. In the last 10 years, neither important advancements nor new therapeutic strategies have significantly impacted patient survival, highlighting the need to pursue new avenues for drug development discovery and [...] Read more.
Pancreatic cancer, the fourth most common cancer worldwide, shows a highly unsuccessful therapeutic response. In the last 10 years, neither important advancements nor new therapeutic strategies have significantly impacted patient survival, highlighting the need to pursue new avenues for drug development discovery and design. Advanced cellular models, resembling as much as possible the original in vivo tumor environment, may be more successful in predicting the efficacy of future anti-cancer candidates in clinical trials. In this review, we discuss novel bioengineered platforms for anticancer drug discovery in pancreatic cancer, from traditional two-dimensional models to innovative three-dimensional ones. Full article
(This article belongs to the Special Issue 3D Cell Culture Cancer Models: Development and Applications)
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Open AccessArticle
Germline and Somatic Whole-Exome Sequencing Identifies New Candidate Genes Involved in Familial Predisposition to Serrated Polyposis Syndrome
Cancers 2021, 13(4), 929; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040929 - 23 Feb 2021
Viewed by 712
Abstract
The serrated polyposis syndrome (SPS) is the most common and yet underdiagnosed colorectal polyposis syndrome. It is characterized by multiple and/or large colonic serrated polyps and a higher associated risk for colorectal cancer (CRC). The main objective of this study was to identify [...] Read more.
The serrated polyposis syndrome (SPS) is the most common and yet underdiagnosed colorectal polyposis syndrome. It is characterized by multiple and/or large colonic serrated polyps and a higher associated risk for colorectal cancer (CRC). The main objective of this study was to identify new candidate genes involved in the germline predisposition to SPS/CRC. Thirty-nine SPS patients from 16 families (≥2 patients per family) were recruited without alterations in well-known hereditary CRC genes, and germline and somatic whole-exome sequencing were performed. Germline rare variants with plausible pathogenicity, located in genes involved in cancer development, senescence and epigenetic regulation were selected. Somatic mutational profiling and signature analysis was pursued in one sample per family, when possible. After data filtering, ANXA10, ASXL1, CFTR, DOT1L, HIC1, INO80, KLF3, MCM3AP, MCM8, PDLIM2, POLD1, TP53BP1, WNK2 and WRN were highlighted as the more promising candidate genes for SPS germline predisposition with potentially pathogenic variants shared within families. Somatic analysis characterized mutational profiles in advanced serrated polyps/tumors, revealing a high proportion of hypermutated samples, with a prevalence of clock-like mutational signatures in most samples and the presence of DNA mismatch repair-defective signatures in some cases. In conclusion, we identified new candidate genes to be involved in familial SPS. Further functional studies and replication in additional cohorts are required to confirm the selected candidates. Full article
(This article belongs to the Special Issue New Insights into Colorectal Cancer)
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Open AccessArticle
A 10-Year Probability Deep Neural Network Prediction Model for Lung Cancer
Cancers 2021, 13(4), 928; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040928 - 23 Feb 2021
Viewed by 512
Abstract
Cancer is the leading cause of death in Taiwan. According to the Cancer Registration Report of Taiwan’s Ministry of Health and Welfare, a total of 13,488 people suffered from lung cancer in 2016, making it the second-most common cancer and the leading cancer [...] Read more.
Cancer is the leading cause of death in Taiwan. According to the Cancer Registration Report of Taiwan’s Ministry of Health and Welfare, a total of 13,488 people suffered from lung cancer in 2016, making it the second-most common cancer and the leading cancer in men. Compared with other types of cancer, the incidence of lung cancer is high. In this study, the National Health Insurance Research Database (NHIRDB) was used to determine the diseases and symptoms associated with lung cancer, and a 10-year probability deep neural network prediction model for lung cancer was developed. The proposed model could allow patients with a high risk of lung cancer to receive an earlier diagnosis and support the physicians’ clinical decision-making. The study was designed as a cohort study. The subjects were patients who were diagnosed with lung cancer between 2000 and 2009, and the patients’ disease histories were back-tracked for a period, extending to ten years before the diagnosis of lung cancer. As a result, a total of 13 diseases were selected as the predicting factors. A nine layers deep neural network model was created to predict the probability of lung cancer, depending on the different pre-diagnosed diseases, and to benefit the earlier detection of lung cancer in potential patients. The model is trained 1000 times, the batch size is set to 100, the SGD (Stochastic gradient descent) optimizer is used, the learning rate is set to 0.1, and the momentum is set to 0.1. The proposed model showed an accuracy of 85.4%, a sensitivity of 72.4% and a specificity of 85%, as well as an 87.4% area under ROC (AUROC) (95%, 0.8604–0.8885) model precision. Based on data analysis and deep learning, our prediction model discovered some features that had not been previously identified by clinical knowledge. This study tracks a decade of clinical diagnostic records to identify possible symptoms and comorbidities of lung cancer, allows early prediction of the disease, and assists more patients with early diagnosis. Full article
(This article belongs to the Special Issue Machine Learning Techniques in Cancer)
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Open AccessArticle
Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling
Cancers 2021, 13(4), 927; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040927 - 23 Feb 2021
Viewed by 524
Abstract
The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the [...] Read more.
The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator galectin-3 downstream of the Hsp90 client HIF-1α. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1α-high and/or Gal3-high cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for Hsp90/Cdc37 interface inhibitors. We therefore computationally screened >7 M compounds, and identified four novel small molecules with activities of 4 μM–44 μM in vitro. All of the compounds were K-Ras selective, and potently decreased the Hsp90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved Hsp90/Cdc37 interface inhibitors in cancer and other aging-associated diseases. Full article
(This article belongs to the Section Molecular Cancer Biology)
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Open AccessReview
Clinical Perspectives in Addressing Unsolved Issues in (Neo)Adjuvant Therapy for Primary Breast Cancer
Cancers 2021, 13(4), 926; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040926 - 23 Feb 2021
Viewed by 406
Abstract
The treatment of primary breast cancer has evolved over the past 50 years based on the concept that breast cancer is a systemic disease, with the escalation of adjuvant and neoadjuvant therapies and de-escalation of breast cancer surgery. Despite the development of these [...] Read more.
The treatment of primary breast cancer has evolved over the past 50 years based on the concept that breast cancer is a systemic disease, with the escalation of adjuvant and neoadjuvant therapies and de-escalation of breast cancer surgery. Despite the development of these therapies, recurrence with distant metastasis during the 10 years after surgical treatment is observed, albeit infrequently. Recent advances in genomic analysis based on circulating tumor cells and circulating tumor DNA have enabled the development of targeted therapies based on genetic mutations in residual tumor cells. A paradigm shift involving the application of neoadjuvant chemotherapy (NAC) has enabled the prediction of treatment response and long-term prognoses; additional adjuvant chemotherapy targeting remaining tumor cells after NAC improves survival. The activation of antitumor immunity by anticancer agents may be involved in the eradication of residual tumor cells. Elucidation of the manner in which antitumor immunity is induced by anticancer agents and unknown factors, and the overcoming of drug resistance via the targeted eradication of residual tumor cells based on genomic profiles, will inevitably lead to the achievement of 0% distant recurrence and a complete cure for primary breast cancer. Full article
(This article belongs to the Section Cancer Therapy)
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Open AccessSystematic Review
Interventions Facilitating Family Communication of Genetic Testing Results and Cascade Screening in Hereditary Breast/Ovarian Cancer or Lynch Syndrome: A Systematic Review and Meta-Analysis
Cancers 2021, 13(4), 925; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040925 - 23 Feb 2021
Viewed by 488
Abstract
Evidence-based guidelines recommend cascade genetic testing of blood relatives of known Hereditary Breast and Ovarian Cancer (HBOC) or Lynch Syndrome (LS) cases, to inform individualized cancer screening and prevention plans. The study identified interventions designed to facilitate family communication of genetic testing results [...] Read more.
Evidence-based guidelines recommend cascade genetic testing of blood relatives of known Hereditary Breast and Ovarian Cancer (HBOC) or Lynch Syndrome (LS) cases, to inform individualized cancer screening and prevention plans. The study identified interventions designed to facilitate family communication of genetic testing results and/or cancer predisposition cascade genetic testing for HBOC and LS. We conducted a systematic review and meta-analysis of randomized trials that assessed intervention efficacy for these two outcomes. Additional outcomes were also recorded and synthesized when possible. Fourteen articles met the inclusion criteria and were included in the narrative synthesis and 13 in the meta-analysis. Lack of participant blinding was the most common risk of bias. Interventions targeted HBOC (n = 5); both HBOC and LS (n = 4); LS (n = 3); or ovarian cancer (n = 2). All protocols (n = 14) included a psychoeducational and/or counseling component. Additional components were decision aids (n = 4), building communication skills (n = 4), or motivational interviewing (n = 1). The overall effect size for family communication was small (g = 0.085) and not significant (p = 0.344), while for cascade testing, it was small (g = 0.169) but significant (p = 0.014). Interventions show promise for improving cancer predisposition cascade genetic testing for HBOC and LS. Future studies should employ family-based approaches and include racially diverse samples. Full article
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Open AccessEditorial
Drug Resistance and Novel Therapies in Cancers in 2019
Cancers 2021, 13(4), 924; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040924 - 23 Feb 2021
Viewed by 375
Abstract
After the successful launch in the second half of 2018 by Cancers, the topic collection “Drug Resistance and Novel Therapies in Cancers” experienced its productive first full year in 2019 [...] Full article
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
Open AccessArticle
Evolution of Angiogenic Factors in Pregnant Patients with Breast Cancer Treated with Chemotherapy
Cancers 2021, 13(4), 923; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040923 - 23 Feb 2021
Viewed by 571
Abstract
High prevalence of placental-derived complications, such as preeclampsia and intrauterine growth restriction, has been reported in women with breast cancer (BC) treated with chemotherapy during pregnancy (PBC-CHT). Aim: To ascertain whether PBC-CHT is associated with an imbalance of angiogenic factors, surrogate markers for [...] Read more.
High prevalence of placental-derived complications, such as preeclampsia and intrauterine growth restriction, has been reported in women with breast cancer (BC) treated with chemotherapy during pregnancy (PBC-CHT). Aim: To ascertain whether PBC-CHT is associated with an imbalance of angiogenic factors, surrogate markers for placental insufficiency, that could explain perinatal outcomes. Methods: Prospective study between 2012 and 2016 in a single institution. Soluble fms-like tyrosine kinase (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng) in maternal blood were assessed throughout pregnancy in 12 women with BC and 215 controls. Results: Cancer patients were treated with doxorubicin-based regimes and with taxanes. Ten PBC-CHT (83%) developed obstetrical complications. At the end of the third trimester, significantly higher levels of sFlt-1; sFlt-1/PGF ratio, and sEng levels were observed in BC women as compared to controls. Moreover; there was a significant correlation between plasma levels of sFlt-1 and the number of chemotherapy cycles administered. Besides, more chemotherapy cycles correlated with lower birthweight and head circumference at birth. Conclusions: Women with BC treated during pregnancy showed an antiangiogenic state compatible with placental insufficiency. Angiogenic factors could be useful in the clinical obstetric management of these patients; although further studies will be required to guide clinical decision-making. Full article
(This article belongs to the Special Issue Cancer and Pregnancy)
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Open AccessArticle
Detection of Tumor-Associated Membrane Receptors on Extracellular Vesicles from Non-Small Cell Lung Cancer Patients via Immuno-PCR
Cancers 2021, 13(4), 922; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040922 - 22 Feb 2021
Viewed by 514
Abstract
Precision cancer medicine for non-small-cell lung cancer (NSCLC) has increased patient survival. Nevertheless, targeted agents towards tumor-associated membrane receptors only result in partial remission for a limited time, calling for approaches which allow longitudinal treatment monitoring. Rebiopsy of tumors in the lung is [...] Read more.
Precision cancer medicine for non-small-cell lung cancer (NSCLC) has increased patient survival. Nevertheless, targeted agents towards tumor-associated membrane receptors only result in partial remission for a limited time, calling for approaches which allow longitudinal treatment monitoring. Rebiopsy of tumors in the lung is challenging, and metastatic lesions may have heterogeneous signaling. One way ahead is to use liquid biopsies such as circulating tumor DNA or small extracellular vesicles (sEVs) secreted by the tumor into blood or other body fluids. Herein, an immuno-PCR-based detection of the tumor-associated membrane receptors EGFR, HER2, and IGF-1R on CD9-positive sEVs from NSCLC cells and pleural effusion fluid (PE) of NSCLC patients is developed utilizing DNA conjugates of antibody mimetics and affibodies, as detection agents. Results on sEVs purified from culture media of NSCLC cells treated with anti-EGFR siRNA, showed that the reduction of EGFR expression can be detected via immuno-PCR. Protein profiling of sEVs from NSCLC patient PE samples revealed the capacity to monitor EGFR, HER2, and IGF-1R with the immuno-PCR method. We detected a significantly higher EGFR level in sEVs derived from a PE sample of a patient with an EGFR-driven NSCLC adenocarcinoma than in sEVs from PE samples of non-EGFR driven adenocarcinoma patients or in samples from patients with benign lung disease. In summary, we have developed a diagnostic method for sEVs in liquid biopsies of cancer patients which may be used for longitudinal treatment monitoring to detect emerging bypassing resistance mechanisms in a noninvasive way. Full article
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Open AccessFeature PaperReview
Inflammation-Related Carcinogenesis: Lessons from Animal Models to Clinical Aspects
Cancers 2021, 13(4), 921; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040921 - 22 Feb 2021
Viewed by 437
Abstract
Inflammation-related carcinogenesis has long been known as one of the carcinogenesis patterns in humans. Common carcinogenic factors are inflammation caused by infection with pathogens or the uptake of foreign substances from the environment into the body. Inflammation-related carcinogenesis as a cause for cancer-related [...] Read more.
Inflammation-related carcinogenesis has long been known as one of the carcinogenesis patterns in humans. Common carcinogenic factors are inflammation caused by infection with pathogens or the uptake of foreign substances from the environment into the body. Inflammation-related carcinogenesis as a cause for cancer-related death worldwide accounts for approximately 20%, and the incidence varies widely by continent, country, and even region of the country and can be affected by economic status or development. Many novel approaches are currently available concerning the development of animal models to elucidate inflammation-related carcinogenesis. By learning from the oldest to the latest animal models for each organ, we sought to uncover the essential common causes of inflammation-related carcinogenesis. This review confirmed that a common etiology of organ-specific animal models that mimic human inflammation-related carcinogenesis is prolonged exudation of inflammatory cells. Genotoxicity or epigenetic modifications by inflammatory cells resulted in gene mutations or altered gene expression, respectively. Inflammatory cytokines/growth factors released from inflammatory cells promote cell proliferation and repair tissue injury, and inflammation serves as a “carcinogenic niche”, because these fundamental biological events are common to all types of carcinogenesis, not just inflammation-related carcinogenesis. Since clinical strategies are needed to prevent carcinogenesis, we propose the therapeutic apheresis of inflammatory cells as a means of eliminating fundamental cause of inflammation-related carcinogenesis. Full article
(This article belongs to the Special Issue Carcinogenesis Model)
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Open AccessReview
Taccalonolides: A Novel Class of Microtubule-Stabilizing Anticancer Agents
Cancers 2021, 13(4), 920; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040920 - 22 Feb 2021
Viewed by 353
Abstract
Microtubule stabilizing agents, such as paclitaxel, docetaxel, and cabazitaxel have been among the most used chemotherapeutic agents in the last decades for the treatment of a wide range of cancers in the clinic. One of the concerns that limit their use in clinical [...] Read more.
Microtubule stabilizing agents, such as paclitaxel, docetaxel, and cabazitaxel have been among the most used chemotherapeutic agents in the last decades for the treatment of a wide range of cancers in the clinic. One of the concerns that limit their use in clinical practice is their intrinsic and acquired drug resistance, which is common to most anti-cancer chemotherapeutics. Taccalonolides are a new class of microtubule stabilizers isolated from the roots of a few species in the genus of Tacca. In early studies, taccalonolides demonstrated different effects on interphase and mitotic microtubules from those of paclitaxel and laulimalide suggesting a unique mechanism of action. This prompts the exploration of new taccalonolides with various functionalities through the identification of minor constituents of natural origin and semi-synthesis. The experiments on the new highly potent taccalonolides indicated that taccalonolides possessed a unique mechanism of covalently binding to the microtubule. An X-ray diffraction analysis of a crystal of taccalonolides AJ binding to tubulin indicated that the covalent binding site is at β-tubulin D226. Taccalonolides circumvent all three mechanisms of taxane drug resistance both in vitro and in vivo. To improve the activity, the structure modification through semi-synthesis was conducted and the structure-activity relationships (SARs) was analyzed based on natural and semi-synthetical taccalonolides. The C22–C23 epoxide can significantly increase the antiproliferation potency of taccalonolides due to the covalent link of C22 and the carboxylic group of D226. Great progress has been seen in the last few years in the understanding of the mechanism of this class of microtube-stabilizing agents. This review summarizes the structure diversity, structure-activity relationships (SARs), mechanism of action, and in vivo activities of taccalonolides. Full article
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Open AccessEditorial
Research Progress of Biliary Tract Cancers
Cancers 2021, 13(4), 919; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040919 - 22 Feb 2021
Viewed by 325
Abstract
This series of nine articles (three original articles, six reviews) is presented by international leaders in biliary tract cancers (BTC) [...] Full article
(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)
Open AccessReview
Plasticity in Colorectal Cancer: Why Cancer Cells Differentiate
Cancers 2021, 13(4), 918; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040918 - 22 Feb 2021
Viewed by 546
Abstract
The cancer stem cell hypothesis poses that the bulk of differentiated cells are non-tumorigenic and only a subset of cells with self-renewal capabilities drive tumor initiation and progression. This means that differentiation could have a tumor-suppressive effect. Accumulating evidence shows, however, that in [...] Read more.
The cancer stem cell hypothesis poses that the bulk of differentiated cells are non-tumorigenic and only a subset of cells with self-renewal capabilities drive tumor initiation and progression. This means that differentiation could have a tumor-suppressive effect. Accumulating evidence shows, however, that in some solid tumors, like colorectal cancer, such a hierarchical organization is necessary. The identification of Lgr5 as a reliable marker of normal intestinal epithelial stem cells, together with strategies to trace cell lineages within tumors and the possibility to selectively ablate these cells, have proven the relevance of Lgr5+ cells for cancer progression. On the contrary, the role of Lgr5 cells during this process remains largely unknown. In this review, we explore available evidence pointing towards possible selective advantages of cancer cells organized hierarchically and its resulting cell heterogeneity. Clear evidence of plasticity between cell states, in which loss of Lgr5+ cells can be replenished by dedifferentiation of Lgr5 cells, shows that cell hierarchies could grant adaptive traits to tumors upon changing selective pressures, including those derived from anticancer therapy, as well as during tumor progression to metastasis. Full article
(This article belongs to the Special Issue Stemness and Differentiation in Cancer)
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Open AccessArticle
Novel Gene Signatures Predictive of Patient Recurrence-Free Survival and Castration Resistance in Prostate Cancer
Cancers 2021, 13(4), 917; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040917 - 22 Feb 2021
Viewed by 590
Abstract
Molecular signatures predictive of recurrence-free survival (RFS) and castration resistance are critical for treatment decision-making in prostate cancer (PCa), but the robustness of current signatures is limited. Here, we applied the Robust Rank Aggregation (RRA) method to PCa transcriptome profiles and identified 287 [...] Read more.
Molecular signatures predictive of recurrence-free survival (RFS) and castration resistance are critical for treatment decision-making in prostate cancer (PCa), but the robustness of current signatures is limited. Here, we applied the Robust Rank Aggregation (RRA) method to PCa transcriptome profiles and identified 287 genes differentially expressed between localized castration-resistant PCa (CRPC) and hormone-sensitive PCa (HSPC). Least absolute shrinkage and selection operator (LASSO) and stepwise Cox regression analyses of the 287 genes developed a 6-gene signature predictive of RFS in PCa. This signature included NPEPL1, VWF, LMO7, ALDH2, NUAK1, and TPT1, and was named CRPC-derived prognosis signature (CRPCPS). Interestingly, three of these 6 genes constituted another signature capable of distinguishing CRPC from HSPC. The CRPCPS predicted RFS in 5/9 cohorts in the multivariate analysis and remained valid in patients stratified by tumor stage, Gleason score, and lymph node status. The signature also predicted overall survival and metastasis-free survival. The signature’s robustness was demonstrated by the C-index (0.55–0.74) and the calibration plot in all nine cohorts and the 3-, 5-, and 8-year area under the receiver operating characteristic curve (0.67–0.77) in three cohorts. The nomogram analyses demonstrated CRPCPS’ clinical applicability. The CRPCPS thus appears useful for RFS prediction in PCa. Full article
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Open AccessReview
Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair
Cancers 2021, 13(4), 916; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040916 - 22 Feb 2021
Viewed by 518
Abstract
Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with [...] Read more.
Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with cytotoxic chemotherapies. In addition, less than 20% of patients respond to immunotherapy. TP53 mutations are particularly frequent in gastric cancer (±50% and up to 70% in metastatic) and are considered an early event in the tumorigenic process. Alterations in the expression of other members of the p53 family, i.e., p63 and p73, have also been described. In this context, the role of the members of the p53 family and their isoforms have been investigated over the years, resulting in conflicting data. For instance, whether mutations of TP53 or the dysregulation of its homologs may represent biomarkers for aggressivity or response to therapy still remains a matter of debate. This uncertainty illustrates the lack of information on the molecular pathways involving the p53 family in gastric cancer. In this review, we summarize and discuss the most relevant molecular and clinical data on the role of the p53 family in gastric cancer and enumerate potential therapeutic innovative strategies. Full article
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Open AccessReview
Preclinical Models in Prostate Cancer: Resistance to AR Targeting Therapies in Prostate Cancer
Cancers 2021, 13(4), 915; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040915 - 22 Feb 2021
Viewed by 510
Abstract
Prostate cancer is an androgen-driven tumor. Different prostate cancer therapies consequently focus on blocking the androgen receptor pathway. Clinical studies reported tumor resistance mechanisms by reactivating and bypassing the androgen pathway. Preclinical models allowed the identification, confirmation, and thorough study of these pathways. [...] Read more.
Prostate cancer is an androgen-driven tumor. Different prostate cancer therapies consequently focus on blocking the androgen receptor pathway. Clinical studies reported tumor resistance mechanisms by reactivating and bypassing the androgen pathway. Preclinical models allowed the identification, confirmation, and thorough study of these pathways. This review looks into the current and future role of preclinical models to understand resistance to androgen receptor-targeted therapies. Increasing knowledge on this resistance will greatly improve insights into tumor pathophysiology and future treatment strategies in prostate cancer. Full article
(This article belongs to the Special Issue Prostate Cancer—from Molecular Mechanisms to Clinical Care)
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Open AccessReview
Epigenetic Mechanisms beyond Tumour–Stroma Crosstalk
Cancers 2021, 13(4), 914; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040914 - 22 Feb 2021
Cited by 1 | Viewed by 487
Abstract
Despite cancer having been usually considered the result of genetic mutations, it is now well established that epigenetic dysregulations play pivotal roles in cancer onset and progression. Hence, inactivation of tumour suppressor genes can be gained not only by genetic mutations, but also [...] Read more.
Despite cancer having been usually considered the result of genetic mutations, it is now well established that epigenetic dysregulations play pivotal roles in cancer onset and progression. Hence, inactivation of tumour suppressor genes can be gained not only by genetic mutations, but also by epigenetic mechanisms such as DNA methylation and histone modifications. To occur, epigenetic events need to be triggered by genetic alterations of the epigenetic regulators, or they can be mediated by intracellular and extracellular stimuli. In this last setting, the tumour microenvironment (TME) plays a fundamental role. Therefore, to decipher how epigenetic changes are associated with TME is a challenge still open. The complex signalling between tumour cells and stroma is currently under intensive investigation, and most of the molecules and pathways involved still need to be identified. Neoplastic initiation and development are likely to involve a back-and-forth crosstalk among cancer and stroma cells. An increasing number of studies have highlighted that the cancer epigenome can be influenced by tumour microenvironment and vice versa. Here, we discuss about the recent literature on tumour–stroma interactions that focus on epigenetic mechanisms and the reciprocal regulation between cancer and TME cells. Full article
(This article belongs to the Special Issue Targeting the Tumor Microenvironment)
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Open AccessArticle
A MYC-Driven Plasma Polyamine Signature for Early Detection of Ovarian Cancer
Cancers 2021, 13(4), 913; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040913 - 22 Feb 2021
Viewed by 491
Abstract
MYC is an oncogenic driver in the pathogenesis of ovarian cancer. We previously demonstrated that MYC regulates polyamine metabolism in triple-negative breast cancer (TNBC) and that a plasma polyamine signature is associated with TNBC development and progression. We hypothesized that a similar plasma [...] Read more.
MYC is an oncogenic driver in the pathogenesis of ovarian cancer. We previously demonstrated that MYC regulates polyamine metabolism in triple-negative breast cancer (TNBC) and that a plasma polyamine signature is associated with TNBC development and progression. We hypothesized that a similar plasma polyamine signature may associate with ovarian cancer (OvCa) development. Using mass spectrometry, four polyamines were quantified in plasma from 116 OvCa cases and 143 controls (71 healthy controls + 72 subjects with benign pelvic masses) (Test Set). Findings were validated in an independent plasma set from 61 early-stage OvCa cases and 71 healthy controls (Validation Set). Complementarity of polyamines with CA125 was also evaluated. Receiver operating characteristic area under the curve (AUC) of individual polyamines for distinguishing cases from healthy controls ranged from 0.74–0.88. A polyamine signature consisting of diacetylspermine + N-(3-acetamidopropyl)pyrrolidin-2-one in combination with CA125 developed in the Test Set yielded improvement in sensitivity at >99% specificity relative to CA125 alone (73.7% vs 62.2%; McNemar exact test 2-sided P: 0.019) in the validation set and captured 30.4% of cases that were missed with CA125 alone. Our findings reveal a MYC-driven plasma polyamine signature associated with OvCa that complemented CA125 in detecting early-stage ovarian cancer. Full article
(This article belongs to the Section Cancer Biomarkers)
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Open AccessCommentary
Quality Assurance in Modern Gynecological HDR-Brachytherapy (Interventional Radiotherapy): Clinical Considerations and Comments
Cancers 2021, 13(4), 912; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040912 - 22 Feb 2021
Cited by 1 | Viewed by 385
Abstract
The use of brachytherapy (interventional radiotherapy) in the treatment of gynecological cancers is a crucial element in both definitive and adjuvant settings. The recent developments in high-dose rate remote afterloaders, modern applicators, treatment-planning software, image guidance, and dose monitoring systems have led to [...] Read more.
The use of brachytherapy (interventional radiotherapy) in the treatment of gynecological cancers is a crucial element in both definitive and adjuvant settings. The recent developments in high-dose rate remote afterloaders, modern applicators, treatment-planning software, image guidance, and dose monitoring systems have led to improvement in the local control rates and in some cases improved the survival rates. The development of these highly advanced and complicated treatment modalities has been accompanied by challenges, which have made the existence of quality assurance protocols a must to ensure the integrity of the treatment process. Quality assurance aims at standardizing the technical and clinical procedures involved in the treatment of patients, which could eventually decrease the source of uncertainties whether technical (source/equipment related) or clinical. This commentary review sheds light (from a clinical point of view) on some potential sources of uncertainties associated with the use of modern brachytherapy in the treatment of gynecological cancers. Full article
(This article belongs to the Special Issue Interventional Radiotherapy in Gynecological Cancer)
Open AccessArticle
Vaccination against PD-L1 with IO103 a Novel Immune Modulatory Vaccine in Basal Cell Carcinoma: A Phase IIa Study
Cancers 2021, 13(4), 911; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040911 - 22 Feb 2021
Viewed by 404
Abstract
Antitumor activity of immune checkpoint blocking antibodies against programmed death 1 (PD-1) in basal cell carcinoma (BCC) has been described. IO103 is a peptide vaccine against the major PD-1 ligand PD-L1. A phase IIa study of vaccination with IO103 and Montanide adjuvant was [...] Read more.
Antitumor activity of immune checkpoint blocking antibodies against programmed death 1 (PD-1) in basal cell carcinoma (BCC) has been described. IO103 is a peptide vaccine against the major PD-1 ligand PD-L1. A phase IIa study of vaccination with IO103 and Montanide adjuvant was conducted in patients with resectable BCC (NCT03714529). Vaccinations were given six times every 2 weeks (q2w), followed by three vaccines q4w in responders. Primary endpoints were clinical responses of target tumors, change in target tumor size and immune responses to the vaccine. Secondary endpoint was safety. One tumor per patient was designated target tumor and biopsied twice during the course of vaccination. Synchronous non-target BCCs were not biopsied during vaccinations. Ten patients were vaccinated (six patients received six vaccinations and four patients received nine vaccinations). A partial response (PR) was seen in two target tumors. Two complete responses (CR) and one PR were observed in eight non-target tumors in four patients. No tumors progressed. Related adverse events were grade 1 and reversible. Immune responses against IO103 were induced in blood samples from nine of ten and skin-infiltrating lymphocytes from five of the nine patients. The regressions seen in non-target tumors suggest that IO103 may be effective against a subtype of BCC. Full article
(This article belongs to the Special Issue Cancer Immunotherapy and Immune-Related Adverse Events)
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Open AccessArticle
Picturing Breast Cancer Brain Metastasis Development to Unravel Molecular Players and Cellular Crosstalk
Cancers 2021, 13(4), 910; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040910 - 22 Feb 2021
Viewed by 499
Abstract
With breast cancer (BC) therapy improvements, the appearance of brain metastases has been increasing, representing a life-threatening condition. Brain metastasis formation involves BC cell (BCC) extravasation across the blood–brain barrier (BBB) and brain colonization by unclear mechanisms. We aimed to disclose the actors [...] Read more.
With breast cancer (BC) therapy improvements, the appearance of brain metastases has been increasing, representing a life-threatening condition. Brain metastasis formation involves BC cell (BCC) extravasation across the blood–brain barrier (BBB) and brain colonization by unclear mechanisms. We aimed to disclose the actors involved in BC brain metastasis formation, focusing on BCCs’ phenotype, growth factor expression, and signaling pathway activation, correlating with BBB alterations and intercellular communication. Hippocampi of female mice inoculated with 4T1 BCCs were examined over time by hematoxylin-eosin, immunohistochemistry and immunofluorescence. Well-established metastases were observed at seven days, increasing thereafter. BCCs entering brain parenchyma presented mesenchymal, migratory, and proliferative features; however, with time, they increasingly expressed epithelial markers, reflecting a mesenchymal–epithelial transition. BCCs also expressed platelet-derived growth factor-B, β4 integrin, and focal adhesion kinase, suggesting autocrine and/or paracrine regulation with adhesion signaling activation, while balance between Rac1 and RhoA was associated with the motility status. Intercellular communication via gap junctions was clear among BCCs, and between BCCs and endothelial cells. Thrombin accumulation, junctional protein impairment, and vesicular proteins increase reflect BBB alterations related with extravasation. Expression of plasmalemma vesicle-associated protein was increased in BCCs, along with augmented vascularization, whereas pericyte contraction indicated mural cells’ activation. Our results provide further understanding of BC brain metastasis formation, disclosing potential therapeutic targets. Full article
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Open AccessReview
Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets
Cancers 2021, 13(4), 909; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040909 - 22 Feb 2021
Viewed by 549
Abstract
Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is [...] Read more.
Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options. Full article
(This article belongs to the Special Issue Targeting Cancer Metastasis)
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Open AccessReview
Role of Thermal Ablation in Colorectal Cancer Lung Metastases
Cancers 2021, 13(4), 908; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040908 - 22 Feb 2021
Viewed by 380
Abstract
Background: Consensus guidelines of the European Society for Medical Oncology (ESMO) (2016) provided recommendations for the management of lung metastases. Thermal ablation appears as a tool in the management of these secondary pulmonary lesions, in the same manner as surgical resection or [...] Read more.
Background: Consensus guidelines of the European Society for Medical Oncology (ESMO) (2016) provided recommendations for the management of lung metastases. Thermal ablation appears as a tool in the management of these secondary pulmonary lesions, in the same manner as surgical resection or stereotactic ablative radiotherapy (SABR). Methods: Indications, technical considerations, oncological outcomes such as survival (OS) or local control (LC), prognostic factors and complications of thermal ablation in colorectal cancer lung metastases were reviewed and put into perspective with results of surgery and SABR. Results: LC rates varied from 62 to 91%, with size of the metastasis (<2 cm), proximity to the bronchi or vessels, and size of ablation margins (>5 mm) as predictive factors of LC. Median OS varied between 33 and 68 months. Pulmonary free disease interval <12 months, positive carcinoembryonic antigen, absence of neoadjuvant chemotherapy and uncontrolled extra-pulmonary metastases were poor prognostic factors for OS. While chest drainage for less than 48 h was required in 13 to 47% of treatments, major complications were rare. Conclusions: Thermal ablation of a selected subpopulation of patients with colorectal cancer lung metastases is safe and can provide excellent LC and delay systemic chemotherapy. Full article
(This article belongs to the Special Issue Management of Colorectal Cancer Metastatic Disease)
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Open AccessArticle
Fine-Needle Aspiration Cytology and Histological Types of Thyroid Cancer in the Elderly: Evaluation of 9070 Patients from a Single Referral Centre
Cancers 2021, 13(4), 907; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040907 - 22 Feb 2021
Viewed by 353
Abstract
Background. The prevalence of thyroid nodules increases with age. Their management takes into account the presence of co-morbidities, which are frequent among the elderly. We sought to highlight the differences between the elderly and the general population in cytological and histological diagnoses. Methods. [...] Read more.
Background. The prevalence of thyroid nodules increases with age. Their management takes into account the presence of co-morbidities, which are frequent among the elderly. We sought to highlight the differences between the elderly and the general population in cytological and histological diagnoses. Methods. In this retrospective cohort study, we gathered 13,747 nodule data and compared cytological and histological diagnoses between patients aged over 65 years and a control group. Results. Elderly patients had a higher prevalence of cytologically benign nodules and, consequently, they were less frequently subject to surgery. However, there were no differences in terms of malignancy-risk after surgery. At histology, elderly patients often presented aggressive histology such as medullary thyroid carcinoma, poorly-differentiated and anaplastic cancer, tall cell variant of papillary thyroid carcinoma and Hürthle cell carcinoma. Even in presence of well-differentiated cancer, older patients had higher rates of local invasiveness, lateral lymph node involvement and vascular invasion. Conclusion. Thyroid nodules in elderly patients represent a challenging entity since they are very often benign, but, in case of malignancy, aggressive histotypes and high-risk features are more frequent. Therefore, presurgical characterization of nodules in older patients is crucial and might require strict monitoring. Full article
(This article belongs to the Special Issue Thyroid Cancer in the Elderly)
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Open AccessArticle
The Claudin-Low Subtype of High-Grade Serous Ovarian Carcinoma Exhibits Stem Cell Features
Cancers 2021, 13(4), 906; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040906 - 22 Feb 2021
Viewed by 549
Abstract
Claudin-low cancer (CL) represents a rare and biologically aggressive variant of epithelial tumor. Here, we identified a claudin-low molecular profile of ovarian high-grade serous carcinoma (HGSOC), which exhibits the main characteristics of the homonym breast cancer subtype, including low epithelial differentiation and high [...] Read more.
Claudin-low cancer (CL) represents a rare and biologically aggressive variant of epithelial tumor. Here, we identified a claudin-low molecular profile of ovarian high-grade serous carcinoma (HGSOC), which exhibits the main characteristics of the homonym breast cancer subtype, including low epithelial differentiation and high mesenchymal signature. Hierarchical clustering and a centroid based algorithm applied to cell line collection expression dataset labeled 6 HGSOC cell lines as CL. These have a high energy metabolism and are enriched in CD44+/CD24 mesenchymal stem-like cells expressing low levels of cell-cell adhesion molecules (claudins and E-Cadherin) and high levels of epithelial-to-mesenchymal transition (EMT) induction transcription factors (Zeb1, Snai2, Twist1 and Twist2). Accordingly, the centroid base algorithm applied to large retrospective collections of primary HGSOC samples reveals a tumor subgroup with transcriptional features consistent with the CL profile, and reaffirms EMT as the dominant biological pathway functioning in CL-HGSOC. HGSOC patients carrying CL profiles have a worse overall survival when compared to others, likely to be attributed to its undifferentiated/stem component. These observations highlight the lack of a molecular diagnostic in the management of HGSOC and suggest a potential prognostic utility of this molecular subtyping. Full article
(This article belongs to the Special Issue Gene Expression and Molecular Profiling of Human Cancer Stem Cells)
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Open AccessArticle
Amongst Women Stratified to Receive Endocrine Therapy on the Basis of Their Tumor Estrogen and Progesterone Receptor Levels, Those with Higher Tumor Progesterone Receptor Levels Had a Better Outcome Than Those with Lower Levels of Tumor Progesterone Receptor
Cancers 2021, 13(4), 905; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040905 - 21 Feb 2021
Viewed by 470
Abstract
Background: To realize the association between stratified expression levels of ER and PgR and long-term prognosis of breast cancer patients who received adjuvant hormone therapy, this study aimed to propose better prognostic cut-off levels for estrogen receptor (ER) and progesterone receptor (PgR). Methods: [...] Read more.
Background: To realize the association between stratified expression levels of ER and PgR and long-term prognosis of breast cancer patients who received adjuvant hormone therapy, this study aimed to propose better prognostic cut-off levels for estrogen receptor (ER) and progesterone receptor (PgR). Methods: Patients who received adjuvant hormone therapy after surgical intervention were selected. The ER and PgR status and their effects on breast cancer-specific survival (BCSS) and disease-free survival (DFS) over 5 and 10 years were evaluated. Next, subgroups were generated based on ER and PgR expression percentage and Allred scores. Survival curves were constructed using the Kaplan–Meier method. Results: ER and PgR expression were significantly associated with better prognosis in 5 years, whereas only PgR expression was significantly associated during the 10-year follow-up. The optimal cut-off values for better 5-year BCSS were ER > 50%; ER Allred score > 7; PgR ≥ 1%; or PgR Allred score ≥ 3; the corresponding values for DFS were ER > 40%; ER Allred score > 6; PgR > 10%; or PgR Allred score ≥ 3. In the long-term follow-up, PgR of > 50% or Allred score of > 5 carriers revealed a better prognosis of both BCSS and DFS. Conclusion: Patients with a PgR expression > 50% or an Allred score > 5 exhibited better 10-year BCSS and DFS. Full article
(This article belongs to the Special Issue Estrogen Receptor-Positive (ER+) Breast Cancers)
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Open AccessReview
Metabolism of Innate Immune Cells in Cancer
Cancers 2021, 13(4), 904; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040904 - 21 Feb 2021
Viewed by 555
Abstract
Cancer cells possess specific metabolic requirements for their survival, proliferation, and progression. Within a shared microenvironment, immune cells depend on competing metabolic pathways for their development and effector function. As a result, local acidification, hypoxia, and nutrient depletion in the tumor microenvironment can [...] Read more.
Cancer cells possess specific metabolic requirements for their survival, proliferation, and progression. Within a shared microenvironment, immune cells depend on competing metabolic pathways for their development and effector function. As a result, local acidification, hypoxia, and nutrient depletion in the tumor microenvironment can alter the antitumor immune response and even promote resistance to immunotherapies such as immune checkpoint blockade and adoptive cell transfer. Although T cells are the primary effectors of the antitumor response, growing evidence demonstrates that innate immune cells are critical to successful tumor clearance. This review aims to summarize current research related to the innate immune system, metabolism, and cancer. We first discuss the specific metabolic requirements of innate immune cells for immune activation and suppression and conclude by highlighting ongoing clinical applications of these findings. Full article
(This article belongs to the Special Issue Targeting Innate Immunity to Treat Cancer)
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Open AccessArticle
Molecular Profiling of 22 Primary Atypical Meningiomas Shows the Prognostic Significance of 18q Heterozygous Loss and CDKN2A/B Homozygous Deletion on Recurrence-Free Survival
Cancers 2021, 13(4), 903; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040903 - 21 Feb 2021
Viewed by 498
Abstract
The use of adjuvant therapy is controversial in atypical meningiomas with gross total resection. Predictors of recurrence risk could be useful in selecting patients for additional treatments. The aim of this study was to investigate whether molecular features are associated with recurrence risk [...] Read more.
The use of adjuvant therapy is controversial in atypical meningiomas with gross total resection. Predictors of recurrence risk could be useful in selecting patients for additional treatments. The aim of this study was to investigate whether molecular features are associated with recurrence risk of atypical meningiomas. According to WHO classification, the diagnosis of atypical meningioma was based on the presence of one major criteria (mitotic activity, brain invasion) or three or more minor criteria. The molecular profile of 22 cases (eight mitotically active, eight brain-invasive, and six with minor criteria) was assessed exploring the mutational status and copy number variation of 409 genes using next generation sequencing. Of the 22 patients with a median follow up of 53.5 months, 13 had recurrence of disease within 68 months. NF2 mutation was the only recurrent alteration (11/22) and was unrelated to clinical-pathological features. Recurring meningiomas featured a significantly higher proportion of copy number losses than non-recurring ones (p = 0.027). Chromosome 18q heterozygous loss or CDKN2A/B homozygous deletion was significantly associated with shorter recurrence-free survival (p = 0.008; hazard ratio: 5.3). Atypical meningiomas could be tested routinely for these genetic alterations to identify cases for adjuvant treatment. Full article
(This article belongs to the Special Issue Meningiomas and Low Grade Gliomas)
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Open AccessReview
Neoadjuvant Endocrine Therapy in Breast Cancer Management: State of the Art
Cancers 2021, 13(4), 902; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040902 - 21 Feb 2021
Viewed by 414
Abstract
Endocrine therapy is the mainstay of treatment in HR+/HER2- breast cancers, which represent about 70% of all breast cancers. Neoadjuvant therapy has been developed since the 1990s to address several issues, including breast-conserving surgery (BCS) and improvement of survival rates. For a long [...] Read more.
Endocrine therapy is the mainstay of treatment in HR+/HER2- breast cancers, which represent about 70% of all breast cancers. Neoadjuvant therapy has been developed since the 1990s to address several issues, including breast-conserving surgery (BCS) and improvement of survival rates. For a long time, neoadjuvant endocrine therapy (NET) was confined to frail patients in order to improve surgery outcome. Since the 2000s, NET now plays a central role as a research tool for predictive endocrine sensitivity biomarkers and targeted therapies. One of the major issues in early HR+/HER2- breast cancer is to identify patients in whom chemotherapy can be safely withheld. In vivo assessment of response to NET might be the best treatment strategy to address this issue. Full article
(This article belongs to the Special Issue Neoadjuvant Systemic Therapy in Early Breast Cancer)
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Open AccessArticle
STAT3β Enhances Sensitivity to Concurrent Chemoradiotherapy by Inducing Cellular Necroptosis in Esophageal Squamous Cell Carcinoma
Cancers 2021, 13(4), 901; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040901 - 21 Feb 2021
Viewed by 489
Abstract
Concurrent chemoradiotherapy (CCRT), especially platinum plus radiotherapy, is considered to be one of the most promising treatment modalities for patients with advanced esophageal cancer. STAT3β regulates specific target genes and inhibits the process of tumorigenesis and development. It is also a good prognostic [...] Read more.
Concurrent chemoradiotherapy (CCRT), especially platinum plus radiotherapy, is considered to be one of the most promising treatment modalities for patients with advanced esophageal cancer. STAT3β regulates specific target genes and inhibits the process of tumorigenesis and development. It is also a good prognostic marker and a potential marker for response to adjuvant chemoradiotherapy (ACRT). We aimed to investigate the relationship between STAT3β and CCRT. We examined the expression of STAT3α and STAT3β in pretreatment tumor biopsies of 105 ESCC patients who received CCRT by immunohistochemistry. The data showed that ESCC patients who demonstrate both high STAT3α expression and high STAT3β expression in the cytoplasm have a significantly better survival rate, and STAT3β expression is an independent protective factor (HR = 0.424, p = 0.003). Meanwhile, ESCC patients with high STAT3β expression demonstrated a complete response to CCRT in 65 patients who received platinum plus radiation therapy (p = 0.014). In ESCC cells, high STAT3β expression significantly inhibits the ability of colony formation and cell proliferation, suggesting that STAT3β enhances sensitivity to CCRT (platinum plus radiation therapy). Mechanistically, through RNA-seq analysis, we found that the TNF signaling pathway and necrotic cell death pathway were significantly upregulated in highly expressed STAT3β cells after CCRT treatment. Overall, our study highlights that STAT3β could potentially be used to predict the response to platinum plus radiation therapy, which may provide an important insight into the treatment of ESCC. Full article
(This article belongs to the Special Issue Neoadjuvant- and Immuno-Therapy in Esophageal Cancer)
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