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Cancers, Volume 13, Issue 13 (July-1 2021) – 277 articles

Cover Story (view full-size image): The rapid improvement of next-generation sequencing (NGS) technologies, as well as their numerous applications in large-scale cohorts, has enabled vital advances in cancer research. However, the accumulation of NGS data has led to challenges that are commonly related to big data. Thus, sophisticated data analysis methods that incorporate systems biology and machine learning (ML) have become indispensable. The review by Park et al. provides a detailed summary of tailored ML and systems biology approaches and combinations thereof that tackle the various difficulties that arise in the face of big data. Moreover, it gives an overview of the numerous applications of artificial intelligence, aiding the analysis and interpretation of NGS data for molecular characterization, tumor heterogeneity, or cancer drug discovery, for instance. View this paper
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Review
NUAK1 and NUAK2 Fine-Tune TGF-β Signaling
Cancers 2021, 13(13), 3377; https://doi.org/10.3390/cancers13133377 - 05 Jul 2021
Cited by 2 | Viewed by 1739
Abstract
Transforming growth factor-β (TGF-β) signaling plays a key role in governing various cellular processes, extending from cell proliferation and apoptosis to differentiation and migration. Due to this extensive involvement in the regulation of cellular function, aberrant TGF-β signaling is frequently implicated in the [...] Read more.
Transforming growth factor-β (TGF-β) signaling plays a key role in governing various cellular processes, extending from cell proliferation and apoptosis to differentiation and migration. Due to this extensive involvement in the regulation of cellular function, aberrant TGF-β signaling is frequently implicated in the formation and progression of tumors. Therefore, a full understanding of the mechanisms of TGF-β signaling and its key components will provide valuable insights into how this intricate signaling cascade can shift towards a detrimental course. In this review, we discuss the interplay between TGF-β signaling and the AMP-activated protein kinase (AMPK)-related NUAK kinase family. We highlight the function and regulation of these kinases with focus on the pivotal role NUAK1 and NUAK2 play in regulating TGF-β signaling. Specifically, TGF-β induces the expression of NUAK1 and NUAK2 that regulates TGF-β signaling output in an opposite manner. Besides the focus on the TGF-β pathway, we also present a broader perspective on the expression and signaling interactions of the NUAK kinases to outline the broader functions of these protein kinases. Full article
(This article belongs to the Special Issue Effects of TGF-Beta on Cancer Cell Metabolism)
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Article
Pursuit of Gene Fusions in Daily Practice: Evidence from Real-World Data in Wild-Type and Microsatellite Instable Patients
Cancers 2021, 13(13), 3376; https://doi.org/10.3390/cancers13133376 - 05 Jul 2021
Cited by 3 | Viewed by 1094
Abstract
Agnostic biomarkers such as gene fusions allow to address cancer patients to targeted therapies; however, the low prevalence of these alterations across common malignancies poses challenges and needs a feasible and sensitive diagnostic process. RNA-based targeted next generation sequencing was performed on 125 [...] Read more.
Agnostic biomarkers such as gene fusions allow to address cancer patients to targeted therapies; however, the low prevalence of these alterations across common malignancies poses challenges and needs a feasible and sensitive diagnostic process. RNA-based targeted next generation sequencing was performed on 125 samples of patients affected either by colorectal carcinoma, melanoma, or lung adenocarcinoma lacking genetic alterations in canonical driver genes, or by a colorectal carcinoma with microsatellite instability. Gene fusion rates were compared with in silico data from MSKCC datasets. For NTRK gene fusion detection we also employed a multitarget qRT-PCR and pan-TRK immunohistochemistry. Gene fusions were detected in 7/55 microsatellite instable colorectal carcinomas (12.73%), and in 4/70 of the “gene driver free” population (5.71%: 3/28 melanomas, 10.7%, and 1/12 lung adenocarcinomas, 8.3%). Fusion rates were significantly higher compared with the microsatellite stable and “gene driver positive” MSKCC cohorts. Pan-TRK immunohistochemistry showed 100% sensitivity, 91.7% specificity, and the occurrence of heterogeneous and/or subtle staining patterns. The enrichment of gene fusions in this “real-world” cohort highlights the feasibility of a workflow applicable in clinical practice. The heterogeneous expression in NTRK fusion positive tumours unveils challenging patterns to recognize and raises questions on the effective translation of the chimeric protein. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Article
Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma
Cancers 2021, 13(13), 3375; https://doi.org/10.3390/cancers13133375 - 05 Jul 2021
Cited by 1 | Viewed by 973
Abstract
Dendritic cells (DC) as professional antigen presenting cells are able to prime T-cells against the tumor-associated antigen α-fetoprotein (AFP) for immunotherapy of hepatocellular carcinoma (HCC). However, a strong immunosuppressive tumor environment limits their efficacy in patients. The co-stimulation with CD40Ligand (CD40L) is critical [...] Read more.
Dendritic cells (DC) as professional antigen presenting cells are able to prime T-cells against the tumor-associated antigen α-fetoprotein (AFP) for immunotherapy of hepatocellular carcinoma (HCC). However, a strong immunosuppressive tumor environment limits their efficacy in patients. The co-stimulation with CD40Ligand (CD40L) is critical in the maturation of DC and T-cell priming. In this study, the impact of intratumoral (i.t.) CD40L-expressing DC to improve vaccination with murine (m)AFP-transduced DC (Ad-mAFP-DC) was analyzed in subcutaneous (s.c.) and orthotopic murine HCC. Murine DC were adenovirally transduced with Ad-mAFP or Ad-CD40L. Hepa129-mAFP-cells were injected into the right flank or the liver of C3H-mice to induce subcutaneous (s.c.) and orthotopic HCC. For treatments, 106 Ad-mAFP-transduced DC were inoculated s.c. followed by 106 CD40L-expressing DC injected intratumorally (i.t.). S.c. inoculation with Ad-mAFP-transduced DC, as vaccine, induced a delay of tumor-growth of AFP-positive HCC compared to controls. When s.c.-inoculation of Ad-mAFP-DC was combined with i.t.-application of Ad-CD40L-DC synergistic antitumoral effects were observed and complete remissions and long-term survival in 62% of tumor-bearing animals were achieved. Analysis of the tumor environment at different time points revealed that s.c.-vaccination with Ad-mAFP-DC seems to stimulate tumor-specific effector cells, allowing an earlier recruitment of effector T-cells and a Th1 shift within the tumors. After i.t. co-stimulation with Ad-CD40L-DC, production of Th1-cytokines was strongly increased and accompanied by a robust tumor infiltration of mature DC, activated CD4+-, CD8+-T-cells as well as reduction of regulatory T-cells. Moreover, Ad-CD40L-DC induced tumor cell apoptosis. Intratumoral co-stimulation with CD40L-expressing DC significantly improves vaccination with Ad-mAFP-DC in pre-established HCC in vivo. Combined therapy caused an early and strong Th1-shift in the tumor environment as well as higher tumor apoptosis, leading to synergistic tumor regression of HCC. Thus, CD40L co-stimulation represents a promising tool for improving DC-based immunotherapy of HCC. Full article
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Article
Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus
Cancers 2021, 13(13), 3374; https://doi.org/10.3390/cancers13133374 - 05 Jul 2021
Cited by 3 | Viewed by 906
Abstract
Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics [...] Read more.
Childhood papillary thyroid carcinoma (PTC) diagnosed after the Chernobyl accident in Belarus displayed a high frequency of gene rearrangements and low frequency of point mutations. Since 2001, only sporadic thyroid cancer occurs in children aged up to 14 years but its molecular characteristics have not been reported. Here, we determine the major oncogenic events in PTC from non-exposed Belarusian children and assess their clinicopathological correlations. Among the 34 tumors, 23 (67.6%) harbored one of the mutually exclusive oncogenes: 5 (14.7%) BRAFV600E, 4 (11.8%) RET/PTC1, 6 (17.6%) RET/PTC3, 2 (5.9%) rare fusion genes, and 6 (17.6%) ETV6ex4/NTRK3. No mutations in codons 12, 13, and 61 of K-, N- and H-RAS, BRAFK601E, or ETV6ex5/NTRK3 or AKAP9/BRAF were detected. Fusion genes were significantly more frequent than BRAFV600E (p = 0.002). Clinicopathologically, RET/PTC3 was associated with solid growth pattern and higher tumor aggressiveness, BRAFV600E and RET/PTC1 with classic papillary morphology and mild clinical phenotype, and ETV6ex4/NTRK3 with follicular-patterned PTC and reduced aggressiveness. The spectrum of driver mutations in sporadic childhood PTC in Belarus largely parallels that in Chernobyl PTC, yet the frequencies of some oncogenes may likely differ from those in the early-onset Chernobyl PTC; clinicopathological features correlate with the oncogene type. Full article
(This article belongs to the Special Issue Biomarkers of Thyroid Cancer)
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Review
Prostate Cancer Liquid Biopsy Biomarkers’ Clinical Utility in Diagnosis and Prognosis
Cancers 2021, 13(13), 3373; https://doi.org/10.3390/cancers13133373 - 05 Jul 2021
Cited by 4 | Viewed by 2069
Abstract
Prostate cancer (PCa) is the most common cancer in men worldwide. The current gold standard for diagnosing PCa relies on a transrectal ultrasound-guided systematic core needle biopsy indicated after detection changes in a digital rectal examination (DRE) and elevated prostate-specific antigen (PSA) level [...] Read more.
Prostate cancer (PCa) is the most common cancer in men worldwide. The current gold standard for diagnosing PCa relies on a transrectal ultrasound-guided systematic core needle biopsy indicated after detection changes in a digital rectal examination (DRE) and elevated prostate-specific antigen (PSA) level in the blood serum. PSA is a marker produced by prostate cells, not just cancer cells. Therefore, an elevated PSA level may be associated with other symptoms such as benign prostatic hyperplasia or inflammation of the prostate gland. Due to this marker’s low specificity, a common problem is overdiagnosis, which leads to unnecessary biopsies and overtreatment. This is associated with various treatment complications (such as bleeding or infection) and generates unnecessary costs. Therefore, there is no doubt that the improvement of the current procedure by applying effective, sensitive and specific markers is an urgent need. Several non-invasive, cost-effective, high-accuracy liquid biopsy diagnostic biomarkers such as Progensa PCA3, MyProstateScore ExoDx, SelectMDx, PHI, 4K, Stockholm3 and ConfirmMDx have been developed in recent years. This article compares current knowledge about them and their potential application in clinical practice. Full article
(This article belongs to the Special Issue Cancer Biomarkers in Body Fluids)
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Review
Epitranscriptomics: A New Layer of microRNA Regulation in Cancer
Cancers 2021, 13(13), 3372; https://doi.org/10.3390/cancers13133372 - 05 Jul 2021
Cited by 4 | Viewed by 1529
Abstract
MicroRNAs are pervasive regulators of gene expression at the post-transcriptional level in metazoan, playing key roles in several physiological and pathological processes. Accordingly, these small non-coding RNAs are also involved in cancer development and progression. Furthermore, miRNAs represent valuable diagnostic and prognostic biomarkers [...] Read more.
MicroRNAs are pervasive regulators of gene expression at the post-transcriptional level in metazoan, playing key roles in several physiological and pathological processes. Accordingly, these small non-coding RNAs are also involved in cancer development and progression. Furthermore, miRNAs represent valuable diagnostic and prognostic biomarkers in malignancies. In the last twenty years, the role of RNA modifications in fine-tuning gene expressions at several levels has been unraveled. All RNA species may undergo post-transcriptional modifications, collectively referred to as epitranscriptomic modifications, which, in many instances, affect RNA molecule properties. miRNAs are not an exception, in this respect, and they have been shown to undergo several post-transcriptional modifications. In this review, we will summarize the recent findings concerning miRNA epitranscriptomic modifications, focusing on their potential role in cancer development and progression. Full article
(This article belongs to the Collection miRNAs: New Insights in Tumor Biology)
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Article
Meta-Analysis of Microdissected Breast Tumors Reveals Genes Regulated in the Stroma but Hidden in Bulk Analysis
Cancers 2021, 13(13), 3371; https://doi.org/10.3390/cancers13133371 - 05 Jul 2021
Cited by 2 | Viewed by 1084
Abstract
Transcriptome data provide a valuable resource for the study of cancer molecular mechanisms, but technical biases, sample heterogeneity, and small sample sizes result in poorly reproducible lists of regulated genes. Additionally, the presence of multiple cellular components contributing to cancer development complicates the [...] Read more.
Transcriptome data provide a valuable resource for the study of cancer molecular mechanisms, but technical biases, sample heterogeneity, and small sample sizes result in poorly reproducible lists of regulated genes. Additionally, the presence of multiple cellular components contributing to cancer development complicates the interpretation of bulk transcriptomic profiles. To address these issues, we collected 48 microarray datasets derived from laser capture microdissected stroma or epithelium in breast tumors and performed a meta-analysis identifying robust lists of differentially expressed genes. This was used to create a database with carefully harmonized metadata that we make freely available to the research community. As predicted, combining the results of multiple datasets improved statistical power. Moreover, the separate analysis of stroma and epithelium allowed the identification of genes with different contributions in each compartment, which would not be detected by bulk analysis due to their distinct regulation in the two compartments. Our method can be profitably used to help in the discovery of biomarkers and the identification of functionally relevant genes in both the stroma and the epithelium. This database was made to be readily accessible through a user-friendly web interface. Full article
(This article belongs to the Special Issue Identification of Candidate Genes in Breast and Ovarian Cancer)
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Article
Serum HPV16 E7 Oncoprotein Is a Recurrence Marker of Oropharyngeal Squamous Cell Carcinomas
Cancers 2021, 13(13), 3370; https://doi.org/10.3390/cancers13133370 - 05 Jul 2021
Cited by 1 | Viewed by 923
Abstract
Despite improved prognosis for many HPV-positive head and neck squamous cell carcinomas (HNSCCs), some cases are still marked by recurrence and metastasis. Our study aimed to identify novel biomarkers for patient stratification. Classical HPV markers: HPV-DNA, p16 and HPV mRNA expression were studied [...] Read more.
Despite improved prognosis for many HPV-positive head and neck squamous cell carcinomas (HNSCCs), some cases are still marked by recurrence and metastasis. Our study aimed to identify novel biomarkers for patient stratification. Classical HPV markers: HPV-DNA, p16 and HPV mRNA expression were studied in HNSCC (n = 67) and controls (n = 58) by qPCR. Subsequently, ELISA tests were used for HPV16 L1 antibody and HPV16 E7 oncoprotein detection in serum at diagnosis and follow-up. All markers were correlated to relapse-free survival (RFS) and overall survival (OS). HPV-DNA was found in HNSCCs (29.85%), HPV16-DNA in 95% of cases, HPV16 E7 mRNA was revealed in 93.75%. p16 was overexpressed in 75% of HPV-positive HNSCC compared to negative samples and controls (p < 0.001). Classical markers correlated with improved OS (p < 0.05). Serological studies showed similar proportions of HPV16 L1 antibodies in all HNSCCs (p > 0.05). Serum E7 oncoprotein was present in 30% HPV-positive patients at diagnosis (p > 0.05) and correlated to HNSCC HPV16 E7 mRNA (p < 0.01), whereas it was associated to worse RFS and OS, especially for oropharyngeal squamous cell carcinoma (OPSCC) (p < 0.01). Detection of circulating HPV16 E7 oncoprotein at diagnosis may be useful for stratifying and monitoring HPV-positive HNSCC patients for worse prognosis, providing clinicians a tool for selecting patients for treatment de-escalation. Full article
(This article belongs to the Special Issue Cancer Biomarkers in Body Fluids)
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Systematic Review
The Incidence and Treatment Response of Double Expression of MYC and BCL2 in Patients with Diffuse Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis
Cancers 2021, 13(13), 3369; https://doi.org/10.3390/cancers13133369 - 05 Jul 2021
Viewed by 1544
Abstract
MYC/BCL2 protein co-expression (i.e., double expressor) has been shown to be a negative predictor of outcome in diffuse large B-cell lymphoma (DLBCL). We aimed to establish the incidence of double expressor status in patients with de novo DLBCL and identify the predictive value [...] Read more.
MYC/BCL2 protein co-expression (i.e., double expressor) has been shown to be a negative predictor of outcome in diffuse large B-cell lymphoma (DLBCL). We aimed to establish the incidence of double expressor status in patients with de novo DLBCL and identify the predictive value of this biomarker on treatment response through systematic review and meta-analysis. PubMed and Embase were searched for studies published through December 2019 that reported proportions of double expressor DLBCL. The pooled proportions of MYC and BCL2 expression, both alone and in combination, were computed using the inverse variance method for calculating weights and by the DerSimonian–Laird method. The pooled odds ratios (ORs) of complete remission (CR) rate were calculated, and meta-regression analysis was conducted to explore heterogeneity. Forty-one studies (7054 patients) were included. The pooled incidence of double expressor status in DLBCL was 23% (95% confidence interval [CI], 20–26%), with an adjusted estimate of 31% (95% CI, 27–36%). Neither MYC/BCL2 protein cutoff values, race, mean, or median age of included patients, or overall study quality was a significant factor of heterogeneity (p ≥ 0.20). Cases without double expressor status demonstrated a higher probability of CR to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone treatment (OR, 2.69; 95% CI, 1.55–4.67). Our results reaffirm the predictive power of this important biomarker. Full article
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Article
Physical Comorbidities and Depression in Recent and Long-Term Adult Cancer Survivors: NHANES 2007–2018
Cancers 2021, 13(13), 3368; https://doi.org/10.3390/cancers13133368 - 05 Jul 2021
Cited by 4 | Viewed by 1722
Abstract
Many adult cancer patients present one or more physical comorbidities. Besides interfering with treatment and prognosis, physical comorbidities could also increase the already heightened psychological risk of cancer patients. To test this possibility, we investigated the relationship between physical comorbidities with depression symptoms [...] Read more.
Many adult cancer patients present one or more physical comorbidities. Besides interfering with treatment and prognosis, physical comorbidities could also increase the already heightened psychological risk of cancer patients. To test this possibility, we investigated the relationship between physical comorbidities with depression symptoms in a sample of 2073 adult cancer survivors drawn from the nationally representative National Health and Nutrition Examination Survey (NHANES) (2007–2018) in the U.S. Based on information regarding 16 chronic conditions, the number of comorbidities diagnosed before and after the cancer diagnosis was calculated. The number of comorbidities present at the moment of cancer diagnosis was significantly related to depression risk in recent but not in long-term survivors. Recent survivors who suffered multimorbidity had 3.48 (95% CI 1.26–9.55) times the odds of reporting significant depressive symptoms up to 5 years after the cancer diagnosis. The effect of comorbidities was strongest among survivors of breast cancer. The comorbidities with strongest influence on depression risk were stroke, kidney disease, hypertension, obesity, asthma, and arthritis. Information about comorbidities is usually readily available and could be useful in streamlining depression screening or targeting prevention efforts in cancer patients and survivors. A multidimensional model of the interaction between cancer and other physical comorbidities on mental health is proposed. Full article
(This article belongs to the Special Issue Psychosocial Oncology: Recent Advances and Challenges)
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Article
Potent Anticancer Effects of Epidithiodiketopiperazine NT1721 in Cutaneous T Cell Lymphoma
Cancers 2021, 13(13), 3367; https://doi.org/10.3390/cancers13133367 - 05 Jul 2021
Cited by 1 | Viewed by 929 | Correction
Abstract
Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of debilitating, incurable malignancies. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes, accounting for ~65% of CTCL cases. Patients with advanced disease have a poor prognosis and low median survival [...] Read more.
Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of debilitating, incurable malignancies. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes, accounting for ~65% of CTCL cases. Patients with advanced disease have a poor prognosis and low median survival rates of four years. CTCLs develop from malignant skin-homing CD4+ T cells that spread to lymph nodes, blood, bone marrow and viscera in advanced stages. Current treatments options for refractory or advanced CTCL, including chemotherapeutic and biological approaches, rarely lead to durable responses. The exact molecular mechanisms of CTCL pathology remain unclear despite numerous genomic and gene expression profile studies. However, apoptosis resistance is thought to play a major role in the accumulation of malignant T cells. Here we show that NT1721, a synthetic epidithiodiketopiperazine based on a natural product, reduced cell viability at nanomolar concentrations in CTCL cell lines, while largely sparing normal CD4+ cells. Treatment of CTCL cells with NT1721 reduced proliferation and potently induced apoptosis. NT1721 mediated the downregulation of GLI1 transcription factor, which was associated with decreased STAT3 activation and the reduced expression of downstream antiapoptotic proteins (BCL2 and BCL-xL). Importantly, NT1721, which is orally available, reduced tumor growth in two CTCL mouse models significantly better than two clinically used drugs (romidepsin, gemcitabine). Moreover, a combination of NT1721 with gemcitabine reduced the tumor growth significantly better than the single drugs. Taken together, these results suggest that NT1721 may be a promising new agent for the treatment of CTCLs. Full article
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Article
Single Cell Genetic Profiling of Tumors of Breast Cancer Patients Aged 50 Years and Older Reveals Enormous Intratumor Heterogeneity Independent of Individual Prognosis
Cancers 2021, 13(13), 3366; https://doi.org/10.3390/cancers13133366 - 05 Jul 2021
Cited by 2 | Viewed by 1012
Abstract
Purpose: Older breast cancer patients are underrepresented in cancer research even though the majority (81.4%) of women dying of breast cancer are 55 years and older. Here we study a common phenomenon observed in breast cancer which is a large inter- and intratumor [...] Read more.
Purpose: Older breast cancer patients are underrepresented in cancer research even though the majority (81.4%) of women dying of breast cancer are 55 years and older. Here we study a common phenomenon observed in breast cancer which is a large inter- and intratumor heterogeneity; this poses a tremendous clinical challenge, for example with respect to treatment stratification. To further elucidate genomic instability and tumor heterogeneity in older patients, we analyzed the genetic aberration profiles of 39 breast cancer patients aged 50 years and older (median 67 years) with either short (median 2.4 years) or long survival (median 19 years). The analysis was based on copy number enumeration of eight breast cancer-associated genes using multiplex interphase fluorescence in situ hybridization (miFISH) of single cells, and by targeted next-generation sequencing of 563 cancer-related genes. Results: We detected enormous inter- and intratumor heterogeneity, yet maintenance of common cancer gene mutations and breast cancer specific chromosomal gains and losses. The gain of COX2 was most common (72%), followed by MYC (69%); losses were most prevalent for CDH1 (74%) and TP53 (69%). The degree of intratumor heterogeneity did not correlate with disease outcome. Comparing the miFISH results of diploid with aneuploid tumor samples significant differences were found: aneuploid tumors showed significantly higher average signal numbers, copy number alterations (CNAs) and instability indices. Mutations in PIKC3A were mostly restricted to luminal A tumors. Furthermore, a significant co-occurrence of CNAs of DBC2/MYC, HER2/DBC2 and HER2/TP53 and mutual exclusivity of CNAs of HER2 and PIK3CA mutations and CNAs of CCND1 and PIK3CA mutations were revealed. Conclusion: Our results provide a comprehensive picture of genome instability profiles with a large variety of inter- and intratumor heterogeneity in breast cancer patients aged 50 years and older. In most cases, the distribution of chromosomal aneuploidies was consistent with previous results; however, striking exceptions, such as tumors driven by exclusive loss of chromosomes, were identified. Full article
(This article belongs to the Collection DNA Damage in Cancer)
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Article
Neuroblastoma Molecular Risk-Stratification of DNA Copy Number and ALK Genotyping via Cell-Free Circulating Tumor DNA Profiling
Cancers 2021, 13(13), 3365; https://doi.org/10.3390/cancers13133365 - 05 Jul 2021
Cited by 7 | Viewed by 1354
Abstract
Background: MYCN amplification (MNA), segmental chromosomal aberrations (SCA) and ALK activating mutations are biomarkers for risk-group stratification and for targeted therapeutics for neuroblastoma, both of which are currently assessed on tissue biopsy. Increase in demand for tumor genetic testing for neuroblastoma diagnosis is [...] Read more.
Background: MYCN amplification (MNA), segmental chromosomal aberrations (SCA) and ALK activating mutations are biomarkers for risk-group stratification and for targeted therapeutics for neuroblastoma, both of which are currently assessed on tissue biopsy. Increase in demand for tumor genetic testing for neuroblastoma diagnosis is posing a challenge to current practice, as the small size of the core needle biopsies obtained are required for multiple molecular tests. We evaluated the utility of detecting these biomarkers in the circulation. Methods: Various pre-analytical conditions tested to optimize circulating-tumor DNA (ctDNA) copy number changes evaluations. Plasma samples from 10 patients diagnosed with neuroblastoma assessed for SCA and MNA using single nucleotide polymorphism (SNP) array approach currently used for neuroblastoma diagnosis, with MNA status assessed independently using digital-droplet PCR (ddPCR). Three patients (one in common with the previous 10) tested for ALK activating mutations p.F1174L and p.F1245I using ddPCR. Results: Copy number detection is highly affected by physical perturbations of the blood sample (mimicking suboptimal sample shipment), which could be overcome using specialized preservative collection tubes. Pre-analytical DNA repair procedures on ctDNA before SNP chromosome microarray processing improved the lower limit of detection for SCA and MNA, defined as 20% and 10%, respectively. We detected SCA in 10/10 (100%) patients using SNP array, 7 of which also presented MNA. Circulating-free DNA (cfDNA) and matched tumor DNA profiles were generally identical. MNA was detected using ddPCR in 7/7 (100%) of MNA and 0/12 (0%) non-MNA cases. MNA and ALK mutation dynamic change was assessed in longitudinal samples from 4 and 3 patients (one patient with both), respectively, accurately reflected response to treatment in 6/6 (100%) and disease recurrence in 5/6 (83%) of cases. Samples taken prior to targeted treatment with the ALK inhibitor Lorlatinib and 6–8 weeks on treatment showed reduction/increase in ALK variants according to response to treatment. Conclusions: These results demonstrate the feasibility of ctDNA profiling for molecular risk-stratification, and treatment monitoring in a clinically relevant time frame and the potential to reduce fresh tissue requirements currently embedded in the management of neuroblastoma. Full article
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Correction
Correction: Görte et al. Comparative Proton and Photon Irradiation Combined with Pharmacological Inhibitors in 3D Pancreatic Cancer Cultures. Cancers 2020, 12, 3216
Cancers 2021, 13(13), 3364; https://doi.org/10.3390/cancers13133364 - 05 Jul 2021
Cited by 1 | Viewed by 794
Abstract
The authors wish to make the following corrections to this paper [...] Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Article
Combination of the G-8 Screening Tool and Hand-Grip Strength to Predict Long-Term Overall Survival in Non-Small Cell Lung Cancer Patients Undergoing Stereotactic Body Radiotherapy
Cancers 2021, 13(13), 3363; https://doi.org/10.3390/cancers13133363 - 05 Jul 2021
Cited by 3 | Viewed by 1007
Abstract
The Geriatric 8 (G-8) is a known predictor of overall survival (OS) in older cancer patients, but is mainly based on nutritional aspects. This study aimed to assess if the G-8 combined with a hand-grip strength test (HGST) in patients with NSCLC treated [...] Read more.
The Geriatric 8 (G-8) is a known predictor of overall survival (OS) in older cancer patients, but is mainly based on nutritional aspects. This study aimed to assess if the G-8 combined with a hand-grip strength test (HGST) in patients with NSCLC treated with stereotactic body radiotherapy can predict long-term OS better than the G-8 alone. A total of 46 SBRT-treated patients with NSCLC of stage T1-T2N0M0 were included. Patients were divided into three groups: fit (normal G-8 and HGST), vulnerable (abnormal G-8 or HGST), or frail (abnormal G-8 and HGST). Statistically significant differences were found in 4-year OS between the fit, vulnerable, and frail groups (70% vs. 46% vs. 25%, p = 0.04), as well as between the normal and abnormal G-8 groups (69% vs. 39%, p = 0.02). In a multivariable analysis of OS, being vulnerable with a hazard ratio (HR) of 2.03 or frail with an HR of 3.80 indicated poorer OS, but this did not reach statistical significance. This study suggests that there might be a benefit of adding a physical test to the G-8 for more precisely predicting overall survival in SBRT-treated patients with localized NSCLC. However, this should be confirmed in a larger study population. Full article
(This article belongs to the Special Issue Geriatric Oncology: From Research to Clinical Practice)
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Article
TP53 Mutation as a Prognostic and Predictive Marker in Sarcoma: Pooled Analysis of MOSCATO and ProfiLER Precision Medicine Trials
Cancers 2021, 13(13), 3362; https://doi.org/10.3390/cancers13133362 - 05 Jul 2021
Viewed by 1070
Abstract
(1) Background: locally resected high-grade sarcomas relapse in 40% of cases. There is no prognostic or predictive genomic marker for response to peri-operative chemotherapy. (2) Methods: MOSCATO and ProfiLER are pan-tumor prospective precision medicine trials for advanced tumors. Molecular analysis in both trials [...] Read more.
(1) Background: locally resected high-grade sarcomas relapse in 40% of cases. There is no prognostic or predictive genomic marker for response to peri-operative chemotherapy. (2) Methods: MOSCATO and ProfiLER are pan-tumor prospective precision medicine trials for advanced tumors. Molecular analysis in both trials comprised targeted next-generation sequencing and comparative genomic hybridization array. We investigated if molecular alterations identified in these trials in sarcomas were associated with disease-free survival (DFS) and response to anthracyclines. (3) Results: this analysis included 215 sarcomas, amongst which 53 leiomyosarcomas, 27 rhabdomyosarcomas, 20 undifferentiated pleomorphic sarcomas, and 17 liposarcomas. The most frequently altered gene was TP53 (46 mutations and eight deletions). There were 149 surgically resected localized sarcomas. Median DFS in TP53 wild type (WT), deleted, and mutated sarcomas was 16, 10, and 10 months, respectively (p = 0.028; deletions: HR = 1.55; 95% CI = 0.75–3.19; mutations: HR = 1.70; 95%CI = 1.13–2.64). In multivariate analysis, TP53 mutations remained associated with shorter DFS (p = 0.027; HR = 2.30; 95%CI = 1.10–4.82). There were 161 localized and advanced sarcomas evaluable for response to anthracyclines. Objective response rates were 35% and 55% in TP53 WT and mutated sarcomas, respectively (OR = 2.24; 95%CI = 1.01–5.03; p = 0.05). In multivariate analysis, TP53 mutations remained associated with increased response (OR = 3.24; 95%CI = 1.30–8.45; p = 0.01). (4) Conclusions: TP53 mutations are associated with shorter DFS and increased response to anthracyclines. Post-validation, these findings could assist in decision-making for peri-operative treatments. Full article
(This article belongs to the Special Issue Biomarkers in the Era of Precision Oncology)
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Article
Cancer-Associated Fibroblasts Modulate Transcriptional Signatures Involved in Proliferation, Differentiation and Metastasis in Head and Neck Squamous Cell Carcinoma
Cancers 2021, 13(13), 3361; https://doi.org/10.3390/cancers13133361 - 04 Jul 2021
Cited by 4 | Viewed by 1400
Abstract
Cancer-associated fibroblasts (CAFs) are known to increase tumor growth and to stimulate invasion and metastasis. Increasing evidence suggests that CAFs mediate response to various treatments. HNSCC cell lines were co-cultured with their patient-matched CAFs in 2D and 3D in vitro models, and the [...] Read more.
Cancer-associated fibroblasts (CAFs) are known to increase tumor growth and to stimulate invasion and metastasis. Increasing evidence suggests that CAFs mediate response to various treatments. HNSCC cell lines were co-cultured with their patient-matched CAFs in 2D and 3D in vitro models, and the tumor cell gene expression profiles were investigated by cDNA microarray and qRT-PCR. The mRNA expression of eight candidate genes was examined in tumor biopsies from 32 HNSCC patients and in five biopsies from normal oral tissue. Differences in overall survival (OS) were tested with Kaplan–Meier long-rank analysis. Thirteen protein coding genes were found to be differentially expressed in tumor cells co-cultured with CAFs in 2D and 81 in 3D when compared to tumor cells cultured without CAFs. Six of these genes were upregulated both in 2D and 3D (POSTN, GREM1, BGN, COL1A2, COL6A3, and COL1A1). Moreover, two genes upregulated in 3D, MMP9 and FMOD, were significantly associated with the OS. In conclusion, we demonstrated in vitro that CAF-derived signals alter the tumor cell expression of multiple genes, several of which are associated with differentiation, epithelial-to-mesenchymal transition (EMT) phenotype, and metastasis. Moreover, six of the most highly upregulated genes were found to be overexpressed in tumor tissue compared to normal tissue. Full article
(This article belongs to the Section Methods and Technologies Development)
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Article
Extending Age Ranges in Breast Cancer Screening in Four European Countries: Model Estimations of Harm-to-Benefit Ratios
Cancers 2021, 13(13), 3360; https://doi.org/10.3390/cancers13133360 - 04 Jul 2021
Cited by 1 | Viewed by 965
Abstract
The main benefit of breast cancer (BC) screening is a reduction in mortality from BC. However, screening also causes harms such as overdiagnosis and false-positive results. The balance between benefits and harms varies by age. This study aims to assess how harm-to-benefit ratios [...] Read more.
The main benefit of breast cancer (BC) screening is a reduction in mortality from BC. However, screening also causes harms such as overdiagnosis and false-positive results. The balance between benefits and harms varies by age. This study aims to assess how harm-to-benefit ratios of BC screening vary by age in the Netherlands, Finland, Italy and Slovenia. Using microsimulation models, we simulated biennial screening with 100% attendance at varying ages for cohorts of women followed over a lifetime. The number of overdiagnoses, false-positive diagnoses, BC deaths averted and life-years gained (LYG) were calculated per 1000 women. We compared four strategies (50–69, 45–69, 45–74 and 50–74) by calculating four harm-to-benefit ratios, respectively. Compared to the reference strategy 50–69, screening women at 45–74 or 50–74 years would be less beneficial in any of the four countries than screening women at 45–69, which would result in relatively fewer overdiagnoses per death averted or LYG. At the same time, false-positive results per death averted would increase substantially. Adapting the age range of BC screening is an option to improve harm-to-benefit ratios in all four countries. Prioritization of considered harms and benefits affects the interpretation of results. Full article
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Article
Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis
Cancers 2021, 13(13), 3359; https://doi.org/10.3390/cancers13133359 - 04 Jul 2021
Cited by 6 | Viewed by 2066
Abstract
Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it [...] Read more.
Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only. Full article
(This article belongs to the Special Issue Metastatic Uveal Melanoma)
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Article
Comprehensive Profiling of Hypoxia-Related miRNAs Identifies miR-23a-3p Overexpression as a Marker of Platinum Resistance and Poor Prognosis in High-Grade Serous Ovarian Cancer
Cancers 2021, 13(13), 3358; https://doi.org/10.3390/cancers13133358 - 04 Jul 2021
Cited by 4 | Viewed by 1187
Abstract
The onset of chemo-resistant recurrence represents the principal cause of high-grade serous ovarian carcinoma (HGSOC) death. HGSOC masses are characterized by a hypoxic microenvironment, which contributes to the development of this chemo-resistant phenotype. Hypoxia regulated-miRNAs (HRMs) represent a molecular response of cancer cells [...] Read more.
The onset of chemo-resistant recurrence represents the principal cause of high-grade serous ovarian carcinoma (HGSOC) death. HGSOC masses are characterized by a hypoxic microenvironment, which contributes to the development of this chemo-resistant phenotype. Hypoxia regulated-miRNAs (HRMs) represent a molecular response of cancer cells to hypoxia and are involved in tumor progression. We investigated the expression of HRMs using miRNA expression data from a total of 273 advanced-stage HGSOC samples. The miRNAs associated with chemoresistance and survival were validated by RT-qPCR and target prediction, and comparative pathway analysis was conducted for target gene identification. Analysis of miRNA expression profiles indicated miR-23a-3p and miR-181c-5p over-expression as associated with chemoresistance and poor PFS. RT-qPCR data confirmed upregulation of miR-23a-3p in tumors from chemoresistant HGSOC patients and its significant association with shorter PFS. In silico miR-23a-3p target prediction and comparative pathway analysis identified platinum drug resistance as the pathway with the highest number of miR-23a-3p target genes. Among them, APAF-1 emerged as the most promising, being downregulated in platinum-resistant patients and in HGSOC chemo-resistant cells. These results highlight miR-23a-3p as a potential biomarker for HGSOC platinum response and prognosis and the miR23a-3p/APAF1 axis as a possible target to overcome platinum-resistance. Full article
(This article belongs to the Special Issue Preclinical and Translational Research in Gynecological Cancers)
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Review
Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation
Cancers 2021, 13(13), 3357; https://doi.org/10.3390/cancers13133357 - 04 Jul 2021
Cited by 8 | Viewed by 1606
Abstract
Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and [...] Read more.
Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC. Full article
(This article belongs to the Special Issue Cancer Immunology)
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Article
Evaluation of In Vitro Phototoxicity of a Minibody-IR700 Conjugate Using Cell Monolayer and Multicellular Tumor Spheroid Models
Cancers 2021, 13(13), 3356; https://doi.org/10.3390/cancers13133356 - 04 Jul 2021
Cited by 1 | Viewed by 1331 | Correction
Abstract
Photodynamic therapy (PDT) is a treatment strategy that utilizes photosensitizers (PSs) and light of a specific wavelength to kill cancer cells. However, limited tumor specificity is still a drawback for the clinical application of PDT. To increase the therapeutic efficacy and specificity of [...] Read more.
Photodynamic therapy (PDT) is a treatment strategy that utilizes photosensitizers (PSs) and light of a specific wavelength to kill cancer cells. However, limited tumor specificity is still a drawback for the clinical application of PDT. To increase the therapeutic efficacy and specificity of PDT, a novel human minibody (MS5) that recognizes a cell surface receptor expressed on various cancer cells was labeled with the hydrophilic phthalocyanine PS IR700 to generate an MS5-IR700 conjugate that is activated by near-infrared (NIR) light. The phototoxicity of the conjugate was mainly tested against the PC3 prostate cancer cell line. The MS5-IR700 conjugate killed PC3 cells after NIR light irradiation as compared to untreated cells or cells treated with IR700 alone. Time-course analysis of cell viability revealed a high percentage of cell death during the first hour in PC3 cells exposed to the MS5-IR700 conjugate and NIR light irradiation. After irradiation, the MS5-IR700 conjugate-treated PC3 cells displayed cellular swelling, round shape, and rupture of the cell and nuclear membranes. In a co-culture model, the MS5-IR700 conjugate killed MS5-positive Ramos lymphoma cells specifically, while leaving MS5-negative cells unaffected. In line with the data obtained with the monolayer cultures, the MS5-IR700 conjugate also killed PC3 cancer cell spheroids. The treatment induced relocation of heat shock protein 70 and calreticulin to the cell surface, implying the induction of immunogenic cell death. Overall, the data suggest that the developed MS5-IR700 conjugate is a promising therapeutic agent that warrants further preclinical studies. Full article
(This article belongs to the Section Cancer Therapy)
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Article
Vascular Involvement in Thymic Epithelial Tumors: Surgical and Oncological Outcomes
Cancers 2021, 13(13), 3355; https://doi.org/10.3390/cancers13133355 - 04 Jul 2021
Cited by 2 | Viewed by 837
Abstract
Background: The involvement of mediastinal great vessels is common in advanced stage thymic tumors, which makes their surgical resection challenging. Moreover, the impact of vascular involvement on the oncological prognosis is still unclear. The aim of this study is to investigate the surgical [...] Read more.
Background: The involvement of mediastinal great vessels is common in advanced stage thymic tumors, which makes their surgical resection challenging. Moreover, the impact of vascular involvement on the oncological prognosis is still unclear. The aim of this study is to investigate the surgical and oncological outcomes and the impact of vascular involvement in a population of patients operated for advanced stage thymic tumors. Methods: A retrospective analysis on four hundred and sixty-five patients undergoing resection for advanced stage (Masaoka III–IV) thymic tumors in a single high-volume center was performed. One hundred forty-four patients met the inclusion criteria and were eligible for the study. Patients were divided in two groups according to the presence or absence of vascular involvement. Results: the two groups did not differ for the baseline characteristics and showed comparable surgical outcomes. Vascular involvement was not associated with worse overall survival but with an increased recurrence rate (p = 0.03). Multivariable analysis demonstrated a higher risk of recurrence in patients without R0 resection (HR 0.11, 0.02–0.54, p = 0.006) and with thymic carcinoma (HR 2.27, 1.22–4.24, p = 0.01). Conclusions: resection of thymic tumors with vascular involvement can be performed with optimal surgical results in a high volume center. From the oncological point of view, the involvement of the great vessels seems to be associated with a higher recurrence rate without affecting long-term survival. Full article
(This article belongs to the Special Issue Thymic Tumors: From Diagnosis to Treatment)
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Systematic Review
Treatment Options and Post-Treatment Malignant Transformation Rate of Actinic Cheilitis: A Systematic Review
Cancers 2021, 13(13), 3354; https://doi.org/10.3390/cancers13133354 - 04 Jul 2021
Cited by 2 | Viewed by 1010
Abstract
Actinic cheilitis is a premalignant condition that may evolve to squamous cell carcinoma. A consensus on its management has not been established, and large clinical trials are lacking. We aimed to review the existing data regarding the treatment of actinic cheilitis with various [...] Read more.
Actinic cheilitis is a premalignant condition that may evolve to squamous cell carcinoma. A consensus on its management has not been established, and large clinical trials are lacking. We aimed to review the existing data regarding the treatment of actinic cheilitis with various modalities regarding safety, efficacy, recursions, and post-treatment malignant transformation. A systematic review was conducted through Pubmed, Ovid and the Cochrane library for studies in English language and the references of included papers from inception to January 2021. Case series were considered if ≥6 patients were included. Of the 698 articles, 36 studies and, overall, 699 patients were eventually reviewed. Laser ablation and vermilionectomy provided the best clinical and aesthetic outcomes with few recurrences, while photodynamic therapy was linked to more relapses. Generally, the adverse events were minor and there was no risk of post-treatment malignant transformation. The limitations of our review include the heterogeneity and the small number of patients across studies. Conclusively, invasive treatments demonstrated superior therapeutic and safety profile. Nevertheless, high-quality head-to-head studies that assess different modalities for actinic cheilitis and report patient preferences are lacking. Full article
(This article belongs to the Special Issue Prevention, Diagnosis and Treatment of Skin Cancer)
Article
Combined Assessment of Preoperative Frailty and Sarcopenia Allows the Prediction of Overall Survival in Patients with Lung Cancer (NSCLC) and Surgically Treated Brain Metastasis
Cancers 2021, 13(13), 3353; https://doi.org/10.3390/cancers13133353 - 03 Jul 2021
Cited by 4 | Viewed by 1437
Abstract
Neurosurgical resection represents an important therapeutic pillar in patients with brain metastasis (BM). Such extended treatment modalities require preoperative assessment of patients’ physical status to estimate individual treatment success. The aim of the present study was to analyze the predictive value of frailty [...] Read more.
Neurosurgical resection represents an important therapeutic pillar in patients with brain metastasis (BM). Such extended treatment modalities require preoperative assessment of patients’ physical status to estimate individual treatment success. The aim of the present study was to analyze the predictive value of frailty and sarcopenia as assessment tools for physiological integrity in patients with non-small cell lung cancer (NSCLC) who had undergone surgery for BM. Between 2013 and 2018, 141 patients were surgically treated for BM from NSCLC at the authors’ institution. The preoperative physical condition was assessed by the temporal muscle thickness (TMT) as a surrogate parameter for sarcopenia and the modified frailty index (mFI). For the ≥65 aged group, median overall survival (mOS) significantly differed between patients classified as ‘frail’ (mFI ≥ 0.27) and ‘least and moderately frail’ (mFI < 0.27) (15 months versus 11 months (p = 0.02)). Sarcopenia revealed significant differences in mOS for the <65 aged group (10 versus 18 months for patients with and without sarcopenia (p = 0.036)). The present study confirms a predictive value of preoperative frailty and sarcopenia with respect to OS in patients with NSCLC and surgically treated BM. A combined assessment of mFI and TMT allows the prediction of OS across all age groups. Full article
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Review
Molecular Update and Evolving Classification of Large B-Cell Lymphoma
Cancers 2021, 13(13), 3352; https://doi.org/10.3390/cancers13133352 - 03 Jul 2021
Cited by 6 | Viewed by 1274
Abstract
Diffuse large B-cell lymphomas (DLBCLs) are aggressive B-cell neoplasms with considerable clinical, biologic, and pathologic diversity. The application of high throughput technologies to the study of lymphomas has yielded abundant molecular data leading to the identification of distinct molecular identities and novel pathogenetic [...] Read more.
Diffuse large B-cell lymphomas (DLBCLs) are aggressive B-cell neoplasms with considerable clinical, biologic, and pathologic diversity. The application of high throughput technologies to the study of lymphomas has yielded abundant molecular data leading to the identification of distinct molecular identities and novel pathogenetic pathways. In light of this new information, newly refined diagnostic criteria have been established in the fourth edition of the World Health Organization (WHO) consensus classification of lymphomas, which was revised in 2016. This article reviews the histopathological and molecular features of the various aggressive B-cell lymphoma subtypes included in the updated classification. Full article
(This article belongs to the Special Issue Molecular Advances in Diffuse Large B-Cell Lymphoma)
Review
Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?
Cancers 2021, 13(13), 3351; https://doi.org/10.3390/cancers13133351 - 03 Jul 2021
Cited by 5 | Viewed by 1202
Abstract
Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries [...] Read more.
Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries with the potential to improve cancer patient care. However, an increasing understanding of the crosstalk between cancer hallmarks has highlighted the complexity of the mechanisms of drug resistance, co-opting pathways outside of the canonical “cell death” machinery to facilitate cell survival in the face of cytotoxic stress. Rewiring of cellular metabolism is vital to drive and support increased proliferative demands in cancer cells, and recent discoveries in the field of cancer metabolism have uncovered a novel role for these programs in facilitating drug resistance. As a key organelle in both metabolic and apoptotic homeostasis, the mitochondria are at the forefront of these mechanisms of resistance, coordinating crosstalk in the event of cellular stress, and promoting cellular survival. Importantly, the appreciation of this role metabolism plays in the cytotoxic response to therapy, and the ability to profile metabolic adaptions in response to treatment, has encouraged new avenues of investigation into the potential of exploiting metabolic addictions to improve therapeutic efficacy and overcome drug resistance in cancer. Here, we review the role cancer metabolism can play in mediating drug resistance, and the exciting opportunities presented by imposed metabolic vulnerabilities. Full article
(This article belongs to the Special Issue Drug Resistance and Cell Death in Cancer)
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Article
Enhanced Paclitaxel Efficacy to Suppress Triple-Negative Breast Cancer Progression Using Metronomic Chemotherapy with a Controlled Release System of Electrospun Poly-d-l-Lactide-Co-Glycolide (PLGA) Nanofibers
Cancers 2021, 13(13), 3350; https://doi.org/10.3390/cancers13133350 - 03 Jul 2021
Cited by 4 | Viewed by 1125
Abstract
Triple-negative breast cancer (TNBC) is highly aggressive and responds poorly to conventional chemotherapy. The challenge of TNBC therapy is to maximize the efficacies of conventional chemotherapeutic agents and reduce their toxicities. Metronomic chemotherapy using continuous low-dose chemotherapy has been proposed as a new [...] Read more.
Triple-negative breast cancer (TNBC) is highly aggressive and responds poorly to conventional chemotherapy. The challenge of TNBC therapy is to maximize the efficacies of conventional chemotherapeutic agents and reduce their toxicities. Metronomic chemotherapy using continuous low-dose chemotherapy has been proposed as a new treatment option, but this approach is limited by the selection of drugs. To improve antitumor therapeutic effects, we developed electrospun paclitaxel-loaded poly-d-l-lactide-co-glycolide (PLGA) nanofibers as a topical implantable delivery device for controlled drug release and site-specific treatment. The subcutaneously implanted paclitaxel-loaded nanofibrous membrane in mice was compatible with the concept of metronomic chemotherapy; it significantly enhanced antitumor activity, inhibited local tumor growth, constrained distant metastasis, and prolonged survival compared with intraperitoneal paclitaxel injection. Furthermore, under paclitaxel-loaded nanofiber treatment, systemic toxicity was low with a persistent increase in lean body weight in mice; in contrast, body weight decreased in other groups. The paclitaxel-loaded nanofibrous membranes provided sustained drug release and site-specific treatment by directly targeting and changing the tumor microenvironment, resulting in low systemic toxicity and a significant improvement in the therapeutic effect and safety compared with conventional chemotherapy. Thus, metronomic chemotherapy with paclitaxel-loaded nanofibrous membranes offers a promising strategy for the treatment of TNBC. Full article
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Review
Changes in Stem Cell Regulation and Epithelial Organisation during Carcinogenesis and Disease Progression in Gynaecological Malignancies
Cancers 2021, 13(13), 3349; https://doi.org/10.3390/cancers13133349 - 03 Jul 2021
Cited by 1 | Viewed by 1503
Abstract
Gynaecological malignancies represent a heterogeneous group of neoplasms with vastly different aetiology, risk factors, molecular drivers, and disease outcomes. From HPV-driven cervical cancer where early screening and molecular diagnostics efficiently reduced the number of advanced-stage diagnosis, prevalent and relatively well-treated endometrial cancers, to [...] Read more.
Gynaecological malignancies represent a heterogeneous group of neoplasms with vastly different aetiology, risk factors, molecular drivers, and disease outcomes. From HPV-driven cervical cancer where early screening and molecular diagnostics efficiently reduced the number of advanced-stage diagnosis, prevalent and relatively well-treated endometrial cancers, to highly aggressive and mostly lethal high-grade serous ovarian cancer, malignancies of the female genital tract have unique presentations and distinct cell biology features. Recent discoveries of stem cell regulatory mechanisms, development of organoid cultures, and NGS analysis have provided valuable insights into the basic biology of these cancers that could help advance new-targeted therapeutic approaches. This review revisits new findings on stemness and differentiation, considering main challenges and open questions. We focus on the role of stem cell niche and tumour microenvironment in early and metastatic stages of the disease progression and highlight the potential of patient-derived organoid models to study key events in tumour evolution, the appearance of resistance mechanisms, and as screening tools to enable personalisation of drug treatments. Full article
(This article belongs to the Special Issue Stemness and Differentiation in Cancer)
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Review
Circulating MicroRNAs in Gastrointestinal Cancer
Cancers 2021, 13(13), 3348; https://doi.org/10.3390/cancers13133348 - 03 Jul 2021
Cited by 2 | Viewed by 920
Abstract
Gastrointestinal cancer (GIC) is a common disease and is considered to be the leading cause of cancer-related death worldwide; thus, new diagnostic and therapeutic strategies for GIC are urgently required. Noncoding RNAs (ncRNAs) are functional RNAs that are transcribed from the genome but [...] Read more.
Gastrointestinal cancer (GIC) is a common disease and is considered to be the leading cause of cancer-related death worldwide; thus, new diagnostic and therapeutic strategies for GIC are urgently required. Noncoding RNAs (ncRNAs) are functional RNAs that are transcribed from the genome but do not encode proteins. MicroRNAs (miRNAs) are short ncRNAs that are reported to function as both oncogenes and tumor suppressors. Moreover, several miRNA-based drugs are currently proceeding to clinical trials for various diseases, including cancer. In recent years, the stability of circulating miRNAs in blood has been demonstrated. This is of interest because these miRNAs could be potential noninvasive biomarkers of cancer. In this review, we focus on circulating miRNAs associated with GIC and discuss their potential as novel biomarkers. Full article
(This article belongs to the Special Issue Circulating miRNAs as Tumor Biomarkers)
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