Cancers

21 pages, 5483 KiB

Open AccessArticle

by Jiazhou Ye, Yan Lin, Xing Gao, Lu Lu, Xi Huang, Shilin Huang, Tao Bai, Guobin Wu, Xiaoling Luo, Yongqiang Li and Rong Liang

Cancers 2022, 14(22), 5721; https://doi.org/10.3390/cancers14225721 - 21 Nov 2022

Cited by 3 | Viewed by 1947

Abstract

Bioinformatics tools were used to identify prognosis-related molecular subtypes and biomarkers of hepatocellular carcinoma (HCC). Differential expression analysis of four datasets identified 3330 overlapping differentially expressed genes (DEGs) in the same direction in all four datasets. Those genes were involved in the cell [...] Read more.

Bioinformatics tools were used to identify prognosis-related molecular subtypes and biomarkers of hepatocellular carcinoma (HCC). Differential expression analysis of four datasets identified 3330 overlapping differentially expressed genes (DEGs) in the same direction in all four datasets. Those genes were involved in the cell cycle, FOXO signaling pathway, as well as complement and coagulation cascades. Based on non-negative matrix decomposition, two molecular subtypes of HCC with different prognoses were identified, with subtype C2 showing better overall survival than subtype C1. Cox regression and Kaplan-Meier analysis showed that 217 of the overlapping DEGs were closely associated with HCC prognosis. The subset of those genes showing an area under the curve >0.80 was used to construct random survival forest and least absolute shrinkage and selection operator models, which identified seven feature genes (SORBS2, DHRS1, SLC16A2, RCL1, IGFALS, GNA14, and FANCI) that may be involved in HCC occurrence and prognosis. Based on the feature genes, risk score and recurrence models were constructed, while a univariate Cox model identified FANCI as a key gene involved mainly in the cell cycle, DNA replication, and mismatch repair. Further analysis showed that FANCI had two mutation sites and that its gene may undergo methylation. Single-sample gene set enrichment analysis showed that Th2 and T helper cells are significantly upregulated in HCC patients compared to controls. Our results identify FANCI as a potential prognostic biomarker for HCC. Full article

(This article belongs to the Collection Application of Bioinformatics in Cancers)

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13 pages, 888 KiB

Open AccessReview

Effect of Opioids on Survival in Patients with Cancer

by Jason W. Boland

Cancers 2022, 14(22), 5720; https://doi.org/10.3390/cancers14225720 - 21 Nov 2022

Cited by 6 | Viewed by 1715

Abstract

Opioids are commonly used for pain management in patients with cancer. They have a range of unwanted effects, including some that potentially influence cancer growth. This article reviews the data assessing the effects of opioids on survival in patients with cancer. Many studies [...] Read more.

Opioids are commonly used for pain management in patients with cancer. They have a range of unwanted effects, including some that potentially influence cancer growth. This article reviews the data assessing the effects of opioids on survival in patients with cancer. Many studies assessing this show an association between opioids and decreased survival. This effect is present even at very low doses of opioids. These studies do not assess causality, so it is not known if it is a direct effect of opioids on survival. As the control groups are not matched to the opioid group it might be that opioids are being used to control pain and patients receiving opioids have more aggressive cancers and it is the underlying cancer which is causing the decreased survival. Furthermore, although some studies allude to different opioids having different effects on survival, often all opioids are pooled in analysis. Future work needs to try to ascertain causality and differentiate between different opioids, pain, and cancer-mediated effects on survival in specific cancer types. Until then, opioids should continue to be used in patients with cancer as part of measures to optimise comfort and quality of life. Full article

(This article belongs to the Special Issue Palliative and Supportive Care in Oncology: An Update)

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16 pages, 719 KiB

Open AccessReview

Current Developments in Cellular Therapy for Castration Resistant Prostate Cancer: A Systematic Review of Clinical Studies

by Christina Steinbach, Almas Merchant, Alexandru-Teodor Zaharie, Peter Horak, Maximilian Marhold and Michael Krainer

Cancers 2022, 14(22), 5719; https://doi.org/10.3390/cancers14225719 - 21 Nov 2022

Cited by 1 | Viewed by 1655

Abstract

Recently, the development of immunotherapies such as cellular therapy, monoclonal antibodies, vaccines and immunomodulators has revolutionized the treatment of various cancer entities. In order to close the existing gaps in knowledge about cellular immunotherapy, specifically focusing on the chimeric antigen receptors (CAR) T-cells, [...] Read more.

Recently, the development of immunotherapies such as cellular therapy, monoclonal antibodies, vaccines and immunomodulators has revolutionized the treatment of various cancer entities. In order to close the existing gaps in knowledge about cellular immunotherapy, specifically focusing on the chimeric antigen receptors (CAR) T-cells, their benefits and application in clinical settings, we conducted a comprehensive systematic review. Two co-authors independently searched the literature and characterized the results. Out of 183 records, 26 were considered eligible. This review provides an overview of the cellular immunotherapy landscape in treating prostate cancer, honing in on the challenges of employing CAR T-cell therapy. CAR T-cell therapy is a promising avenue for research due to the presence of an array of different tumor specific antigens. In prostate cancer, the complex microenvironment of the tumor vastly contributes to the success or failure of immunotherapies. Full article

(This article belongs to the Topic Anti-Tumor Immune Responses)

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13 pages, 1134 KiB

Open AccessArticle

Oocyte Quality Assessment in Breast Cancer: Implications for Fertility Preservation

by Cristina Fabiani, Antonella Guarino, Caterina Meneghini, Emanuele Licata, Gemma Paciotti, Donatella Miriello, Michele Carlo Schiavi, Vincenzo Spina, Roberta Corno, Mariagrazia Gallo and Rocco Rago

Cancers 2022, 14(22), 5718; https://doi.org/10.3390/cancers14225718 - 21 Nov 2022

Cited by 5 | Viewed by 1534

Abstract

Background: The aim of this study was to evaluate the effects of breast cancer on the ovarian response and on oocyte quality following controlled ovarian hyperstimulation (COH). Methods: This retrospective case-control study evaluated the effects of breast cancer on the ovarian response and [...] Read more.

Background: The aim of this study was to evaluate the effects of breast cancer on the ovarian response and on oocyte quality following controlled ovarian hyperstimulation (COH). Methods: This retrospective case-control study evaluated the effects of breast cancer on the ovarian response and on the oocyte quality. Oncological patients with breast cancer undergoing controlled ovarian stimulation cycles for fertility preservation, and age- and date-matched controls undergoing COH for in vitro fertilization (IVF) for male or tubal factor infertility were included in the study. Two hundred and ninety-four women were enrolled: 105 affected by breast cancer and 189 healthy women in the control group. Both groups were comparable in terms of age, BMI, and AMH value. Maximal estradiol levels on the triggering day, duration of stimulation, total amount of gonadotropins administered, number of oocytes retrieved, rate of metaphase 2 oocyte production, and numbers of immature and dysmorphic oocytes were analyzed. Results: Considering factors influencing the oocyte quality, such as age, BMI, AMH, duration of stimulation, E2 level on the triggering day, total FSH cumulative dose, stage, histotype, BRCA status, and hormone receptors, the univariate and multivariate analyses identified breast cancer as a risk factor for the presence of dysmorphic oocytes. Conclusions: The diagnosis of breast cancer does not seem to be associated with the impairment of the ovarian reserve, but is linked to a worsening oocyte quality. Full article

(This article belongs to the Special Issue Fertility and Pregnancy in Cancer Patients: Illusion or Reality)

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15 pages, 2367 KiB

Open AccessArticle

Epidemiological Study of p16 Incidence in Head and Neck Squamous Cell Carcinoma 2005–2015 in a Representative Northern European Population

by Mari Mylly, Linda Nissi, Teemu Huusko, Johannes Routila, Samuli Vaittinen, Heikki Irjala, Ilmo Leivo and Sami Ventelä

Cancers 2022, 14(22), 5717; https://doi.org/10.3390/cancers14225717 - 21 Nov 2022

Cited by 3 | Viewed by 1410

Abstract

The incidence of human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCC) has increased globally. Our research goal was to study HNSCC incidence in a representative Northern European population and evaluate the utility of the HPV surrogate marker p16 in clinical decision-making. [...] Read more.

The incidence of human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCC) has increased globally. Our research goal was to study HNSCC incidence in a representative Northern European population and evaluate the utility of the HPV surrogate marker p16 in clinical decision-making. All new HNSCC patients diagnosed and treated in Southwest Finland from 2005–2015 (n = 1033) were identified and analyzed. During the follow-up period, the incidence of oropharyngeal (OPSCC) and oral cavity squamous cell carcinoma (OSCC) increased, while the incidence of laryngeal squamous cell carcinoma (LSCC) decreased. This clinical cohort was used to generate a population-validated tissue microarray (PV-TMA) archive for p16 analyses. The incidence of p16 positivity in HNSCC and OPSCC increased in southwest Finland between 2005 and 2015. p16 positivity was mainly found in the oropharynx and was a significant factor for improved survival. p16-positive OPSCC patients had a better prognosis, regardless of treatment modality. All HNSCC patients benefited from a combination of chemotherapy and radiotherapy, regardless of p16 expression. Our study reaffirms that p16 expression offers a prognostic biomarker in OPSCC and could potentially be used in cancer treatment stratification. Focusing on p16 testing for only OPSCC might be the most cost-effective approach in clinical practice. Full article

(This article belongs to the Special Issue Study and Treatment of Oral Squamous Cell Carcinoma)

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25 pages, 39567 KiB

Open AccessArticle

Integrated Design of Optimized Weighted Deep Feature Fusion Strategies for Skin Lesion Image Classification

by Niharika Mohanty, Manaswini Pradhan, Annapareddy V. N. Reddy, Sachin Kumar and Ahmed Alkhayyat

Cancers 2022, 14(22), 5716; https://doi.org/10.3390/cancers14225716 - 21 Nov 2022

Cited by 5 | Viewed by 4064

Abstract

This study mainly focuses on pre-processing the HAM10000 and BCN20000 skin lesion datasets to select important features that will drive for proper skin cancer classification. In this work, three feature fusion strategies have been proposed by utilizing three pre-trained Convolutional Neural Network (CNN) [...] Read more.

This study mainly focuses on pre-processing the HAM10000 and BCN20000 skin lesion datasets to select important features that will drive for proper skin cancer classification. In this work, three feature fusion strategies have been proposed by utilizing three pre-trained Convolutional Neural Network (CNN) models, namely VGG16, EfficientNet B0, and ResNet50 to select the important features based on the weights of the features and are coined as Adaptive Weighted Feature Set (AWFS). Then, two other strategies, Model-based Optimized Weighted Feature Set (MOWFS) and Feature-based Optimized Weighted Feature Set (FOWFS), are proposed by optimally and adaptively choosing the weights using a meta-heuristic artificial jellyfish (AJS) algorithm. The MOWFS-AJS is a model-specific approach whereas the FOWFS-AJS is a feature-specific approach for optimizing the weights chosen for obtaining optimal feature sets. The performances of those three proposed feature selection strategies are evaluated using Decision Tree (DT), Naïve Bayesian (NB), Multi-Layer Perceptron (MLP), and Support Vector Machine (SVM) classifiers and the performance are measured through accuracy, precision, sensitivity, and F1-score. Additionally, the area under the receiver operating characteristics curves (AUC-ROC) is plotted and it is observed that FOWFS-AJS shows the best accuracy performance based on the SVM with 94.05% and 94.90%, respectively, for HAM 10000 and BCN 20000 datasets. Finally, the experimental results are also analyzed using a non-parametric Friedman statistical test and the computational times are recorded; the results show that, out of those three proposed feature selection strategies, the FOWFS-AJS performs very well because its quick converging nature is inculcated with the help of AJS. Full article

(This article belongs to the Special Issue Recent Advances in Deep Learning and Medical Imaging for Cancer Treatment)

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26 pages, 2429 KiB

Open AccessArticle

Insights into Biochemical Sources and Diffuse Reflectance Spectral Features for Colorectal Cancer Detection and Localization

by Marcelo Saito Nogueira, Siddra Maryam, Michael Amissah, Andrew McGuire, Chloe Spillane, Shane Killeen, Stefan Andersson-Engels and Micheal O’Riordain

Cancers 2022, 14(22), 5715; https://doi.org/10.3390/cancers14225715 - 21 Nov 2022

Cited by 7 | Viewed by 1760

Abstract

Colorectal cancer (CRC) is the third most common and second most deadly type of cancer worldwide. Early detection not only reduces mortality but also improves patient prognosis by allowing the use of minimally invasive techniques to remove cancer while avoiding major surgery. Expanding [...] Read more.

Colorectal cancer (CRC) is the third most common and second most deadly type of cancer worldwide. Early detection not only reduces mortality but also improves patient prognosis by allowing the use of minimally invasive techniques to remove cancer while avoiding major surgery. Expanding the use of microsurgical techniques requires accurate diagnosis and delineation of the tumor margins in order to allow complete excision of cancer. We have used diffuse reflectance spectroscopy (DRS) to identify the main optical CRC biomarkers and to optimize parameters for the integration of such technologies into medical devices. A total number of 2889 diffuse reflectance spectra were collected in ex vivo specimens from 47 patients. Short source-detector distance (SDD) and long-SDD fiber-optic probes were employed to measure tissue layers from 0.5 to 1 mm and from 0.5 to 1.9 mm deep, respectively. The most important biomolecules contributing to differentiating DRS between tissue types were oxy- and deoxy-hemoglobin (Hb and HbO₂), followed by water and lipid. Accurate tissue classification and potential DRS device miniaturization using Hb, HbO₂, lipid and water data were achieved particularly well within the wavelength ranges 350–590 nm and 600–1230 nm for the short-SDD probe, and 380–400 nm, 420–610 nm, and 650–950 nm for the long-SDD probe. Full article

(This article belongs to the Special Issue Biophotonics and Imaging for Cancer Screening, Diagnosis and Treatment Monitoring)

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19 pages, 2103 KiB

Open AccessArticle

JAG1 Intracellular Domain Enhances AR Expression and Signaling and Promotes Stem-like Properties in Prostate Cancer Cells

by Tuyen Thanh Tran and Keesook Lee

Cancers 2022, 14(22), 5714; https://doi.org/10.3390/cancers14225714 - 21 Nov 2022

Cited by 2 | Viewed by 1707

Abstract

JAG1 expression is upregulated in high-grade metastatic prostate carcinomas and associated with poor disease-free survival of patients with prostate cancer. Intriguingly, all JAG1-positive prostate carcinomas express JICD although JICD function in prostate cancer (PC) cells is poorly understood. In this study, we found [...] Read more.

JAG1 expression is upregulated in high-grade metastatic prostate carcinomas and associated with poor disease-free survival of patients with prostate cancer. Intriguingly, all JAG1-positive prostate carcinomas express JICD although JICD function in prostate cancer (PC) cells is poorly understood. In this study, we found that JICD overexpression increased the expression levels of AR, especially AR-Vs, in PC cell lines and significantly enhanced androgen-independent and androgen-dependent function of ARs. Interestingly, JICD overexpression upregulated the expression of the PCSC marker CD133 in PC cells as the expression of self-renewal markers; namely, NANOG and OCT3/4 increased. In addition, JICD overexpression highly increased the expression of anti-apoptotic BCL-XL protein, while it little affected the expression of apoptotic BIM protein. In 3D cell culture assays, the spheres formed by JICD-overexpressing PC subline cells (C4-2 and CWR22Rv1) were larger than those formed by control (EV) subline cells with undifferentiated morphology. Although JICD overexpression caused quiescence in cell proliferation, it activated the expression of components in PCSC-related signaling pathways, increased PC cell mobility, and promoted in vivo xenograft mouse tumorigenesis. Therefore, JICD may play a crucial role in enhancing androgen independence and promoting stem-like properties in PC cells and should be considered a novel target for CRPC and PCSC diagnostic therapy. Full article

(This article belongs to the Section Molecular Cancer Biology)

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18 pages, 3861 KiB

Open AccessArticle

Comprehensive Analysis of Cuproptosis-Related Genes in Prognosis and Immune Infiltration of Hepatocellular Carcinoma Based on Bulk and Single-Cell RNA Sequencing Data

by Chenglei Yang, Yanlin Guo, Zongze Wu, Juntao Huang and Bangde Xiang

Cancers 2022, 14(22), 5713; https://doi.org/10.3390/cancers14225713 - 21 Nov 2022

Cited by 5 | Viewed by 2352

Abstract

Background: Studies on prognostic potential and tumor immune microenvironment (TIME) characteristics of cuproptosis-related genes (CRGs) in hepatocellular carcinoma (HCC) are limited. Methods: A multigene signature model was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. The cuproptosis-related multivariate [...] Read more.

Background: Studies on prognostic potential and tumor immune microenvironment (TIME) characteristics of cuproptosis-related genes (CRGs) in hepatocellular carcinoma (HCC) are limited. Methods: A multigene signature model was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. The cuproptosis-related multivariate cox regression analysis and bulk RNA-seq-based immune infiltration analysis were performed. The results were verified using two cohorts. The enrichment of CRGs in T cells based on single-cell RNA sequencing (scRNA-seq) was performed. Real-time polymerase chain reaction (RT-PCR) and multiplex immunofluorescence staining were performed to verify the reliability of the conclusions. Results: A four-gene risk scoring model was constructed. Kaplan–Meier curve analysis showed that the high-risk group had a worse prognosis (p < 0.001). The time-dependent receiver operating characteristic (ROC) curve showed that the OS risk score prediction performance was good. These results were further confirmed in the validation queue. Meanwhile, the Tregs and macrophages were enriched in the cuproptosis-related TIME of HCC. Conclusions: The CRGs-based signature model could predict the prognosis of HCC. Treg and macrophages were significantly enriched in cuproptosis-related HCC, which was associated with the depletion of proliferating T cells. Full article

(This article belongs to the Special Issue Tumor Microenvironment in Primary Liver Cancer)

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15 pages, 7832 KiB

Open AccessArticle

ONX-0914 Induces Apoptosis and Autophagy with p53 Regulation in Human Glioblastoma Cells

by Hsin-Han Chang, Yi-Hsuan Lin, Tzu-Min Chen, Yu-Ling Tsai, Chien-Rui Lai, Wen-Chiuan Tsai, Yu-Chen Cheng and Ying Chen

Cancers 2022, 14(22), 5712; https://doi.org/10.3390/cancers14225712 - 21 Nov 2022

Cited by 4 | Viewed by 1491

Abstract

Glioblastoma is believed to be one of the most aggressive brain tumors in the world. ONX-0914 (PR957) is a selective inhibitor of proteasome subunit beta type-8 (PSMB8). Previous studies have shown that inhibiting PSMB8 expression in glioblastoma reduces tumor progression. Therefore, this study [...] Read more.

Glioblastoma is believed to be one of the most aggressive brain tumors in the world. ONX-0914 (PR957) is a selective inhibitor of proteasome subunit beta type-8 (PSMB8). Previous studies have shown that inhibiting PSMB8 expression in glioblastoma reduces tumor progression. Therefore, this study aimed to determine whether ONX-0914 has antitumor effects on human glioblastoma. The results indicated that ONX-0914 treatment inhibited survival in LN229, GBM8401, and U87MG glioblastoma cells. Cell cycle analysis showed that ONX-0914 treatment caused cell cycle arrest at the G1 phase and apoptosis in glioblastoma cells. The protein expression of BCL-2 was reduced and PARP was cleaved after ONX-0914 treatment. Furthermore, the levels of p53 and phosphorylated p53 were increased by ONX-0914 treatment in glioblastoma cells. ONX-0914 also induced autophagy in glioblastoma cells. Furthermore, the p53 inhibitor pifithrin attenuated apoptosis but enhanced autophagy caused by ONX-0914. In an orthotopic mouse model, TMZ plus ONX-0914 reduced tumor progression better than the control or TMZ alone. These data suggest that ONX-0914 is a novel therapeutic drug for glioblastoma. Full article

(This article belongs to the Special Issue The Role of Autophagy in Brain Tumors)

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32 pages, 1084 KiB

Open AccessReview

Circular RNAs in Epithelial Ovarian Cancer: From Biomarkers to Therapeutic Targets

by Yumin Qiu, Yan Chen, Oluwatobi Agbede, Esra Eshaghi and Chun Peng

Cancers 2022, 14(22), 5711; https://doi.org/10.3390/cancers14225711 - 21 Nov 2022

Cited by 4 | Viewed by 2505

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, and more than 70% of patients are diagnosed at advanced stages. Despite the application of surgery and chemotherapy, the prognosis remains poor due to the high relapse rate. It is urgent to identify [...] Read more.

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, and more than 70% of patients are diagnosed at advanced stages. Despite the application of surgery and chemotherapy, the prognosis remains poor due to the high relapse rate. It is urgent to identify novel biomarkers and develop novel therapeutic strategies for EOC. Circular RNAs (circRNAs) are a class of noncoding RNAs generated from the “back-splicing” of precursor mRNA. CircRNAs exert their functions via several mechanisms, including acting as miRNA sponges, interacting with proteins, regulating transcription, and encoding functional proteins. Recent studies have identified many circRNAs that are dysregulated in EOC and may be used as diagnostic and prognostic markers. Increasing evidence has revealed that circRNAs play a critical role in ovarian cancer progression by regulating various cellular processes, including proliferation, apoptosis, metastasis, and chemosensitivity. The circRNA-based therapy may be a novel strategy that is worth exploring in the future. Here, we provide an overview of EOC and circRNA biogenesis and functions. We then discuss the dysregulations of circRNAs in EOC and the possibility of using them as diagnostic/prognostic markers. We also summarize the role of circRNAs in regulating ovarian cancer development and speculate their potential as therapeutic targets. Full article

(This article belongs to the Topic Molecular Profiling and Identification of Molecular Signatures Associated with Tissue Development, Tumorigenesis, and Anticancer Agents’ Action)

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17 pages, 17982 KiB

Open AccessArticle

Tat-hspb1 Suppresses Clear Cell Renal Cell Carcinoma (ccRCC) Growth via Lysosomal Membrane Permeabilization

by Lin Zhang, Guang-Zhi Jin and Dong Li

Cancers 2022, 14(22), 5710; https://doi.org/10.3390/cancers14225710 - 21 Nov 2022

Cited by 2 | Viewed by 1384

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer, of which the incidence is increasing worldwide with a high mortality rate. Bioactive peptides are considered a significant class of natural medicines. We applied mass spectrometry-based peptidomic analysis to explore the [...] Read more.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer, of which the incidence is increasing worldwide with a high mortality rate. Bioactive peptides are considered a significant class of natural medicines. We applied mass spectrometry-based peptidomic analysis to explore the peptide profile of human renal clear cell carcinoma and adjacent normal tissues. A total of 18,031 peptides were identified, of which 105 unique peptides were differentially expressed (44 were up-regulated and 61 were down-regulated in ccRCC tissues). Through bioinformatic analysis, we finally selected one peptide derived from the HSPB1 protein (amino acids 12–35 of the N-terminal region of HSPB1). Next, we fused this peptide to the HIV-Tat, generated a novel peptide named Tat-hspb1, and found that Tat-hspb1 inhibited ccRCC cells’ viability while being less cytotoxic to normal epithelial cells. Furthermore, Tat-hspb1 induced apoptosis and inhibited the proliferation and migration of ccRCC cells. Furthermore, we demonstrated that Tat-hspb1 was predominantly localized in lysosomes after entering the ccRCC cell and induced lysosomal membrane permeabilization (LMP) and the release of cathepsin D from lysosomes. Taken together, Tat-hspb1 has the potential to serve as a new anticancer drug candidate. Full article

(This article belongs to the Special Issue Emerging Therapies in Renal Cell Carcinoma)

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13 pages, 915 KiB

Open AccessReview

How We Treat Localized Rectal Cancer—An Institutional Paradigm for Total Neoadjuvant Therapy

by Falk Roeder, Sabine Gerum, Stefan Hecht, Florian Huemer, Tarkan Jäger, Reinhard Kaufmann, Eckhard Klieser, Oliver Owen Koch, Daniel Neureiter, Klaus Emmanuel, Felix Sedlmayer, Richard Greil and Lukas Weiss

Cancers 2022, 14(22), 5709; https://doi.org/10.3390/cancers14225709 - 21 Nov 2022

Cited by 4 | Viewed by 2151

Abstract

Total neoadjuvant therapy (TNT)—the neoadjuvant employment of radiotherapy (RT) or chemoradiation (CRT) as well as chemotherapy (CHT) before surgery—may lead to increased pathological complete response (pCR) rates as well as a reduction in the risk of distant metastases in locally advanced rectal cancer. [...] Read more.

Total neoadjuvant therapy (TNT)—the neoadjuvant employment of radiotherapy (RT) or chemoradiation (CRT) as well as chemotherapy (CHT) before surgery—may lead to increased pathological complete response (pCR) rates as well as a reduction in the risk of distant metastases in locally advanced rectal cancer. Furthermore, increased response rates may allow organ-sparing strategies in a growing number of patients with low rectal cancer and upfront immunotherapy has shown very promising early results in patients with microsatellite instability (MSI)-high/mismatch-repair-deficient (dMMR) tumors. Despite the lack of a generally accepted treatment standard, we strongly believe that existing data is sufficient to adopt the concept of TNT and immunotherapy in clinical practice. The treatment algorithm presented in the following is based on our interpretation of the current data and should serve as a practical guide for treating physicians—without any claim to general validity. Full article

(This article belongs to the Special Issue Current Management of Early and Advanced Rectal Cancer)

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28 pages, 4011 KiB

Open AccessArticle

The Somatic Mutation Landscape of UDP-Glycosyltransferase (UGT) Genes in Human Cancers

by Dong Gui Hu, Shashikanth Marri, Julie-Ann Hulin, Ross A. McKinnon, Peter I. Mackenzie and Robyn Meech

Cancers 2022, 14(22), 5708; https://doi.org/10.3390/cancers14225708 - 21 Nov 2022

Cited by 3 | Viewed by 1420

Abstract

The human UDP-glycosyltransferase (UGTs) superfamily has a critical role in the metabolism of anticancer drugs and numerous pro/anti-cancer molecules (e.g., steroids, lipids, fatty acids, bile acids and carcinogens). Recent studies have shown wide and abundant expression of UGT genes in human cancers. However, [...] Read more.

The human UDP-glycosyltransferase (UGTs) superfamily has a critical role in the metabolism of anticancer drugs and numerous pro/anti-cancer molecules (e.g., steroids, lipids, fatty acids, bile acids and carcinogens). Recent studies have shown wide and abundant expression of UGT genes in human cancers. However, the extent to which UGT genes acquire somatic mutations within tumors remains to be systematically investigated. In the present study, our comprehensive analysis of the somatic mutation profiles of 10,069 tumors from 33 different TCGA cancer types identified 3427 somatic mutations in UGT genes. Overall, nearly 18% (1802/10,069) of the assessed tumors had mutations in UGT genes with huge variations in mutation frequency across different cancer types, ranging from over 25% in five cancers (COAD, LUAD, LUSC, SKCM and UCSC) to less than 5% in eight cancers (LAML, MESO, PCPG, PAAD, PRAD, TGCT, THYM and UVM). All 22 UGT genes showed somatic mutations in tumors, with UGT2B4, UGT3A1 and UGT3A2 showing the largest number of mutations (289, 307 and 255 mutations, respectively). Nearly 65% (2260/3427) of the mutations were missense, frame-shift and nonsense mutations that have been predicted to code for variant UGT proteins. Furthermore, about 10% (362/3427) of the mutations occurred in non-coding regions (5′ UTR, 3′ UTR and splice sites) that may be able to alter the efficiency of translation initiation, miRNA regulation or the splicing of UGT transcripts. In conclusion, our data show widespread somatic mutations of UGT genes in human cancers that may affect the capacity of cancer cells to metabolize anticancer drugs and endobiotics that control pro/anti-cancer signaling pathways. This highlights their potential utility as biomarkers for predicting therapeutic efficacy and clinical outcomes. Full article

(This article belongs to the Section Cancer Biomarkers)

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15 pages, 3888 KiB

Open AccessArticle

Lipocalin 2 Reduces MET Levels by Inhibiting MEK/ERK Signaling to Inhibit Nasopharyngeal Carcinoma Cell Migration

by Ju-Pi Li, Chiao-Wen Lin, Cheng-Chen Huang, Yen-Ting Lu, Yu-Ting Ho, Shun-Fa Yang and Chung-Han Hsin

Cancers 2022, 14(22), 5707; https://doi.org/10.3390/cancers14225707 - 21 Nov 2022

Cited by 8 | Viewed by 1263

Abstract

Nasopharyngeal carcinoma (NPC) is the most common cancer that occurs in the nasopharynx, and it is difficult to detect early. The main cause of death of NPC patients is cancer metastasis. Lipocalin 2 (LCN2) has been shown to be involved in a variety [...] Read more.

Nasopharyngeal carcinoma (NPC) is the most common cancer that occurs in the nasopharynx, and it is difficult to detect early. The main cause of death of NPC patients is cancer metastasis. Lipocalin 2 (LCN2) has been shown to be involved in a variety of carcinogenesis processes. Here, we aimed to study the role of LCN2 in NPC cells and determine its underlying mechanism. We found that LCN2 was expressed differently in NPC cell lines, namely HONE-1, NPC-39, and NPC-BM. The down-regulation of LCN2 levels by siRNA targeting LCN2 (siLCN2) increased cell migration and invasion in HONE-1 cells, while the up-regulation of LCN2 levels by transfection with the LCN2 expression plasmid decreased cell migration and invasion in NPC-BM cells. Furthermore, LCN2 levels negatively regulated the phosphorylation of MEK/ERK pathways. The treatment of the specific MEK/ERK inhibitor, U0126, reduced cell migration in HONE-1 cells, whereas the treatment of tBHQ, an ERK activator, enhanced cell migration in NPC-BM cells. Based on the bioinformatics data, there was a moderately negative correlation between LCN2 and MET in metastatic NPC tissues (r = −0.5946, p = 0.0022). Indeed, the manipulation of LCN2 levels negatively regulated MET levels in these NPC cells. The treatment of U0126 reduced siLCN2-increased MET levels, while the treatment of tBHQ enhanced LCN2-enhanced MET levels. Interestingly, the down-regulation of MET levels by siMET further decreased siLCN2-enhanced MET levels and cell migration. Therefore, LCN2 inhibits NPC cell migration by reducing MET levels through MEK/ERK signaling. Full article

(This article belongs to the Special Issue Factors Regulating Cancer Cell Growth, Migration, Invasion, and Apoptosis)

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11 pages, 1304 KiB

Open AccessSystematic Review

COVID-19 and Lung Cancer Survival: An Updated Systematic Review and Meta-Analysis

by Simone Oldani, Fausto Petrelli, Giuseppina Dognini, Karen Borgonovo, Maria Chiara Parati, Mara Ghilardi, Lorenzo Dottorini, Mary Cabiddu and Andrea Luciani

Cancers 2022, 14(22), 5706; https://doi.org/10.3390/cancers14225706 - 21 Nov 2022

Cited by 14 | Viewed by 1955

Abstract

Introduction: The outbreak of COVID-19 poses an unprecedented challenge to global public health. Patients with cancer are at a higher risk during the SARS-CoV-2 pandemic. Patients with lung cancer and COVID-19 were compared to those without cancer and those with other malignancies for [...] Read more.

Introduction: The outbreak of COVID-19 poses an unprecedented challenge to global public health. Patients with cancer are at a higher risk during the SARS-CoV-2 pandemic. Patients with lung cancer and COVID-19 were compared to those without cancer and those with other malignancies for the main outcome of this study. The aim of this study was to evaluate the differences in susceptibility, disease severity, and mortality between lung cancer patients and the general population. Methods: Using PRISMA reporting guidelines, we conducted a systematic review and meta-analysis of the published literature. The Cochrane Library database, PubMed, EMBASE, and PubMed Central were comprehensively searched for published papers until 31 May 2022. A pooled risk ratio (OR) with 95% CI was presented as the result of this meta-analysis. Results: We included 29 studies involved 21,257 patients with lung cancer and SARS-CoV-2 infection. Analysis data showed that mortality in patients with lung cancer was significantly higher than that in patients without cancer (HR = 2.00 [95%CI 1.52, 2.63], p < 0.01) or with other malignancies (HR = 1.91 [95%CI 1.53, 2.39], p < 0.01). In addition, we also observed a higher risk of severe infection in terms of life-threatening or required ICU admission/mechanical ventilation for lung cancer patients (HR = 1.47 [95%CI 1.06, 2.03], p = 0.02) than for patients with no cancer or other malignancies. Regarding lung cancer as a risk factor for acquiring SARS-CoV-2 infection, we could not reach statistical significance (hazard ratio [HR] =2.73 [95%CI 0.84, 8.94], p = 0.1). Conclusion: Lung cancer represents an important comorbidity and modifies COVID-19 prognosis in terms of disease severity and mortality. More patients experience severe or even fatal events. Considering their inherent fragility, patients with lung cancer, and generally all oncological populations, should be treated more carefully during the COVID-19 pandemic. Full article

(This article belongs to the Section Infectious Agents and Cancer)

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22 pages, 661 KiB

Open AccessReview

Review of Intraoperative Adjuncts for Maximal Safe Resection of Gliomas and Its Impact on Outcomes

by Hani Chanbour and Silky Chotai

Cancers 2022, 14(22), 5705; https://doi.org/10.3390/cancers14225705 - 21 Nov 2022

Cited by 5 | Viewed by 1888

Abstract

Maximal safe resection is the mainstay of treatment in the neurosurgical management of gliomas, and preserving functional integrity is linked to favorable outcomes. How these modalities differ in their effectiveness on the extent of resection (EOR), survival, and complications remains unknown. A systematic [...] Read more.

Maximal safe resection is the mainstay of treatment in the neurosurgical management of gliomas, and preserving functional integrity is linked to favorable outcomes. How these modalities differ in their effectiveness on the extent of resection (EOR), survival, and complications remains unknown. A systematic literature search was performed with the following inclusion criteria: published between 2005 and 2022, involving brain glioma surgery, and including one or a combination of intraoperative modalities: intraoperative magnetic resonance imaging (iMRI), awake/general anesthesia craniotomy mapping (AC/GA), fluorescence-guided imaging, or combined modalities. Of 525 articles, 464 were excluded and 61 articles were included, involving 5221 glioma patients, 7(11.4%) articles used iMRI, 21(36.8%) used cortical mapping, 15(24.5%) used 5-aminolevulinic acid (5-ALA) or fluorescein sodium, and 18(29.5%) used combined modalities. The heterogeneity in reporting the amount of surgical resection prevented further analysis. Progression-free survival/overall survival (PFS/OS) were reported in 18/61(29.5%) articles, while complications and permanent disability were reported in 38/61(62.2%) articles. The reviewed studies demonstrate that intraoperative adjuncts such as iMRI, AC/GA mapping, fluorescence-guided imaging, and a combination of these modalities improve EOR. However, PFS/OS were underreported. Combining multiple intraoperative modalities seems to have the highest effect compared to each adjunct alone. Full article

(This article belongs to the Collection Treatment of Glioma)

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20 pages, 5659 KiB

Open AccessArticle

ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway

by Wulin Shan, Chunyang Dai, Huanhuan Zhang, Dan Han, Qiyi Yi and Bairong Xia

Cancers 2022, 14(22), 5704; https://doi.org/10.3390/cancers14225704 - 21 Nov 2022

Viewed by 1558

Abstract

Treatment of cetuximab-resistant colorectal cancer (CRC) is a global healthcare problem. This study aimed to assess the effects of radiotherapy on cetuximab-resistant CRC and explore the underlying mechanism. We established a cetuximab-resistant HCT116 cell line (HCT116-R) by extracorporeal shock. Differentially expressed mRNAs were [...] Read more.

Treatment of cetuximab-resistant colorectal cancer (CRC) is a global healthcare problem. This study aimed to assess the effects of radiotherapy on cetuximab-resistant CRC and explore the underlying mechanism. We established a cetuximab-resistant HCT116 cell line (HCT116-R) by extracorporeal shock. Differentially expressed mRNAs were screened from cells treated with different radiation doses using second-generation high-throughput sequencing. Sequence data showed that ACY1 was significantly downregulated in HCT116-R cells after irradiation. Analysis of the GEO and TCGA datasets revealed that high ACY1 expression was associated with lymph node metastasis and a poor prognosis in CRC patients. In addition, immunohistochemistry results from CRC patients revealed that ACY1 protein expression was related to cetuximab resistance and lymph node metastasis. These findings suggested that ACY1 may function as an oncogene to promote CRC progression and regulate the radiosensitivity of cetuximab-resistant CRC. As expected, ACY1 silencing weakened the proliferation, migration, and invasion abilities of HCT116-R cells after radiotherapy. Mechanistically, TCGA data demonstrated that ACY1 expression was closely related to the Wnt/β-catenin pathway in CRC. We validated that radiotherapy first reduced β-catenin levels, followed by decreased expression of the metastasis-related protein E-cadherin. Silencing ACY1 dramatically enhanced these changes in β-catenin and E-cadherin after radiotherapy. In conclusion, ACY1 downregulation could enhance the radiosensitivity of cetuximab-resistant CRC by inactivating Wnt/β-catenin signaling, implying that ACY1 may serve as a radiotherapy target for cetuximab-resistant CRC. Full article

(This article belongs to the Special Issue Adjuvant Therapy in Cancer)

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18 pages, 2312 KiB

Open AccessArticle

Dietary EPA+DHA Mitigate Hepatic Toxicity and Modify the Oxylipin Profile in an Animal Model of Colorectal Cancer Treated with Chemotherapy

by Md Monirujjaman, Oliver F. Bathe and Vera C. Mazurak

Cancers 2022, 14(22), 5703; https://doi.org/10.3390/cancers14225703 - 21 Nov 2022

Cited by 1 | Viewed by 2318

Abstract

Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are commonly used to treat metastatic colorectal cancer, but chemotherapy-associated steatosis/steatohepatitis (CASSH) frequently accompanies their use. The objective of this study was to determine effect of CPT-11+5-FU on liver toxicity, liver oxylipins, and cytokines, and to explore whether [...] Read more.

Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are commonly used to treat metastatic colorectal cancer, but chemotherapy-associated steatosis/steatohepatitis (CASSH) frequently accompanies their use. The objective of this study was to determine effect of CPT-11+5-FU on liver toxicity, liver oxylipins, and cytokines, and to explore whether these alterations could be modified by dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of fish oil (EPA+DHA). Tumor-bearing animals were administered CPT-11+5-FU and maintained on a control diet or a diet containing EPA+DHA (2.3 g/100 g). Livers were collected one week after chemotherapy for the analysis of oxylipins, cytokines, and markers of liver pathology (oxidized glutathione, GSSH; 4-hydroxynonenal, 4-HNE, and type-I collagen fiber). Dietary EPA+DHA prevented the chemotherapy-induced increases in liver GSSH (p < 0.011) and 4-HNE (p < 0.006). Compared with the tumor-bearing animals, ten oxylipins were altered (three/ten n-6 oxylipins were elevated while seven/ten n-3 oxylipins were reduced) following chemotherapy. Reductions in the n-3 fatty-acid-derived oxylipins that were evident following chemotherapy were restored by dietary EPA+DHA. Liver TNF-α, IL-6 and IL-10 were elevated (p < 0.05) following chemotherapy; dietary EPA+DHA reduced IL-6 (p = 0.09) and eotaxin (p = 0.007) levels. Chemotherapy-induced liver injury results in distinct alterations in oxylipins and cytokines, and dietary EPA+DHA attenuates these pathophysiological effects. Full article

(This article belongs to the Topic Non Herbal Nutraceutical, Probiotic, Vitamins and Fatty Acids in Cancer)

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10 pages, 1331 KiB

Open AccessReview

Surgical Extent for Oral Cancer: Emphasis on a Cut-Off Value for the Resection Margin Status: A Narrative Literature Review

by Jeon Yeob Jang, Nayeon Choi and Han-Sin Jeong

Cancers 2022, 14(22), 5702; https://doi.org/10.3390/cancers14225702 - 21 Nov 2022

Cited by 3 | Viewed by 3294

Abstract

The optimal cut-off point of the resection margin was recently debated in oral cancer. To evaluate the current evidence of the dynamic criteria of the resection margin, a review of the available literature was performed. Studies were sourced from PubMed and EMBASE by [...] Read more.

The optimal cut-off point of the resection margin was recently debated in oral cancer. To evaluate the current evidence of the dynamic criteria of the resection margin, a review of the available literature was performed. Studies were sourced from PubMed and EMBASE by searching for the keywords “mouth neoplasm”, “oral cancer”, “oral cavity cancer”, “oral squamous cell carcinoma”, “tongue cancer”, “margins of excision”, “surgical margin” and “resection margin”. We found approximately 998 articles on PubMed and 2227 articles on EMBASE. A total of 3225 articles was identified, and 2763 of those were left after removing the duplicates. By applying advanced filters about the relevance of the subjects, these were narrowed down to 111 articles. After the final exclusion, 42 full-text articles were reviewed. The universal cut-off criteria of 5 mm used for determining the resection margin status has been debated due to recent studies evaluating the impact of different margin criteria on patient prognosis. Of note, the degree of the microscopic extension from the gross tumor border correlates with tumor dimensions. Therefore, a relatively narrow safety margin can be justified in early-stage oral cancer without the additional risk of recurrence, while a wide safety margin might be required for advanced-stage oral cancer. This review suggests a surgical strategy to adjust the criteria for risk grouping and adjuvant treatments, according to individual tumor dimensions or characteristics. In the future, it might be possible to establish individual tumor-specific surgical margins and risk stratification during or after surgery. However, the results should be interpreted with caution because there is no strong evidence (e.g., prospective randomized controlled studies) yet to support the conclusions. Our study is meaningful in suggesting future research directions and discussions. Full article

(This article belongs to the Special Issue Advances in Oral Cancer: From Pathology to Treatment)

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13 pages, 1619 KiB

Open AccessArticle

Elevated Levels of Circulating Hsp70 and an Increased Prevalence of CD94+/CD69+ NK Cells Is Predictive for Advanced Stage Non-Small Cell Lung Cancer

by Sophie Seier, Ali Bashiri Dezfouli, Philipp Lennartz, Alan Graham Pockley, Henriette Klein and Gabriele Multhoff

Cancers 2022, 14(22), 5701; https://doi.org/10.3390/cancers14225701 - 21 Nov 2022

Cited by 5 | Viewed by 1912

Abstract

Non-small cell lung cancer (NSCLC) is the second most frequently diagnosed tumor worldwide. Despite the clinical progress which has been achieved by multimodal therapies, including radiochemotherapy, and immune checkpoint inhibitor blockade, the overall survival of patients with advanced-stage NSCLC remains poor, with less [...] Read more.

Non-small cell lung cancer (NSCLC) is the second most frequently diagnosed tumor worldwide. Despite the clinical progress which has been achieved by multimodal therapies, including radiochemotherapy, and immune checkpoint inhibitor blockade, the overall survival of patients with advanced-stage NSCLC remains poor, with less than 16 months. It is well established that many aggressive tumor entities, including NSCLC, overexpress the major stress-inducible heat shock protein 70 (Hsp70) in the cytosol, present it on the plasma membrane in a tumor-specific manner, and release Hsp70 into circulation. Although high Hsp70 levels are associated with tumor aggressiveness and therapy resistance, membrane-bound Hsp70 can serve as a tumor-specific antigen for Hsp70-primed natural killer (NK) cells, expressing the C-type lectin receptor CD94, which is part of the activator receptor complex CD94/NKG2C. Therefore, we investigated circulating Hsp70 levels and changes in the composition of peripheral blood lymphocyte subsets as potential biomarkers for the advanced Union for International Cancer Control (UICC) stages in NSCLC. As expected, circulating Hsp70 levels were significantly higher in NSCLC patients compared to the healthy controls, as well as in patients with advanced UICC stages compared to those in UICC stage I. Smoking status did not influence the circulating Hsp70 levels significantly. Concomitantly, the proportions of CD4+ T helper cells were lower compared to the healthy controls and stage I tumor patients, whereas that of CD8+ cytotoxic T cells was progressively higher. The prevalence of CD3−/CD56+, CD3−/NKp30, CD3−/NKp46+, and CD3−/NKG2D+ NK cells was higher in stage IV/IIIB of the disease than in stage IIIA but were not statistically different from that in healthy individuals. However, the proportion of NK cells expressing CD94 and the activation/exhaustion marker CD69 significantly increased in higher tumor stages compared with stage I and the healthy controls. We speculate that although elevated circulating Hsp70 levels might promote the prevalence of CD94+ NK cells in patients with advanced-stage NSCLC, the cytolytic activity of these NK cells also failed to control tumor growth due to insufficient support by pro-inflammatory cytokines from CD4+ T helper cells. This hypothesis is supported by a comparative multiplex cytokine analysis of the blood in lung cancer patients with a low proportion of CD4+ T cells, a high proportion of NK cells, and high Hsp70 levels versus patients with a high proportion of CD4+ T cells exhibiting lower IL-2, IL-4, IL-6, IFN-γ, granzyme B levels. Full article

(This article belongs to the Special Issue Advances in Radiation Immuno-Oncology: Progress at the Interface of Radiation Oncology and Immunotherapy—A Themed Issue in Honor of Prof. Dr. Gabriele Multhoff)

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22 pages, 5500 KiB

Open AccessArticle

The Multidisciplinary Approach in Stage III Non-Small Cell Lung Cancer over Ten Years: From Radiation Therapy Optimisation to Innovative Systemic Treatments

by Alessandra Ferro, Matteo Sepulcri, Marco Schiavon, Elena Scagliori, Edoardo Mancin, Francesca Lunardi, Gisella Gennaro, Stefano Frega, Alessandro Dal Maso, Laura Bonanno, Chiara Paronetto, Francesca Caumo, Fiorella Calabrese, Federico Rea, Valentina Guarneri and Giulia Pasello

Cancers 2022, 14(22), 5700; https://doi.org/10.3390/cancers14225700 - 20 Nov 2022

Cited by 7 | Viewed by 2413

Abstract

Background: About 30% of new non-small cell lung cancer (NSCLC) cases are diagnosed at a locally advanced stage, which includes a highly heterogeneous group of patients with a wide spectrum of treatment options. The management of stage III NSCLC involves a multidisciplinary team, [...] Read more.

Background: About 30% of new non-small cell lung cancer (NSCLC) cases are diagnosed at a locally advanced stage, which includes a highly heterogeneous group of patients with a wide spectrum of treatment options. The management of stage III NSCLC involves a multidisciplinary team, adequate staging, and a careful patient selection for surgery or radiation therapy integrated with systemic treatment. Methods: This is a single-center observational retrospective and prospective study including a consecutive series of stage III NSCLC patients who were referred to the Veneto Institute of Oncology and University Hospital of Padova (Italy) between 2012 and 2021. We described clinico-pathological characteristics, therapeutic pathways, and treatment responses in terms of radiological response in the entire study population and in terms of pathological response in patients who underwent surgery after induction therapy. Furthermore, we analysed survival outcomes in terms of relapse-free survival (RFS) and overall survival (OS). Results: A total of 301 patients were included. The majority of patients received surgical multimodality treatment (n = 223, 74.1%), while the remaining patients (n = 78, 25.9%) underwent definitive CRT followed or not by durvalumab as consolidation therapy. At data cut-off, 188 patients (62.5%) relapsed and the median RFS (mRFS) of the entire population was 18.2 months (95% CI: 15.83–20.57). At the time of analyses 140 patients (46.5%) were alive and the median OS (mOS) was 44.7 months (95% CI: 38.4–51.0). A statistically significant difference both in mRFS (p = 0.002) and in mOS (p < 0.001) was observed according to the therapeutic pathway in the entire population, and selecting patients treated after 2018, a significant difference in mRFS (p = 0.006) and mOS (p < 0.001) was observed according to treatment modality. Furthermore, considering only patients diagnosed with stage IIIB-C (N = 131, 43.5%), there were significant differences both in mRFS (p = 0.047) and in mOS (p = 0.022) as per the treatment algorithm. The mRFS of the unresectable population was 16.3 months (95% CI: 11.48–21.12), with a significant difference among subgroups (p = 0.030) in favour of patients who underwent the PACIFIC-regimen; while the mOS was 46.5 months (95% CI: 26.46–66.65), with a significant difference between two subgroups (p = 0.003) in favour of consolidation immunotherapy. Conclusions: Our work provides insights into the management and the survival outcomes of stage III NSCLC over about 10 years. We found that the choice of radical treatment impacts on outcome, thus suggesting the importance of appropriate staging at diagnosis, patient selection, and of the multidisciplinary approach in the decision-making process. Our results confirmed that the PACIFIC trial and the following introduction of durvalumab as consolidation treatment may be considered as a turning point for several improvements in the diagnostic-therapeutic pathway of stage III NSCLC patients. Full article

(This article belongs to the Special Issue Radiation Therapy in Lung Cancer: From a Technical Revolution to a Combination with New Systemic Approaches)

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19 pages, 1437 KiB

Open AccessReview

Targeting TET2 as a Therapeutic Approach for Angioimmunoblastic T Cell Lymphoma

by Lina Hu, Xuanye Zhang, Huifeng Li, Suxia Lin and Shengbing Zang

Cancers 2022, 14(22), 5699; https://doi.org/10.3390/cancers14225699 - 20 Nov 2022

Cited by 2 | Viewed by 2832

Abstract

Angioimmunoblastic T-cell lymphoma (AITL), a type of malignant lymphoma with unique genomic aberrations, significant clinicopathological features, and poor prognosis, is characterized by immune system dysregulation. Recent sequencing studies have identified recurrent mutations and interactions in tet methylcytosine dioxygenase 2 (TET2), ras [...] Read more.

Angioimmunoblastic T-cell lymphoma (AITL), a type of malignant lymphoma with unique genomic aberrations, significant clinicopathological features, and poor prognosis, is characterized by immune system dysregulation. Recent sequencing studies have identified recurrent mutations and interactions in tet methylcytosine dioxygenase 2 (TET2), ras homology family member A (RHOA), DNA methyltransferase 3 alpha (DNMT3A), and mitochondrial isocitrate dehydrogenase II (IDH2). Notably, since B-cell lymphomas are frequently observed along with AITL, this review first summarizes its controversial mechanisms based on traditional and recent views. Epigenetic regulation represented by TET2 plays an increasingly important role in understanding the multi-step and multi-lineage tumorigenesis of AITL, providing new research directions and treatment strategies for patients with AITL. Here, we review the latest advances in our understanding of AITL and highlight relevant issues that have yet to be addressed in clinical practice. Full article

(This article belongs to the Special Issue Advances in Cancer Therapeutics)

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22 pages, 1192 KiB

Open AccessReview

Approaches to the Management of Metastatic Adenoid Cystic Carcinoma

by Rex H. Lee, Katherine C. Wai, Jason W. Chan, Patrick K. Ha and Hyunseok Kang

Cancers 2022, 14(22), 5698; https://doi.org/10.3390/cancers14225698 - 20 Nov 2022

Cited by 11 | Viewed by 5868

Abstract

High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents [...] Read more.

High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents — cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR — in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC. Full article

(This article belongs to the Section Molecular Cancer Biology)

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16 pages, 3001 KiB

Open AccessArticle

RAD51 Is Implicated in DNA Damage, Chemoresistance and Immune Dysregulation in Solid Tumors

by Chengcheng Liao, Srikanth Talluri, Jiangning Zhao, Shidai Mu, Subodh Kumar, Jialan Shi, Leutz Buon, Nikhil C. Munshi and Masood A. Shammas

Cancers 2022, 14(22), 5697; https://doi.org/10.3390/cancers14225697 - 20 Nov 2022

Cited by 5 | Viewed by 2260

Abstract

Background: In normal cells, homologous recombination (HR) is tightly regulated and plays an important role in the maintenance of genomic integrity and stability through precise repair of DNA damage. RAD51 is a recombinase that mediates homologous base pairing and strand exchange during DNA [...] Read more.

Background: In normal cells, homologous recombination (HR) is tightly regulated and plays an important role in the maintenance of genomic integrity and stability through precise repair of DNA damage. RAD51 is a recombinase that mediates homologous base pairing and strand exchange during DNA repair by HR. Our previous data in multiple myeloma and esophageal adenocarcinoma (EAC) show that dysregulated HR mediates genomic instability. Purpose of this study was to investigate role of HR in genomic instability, chemoresistance and immune dysregulation in solid tumors including colon and breast cancers. Methods: The GEO dataset were used to investigate correlation of RAD51 expression with patient survival and expression of various immune markers in EAC, breast and colorectal cancers. RAD51 was inhibited in cancer cell lines using shRNAs and a small molecule inhibitor. HR activity was evaluated using a plasmid-based assay, DNA breaks assessed by evaluating expression of γ-H2AX (a marker of DNA breaks) and p-RPA32 (a marker of DNA end resection) using Western blotting. Genomic instability was monitored by investigating micronuclei (a marker of genomic instability). Impact of RAD51 inhibitor and/or a DNA-damaging agent was assessed on viability and apoptosis in EAC, breast and colon cancer cell lines in vitro and in a subcutaneous tumor model of EAC. Impact of RAD51 inhibitor on expression profile was monitored by RNA sequencing. Results: Elevated RAD51 expression correlated with poor survival of EAC, breast and colon cancer patients. RAD51 knockdown in cancer cell lines inhibited DNA end resection and strand exchange activity (key steps in the initiation of HR) as well as spontaneous DNA breaks, whereas its overexpression increased DNA breaks and genomic instability. Treatment of EAC, colon and breast cancer cell lines with a small molecule inhibitor of RAD51 inhibited DNA breaking agent-induced DNA breaks and genomic instability. RAD51 inhibitor potentiated cytotoxicity of DNA breaking agent in all cancer cell types tested in vitro as well as in a subcutaneous model of EAC. Evaluation by RNA sequencing demonstrated that DNA repair and cell cycle related pathways were induced by DNA breaking agent whereas their induction either prevented or reversed by RAD51 inhibitor. In addition, immune-related pathways such as PD-1 and Interferon Signaling were also induced by DNA breaking agent whereas their induction prevented by RAD51 inhibitor. Consistent with these observations, elevated RAD51 expression also correlated with that of genes involved in inflammation and other immune surveillance. Conclusions: Elevated expression of RAD51 and associated HR activity is involved in spontaneous and DNA damaging agent-induced DNA breaks and genomic instability thus contributing to chemoresistance, immune dysregulation and poor prognosis in cancer. Therefore, inhibitors of RAD51 have great potential as therapeutic agents for EAC, colon, breast and probably other solid tumors. Full article

(This article belongs to the Special Issue Genomic Instability in Multiple Myeloma and Solid Malignancies: Role of DNA Repair from Prognostic Marker to Therapeutic Target)

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10 pages, 926 KiB

Open AccessArticle

Acute Pancreatitis Increases the Risk of Gastrointestinal Cancer in Type 2 Diabetic Patients: A Korean Nationwide Cohort Study

by Jin Ho Choi, Woo Hyun Paik, Dong Kee Jang, Min Kyu Kim, Ji Kon Ryu, Yong-Tae Kim, Kyungdo Han and Sang Hyub Lee

Cancers 2022, 14(22), 5696; https://doi.org/10.3390/cancers14225696 - 20 Nov 2022

Cited by 1 | Viewed by 1727

Abstract

The association between acute pancreatitis (AP) and gastrointestinal cancers in diabetic patients is currently not well understood. The study aim was to investigate the association between AP and gastrointestinal cancers in diabetic patients. Data from the Korean National Health Insurance Service database were [...] Read more.

The association between acute pancreatitis (AP) and gastrointestinal cancers in diabetic patients is currently not well understood. The study aim was to investigate the association between AP and gastrointestinal cancers in diabetic patients. Data from the Korean National Health Insurance Service database were analyzed. Participants with diabetes who underwent a health examination between 2009 and 2012 were followed up till December 2018. The primary outcome was the occurrence of gastrointestinal cancer. A total of 2,263,184 patients were included in the final analysis. Patients with a history of AP (n = 2390) were found to have a significantly higher risk of gastrointestinal cancer, except for esophageal cancer, as follows: gastric cancer (aHR = 1.637, 95% CI: 1.323–2.025), colorectal cancer (aHR = 2.183, 95% CI: 1.899–2.51), liver cancer (aHR = 2.216, 95% CI: 1.874–2.621), pancreatic cancer (aHR = 4.558, 95% CI: 4.078–5.095), bile duct cancer (aHR = 3.996, 95% CI: 3.091–5.269), and gallbladder cancer (aHR = 2.445, 95% CI: 1.459–4.099). The history of AP is associated with the increased risk of gastrointestinal cancer in diabetic patients. It is necessary to investigate the history of AP and more actively recommend screening for gastrointestinal cancers in such patients. Full article

(This article belongs to the Topic Big Data in Healthcare, Bioinformatics and Precision Medicine)

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25 pages, 3332 KiB

Open AccessSystematic Review

Plasticity in Classical Hodgkin Composite Lymphomas: A Systematic Review

by Alexis Trecourt, Marie Donzel, Juliette Fontaine, Hervé Ghesquières, Laurent Jallade, Gabriel Antherieu, Camille Laurent, Claire Mauduit and Alexsandra Traverse-Glehen

Cancers 2022, 14(22), 5695; https://doi.org/10.3390/cancers14225695 - 19 Nov 2022

Cited by 4 | Viewed by 1905

Abstract

The co-occurrence of several lymphomas in a patient defines composite/synchronous lymphoma. A common cellular origin has been reported for both contingents of such entities. In the present review, we aimed to gather the available data on composite lymphomas associating a classical Hodgkin lymphoma [...] Read more.

The co-occurrence of several lymphomas in a patient defines composite/synchronous lymphoma. A common cellular origin has been reported for both contingents of such entities. In the present review, we aimed to gather the available data on composite lymphomas associating a classical Hodgkin lymphoma (cHL) with another lymphoma, to better understand the plasticity of mature B and T-cells. This review highlights that >70% of patients with a composite lymphoma are ≥55 years old, with a male predominance. The most reported associations are cHL with follicular lymphoma or diffuse large B-cell lymphoma, with over 130 cases reported. The cHL contingent is often of mixed cellularity type, with a more frequent focal/weak CD20 expression (30% to 55.6%) compared to de novo cHL, suggesting a particular pathophysiology. Moreover, Hodgkin cells may express specific markers of the associated lymphoma (e.g., BCL2/BCL6 for follicular lymphoma and Cyclin D1 for mantle cell lymphoma), sometimes combined with common BCL2/BCL6 or CCND1 rearrangements, respectively. In addition, both contingents may share similar IgH/IgK rearrangements and identical pathogenic variants, reinforcing the hypothesis of a common clonal origin. Finally, cHL appears to be endowed with a greater plasticity than previously thought, supporting a common clonal origin and a transdifferentiation process during lymphomagenesis of composite lymphomas. Full article

(This article belongs to the Special Issue Frontiers in Hodgkin Lymphoma)

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12 pages, 657 KiB

Open AccessArticle

Systemic Therapy in Advanced Nodular Melanoma versus Superficial Spreading Melanoma: A Nation-Wide Study of the Dutch Melanoma Treatment Registry

by Daan Jan Willem Rauwerdink, Remco van Doorn, Jos van der Hage, Alfonsus J. M. Van den Eertwegh, John B. A. G. Haanen, Maureen Aarts, Franchette Berkmortel, Christian U. Blank, Marye J. Boers-Sonderen, Jan Willem B. De Groot, Geke A. P. Hospers, Melissa de Meza, Djura Piersma, Rozemarijn S. Van Rijn, Marion Stevense, Astrid Van der Veldt, Gerard Vreugdenhil, Michel W. J. M. Wouters, Karijn Suijkerbuijk, Monique van der Kooij and Ellen Kapiteijn Show full author list Hide full author list

Cancers 2022, 14(22), 5694; https://doi.org/10.3390/cancers14225694 - 19 Nov 2022

Cited by 3 | Viewed by 1602

Abstract

Nodular melanoma (NM) is associated with a higher locoregional and distant recurrence rate compared with superficial spreading melanoma (SSM); it is unknown whether the efficacy of systemic therapy is limited. Here, we compare the efficacy of immunotherapy and BRAF/MEK inhibitors (BRAF/MEKi) in advanced [...] Read more.

Nodular melanoma (NM) is associated with a higher locoregional and distant recurrence rate compared with superficial spreading melanoma (SSM); it is unknown whether the efficacy of systemic therapy is limited. Here, we compare the efficacy of immunotherapy and BRAF/MEK inhibitors (BRAF/MEKi) in advanced NM to SSM. Patients with advanced stage IIIc and stage IV NM and SSM treated with anti-CTLA-4 and/or anti-PD-1, or BRAF/MEKi in the first line, were included from the prospective Dutch Melanoma Treatment Registry. The primary objectives were distant metastasis-free survival (DMFS) and overall survival (OS). In total, 1086 NM and 2246 SSM patients were included. DMFS was significantly shorter for advanced NM patients at 1.9 years (CI 95% 0.7–4.2) compared with SSM patients at 3.1 years (CI 95% 1.3–6.2) (p < 0.01). Multivariate survival analysis for immunotherapy and BRAF/MEKi demonstrated a hazard ratio for immunotherapy of 1.0 (CI 95% 0.85–1.17) and BRAF/MEKi of 0.95 (CI 95% 0.81–1.11). A shorter DMFS for NM patients developing advanced disease compared with SSM patients was observed, while no difference was observed in the efficacy of systemic immunotherapy or BRAF/MEKi between NM and SSM patients. Our results suggests that the worse overall survival of NM is mainly driven by propensity of metastatic outgrowth of NM after primary diagnosis. Full article

(This article belongs to the Section Cancer Therapy)

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25 pages, 1188 KiB

Open AccessReview

Non-Coding RNAs of Extracellular Vesicles: Key Players in Organ-Specific Metastasis and Clinical Implications

by Qian Jiang, Xiao-Ping Tan, Cai-Hua Zhang, Zhi-Yuan Li, Du Li, Yan Xu, Yu Xuan Liu, Lingzhi Wang and Zhaowu Ma

Cancers 2022, 14(22), 5693; https://doi.org/10.3390/cancers14225693 - 19 Nov 2022

Cited by 3 | Viewed by 1821

Abstract

Extracellular vesicles (EVs) are heterogeneous membrane-encapsulated vesicles released by most cells. They act as multifunctional regulators of intercellular communication by delivering bioactive molecules, including non-coding RNAs (ncRNAs). Metastasis is a major cause of cancer-related death. Most cancer cells disseminate and colonize a specific [...] Read more.

Extracellular vesicles (EVs) are heterogeneous membrane-encapsulated vesicles released by most cells. They act as multifunctional regulators of intercellular communication by delivering bioactive molecules, including non-coding RNAs (ncRNAs). Metastasis is a major cause of cancer-related death. Most cancer cells disseminate and colonize a specific target organ via EVs, a process known as “organ-specific metastasis”. Mounting evidence has shown that EVs are enriched with ncRNAs, and various EV-ncRNAs derived from tumor cells influence organ-specific metastasis via different mechanisms. Due to the tissue-specific expression of EV-ncRNAs, they could be used as potential biomarkers and therapeutic targets for the treatment of tumor metastasis in various types of cancer. In this review, we have discussed the underlying mechanisms of EV-delivered ncRNAs in the most common organ-specific metastases of liver, bone, lung, brain, and lymph nodes. Moreover, we summarize the potential clinical applications of EV-ncRNAs in organ-specific metastasis to fill the gap between benches and bedsides. Full article

(This article belongs to the Special Issue Targeting Cancer Metastasis (Volume II))

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Open AccessArticle

Can Pre-Operative Neutrophil-to-Lymphocyte Ratio (NLR) Help Predict Non-Metastatic Renal Carcinoma Recurrence after Nephrectomy? (UroCCR-61 Study)

by Clément Allenet, Clément Klein, Benjamin Rouget, Gaëlle Margue, Grégoire Capon, Eric Alezra, Peggy Blanc, Vincent Estrade, Franck Bladou, Grégoire Robert and Jean-Christophe Bernhard

Cancers 2022, 14(22), 5692; https://doi.org/10.3390/cancers14225692 - 19 Nov 2022

Cited by 6 | Viewed by 1200

Abstract

Recent studies suggested that the neutrophil-to-lymphocyte ratio (NLR) could play a key role in tumor initiation, progression and response to treatments. The main objective was to assess the prognostic value of the pre-operative NLR on recurrence-free survival (RFS) in patients with non-hereditary localized [...] Read more.

Recent studies suggested that the neutrophil-to-lymphocyte ratio (NLR) could play a key role in tumor initiation, progression and response to treatments. The main objective was to assess the prognostic value of the pre-operative NLR on recurrence-free survival (RFS) in patients with non-hereditary localized renal cell carcinoma. From the UroCCR database (NCT03293563), factors influencing the disease recurrence of consecutive patients who underwent nephrectomy for cT1-T4 N0M0 were analyzed using multi-variate cox regression and log-rank methods. We included 786 patients, among which 135 (17.2%) experienced a recurrence at a median time of 23.7 [8.5–48.6] months. RFS for patients with a pre-operative NLR of <2.7 was 94% and 88% at 3 and 5 years, respectively, versus 76% and 63% for patients with a NLR of ≥2.7 (p < 0.001, log-rank test). To predict the risk of post-operative recurrence, the NLR was combined with the UCLA integrated staging system (UISS), and we defined four groups of the UroCCR-61 predictive model. The RFS rates at 3 and 5 years were 100% and 97% in the very-low-risk group, 93% and 86% in the low-risk group, 78% and 68% in the intermediate-risk group and 63% and 46% in the high-risk group (p < 0.0001). The pre-operative NLR seems to be an inexpensive and easily accessible prognostic bio-marker for non-metastatic RCCs. Full article

(This article belongs to the Section Cancer Biomarkers)

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Cancers, Volume 14, Issue 22 (November-2 2022) – 248 articles

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