Cancers

13 pages, 1189 KiB

Open AccessEditor’s ChoiceArticle

Validation of Inflammatory Prognostic Biomarkers in Pleural Mesothelioma

by Stephanie Iser, Sarah Hintermair, Alexander Varga, Ali Çelik, Muhammet Sayan, Aykut Kankoç, Nalan Akyürek, Betül Öğüt, Pietro Bertoglio, Enrico Capozzi, Piergiorgio Solli, Luigi Ventura, David Waller, Michael Weber, Elisabeth Stubenberger and Bahil Ghanim

Cancers 2024, 16(1), 93; https://doi.org/10.3390/cancers16010093 - 24 Dec 2023

Viewed by 1363

Abstract

Evoked from asbestos-induced inflammation, pleural mesothelioma represents a fatal diagnosis. Therapy ranges from nihilism to aggressive multimodality regimens. However, it is still unclear who ultimately benefits from which treatment. We aimed to re-challenge inflammatory-related biomarkers’ prognostic value in times of modern immune-oncology and [...] Read more.

Evoked from asbestos-induced inflammation, pleural mesothelioma represents a fatal diagnosis. Therapy ranges from nihilism to aggressive multimodality regimens. However, it is still unclear who ultimately benefits from which treatment. We aimed to re-challenge inflammatory-related biomarkers’ prognostic value in times of modern immune-oncology and lung-sparing surgery. The biomarkers (leukocytes, hemoglobin, platelets, neutrophils, lymphocytes, monocytes, neutrophil–lymphocyte ratio (NLR), lymphocyte–monocyte ratio (LMR), platelet–lymphocyte ratio (PLR), C-reactive protein (CRP)) and clinical characteristics (age, sex, histology, therapy) of 98 PM patients were correlated to overall survival (OS). The median OS was 19.4 months. Significant OS advantages (Log-Rank) were observed in multimodal treatment vs. others (26.1 vs. 7.2 months, p < 0.001), surgery (pleurectomy/decortication) vs. no surgery (25.5 vs. 3.8 months, p < 0.001), a high hemoglobin level (cut-off 12 g/dL, 15 vs. 24.2 months, p = 0.021), a low platelet count (cut-off 280 G/L, 26.1 vs. 11.7 months, p < 0.001), and a low PLR (cut-off 194.5, 25.5 vs. 12.3 months, p = 0.023). Histology (epithelioid vs. non-epithelioid, p = 0.002), surgery (p = 0.004), CRP (cut-off 1 mg/dL, p = 0.039), and platelets (p = 0.025) were identified as independent prognostic variables for this cohort in multivariate analysis (Cox regression, covariates: age, sex, histology, stage, CRP, platelets). Our data verified the previously shown prognostic role of systemic inflammatory parameters in patients treated with lung-sparing surgery within multimodality therapy. Full article

(This article belongs to the Special Issue Recent Research on Mesothelioma)

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33 pages, 1918 KiB

Open AccessEditor’s ChoiceReview

Promises and Pitfalls of Next-Generation Treg Adoptive Immunotherapy

by Panayiota Christofi, Chrysoula Pantazi, Nikoleta Psatha, Ioanna Sakellari, Evangelia Yannaki and Anastasia Papadopoulou

Cancers 2023, 15(24), 5877; https://doi.org/10.3390/cancers15245877 - 17 Dec 2023

Cited by 1 | Viewed by 1487

Abstract

Regulatory T cells (Tregs) are fundamental to maintaining immune homeostasis by inhibiting immune responses to self-antigens and preventing the excessive activation of the immune system. Their functions extend beyond immune surveillance and subpopulations of tissue-resident Treg cells can also facilitate tissue repair and [...] Read more.

Regulatory T cells (Tregs) are fundamental to maintaining immune homeostasis by inhibiting immune responses to self-antigens and preventing the excessive activation of the immune system. Their functions extend beyond immune surveillance and subpopulations of tissue-resident Treg cells can also facilitate tissue repair and homeostasis. The unique ability to regulate aberrant immune responses has generated the concept of harnessing Tregs as a new cellular immunotherapy approach for reshaping undesired immune reactions in autoimmune diseases and allo-responses in transplantation to ultimately re-establish tolerance. However, a number of issues limit the broad clinical applicability of Treg adoptive immunotherapy, including the lack of antigen specificity, heterogeneity within the Treg population, poor persistence, functional Treg impairment in disease states, and in vivo plasticity that results in the loss of suppressive function. Although the early-phase clinical trials of Treg cell therapy have shown the feasibility and tolerability of the approach in several conditions, its efficacy has remained questionable. Leveraging the smart tools and platforms that have been successfully developed for primary T cell engineering in cancer, the field has now shifted towards “next-generation” adoptive Treg immunotherapy, where genetically modified Treg products with improved characteristics are being generated, as regards antigen specificity, function, persistence, and immunogenicity. Here, we review the state of the art on Treg adoptive immunotherapy and progress beyond it, while critically evaluating the hurdles and opportunities towards the materialization of Tregs as a living drug therapy for various inflammation states and the broad clinical translation of Treg therapeutics. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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20 pages, 1599 KiB

Open AccessEditor’s ChoiceReview

Human Intestinal Organoids and Microphysiological Systems for Modeling Radiotoxicity and Assessing Radioprotective Agents

by Eloïse Bouges, Charlotte Segers, Natalie Leys, Sarah Lebeer, Jianbo Zhang and Felice Mastroleo

Cancers 2023, 15(24), 5859; https://doi.org/10.3390/cancers15245859 - 15 Dec 2023

Cited by 1 | Viewed by 1419

Abstract

Radiotherapy is a commonly employed treatment for colorectal cancer, yet its radiotoxicity-related impact on healthy tissues raises significant health concerns. This highlights the need to use radioprotective agents to mitigate these side effects. This review presents the current landscape of human translational radiobiology, [...] Read more.

Radiotherapy is a commonly employed treatment for colorectal cancer, yet its radiotoxicity-related impact on healthy tissues raises significant health concerns. This highlights the need to use radioprotective agents to mitigate these side effects. This review presents the current landscape of human translational radiobiology, outlining the limitations of existing models and proposing engineering solutions. We delve into radiotherapy principles, encompassing mechanisms of radiation-induced cell death and its influence on normal and cancerous colorectal cells. Furthermore, we explore the engineering aspects of microphysiological systems to represent radiotherapy-induced gastrointestinal toxicity and how to include the gut microbiota to study its role in treatment failure and success. This review ultimately highlights the main challenges and future pathways in translational research for pelvic radiotherapy-induced toxicity. This is achieved by developing a humanized in vitro model that mimics radiotherapy treatment conditions. An in vitro model should provide in-depth analyses of host-gut microbiota interactions and a deeper understanding of the underlying biological mechanisms of radioprotective food supplements. Additionally, it would be of great value if these models could produce high-throughput data using patient-derived samples to address the lack of human representability to complete clinical trials and improve patients’ quality of life. Full article

(This article belongs to the Section Methods and Technologies Development)

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22 pages, 563 KiB

Open AccessEditor’s ChoiceReview

Challenges and Future Directions in the Management of Tumor Mutational Burden-High (TMB-H) Advanced Solid Malignancies

by Jibran Ahmed, Biswajit Das, Sarah Shin and Alice Chen

Cancers 2023, 15(24), 5841; https://doi.org/10.3390/cancers15245841 - 14 Dec 2023

Viewed by 1048

Abstract

A standardized assessment of Tumor Mutational Burden (TMB) poses challenges across diverse tumor histologies, treatment modalities, and testing platforms, requiring careful consideration to ensure consistency and reproducibility. Despite clinical trials demonstrating favorable responses to immune checkpoint inhibitors (ICIs), not all patients with elevated [...] Read more.

A standardized assessment of Tumor Mutational Burden (TMB) poses challenges across diverse tumor histologies, treatment modalities, and testing platforms, requiring careful consideration to ensure consistency and reproducibility. Despite clinical trials demonstrating favorable responses to immune checkpoint inhibitors (ICIs), not all patients with elevated TMB exhibit benefits, and certain tumors with a normal TMB may respond to ICIs. Therefore, a comprehensive understanding of the intricate interplay between TMB and the tumor microenvironment, as well as genomic features, is crucial to refine its predictive value. Bioinformatics advancements hold potential to improve the precision and cost-effectiveness of TMB assessments, addressing existing challenges. Similarly, integrating TMB with other biomarkers and employing comprehensive, multiomics approaches could further enhance its predictive value. Ongoing collaborative endeavors in research, standardization, and clinical validation are pivotal in harnessing the full potential of TMB as a biomarker in the clinic settings. Full article

(This article belongs to the Special Issue Tissue Agnostic Drug Development in Cancer)

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19 pages, 5749 KiB

Open AccessEditor’s ChoiceArticle

Generation of a Zebrafish Knock-In Model Recapitulating Childhood ETV6::RUNX1-Positive B-Cell Precursor Acute Lymphoblastic Leukemia

by Veronika Zapilko, Sanni Moisio, Mataleena Parikka, Merja Heinäniemi and Olli Lohi

Cancers 2023, 15(24), 5821; https://doi.org/10.3390/cancers15245821 - 13 Dec 2023

Viewed by 1533

Abstract

Approximately 25% of children with B-cell precursor acute lymphoblastic leukemia (pB-ALL) harbor the t(12;21)(p13;q22) translocation, leading to the ETV6::RUNX1 (E::R) fusion gene. This translocation occurs in utero, but the disease is much less common than the prevalence of the fusion in newborns, suggesting [...] Read more.

Approximately 25% of children with B-cell precursor acute lymphoblastic leukemia (pB-ALL) harbor the t(12;21)(p13;q22) translocation, leading to the ETV6::RUNX1 (E::R) fusion gene. This translocation occurs in utero, but the disease is much less common than the prevalence of the fusion in newborns, suggesting that secondary mutations are required for overt leukemia. The role of these secondary mutations remains unclear and may contribute to treatment resistance and disease recurrence. We developed a zebrafish model for E::R leukemia using CRISPR/Cas9 to introduce the human RUNX1 gene into zebrafish etv6 intron 5, resulting in E::R fusion gene expression controlled by the endogenous etv6 promoter. As seen by GFP fluorescence at a single-cell level, the model correctly expressed the fusion protein in the right places in zebrafish embryos. The E::R fusion expression induced an expansion of the progenitor cell pool and led to a low 2% frequency of leukemia. The introduction of targeted pax5 and cdkn2a/b gene mutations, mimicking secondary mutations, in the E::R line significantly increased the incidence in leukemia. Transcriptomics revealed that the E::R;pax5mut leukemias exclusively represented B-lineage disease. This novel E::R zebrafish model faithfully recapitulates human disease and offers a valuable tool for a more detailed analysis of disease biology in this subtype. Full article

(This article belongs to the Topic Animal Model in Biomedical Research, 2nd Volume)

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18 pages, 1560 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Targeting of Glioblastoma and the Interactions with Its Microenvironment

by Vassilis Genoud, Ben Kinnersley, Nicholas F. Brown, Diego Ottaviani and Paul Mulholland

Cancers 2023, 15(24), 5790; https://doi.org/10.3390/cancers15245790 - 10 Dec 2023

Cited by 1 | Viewed by 1262

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumour, and it confers a dismal prognosis despite intensive multimodal treatments. Whilst historically, research has focussed on the evolution of GBM tumour cells themselves, there is growing recognition of the importance of studying the [...] Read more.

Glioblastoma (GBM) is the most common primary malignant brain tumour, and it confers a dismal prognosis despite intensive multimodal treatments. Whilst historically, research has focussed on the evolution of GBM tumour cells themselves, there is growing recognition of the importance of studying the tumour microenvironment (TME). Improved characterisation of the interaction between GBM cells and the TME has led to a better understanding of therapeutic resistance and the identification of potential targets to block these escape mechanisms. This review describes the network of cells within the TME and proposes treatment strategies for simultaneously targeting GBM cells, the surrounding immune cells, and the crosstalk between them. Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

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18 pages, 1106 KiB

Open AccessEditor’s ChoiceReview

The Prospect of Harnessing the Microbiome to Improve Immunotherapeutic Response in Pancreatic Cancer

by Sherise Rogers, Angel Charles and Ryan M. Thomas

Cancers 2023, 15(24), 5708; https://doi.org/10.3390/cancers15245708 - 05 Dec 2023

Viewed by 1268

Abstract

Pancreatic ductal adenocarcinoma cancer (PDAC) is projected to become the second leading cause of cancer-related death in the United States by 2030. Patients are often diagnosed with advanced disease, which explains the dismal 5-year median overall survival rate of ~12%. Immunotherapy has been [...] Read more.

Pancreatic ductal adenocarcinoma cancer (PDAC) is projected to become the second leading cause of cancer-related death in the United States by 2030. Patients are often diagnosed with advanced disease, which explains the dismal 5-year median overall survival rate of ~12%. Immunotherapy has been successful in improving outcomes in the past decade for a variety of malignancies, including gastrointestinal cancers. However, PDAC is historically an immunologically “cold” tumor, one with an immunosuppressive environment and with restricted entry of immune cells that have limited the success of immunotherapy in these tumors. The microbiome, the intricate community of microorganisms present on and within humans, has been shown to contribute to many cancers, including PDAC. Recently, its role in tumor immunology and response to immunotherapy has generated much interest. Herein, the current state of the interaction of the microbiome and immunotherapy in PDAC is discussed with a focus on needed areas of study in order to harness the immune system to combat pancreatic cancer. Full article

(This article belongs to the Special Issue Microbiome-Based Interventions in Cancer Immunotherapy)

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22 pages, 7073 KiB

Open AccessEditor’s ChoiceArticle

Nuclear Glycoprotein A Repetitions Predominant (GARP) Is a Common Trait of Glioblastoma Stem-like Cells and Correlates with Poor Survival in Glioblastoma Patients

by Niklas Zimmer, Emily R. Trzeciak, Andreas Müller, Philipp Licht, Bettina Sprang, Petra Leukel, Volker Mailänder, Clemens Sommer, Florian Ringel, Jochen Tuettenberg, Ella Kim and Andrea Tuettenberg

Cancers 2023, 15(24), 5711; https://doi.org/10.3390/cancers15245711 - 05 Dec 2023

Viewed by 1034

Abstract

Glioblastoma (GB) is notoriously resistant to therapy. GB genesis and progression are driven by glioblastoma stem-like cells (GSCs). One goal for improving treatment efficacy and patient outcomes is targeting GSCs. Currently, there are no universal markers for GSCs. Glycoprotein A repetitions predominant (GARP), [...] Read more.

Glioblastoma (GB) is notoriously resistant to therapy. GB genesis and progression are driven by glioblastoma stem-like cells (GSCs). One goal for improving treatment efficacy and patient outcomes is targeting GSCs. Currently, there are no universal markers for GSCs. Glycoprotein A repetitions predominant (GARP), an anti-inflammatory protein expressed by activated regulatory T cells, was identified as a possible marker for GSCs. This study evaluated GARP for the detection of human GSCs utilizing a multidimensional experimental design that replicated several features of GB: (1) intratumoral heterogeneity, (2) cellular hierarchy (GSCs with varied degrees of self-renewal and differentiation), and (3) longitudinal GSC evolution during GB recurrence (GSCs from patient-matched newly diagnosed and recurrent GB). Our results indicate that GARP is expressed by GSCs across various cellular states and disease stages. GSCs with an increased GARP expression had reduced self-renewal but no alterations in proliferative capacity or differentiation commitment. Rather, GARP correlated inversely with the expression of GFAP and PDGFR-α, markers of astrocyte or oligodendrocyte differentiation. GARP had an abnormal nuclear localization (GARP^NU+) in GSCs and was negatively associated with patient survival. The uniformity of GARP/GARP^NU+ expression across different types of GSCs suggests a potential use of GARP as a marker to identify GSCs. Full article

(This article belongs to the Special Issue Targeting Human Glioblastoma Stem-Like Cells (GSCs))

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16 pages, 1190 KiB

Open AccessEditor’s ChoiceArticle

Increased Plasmatic Levels of Exosomes Are Significantly Related to Relapse Rate in Patients with Oral Squamous Cell Carcinoma: A Cohort Study

by Samuel Rodríguez-Zorrilla, Alejandro I. Lorenzo-Pouso, Stefano Fais, Maria A. Logozzi, Davide Mizzoni, Rossella Di Raimo, Alessandro Giuliani, Abel García-García, Alba Pérez-Jardón, Karem L. Ortega, Ángel Martínez-González and Mario Pérez-Sayáns

Cancers 2023, 15(23), 5693; https://doi.org/10.3390/cancers15235693 - 02 Dec 2023

Cited by 1 | Viewed by 988

Abstract

Background: Oral squamous cell carcinoma (OSCC) is characterized by an immunosuppressive tumor microenvironment. Their plasma-derived exosomes deliver immunomodulatory molecules and cargo that correlate significantly with clinical parameters. This study aims to assess the exosomal profile as a potential tool for early detection of [...] Read more.

Background: Oral squamous cell carcinoma (OSCC) is characterized by an immunosuppressive tumor microenvironment. Their plasma-derived exosomes deliver immunomodulatory molecules and cargo that correlate significantly with clinical parameters. This study aims to assess the exosomal profile as a potential tool for early detection of relapse and long-term outcomes in OSCC patients undergoing conventional therapy. Methods: 27 OSCC patients with a median 38-month follow-up were included in this study. The relationship between NTA-derived parameters and clinical pathological parameters was examined, and receiver operating characteristic (ROC) curves were utilized to evaluate the diagnostic efficacy of these values in detecting cancer relapse. Results: Plasmatic levels of exosomes prior to surgery showed a drastic reduction after surgical intervention (8.08E vs. 1.41 × 10⁹ particles/mL, p = 0.006). Postsurgical concentrations of exosomes were higher in patients who experienced relapse compared to those who remained disease-free (2.97 × 10⁹ vs. 1.11 × 10⁹ particles/mL, p = 0.046). Additionally, patients who relapsed exhibited larger exosome sizes after surgery (141.47 vs. 132.31 nm, p = 0.03). Patients with lower concentrations of exosomes prior to surgery demonstrated better disease-free survival compared to those with higher levels (p = 0.012). ROC analysis revealed an area under the curve of 0.82 for presurgical exosome concentration in identifying relapse. Conclusions: Presurgical exosomal plasmatic levels serve as independent predictors of early recurrence and survival in OSCC. All in all, our findings indicate that the detection of peripheral exosomes represents a novel tool for the clinical management of OSCC, with potential implications for prognosis assessment. Full article

(This article belongs to the Special Issue Current and Emerging Utility of Liquid Biopsy in Cancers. More than Surrogate Biomarkers)

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22 pages, 11501 KiB

Open AccessEditor’s ChoiceArticle

Radiation-Induced Innate Neutrophil Response in Tumor Is Mediated by the CXCLs/CXCR2 Axis

by Faya Zhang, Oscar Mulvaney, Erica Salcedo, Subrata Manna, James Z. Zhu, Tao Wang, Chul Ahn, Laurentiu M. Pop and Raquibul Hannan

Cancers 2023, 15(23), 5686; https://doi.org/10.3390/cancers15235686 - 01 Dec 2023

Viewed by 1234

Abstract

The early events that lead to the inflammatory and immune-modulatory effects of radiation therapy (RT) in the tumor microenvironment (TME) after its DNA damage response activating the innate DNA-sensing pathways are largely unknown. Neutrophilic infiltration into the TME in response to RT is [...] Read more.

The early events that lead to the inflammatory and immune-modulatory effects of radiation therapy (RT) in the tumor microenvironment (TME) after its DNA damage response activating the innate DNA-sensing pathways are largely unknown. Neutrophilic infiltration into the TME in response to RT is an early innate inflammatory response that occurs within 24–48 h. Using two different syngeneic murine tumor models (RM-9 and MC-38), we demonstrated that CXCR2 blockade significantly reduced RT-induced neutrophilic infiltration. CXCR2 blockade showed the same effects on RT-induced tumor inhibition and host survival as direct neutrophil depletion. Neutrophils highly and preferentially expressed CXCR2 compared to other immune cells. Importantly, RT induced both gene and protein expression of CXCLs in the TME within 24 h, attracting neutrophils into the tumor. Expectedly, RT also upregulated the gene expression of both cGAS and AIM2 DNA-sensing pathways in cGAS-positive MC-38 tumors but not in cGAS-negative RM-9 tumors. Activation of these pathways resulted in increased IL-1β, which is known to activate the CXCLs/CXCR2 axis. Gene ontology analysis of mRNA-Seq supported these findings. Taken together, the findings suggest that the CXCLs/CXCR2 axis mediates the RT-induced innate inflammatory response in the TME, likely translating the effects of innate DNA-sensing pathways that are activated in response to RT-induced DNA damage. Full article

(This article belongs to the Topic Inflammatory Tumor Immune Microenvironment)

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20 pages, 2725 KiB

Open AccessEditor’s ChoiceReview

Targeting Proteasomes and the MHC Class I Antigen Presentation Machinery to Treat Cancer, Infections and Age-Related Diseases

by Priyanka S. Rana, James J. Ignatz-Hoover and James J. Driscoll

Cancers 2023, 15(23), 5632; https://doi.org/10.3390/cancers15235632 - 29 Nov 2023

Viewed by 1447

Abstract

The majority of T-cell responses involve proteasome-dependent protein degradation and the downstream presentation of oligopeptide products complexed with major histocompatibility complex (MHC) class I (MHC-I) molecules to peptide-restricted CD8⁺ T-cells. However, evasion of host immunity is a cancer hallmark that is achieved [...] Read more.

The majority of T-cell responses involve proteasome-dependent protein degradation and the downstream presentation of oligopeptide products complexed with major histocompatibility complex (MHC) class I (MHC-I) molecules to peptide-restricted CD8⁺ T-cells. However, evasion of host immunity is a cancer hallmark that is achieved by disruption of host antigen processing and presentation machinery (APM). Consequently, mechanisms of immune evasion promote cancer growth and survival as well as de novo and acquired resistance to immunotherapy. A multitude of cell signaling pathways modulate the APM and MHC-I-dependent antigen presentation. Pharmacologics that specifically target and modulate proteasome structure and activity represent a novel emerging strategy to improve the treatment of cancers and other diseases characterized by aberrant protein accumulation. FDA-approved pharmacologics that selectively activate proteasomes and/or immunoproteasomes can be repositioned to overcome the current bottlenecks that hinder drug development to enhance antigen presentation, modulate the immunopeptidome, and enhance the cytotoxic activity of endogenous or engineered T-cells. Strategies to enhance antigen presentation may also improve the antitumor activity of T-cell immunotherapies, checkpoint inhibitors, and cancer vaccines. Proteasomes represent actionable therapeutic targets to treat difficult-to-treat infectious processes and neurodegenerative diseases that are characterized by the unwanted accrual of insoluble, deleterious, and potentially toxic proteins. Taken together, we highlight the breadth and magnitude of the proteasome and the immense potential to amplify and unmask the immunopeptidomic landscape to improve the treatment of a spectrum of human diseases. Full article

(This article belongs to the Special Issue Inflammation, Immunity, and Cancer Progression)

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14 pages, 6258 KiB

Open AccessEditor’s ChoiceArticle

Development of MDS in Pediatric Patients with GATA2 Deficiency: Increased Histone Trimethylation and Deregulated Apoptosis as Potential Drivers of Transformation

by Franziska Schreiber, Guido Piontek, Yuki Schneider-Kimoto, Stephan Schwarz-Furlan, Rita De Vito, Franco Locatelli, Carole Gengler, Ayami Yoshimi, Andreas Jung, Frederick Klauschen, Charlotte M. Niemeyer, Miriam Erlacher and Martina Rudelius

Cancers 2023, 15(23), 5594; https://doi.org/10.3390/cancers15235594 - 26 Nov 2023

Viewed by 1066

Abstract

GATA2 deficiency is a heterogeneous, multisystem disorder associated with a high risk of developing myelodysplastic syndrome (MDS) and the progression to acute myeloid leukemia. The mechanisms underlying malignant transformation in GATA2 deficiency remain poorly understood, necessitating predictive markers to assess an individual’s risk [...] Read more.

GATA2 deficiency is a heterogeneous, multisystem disorder associated with a high risk of developing myelodysplastic syndrome (MDS) and the progression to acute myeloid leukemia. The mechanisms underlying malignant transformation in GATA2 deficiency remain poorly understood, necessitating predictive markers to assess an individual’s risk of progression and guide therapeutic decisions. In this study, we performed a systematic analysis of bone marrow biopsies from 57 pediatric MDS patients. Focusing on hematopoiesis and the hematopoietic niche, including its microenvironment, we used multiplex immunofluorescence combined with multispectral imaging, gene expression profiling, and multiplex RNA in situ hybridization. Patients with a GATA2 deficiency exhibited a dysregulated GATA2 transcriptional network. Disease progression (GATA2-EB, n = 6) was associated with increased GATA2 mRNA levels, restored expression of the GATA2 target EZH2, and increased H3K27me3. GATA2-EB was further characterized by the high expression of the anti-apoptotic protein BCL2, a feature absent in children with a GATA2 deficiency and refractory cytopenia of childhood (GATA2-RCC, n = 24) or other pediatric MDS subgroups (RCC, n = 17; MDS-EB, n = 10). The multispectral imaging analysis of additional BCL2 family members revealed significantly elevated Mediators of Apoptosis Combinatorial (MAC) scores in GATA2-EB patients. Taken together, our findings highlight the potential drivers of disease progression in GATA2 deficiency, particularly increased histone trimethylation and dysregulated apoptosis. Furthermore, upregulated BCL2 and EZH2 and increased MAC scores provide a strong rationale for the use of venetoclax and azacitidine in therapeutic regimens for GATA2-EB. Full article

(This article belongs to the Special Issue Recent Advances in Myelodysplastic Syndromes: Diagnosis, Prognosis and Clinical Therapy)

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13 pages, 1544 KiB

Open AccessEditor’s ChoiceReview

Melanin—The Éminence Grise of Melanoma and Parkinson’s Disease Development

by Danuta Krasowska, Agata Małek, Joanna Kurzepa, Lucyna Kapka-Skrzypczak, Dorota Krasowska and Jacek Kurzepa

Cancers 2023, 15(23), 5541; https://doi.org/10.3390/cancers15235541 - 23 Nov 2023

Viewed by 975

Abstract

A common feature of Parkinson’s disease (PD) and melanoma is their starting points being based on cells capable of converting tyrosine into melanin. Melanocytes produce two types of melanin: eumelanin and pheomelanin. These dyes are designed to protect epidermal cells from the harmful [...] Read more.

A common feature of Parkinson’s disease (PD) and melanoma is their starting points being based on cells capable of converting tyrosine into melanin. Melanocytes produce two types of melanin: eumelanin and pheomelanin. These dyes are designed to protect epidermal cells from the harmful effects of UV radiation. Neurones of the substantia nigra, which degenerate during PD, produce neuromelanin, the physiological role of which is not fully explained. This article discusses the potential role of melanins in the pathogenesis of both diseases. Melanins, due to their ability to accumulate toxic substances, may become their sources over time. The use of glutathione for the synthesis of pheomelanins and neuromelanins may reduce the antioxidant capacity of cells, leading to an excessive synthesis of free radicals. This study also tested the hypothesis that certain drugs used in the treatment of PD (L-DOPA, MAO-B and COMT inhibitors, and amantadine), aimed at increasing dopamine concentration, could potentially contribute to the development of melanoma. The role and properties of melanins should continue to be researched. Whether excessive melanin synthesis or its accumulation in the extracellular space may be factors initiating the development of diseases remains an open question. Full article

(This article belongs to the Special Issue Mechanisms of Melanoma Progression)

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20 pages, 7360 KiB

Open AccessEditor’s ChoiceArticle

Chimeric Antigen Receptor T Cell Therapy Targeting Epithelial Cell Adhesion Molecule in Gastric Cancer: Mechanisms of Tumor Resistance

by Yanping Yang, Raymond Louie, Janusz Puc, Yogindra Vedvyas, Yago Alcaina, Irene M. Min, Matt Britz, Fabio Luciani and Moonsoo M. Jin

Cancers 2023, 15(23), 5552; https://doi.org/10.3390/cancers15235552 - 23 Nov 2023

Cited by 1 | Viewed by 1152

Abstract

Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen that is frequently overexpressed in various carcinomas. We have developed chimeric antigen receptor (CAR) T cells specifically targeting EpCAM for the treatment of gastric cancer. This study sought to unravel the precise mechanisms by [...] Read more.

Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen that is frequently overexpressed in various carcinomas. We have developed chimeric antigen receptor (CAR) T cells specifically targeting EpCAM for the treatment of gastric cancer. This study sought to unravel the precise mechanisms by which tumors evade immune surveillance and develop resistance to CAR T cell therapy. Through a combination of whole-body CAR T cell imaging and single-cell multiomic analyses, we uncovered intricate interactions between tumors and tumor-infiltrating lymphocytes (TILs). In a gastric cancer model, tumor-infiltrating CD8 T cells exhibited both cytotoxic and exhausted phenotypes, while CD4 T cells were mainly regulatory T cells. A T cell receptor (TCR) clonal analysis provided evidence of CAR T cell proliferation and clonal expansion within resistant tumors, which was substantiated by whole-body CAR T cell imaging. Furthermore, single-cell transcriptomics showed that tumor cells in mice with refractory or relapsing outcomes were enriched for genes involved in major histocompatibility complex (MHC) and antigen presentation pathways, interferon-γ and interferon-α responses, mitochondrial activities, and a set of genes (e.g., CD74, IDO1, IFI27) linked to tumor progression and unfavorable disease prognoses. This research highlights an approach that combines imaging and multiomic methodologies to concurrently characterize the evolution of tumors and the differentiation of CAR T cells. Full article

(This article belongs to the Special Issue Antigens in Cancer)

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15 pages, 1894 KiB

Open AccessEditor’s ChoiceArticle

CX3CR1-Expressing Immune Cells Infiltrate the Tumor Microenvironment and Promote Radiation Resistance in a Mouse Model of Lung Cancer

by Tamar Ben-Mordechai, Yaacov R. Lawrence, Zvi Symon, Ariel Shimoni-Sebag and Uri Amit

Cancers 2023, 15(22), 5472; https://doi.org/10.3390/cancers15225472 - 19 Nov 2023

Viewed by 1314

Abstract

Introduction: Chemokine (C-X3-C Motif) Receptor 1 (CX3CR1) is present in a subset of the immune cells in the tumor microenvironment (TME) and plays an essential and diverse role in cancer progression. However, its potential function in the irradiated TME remains unknown. Materials and [...] Read more.

Introduction: Chemokine (C-X3-C Motif) Receptor 1 (CX3CR1) is present in a subset of the immune cells in the tumor microenvironment (TME) and plays an essential and diverse role in cancer progression. However, its potential function in the irradiated TME remains unknown. Materials and Methods: A mouse lung cancer model was performed by subcutaneously inoculating Lewis Lung Carcinoma (LLC) cells expressing luciferase (Luc-2) and mCherry cells in CX3CR1^GFP/GFP, CX3CR1^DTR/+, and wild–type (WT) mice. Bioluminescence imaging, clonogenic assay, and flow cytometry were used to assess tumor progression, proliferation, and cell composition after radiation. Results: Radiation provoked a significant influx of CX3CR1-expressing immune cells, notably monocytes and macrophages, into the TME. Co-culturing irradiated LLC cells with CX3CR1-deficient monocytes, and macrophages resulted in reduced clonogenic survival and increased apoptosis of the cancer cells. Interestingly, deficiency of CX3CR1 in macrophages led to a redistribution of the irradiated LLC cells in the S-phase, parallel to increased expression of cyclin E1, required for cell cycle G1/S transition. In addition, the deficiency of CX3CR1 expression in macrophages altered the cytokine secretion with a decrease in interleukin 6, a crucial mediator of cancer cell survival and proliferation. Next, LLC cells were injected subcutaneously into CX3CR1^DTR/+ mice, sensitive to diphtheria toxin (DT), and WT mice. After injection, tumors were irradiated with 8 Gy, and mice were treated with DT, leading to conditional ablation of CX3CR1-expressing cells. After three weeks, CX3CR1-depleted mice displayed reduced tumor progression. Furthermore, combining the S-phase-specific chemotherapeutic gemcitabine with CX3CR1 cell ablation resulted in additional attenuation of tumor progression. Conclusions: CX3CR1-expressing mononuclear cells invade the TME after radiation therapy in a mouse lung cancer model. CX3CR1 cell depletion attenuates tumor progression following radiation and sensitizes the tumor to S–phase-specific chemotherapy. Thus, we propose a novel strategy to improve radiation sensitivity by targeting the CX3CR1-expressing immune cells. Full article

(This article belongs to the Topic The Tumor Microenvironment, Immuno-Oncology, and Immune Checkpoint: Implications for Current and Emergent Immunotherapies, 2nd Edition)

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13 pages, 1805 KiB

Open AccessEditor’s ChoiceArticle

Real-World Outcomes of Immunotherapy in Second- or Later-Line Non-Small Cell Lung Cancer with Actionable Genetic Alterations

by Soojin Jun, Sehhoon Park, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn, Juhee Cho and Hyun Ae Jung

Cancers 2023, 15(22), 5450; https://doi.org/10.3390/cancers15225450 - 16 Nov 2023

Cited by 1 | Viewed by 1050

Abstract

Introduction: While the efficacy of immune checkpoint inhibitors (ICIs) in treating non-small cell lung cancer (NSCLC) patients with actionable genetic alterations (AGAs) is modest, certain patients demonstrate improved survival. Thus, this study aimed to evaluate the benefits of ICIs in NSCLC patients with [...] Read more.

Introduction: While the efficacy of immune checkpoint inhibitors (ICIs) in treating non-small cell lung cancer (NSCLC) patients with actionable genetic alterations (AGAs) is modest, certain patients demonstrate improved survival. Thus, this study aimed to evaluate the benefits of ICIs in NSCLC patients with diverse AGAs and verify the predictive biomarkers of ICI efficacy. Methods: From January 2018 to July 2022, this study compared the progression-free survival (PFS) of NSCLC patients with different AGAs treated with ICI monotherapy as second- or later-line therapy at Samsung Medical Center. To ascertain the predictors of ICIs efficacy, we adjusted ICIs’ effects on PFS in terms of clinical and molecular biomarkers. Results: EGFR (46.0%) was the most prevalent mutation in 324 patients. In multivariate analysis, PD-L1 positivity (tumor proportion score (TPS) ≥ 1%) (HR = 0.41) and the use of steroids for immune-related adverse events (HR = 0.46) were positive factors for ICI therapy in the AGAs group. Co-existing mutation of STK11 with KRAS mutation (HR = 4.53) and TP53 with MET mutation (HR = 9.78) was negatively associated with survival. Conclusions: The efficacy of ICI treatment varied across AGA subtypes, but patients with KRAS, MET, and BRAF mutations demonstrated relatively long-duration benefits of ICI therapy. PD-L1 was a significant positive predictive biomarker in all AGA groups. Full article

(This article belongs to the Special Issue Precision Immuno-Oncology in NSCLC)

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11 pages, 1576 KiB

Open AccessEditor’s ChoiceArticle

Primary Tumor Resection in Synchronous Metastatic Colorectal Cancer Patients Treated with Upfront Chemotherapy plus Bevacizumab: A Pooled Analysis of TRIBE and TRIBE2 Studies

by Valentina Fanotto, Daniele Rossini, Mariaelena Casagrande, Francesca Bergamo, Andrea Spagnoletti, Daniele Santini, Carlotta Antoniotti, Samanta Cupini, Francesca Daniel, Vincenzo Nasca, Guglielmo Vetere, Alberto Zaniboni, Beatrice Borelli, Martina Carullo, Veronica Conca, Alessandro Passardi, Emiliano Tamburini, Gianluca Masi, Nicoletta Pella and Chiara Cremolini

Cancers 2023, 15(22), 5451; https://doi.org/10.3390/cancers15225451 - 16 Nov 2023

Viewed by 979

Abstract

Background: The decision to resect or not the primary tumor in asymptomatic patients with synchronous metastatic colorectal cancer (mCRC) is a complex and challenging issue for oncologists, especially when an antiangiogenic-based therapy is planned. Methods: Patients enrolled in the phase III TRIBE and [...] Read more.

Background: The decision to resect or not the primary tumor in asymptomatic patients with synchronous metastatic colorectal cancer (mCRC) is a complex and challenging issue for oncologists, especially when an antiangiogenic-based therapy is planned. Methods: Patients enrolled in the phase III TRIBE and TRIBE2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively, were included. We assessed the association of primary tumor resection (PTR) with progression-free survival (PFS), overall survival (OS), response rate (ORR), rate of grade > 2 adverse events (AEs), and serious gastrointestinal and surgical AEs in the overall population and according to the treatment arm. Results: Of the 999 patients included, 513 (51%) underwent PTR at baseline. Longer PFS and OS were observed in resected patients compared to those with unresected primary tumors: 11.2 vs. 10.0 months (p < 0.001) and 26.6 vs. 22.5 (p < 0.001), respectively. In multivariate models, PTR was confirmed as an independent prognostic factor for better PFS (p = 0.032) and OS (p = 0.018). Patients with PTR experienced a higher incidence of grade 3 or 4 diarrhea (p = 0.055) and lower incidence of anemia (p = 0.053), perforation (p = 0.015), and serious gastrointestinal and surgical AEs (p < 0.001). No statistically significant differences were noted in incidence of bleeding (p = 0.39). The benefit of FOLFOXIRI + bevacizumab in terms of PFS (p for interaction: 0.46), OS (p for interaction: 0.80), ORR (p for interaction: 0.36), and incidence of grade 3 or 4 AEs was independent of PTR. Conclusions: PTR at baseline was independently associated with good prognosis in synchronous mCRC patients and with lower incidence of serious gastrointestinal and surgical AEs during upfront chemotherapy plus bevacizumab. The benefit and toxicity profile of FOLFOXIRI plus bevacizumab was independent of PTR. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer 2.0)

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15 pages, 1433 KiB

Open AccessEditor’s ChoiceArticle

Population-Based External Validation of the EASIX Scores to Predict CAR T-Cell-Related Toxicities

by Janneke W. de Boer, Kylie Keijzer, Elise R. A. Pennings, Jaap A. van Doesum, Anne M. Spanjaart, Margot Jak, Pim G. N. J. Mutsaers, Suzanne van Dorp, Joost S. P. Vermaat, Marjolein W. M. van der Poel, Lisanne V. van Dijk, Marie José Kersten, Anne G. H. Niezink and Tom van Meerten

Cancers 2023, 15(22), 5443; https://doi.org/10.3390/cancers15225443 - 16 Nov 2023

Viewed by 1117

Abstract

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index [...] Read more.

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61–0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment. Full article

(This article belongs to the Special Issue CAR T Cell Therapy for Cancers)

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15 pages, 1056 KiB

Open AccessEditor’s ChoiceArticle

Time Trends in the Treatment and Survival of 5036 Uveal Melanoma Patients in The Netherlands over a 30-Year Period

by Thaïs M. L. Tong, Esther Bastiaannet, Frank M. Speetjens, Christian U. Blank, Gregorius P. M. Luyten, Martine J. Jager, Marina Marinkovic, T. H. Khanh Vu, Coen R. N. Rasch, Carien L. Creutzberg, Jan-Willem M. Beenakker, Henk H. Hartgrink, Jacobus J. J. Bosch, Emine Kiliç, Nicole C. Naus, Serdar Yavuzyigitoglu, Caroline M. van Rij, Mark C. Burgmans and Ellen H. W. Kapiteijn

Cancers 2023, 15(22), 5419; https://doi.org/10.3390/cancers15225419 - 15 Nov 2023

Cited by 1 | Viewed by 818

Abstract

Background: Uveal melanoma (UM) is a rare intraocular tumor with a dismal prognosis once metastasized. This study provides a nationwide overview and time trends of patients diagnosed with primary UM in the Netherlands between 1989 and 2019. Methods: A retrospective population-based cohort study [...] Read more.

Background: Uveal melanoma (UM) is a rare intraocular tumor with a dismal prognosis once metastasized. This study provides a nationwide overview and time trends of patients diagnosed with primary UM in the Netherlands between 1989 and 2019. Methods: A retrospective population-based cohort study based on patients with primary UM from the database of the Netherlands Cancer Registry (NCR), linked with the national population registry Statistics Netherlands on inhabitants’ cause of death. Two time periods (1989–2004, 2005–2019) were compared with descriptive statistics. Kaplan–Meier and (multivariate) Cox proportional hazard models were used to assess changes over time for overall survival (OS) and cancer-specific survival (CSS). Results: In total, 5036 patients were analyzed with a median age of 64.0 years at the time of diagnosis. The number of patients increased over time. In the first (1989–2004) and second (2005–2019) period, 32% versus 54% of the patients received radiotherapy (p < 0.001). The median FU time was 13.4 years. The median OS of the first and second periods was 9.5 (95% CI 8.7–10.3) versus 11.3 years (95% CI 10.3–12.3; p < 0.001). The median CSS was 30.0 years (95% CI NA) in the first period and not reached in the second period (p = 0.008). In multivariate analysis (MVA), female gender (HR 0.85; 95% CI 0.79–0.92, p < 0.001) and radiotherapy treatment (HR 0.73; 95% CI 0.64–0.83, p < 0.001) were associated with better OS. Radiotherapy treatment (HR 0.74; 95% CI 0.61–0.90, p = 0.002) was also associated with better CSS. The period of diagnosis was not associated with OS or CSS. Conclusions: In this study of patients with primary UM, there was a shift to the diagnosis of smaller tumors, possibly due to stage migration. There was also an increase in eye-preserving treatments over time. OS and CSS were modestly improved in the second time period; however, the time period was not associated with OS or CSS in multivariate analyses. Full article

(This article belongs to the Special Issue Uveal Melanoma Biology, Biomarkers for Metastatic Risk and Personalized Treatment)

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34 pages, 1963 KiB

Open AccessEditor’s ChoiceSystematic Review

A Systematic Review and Critical Assessment of Breast Cancer Risk Prediction Tools Incorporating a Polygenic Risk Score for the General Population

by Cynthia Mbuya-Bienge, Nora Pashayan, Cornelia D. Kazemali, Julie Lapointe, Jacques Simard and Hermann Nabi

Cancers 2023, 15(22), 5380; https://doi.org/10.3390/cancers15225380 - 12 Nov 2023

Cited by 1 | Viewed by 1363

Abstract

Single nucleotide polymorphisms (SNPs) in the form of a polygenic risk score (PRS) have emerged as a promising factor that could improve the predictive performance of breast cancer (BC) risk prediction tools. This study aims to appraise and critically assess the current evidence [...] Read more.

Single nucleotide polymorphisms (SNPs) in the form of a polygenic risk score (PRS) have emerged as a promising factor that could improve the predictive performance of breast cancer (BC) risk prediction tools. This study aims to appraise and critically assess the current evidence on these tools. Studies were identified using Medline, EMBASE and the Cochrane Library up to November 2022 and were included if they described the development and/ or validation of a BC risk prediction model using a PRS for women of the general population and if they reported a measure of predictive performance. We identified 37 articles, of which 29 combined genetic and non-genetic risk factors using seven different risk prediction tools. Most models (55.0%) were developed on populations from European ancestry and performed better than those developed on populations from other ancestry groups. Regardless of the number of SNPs in each PRS, models combining a PRS with genetic and non-genetic risk factors generally had better discriminatory accuracy (AUC from 0.52 to 0.77) than those using a PRS alone (AUC from 0.48 to 0.68). The overall risk of bias was considered low in most studies. BC risk prediction tools combining a PRS with genetic and non-genetic risk factors provided better discriminative accuracy than either used alone. Further studies are needed to cross-compare their clinical utility and readiness for implementation in public health practices. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

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21 pages, 11726 KiB

Open AccessEditor’s ChoiceReview

Hepatocellular Carcinoma: Surveillance, Diagnosis, Evaluation and Management

by Jessica Elderkin, Najeeb Al Hallak, Asfar S. Azmi, Hussein Aoun, Jeffrey Critchfield, Miguel Tobon and Eliza W. Beal

Cancers 2023, 15(21), 5118; https://doi.org/10.3390/cancers15215118 - 24 Oct 2023

Cited by 2 | Viewed by 1712

Abstract

Hepatocellular carcinoma (HCC) ranks fourth in cancer-related deaths worldwide. Semiannual surveillance of the disease for patients with cirrhosis or hepatitis B virus allows for early detection with more favorable outcomes. The current underuse of surveillance programs demonstrates the need for intervention at both [...] Read more.

Hepatocellular carcinoma (HCC) ranks fourth in cancer-related deaths worldwide. Semiannual surveillance of the disease for patients with cirrhosis or hepatitis B virus allows for early detection with more favorable outcomes. The current underuse of surveillance programs demonstrates the need for intervention at both the patient and provider level. Mail outreach along with navigation provision has proven to increase surveillance follow-up in patients, while provider-targeted electronic medical record reminders and compliance reports have increased provider awareness of HCC surveillance. Imaging is the primary mode of diagnosis in HCC with The Liver Imaging Reporting and Data System (LI-RADS) being a widely accepted comprehensive system that standardizes the reporting and data collection for HCC. The management of HCC is complex and requires multidisciplinary team evaluation of each patient based on their preference, the state of the disease, and the available medical and surgical interventions. Staging systems are useful in determining the appropriate intervention for HCC. Early-stage HCC is best managed by curative treatment modalities, such as liver resection, transplant, or ablation. For intermediate stages of the disease, transarterial local regional therapies can be applied. Advanced stages of the disease are treated with systemic therapies, for which there have been recent advances with new drug combinations. Previously sorafenib was the mainstay systemic treatment, but the recent introduction of atezolizumab plus bevacizumab proves to have a greater impact on overall survival. Although there is a current lack of improved outcomes in Phase III trials, neoadjuvant therapies are a potential avenue for HCC management in the future. Full article

(This article belongs to the Special Issue Surgical Management of Gastrointestinal Cancers)

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16 pages, 318 KiB

Open AccessEditor’s ChoiceReview

The Role of Artificial Intelligence in Colorectal Cancer Screening: Lesion Detection and Lesion Characterization

by Edward Young, Louisa Edwards and Rajvinder Singh

Cancers 2023, 15(21), 5126; https://doi.org/10.3390/cancers15215126 - 24 Oct 2023

Cited by 4 | Viewed by 1209

Abstract

Colorectal cancer remains a leading cause of cancer-related morbidity and mortality worldwide, despite the widespread uptake of population surveillance strategies. This is in part due to the persistent development of ‘interval colorectal cancers’, where patients develop colorectal cancer despite appropriate surveillance intervals, implying [...] Read more.

Colorectal cancer remains a leading cause of cancer-related morbidity and mortality worldwide, despite the widespread uptake of population surveillance strategies. This is in part due to the persistent development of ‘interval colorectal cancers’, where patients develop colorectal cancer despite appropriate surveillance intervals, implying pre-malignant polyps were not resected at a prior colonoscopy. Multiple techniques have been developed to improve the sensitivity and accuracy of lesion detection and characterisation in an effort to improve the efficacy of colorectal cancer screening, thereby reducing the incidence of interval colorectal cancers. This article presents a comprehensive review of the transformative role of artificial intelligence (AI), which has recently emerged as one such solution for improving the quality of screening and surveillance colonoscopy. Firstly, AI-driven algorithms demonstrate remarkable potential in addressing the challenge of overlooked polyps, particularly polyp subtypes infamous for escaping human detection because of their inconspicuous appearance. Secondly, AI empowers gastroenterologists without exhaustive training in advanced mucosal imaging to characterise polyps with accuracy similar to that of expert interventionalists, reducing the dependence on pathologic evaluation and guiding appropriate resection techniques or referrals for more complex resections. AI in colonoscopy holds the potential to advance the detection and characterisation of polyps, addressing current limitations and improving patient outcomes. The integration of AI technologies into routine colonoscopy represents a promising step towards more effective colorectal cancer screening and prevention. Full article

(This article belongs to the Special Issue The Application of Endoscopy in Gastrointestinal Cancers)

16 pages, 2199 KiB

Open AccessEditor’s ChoiceArticle

A Phase II Study of Osimertinib in Patients with Advanced-Stage Non-Small Cell Lung Cancer following Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Therapy with EGFR and T790M Mutations Detected in Plasma Circulating Tumour DNA (PLASMA Study)

by Yvonne L. E. Ang, Xiaotian Zhao, Thanyanan Reungwetwattana, Byoung-Chul Cho, Bin-Chi Liao, Rebecca Yeung, Herbert H. Loong, Dong-Wan Kim, James Chih-Hsin Yang, Sun Min Lim, Myung-Ju Ahn, Se-Hoon Lee, Thitiporn Suwatanapongched, Kanchaporn Kongchauy, Qiuxiang Ou, Ruoying Yu, Bee Choo Tai, Boon Cher Goh, Tony S. K. Mok and Ross A. Soo

Cancers 2023, 15(20), 4999; https://doi.org/10.3390/cancers15204999 - 16 Oct 2023

Cited by 2 | Viewed by 1857

Abstract

Epidermal growth factor receptor (EGFR) T790M mutations drive resistance in 50% of patients with advanced non-small cell lung cancer (NSCLC) who progress on first/second generation (1G/2G) EGFR tyrosine kinase inhibitors (TKIs) and are sensitive to Osimertinib. Tissue sampling is the gold-standard [...] Read more.

Epidermal growth factor receptor (EGFR) T790M mutations drive resistance in 50% of patients with advanced non-small cell lung cancer (NSCLC) who progress on first/second generation (1G/2G) EGFR tyrosine kinase inhibitors (TKIs) and are sensitive to Osimertinib. Tissue sampling is the gold-standard modality of T790M testing, but it is invasive. We evaluated the efficacy of Osimertinib in patients with EGFR mutant NSCLC and T790M in circulating tumour DNA (ctDNA). PLASMA is a prospective, open-label, multicentre single-arm Phase II study. Patients with advanced NSCLC harbouring sensitizing EGFR and T790M mutations in plasma at progression from ≥one 1G/2G TKI were treated with 80 mg of Osimertinib daily until progression. The primary endpoint was the objective response rate (ORR); the secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and toxicities. Plasma next-generation sequencing was performed to determine Osimertinib resistance mechanisms and assess serial ctDNA. A total of 110 patients from eight centres in five countries were enrolled from 2017 to 2019. The median follow-up duration was 2.64 (IQR 2.44–3.12) years. The ORR was 50.9% (95% CI 41.2–60.6) and the DCR was 84.5% (95% CI 76.4–90.7). Median PFS was 7.4 (95% CI 6.0–9.3) months; median OS was 1.63 (95% CI 1.35–2.16) years. Of all of the patients, 76% had treatment-related adverse events (TRAEs), most commonly paronychia (22.7%); 11% experienced ≥ Grade 3 TRAEs. The ctDNA baseline load and dynamics were prognostic. Osimertinib is active in NSCLC harbouring sensitizing EGFR and T790M mutations in ctDNA testing post 1G/2G TKIs. Full article

(This article belongs to the Special Issue Liquid Biopsy for Lung Cancer Treatment)

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25 pages, 3586 KiB

Open AccessEditor’s ChoiceArticle

Serum Insights: Leveraging the Power of miRNA Profiling as an Early Diagnostic Tool for Non-Small Cell Lung Cancer

by Radoslaw Charkiewicz, Anetta Sulewska, Robert Mroz, Alicja Charkiewicz, Wojciech Naumnik, Marcin Kraska, Attila Gyenesei, Bence Galik, Sini Junttila, Borys Miskiewicz, Rafal Stec, Piotr Karabowicz, Magdalena Zawada, Wojciech Miltyk and Jacek Niklinski

Cancers 2023, 15(20), 4910; https://doi.org/10.3390/cancers15204910 - 10 Oct 2023

Cited by 2 | Viewed by 1088

Abstract

Non-small cell lung cancer is the predominant form of lung cancer and is associated with a poor prognosis. MiRNAs implicated in cancer initiation and progression can be easily detected in liquid biopsy samples and have the potential to serve as non-invasive biomarkers. In [...] Read more.

Non-small cell lung cancer is the predominant form of lung cancer and is associated with a poor prognosis. MiRNAs implicated in cancer initiation and progression can be easily detected in liquid biopsy samples and have the potential to serve as non-invasive biomarkers. In this study, we employed next-generation sequencing to globally profile miRNAs in serum samples from 71 early-stage NSCLC patients and 47 non-cancerous pulmonary condition patients. Preliminary analysis of differentially expressed miRNAs revealed 28 upregulated miRNAs in NSCLC compared to the control group. Functional enrichment analyses unveiled their involvement in NSCLC signaling pathways. Subsequently, we developed a gradient-boosting decision tree classifier based on 2588 miRNAs, which demonstrated high accuracy (0.837), sensitivity (0.806), and specificity (0.859) in effectively distinguishing NSCLC from non-cancerous individuals. Shapley Additive exPlanations analysis improved the model metrics by identifying the top 15 miRNAs with the strongest discriminatory value, yielding an AUC of 0.96 ± 0.04, accuracy of 0.896, sensitivity of 0.884, and specificity of 0.903. Our study establishes the potential utility of a non-invasive serum miRNA signature as a supportive tool for early detection of NSCLC while also shedding light on dysregulated miRNAs in NSCLC biology. For enhanced credibility and understanding, further validation in an independent cohort of patients is warranted. Full article

(This article belongs to the Section Cancer Biomarkers)

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21 pages, 2132 KiB

Open AccessEditor’s ChoiceArticle

Enhancing Healthcare for Sarcoma Patients: Lessons from a Diagnostic Pathway Efficiency Analysis

by Maria Elyes, Philip Heesen, Georg Schelling, Beata Bode-Lesniewska, Gabriela Studer and Bruno Fuchs

Cancers 2023, 15(19), 4892; https://doi.org/10.3390/cancers15194892 - 09 Oct 2023

Cited by 1 | Viewed by 844

Abstract

Sarcomas, rare and with lower survival rates than common tumors, offer insights into healthcare efficiency via the analysis of the total interval of the diagnostic pathway, combining the patient interval (time between the first symptom and visit with a physician) and diagnostic interval [...] Read more.

Sarcomas, rare and with lower survival rates than common tumors, offer insights into healthcare efficiency via the analysis of the total interval of the diagnostic pathway, combining the patient interval (time between the first symptom and visit with a physician) and diagnostic interval (time between first physician visit and histological diagnosis). Switzerland’s healthcare system, Europe’s costliest, lacks research on treating rare conditions, like mesenchymal tumors. This study examines the total interval of the diagnostic pathway for optimization strategies. Analyzing a dataset of 1028 patients presented from 2018 to 2021 to the Swiss Sarcoma Board (MDT/SB-SSN), this retrospective analysis delves into bone sarcoma (BS), soft-tissue sarcoma (STS), and their benign counterparts. Demographic and treatment data were extracted from medical records. The patient interval accounted for the largest proportion of the total interval and secondary care interval for the largest proportion of the diagnostic interval. Age, grade, and localization could be elicited as influencing factors of the length of different components of the total interval. An increasing age and tumor size, as well as the axial localization, could be elicited as factors increasing the probability of sarcoma. The patient and secondary care interval (SCI) offer the greatest potential for optimization, with SCI being the bottleneck of the diagnostic interval. New organizational structures for care work-ups are needed, such as integrated practice units (IPU) as integral part of value-based healthcare (VBHC). Full article

(This article belongs to the Special Issue Global Management of Sarcoma Data: Is Real-Time Predictive Analytics on the Horizon?)

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14 pages, 281 KiB

Open AccessEditor’s ChoiceReview

The Gut Microbiome as a Biomarker and Therapeutic Target in Hepatocellular Carcinoma

by Betul Gok Yavuz, Saumil Datar, Shadi Chamseddine, Yehia I. Mohamed, Michael LaPelusa, Sunyoung S. Lee, Zishuo Ian Hu, Eugene J. Koay, Hop S. Tran Cao, Prasun Kumar Jalal, Carrie Daniel-MacDougall, Manal Hassan, Dan G. Duda, Hesham M. Amin and Ahmed O. Kaseb

Cancers 2023, 15(19), 4875; https://doi.org/10.3390/cancers15194875 - 07 Oct 2023

Viewed by 1591

Abstract

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut [...] Read more.

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, it could be used as a predictive biomarker. In this review, we will dissect the gut microbiome’s role as a potential predictive and diagnostic marker in HCC and evaluate the latest progress in leveraging the gut microbiome as a novel therapeutic avenue for HCC patients, with a special emphasis on immunotherapy. Full article

(This article belongs to the Section Cancer Biomarkers)

15 pages, 17662 KiB

Open AccessEditor’s ChoiceArticle

Molecular Characterization of Primary Mediastinal Large B-Cell Lymphomas

by Marie Donzel, Florian Pesce, Alexis Trecourt, Razika Groussel, Emmanuel Bachy, Hervé Ghesquières, Juliette Fontaine, Nazim Benzerdjeb, Claire Mauduit and Alexandra Traverse-Glehen

Cancers 2023, 15(19), 4866; https://doi.org/10.3390/cancers15194866 - 06 Oct 2023

Cited by 2 | Viewed by 1352

Abstract

Since the description of primary mediastinal large B-cell lymphoma (PMBL) as a distinct entity from diffuse large B-cell lymphomas (DLBCL), numerous studies have made it possible to improve their definition. Despite this, this differential diagnosis can be challenging in daily practice. However, in [...] Read more.

Since the description of primary mediastinal large B-cell lymphoma (PMBL) as a distinct entity from diffuse large B-cell lymphomas (DLBCL), numerous studies have made it possible to improve their definition. Despite this, this differential diagnosis can be challenging in daily practice. However, in some centers, PMBL may be treated according to a particular regimen, distinct from those used in DLBCL, emphasizing the importance of accurate identification at diagnosis. This study aimed to describe the histological and molecular characteristics of PMBL to improve the accuracy of their diagnosis. Forty-nine cases of PMBL were retrospectively retrieved. The mean age at diagnosis was 39 years (21–83), with a sex ratio of 0.88. All cases presented a fibrous background with diffuse growth of intermediate to large cells with an eosinophil (26/49, 53%) or retracted cytoplasm (23/49, 47%). “Hodgkin-like” cells were observed in 65% of cases (32/49, 65%). The phenotype was: BCL6+ (47/49, 96%), MUM1+ (40/49, 82%), CD30+ (43/49, 88%), and CD23+ (37/49, 75%). Genomic DNAs were tested by next generation sequencing of 33 cases using a custom design panel. Pathogenic variants were found in all cases. The most frequent mutations were: SOCS1 (30/33, 91%), TNFAIP3 (18/33, 54.5%), ITPKB (17/33, 51.5%), GNA13 (16/33, 48.5%), CD58 (12/33, 36.4%), B2M (12/33; 36.4%), STAT6 (11/33, 33.3%) as well as ARID1A (10/33, 30.3%), XPO1 (9/33, 27.3%), CIITA (8/33, 24%), and NFKBIE (8/33, 24%). The present study describes a PMBL cohort on morphological, immunohistochemical, and molecular levels to provide pathologists with daily routine tools. These data also reinforce interest in an integrated histomolecular diagnosis to allow a precision diagnosis as early as possible. Full article

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12 pages, 707 KiB

Open AccessEditor’s ChoiceArticle

Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Lenvatinib following Immunotherapy: A Real World Evidence Study

by Mathias E. Palmer, Jennifer J. Gile, Michael H. Storandt, Zhaohui Jin, Tyler J. Zemla, Nguyen H. Tran and Amit Mahipal

Cancers 2023, 15(19), 4867; https://doi.org/10.3390/cancers15194867 - 06 Oct 2023

Viewed by 1305

Abstract

Background: Lenvatinib, a multikinase inhibitor, is an FDA-approved treatment for advanced hepatocellular carcinoma (HCC) in the first-line setting. Recent trial data have established atezolizumab plus bevacizumab as well as tremelimumab plus durvalumab as preferred first-line treatment options for advanced HCC. The role of [...] Read more.

Background: Lenvatinib, a multikinase inhibitor, is an FDA-approved treatment for advanced hepatocellular carcinoma (HCC) in the first-line setting. Recent trial data have established atezolizumab plus bevacizumab as well as tremelimumab plus durvalumab as preferred first-line treatment options for advanced HCC. The role of lenvatinib following progression on immunotherapy in patients with advanced HCC remains unclear. Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010 and 2021 at the Mayo Clinic in Minnesota, Arizona, and Florida who received immunotherapy followed by lenvatinib. Median overall survival and progression-free survival analyses were performed using the Kaplan–Meier method, and responses were determined using RECIST 1.1. Adverse events were determined using CTCAE v 4.0. Results: We identified 53 patients with advanced HCC who received lenvatinib following progression on immunotherapy. Forty five (85%) patients had a Child Pugh class A at diagnosis, while 30 (58%) patients were still Child Pugh A at time of lenvatinib initiation. Lenvatinib was administered as a second-line treatment in 85% of the patients. The median PFS was 3.7 months (95% CI: 3.2–6.6), and the median OS from the time of lenvatinib initiation was 12.8 months (95% CI: 6.7–19.5). In patients with Child Pugh class A, the median OS and PFS was 14 and 5.2 months, respectively. Race, gender, and Child Pugh class was associated with OS on multivariate analysis. Discussion: Our study, using real-world data, suggests that patients benefit from treatment with lenvatinib following progression on immunotherapy in advanced HCC. The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown, and these results need to be validated in a clinical trial. Full article

(This article belongs to the Special Issue Diagnosis and Treatment for Hepatocellular Tumors (Volume II))

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20 pages, 4962 KiB

Open AccessEditor’s ChoiceArticle

Combined Effect of Plasma-Activated Water and Topotecan in Glioblastoma Cells

by Beatriz Pinheiro Lopes, Liam O’Neill, Paula Bourke and Daniela Boehm

Cancers 2023, 15(19), 4858; https://doi.org/10.3390/cancers15194858 - 05 Oct 2023

Cited by 2 | Viewed by 944

Abstract

The increase in cancer diagnoses and cancer deaths, severe side effects of existing treatments and resistance to traditional treatments have generated a need for new anticancer treatments. Glioblastoma multiforme (GBM) is the most common, malignant and aggressive brain cancer. Despite many innovations regarding [...] Read more.

The increase in cancer diagnoses and cancer deaths, severe side effects of existing treatments and resistance to traditional treatments have generated a need for new anticancer treatments. Glioblastoma multiforme (GBM) is the most common, malignant and aggressive brain cancer. Despite many innovations regarding GBM treatment, the final outcome is still very poor, making it necessary to develop new therapeutic approaches. Cold atmospheric plasma (CAP) as well as plasma-activated liquids (PAL) are being studied as new possible approaches against cancer. The anticancer activity of PAL such as “plasma-activated water” (PAW) is dependent on the reactive chemical compounds present in the solution. Possible combinatory effects with conventional therapies, such as chemotherapeutics, may expand the potential of PAL for cancer treatment. We aim to explore the therapeutic properties of a combination of PAW and topotecan (TPT), an antineoplastic agent with major cytotoxic effects during the S phase of the cell cycle, on a GBM cancer cell line (U-251mg). Combined treatments with PAW and TPT showed a reduction in the metabolic activity and cell mass, an increase in apoptotic cell death and a reduction in the long-term survival. Single applications of PAW+TPT treatments showed a cytotoxic effect in the short term and an antiproliferative effect in the long term, warranting future exploration of combining PAW with chemotherapeutic agents as new therapeutic approaches. Full article

(This article belongs to the Special Issue Cold Plasma plus Concomitant and Adjuvant Therapies for Cancer Treatment)

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0 pages, 1030 KiB

Open AccessEditor’s ChoiceArticle

Early Salvage Chemo-Immunotherapy with Irinotecan, Temozolomide and Naxitamab Plus GM-CSF (HITS) for Patients with Primary Refractory High-Risk Neuroblastoma Provide the Best Chance for Long-Term Outcomes

by Juan Pablo Muñoz, Cristina Larrosa, Saray Chamorro, Sara Perez-Jaume, Margarida Simao, Nazaret Sanchez-Sierra, Amalia Varo, Maite Gorostegui, Alicia Castañeda, Moira Garraus, Sandra Lopez-Miralles and Jaume Mora

Cancers 2023, 15(19), 4837; https://doi.org/10.3390/cancers15194837 - 03 Oct 2023

Cited by 3 | Viewed by 1552

Abstract

Patients with high-risk neuroblastoma (HR-NB) who are unable to achieve a complete response (CR) to induction therapy have worse outcomes. We investigated the combination of humanized anti-GD2 mAb naxitamab (Hu3F8), irinotecan (I), temozolomide (T), and sargramostim (GM-CSF)—HITS—against primary resistant HR-NB. Eligibility criteria included [...] Read more.

Patients with high-risk neuroblastoma (HR-NB) who are unable to achieve a complete response (CR) to induction therapy have worse outcomes. We investigated the combination of humanized anti-GD2 mAb naxitamab (Hu3F8), irinotecan (I), temozolomide (T), and sargramostim (GM-CSF)—HITS—against primary resistant HR-NB. Eligibility criteria included having a measurable chemo-resistant disease at the end of induction (EOI) treatment. Patients were excluded if they had progressive disease (PD) during induction. Prior anti-GD2 mAb and/or I/T therapy was permitted. Each cycle, administered four weeks apart, comprised Irinotecan 50 mg/m²/day intravenously (IV) plus Temozolomide 150 mg/m²/day orally (days 1–5); naxitamab 2.25 mg/kg/day IV on days 2, 4, 8 and 10, (total 9 mg/kg or 270 mg/m² per cycle), and GM-CSF 250 mg/m²/day subcutaneously was used (days 6–10). Toxicity was measured using CTCAE v4.0 and responses through the modified International Neuroblastoma Response Criteria (INRC). Thirty-four patients (median age at treatment initiation, 4.9 years) received 164 (median 4; 1–12) HITS cycles. Toxicities included myelosuppression and diarrhea, which was expected with I/T, and pain and hypertension, expected with naxitamab. Grade ≥3-related toxicities occurred in 29 (85%) of the 34 patients; treatment was outpatient. The best responses were CR = 29% (n = 10); PR = 3% (n = 1); SD = 53% (n = 18); PD = 5% (n = 5). For cohort 1 (early treatment), the best responses were CR = 47% (n = 8) and SD = 53% (n = 9). In cohort 2 (late treatment), the best responses were CR = 12% (n = 2); PR = 6% (n = 1); SD = 53% (n = 9); and PD = 29% (n = 5). Cohort 1 had a 3-year OS of 84.8% and EFS 54.4%, which are statistically significant improvements (EFS p = 0.0041 and OS p = 0.0037) compared to cohort 2. In conclusion, naxitamab-based chemo-immunotherapy is effective against primary chemo-resistant HR-NB, increasing long-term outcomes when administered early during the course of treatment. Full article

(This article belongs to the Section Pediatric Oncology)

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13 pages, 2694 KiB

Open AccessEditor’s ChoiceReview

Pediatric Hepatocellular Adenomas: What Is Known and What Is New?

by Andres F. Espinoza, Sanjeev A. Vasudevan, Prakash M. Masand, Dolores H. Lòpez-Terrada and Kalyani R. Patel

Cancers 2023, 15(19), 4790; https://doi.org/10.3390/cancers15194790 - 29 Sep 2023

Cited by 1 | Viewed by 906

Abstract

Current understanding and classification of pediatric hepatocellular adenomas (HCA) are largely based on adult data. HCAs are rare in children and, unlike in adults, are often seen in the context of syndromes or abnormal background liver. Attempts to apply the adult classification to [...] Read more.

Current understanding and classification of pediatric hepatocellular adenomas (HCA) are largely based on adult data. HCAs are rare in children and, unlike in adults, are often seen in the context of syndromes or abnormal background liver. Attempts to apply the adult classification to pediatric tumors have led to several “unclassifiable” lesions. Although typically considered benign, few can show atypical features and those with beta-catenin mutations have a risk for malignant transformation. Small lesions can be monitored while larger (>5.0 cm) lesions are excised due to symptoms or risk of bleeding/rupture, etc. Management depends on gender, age, underlying liver disease, multifocality, size of lesion, histologic subtype and presence of mutation, if any. In this review, we summarize the data on pediatric HCAs and highlight our experience with their diagnosis and management. Full article

(This article belongs to the Special Issue Pediatric Liver Tumors (Hepatoblastoma and Hepatocellular Carcinoma))

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15 pages, 2057 KiB

Open AccessEditor’s ChoiceArticle

Immunotherapy-Related Oral Adverse Effects: Immediate Sequelae, Chronicity and Secondary Cancer

by Sharon Elad, Noam Yarom and Yehuda Zadik

Cancers 2023, 15(19), 4781; https://doi.org/10.3390/cancers15194781 - 28 Sep 2023

Cited by 1 | Viewed by 1243

Abstract

(1) Background: Immunotherapy-related adverse effects (irAEs) have been reported to manifest in oral tissues, mainly as lichenoid and non-lichenoid lesions and salivary gland dysfunction; however, the characterization of oral irAEs and their clinical impact is limited. (2) Methods: This is a retrospective clinical [...] Read more.

(1) Background: Immunotherapy-related adverse effects (irAEs) have been reported to manifest in oral tissues, mainly as lichenoid and non-lichenoid lesions and salivary gland dysfunction; however, the characterization of oral irAEs and their clinical impact is limited. (2) Methods: This is a retrospective clinical chart review of 14 patients with oral irAEs, describing the impact of the oral irAEs in terms of the immediate effect, treatment, chronicity of the irAEs and the development of oral cancer. (3) Results: Common symptoms were pain and dry mouth, causing no-to-severe pain and/or dry mouth sensation. The immediate sequala ranged from sensitivity to certain foods up to elimination of oral intake. Treatment included conventional palliation techniques with or without systemic steroids. Discontinuation of the immunotherapy agents was required in 6 patients. Innovative treatment modalities included photobiomodulation for oral mucosal pain relief, and salivary gland intraductal irrigations for relief of salivary gland hypofunction. Late sequala included the development of proliferative leukoplakia and oral cancer. (4) Conclusions: Patients treated with immunotherapy may develop debilitating oral irAEs. They should be followed for oral involvement so treatment may be initiated when the symptoms are mild to avoid discontinuation of the immunotherapy. Patients that develop oral lichenoid lesions should receive long-term follow-up, as they may have higher risk for oral cancer. Full article

(This article belongs to the Special Issue Supportive Care for Patients with Cancer)

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25 pages, 3422 KiB

Open AccessEditor’s ChoiceArticle

Optical Genome Mapping Reveals the Complex Genetic Landscape of Myeloma

by Amélie Giguère, Isabelle Raymond-Bouchard, Vanessa Collin, Jean-Sébastien Claveau, Josée Hébert and Richard LeBlanc

Cancers 2023, 15(19), 4687; https://doi.org/10.3390/cancers15194687 - 22 Sep 2023

Cited by 2 | Viewed by 1607

Abstract

Fluorescence in situ hybridization (FISH) on enriched CD138 plasma cells is the standard method for identification of clinically relevant genetic abnormalities in multiple myeloma. However, FISH is a targeted analysis that can be challenging due to the genetic complexity of myeloma. The aim [...] Read more.

Fluorescence in situ hybridization (FISH) on enriched CD138 plasma cells is the standard method for identification of clinically relevant genetic abnormalities in multiple myeloma. However, FISH is a targeted analysis that can be challenging due to the genetic complexity of myeloma. The aim of this study was to evaluate the potential of optical genome mapping (OGM) to detect clinically significant cytogenetic abnormalities in myeloma and to provide larger pangenomic information. OGM and FISH analyses were performed on CD138-purified cells of 20 myeloma patients. OGM successfully detected structural variants (SVs) (IGH and MYC rearrangements), copy number variants (CNVs) (17p/TP53 deletion, 1p deletion and 1q gain/amplification) and aneuploidy (gains of odd-numbered chromosomes, monosomy 13) classically expected with myeloma and led to a 30% increase in prognosis yield at our institution when compared to FISH. Despite challenges in the interpretation of OGM calls for CNV and aneuploidy losses in non-diploid genomes, OGM has the potential to replace FISH as the standard of care analysis in clinical settings and to efficiently change how we identify prognostic and predictive markers for therapies in the future. To our knowledge, this is the first study highlighting the feasibility and clinical utility of OGM in myeloma. Full article

(This article belongs to the Special Issue Optical Genome Mapping in Hematological Malignancies)

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13 pages, 1057 KiB

Open AccessEditor’s ChoiceArticle

Blinatumomab and Inotuzumab Ozogamicin Sequential Use for the Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia: A Real-Life Campus All Study

by Nicola Stefano Fracchiolla, Mariarita Sciumè, Cristina Papayannidis, Antonella Vitale, Sabina Chiaretti, Mario Annunziata, Fabio Giglio, Prassede Salutari, Fabio Forghieri, Davide Lazzarotto, Monia Lunghi, Annalisa Imovilli, Barbara Scappini, Massimiliano Bonifacio, Michelina Dargenio, Carmela Gurrieri, Elisabetta Todisco, Marzia Defina, Maria Ilaria Del Principe, Patrizia Zappasodi, Marco Cerrano, Lidia Santoro, Elena Tagliaferri, Enrico Barozzi, Pasquale De Roberto, Marta Canzi, Elisa Buzzatti, Chiara Sartor, Francesco Passamonti, Robin Foà and Antonio Curti Show full author list Hide full author list

Cancers 2023, 15(18), 4623; https://doi.org/10.3390/cancers15184623 - 19 Sep 2023

Cited by 1 | Viewed by 1434

Abstract

Background: Blinatumomab (Blina) and inotuzumab ozogamicin (InO) has improved the outcome of relapsed/refractory B-lymphoblastic leukemia (R/R B-ALL). However, little is known about the outcome after recurrence and re-treatment with immunotherapy. Methods: We describe 71 R/R B-ALL patients treated for different relapses with Blina [...] Read more.

Background: Blinatumomab (Blina) and inotuzumab ozogamicin (InO) has improved the outcome of relapsed/refractory B-lymphoblastic leukemia (R/R B-ALL). However, little is known about the outcome after recurrence and re-treatment with immunotherapy. Methods: We describe 71 R/R B-ALL patients treated for different relapses with Blina and InO. Blina was the first treatment in 57 patients and InO in 14. Twenty-seven patients had a previous allogeneic hematopoietic stem cell transplantation (allo-HSCT). Results: In the Blina/InO group, after Blina, 36 patients (63%) achieved a complete remission (CR), with 42% of negative minimal residual disease (MRD−); after InO, a CR was achieved in 47 patients (82%, 34 MRD−). In the InO/Blina group, after InO, 13 cases (93%) reached a CR (6 MRD−); after Blina, a CR was re-achieved in 6 cases (43%, 3 MRD−). Twenty-six patients proceeded to allo-HSCT. In the Blina/InO group, the median overall survival (OS) was 19 months; the disease-free survival (DFS) after Blina was 7.4 months (11.6 vs. 2.7 months in MRD− vs. MRD+, p = 0.03) and after InO, 5.4 months. In the InO/Blina group, the median OS was 9.4 months; the median DFS after InO was 5.1 months and 1.5 months after Blina (8.7 vs. 2.5 months in MRD− vs. MRD+, p = 0.02). With a median follow-up of 16.5 months from the start of immunotherapy, 24 patients (34%) are alive and 16 (22%) are alive in CR. Conclusion: In our series of R/R B-ALL, Blina and InO treatment demonstrate efficacy for subsequent relapses in terms of MRD response, OS and DFS, and as a bridge to allo-HSCT. Full article

(This article belongs to the Topic Myeloma and Leukemia-Challenges and Current Treatment Options)

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17 pages, 4751 KiB

Open AccessEditor’s ChoiceSystematic Review

Neo-Adjuvant Treatment in Primary Resectable Pancreatic Cancer: A Systematic Review and PRISMA-Compliant Updated Metanalysis of Oncological Outcomes

by Raffaello Roesel, Letizia Deantonio, Lorenzo Bernardi, Maria Luisa Garo, Pietro Majno-Hurst, Alberto Vannelli, Marco Cefalì, Maria Celeste Palmarocchi, Maria Carla Valli, Guido Pesola, Alessandra Cristaudi and Sara De Dosso

Cancers 2023, 15(18), 4627; https://doi.org/10.3390/cancers15184627 - 19 Sep 2023

Cited by 2 | Viewed by 1162

Abstract

Background: Despite advances in treatment, the prognosis of resectable pancreatic adenocarcinoma remains poor. Neoadjuvant therapy (NAT) has gained great interest in hopes of improving survival. However, the results of available studies based on different treatment approaches, such as chemotherapy and chemoradiotherapy, showed contrasting [...] Read more.

Background: Despite advances in treatment, the prognosis of resectable pancreatic adenocarcinoma remains poor. Neoadjuvant therapy (NAT) has gained great interest in hopes of improving survival. However, the results of available studies based on different treatment approaches, such as chemotherapy and chemoradiotherapy, showed contrasting results. The aim of this systematic review and meta-analysis is to clarify the benefit of NAT compared to upfront surgery (US) in primarily resectable pancreatic adenocarcinoma. Methods: A PRISMA literature review identified 139 studies, of which 15 were finally included in the systematic review and meta-analysis. All data from eligible articles was summarized in a systematic summary and then used for the meta-analysis. Specifically, we used HR for OS and DFS and risk estimates (odds ratios) for the R0 resection rate and the N+ rate. The risk of bias was correctly assessed according to the nature of the studies included. Results: From the pooled HRs, OS for NAT patients was better, with an HR for death of 0.80 (95% CI: 0.72–0.90) at a significance level of less than 1%. In the sub-group analysis, no difference was found between patients treated with chemoradiotherapy or chemotherapy exclusively. The meta-analysis of seven studies that reported DFS for NAT resulted in a pooled HR for progression of 0.66 (95% CI: 0.56–0.79) with a significance level of less than 1%. A significantly lower risk of positive lymph nodes (OR: 0.45; 95% CI: 0.32–0.63) and an improved R0 resection rate (OR: 1.70; 95% CI: 1.23–2.36) were also found in patients treated with NAT, despite high heterogeneity. Conclusions: NAT is associated with improved survival for patients with resectable pancreatic adenocarcinoma; however, the optimal treatment strategy has yet to be defined, and further studies are required. Full article

(This article belongs to the Collection Recent Advances in Pancreatic Ductal Adenocarcinoma)

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23 pages, 2732 KiB

Open AccessEditor’s ChoiceReview

Optimizing Treatment for Relapsed/Refractory Classic Hodgkin Lymphoma in the Era of Immunotherapy

by Michael P. Randall and Michael A. Spinner

Cancers 2023, 15(18), 4509; https://doi.org/10.3390/cancers15184509 - 11 Sep 2023

Cited by 2 | Viewed by 2376

Abstract

Most patients with classic Hodgkin lymphoma (cHL) are cured with combination chemotherapy, but approximately 10–20% will relapse, and another 5–10% will have primary refractory disease. The treatment landscape of relapsed/refractory (R/R) cHL has evolved significantly over the past decade following the approval of [...] Read more.

Most patients with classic Hodgkin lymphoma (cHL) are cured with combination chemotherapy, but approximately 10–20% will relapse, and another 5–10% will have primary refractory disease. The treatment landscape of relapsed/refractory (R/R) cHL has evolved significantly over the past decade following the approval of brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, and the PD-1 inhibitors nivolumab and pembrolizumab. These agents have significantly expanded options for salvage therapy prior to autologous hematopoietic cell transplantation (AHCT), post-transplant maintenance, and treatment of relapse after AHCT, which have led to improved survival in the modern era. In this review, we highlight our approach to the management of R/R cHL in 2023 with a focus on choosing first salvage therapy, post-transplant maintenance, and treatment of relapse after AHCT. We also discuss the management of older adults and transplant-ineligible patients, who require a separate approach. Finally, we review novel immunotherapy approaches in clinical trials, including combinations of PD-1 inhibitors with other immune-activating agents as well as novel antibody-drug conjugates, bispecific antibodies, and cellular immunotherapies. Ongoing studies assessing biomarkers of response to immunotherapy and dynamic biomarkers such as circulating tumor DNA may further inform treatment decisions and enable a more personalized approach in the future. Full article

(This article belongs to the Special Issue Hodgkin Lymphoma: Present Status and Future Strategies)

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9 pages, 1034 KiB

Open AccessEditor’s ChoiceArticle

Innovation in Actinic Keratosis Assessment: Artificial Intelligence-Based Approach to LC-OCT PRO Score Evaluation

by Fabia Daxenberger, Maximilian Deußing, Quirine Eijkenboom, Charlotte Gust, Janis Thamm, Daniela Hartmann, Lars E. French, Julia Welzel, Sandra Schuh and Elke C. Sattler

Cancers 2023, 15(18), 4457; https://doi.org/10.3390/cancers15184457 - 07 Sep 2023

Cited by 4 | Viewed by 955

Abstract

Actinic keratosis (AK) is a common skin cancer in situ that can progress to invasive SCC. Line-field confocal optical coherence tomography (LC-OCT) has emerged as a non-invasive imaging technique that can aid in diagnosis. Recently, machine-learning algorithms have been developed that can automatically [...] Read more.

Actinic keratosis (AK) is a common skin cancer in situ that can progress to invasive SCC. Line-field confocal optical coherence tomography (LC-OCT) has emerged as a non-invasive imaging technique that can aid in diagnosis. Recently, machine-learning algorithms have been developed that can automatically assess the PRO score of AKs based on the dermo-epidermal junction’s (DEJ’s) protrusion on LC-OCT images. A dataset of 19.898 LC-OCT images from 80 histologically confirmed AK lesions was used to test the performance of a previous validated artificial intelligence (AI)-based LC-OCT assessment algorithm. AI-based PRO score assessment was compared to the imaging experts’ visual score. Additionally, undulation of the DEJ, the number of protrusions detected within the image, and the maximum depth of the protrusions were computed. Our results show that AI-automated PRO grading is highly comparable to the visual score, with an agreement of 71.3% for the lesions evaluated. Furthermore, this AI-based assessment was significantly faster than the regular visual PRO score assessment. The results confirm our previous findings of the pilot study in a larger cohort that the AI-based grading of LC-OCT images is a reliable and fast tool to optimize the efficiency of visual PRO score grading. This technology has the potential to improve the accuracy and speed of AK diagnosis and may lead to better clinical outcomes for patients. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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15 pages, 1938 KiB

Open AccessEditor’s ChoiceReview

Sex Differences in the Efficacy of Immune Checkpoint Inhibitors in Neoadjuvant Therapy of Non-Small Cell Lung Cancer: A Meta-Analysis

by Guillermo Suay, Juan-Carlos Garcia-Cañaveras, Francisco Aparisi, Agustin Lahoz and Oscar Juan-Vidal

Cancers 2023, 15(18), 4433; https://doi.org/10.3390/cancers15184433 - 06 Sep 2023

Cited by 4 | Viewed by 1372

Abstract

Non-small cell lung cancer (NSCLC) is one of the world’s leading causes of morbidity and mortality. ICIs alone or combined with chemotherapy have become the standard first-line treatment of metastatic NSCLC. The impressive results obtained have stimulated our interest in applying these therapies [...] Read more.

Non-small cell lung cancer (NSCLC) is one of the world’s leading causes of morbidity and mortality. ICIs alone or combined with chemotherapy have become the standard first-line treatment of metastatic NSCLC. The impressive results obtained have stimulated our interest in applying these therapies in early disease stage treatments, as neoadjuvant immunotherapy has shown promising results. Among many of the factors that may influence responses, the role played by sex is attracting increased interest and needs to be addressed. Here, we aim to first review the state of the art regarding neoadjuvant ICIs, whether they are administered in monotherapy or in combination with chemotherapy at stages IB-IIIA, particularly at stage IIIA, before analyzing whether sex may influence responses. To this end, a meta-analysis of publicly available data comparing male and female major pathological responses (MPR) and pathological complete responses (pCR) was performed. In our meta-analysis, MPR was found to be significantly higher in females than in males, with an odds ratio (OR) of 1.82 (95% CI 1.13–2.93; p = 0.01), while pCR showed a trend to be more favorable in females than in males, but the OR of 1.62 was not statistically significant (95% CI 0.97–2.75; p = 0.08). Overall, our results showed that sex should be systematically considered in future clinical trials settings in order to establish the optimal treatment sequence. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Epidemiology and Prevention” in 2022–2023)

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20 pages, 1599 KiB

Open AccessEditor’s ChoiceReview

The Influence of the Microbiome on Immunotherapy for Gastroesophageal Cancer

by Neda Dadgar, Vinay Edlukudige Keshava, Moses S. Raj and Patrick L. Wagner

Cancers 2023, 15(18), 4426; https://doi.org/10.3390/cancers15184426 - 05 Sep 2023

Cited by 1 | Viewed by 1228

Abstract

Immunotherapy has shown promise as a treatment option for gastroesophageal cancer, but its effectiveness is limited in many patients due to the immunosuppressive tumor microenvironment (TME) commonly found in gastrointestinal tumors. This paper explores the impact of the microbiome on the TME and [...] Read more.

Immunotherapy has shown promise as a treatment option for gastroesophageal cancer, but its effectiveness is limited in many patients due to the immunosuppressive tumor microenvironment (TME) commonly found in gastrointestinal tumors. This paper explores the impact of the microbiome on the TME and immunotherapy outcomes in gastroesophageal cancer. The microbiome, comprising microorganisms within the gastrointestinal tract, as well as within malignant tissue, plays a crucial role in modulating immune responses and tumor development. Dysbiosis and reduced microbial diversity are associated with poor response rates and treatment resistance, while specific microbial profiles correlate with improved outcomes. Understanding the complex interactions between the microbiome, tumor biology, and immunotherapy is crucial for developing targeted interventions. Microbiome-based biomarkers may enable personalized treatment approaches and prediction of patient response. Interventions targeting the microbiome, such as microbiota-based therapeutics and dietary modifications, offer the potential for reshaping the gut microbiota and creating a favorable TME that enhances immunotherapy efficacy. Further research is needed to reveal the underlying mechanisms, and large-scale clinical trials will be required to validate the efficacy of microbiome-targeted interventions. Full article

(This article belongs to the Special Issue Role of Immunotherapy in Gastroesophageal Cancers: Advances, Challenges and Future Strategies)

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19 pages, 356 KiB

Open AccessEditor’s ChoiceReview

Radiomics: The New Promise for Differentiating Progression, Recurrence, Pseudoprogression, and Radionecrosis in Glioma and Glioblastoma Multiforme

by Mohammadreza Alizadeh, Nima Broomand Lomer, Mobin Azami, Mohammad Khalafi, Parnian Shobeiri, Melika Arab Bafrani and Houman Sotoudeh

Cancers 2023, 15(18), 4429; https://doi.org/10.3390/cancers15184429 - 05 Sep 2023

Cited by 1 | Viewed by 1603

Abstract

Glioma and glioblastoma multiform (GBM) remain among the most debilitating and life-threatening brain tumors. Despite advances in diagnosing approaches, patient follow-up after treatment (surgery and chemoradiation) is still challenging for differentiation between tumor progression/recurrence, pseudoprogression, and radionecrosis. Radiomics emerges as a promising tool [...] Read more.

Glioma and glioblastoma multiform (GBM) remain among the most debilitating and life-threatening brain tumors. Despite advances in diagnosing approaches, patient follow-up after treatment (surgery and chemoradiation) is still challenging for differentiation between tumor progression/recurrence, pseudoprogression, and radionecrosis. Radiomics emerges as a promising tool in initial diagnosis, grading, and survival prediction in patients with glioma and can help differentiate these post-treatment scenarios. Preliminary published studies are promising about the role of radiomics in post-treatment glioma/GBM. However, this field faces significant challenges, including a lack of evidence-based solid data, scattering publication, heterogeneity of studies, and small sample sizes. The present review explores radiomics’s capabilities in following patients with glioma/GBM status post-treatment and to differentiate tumor progression, recurrence, pseudoprogression, and radionecrosis. Full article

(This article belongs to the Special Issue The Current Status of Brain Tumors Imaging)

14 pages, 286 KiB

Open AccessEditor’s ChoiceArticle

Changes in the Number of Gastrointestinal Cancers and Stage at Diagnosis with COVID-19 Pandemic in Japan: A Multicenter Cohort Study

by Kento Kuzuu, Noboru Misawa, Keiichi Ashikari, Shigeki Tamura, Shingo Kato, Kunihiro Hosono, Masato Yoneda, Takashi Nonaka, Shozo Matsushima, Tatsuji Komatsu, Atsushi Nakajima and Takuma Higurashi

Cancers 2023, 15(17), 4410; https://doi.org/10.3390/cancers15174410 - 04 Sep 2023

Cited by 4 | Viewed by 1156

Abstract

This retrospective cohort study compared the number of newly diagnosed patients, stage at diagnosis, and detection process of gastrointestinal cancers based on hospital-based cancer registry data at two tertiary Japanese hospitals. The pre-COVID-19 period was from January 2017 to February 2020, with phase [...] Read more.

This retrospective cohort study compared the number of newly diagnosed patients, stage at diagnosis, and detection process of gastrointestinal cancers based on hospital-based cancer registry data at two tertiary Japanese hospitals. The pre-COVID-19 period was from January 2017 to February 2020, with phase 1 (midst of COVID-19 pandemic) from March to December 2020 and phase 2 (the transition period to the “new normal”) from January to December 2021. Each month, the number of patients diagnosed with esophageal, gastric, colorectal, pancreatic, liver, and biliary tract cancers were aggregated, classified by stage and detection process, and compared, including a total of 6453 patients. The number of colorectal Stage 0-II patients decreased significantly in phase 1 and increased in phase 2. The total number of colorectal cancer patients returned to pre-COVID-19 levels (mean monthly patients [SD]: 41.61 [6.81] vs. 36.00 [6.72] vs. 46.00 [11.32]). The number of patients with gastric cancer Stage I significantly decreased in phase 2 following phase 1. The number of gastric cancer patients decreased significantly from pre-COVID-19 levels (30.63 [6.62] vs. 22.40 [5.85] vs. 24.50 [4.15]). During phase 2, the number of patients diagnosed after screening with colorectal cancer increased significantly, whereas that with gastric cancer remained considerably lower. The number of Stage III colorectal and gastric cancer patients increased significantly from the pre-COVID-19 levels. Thus, gastric cancer may not be optimally screened during phases 1 and 2. There was a significant increase in patients with Stage III colorectal and gastric cancers from the pre-COVID-19 period; hence, the stage at diagnosis may have progressed. Full article

(This article belongs to the Collection The Impact of COVID-19 Infection in Cancer)

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17 pages, 3895 KiB

Open AccessEditor’s ChoiceArticle

Unlocking the Power of Benchmarking: Real-World-Time Data Analysis for Enhanced Sarcoma Patient Outcomes

by Bruno Fuchs, Georg Schelling, Maria Elyes, Gabriela Studer, Beata Bode-Lesniewska, Mario F. Scaglioni, Pietro Giovanoli, Philip Heesen and on behalf of the SwissSarcomaNetwork

Cancers 2023, 15(17), 4395; https://doi.org/10.3390/cancers15174395 - 02 Sep 2023

Cited by 3 | Viewed by 1159

Abstract

Benchmarking is crucial for healthcare providers to enhance quality and efficiency, notably for complex conditions like sarcomas. Multidisciplinary teams/sarcoma boards (MDT/SBs) are vital in sarcoma management, but differences in their processes can affect patient outcomes and treatment costs, despite adherence to international guidelines. [...] Read more.

Benchmarking is crucial for healthcare providers to enhance quality and efficiency, notably for complex conditions like sarcomas. Multidisciplinary teams/sarcoma boards (MDT/SBs) are vital in sarcoma management, but differences in their processes can affect patient outcomes and treatment costs, despite adherence to international guidelines. To address this issue, this study aimed to compare two MDT/SBs and establish an interoperable digital platform, Sarconnector^®, for real-time-world data assessment and automated analysis. The study included 983 patients, 46.0% of whom female, with a median age of 58 years, and 4.5% of patients presented with metastasis at diagnosis. Differences were observed in the number of first-time presentations, follow-up presentations, primary sarcomas, biopsies and chemotherapy indications between the two MDT/SB. The results highlight the importance of benchmarking and utilizing a harmonized data approach, such as the RWT approach provided by the Sarconnector^®, to standardize and evaluate quality and cost metrics. By identifying areas of improvement and making data-driven decisions on the meta-level, healthcare providers can optimize resources and improve patient outcomes. In conclusion, benchmarking with the RWT harmonized data approach provided by the Sarconnector^® can help healthcare providers improve the overall effectiveness of the healthcare system and achieve better outcomes for their patients in terms of both outcomes and costs. Full article

(This article belongs to the Special Issue Global Management of Sarcoma Data: Is Real-Time Predictive Analytics on the Horizon?)

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15 pages, 1306 KiB

Open AccessEditor’s ChoiceArticle

Efficacy of Thermal Ablation for Small-Size (0–3 cm) versus Intermediate-Size (3–5 cm) Colorectal Liver Metastases: Results from the Amsterdam Colorectal Liver Met Registry (AmCORE)

by Madelon Dijkstra, Susan van der Lei, Robbert S. Puijk, Hannah H. Schulz, Danielle J. W. Vos, Florentine E. F. Timmer, Hester J. Scheffer, Tineke E. Buffart, M. Petrousjka van den Tol, Birgit I. Lissenberg-Witte, Rutger-Jan Swijnenburg, Kathelijn S. Versteeg and Martijn R. Meijerink

Cancers 2023, 15(17), 4346; https://doi.org/10.3390/cancers15174346 - 31 Aug 2023

Cited by 3 | Viewed by 1295

Abstract

Purpose: Thermal ablation is widely recognized as the standard of care for small-size unresectable colorectal liver metastases (CRLM). For larger CRLM safety, local control and overall efficacy are not well established and insufficiently validated. The purpose of this comparative series was to analyze [...] Read more.

Purpose: Thermal ablation is widely recognized as the standard of care for small-size unresectable colorectal liver metastases (CRLM). For larger CRLM safety, local control and overall efficacy are not well established and insufficiently validated. The purpose of this comparative series was to analyze outcomes for intermediate-size versus small-size CRLM. Material and methods: Patients treated with thermal ablation between December 2000 and November 2021 for small-size and intermediate-size CRLM were included. The primary endpoints were complication rate and local control (LC). Secondary endpoints included local tumor progression-free survival (LTPFS) and overall survival (OS). Results: In total, 59 patients were included in the intermediate-size (3–5 cm) group and 221 in the small-size (0–3 cm) group. Complications were not significantly different between the two groups (p = 0.546). No significant difference between the groups was found in an overall comparison of OS (HR 1.339; 95% CI 0.824–2.176; p = 0.239). LTPFS (HR 3.388; p < 0.001) and LC (HR 3.744; p = 0.004) were superior in the small-size group. Nevertheless, the 1-, 3-, and 5-year LC for intermediate-size CRLM was still 93.9%, 85.4%, and 81.5%, and technical efficacy improved over time. Conclusions: Thermal ablation for intermediate-size unresectable CRLM is safe and induces long-term LC in the vast majority. The results of the COLLISION-XL trial (unresectable colorectal liver metastases: stereotactic body radiotherapy versus microwave ablation—a phase II randomized controlled trial for CRLM 3–5 cm) are required to provide further clarification of the role of local ablative methods for intermediate-size unresectable CRLM. Full article

(This article belongs to the Special Issue Thermal Ablation in the Management for Colorectal Liver Metastases)

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11 pages, 3134 KiB

Open AccessEditor’s ChoiceArticle

Antagonizing MDM2 Overexpression Induced by MDM4 Inhibitor CEP-1347 Effectively Reactivates Wild-Type p53 in Malignant Brain Tumor Cells

by Yuta Mitobe, Shuhei Suzuki, Yurika Nakagawa-Saito, Keita Togashi, Asuka Sugai, Yukihiko Sonoda, Chifumi Kitanaka and Masashi Okada

Cancers 2023, 15(17), 4326; https://doi.org/10.3390/cancers15174326 - 30 Aug 2023

Cited by 3 | Viewed by 1309

Abstract

The development of MDM4 inhibitors as an approach to reactivating p53 in human cancer is attracting increasing attention; however, whether they affect the function of MDM2 and how they interact with MDM2 inhibitors remain unknown. We addressed this question in the present study [...] Read more.

The development of MDM4 inhibitors as an approach to reactivating p53 in human cancer is attracting increasing attention; however, whether they affect the function of MDM2 and how they interact with MDM2 inhibitors remain unknown. We addressed this question in the present study using CEP-1347, an inhibitor of MDM4 protein expression. The effects of CEP-1347, the genetic and/or pharmacological inhibition of MDM2, and their combination on the p53 pathway in malignant brain tumor cell lines expressing wild-type p53 were investigated by RT-PCR and Western blot analyses. The growth inhibitory effects of CEP-1347 alone or in combination with MDM2 on inhibition were examined by dye exclusion and/or colony formation assays. The treatment of malignant brain tumor cell lines with CEP-1347 markedly increased MDM2 protein expression, while blocking CEP-1347-induced MDM2 overexpression by genetic knockdown augmented the effects of CEP-1347 on the p53 pathway and cell growth. Blocking the MDM2–p53 interaction using the small molecule MDM2 inhibitor RG7112, but not MDM2 knockdown, reduced MDM4 expression. Consequently, RG7112 effectively cooperated with CEP-1347 to reduce MDM4 expression, activate the p53 pathway, and inhibit cell growth. The present results suggest the combination of CEP-1347-induced MDM2 overexpression with the selective inhibition of MDM2′s interaction with p53, while preserving its ability to inhibit MDM4 expression, as a novel and rational strategy to effectively reactivate p53 in wild-type p53 cancer cells. Full article

(This article belongs to the Special Issue The 10th International MDM2 Workshop—Opening Up New Avenues for MDM2 and p53 Research)

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18 pages, 3065 KiB

Open AccessEditor’s ChoiceArticle

Environmental and Lifestyle Cancer Risk Factors: Shaping Extracellular Vesicle OncomiRs and Paving the Path to Cancer Development

by Valentina Bollati, Paola Monti, Davide Biganzoli, Giuseppe Marano, Chiara Favero, Simona Iodice, Luca Ferrari, Laura Dioni, Francesca Bianchi, Angela Cecilia Pesatori and Elia Mario Biganzoli

Cancers 2023, 15(17), 4317; https://doi.org/10.3390/cancers15174317 - 29 Aug 2023

Cited by 2 | Viewed by 1131

Abstract

Intercellular communication has been transformed by the discovery of extracellular vesicles (EVs) and their cargo, including microRNAs (miRNAs), which play crucial roles in intercellular signaling. These EVs were previously disregarded as cellular debris but are now recognized as vital mediators of biological information [...] Read more.

Intercellular communication has been transformed by the discovery of extracellular vesicles (EVs) and their cargo, including microRNAs (miRNAs), which play crucial roles in intercellular signaling. These EVs were previously disregarded as cellular debris but are now recognized as vital mediators of biological information transfer between cells. Furthermore, they respond not only to internal stimuli but also to environmental and lifestyle factors. Identifying EV-borne oncomiRs, a subset of miRNAs implicated in cancer development, could revolutionize our understanding of how environmental and lifestyle exposures contribute to oncogenesis. To investigate this, we studied the plasma levels of EV-borne oncomiRs in a population of 673 women and 238 men with a body mass index > 25 kg/m² (SPHERE population). The top fifty oncomiRs associated with the three most common cancers in women (breast, colorectal, and lung carcinomas) and men (lung, prostate, and colorectal carcinomas) were selected from the OncomiR database. Only oncomiRs expressed in more than 20% of the population were considered for statistical analysis. Using a Multivariate Adaptive Regression Splines (MARS) model, we explored the interactions between environmental/lifestyle exposures and EV oncomiRs to develop optimized predictor combinations for each EV oncomiR. This innovative approach allowed us to better understand miRNA regulation in response to multiple environmental and lifestyle influences. By uncovering non-linear relationships among variables, we gained valuable insights into the complexity of miRNA regulatory networks. Ultimately, this research paves the way for comprehensive exposome studies in the future. Full article

(This article belongs to the Special Issue Non-coding RNAs and Extracellular Vesicles in Cancer Crosstalk: Diagnostic and Therapeutic Implications)

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22 pages, 402 KiB

Open AccessEditor’s ChoiceReview

Recurrent Glioblastoma: A Review of the Treatment Options

by Maria Angeles Vaz-Salgado, María Villamayor, Víctor Albarrán, Víctor Alía, Pilar Sotoca, Jesús Chamorro, Diana Rosero, Ana M. Barrill, Mercedes Martín, Eva Fernandez, José Antonio Gutierrez, Luis Mariano Rojas-Medina and Luis Ley

Cancers 2023, 15(17), 4279; https://doi.org/10.3390/cancers15174279 - 26 Aug 2023

Cited by 7 | Viewed by 2744

Abstract

Glioblastoma is a disease with a poor prognosis. Multiple efforts have been made to improve the long-term outcome, but the 5-year survival rate is still 5–10%. Recurrence of the disease is the usual way of progression. In this situation, there is no standard [...] Read more.

Glioblastoma is a disease with a poor prognosis. Multiple efforts have been made to improve the long-term outcome, but the 5-year survival rate is still 5–10%. Recurrence of the disease is the usual way of progression. In this situation, there is no standard treatment. Different treatment options can be considered. Among them would be reoperation or reirradiation. There are different studies that have assessed the impact on survival and the selection of patients who may benefit most from these strategies. Chemotherapy treatments have also been considered in several studies, mainly with alkylating agents, with data mostly from phase II studies. On the other hand, multiple studies have been carried out with target-directed treatments. Bevacizumab, a monoclonal antibody with anti-angiogenic activity, has demonstrated activity in several studies, and the FDA has approved it for this indication. Several other TKI drugs have been evaluated in this setting, but no clear benefit has been demonstrated. Immunotherapy treatments have been shown to be effective in other types of tumors, and several studies have evaluated their efficacy in this disease, both immune checkpoint inhibitors, oncolytic viruses, and vaccines. This paper reviews data from different studies that have evaluated the efficacy of different forms of relapsed glioblastoma. Full article

(This article belongs to the Topic Findings, Insights and Perspectives on Central Nervous System Tumors)

12 pages, 2296 KiB

Open AccessEditor’s ChoiceReview

Proton Therapy in the Adolescent and Young Adult Population

by Safia K. Ahmed and Sameer R. Keole

Cancers 2023, 15(17), 4269; https://doi.org/10.3390/cancers15174269 - 25 Aug 2023

Cited by 1 | Viewed by 1469

Abstract

Background: Adolescent and young adult cancer patients are at high risk of developing radiation-associated side effects after treatment. Proton beam radiation therapy might reduce the risk of these side effects for this population without compromising treatment efficacy. Methods: We review the current literature [...] Read more.

Background: Adolescent and young adult cancer patients are at high risk of developing radiation-associated side effects after treatment. Proton beam radiation therapy might reduce the risk of these side effects for this population without compromising treatment efficacy. Methods: We review the current literature describing the utility of proton beam radiation therapy in the treatment of central nervous system tumors, sarcomas, breast cancer and Hodgkin lymphoma for the adolescent and young adult cancer population. Results: Proton beam radiation therapy has utility for the treatment of certain cancers in the young adult population. Preliminary data suggest reduced radiation dose to normal tissues, which might reduce radiation-associated toxicities. Research is ongoing to further establish the role of proton therapy in this population. Conclusion: This report highlights the potential utility of proton beam radiation for certain adolescent young adult cancers, especially with reducing radiation doses to organs at risk and thereby potentially lowering risks of certain treatment-associated toxicities. Full article

(This article belongs to the Special Issue Proton Therapy Promises and Perils: What Progress Has Been Made?)

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27 pages, 1195 KiB

Open AccessEditor’s ChoiceReview

Advances in Immunotherapeutics in Pancreatic Ductal Adenocarcinoma

by Tarak Chouari, Francesca Soraya La Costa, Nabeel Merali, Maria-Danae Jessel, Shivan Sivakumar, Nicola Annels and Adam E. Frampton

Cancers 2023, 15(17), 4265; https://doi.org/10.3390/cancers15174265 - 25 Aug 2023

Cited by 3 | Viewed by 1930

Abstract

Pancreatic ductal adenocarcinoma (PDAC) accounts for up to 95% of all pancreatic cancer cases and is the seventh-leading cause of cancer death. Poor prognosis is a result of late presentation, a lack of screening tests and the fact some patients develop resistance to [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) accounts for up to 95% of all pancreatic cancer cases and is the seventh-leading cause of cancer death. Poor prognosis is a result of late presentation, a lack of screening tests and the fact some patients develop resistance to chemotherapy and radiotherapy. Novel therapies like immunotherapeutics have been of recent interest in pancreatic cancer. However, this field remains in its infancy with much to unravel. Immunotherapy and other targeted therapies have yet to yield significant progress in treating PDAC, primarily due to our limited understanding of the disease immune mechanisms and its intricate interactions with the tumour microenvironment (TME). In this review we provide an overview of current novel immunotherapies which have been studied in the field of pancreatic cancer. We discuss their mechanisms, evidence available in pancreatic cancer as well as the limitations of such therapies. We showcase the potential role of combining novel therapies in PDAC, postulate their potential clinical implications and the hurdles associated with their use in PDAC. Therapies discussed with include programmed death checkpoint inhibitors, Cytotoxic T-lymphocyte-associated protein 4, Chimeric Antigen Receptor-T cell therapy, oncolytic viral therapy and vaccine therapies including KRAS vaccines, Telomerase vaccines, Gastrin Vaccines, Survivin-targeting vaccines, Heat-shock protein (HSP) peptide complex-based vaccines, MUC-1 targeting vaccines, Listeria based vaccines and Dendritic cell-based vaccines. Full article

(This article belongs to the Special Issue Modern Evaluation and Treatment of Malignant Pancreatic, Liver and Biliary Tract Tumours)

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29 pages, 4688 KiB

Open AccessEditor’s ChoiceArticle

Brain Tumor Detection Based on Deep Learning Approaches and Magnetic Resonance Imaging

by Akmalbek Bobomirzaevich Abdusalomov, Mukhriddin Mukhiddinov and Taeg Keun Whangbo

Cancers 2023, 15(16), 4172; https://doi.org/10.3390/cancers15164172 - 18 Aug 2023

Cited by 16 | Viewed by 4402

Abstract

The rapid development of abnormal brain cells that characterizes a brain tumor is a major health risk for adults since it can cause severe impairment of organ function and even death. These tumors come in a wide variety of sizes, textures, and locations. [...] Read more.

The rapid development of abnormal brain cells that characterizes a brain tumor is a major health risk for adults since it can cause severe impairment of organ function and even death. These tumors come in a wide variety of sizes, textures, and locations. When trying to locate cancerous tumors, magnetic resonance imaging (MRI) is a crucial tool. However, detecting brain tumors manually is a difficult and time-consuming activity that might lead to inaccuracies. In order to solve this, we provide a refined You Only Look Once version 7 (YOLOv7) model for the accurate detection of meningioma, glioma, and pituitary gland tumors within an improved detection of brain tumors system. The visual representation of the MRI scans is enhanced by the use of image enhancement methods that apply different filters to the original pictures. To further improve the training of our proposed model, we apply data augmentation techniques to the openly accessible brain tumor dataset. The curated data include a wide variety of cases, such as 2548 images of gliomas, 2658 images of pituitary, 2582 images of meningioma, and 2500 images of non-tumors. We included the Convolutional Block Attention Module (CBAM) attention mechanism into YOLOv7 to further enhance its feature extraction capabilities, allowing for better emphasis on salient regions linked with brain malignancies. To further improve the model’s sensitivity, we have added a Spatial Pyramid Pooling Fast+ (SPPF+) layer to the network’s core infrastructure. YOLOv7 now includes decoupled heads, which allow it to efficiently glean useful insights from a wide variety of data. In addition, a Bi-directional Feature Pyramid Network (BiFPN) is used to speed up multi-scale feature fusion and to better collect features associated with tumors. The outcomes verify the efficiency of our suggested method, which achieves a higher overall accuracy in tumor detection than previous state-of-the-art models. As a result, this framework has a lot of potential as a helpful decision-making tool for experts in the field of diagnosing brain tumors. Full article

(This article belongs to the Special Issue Brain Tumor: Recent Advances and Challenges)

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26 pages, 5728 KiB

Open AccessEditor’s ChoiceArticle

Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib

by Aoife Nolan, Cinzia Raso, Walter Kolch, Alex von Kriegsheim, Kieran Wynne and David Matallanas

Cancers 2023, 15(16), 4141; https://doi.org/10.3390/cancers15164141 - 17 Aug 2023

Cited by 1 | Viewed by 2279

Abstract

RAS proteins are key regulators of cell signalling and control different cell functions including cell proliferation, differentiation, and cell death. Point mutations in the genes of this family are common, particularly in KRAS. These mutations were thought to cause the constitutive activation [...] Read more.

RAS proteins are key regulators of cell signalling and control different cell functions including cell proliferation, differentiation, and cell death. Point mutations in the genes of this family are common, particularly in KRAS. These mutations were thought to cause the constitutive activation of KRAS, but recent findings showed that some mutants can cycle between active and inactive states. This observation, together with the development of covalent KRASG12C inhibitors, has led to the arrival of KRAS inhibitors in the clinic. However, most patients develop resistance to these targeted therapies, and we lack effective treatments for other KRAS mutants. To accelerate the development of RAS targeting therapies, we need to fully characterise the molecular mechanisms governing KRAS signalling networks and determine what differentiates the signalling downstream of the KRAS mutants. Here we have used affinity purification mass-spectrometry proteomics to characterise the interactome of KRAS wild-type and three KRAS mutants. Bioinformatic analysis associated with experimental validation allows us to map the signalling network mediated by the different KRAS proteins. Using this approach, we characterised how the interactome of KRAS wild-type and mutants is regulated by the clinically approved KRASG12C inhibitor Sotorasib. In addition, we identified novel crosstalks between KRAS and its effector pathways including the AKT and JAK-STAT signalling modules. Full article

(This article belongs to the Special Issue RAS Signaling Pathway in Cancer Therapy)

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