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Cancers, Volume 15, Issue 5 (March-1 2023) – 276 articles

Cover Story (view full-size image): Breast cancer is the most common cancer in women. Approximately 15% of breast cancers harbor an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein and are thus classified as HER2-positive. However, HER2 protein expression could be heterogeneous, showing different patterns of spatial distribution. This feature, also called “spatial heterogeneity”, may potentially affect treatment, response, and assessment of HER2 status, ultimately impacting the best treatment strategy. The activity of some new pharmacological agents, belonging to the group of antibody–drug conjugates, may represent an opportunity for overcoming this issue. In this review, we summarize the currently known mechanisms of resistance to anti-HER2 therapy, focusing on available evidence on HER2 heterogeneity and spatial distribution and their treatment implications. View this paper
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19 pages, 4390 KiB  
Article
DNA Methylation and Prospects for Predicting the Therapeutic Effect of Neoadjuvant Chemotherapy for Triple-Negative and Luminal B Breast Cancer
by Vladimir O. Sigin, Alexey I. Kalinkin, Alexandra F. Nikolaeva, Ekaterina O. Ignatova, Ekaterina B. Kuznetsova, Galina G. Chesnokova, Nikolai V. Litviakov, Matvey M. Tsyganov, Marina K. Ibragimova, Ilya I. Vinogradov, Maxim I. Vinogradov, Igor Y. Vinogradov, Dmitry V. Zaletaev, Marina V. Nemtsova, Sergey I. Kutsev, Alexander S. Tanas and Vladimir V. Strelnikov
Cancers 2023, 15(5), 1630; https://doi.org/10.3390/cancers15051630 - 6 Mar 2023
Cited by 2 | Viewed by 2354
Abstract
Despite advances in the diagnosis and treatment of breast cancer (BC), the main cause of deaths is resistance to existing therapies. An approach to improve the effectiveness of therapy in patients with aggressive BC subtypes is neoadjuvant chemotherapy (NACT). Yet, the response to [...] Read more.
Despite advances in the diagnosis and treatment of breast cancer (BC), the main cause of deaths is resistance to existing therapies. An approach to improve the effectiveness of therapy in patients with aggressive BC subtypes is neoadjuvant chemotherapy (NACT). Yet, the response to NACT for aggressive subtypes is less than 65% according to large clinical trials. An obvious fact is the lack of biomarkers predicting the therapeutic effect of NACT. In a search for epigenetic markers, we performed genome-wide differential methylation screening by XmaI-RRBS in cohorts of NACT responders and nonresponders, for triple-negative (TN) and luminal B tumors. The predictive potential of the most discriminative loci was further assessed in independent cohorts by methylation-sensitive restriction enzyme quantitative PCR (MSRE-qPCR), a promising method for the implementation of DNA methylation markers in diagnostic laboratories. The selected most informative individual markers were combined into panels demonstrating cvAUC = 0.83 (TMEM132D and MYO15B markers panel) for TN tumors and cvAUC = 0.76 (TTC34, LTBR and CLEC14A) for luminal B tumors. The combination of methylation markers with clinical features that correlate with NACT effect (clinical stage for TN and lymph node status for luminal B tumors) produces better classifiers, with cvAUC = 0.87 for TN tumors and cvAUC = 0.83 for luminal B tumors. Thus, clinical characteristics predictive of NACT response are independently additive to the epigenetic classifier and in combination improve prediction. Full article
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35 pages, 996 KiB  
Review
Predictive Biomarkers for Checkpoint Inhibitor Immune-Related Adverse Events
by Iñigo Les, Mireia Martínez, Inés Pérez-Francisco, María Cabero, Lucía Teijeira, Virginia Arrazubi, Nuria Torrego, Ana Campillo-Calatayud, Iñaki Elejalde, Grazyna Kochan and David Escors
Cancers 2023, 15(5), 1629; https://doi.org/10.3390/cancers15051629 - 6 Mar 2023
Cited by 12 | Viewed by 5944
Abstract
Immune-checkpoint inhibitors (ICIs) are antagonists of inhibitory receptors in the immune system, such as the cytotoxic T-lymphocyte-associated antigen-4, the programmed cell death protein-1 and its ligand PD-L1, and they are increasingly used in cancer treatment. By blocking certain suppressive pathways, ICIs promote T-cell [...] Read more.
Immune-checkpoint inhibitors (ICIs) are antagonists of inhibitory receptors in the immune system, such as the cytotoxic T-lymphocyte-associated antigen-4, the programmed cell death protein-1 and its ligand PD-L1, and they are increasingly used in cancer treatment. By blocking certain suppressive pathways, ICIs promote T-cell activation and antitumor activity but may induce so-called immune-related adverse events (irAEs), which mimic traditional autoimmune disorders. With the approval of more ICIs, irAE prediction has become a key factor in improving patient survival and quality of life. Several biomarkers have been described as potential irAE predictors, some of them are already available for clinical use and others are under development; examples include circulating blood cell counts and ratios, T-cell expansion and diversification, cytokines, autoantibodies and autoantigens, serum and other biological fluid proteins, human leucocyte antigen genotypes, genetic variations and gene profiles, microRNAs, and the gastrointestinal microbiome. Nevertheless, it is difficult to generalize the application of irAE biomarkers based on the current evidence because most studies have been retrospective, time-limited and restricted to a specific type of cancer, irAE or ICI. Long-term prospective cohorts and real-life studies are needed to assess the predictive capacity of different potential irAE biomarkers, regardless of the ICI type, organ involved or cancer site. Full article
(This article belongs to the Special Issue Targeted Treatment for Immunochemotherapy in Cancer)
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14 pages, 1198 KiB  
Review
A Comprehensive Review of Prognostic Factors in Patients with Gastric Adenocarcinoma
by Styliani Mantziari, Penelope St Amour, Francesco Abboretti, Hugo Teixeira-Farinha, Sergio Gaspar Figueiredo, Caroline Gronnier, Dimitrios Schizas, Nicolas Demartines and Markus Schäfer
Cancers 2023, 15(5), 1628; https://doi.org/10.3390/cancers15051628 - 6 Mar 2023
Cited by 3 | Viewed by 2518
Abstract
Gastric adenocarcinoma remains associated with a poor long-term survival, despite recent therapeutical advances. In most parts of the world where systematic screening programs do not exist, diagnosis is often made at advanced stages, affecting long-term prognosis. In recent years, there is increasing evidence [...] Read more.
Gastric adenocarcinoma remains associated with a poor long-term survival, despite recent therapeutical advances. In most parts of the world where systematic screening programs do not exist, diagnosis is often made at advanced stages, affecting long-term prognosis. In recent years, there is increasing evidence that a large bundle of factors, ranging from the tumor microenvironment to patient ethnicity and variations in therapeutic strategy, play an important role in patient outcome. A more thorough understanding of these multi-faceted parameters is needed in order to provide a better assessment of long-term prognosis in these patients, which probably also require the refinement of current staging systems. This study aims to review existing knowledge on the clinical, biomolecular and treatment-related parameters that have some prognostic value in patients with gastric adenocarcinoma. Full article
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25 pages, 13138 KiB  
Article
Pro-Apoptotic and Anti-Cancer Activity of the Vernonanthura Nudiflora Hydroethanolic Extract
by Almog Nadir, Anna Shteinfer-Kuzmine, Swaroop Kumar Pandey, Juan Ortas, Daniel Kerekes and Varda Shoshan-Barmatz
Cancers 2023, 15(5), 1627; https://doi.org/10.3390/cancers15051627 - 6 Mar 2023
Cited by 1 | Viewed by 2451
Abstract
The mitochondrial voltage-dependent anion channel 1 (VDAC1) protein is involved in several essential cancer hallmarks, including energy and metabolism reprogramming and apoptotic cell death evasion. In this study, we demonstrated the ability of hydroethanolic extracts from three different plants, Vernonanthura nudiflora (Vern), Baccharis [...] Read more.
The mitochondrial voltage-dependent anion channel 1 (VDAC1) protein is involved in several essential cancer hallmarks, including energy and metabolism reprogramming and apoptotic cell death evasion. In this study, we demonstrated the ability of hydroethanolic extracts from three different plants, Vernonanthura nudiflora (Vern), Baccharis trimera (Bac), and Plantago major (Pla), to induce cell death. We focused on the most active Vern extract. We demonstrated that it activates multiple pathways that lead to impaired cell energy and metabolism homeostasis, elevated ROS production, increased intracellular Ca2+, and mitochondria-mediated apoptosis. The massive cell death generated by this plant extract’s active compounds involves the induction of VDAC1 overexpression and oligomerization and, thereby, apoptosis. Gas chromatography of the hydroethanolic plant extract identified dozens of compounds, including phytol and ethyl linoleate, with the former producing similar effects as the Vern hydroethanolic extract but at 10-fold higher concentrations than those found in the extract. In a xenograft glioblastoma mouse model, both the Vern extract and phytol strongly inhibited tumor growth and cell proliferation and induced massive tumor cell death, including of cancer stem cells, inhibiting angiogenesis and modulating the tumor microenvironment. Taken together, the multiple effects of Vern extract make it a promising potential cancer therapeutic. Full article
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12 pages, 1264 KiB  
Review
Impact of Epstein Barr Virus Infection on Treatment Opportunities in Patients with Nasopharyngeal Cancer
by Francesco Perri, Francesco Sabbatino, Alessandro Ottaiano, Roberta Fusco, Michele Caraglia, Marco Cascella, Francesco Longo, Rosalia Anna Rega, Giovanni Salzano, Monica Pontone, Maria Luisa Marciano, Arianna Piccirillo, Massimo Montano, Morena Fasano, Fortunato Ciardiello, Giuseppina Della Vittoria Scarpati and Franco Ionna
Cancers 2023, 15(5), 1626; https://doi.org/10.3390/cancers15051626 - 6 Mar 2023
Cited by 2 | Viewed by 2255
Abstract
Chemical, physical, and infectious agents may induce carcinogenesis, and in the latter case, viruses are involved in most cases. The occurrence of virus-induced carcinogenesis is a complex process caused by an interaction across multiple genes, mainly depending by the type of the virus. [...] Read more.
Chemical, physical, and infectious agents may induce carcinogenesis, and in the latter case, viruses are involved in most cases. The occurrence of virus-induced carcinogenesis is a complex process caused by an interaction across multiple genes, mainly depending by the type of the virus. Molecular mechanisms at the basis of viral carcinogenesis, mainly suggest the involvement of a dysregulation of the cell cycle. Among the virus-inducing carcinogenesis, Epstein Barr Virus (EBV) plays a major role in the development of both hematological and oncological malignancies and importantly, several lines of evidence demonstrated that nasopharyngeal carcinoma (NPC) is consistently associated with EBV infection. Cancerogenesis in NPC may be induced by the activation of different EBV “oncoproteins” which are produced during the so called “latency phase” of EBV in the host cells. Moreover, EBV presence in NPC does affect the tumor microenvironment (TME) leading to a strongly immunosuppressed status. Translational implications of the above-mentioned statements are that EBV-infected NPC cells can express proteins potentially recognized by immune cells in order to elicit a host immune response (tumor associated antigens). Three immunotherapeutic approaches have been implemented for the treatment of NPC including active, adoptive immunotherapy, and modulation of immune regulatory molecules by use of the so-called checkpoint inhibitors. In this review, we will highlight the role of EBV infection in NPC development and analyze its possible implications on therapy strategies. Full article
(This article belongs to the Special Issue Multimodality Treatment in Recurrent Metastatic Head and Neck Cancer)
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24 pages, 2658 KiB  
Systematic Review
Breast Cancer Risk and Breast-Cancer-Specific Mortality following Risk-Reducing Salpingo-Oophorectomy in BRCA Carriers: A Systematic Review and Meta-Analysis
by Faiza Gaba, Oleg Blyuss, Alex Tan, Daniel Munblit, Samuel Oxley, Khalid Khan, Rosa Legood and Ranjit Manchanda
Cancers 2023, 15(5), 1625; https://doi.org/10.3390/cancers15051625 - 6 Mar 2023
Cited by 5 | Viewed by 3054
Abstract
Background: Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard method of ovarian cancer risk reduction, but the data are conflicting regarding the impact on breast cancer (BC) outcomes. This study aimed to quantify BC risk/mortality in BRCA1/BRCA2 carriers after RRSO. Methods: We [...] Read more.
Background: Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard method of ovarian cancer risk reduction, but the data are conflicting regarding the impact on breast cancer (BC) outcomes. This study aimed to quantify BC risk/mortality in BRCA1/BRCA2 carriers after RRSO. Methods: We conducted a systematic review (CRD42018077613) of BRCA1/BRCA2 carriers undergoing RRSO, with the outcomes including primary BC (PBC), contralateral BC (CBC) and BC-specific mortality (BCSM) using a fixed-effects meta-analysis, with subgroup analyses stratified by mutation and menopause status. Results: RRSO was not associated with a significant reduction in the PBC risk (RR = 0.84, 95%CI: 0.59–1.21) or CBC risk (RR = 0.95, 95%CI: 0.65–1.39) in BRCA1 and BRCA2 carriers combined but was associated with reduced BC-specific mortality in BC-affected BRCA1 and BRCA2 carriers combined (RR = 0.26, 95%CI: 0.18–0.39). Subgroup analyses showed that RRSO was not associated with a reduction in the PBC risk (RR = 0.89, 95%CI: 0.68–1.17) or CBC risk (RR = 0.85, 95%CI: 0.59–1.24) in BRCA1 carriers nor a reduction in the CBC risk in BRCA2 carriers (RR = 0.35, 95%CI: 0.07–1.74) but was associated with a reduction in the PBC risk in BRCA2 carriers (RR = 0.63, 95%CI: 0.41–0.97) and BCSM in BC-affected BRCA1 carriers (RR = 0.46, 95%CI: 0.30–0.70). The mean NNT = 20.6 RRSOs to prevent one PBC death in BRCA2 carriers, while 5.6 and 14.2 RRSOs may prevent one BC death in BC-affected BRCA1 and BRCA2 carriers combined and BRCA1 carriers, respectively. Conclusions: RRSO was not associated with PBC or CBC risk reduction in BRCA1 and BRCA2 carriers combined but was associated with improved BC survival in BC-affected BRCA1 and BRCA2 carriers combined and BRCA1 carriers and a reduced PBC risk in BRCA2 carriers. Full article
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18 pages, 8336 KiB  
Article
PKCθ Regulates Pituitary Adenoma Bone Invasion by Activating Osteoclast in NF-κB/IL-1β-Dependent Manner
by Quanji Wang, Zhuowei Lei, Zihan Wang, Qian Jiang, Zhuo Zhang, Xiaojin Liu, Biao Xing, Sihan Li, Xiang Guo, Yanchao Liu, Xingbo Li, Kai Shu, Huaqiu Zhang, Yimin Huang and Ting Lei
Cancers 2023, 15(5), 1624; https://doi.org/10.3390/cancers15051624 - 6 Mar 2023
Cited by 4 | Viewed by 1567
Abstract
Background: Pituitary adenoma (PA) bone invasion results in adverse outcomes, such as reduced rates of complete surgical resection and biochemical remission as well as increased recurrence rates, though few studies have been conducted. Methods: We collected clinical specimens of PAs for staining and [...] Read more.
Background: Pituitary adenoma (PA) bone invasion results in adverse outcomes, such as reduced rates of complete surgical resection and biochemical remission as well as increased recurrence rates, though few studies have been conducted. Methods: We collected clinical specimens of PAs for staining and statistical analysis. Evaluation of the ability of PA cells to induce monocyte–osteoclast differentiation by coculturing PA cells with RAW264.7 in vitro. An in vivo model of bone invasion was used to simulate the process of bone erosion and evaluate the effect of different interventions in alleviating bone invasion. Results: We found an overactivation of osteoclasts in bone-invasive PAs and concomitant aggregation of inflammatory factors. Furthermore, activation of PKCθ in PAs was established as a central signaling promoting PA bone invasion through the PKCθ/NF-κB/IL-1β pathway. By inhibiting PKCθ and blocking IL1β, we were able to significantly reverse bone invasion in an in vivo study. Meanwhile, we also found that celastrol, as a natural product, can obviously reduce the secretion of IL-1β as well as alleviate the progression of bone invasion. Conclusions: By activating the PKCθ/NF-κB/IL-1β pathway, pituitary tumors are able to induce monocyte–osteoclast differentiation in a paracrine manner and promote bone invasion, which can be alleviated by celastrol. Full article
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11 pages, 1630 KiB  
Communication
Routine EWS Fusion Analysis in the Oncology Clinic to Identify Cancer-Specific Peptide Sequence Patterns That Span Breakpoints in Ewing Sarcoma and DSRCT
by Peter M. Anderson, Zheng Jin Tu, Scott E. Kilpatrick, Matteo Trucco, Rabi Hanna and Timothy Chan
Cancers 2023, 15(5), 1623; https://doi.org/10.3390/cancers15051623 - 6 Mar 2023
Cited by 2 | Viewed by 1879
Abstract
(1) Background: EWS fusion genes are associated with Ewing sarcoma and other Ewing family tumors including desmoplastic small round tumor, DSRCT. We utilize a clinical genomics workflow to reveal real-world frequencies of EWS fusion events, cataloging events that are similar, or divergent at [...] Read more.
(1) Background: EWS fusion genes are associated with Ewing sarcoma and other Ewing family tumors including desmoplastic small round tumor, DSRCT. We utilize a clinical genomics workflow to reveal real-world frequencies of EWS fusion events, cataloging events that are similar, or divergent at the EWS breakpoint. (2) Methods: EWS fusion events from our next-generation sequencing panel (NGS) samples were first sorted by breakpoint or fusion junctions to map out the frequency of breakpoints. Fusion results were illustrated as in-frame fusion peptides involving EWS and a partner gene. (3) Results: From 2471 patient pool samples for fusion analysis at the Cleveland Clinic Molecular Pathology Laboratory, we identified 182 fusion samples evolved with the EWS gene. They are clustered in several breakpoints: chr22:29683123 (65.9%), and chr22:29688595 (2.7%). About 3/4 of Ewing sarcoma and DSRCT tumors have an identical EWS breakpoint motif at Exon 7 (SQQSSSYGQQ-) fused to a specific part of FLI1 (NPSYDSVRRG or-SSLLAYNTSS), ERG (NLPYEPPRRS), FEV (NPVGDGLFKD) or WT1 (SEKPYQCDFK). Our method also worked with Caris transcriptome data, too. Our primary clinical utility is to use this information to identify neoantigens for therapeutic purposes. (4) Conclusions and future perspectives: our method allows interpretation of what peptides result from the in-frame translation of EWS fusion junctions. These sequences, coupled with HLA-peptide binding data, are used to identify potential sequences of cancer-specific immunogenic peptides for Ewing sarcoma or DSRCT patients. This information may also be useful for immune monitoring (e.g., circulating T-cells with fusion-peptide specificity) to detect vaccine candidates, responses, or residual disease. Full article
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13 pages, 1858 KiB  
Article
Independent Validation of a Deep Learning nnU-Net Tool for Neuroblastoma Detection and Segmentation in MR Images
by Diana Veiga-Canuto, Leonor Cerdà-Alberich, Ana Jiménez-Pastor, José Miguel Carot Sierra, Armando Gomis-Maya, Cinta Sangüesa-Nebot, Matías Fernández-Patón, Blanca Martínez de las Heras, Sabine Taschner-Mandl, Vanessa Düster, Ulrike Pötschger, Thorsten Simon, Emanuele Neri, Ángel Alberich-Bayarri, Adela Cañete, Barbara Hero, Ruth Ladenstein and Luis Martí-Bonmatí
Cancers 2023, 15(5), 1622; https://doi.org/10.3390/cancers15051622 - 6 Mar 2023
Cited by 5 | Viewed by 2744
Abstract
Objectives. To externally validate and assess the accuracy of a previously trained fully automatic nnU-Net CNN algorithm to identify and segment primary neuroblastoma tumors in MR images in a large children cohort. Methods. An international multicenter, multivendor imaging repository of patients with neuroblastic [...] Read more.
Objectives. To externally validate and assess the accuracy of a previously trained fully automatic nnU-Net CNN algorithm to identify and segment primary neuroblastoma tumors in MR images in a large children cohort. Methods. An international multicenter, multivendor imaging repository of patients with neuroblastic tumors was used to validate the performance of a trained Machine Learning (ML) tool to identify and delineate primary neuroblastoma tumors. The dataset was heterogeneous and completely independent from the one used to train and tune the model, consisting of 300 children with neuroblastic tumors having 535 MR T2-weighted sequences (486 sequences at diagnosis and 49 after finalization of the first phase of chemotherapy). The automatic segmentation algorithm was based on a nnU-Net architecture developed within the PRIMAGE project. For comparison, the segmentation masks were manually edited by an expert radiologist, and the time for the manual editing was recorded. Different overlaps and spatial metrics were calculated to compare both masks. Results. The median Dice Similarity Coefficient (DSC) was high 0.997; 0.944–1.000 (median; Q1–Q3). In 18 MR sequences (6%), the net was not able neither to identify nor segment the tumor. No differences were found regarding the MR magnetic field, type of T2 sequence, or tumor location. No significant differences in the performance of the net were found in patients with an MR performed after chemotherapy. The time for visual inspection of the generated masks was 7.9 ± 7.5 (mean ± Standard Deviation (SD)) seconds. Those cases where manual editing was needed (136 masks) required 124 ± 120 s. Conclusions. The automatic CNN was able to locate and segment the primary tumor on the T2-weighted images in 94% of cases. There was an extremely high agreement between the automatic tool and the manually edited masks. This is the first study to validate an automatic segmentation model for neuroblastic tumor identification and segmentation with body MR images. The semi-automatic approach with minor manual editing of the deep learning segmentation increases the radiologist’s confidence in the solution with a minor workload for the radiologist. Full article
(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)
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23 pages, 2487 KiB  
Review
Anti-Cancer Stem-Cell-Targeted Therapies in Prostate Cancer
by Samantha Gogola, Michael Rejzer, Hisham F. Bahmad, Ferial Alloush, Yumna Omarzai and Robert Poppiti
Cancers 2023, 15(5), 1621; https://doi.org/10.3390/cancers15051621 - 6 Mar 2023
Cited by 8 | Viewed by 2916
Abstract
Prostate cancer (PCa) is the second-most commonly diagnosed cancer in men around the world. It is treated using a risk stratification approach in accordance with the National Comprehensive Cancer Network (NCCN) in the United States. The main treatment options for early PCa include [...] Read more.
Prostate cancer (PCa) is the second-most commonly diagnosed cancer in men around the world. It is treated using a risk stratification approach in accordance with the National Comprehensive Cancer Network (NCCN) in the United States. The main treatment options for early PCa include external beam radiation therapy (EBRT), brachytherapy, radical prostatectomy, active surveillance, or a combination approach. In those with advanced disease, androgen deprivation therapy (ADT) is considered as a first-line therapy. However, the majority of cases eventually progress while receiving ADT, leading to castration-resistant prostate cancer (CRPC). The near inevitable progression to CRPC has spurred the recent development of many novel medical treatments using targeted therapies. In this review, we outline the current landscape of stem-cell-targeted therapies for PCa, summarize their mechanisms of action, and discuss avenues of future development. Full article
(This article belongs to the Special Issue The Role of Cancer Stem Cells in Cancer Targeted Therapy)
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17 pages, 5843 KiB  
Article
Cancer-Associated Fibroblasts Exposed to High-Dose Ionizing Radiation Promote M2 Polarization of Macrophages, Which Induce Radiosensitivity in Cervical Cancer
by Yuhan Sheng, Baofang Zhang, Biyuan Xing, Zhao Liu, Yu Chang, Gang Wu and Yingchao Zhao
Cancers 2023, 15(5), 1620; https://doi.org/10.3390/cancers15051620 - 6 Mar 2023
Cited by 5 | Viewed by 1700
Abstract
Radiotherapy, including brachytherapy, is a major therapeutic regimen for cervical cancer. Radioresistance is a decisive factor in radiation treatment failure. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor microenvironment are critical factors in the curative effects of cancer therapies. However, the [...] Read more.
Radiotherapy, including brachytherapy, is a major therapeutic regimen for cervical cancer. Radioresistance is a decisive factor in radiation treatment failure. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor microenvironment are critical factors in the curative effects of cancer therapies. However, the interactions between TAMs and CAFs in the context of ionizing radiation are not fully understood. This study was undertaken to investigate whether M2 macrophages induce radioresistance in cervical cancer and to explore the TAMs’ phenotypic transformation after IR and its underlying mechanisms. The radioresistance of cervical cancer cells was enhanced after being co-cultured with M2 macrophages. TAMs tended to undergo M2 polarization after high-dose irradiation, which was strongly associated with CAFs in both mouse models and patients with cervical cancer. Additionally, cytokine and chemokine analysis was performed to find that high-dose irradiated CAFs promoted macrophage polarization towards the M2 phenotype through chemokine (C-C motif) ligand 2. Collectively, our results highlight the crucial role that high-dose irradiated CAFs play in the regulation of M2 phenotype polarization, which ultimately induces radioresistance in cervical cancer. Full article
(This article belongs to the Section Tumor Microenvironment)
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24 pages, 3072 KiB  
Review
DNA Repair Deficiency Regulates Immunity Response in Cancers: Molecular Mechanism and Approaches for Combining Immunotherapy
by Yi Xu, Somaira Nowsheen and Min Deng
Cancers 2023, 15(5), 1619; https://doi.org/10.3390/cancers15051619 - 6 Mar 2023
Cited by 6 | Viewed by 3535
Abstract
Defects in DNA repair pathways can lead to genomic instability in multiple tumor types, which contributes to tumor immunogenicity. Inhibition of DNA damage response (DDR) has been reported to increase tumor susceptibility to anticancer immunotherapy. However, the interplay between DDR and the immune [...] Read more.
Defects in DNA repair pathways can lead to genomic instability in multiple tumor types, which contributes to tumor immunogenicity. Inhibition of DNA damage response (DDR) has been reported to increase tumor susceptibility to anticancer immunotherapy. However, the interplay between DDR and the immune signaling pathways remains unclear. In this review, we will discuss how a deficiency in DDR affects anti-tumor immunity, highlighting the cGAS-STING axis as an important link. We will also review the clinical trials that combine DDR inhibition and immune-oncology treatments. A better understanding of these pathways will help exploit cancer immunotherapy and DDR pathways to improve treatment outcomes for various cancers. Full article
(This article belongs to the Collection Mechanism of Immunotherapy in Cancers)
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9 pages, 274 KiB  
Article
Evaluating the Protective Effect of Intravesical Bacillus Calmette-Guerin against SARS-CoV-2 in Non-Muscle Invasive Bladder Cancer Patients: A Multicenter Observational Trial
by Rodolfo Hurle, Francesco Soria, Roberto Contieri, Pier Paolo Avolio, Stefano Mancon, Massimo Lazzeri, Valentina Bernasconi, Simone Mazzoli, Giuseppe Pizzuto, Matteo De Bellis, Matteo Rosazza, Simone Livoti, Tommaso Lupia, Silvia Corcione, Beatrice Lillaz, Francesco Giuseppe De Rosa, Nicolò Maria Buffi, Ashish M. Kamat, Paolo Gontero and Paolo Casale
Cancers 2023, 15(5), 1618; https://doi.org/10.3390/cancers15051618 - 6 Mar 2023
Cited by 2 | Viewed by 1850
Abstract
We aim to evaluate the potential protective role of intravesical Bacillus Calmette-Guerin (BCG) against SARS-CoV-2 in patients with non-muscle invasive bladder cancer (NMIBC). Patients treated with intravesical adjuvant therapy for NMIBC between January 2018 and December 2019 at two Italian referral centers were [...] Read more.
We aim to evaluate the potential protective role of intravesical Bacillus Calmette-Guerin (BCG) against SARS-CoV-2 in patients with non-muscle invasive bladder cancer (NMIBC). Patients treated with intravesical adjuvant therapy for NMIBC between January 2018 and December 2019 at two Italian referral centers were divided into two groups based on the received intravesical treatment regimen (BCG vs. chemotherapy). The study’s primary endpoint was evaluating SARS-CoV-2 disease incidence and severity among patients treated with intravesical BCG compared to the control group. The study’s secondary endpoint was the evaluation of SARS-CoV-2 infection (estimated with serology testing) in the study groups. Overall, 340 patients treated with BCG and 166 treated with intravesical chemotherapy were included in the study. Among patients treated with BCG, 165 (49%) experienced BCG-related adverse events, and serious adverse events occurred in 33 (10%) patients. Receiving BCG or experiencing systemic BCG-related adverse events were not associated with symptomatic proven SARS-CoV-2 infection (p = 0.9) nor with a positive serology test (p = 0.5). The main limitations are related to the retrospective nature of the study. In this multicenter observational trial, a protective role of intravesical BCG against SARS-CoV-2 could not be demonstrated. These results may be used for decision-making regarding ongoing and future trials. Full article
(This article belongs to the Collection The Impact of COVID-19 Infection in Cancer)
21 pages, 1222 KiB  
Review
Molecularly Targeted Therapy in Acute Myeloid Leukemia: Current Treatment Landscape and Mechanisms of Response and Resistance
by Curtis A. Lachowiez, Courtney D. DiNardo and Sanam Loghavi
Cancers 2023, 15(5), 1617; https://doi.org/10.3390/cancers15051617 - 6 Mar 2023
Cited by 4 | Viewed by 4557
Abstract
Treatment for acute myeloid leukemia (AML) has evolved rapidly over the last decade as improved understanding of cytogenetic and molecular drivers of leukemogenesis refined survival prognostication and enabled development of targeted therapeutics. Molecularly targeted therapies are now approved for the treatment of FLT3 [...] Read more.
Treatment for acute myeloid leukemia (AML) has evolved rapidly over the last decade as improved understanding of cytogenetic and molecular drivers of leukemogenesis refined survival prognostication and enabled development of targeted therapeutics. Molecularly targeted therapies are now approved for the treatment of FLT3 and IDH1/2-mutated AML and additional molecularly and cellularly targeted therapeutics are in development for defined patient subgroups. Alongside these welcome therapeutic advancements, increased understanding of leukemic biology and treatment resistance has resulted in clinical trials investigating combinations of cytotoxic, cellular, and molecularly targeted therapeutics resulting in improved response and survival outcomes in patients with AML. Herein, we comprehensively review the current landscape of IDH and FLT3 inhibitors in clinical practice for the treatment of AML, highlight known resistance mechanisms, and discuss new cellular or molecularly targeted therapies currently under investigation in ongoing early phase clinical trials. Full article
(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)
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22 pages, 3232 KiB  
Article
Phenotypic Plasticity in Circulating Tumor Cells Is Associated with Poor Response to Therapy in Metastatic Breast Cancer Patients
by Evan N. Cohen, Gitanjali Jayachandran, Hui Gao, Phillip Peabody, Heather B. McBride, Franklin D. Alvarez, Megumi Kai, Juhee Song, Yu Shen, Jie S. Willey, Bora Lim, Vicente Valero, Naoto T. Ueno and James M. Reuben
Cancers 2023, 15(5), 1616; https://doi.org/10.3390/cancers15051616 - 6 Mar 2023
Cited by 4 | Viewed by 2849
Abstract
Circulating tumor cells (CTCs) are indicators of metastatic spread and progression. In a longitudinal, single-center trial of patients with metastatic breast cancer starting a new line of treatment, a microcavity array was used to enrich CTCs from 184 patients at up to 9 [...] Read more.
Circulating tumor cells (CTCs) are indicators of metastatic spread and progression. In a longitudinal, single-center trial of patients with metastatic breast cancer starting a new line of treatment, a microcavity array was used to enrich CTCs from 184 patients at up to 9 timepoints at 3-month intervals. CTCs were analyzed in parallel samples from the same blood draw by imaging and by gene expression profiling to capture CTC phenotypic plasticity. Enumeration of CTCs by image analysis relying primarily on epithelial markers from samples obtained before therapy or at 3-month follow-up identified the patients at the highest risk of progression. CTC counts decreased with therapy, and progressors had higher CTC counts than non-progressors. CTC count was prognostic primarily at the start of therapy in univariate and multivariate analyses but had less prognostic utility at 6 months to 1 year later. In contrast, gene expression, including both epithelial and mesenchymal markers, identified high-risk patients after 6–9 months of treatment, and progressors had a shift towards mesenchymal CTC gene expression on therapy. Cross-sectional analysis showed higher CTC-related gene expression in progressors 6–15 months after baseline. Furthermore, patients with higher CTC counts and CTC gene expression experienced more progression events. Longitudinal time-dependent multivariate analysis indicated that CTC count, triple-negative status, and CTC expression of FGFR1 significantly correlated with inferior progression-free survival while CTC count and triple-negative status correlated with inferior overall survival. This highlights the utility of protein-agnostic CTC enrichment and multimodality analysis to capture the heterogeneity of CTCs. Full article
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18 pages, 766 KiB  
Article
First-Line Immunotherapy with Check-Point Inhibitors: Prospective Assessment of Cognitive Function
by Jamie S. Myers, Adam C. Parks, Jonathan D. Mahnken, Kate J. Young, Harsh B. Pathak, Rajni V. Puri, Amber Unrein, Phyllis Switzer, Yazan Abdulateef, Samantha Sullivan, John F. Walker, David Streeter and Jeffrey M. Burns
Cancers 2023, 15(5), 1615; https://doi.org/10.3390/cancers15051615 - 6 Mar 2023
Cited by 1 | Viewed by 1814
Abstract
Approximately 40% of patients with cancer are eligible for check-point inhibitor (CPI) therapy. Little research has examined the potential cognitive impact of CPIs. First-line CPI therapy offers a unique research opportunity without chemotherapy-related confounders. The purpose of this prospective, observational pilot was to [...] Read more.
Approximately 40% of patients with cancer are eligible for check-point inhibitor (CPI) therapy. Little research has examined the potential cognitive impact of CPIs. First-line CPI therapy offers a unique research opportunity without chemotherapy-related confounders. The purpose of this prospective, observational pilot was to (1) demonstrate the feasibility of prospective recruitment, retention, and neurocognitive assessment for older adults receiving first-line CPI(s) and (2) provide preliminary evidence of changes in cognitive function associated with CPI(s). Patients receiving first-line CPI(s) (CPI Group) were assessed at baseline (n = 20) and 6 months (n = 13) for self-report of cognitive function and neurocognitive test performance. Results were compared to age-matched controls without cognitive impairment assessed annually by the Alzheimer’s Disease Research Center (ADRC). Plasma biomarkers were measured at baseline and 6 months for the CPI Group. Estimated differences for CPI Group scores prior to initiating CPIs (baseline) trended to lower performance on the Montreal Cognitive Assessment-Blind (MOCA-Blind) test compared to the ADRC controls (p = 0.066). Controlling for age, the CPI Group’s 6-months MOCA-Blind performance was lower than the ADRC control group’s 12-months performance (p = 0.011). No significant differences in biomarkers were detected between baseline and 6 months, although significant correlations were noted for biomarker change and cognitive performance at 6 months. IFNγ, IL-1β, IL-2, FGF2, and VEGF were inversely associated with Craft Story Recall performance (p < 0.05), e.g., higher levels correlated with poorer memory performance. Higher IGF-1 and VEGF correlated with better letter-number sequencing and digit-span backwards performance, respectively. Unexpected inverse correlation was noted between IL-1α and Oral Trail-Making Test B completion time. CPI(s) may have a negative impact on some neurocognitive domains and warrant further investigation. A multi-site study design may be crucial to fully powering prospective investigation of the cognitive impact of CPIs. Establishment of a multi-site observational registry from collaborating cancer centers and ADRCs is recommended. Full article
(This article belongs to the Special Issue Cognitive Outcomes in Cancer: Recent Advances and Challenges)
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17 pages, 13934 KiB  
Article
Sodium New Houttuyfonate Induces Apoptosis of Breast Cancer Cells via ROS/PDK1/AKT/GSK3β Axis
by Lixin He, Huili Feng, Baoyi Yin, Wenxuan Li, Xiao Wang, Talha Umar, Hongbo Gao, Ning Zhou and Changwei Qiu
Cancers 2023, 15(5), 1614; https://doi.org/10.3390/cancers15051614 - 6 Mar 2023
Cited by 3 | Viewed by 1873
Abstract
Background: Sodium new houttuyfonate (SNH) has been reported to have anti-inflammatory, anti-fungal, and anti-cancer effects. However, few studies have investigated the effect of SNH on breast cancer. The aim of this study was to investigate whether SNH has therapeutic potential for targeting breast [...] Read more.
Background: Sodium new houttuyfonate (SNH) has been reported to have anti-inflammatory, anti-fungal, and anti-cancer effects. However, few studies have investigated the effect of SNH on breast cancer. The aim of this study was to investigate whether SNH has therapeutic potential for targeting breast cancer. Methods: Immunohistochemistry and Western blot analysis were used to examine the expression of proteins, flow cytometry was used to detect cell apoptosis and ROS levels, and transmission electron microscopy was used to observe mitochondria. Results: Differentially expressed genes (DEGs) between breast cancer-related gene expression profiles (GSE139038 and GSE109169) from GEO DataSets were mainly involved in the immune signaling pathway and the apoptotic signaling pathway. According to in vitro experiments, SNH significantly inhibited the proliferation, migration, and invasiveness of MCF-7 (human cells) and CMT-1211 (canine cells) and promoted apoptosis. To explore the reason for the above cellular changes, it was found that SNH induced the excessive production of ROS, resulting in mitochondrial impairment, and then promoted apoptosis by inhibiting the activation of the PDK1-AKT-GSK3β pathway. Tumor growth, as well as lung and liver metastases, were suppressed under SNH treatment in a mouse breast tumor model. Conclusions: SNH significantly inhibited the proliferation and invasiveness of breast cancer cells and may have significant therapeutic potential in breast cancer. Full article
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15 pages, 3247 KiB  
Article
Clinical-Radiomics Nomogram Based on Contrast-Enhanced Ultrasound for Preoperative Prediction of Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma
by Liqing Jiang, Zijian Zhang, Shiyan Guo, Yongfeng Zhao and Ping Zhou
Cancers 2023, 15(5), 1613; https://doi.org/10.3390/cancers15051613 - 5 Mar 2023
Cited by 6 | Viewed by 2278
Abstract
This study aimed to establish a new clinical-radiomics nomogram based on ultrasound (US) for cervical lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC). We collected 211 patients with PTC between June 2018 and April 2020, then we randomly divided these patients into [...] Read more.
This study aimed to establish a new clinical-radiomics nomogram based on ultrasound (US) for cervical lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC). We collected 211 patients with PTC between June 2018 and April 2020, then we randomly divided these patients into the training set (n = 148) and the validation set (n = 63). 837 radiomics features were extracted from B-mode ultrasound (BMUS) images and contrast-enhanced ultrasound (CEUS) images. The maximum relevance minimum redundancy (mRMR) algorithm, least absolute shrinkage and selection operator (LASSO) algorithm, and backward stepwise logistic regression (LR) were applied to select key features and establish a radiomics score (Radscore), including BMUS Radscore and CEUS Radscore. The clinical model and clinical-radiomics model were established using the univariate analysis and multivariate backward stepwise LR. The clinical-radiomics model was finally presented as a clinical-radiomics nomogram, the performance of which was evaluated by the receiver operating characteristic curves, Hosmer–Lemeshow test, calibration curves, and decision curve analysis (DCA). The results show that the clinical-radiomics nomogram was constructed by four predictors, including gender, age, US-reported LNM, and CEUS Radscore. The clinical-radiomics nomogram performed well in both the training set (AUC = 0.820) and the validation set (AUC = 0.814). The Hosmer–Lemeshow test and the calibration curves demonstrated good calibration. The DCA showed that the clinical-radiomics nomogram had satisfactory clinical utility. The clinical-radiomics nomogram constructed by CEUS Radscore and key clinical features can be used as an effective tool for individualized prediction of cervical LNM in PTC. Full article
(This article belongs to the Special Issue Head and Neck Cancer Imaging and Image Analysis)
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14 pages, 1931 KiB  
Article
HotSPOT: A Computational Tool to Design Targeted Sequencing Panels to Assess Early Photocarcinogenesis
by Sydney R. Grant, Spencer R. Rosario, Andrew D. Patentreger, Nico Shary, Megan E. Fitzgerald, Prashant K. Singh, Barbara A. Foster, Wendy J. Huss, Lei Wei and Gyorgy Paragh
Cancers 2023, 15(5), 1612; https://doi.org/10.3390/cancers15051612 - 5 Mar 2023
Cited by 1 | Viewed by 1948
Abstract
Mutations found in skin are acquired in specific patterns, clustering around mutation-prone genomic locations. The most mutation-prone genomic areas, mutation hotspots, first induce the growth of small cell clones in healthy skin. Mutations accumulate over time, and clones with driver mutations may give [...] Read more.
Mutations found in skin are acquired in specific patterns, clustering around mutation-prone genomic locations. The most mutation-prone genomic areas, mutation hotspots, first induce the growth of small cell clones in healthy skin. Mutations accumulate over time, and clones with driver mutations may give rise to skin cancer. Early mutation accumulation is a crucial first step in photocarcinogenesis. Therefore, a sufficient understanding of the process may help predict disease onset and identify avenues for skin cancer prevention. Early epidermal mutation profiles are typically established using high-depth targeted next-generation sequencing. However, there is currently a lack of tools for designing custom panels to capture mutation-enriched genomic regions efficiently. To address this issue, we created a computational algorithm that implements a pseudo-exhaustive approach to identify the best genomic areas to target. We benchmarked the current algorithm in three independent mutation datasets of human epidermal samples. Compared to the sequencing panel designs originally used in these publications, the mutation capture efficacy (number of mutations/base pairs sequenced) of our designed panel improved 9.6–12.1-fold. Mutation burden in the chronically sun-exposed and intermittently sun-exposed normal epidermis was measured within genomic regions identified by hotSPOT based on cutaneous squamous cell carcinoma (cSCC) mutation patterns. We found a significant increase in mutation capture efficacy and mutation burden in cSCC hotspots in chronically sun-exposed vs. intermittently sun-exposed epidermis (p < 0.0001). Our results show that our hotSPOT web application provides a publicly available resource for researchers to design custom panels, enabling efficient detection of somatic mutations in clinically normal tissues and other similar targeted sequencing studies. Moreover, hotSPOT also enables the comparison of mutation burden between normal tissues and cancer. Full article
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15 pages, 1378 KiB  
Systematic Review
Systematic Review of the Short-Term versus Long-Term Duration of Antibiotic Management for Neutropenic Fever in Patients with Cancer
by Kazuhiro Ishikawa, Tetsuhiro Masaki, Fujimi Kawai, Erika Ota and Nobuyoshi Mori
Cancers 2023, 15(5), 1611; https://doi.org/10.3390/cancers15051611 - 5 Mar 2023
Cited by 3 | Viewed by 3017
Abstract
Early antibiotic discontinuation has been proposed in patients with hematologic malignancy with fever of unknown origin during febrile neutropenia (FN). We intended to investigate the safety of early antibiotic discontinuation in FN. Two reviewers independently searched for articles from Embase, CENTRAL, and MEDLINE [...] Read more.
Early antibiotic discontinuation has been proposed in patients with hematologic malignancy with fever of unknown origin during febrile neutropenia (FN). We intended to investigate the safety of early antibiotic discontinuation in FN. Two reviewers independently searched for articles from Embase, CENTRAL, and MEDLINE on 30 September 2022. The selection criteria were randomized control trials (RCTs) comparing short- and long-term durations for FN in cancer patients, and evaluating mortality, clinical failure, and bacteremia. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. We identified eleven RCTs (comprising 1128 distinct patients with FN) from 1977 to 2022. A low certainty of evidence was observed, and no significant differences in mortality (RR 1.43, 95% CI, 0.81, 2.53, I2 = 0), clinical failure (RR 1.14, 95% CI, 0.86, 1.49, I2 = 25), or bacteremia (RR 1.32, 95% CI, 0.87, 2.01, I2 = 34) were identified, indicating that the efficacy of short-term treatment may not differ statistically from that of long-term treatment. Regarding patients with FN, our findings provide weak conclusions regarding the safety and efficacy of antimicrobial discontinuation prior to neutropenia resolution. Full article
(This article belongs to the Section Cancer Therapy)
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23 pages, 14741 KiB  
Article
Development and Experimental Validation of a Novel Prognostic Signature for Gastric Cancer
by Chengcheng Liu, Yuying Huo, Yansong Zhang, Fumei Yin, Taoyu Chen, Zhenyi Wang, Juntao Gao, Peng Jin, Xiangyu Li, Minglei Shi and Michael Q. Zhang
Cancers 2023, 15(5), 1610; https://doi.org/10.3390/cancers15051610 - 5 Mar 2023
Viewed by 1907
Abstract
Background: Gastric cancer is a malignant tumor with high morbidity and mortality. Therefore, the accurate recognition of prognostic molecular markers is the key to improving treatment efficacy and prognosis. Methods: In this study, we developed a stable and robust signature through a series [...] Read more.
Background: Gastric cancer is a malignant tumor with high morbidity and mortality. Therefore, the accurate recognition of prognostic molecular markers is the key to improving treatment efficacy and prognosis. Methods: In this study, we developed a stable and robust signature through a series of processes using machine-learning approaches. This PRGS was further experimentally validated in clinical samples and a gastric cancer cell line. Results: The PRGS is an independent risk factor for overall survival that performs reliably and has a robust utility. Notably, PRGS proteins promote cancer cell proliferation by regulating the cell cycle. Besides, the high-risk group displayed a lower tumor purity, higher immune cell infiltration, and lower oncogenic mutation than the low-PRGS group. Conclusions: This PRGS could be a powerful and robust tool to improve clinical outcomes for individual gastric cancer patients. Full article
(This article belongs to the Topic Application of Big Medical Data in Precision Medicine)
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15 pages, 2240 KiB  
Article
Prognostic Value of Measurable Residual Disease in Patients with AML Undergoing HSCT: A Multicenter Study
by Teresa Caballero-Velázquez, Olga Pérez-López, Ana Yeguas Bermejo, Eduardo Rodríguez Arbolí, Enrique Colado Varela, Amparo Sempere Talens, María Belén Vidriales, María Solé-Rodríguez, Covadonga Quirós Caso, Estefanía Pérez López, Marta Reinoso Segura, Concepción Prats-Martín, Pau Montesinos and Jose A. Pérez-Simón
Cancers 2023, 15(5), 1609; https://doi.org/10.3390/cancers15051609 - 5 Mar 2023
Cited by 5 | Viewed by 1809
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) represents the best therapeutic option for many patients with acute myeloid leukemia (AML). However, relapse remains the main cause of mortality after transplantation. The detection of measurable residual disease (MRD) by multiparameter flow cytometry (MFC) in AML, [...] Read more.
Allogeneic hematopoietic stem cell transplantation (HSCT) represents the best therapeutic option for many patients with acute myeloid leukemia (AML). However, relapse remains the main cause of mortality after transplantation. The detection of measurable residual disease (MRD) by multiparameter flow cytometry (MFC) in AML, before and after HSCT, has been described as a powerful predictor of outcome. Nevertheless, multicenter and standardized studies are lacking. A retrospective analysis was performed, including 295 AML patients undergoing HSCT in 4 centers that worked according to recommendations from the Euroflow consortium. Among patients in complete remission (CR), MRD levels prior to transplantation significantly influenced outcomes, with overall (OS) and leukemia free survival (LFS) at 2 years of 76.7% and 67.6% for MRD-negative patients, 68.5% and 49.7% for MRD-low patients (MRD < 0.1), and 50.5% and 36.6% for MRD-high patients (MRD ≥ 0.1) (p < 0.001), respectively. MRD level did influence the outcome, irrespective of the conditioning regimen. In our patient cohort, positive MRD on day +100 after transplantation was associated with an extremely poor prognosis, with a cumulative incidence of relapse of 93.3%. In conclusion, our multicenter study confirms the prognostic value of MRD performed in accordance with standardized recommendations. Full article
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35 pages, 1829 KiB  
Review
Immunotargeting of Cancer Stem Cells
by Ayse Sedef Köseer, Simona Di Gaetano, Claudia Arndt, Michael Bachmann and Anna Dubrovska
Cancers 2023, 15(5), 1608; https://doi.org/10.3390/cancers15051608 - 5 Mar 2023
Cited by 3 | Viewed by 3521
Abstract
The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and [...] Read more.
The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and normal stem cells share many important signaling mechanisms for their maintenance and survival. Furthermore, the efficacy of this therapy is opposed by tumor heterogeneity and CSC plasticity. While there have been considerable efforts to target CSC populations by the chemical inhibition of the developmental pathways such as Notch, Hedgehog (Hh), and Wnt/β-catenin, noticeably fewer attempts were focused on the stimulation of the immune response by CSC-specific antigens, including cell-surface targets. Cancer immunotherapies are based on triggering the anti-tumor immune response by specific activation and targeted redirecting of immune cells toward tumor cells. This review is focused on CSC-directed immunotherapeutic approaches such as bispecific antibodies and antibody-drug candidates, CSC-targeted cellular immunotherapies, and immune-based vaccines. We discuss the strategies to improve the safety and efficacy of the different immunotherapeutic approaches and describe the current state of their clinical development. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Targeted Therapy)
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26 pages, 7936 KiB  
Article
A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis
by Jiaqin Chen, Dong Feng, Yuanyuan Lu, Yanjun Zhang, Hanxiang Jiang, Man Yuan, Yifan Xu, Jianjun Zou, Yubing Zhu, Jingjing Zhang, Chun Ge and Ying Wang
Cancers 2023, 15(5), 1607; https://doi.org/10.3390/cancers15051607 - 5 Mar 2023
Viewed by 1383
Abstract
Background: CPUL1, a phenazine analog, has demonstrated potent antitumor properties against hepatocellular carcinoma (HCC) and indicates a promising prospect in pharmaceutical development. However, the underlying mechanisms remain largely obscure. Methods: Multiple HCC cell lines were used to investigate the in vitro effects of [...] Read more.
Background: CPUL1, a phenazine analog, has demonstrated potent antitumor properties against hepatocellular carcinoma (HCC) and indicates a promising prospect in pharmaceutical development. However, the underlying mechanisms remain largely obscure. Methods: Multiple HCC cell lines were used to investigate the in vitro effects of CPUL1. The antineoplastic properties of CPUL1 were assessed in vivo by establishing a xenograft nude mice model. After that, metabolomics, transcriptomics, and bioinformatics were integrated to elucidate the mechanisms underlying the therapeutic efficacy of CPUL1, highlighting an unanticipated involvement of autophagy dysregulation. Results: CPUL1 suppressed HCC cell proliferation in vitro and in vivo, thereby endorsing the potential as a leading agent for HCC therapy. Integrative omics characterized a deteriorating scenario of metabolic debilitation with CPUL1, presenting an issue in the autophagy contribution of autophagy. Subsequent observations indicated that CPUL1 treatment could impede autophagic flow by suppressing autophagosome degradation rather than its formation, which supposedly exacerbated cellular damage triggered by metabolic impairment. Moreover, the observed late autophagosome degradation may be attributed to lysosome dysfunction, which is essential for the final stage of autophagy and cargo disposal. Conclusions: Our study comprehensively profiled the anti-hepatoma characteristics and molecular mechanisms of CPUL1, highlighting the implications of progressive metabolic failure. This could partially be ascribed to autophagy blockage, which supposedly conveyed nutritional deprivation and intensified cellular vulnerability to stress. Full article
(This article belongs to the Section Cancer Drug Development)
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14 pages, 1570 KiB  
Article
A Propensity-Matched Retrospective Comparative Study with Historical Control to Determine the Real-World Effectiveness of Durvalumab after Concurrent Chemoradiotherapy in Unresectable Stage III Non-Small Cell Lung Cancer
by Cheol-Kyu Park, Nakyung Jeon, Hwa-Kyung Park, Hyung-Joo Oh, Young-Chul Kim, Ha-Lim Jeon, Yong-Hyub Kim, Sung-Ja Ahn and In-Jae Oh
Cancers 2023, 15(5), 1606; https://doi.org/10.3390/cancers15051606 - 5 Mar 2023
Cited by 3 | Viewed by 2023
Abstract
This study aimed to add real-world evidence to the literature regarding the effectiveness and safety of durvalumab consolidation (DC) after concurrent chemoradiotherapy (CCRT) in the treatment of unresectable stage III non-small cell lung cancer (NSCLC). Using a hospital-based NSCLC patient registry and propensity [...] Read more.
This study aimed to add real-world evidence to the literature regarding the effectiveness and safety of durvalumab consolidation (DC) after concurrent chemoradiotherapy (CCRT) in the treatment of unresectable stage III non-small cell lung cancer (NSCLC). Using a hospital-based NSCLC patient registry and propensity score matching in a 2:1 ratio, we conducted a retrospective cohort study of patients with unresectable stage III NSCLC who completed CCRT with and without DC. The co-primary endpoints were 2-year progression-free survival and overall survival. For the safety evaluation, we evaluated the risk of any adverse events requiring systemic antibiotics or steroids. Of 386 eligible patients, 222 patients—including 74 in the DC group—were included in the analysis after propensity score matching. Compared with CCRT alone, CCRT with DC was associated with increased progression-free survival (median: 13.3 vs. 7.6 months, hazard ratio[HR]: 0.63, 95% confidence interval[CI]: 0.42–0.96) and overall survival (HR: 0.47, 95% CI: 0.27–0.82) without an increased risk of adverse events requiring systemic antibiotics or steroids. While there were differences in patient characteristics between the present real-world study and the pivotal randomized controlled trial, we demonstrated significant survival benefits and tolerable safety with DC after the completion of CCRT. Full article
(This article belongs to the Special Issue New Era of Cancer Research: From Large-Scale Cohorts to Big-Data)
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14 pages, 1581 KiB  
Article
Lenalidomide Maintenance and Measurable Residual Disease in a Real-World Multiple Myeloma Transplanted Population Receiving Different Treatment Strategies Guided by Access to Novel Drugs in Brazil
by Anna Beatriz dos Santos Salgado, Roberto Jose Pessoa Magalhães, Robéria M. Pontes, Eduarda da Silva Barbosa, Juan Flores-Montero, Luzalba Sanoja-Flores, Marcelo Gerardin Poirot Land, Glicinia Pimenta, Hélio dos Santos Dutra, Elaine S. Costa, Alberto Orfao and Angelo Maiolino
Cancers 2023, 15(5), 1605; https://doi.org/10.3390/cancers15051605 - 4 Mar 2023
Viewed by 2033
Abstract
Despite recent advances in multiple myeloma (MM), the incorporation of novel agents and measurable residual disease (MRD) monitoring in low-income countries remains a challenge. Although lenalidomide maintenance (M-Len) after autologous stem cell transplantation (ASCT) has been associated with improved outcomes and MRD has [...] Read more.
Despite recent advances in multiple myeloma (MM), the incorporation of novel agents and measurable residual disease (MRD) monitoring in low-income countries remains a challenge. Although lenalidomide maintenance (M-Len) after autologous stem cell transplantation (ASCT) has been associated with improved outcomes and MRD has refined the prognosis of complete response (CR) cases, until now, there have been no data on the benefits of these approaches in Latin America. Here, we evaluate the benefits of M-Len and MRD using next-generation flow cytometry (NGF-MRD) at Day + 100 post-ASCT (n = 53). After ASCT, responses were evaluated based on the International Myeloma Working Group criteria and NGF-MRD. MRD was positive in 60% of patients with a median progression-free survival (PFS) of 31 months vs. not reached (NR) for MRD-negative cases (p = 0.05). The patients who received M-Len continuously had a significantly better PFS and overall survival (OS) than those without M-Len (median PFS: NR vs. 29 months, p = 0.007), with progression in 11% vs. 54% of cases after a median follow-up of 34 months, respectively. In a multivariate analysis, MRD status and M-Len therapy emerged as independent predictors of PFS (median PFS of M-Len/MRD vs. no M-Len/MRD+ of NR vs. 35 months, respectively; p = 0.01). In summary, M-Len was associated with improved survival outcomes in our real-world MM cohort in Brazil, with MRD emerging as a useful reproducible tool to identify patients at an earlier risk of relapse. The inequity in drug access remains a hurdle in countries with financial constraints, with a negative impact on MM survival. Full article
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13 pages, 882 KiB  
Article
Association between Age at Helicobacter pylori Eradication and the Risk of Gastric Cancer Stratified by Family History of Gastric Cancer: A Nationwide Population-Based Study
by Yoon Suk Jung, Mai Thi Xuan Tran, Huiyeon Song, Boyoung Park and Chang Mo Moon
Cancers 2023, 15(5), 1604; https://doi.org/10.3390/cancers15051604 - 4 Mar 2023
Cited by 1 | Viewed by 2236
Abstract
Introduction: This study compares the risk of GC according to age at H. pylori eradication, stratified based on the presence of family history of GC using a population-based large cohort. Method: We analyzed individuals who underwent GC screening between 2013 and 2014 and [...] Read more.
Introduction: This study compares the risk of GC according to age at H. pylori eradication, stratified based on the presence of family history of GC using a population-based large cohort. Method: We analyzed individuals who underwent GC screening between 2013 and 2014 and received H. pylori eradication therapy before screening. Results: Among 1,888,815 H. pylori-treated patients, 2610/294,706 and 9332/1,594,109 patients with and without a family history of GC, respectively, developed GC. After adjusting for confounders, including age at screening, the adjusted hazard ratios (95% confidence intervals) for GC comparison, 70–74, 65–69, 60–64, 55–59, 50–54, 45–49, and <45 years with ≥75 years at H. pylori eradication were 0.98 (0.79–1.21), 0.88 (0.74–1.05), 0.76 (0.59–0.99), 0.62 (0.44–0.88), 0.57 (0.36–0.90), 0.38 (0.22–0.66), and 0.34 (0.17–0.67), respectively, among patients with a family history of GC (p < 0.001) and 1.01 (0.91–1.13), 0.95 (0.86–1.04), 0.86 (0.75–0.98), 0.67 (0.56–0.81), 0.56 (0.44–0.71), 0.51 (0.38–0.68), and 0.33 (0.23–0.47), respectively, among patients without a family history of GC (p < 0.001). Conclusion: In patients with and without a family history of GC, young age at H. pylori eradication was significantly associated with a reduced risk of GC, suggesting that the early treatment of H. pylori infection can maximize GC prevention. Full article
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17 pages, 1978 KiB  
Article
The Change in Social Eating over Time in People with Head and Neck Cancer Treated with Primary (Chemo)Radiotherapy: The Role of Swallowing, Oral Function, and Nutritional Status
by Aurora Ninfa, Femke Jansen, Antonella Delle Fave, Birgit I. Lissenberg-Witte, Nicole Pizzorni, Robert J. Baatenburg de Jong, Femke Lamers, C. René Leemans, Robert P. Takes, Christianus H. J. Terhaard, Antonio Schindler and Irma M. Verdonck-de Leeuw
Cancers 2023, 15(5), 1603; https://doi.org/10.3390/cancers15051603 - 4 Mar 2023
Viewed by 1643
Abstract
This study aimed at investigating the change in social eating problems from diagnosis to 24 months after primary (chemo)radiotherapy and its associations with swallowing, oral function, and nutritional status, in addition to the clinical, personal, physical, psychological, social, and lifestyle dimensions. Adult patients [...] Read more.
This study aimed at investigating the change in social eating problems from diagnosis to 24 months after primary (chemo)radiotherapy and its associations with swallowing, oral function, and nutritional status, in addition to the clinical, personal, physical, psychological, social, and lifestyle dimensions. Adult patients from the NETherlands QUality of life and BIomedical Cohort (NET-QUBIC) treated with curative intent with primary (chemo)radiotherapy for newly-diagnosed HNC and who provided baseline social eating data were included. Social eating problems were measured at baseline and at 3-, 6-, 12-, and 24-month follow-up, with hypothesized associated variables at baseline and at 6 months. Associations were analyzed through linear mixed models. Included patients were 361 (male: 281 (77.8%), age: mean = 63.3, SD = 8.6). Social eating problems increased at the 3-month follow-up and decreased up to 24 months (F = 33.134, p < 0.001). The baseline-to-24 month change in social eating problems was associated with baseline swallowing-related quality of life (F = 9.906, p < 0.001) and symptoms (F = 4.173, p = 0.002), nutritional status (F = 4.692, p = 0.001), tumor site (F = 2.724, p = 0.001), age (F = 3.627, p = 0.006), and depressive symptoms (F = 5.914, p < 0.001). The 6–24-month change in social eating problems was associated with a 6-month nutritional status (F = 6.089, p = 0.002), age (F = 5.727, p = 0.004), muscle strength (F = 5.218, p = 0.006), and hearing problems (F = 5.155, p = 0.006). Results suggest monitoring social eating problems until 12-month follow-up and basing interventions on patients’ features. Full article
(This article belongs to the Special Issue Cancer and Nutrients)
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19 pages, 1327 KiB  
Systematic Review
Tissue vs. Fecal-Derived Bacterial Dysbiosis in Precancerous Colorectal Lesions: A Systematic Review
by Jurate Valciukiene, Kestutis Strupas and Tomas Poskus
Cancers 2023, 15(5), 1602; https://doi.org/10.3390/cancers15051602 - 4 Mar 2023
Cited by 3 | Viewed by 1574
Abstract
Alterations in gut microbiota play a pivotal role in the adenoma-carcinoma sequence. However, there is still a notable lack of the correct implementation of tissue and fecal sampling in the setting of human gut microbiota examination. This study aimed to review the literature [...] Read more.
Alterations in gut microbiota play a pivotal role in the adenoma-carcinoma sequence. However, there is still a notable lack of the correct implementation of tissue and fecal sampling in the setting of human gut microbiota examination. This study aimed to review the literature and to consolidate the current evidence on the use of mucosa and a stool-based matrix investigating human gut microbiota changes in precancerous colorectal lesions. A systematic review of papers from 2012 until November 2022 published on the PubMed and Web of Science databases was conducted. The majority of the included studies have significantly associated gut microbial dysbiosis with premalignant polyps in the colorectum. Although methodological differences hampered the precise fecal and tissue-derived dysbiosis comparison, the analysis revealed several common characteristics in stool-based and fecal-derived gut microbiota structures in patients with colorectal polyps: simple or advanced adenomas, serrated lesions, and carcinomas in situ. The mucosal samples considered were more relevant for the evaluation of microbiota’s pathophysiological involvement in CR carcinogenesis, while non-invasive stool sampling could be beneficial for early CRC detection strategies in the future. Further studies are required to identify and validate mucosa-associated and luminal colorectal microbial patterns and their role in CRC carcinogenesis, as well as in the clinical setting of human microbiota studies. Full article
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11 pages, 538 KiB  
Article
A Biterm Topic Model for Sparse Mutation Data
by Itay Sason, Yuexi Chen, Mark D. M. Leiserson and Roded Sharan
Cancers 2023, 15(5), 1601; https://doi.org/10.3390/cancers15051601 - 4 Mar 2023
Viewed by 1358
Abstract
Mutational signature analysis promises to reveal the processes that shape cancer genomes for applications in diagnosis and therapy. However, most current methods are geared toward rich mutation data that has been extracted from whole-genome or whole-exome sequencing. Methods that process sparse mutation data [...] Read more.
Mutational signature analysis promises to reveal the processes that shape cancer genomes for applications in diagnosis and therapy. However, most current methods are geared toward rich mutation data that has been extracted from whole-genome or whole-exome sequencing. Methods that process sparse mutation data typically found in practice are only in the earliest stages of development. In particular, we previously developed the Mix model that clusters samples to handle data sparsity. However, the Mix model had two hyper-parameters, including the number of signatures and the number of clusters, that were very costly to learn. Therefore, we devised a new method that was several orders-of-magnitude more efficient for handling sparse data, was based on mutation co-occurrences, and imitated word co-occurrence analyses of Twitter texts. We showed that the model produced significantly improved hyper-parameter estimates that led to higher likelihoods of discovering overlooked data and had better correspondence with known signatures. Full article
(This article belongs to the Special Issue Computational Studies of Mutagenic Processes in Cancer)
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