Cancers

27 pages, 15911 KiB

Open AccessEditor’s ChoiceArticle

Pro-Inflammatory Cytokines Transactivate Glycosylated Cytokine Receptors on Cancer Cells to Induce Epithelial–Mesenchymal Transition to the Metastatic Phenotype

by Leili Baghaie, David A. Bunsick, Emilyn B. Aucoin, Elizabeth Skapinker, Abdulrahman M. Yaish, Yunfan Li, William W. Harless and Myron R. Szewczuk

Cancers 2025, 17(7), 1234; https://doi.org/10.3390/cancers17071234 - 5 Apr 2025

Cited by 1 | Viewed by 883

Abstract

Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of [...] Read more.

Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of primary breast, colorectal, and prostate cancer. We also investigated the regulation of their cognate receptors. Methods: All experiments were conducted using the PANC-1, SW620, and MCF-7 cell lines, treated with three different cytokines (TGF-β1, HGF, and IL-6). The effect of these cytokines on the expression of epithelial–mesenchymal transition (EMT) cell surface markers and neuraminidase-1 activity was measured via fluorescent microscopy and image analysis software. Results: The findings show that these cytokines increase the expression of mesenchymal markers while reducing epithelial markers, corresponding to the EMT process. A strong link between cytokine receptor signaling and the Neu-1-MMP-9-GPCR crosstalk was identified, suggesting that cytokine receptor binding leads to increased Neu-1 activity and subsequent signaling pathway activation. Oseltamivir phosphate (OP) prevented sialic acid hydrolysis by neuraminidase-1 (Neu-1), leading to the downregulation of these signaling cascades. Conclusions: In concert with the previous work revealing the role of Neu-1 in regulating other glycosylated receptors implicated in cancer cell proliferation and EMT, targeting Neu-1 may provide effective treatment against a variety of malignancies. Most significantly, the treatment of patients with specific inhibitors of Neu-1 soon after primary cancer surgery may improve our ability to cure early-stage cancer by inhibiting the EMT process and disrupting the ability of any residual cancer cell population to metastasize. Full article

(This article belongs to the Special Issue Role of Cytokines in Cancer)

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16 pages, 3685 KiB

Open AccessEditor’s ChoiceArticle

ASPH Is a Metastatic Factor and Therapeutic Target in Chondrosarcoma

by Xiaojuan Sun, Jesse Hart, Ross Taliano, Janine Molino, Joseph H. Schwab, Sjoerd Nota, Katsuya Nagaoka, Songhua Zhang, Mark Olsen, Rolf Carlson, Jack Wands and Richard M. Terek

Cancers 2025, 17(6), 951; https://doi.org/10.3390/cancers17060951 - 12 Mar 2025

Cited by 2 | Viewed by 1127

Abstract

Background: Chondrosarcoma (CS) is a highly aggressive primary malignant bone tumor for which there are no effective systemic treatments. We assessed aspartate β-hydroxylase (ASPH) as a potential treatment target. ASPH is a transforming cell surface receptor, but its role in chondrosarcoma has not [...] Read more.

Background: Chondrosarcoma (CS) is a highly aggressive primary malignant bone tumor for which there are no effective systemic treatments. We assessed aspartate β-hydroxylase (ASPH) as a potential treatment target. ASPH is a transforming cell surface receptor, but its role in chondrosarcoma has not been evaluated. Our goals were to analyze the expression of ASPH in conventional chondrosarcoma, evaluate its utility as a biomarker, and determine if ASPH inhibition diminishes tumor progression in a preclinical model. Methods: An annotated tissue microarray was constructed with conventional chondrosarcoma tissues. ASPH expression was quantified with immunohistochemistry. A small molecule inhibitor (SMI) designed to inhibit ASPH activity was evaluated in two CS cell lines with intact ASPH expression and after knockout. Cell viability, invasion, and matrix metalloproteinase (MMP) expression were measured. A mouse xenograft chondrosarcoma model was used to evaluate the effect of the SMI on tumor growth, MMP activity in tumors, and lung metastatic burden. Results: Higher ASPH scores were associated with a greater risk of death and metastasis. The SMI decreased CS cell proliferation, invasion, and secretion of MMPs in vitro, and the effects were lost after ASPH knockout. In vivo, systemic administration of the SMI decreased tumor growth, MMP activity and content in xenograft tumors, and lung metastatic burden. Conclusions: These data validate ASPH as a biomarker in CS and as a factor in the metastatic phenotype. Systemic treatment with an SMI directed against ASPH inhibits tumor progression in a preclinical model, suggesting that ASPH-targeted therapy may be a new treatment strategy for chondrosarcoma expressing ASPH. Full article

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

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16 pages, 6502 KiB

Open AccessEditor’s ChoiceArticle

Perceived Gaps in Oncologic Emergency Care for Patients with Cancer: A Qualitative Comparison of Emergency Medicine and Oncologist Physician Perspectives

by Monica K. Wattana, Moira Davenport, Jason J. Bischof, Angela B. Lindsay, Nicholas R. Pettit, Jazmin R. Menendez, Kelsey Harper, Demis N. Lipe and Aiham Qdaisat

Cancers 2025, 17(5), 828; https://doi.org/10.3390/cancers17050828 - 27 Feb 2025

Cited by 1 | Viewed by 949

Abstract

Objective: Providing high-quality, safe, and consistent care for patients with cancer in the emergency department (ED) poses unique challenges. To better understand these challenges, we surveyed oncologists and emergency medicine (EM) physicians across five institutions to identify key areas for improvement in oncologic [...] Read more.

Objective: Providing high-quality, safe, and consistent care for patients with cancer in the emergency department (ED) poses unique challenges. To better understand these challenges, we surveyed oncologists and emergency medicine (EM) physicians across five institutions to identify key areas for improvement in oncologic EM. Methods: In this multi-institutional, cross-sectional qualitative study, a semi-structured survey was administered to EM attending and resident physicians and medical and surgical oncologists across five institutions in 2023. We assessed the open-ended questionnaire responses using thematic analysis; codes were created and collated to generate initial themes. The themes were then reviewed according to specialty for coherence and non-repetition and finalized. Results: Of the 302 surveys accessed, 185 (61.3%) had complete responses. Three main domains of issues emerged: systems-based challenges, direct patient care-related issues, and knowledge gaps. The issues most frequently perceived by oncologist survey respondents were long delays in care (41%), variability in care (25%), and communication issues between the EM physician and oncologist (14%). The issues most frequently perceived by EM physician survey respondents were knowledge gaps in cancer therapeutics (40%) and in general oncologic emergencies (23%); physician comfort level (14%); the timing and/or location of initial discussions about goals of care (13%); and challenges with the follow-up process (12%). Conclusions: Incorporating an interdisciplinary approach to patient care in the ED, improved EM oncologic education, and the development of oncologic specialized EDs may enhance the quality, safety, and consistency of care for patients with cancer in the ED. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

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32 pages, 2615 KiB

Open AccessEditor’s ChoiceReview

The Role of the Gut Microbiota in Modulating Signaling Pathways and Oxidative Stress in Glioma Therapies

by Aleksandra Krawczyk, Gabriela Elzbieta Sladowska and Barbara Strzalka-Mrozik

Cancers 2025, 17(5), 719; https://doi.org/10.3390/cancers17050719 - 20 Feb 2025

Cited by 2 | Viewed by 1853

Abstract

Tumors of the central nervous system (CNS), especially gliomas, pose a significant clinical challenge due to their aggressive nature and limited therapeutic options. Emerging research highlights the critical role of the gut microbiota in regulating CNS health and disease. The composition of the [...] Read more.

Tumors of the central nervous system (CNS), especially gliomas, pose a significant clinical challenge due to their aggressive nature and limited therapeutic options. Emerging research highlights the critical role of the gut microbiota in regulating CNS health and disease. The composition of the gut microbiota is essential for maintaining CNS homeostasis, as it modulates immune responses, oxidative status, and neuroinflammation. The microbiota–gut–brain axis, a bidirectional communication network, plays a pivotal role in cancer and CNS disease treatment, exerting its influence through neural, endocrine, immunological, and metabolic pathways. Recent studies suggest that the gut microbiota influences the solidification of the tumor microenvironment and that dysbiosis may promote glioma development by modulating systemic inflammation and oxidative stress, which contributes to tumorigenesis and CNS tumor progression. This review interrogates the impact of the gut microbiota on glioma, focusing on critical pathways such as NF-κB, MAPK, PI3K/Akt/mTOR, and Kynurenine/AhR that drive tumor proliferation, immune evasion, and therapy resistance. Furthermore, we explore emerging therapeutic strategies, including probiotics and microbiota-based interventions, which show potential in modulating these pathways and enhancing immunotherapies such as checkpoint inhibitors. By focusing on the multifaceted interactions between the gut microbiota, oxidative stress, and CNS tumors, this review highlights the potential of microbiota-targeted therapies and their manipulation to complement and enhance current treatments. Full article

(This article belongs to the Section Molecular Cancer Biology)

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15 pages, 735 KiB

Open AccessEditor’s ChoiceReview

Revolutionizing MASLD: How Artificial Intelligence Is Shaping the Future of Liver Care

by Nicola Pugliese, Arianna Bertazzoni, Cesare Hassan, Jörn M. Schattenberg and Alessio Aghemo

Cancers 2025, 17(5), 722; https://doi.org/10.3390/cancers17050722 - 20 Feb 2025

Cited by 3 | Viewed by 1652

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as a leading cause of chronic liver disease. In recent years, artificial intelligence (AI) has attracted significant attention in healthcare, particularly in diagnostics, patient management, and drug development, demonstrating immense potential for application and implementation. [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as a leading cause of chronic liver disease. In recent years, artificial intelligence (AI) has attracted significant attention in healthcare, particularly in diagnostics, patient management, and drug development, demonstrating immense potential for application and implementation. In the field of MASLD, substantial research has explored the application of AI in various areas, including patient counseling, improved patient stratification, enhanced diagnostic accuracy, drug development, and prognosis prediction. However, the integration of AI in hepatology is not without challenges. Key issues include data management and privacy, algorithmic bias, and the risk of AI-generated inaccuracies, commonly referred to as “hallucinations”. This review aims to provide a comprehensive overview of the applications of AI in hepatology, with a focus on MASLD, highlighting both its transformative potential and its inherent limitations. Full article

(This article belongs to the Special Issue The Applications of Artificial Intelligence in Gastroenterology)

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17 pages, 1172 KiB

Open AccessEditor’s ChoiceSystematic Review

Methylation Biomarkers of Lung Cancer Risk: A Systematic Review and Meta-Analysis

by Jacopo Dolcini, Manuela Chiavarini, Giorgio Firmani, Kasey J. M. Brennan, Andres Cardenas, Andrea A. Baccarelli and Pamela Barbadoro

Cancers 2025, 17(4), 690; https://doi.org/10.3390/cancers17040690 - 18 Feb 2025

Cited by 3 | Viewed by 1594

Abstract

Background: Lung cancer (LC) is the leading cause of cancer deaths worldwide among both men and women, and represents a major public health challenge. DNA methylation (DNAm) has shown potential in identifying individuals at higher risk of LC, but the overall evidence [...] Read more.

Background: Lung cancer (LC) is the leading cause of cancer deaths worldwide among both men and women, and represents a major public health challenge. DNA methylation (DNAm) has shown potential in identifying individuals at higher risk of LC, but the overall evidence has not been systematically evaluated. This review and meta-analysis aims to evaluate and summarize existing research on the association between blood DNAm levels and LC risk. Methods: Searches were conducted in PubMed, Web of Science, and Scopus for studies published until February 2024, following PRISMA and MOOSE guidelines. Eleven studies met the eligibility criteria. Results: Using a random effects model, our pooled analysis showed a significant association between increased DNAm levels and LC risk (OR 1.24, 95% CI 1.10–1.39; I² = 93.90%, p = 0.0001). Stratifying the results by study design showed a stronger association in two prospective cohort studies (OR 1.61; 95% CI 1.36–1.90; I² = 14.42%, p = 0.32), while case–control studies showed a weaker association (OR 1.05; 95% CI 0.99–1.11; I² = 70.57%, p = 0.0001). Sensitivity analyses indicated that omitting individual studies did not significantly alter the LC risk estimates. Conclusions: These findings suggest that higher blood DNAm levels are associated with an increased risk of LC, especially in long-term cohort studies. Further research is recommended to explore the potential of DNAm as a screening biomarker for LC and to clarify the role of other influencing factors. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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21 pages, 4327 KiB

Open AccessEditor’s ChoiceArticle

Interval Analysis-Based Optimization: A Robust Model for Intensity-Modulated Radiotherapy (IMRT)

by Andrés Camilo Sevilla-Moreno, María Eugenia Puerta-Yepes, Niklas Wahl, Rafael Benito-Herce and Gonzalo Cabal-Arango

Cancers 2025, 17(3), 504; https://doi.org/10.3390/cancers17030504 - 3 Feb 2025

Cited by 1 | Viewed by 1441

Abstract

Background: Cancer remains one of the leading causes of mortality worldwide, with radiotherapy playing a crucial role in its treatment. Intensity-modulated radiotherapy (IMRT) enables precise dose delivery to tumors while sparing healthy tissues. However, geometric uncertainties such as patient positioning errors and [...] Read more.

Background: Cancer remains one of the leading causes of mortality worldwide, with radiotherapy playing a crucial role in its treatment. Intensity-modulated radiotherapy (IMRT) enables precise dose delivery to tumors while sparing healthy tissues. However, geometric uncertainties such as patient positioning errors and anatomical deformations can compromise treatment accuracy. Traditional methods use safety margins, which may lead to excessive irradiation of healthy organs or insufficient tumor coverage. Robust optimization techniques, such as minimax approaches, attempt to address these uncertainties but can result in overly conservative treatment plans. This study introduces an interval analysis-based optimization model for IMRT, offering a more flexible approach to uncertainty management. Methods: The proposed model represents geometric uncertainties using interval dose influence matrices and incorporates Bertoluzza’s metric to balance tumor coverage and organ-at-risk (OAR) protection. The

θ

parameter allows controlled robustness modulation. The model was implemented in matRad, an open-source treatment planning system, and evaluated on five prostate cancer cases. Results were compared against traditional Planning Target Volume (PTV) and minimax robust optimization approaches. Results: The interval-based model improved tumor coverage by 5.8% while reducing bladder dose by 4.2% compared to PTV. In contrast, minimax robust optimization improved tumor coverage by 25.8% but increased bladder dose by 23.2%. The interval-based approach provided a better balance between tumor coverage and OAR protection, demonstrating its potential to enhance treatment effectiveness without excessive conservatism. Conclusions: This study presents a novel framework for IMRT planning that improves uncertainty management through interval analysis. By allowing adjustable robustness modulation, the proposed model enables more personalized and clinically adaptable treatment plans. These findings highlight the potential of interval analysis as a powerful tool for optimizing radiotherapy outcomes, balancing treatment efficacy and patient safety. Full article

(This article belongs to the Special Issue The Future of Radiation Research in Cancers, 2nd Edition)

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17 pages, 3414 KiB

Open AccessEditor’s ChoiceArticle

TLR2-Bound Cancer-Secreted Hsp70 Induces MerTK-Mediated Immunosuppression and Tumorigenesis in Solid Tumors

by Ahmet Kaynak, Subrahmanya D. Vallabhapurapu, Harold W. Davis, Eric P. Smith, Petr Muller, Borek Vojtesek, Robert S. Franco, Wen-Hai Shao and Xiaoyang Qi

Cancers 2025, 17(3), 450; https://doi.org/10.3390/cancers17030450 - 28 Jan 2025

Cited by 2 | Viewed by 1543

Abstract

Background: A hallmark of cancer is the presence of an immunosuppressive tumor microenvironment (TME). Immunosuppressive M2 macrophages (MΦs) in the TME facilitate escape from immune surveillance and promote tumor growth; therefore, TME-induced immunosuppression is a potent immunotherapeutic approach to treating cancer. Methods [...] Read more.

Background: A hallmark of cancer is the presence of an immunosuppressive tumor microenvironment (TME). Immunosuppressive M2 macrophages (MΦs) in the TME facilitate escape from immune surveillance and promote tumor growth; therefore, TME-induced immunosuppression is a potent immunotherapeutic approach to treating cancer. Methods: Cancer cell-secreted proteins were detected by using liquid chromatography–mass spectrometry (LC-MS). Neutralizing antibodies (nAbs) were used to assess which proteins were involved in MΦs polarization and differentiation. The protein–protein interaction was characterized using co-immunoprecipitation and immunofluorescence assays. Cancer-secreted heat shock protein 70 (Hsp70) protein was quantified using an enzyme-linked immunosorbent assay (ELISA). MΦ polarization and tumor growth were assessed in vivo with subcutaneous LLC-GFP tumor models and toll-like receptor 2 (TLR2) knockout mice; in vitro assessments were conducted using TLR2 knockout and both LLC-GFP and LN227 lentiviral-mediated knockdown (KD) cells. Results: Cancer cells released a secreted form of Hsp70 that acted on MΦ TLR2 to upregulate Mer receptor tyrosine kinase (MerTK) and induce MΦ M2 polarization. Hsp70 nAbs led to a reduction in CD14 expression by 75% in THP-1 cells in response to Gli36 EMD-CM. In addition, neutralizing TLR2 nAbs resulted in a 30% and 50% reduction in CD14 expression on THP-1 cells in response to MiaPaCa-2 and Gli36 exosome/microparticle-depleted conditioned media (EMD-CMs), respectively. Hsp70, TLR2, and MerTK formed a protein complex. Tumor growth and intra-tumor M2 MΦs were significantly reduced upon cancer cell Hsp70 knockdown and in TLR2 knockout mice. Conclusions: Cancer-secreted Hsp70 interacts with TLR2, upregulates MerTK on MΦs, and induces immunosuppressive MΦ M2 polarization. This previously unreported action of secreted Hsp70 suggests that disrupting the Hsp70-TLR2-MerTK interaction could serve as a promising immunotherapeutic approach to mitigate TME immunosuppression in solid cancers. Full article

(This article belongs to the Special Issue Heat Shock Proteins in Cancers)

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30 pages, 1104 KiB

Open AccessEditor’s ChoiceReview

Heterogeneity in Cancer

by William J. MacDonald, Connor Purcell, Maximilian Pinho-Schwermann, Nolan M. Stubbs, Praveen R. Srinivasan and Wafik S. El-Deiry

Cancers 2025, 17(3), 441; https://doi.org/10.3390/cancers17030441 - 28 Jan 2025

Cited by 4 | Viewed by 4058

Abstract

Cancer heterogeneity is a major challenge in oncology, complicating diagnosis, prognostication, and treatment. The clinical heterogeneity of cancer, which leads to differential treatment outcomes between patients with histopathologically similar cancers, is attributable to molecular diversity manifesting through genetic, epigenetic, transcriptomic, microenvironmental, and host [...] Read more.

Cancer heterogeneity is a major challenge in oncology, complicating diagnosis, prognostication, and treatment. The clinical heterogeneity of cancer, which leads to differential treatment outcomes between patients with histopathologically similar cancers, is attributable to molecular diversity manifesting through genetic, epigenetic, transcriptomic, microenvironmental, and host biology differences. Heterogeneity is observed between patients, individual metastases, and within individual lesions. This review discusses clinical implications of heterogeneity, emphasizing need for personalized approaches to overcome challenges posed by cancer’s diverse presentations. Understanding of emerging molecular diagnostic and analytical techniques can provide a view into the multidimensional complexity of cancer heterogeneity. With over 90% of cancer-related deaths associated with metastasis, we additionally explore the role heterogeneity plays in treatment resistance and recurrence of metastatic lesions. Molecular insights from next-generation sequencing, single-cell transcriptomics, liquid biopsy technology, and artificial intelligence will facilitate the development of combination therapy regimens that can potentially induce lasting and even curative treatment outcomes. Full article

(This article belongs to the Special Issue Molecular and Cellular Heterogeneity in an Evolving Tumor Landscape: When Diversity Gives Rise to Aggressive and Drug Resistant Cells)

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34 pages, 1418 KiB

Open AccessEditor’s ChoiceReview

Advances in the Repurposing and Blood–Brain Barrier Penetrance of Drugs in Pediatric Brain Tumors

by Julian S. Rechberger, Stephanie A. Toll, Subhasree Biswas, Hyo Bin You, William D. Chow, Nicholas Kendall, Pournima Navalkele and Soumen Khatua

Cancers 2025, 17(3), 439; https://doi.org/10.3390/cancers17030439 - 27 Jan 2025

Cited by 1 | Viewed by 3287

Abstract

Central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with prognosis remaining dismal for some of these malignancies. Though the past two decades have seen advancements in surgery, radiation, and targeted therapy, major unresolved hurdles continue to undermine [...] Read more.

Central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with prognosis remaining dismal for some of these malignancies. Though the past two decades have seen advancements in surgery, radiation, and targeted therapy, major unresolved hurdles continue to undermine the therapeutic efficacy. These include challenges in suboptimal drug delivery through the blood–brain barrier (BBB), marked intra-tumoral molecular heterogeneity, and the elusive tumor microenvironment. Drug repurposing or re-tasking FDA-approved drugs with evidence of penetration into the CNS, using newer methods of intracranial drug delivery facilitating optimal drug exposure, has been an area of intense research. This could be a valuable tool, as most of these agents have already gone through the lengthy process of drug development and the evaluation of safety risks and the optimal pharmacokinetic profile. They can now be used and tested in clinics with an accelerated and different approach. Conclusions: The next-generation therapeutic strategy should prioritize repurposing oncologic and non-oncologic drugs that have been used for other indication, and have demonstrated robust preclinical activity against pediatric brain tumors. In combination with novel drug delivery techniques, these drugs could hold significant therapeutic promise in pediatric neurooncology. Full article

(This article belongs to the Special Issue Advances in Drug Repurposing to Overcome Cancers)

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21 pages, 1715 KiB

Open AccessEditor’s ChoiceReview

Exploring Artificial Intelligence Biases in Predictive Models for Cancer Diagnosis

by Aref Smiley, C. Mahony Reategui-Rivera, David Villarreal-Zegarra, Stefan Escobar-Agreda and Joseph Finkelstein

Cancers 2025, 17(3), 407; https://doi.org/10.3390/cancers17030407 - 26 Jan 2025

Cited by 11 | Viewed by 1952

Abstract

The American Society of Clinical Oncology (ASCO) has released the principles for the responsible use of artificial intelligence (AI) in oncology emphasizing fairness, accountability, oversight, equity, and transparency. However, the extent to which these principles are followed is unknown. The goal of this [...] Read more.

The American Society of Clinical Oncology (ASCO) has released the principles for the responsible use of artificial intelligence (AI) in oncology emphasizing fairness, accountability, oversight, equity, and transparency. However, the extent to which these principles are followed is unknown. The goal of this study was to assess the presence of biases and the quality of studies on AI models according to the ASCO principles and examine their potential impact through citation analysis and subsequent research applications. A review of original research articles centered on the evaluation of predictive models for cancer diagnosis published in the ASCO journal dedicated to informatics and data science in clinical oncology was conducted. Seventeen potential bias criteria were used to evaluate the sources of bias in the studies, aligned with the ASCO’s principles for responsible AI use in oncology. The CREMLS checklist was applied to assess the study quality, focusing on the reporting standards, and the performance metrics along with citation counts of the included studies were analyzed. Nine studies were included. The most common biases were environmental and life-course bias, contextual bias, provider expertise bias, and implicit bias. Among the ASCO principles, the least adhered to were transparency, oversight and privacy, and human-centered AI application. Only 22% of the studies provided access to their data. The CREMLS checklist revealed the deficiencies in methodology and evaluation reporting. Most studies reported performance metrics within moderate to high ranges. Additionally, two studies were replicated in the subsequent research. In conclusion, most studies exhibited various types of bias, reporting deficiencies, and failure to adhere to the principles for responsible AI use in oncology, limiting their applicability and reproducibility. Greater transparency, data accessibility, and compliance with international guidelines are recommended to improve the reliability of AI-based research in oncology. Full article

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

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20 pages, 2817 KiB

Open AccessEditor’s ChoiceSystematic Review

Fluorescence-Guided Surgery to Detect Microscopic Disease in Ovarian Cancer: A Systematic Review with Meta-Analysis

by Evrim Erdemoglu, Carrie L. Langstraat, Amanika Kumar, Stuart A. Ostby, Marlene E. Girardo, Andrea Giannini and Kristina A. Butler

Cancers 2025, 17(3), 410; https://doi.org/10.3390/cancers17030410 - 26 Jan 2025

Cited by 1 | Viewed by 1568

Abstract

Background: The objective in epithelial ovarian cancer is to reach maximal cytoreduction with no visible residual tumor. Tumor detection during cytoreductive surgery depends on visual inspection, palpation, or blind biopsy, methods that lack reliability for identifying microscopic disease. Although the importance of [...] Read more.

Background: The objective in epithelial ovarian cancer is to reach maximal cytoreduction with no visible residual tumor. Tumor detection during cytoreductive surgery depends on visual inspection, palpation, or blind biopsy, methods that lack reliability for identifying microscopic disease. Although the importance of microscopic disease in epithelial ovarian cancer is controversial, it may harbor chemoresistant cells and explain the high recurrence rates. Fluorescence-guided surgery (FGS) is an emerging approach. However, the potential in ovarian cancer remains underexplored; the majority of the existing evidence pertains to gastrointestinal tumors and a limited group of ovarian cancer patients. Their comparative effectiveness is still uncertain. Objective: To systematically review and evaluate the role of fluorescence-guided surgical techniques in detecting microscopic disease in ovarian cancer and compare their efficacy to total peritonectomy. Data Sources: A systematic search was made in three databases (PubMed, Web of Science, and Embase). The search was conducted from 1975 to 2024, including randomized controlled trials, observational studies, and conference abstracts in the last 25 years. Study Selection: Clinical studies published in English involving ovarian cancer patients undergoing FGS or total peritonectomy were included. Case reports, reviews, animal studies, and studies involving mixed cancer populations without ovarian cancer-specific data were excluded. Two independent reviewers screened 631 studies, yielding 12 eligible studies for final analysis. Data Extraction and Synthesis: Data were extracted and synthesized in accordance with PRISMA and MOOSE guidelines, using random-effects models for independent analysis. Sensitivity, specificity, positive predictive value (PPV), and odds ratios (ORs) were grouped, accompanied by subgroup analyses based on the fluorescence agent employed. For quality assessment, we utilized the NIH quality tool. Main Outcome(s) and Measure(s): The primary outcome was the rate of change in surgical management due to fluorescence guidance or total peritonectomy. Secondary outcomes comprised lesion-level sensitivity, specificity, and PPV. Safety outcomes included adverse events associated with fluorescence agents. Results: There were 12 studies involving 429 ovarian cancer patients. FGS improved the detection of microscopic disease compared to standard visualization methods, with a pooled sensitivity of 0.77. Folate receptor-targeted agents had high sensitivity (84%) but low specificity (26%). Aminolevulinic acid (5-ALA) showed superior diagnostic accuracy with a sensitivity of 84% and a specificity of 96%. Total peritonectomy showed no significant advantage over FGS for detecting microscopic disease. The adverse events were mild, with no serious events reported. We observed a high heterogeneity across studies and methodologies. Conclusions and Relevance: Fluorescence-guided surgery utilizing fluorescence tracers demonstrates potential in improving the detection of microscopic disease and may change surgical management in epithelial ovarian cancer, particularly with 5-ALA. Variability in performance and limited data on survival outcomes necessitates additional research. Total peritonectomy does not offer further advantage in the detection of microscopic disease. Future trials should focus on standardizing methodology and evaluating the effects of microscopic disease removal on survival outcomes. Registration: The study was registered to PROSPERO as CRD42024578274. Full article

(This article belongs to the Special Issue Paradigm Shifts in Gynaecological Oncology Surgery)

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38 pages, 2883 KiB

Open AccessEditor’s ChoiceReview

Hepatic Iron Overload and Hepatocellular Carcinoma: New Insights into Pathophysiological Mechanisms and Therapeutic Approaches

by Elena Chatzikalil, Konstantinos Arvanitakis, Georgios Kalopitas, Matilda Florentin, Georgios Germanidis, Theocharis Koufakis and Elena E. Solomou

Cancers 2025, 17(3), 392; https://doi.org/10.3390/cancers17030392 - 24 Jan 2025

Cited by 5 | Viewed by 3207

Abstract

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is rising in global incidence and mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disease, is strongly linked to metabolic conditions that can progress to [...] Read more.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is rising in global incidence and mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disease, is strongly linked to metabolic conditions that can progress to liver cirrhosis and HCC. Iron overload (IO), whether inherited or acquired, results in abnormal iron hepatic deposition, significantly impacting MASLD development and progression to HCC. While the pathophysiological connections between hepatic IO, MASLD, and HCC are not fully understood, dysregulation of glucose and lipid metabolism and IO-induced oxidative stress are being investigated as the primary drivers. Genomic analyses of inherited IO conditions reveal inconsistencies in the association of certain mutations with liver malignancies. Moreover, hepatic IO is also associated with hepcidin dysregulation and activation of ferroptosis, representing promising targets for HCC risk assessment and therapeutic intervention. Understanding the relationship between hepatic IO, MASLD, and HCC is essential for advancing clinical strategies against liver disease progression, particularly with recent IO-targeted therapies showing potential at improving liver biochemistry and insulin sensitivity. In this review, we summarize the current evidence on the pathophysiological association between hepatic IO and the progression of MASLD to HCC, underscoring the importance of early diagnosis, risk stratification, and targeted treatment for these interconnected conditions. Full article

(This article belongs to the Special Issue Advanced Research in Oncology in 2024)

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15 pages, 1392 KiB

Open AccessEditor’s ChoiceReview

Unraveling the Role of Fusobacterium nucleatum in Colorectal Cancer: Molecular Mechanisms and Pathogenic Insights

by Linda Galasso, Fabrizio Termite, Irene Mignini, Giorgio Esposto, Raffaele Borriello, Federica Vitale, Alberto Nicoletti, Mattia Paratore, Maria Elena Ainora, Antonio Gasbarrini and Maria Assunta Zocco

Cancers 2025, 17(3), 368; https://doi.org/10.3390/cancers17030368 - 23 Jan 2025

Cited by 13 | Viewed by 4628

Abstract

Fusobacterium nucleatum, a gram-negative anaerobic bacterium, has emerged as a significant player in colorectal cancer (CRC) pathogenesis. The bacterium causes a persistent inflammatory reaction in the colorectal mucosa by stimulating the release of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α, creating an [...] Read more.

Fusobacterium nucleatum, a gram-negative anaerobic bacterium, has emerged as a significant player in colorectal cancer (CRC) pathogenesis. The bacterium causes a persistent inflammatory reaction in the colorectal mucosa by stimulating the release of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α, creating an environment conducive to cancer progression. F. nucleatum binds to and penetrates epithelial cells through adhesins such as FadA, impairing cell junctions and encouraging epithelial-to-mesenchymal transition (EMT), which is associated with cancer advancement. Additionally, the bacterium modulates the host immune system, suppressing immune cell activity and creating conditions favorable for tumor growth. Its interactions with the gut microbiome contribute to dysbiosis, further influencing carcinogenic pathways. Evidence indicates that F. nucleatum can inflict DNA damage either directly via reactive oxygen species or indirectly by creating a pro-inflammatory environment. Additionally, it triggers oncogenic pathways, especially the Wnt/β-catenin signaling pathway, which promotes tumor cell growth and longevity. Moreover, F. nucleatum alters the tumor microenvironment, impacting cancer cell behavior, metastasis, and therapeutic responses. The purpose of this review is to elucidate the molecular mechanisms by which F. nucleatum contributes to CRC. Understanding these mechanisms is crucial for the development of targeted therapies and diagnostic strategies for CRC associated with F. nucleatum. Full article

(This article belongs to the Special Issue Novel Approaches and Advances in Interventional Oncology)

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12 pages, 1306 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Molecular Profiling of Metastatic Pancreatic Adenocarcinomas

by Vijay Antony, Tong Sun, Darin Dolezal and Guoping Cai

Cancers 2025, 17(3), 335; https://doi.org/10.3390/cancers17030335 - 21 Jan 2025

Cited by 1 | Viewed by 1498

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed late, with an extremely poor prognosis. Treatment options like surgery, radiation, and chemotherapy are rarely curative. Tumor progression from primary to metastatic PDAC remains poorly understood at the molecular level. Methods: In the current study, [...] Read more.

Background: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed late, with an extremely poor prognosis. Treatment options like surgery, radiation, and chemotherapy are rarely curative. Tumor progression from primary to metastatic PDAC remains poorly understood at the molecular level. Methods: In the current study, we analyzed the molecular profiles of metastatic PDAC obtained via the Oncomine Comprehensive Assay in comparison to primary PDAC. Results: The current study cohort consisted of 115 metastatic PDAC cases, of which 71 (62%) cases succeeded in molecular testing while the remaining 44 (38%) cases contained insufficient tumor cells. Molecular profiling of 71 cases revealed a total of 239 molecular alterations, 3.4 alterations per case on average, predominantly in the form of gene mutations. The most common gene mutations included KRAS (86%) and TP53 (83%) mutations. Gene copy number alterations were also detected in 19 (27%) cases involving genes such as CCNE1 and ERBB2. Compared to the molecular profiles of primary PDAC reported in our prior study and TCGA database, there seemed to be increased rates of TP53, ARID1A, BRAF, and PIK3CA mutations in the metastatic diseases. Conclusions: These findings suggest that metastatic PDAC possesses unique genetic characteristics, offering potential therapeutic targets in advanced-stage pancreatic cancer. Full article

(This article belongs to the Special Issue Histology and Pathology of Pancreatic Cancer)

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37 pages, 2321 KiB

Open AccessEditor’s ChoiceReview

Triple-Negative Breast Cancer Progression and Drug Resistance in the Context of Epithelial–Mesenchymal Transition

by Ewa Błaszczak, Paulina Miziak, Adrian Odrzywolski, Marzena Baran, Ewelina Gumbarewicz and Andrzej Stepulak

Cancers 2025, 17(2), 228; https://doi.org/10.3390/cancers17020228 - 12 Jan 2025

Cited by 8 | Viewed by 5093

Abstract

Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to [...] Read more.

Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to other breast cancer subtypes. Despite advancements in targeted therapies, traditional chemotherapy (primarily using platinum compounds and taxanes) continues to be the standard treatment for TNBC, often with limited long-term efficacy. TNBC tumors are heterogeneous, displaying a diverse mutation profile and considerable chromosomal instability, which complicates therapeutic interventions. The development of chemoresistance in TNBC is frequently associated with the process of epithelial–mesenchymal transition (EMT), during which epithelial tumor cells acquire a mesenchymal-like phenotype. This shift enhances metastatic potential, while simultaneously reducing the effectiveness of standard chemotherapeutics. It has also been suggested that EMT plays a central role in the development of cancer stem cells. Hence, there is growing interest in exploring small-molecule inhibitors that target the EMT process as a future strategy for overcoming resistance and improving outcomes for patients with TNBC. This review focuses on the progression and drug resistance of TNBC with an emphasis on the role of EMT in these processes. We present TNBC-specific and EMT-related molecular features, key EMT protein markers, and various signaling pathways involved. We also discuss other important mechanisms and factors related to chemoresistance in TNBC within the context of EMT, highlighting treatment advancements to improve patients’ outcomes. Full article

(This article belongs to the Special Issue Triple Negative Breast Cancer Therapy Resistance and Metastasis)

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29 pages, 1367 KiB

Open AccessEditor’s ChoiceReview

Current Paradigm and Future Directions in the Management of Nodal Disease in Locally Advanced Cervical Cancer

by Elki Sze-Nga Cheung and Philip Yuguang Wu

Cancers 2025, 17(2), 202; https://doi.org/10.3390/cancers17020202 - 9 Jan 2025

Cited by 3 | Viewed by 1693

Abstract

Approximately 36% of patients with cervical cancer present with regional nodal metastasis at diagnosis, which is associated with adverse survival outcomes after definitive treatment. In the modern era of chemoradiotherapy (CRT) and image-guided adaptive brachytherapy (IGABT), where excellent local control is achieved for [...] Read more.

Approximately 36% of patients with cervical cancer present with regional nodal metastasis at diagnosis, which is associated with adverse survival outcomes after definitive treatment. In the modern era of chemoradiotherapy (CRT) and image-guided adaptive brachytherapy (IGABT), where excellent local control is achieved for patients with locally advanced cervical cancer (LACC), nodal failure remains a major challenge to cure. To optimize treatment outcomes for node-positive LACC and reduce the incidence of nodal failure, various treatment approaches have been explored, including methods of surgical nodal staging or dissection, RT dose escalation strategies, such as intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) to involved nodes, and elective treatment of subclinical para-aortic (PAO) disease. Additionally, there is growing interest in emerging precision RT techniques, such as magnetic resonance-guided radiotherapy (MRgRT) and proton therapy, which may allow for further improvement in the therapeutic ratio. This review outlines the various methods of detection of nodal metastasis, treatment options for node-positive LACC, techniques of nodal radiotherapy and their clinical evidence in efficacy and toxicity profiles. Furthermore, recent advances in systemic therapy and promising novel therapeutic directions that may shape the management of node-positive LACC are discussed. Full article

(This article belongs to the Special Issue Advanced Research in Oncology in 2024)

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24 pages, 13647 KiB

Open AccessEditor’s ChoiceArticle

Blockade of LIF and PD-L1 Enhances Chemotherapy in Preclinical PDAC Models

by Jian Ye, Shuyang S. Qin, Angela L. Hughson, Gary Hannon, Tara G. Vrooman, Maggie L. Lesch, Sarah L. Eckl, Lauren Benoodt, Bradley N. Mills, Edith M. Lord, Brian A. Belt, David C. Linehan, Nadia Luheshi, Jim Eyles and Scott A. Gerber

Cancers 2025, 17(2), 204; https://doi.org/10.3390/cancers17020204 - 9 Jan 2025

Cited by 1 | Viewed by 1741

Abstract

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC), expecting to be the second leading cause of cancer deaths by 2030, resists immune checkpoint therapies due to its immunosuppressive tumor microenvironment (TME). Leukemia inhibitory factor (LIF) is a key target in PDAC, promoting stemness, epithelial–mesenchymal transition [...] Read more.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC), expecting to be the second leading cause of cancer deaths by 2030, resists immune checkpoint therapies due to its immunosuppressive tumor microenvironment (TME). Leukemia inhibitory factor (LIF) is a key target in PDAC, promoting stemness, epithelial–mesenchymal transition (EMT), and therapy resistance. Phase 1 clinical trials showed anti-LIF therapy is safe but with limited efficacy, suggesting better outcomes when combined with chemotherapy, radiotherapy, or immunotherapy. Methods: We assessed the combination of chemotherapy (gemcitabine/nab-paclitaxel) and dual blockade of LIF and PD-L1 on tumor growth and survival in orthotopic and spontaneous PDAC models. Flow cytometry and scRNA-seq were utilized to monitor the antitumor immune response. The role of key immune cells was further confirmed by depleting these immune cells, including CD4, CD8, or inflammatory monocytes. Results: Sequential treatment with chemotherapy (gemcitabine/nab-paclitaxel) and dual blockade of LIF and PD-L1 significantly improved antitumor efficacy compared to monotherapy or dual combinations of these therapies. This chemo/anti-LIF/anti-PD-L1 approach reduced EMT in tumor cells and enhanced the antitumor immune response, primarily through CD8 T cells, as depleting CD8 cells largely abrogated the effect of treatment. This combination therapy also shifted macrophages and dendritic cells towards an antitumor phenotype. Conclusions: The combination of chemotherapy, anti-LIF, and anti-PD-L1 not only targeted tumor cells but also augmented the anti-tumor immune response. These findings strongly support advancing chemo/anti-LIF/anti-PD-L1 combination therapy to clinical trials in PDAC. Full article

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

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32 pages, 370 KiB

Open AccessEditor’s ChoiceReview

Management of Patients with Vulvar Cancers: A Systematic Comparison of International Guidelines (NCCN–ASCO–ESGO–BGCS–IGCS–FIGO–French Guidelines–RCOG)

by Stefano Restaino, Giulia Pellecchia, Martina Arcieri, Giorgio Bogani, Cristina Taliento, Pantaleo Greco, Lorenza Driul, Vito Chiantera, Rosa Pasqualina De Vincenzo, Giorgia Garganese, Francesco Sopracordevole, Violante Di Donato, Andrea Ciavattini, Paolo Scollo, Giovanni Scambia, Giuseppe Vizzielli and Gynecologic Oncology Group

Cancers 2025, 17(2), 186; https://doi.org/10.3390/cancers17020186 - 8 Jan 2025

Cited by 7 | Viewed by 4453

Abstract

Background: Vulvar carcinoma is an uncommon gynecological tumor primarily affecting older women. Its treatment significantly impacts the quality of life and, not least, aesthetics because of the mutilating surgery it requires. Objectives: The management requires a multidisciplinary team of specialists who know how [...] Read more.

Background: Vulvar carcinoma is an uncommon gynecological tumor primarily affecting older women. Its treatment significantly impacts the quality of life and, not least, aesthetics because of the mutilating surgery it requires. Objectives: The management requires a multidisciplinary team of specialists who know how to care for the patient in her entirety, not neglecting psychological aspects and reconstructive surgery. How do the guidelines address multidisciplinarity, team surgical management, passing through preoperative diagnosis, and follow-up in such a challenging rare tumor to treat? Methods: To answer these questions, we compared the main scientific recommendations to identify similarities and differences in diagnostic and therapeutic management to provide an overview of the gaps that there are currently in European and American international recommendations in providing management guidance in a cancer that is both among the rarest and most difficult to manage. In this way, we aim to encourage an update in practices based on the latest scientific evidence. Results: A review of various international guidelines, some dating back to 2014, shows significant variation in approaches, ranging from initial diagnostic procedures to managing relapses. The most recent guidelines also lacked references to the latest literature, indicating that more robust scientific evidence is needed before new treatments, such as electrochemotherapy for palliation and reconstructive surgery post exenteration, can be widely adopted. Conclusions: From the systematic comparison of the main international guidelines, a strong heterogeneity emerged in the diagnostic and therapeutic recommendations as well as for the multidisciplinary approach that today is essential. Our work certainly stimulated an update of the main guidelines. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

19 pages, 792 KiB

Open AccessEditor’s ChoiceReview

Recurrent and Metastatic Head and Neck Cancer: Mechanisms of Treatment Failure, Treatment Paradigms, and New Horizons

by William T. Barham, Marshall Patrick Stagg, Rula Mualla, Michael DiLeo and Sagar Kansara

Cancers 2025, 17(1), 144; https://doi.org/10.3390/cancers17010144 - 5 Jan 2025

Cited by 2 | Viewed by 2307

Abstract

Background: Head and neck cancer is a deadly disease with over 500,000 cases annually worldwide. Metastatic head and neck cancer accounts for a large proportion of the mortality associated with this disease. Many advances have been made in our understanding of the mechanisms [...] Read more.

Background: Head and neck cancer is a deadly disease with over 500,000 cases annually worldwide. Metastatic head and neck cancer accounts for a large proportion of the mortality associated with this disease. Many advances have been made in our understanding of the mechanisms of metastasis. The application of immunotherapy to locally recurrent or metastatic head and neck cancer has not only improved oncologic outcomes but has also provided valuable insights into the mechanisms of immune evasion and ultimately treatment failure. Objectives: This review paper will review our current understanding of biological mechanisms of treatment failure and metastasis. Published and ongoing clinical trials in the management of metastatic head and neck cancer will also be summarized. Methods: A narrative review was conducted to address the current understanding of the mechanisms of treatment failure and current treatment paradigms in recurrent and metastatic head and neck carcinoma. Conclusions: Our understanding of treatment failure in this disease is rapidly evolving. Immunotherapy represents a valuable new tool in the fight against recurrent and metastatic head and neck squamous cell carcinoma. Integrating patient and tumor specific data via artificial intelligence and deep learning will allow for a precision oncology approach, thereby achieving better prognostication and management of patients with this deadly disease. Full article

(This article belongs to the Collection Advances in Diagnostics and Treatment of Head and Neck Cancer)

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32 pages, 3337 KiB

Open AccessEditor’s ChoiceReview

Exploring the Metabolic Impact of FLASH Radiotherapy

by Febe Geirnaert, Lisa Kerkhove, Pierre Montay-Gruel, Thierry Gevaert, Inès Dufait and Mark De Ridder

Cancers 2025, 17(1), 133; https://doi.org/10.3390/cancers17010133 - 3 Jan 2025

Cited by 5 | Viewed by 2412

Abstract

FLASH radiotherapy (FLASH RT) is an innovative modality in cancer treatment that delivers ultrahigh dose rates (UHDRs), distinguishing it from conventional radiotherapy (CRT). FLASH RT has demonstrated the potential to enhance the therapeutic window by reducing radiation-induced damage to normal tissues while maintaining [...] Read more.

FLASH radiotherapy (FLASH RT) is an innovative modality in cancer treatment that delivers ultrahigh dose rates (UHDRs), distinguishing it from conventional radiotherapy (CRT). FLASH RT has demonstrated the potential to enhance the therapeutic window by reducing radiation-induced damage to normal tissues while maintaining tumor control, a phenomenon termed the FLASH effect. Despite promising outcomes, the precise mechanisms underlying the FLASH effect remain elusive and are a focal point of current research. This review explores the metabolic and cellular responses to FLASH RT compared to CRT, with particular focus on the differential impacts on normal and tumor tissues. Key findings suggest that FLASH RT may mitigate damage in healthy tissues via altered reactive oxygen species (ROS) dynamics, which attenuate downstream oxidative damage. Studies indicate the FLASH RT influences iron metabolism and lipid peroxidation pathways differently than CRT. Additionally, various studies indicate that FLASH RT promotes the preservation of mitochondrial integrity and function, which helps maintain apoptotic pathways in normal tissues, attenuating damage. Current knowledge of the metabolic influences following FLASH RT highlights its potential to minimize toxicity in normal tissues, while also emphasizing the need for further studies in biologically relevant, complex systems to better understand its clinical potential. By targeting distinct metabolic pathways, FLASH RT could represent a transformative advance in RT, ultimately improving the therapeutic window for cancer treatment. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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13 pages, 432 KiB

Open AccessEditor’s ChoiceReview

Advancing Thoracic Surgical Oncology in the Era of Precision Medicine

by Giacomo Argento, Erino Angelo Rendina and Giulio Maurizi

Cancers 2025, 17(1), 115; https://doi.org/10.3390/cancers17010115 - 2 Jan 2025

Cited by 1 | Viewed by 1249

Abstract

The landscape of surgical oncology is rapidly evolving with the advent of precision medicine, driven by breakthroughs in genomics and proteomics. This article explores how integrating molecular data is transforming surgical decision-making and enabling personalized treatment strategies. We examine emerging technologies such as [...] Read more.

The landscape of surgical oncology is rapidly evolving with the advent of precision medicine, driven by breakthroughs in genomics and proteomics. This article explores how integrating molecular data is transforming surgical decision-making and enabling personalized treatment strategies. We examine emerging technologies such as next-generation sequencing, proteomic analysis, and molecular imaging, which provide critical insights into tumor biology and guide surgical interventions. The article also highlights the application of genomic and proteomic data in preoperative planning and the development of personalized resection strategies. Additionally, we will address the current challenges and future opportunities in this rapidly evolving field, emphasizing the need for continuous education, interdisciplinary collaboration, and ongoing research to fully realize the potential of precision medicine in thoracic surgical oncology, paving the way for more effective and individualized cancer treatments. Full article

(This article belongs to the Special Issue Oncogenomic and Multi-Omic Data Science and Data Engineering)

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20 pages, 2716 KiB

Open AccessEditor’s ChoiceArticle

Machine Learning and Computed Tomography Radiomics to Predict Disease Progression to Upfront Pembrolizumab Monotherapy in Advanced Non-Small-Cell Lung Cancer: A Pilot Study

by Ian Janzen, Cheryl Ho, Barbara Melosky, Qian Ye, Jessica Li, Gang Wang, Stephen Lam, Calum MacAulay and Ren Yuan

Cancers 2025, 17(1), 58; https://doi.org/10.3390/cancers17010058 - 28 Dec 2024

Cited by 2 | Viewed by 2310

Abstract

Background/Objectives: Pembrolizumab monotherapy is approved in Canada for first-line treatment of advanced NSCLC with PD-L1 ≥ 50% and no EGFR/ALK aberrations. However, approximately 55% of these patients do not respond to pembrolizumab, underscoring the need for the early intervention of non-responders to optimize [...] Read more.

Background/Objectives: Pembrolizumab monotherapy is approved in Canada for first-line treatment of advanced NSCLC with PD-L1 ≥ 50% and no EGFR/ALK aberrations. However, approximately 55% of these patients do not respond to pembrolizumab, underscoring the need for the early intervention of non-responders to optimize treatment strategies. Distinguishing the 55% sub-cohort prior to treatment is a real-world dilemma. Methods: In this retrospective study, we analyzed two patient cohorts treated with pembrolizumab monotherapy (training set: n = 97; test set: n = 17). The treatment response was assessed using baseline and follow-up CT scans via RECIST 1.1 criteria. Results: A logistic regression model, incorporating pre-treatment CT radiomic features of lung tumors and clinical variables, achieved high predictive accuracy (AUC: 0.85 in training; 0.81 in testing, 95% CI: 0.63–0.99). Notably, radiomic features from the peritumoral region were found to be independent predictors, complementing the standard CT evaluations and other clinical characteristics. Conclusions: This pragmatic model offers a valuable tool to guide first-line treatment decisions in NSCLC patients with high PD-L1 expression and has the potential to advance personalized oncology and improve timely disease management. Full article

(This article belongs to the Special Issue Advances in Oncological Imaging)

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24 pages, 1923 KiB

Open AccessEditor’s ChoiceArticle

Predictive Mortality and Gastric Cancer Risk Using Clinical and Socio-Economic Data: A Nationwide Multicenter Cohort Study

by Seong Uk Kang, Seung-Joo Nam, Oh Beom Kwon, Inhyeok Yim, Tae-Hoon Kim, Na Young Yeo, Myoung Nam Lim, Woo Jin Kim and Sang Won Park

Cancers 2025, 17(1), 30; https://doi.org/10.3390/cancers17010030 - 25 Dec 2024

Cited by 1 | Viewed by 1491

Abstract

Background/Objectives: Gastric cancer is a leading cause of cancer-related mortality, particularly in East Asia, with a notable burden in Republic of Korea. This study aimed to construct and develop machine learning models for the prediction of gastric cancer mortality and the identification of [...] Read more.

Background/Objectives: Gastric cancer is a leading cause of cancer-related mortality, particularly in East Asia, with a notable burden in Republic of Korea. This study aimed to construct and develop machine learning models for the prediction of gastric cancer mortality and the identification of risk factors. Methods: All data were acquired from the Korean Clinical Data Utilization for Research Excellence by multiple medical centers in South Korea. A total of 23,717 gastric cancer patients were divided into two groups by cause of mortality (all-cause of 2664 and disease-specific of 1620) and investigated. We used comprehensive data integrating clinical, pathological, lifestyle, and socio-economic factors. Cox proportional hazards analysis was conducted to estimate hazard ratios for mortality. Five machine learning models (random forest, gradient boosting machine, XGBoost, light GBM, and cat boosting) were developed to predict mortality. The models were interpreted by SHAP, one of the explainable AI techniques. Results: For all-cause mortality, the gradient-boosting machine learning model demonstrated the highest performance with an AUC-ROC of 0.795. For disease-specific mortality, the light GBM model outperformed others, achieving an AUC-ROC of 0.867. Significant predictors included the AJCC7 stage, tumor size, lymph node count, and lifestyle factors such as smoking, drinking, and diabetes. Conclusions: This study underscores the importance of integrating both clinical and lifestyle data to enhance mortality prediction accuracy in gastric cancer patients. The findings highlight the need for personalized treatment approaches in the Korean population and emphasize the role of demographic-specific data in predictive modeling. Full article

(This article belongs to the Section Clinical Research of Cancer)

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21 pages, 911 KiB

Open AccessEditor’s ChoiceReview

Insights into the Relationship Between the Gut Microbiome and Immune Checkpoint Inhibitors in Solid Tumors

by Sona Ciernikova, Aneta Sevcikova, Maria Novisedlakova and Michal Mego

Cancers 2024, 16(24), 4271; https://doi.org/10.3390/cancers16244271 - 23 Dec 2024

Cited by 3 | Viewed by 2778

Abstract

Immunotherapy with immune checkpoint inhibitors represents a revolutionary approach to the treatment of solid tumors, including malignant melanoma, lung cancer, and gastrointestinal malignancies. Anti-CTLA-4 and anti-PD-1/PDL-1 therapies provide prolonged survival for cancer patients, but their efficacy and safety are highly variable. This review [...] Read more.

Immunotherapy with immune checkpoint inhibitors represents a revolutionary approach to the treatment of solid tumors, including malignant melanoma, lung cancer, and gastrointestinal malignancies. Anti-CTLA-4 and anti-PD-1/PDL-1 therapies provide prolonged survival for cancer patients, but their efficacy and safety are highly variable. This review focuses on the crucial role of the gut microbiome in modulating the efficacy and toxicity of immune checkpoint blockade. Studies suggest that the composition of the gut microbiome may influence the response to immunotherapy, with specific bacterial strains able to promote an anti-tumor immune response. On the other hand, dysbiosis may increase the risk of adverse effects, such as immune-mediated colitis. Interventions aimed at modulating the microbiome, including the use of probiotics, prebiotics, fecal microbial transplantation, or dietary modifications, represent promising strategies to increase treatment efficacy and reduce toxicity. The combination of immunotherapy with the microbiome-based strategy opens up new possibilities for personalized treatment. In addition, factors such as physical activity and nutritional supplementation may indirectly influence the gut ecosystem and consequently improve treatment outcomes in refractory patients, leading to enhanced patient responses and prolonged survival. Full article

(This article belongs to the Special Issue Immunotherapy of Solid Tumors and New Ideas of Anti-tumor Metastasis)

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24 pages, 4058 KiB

Open AccessEditor’s ChoiceReview

Targeting of Non-Classical Human Leukocyte Antigens as Novel Therapeutic Strategies in Cancer

by Javier David Benitez Fuentes, Jorge Bartolome Arcilla, Kauzar Mohamed Mohamed, Alfonso Lopez de Sa, Alicia de Luna Aguilar, Kissy Guevara-Hoyer, Pablo Ballestin Martinez, Antonio David Lazaro Sanchez, Edgardo D. Carosella, Alberto Ocaña and Silvia Sánchez-Ramon

Cancers 2024, 16(24), 4266; https://doi.org/10.3390/cancers16244266 - 22 Dec 2024

Cited by 2 | Viewed by 2234

Abstract

Human leukocyte antigens (HLAs) are essential regulators of immune responses against cancer, with classical HLAs well-documented for their role in tumor recognition and immune surveillance. In recent years, non-classical HLAs—including HLA-E, HLA-F, HLA-G, and HLA-H—have emerged as critical players in the immune landscape [...] Read more.

Human leukocyte antigens (HLAs) are essential regulators of immune responses against cancer, with classical HLAs well-documented for their role in tumor recognition and immune surveillance. In recent years, non-classical HLAs—including HLA-E, HLA-F, HLA-G, and HLA-H—have emerged as critical players in the immune landscape of cancer due to their diverse and less conventional functions in immune modulation. These molecules exhibit unique mechanisms that enable tumors to escape immune detection, promote tumor progression, and contribute to therapeutic resistance. This review provides a comprehensive examination of the current understanding of non-classical HLAs in solid cancers, focusing on their specific roles in shaping the tumor microenvironment and influencing immune responses. By analyzing how HLA-E, HLA-F, HLA-G, and HLA-H modulate interactions with immune cells, such as T cells, natural killer cells, and antigen-presenting cells, we highlight key pathways through which these molecules contribute to immune evasion and metastasis. Additionally, we review promising therapeutic strategies aimed at targeting non-classical HLAs, including emerging immunotherapies that could potentially enhance cancer treatment outcomes by reversing immune suppression within tumors. Understanding the influence of these non-classical HLAs in solid cancers may offer new insights into cancer immunology and may lead to the development of innovative and more effective immunotherapeutic approaches. This review underscores the importance of non-classical HLAs as potential therapeutic targets, providing a necessary foundation for future studies in the evolving field of cancer immunotherapy. Full article

(This article belongs to the Special Issue Identification and Clinical Application of Immunological Receptors Targeting Mutated Antigens Expressed by Solid Tumors (2nd Edition))

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20 pages, 1081 KiB

Open AccessEditor’s ChoiceReview

Implication of the Extracellular Matrix in Metastatic Tumor Cell Dormancy

by Chloe Redoute-Timonnier and Patrick Auguste

Cancers 2024, 16(23), 4076; https://doi.org/10.3390/cancers16234076 - 5 Dec 2024

Cited by 3 | Viewed by 1697

Abstract

Metastasis is the main cause of cancer-related deaths. The formation and growth of metastasis is a multistep process. Tumor cells extravasating in the secondary organ are in contact with a new microenvironment and a new extracellular matrix (ECM), called the metastatic niche. Some [...] Read more.

Metastasis is the main cause of cancer-related deaths. The formation and growth of metastasis is a multistep process. Tumor cells extravasating in the secondary organ are in contact with a new microenvironment and a new extracellular matrix (ECM), called the metastatic niche. Some components of the ECM, such as periostin, can induce tumor cell growth in macrometastasis. In contrast, other components, such as Thrombospondin 1 (TSP-1), can maintain isolated cells in a dormant state. During dormancy, intracellular signaling activation, such as p38, maintains tumor cells arrested in the cell-cycle G0 phase for years. At any moment, stress can induce ECM modifications and binding to their specific receptors (mainly integrins) and reactivate dormant tumor cell growth in macrometastasis. In this review, we describe the tumor microenvironment of the different niches implicated in tumor cell dormancy. The role of ECM components and their associated receptors and intracellular signaling in the reactivation of dormant tumor cells in macrometastasis will be emphasized. We also present the different methodologies and experimental approaches used to study tumor cell dormancy. Finally, we discuss the current and future treatment strategies to avoid late metastasis relapse in patients. Full article

(This article belongs to the Special Issue Extracellular Matrix Proteins in Cancer)

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20 pages, 2728 KiB

Open AccessEditor’s ChoiceReview

P53 and the Ultraviolet Radiation-Induced Skin Response: Finding the Light in the Darkness of Triggered Carcinogenesis

by Carla Carvalho, Rita Silva, Teresa M. V. D. Pinho e Melo, Alberto Inga and Lucília Saraiva

Cancers 2024, 16(23), 3978; https://doi.org/10.3390/cancers16233978 - 27 Nov 2024

Cited by 6 | Viewed by 3189

Abstract

This review delves into the significant cellular and molecular responses triggered by UVR exposure in human skin, emphasizing the pivotal role of mutant p53 (mutp53) in the carcinogenic process elicited by radiation. By underlining the role of a functional p53 in safeguarding skin [...] Read more.

This review delves into the significant cellular and molecular responses triggered by UVR exposure in human skin, emphasizing the pivotal role of mutant p53 (mutp53) in the carcinogenic process elicited by radiation. By underlining the role of a functional p53 in safeguarding skin cells from UVR-induced damage, this work underscores the potential significance of targeting mutp53, aiming to restore its wild-type-like activity (reactivation), as a protective strategy against skin cancer (SC), particularly NMSC. Most importantly, an interesting crosstalk between p53 and its vitamin D receptor (VDR) transcriptional target is also highlighted in the suppression of skin carcinogenesis, which opens the way to promising chemopreventive strategies involving synergistic combinations between mutp53 reactivators and vitamin D. Collectively, this review not only opens new avenues for future research, but also offers promising prospects for the development of novel beneficial approaches in the field of SC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology and Therapeutics)

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19 pages, 2052 KiB

Open AccessEditor’s ChoiceArticle

Uterine Carcinosarcoma (UCS): A Literature Review and Survival Analysis from a Retrospective Cohort Study

by Mauro Francesco Pio Maiorano, Gennaro Cormio, Brigida Anna Maiorano and Vera Loizzi

Cancers 2024, 16(23), 3905; https://doi.org/10.3390/cancers16233905 - 21 Nov 2024

Cited by 4 | Viewed by 2454

Abstract

Background/Objectives: Uterine carcinosarcomas (UCSs) are rare and aggressive malignancies with limited epidemiological data. This study aims to evaluate the clinical and pathological features and prognostic factors of UCS in a retrospective cohort of 80 patients, contributing to improved management strategies. Methods: We conducted [...] Read more.

Background/Objectives: Uterine carcinosarcomas (UCSs) are rare and aggressive malignancies with limited epidemiological data. This study aims to evaluate the clinical and pathological features and prognostic factors of UCS in a retrospective cohort of 80 patients, contributing to improved management strategies. Methods: We conducted a retrospective analysis of UCS cases treated from 1995 to 2024 at three institutions. Data on demographics, clinical features, histopathology, treatment, and outcomes were collected. Overall survival (OS) and prognostic factors were assessed using Kaplan–Meier and Cox proportional hazards regression analyses. Results: The median age of patients was 66 years, with a median overall survival of 34.5 months. Disease recurrence occurred in 32.5% of cases, with a median disease-free interval of 17.92 months. Age, tumour stage, and size emerged as significant predictors of survival. Stage I–II patients had a significantly better prognosis than those with Stage III–IV (HR = 0.438, p = 0.008). Tumour size >4 cm was associated with increased mortality (HR = 2.154, p = 0.019). Lymphadenectomy was not independently associated with improved survival. Adjuvant chemotherapy, mainly carboplatin and paclitaxel, was administered to 67.5% of patients, achieving a complete response in 66.67%. Conclusions: Tumour stage and age are significant independent predictors of survival in UCS, underscoring the need for early diagnosis and intervention. Tumour size is also crucial in determining prognosis. The role of lymphadenectomy remains uncertain, emphasizing the importance of individualized treatment approaches. Future research should explore molecular profiling to further refine prognostication and therapeutic strategies for this challenging malignancy. Full article

(This article belongs to the Section Molecular Cancer Biology)

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14 pages, 2192 KiB

Open AccessEditor’s ChoiceSystematic Review

Prostate-Specific Membrane Antigen (PSMA) PET/CT in the Detection and Diagnosis of Hepatocellular Carcinoma (HCC): A Systematic Review and Meta-Analysis

by Nicholas Hannah, Catherine Yu, Leya Nedumannil, James Haridy, Grace Kong, Alex Boussioutas and Siddharth Sood

Cancers 2024, 16(22), 3865; https://doi.org/10.3390/cancers16223865 - 19 Nov 2024

Cited by 4 | Viewed by 1990

Abstract

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is widely used in prostate cancer. Recent studies indicate hepatocellular carcinoma (HCC) demonstrates PSMA PET uptake. The diagnostic accuracy of PSMA PET for HCC is not known. We conducted a systematic review and meta-analysis of [...] Read more.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is widely used in prostate cancer. Recent studies indicate hepatocellular carcinoma (HCC) demonstrates PSMA PET uptake. The diagnostic accuracy of PSMA PET for HCC is not known. We conducted a systematic review and meta-analysis of studies assessing ⁶⁸Ga-PSMA-11 in HCC. Nine studies were included, with 196 patients and a total of 491 HCC lesions. Per-patient analysis yielded a pooled sensitivity of 89.8% (95% CI 78.5–95.5). Specificity was poorly reported, with insufficient data. When per-lesion level analysis was performed on seven studies, the pooled sensitivity was 94.5% (95% CI 82.9–98.4), and specificity was again poorly reported with insufficient data. Among the three studies with adequate data for full per-lesion meta-analysis, 115 lesions in 41 patients demonstrated sensitivity of 97.1% (95% CI 87.8–99.4), while specificity was 42.2% (95% CI 0.3–99.4). Two studies provided sufficient data for meta-analysis on a per-patient level (n = 50 patients), demonstrating a sensitivity of 92.5% (95% CI 64.0–98.9) and specificity of 72.4% (95% CI 1.3–99.8). PSMA PET demonstrates a high sensitivity for HCC and shows promise as an imaging modality for diagnosis and staging of HCC. However, the existing literature does not provide enough data to confidently evaluate its specificity and, therefore, accuracy. Further prospective studies are necessary, with a focus on the accurate reporting of benign lesions and inclusion of patients with an intermediate probability of HCC. Full article

(This article belongs to the Special Issue New Approaches in Radiotherapy for Cancer)

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12 pages, 601 KiB

Open AccessEditor’s ChoiceArticle

First-Line Combination of R-CHOP with the PDE4 Inhibitor Roflumilast for High-Risk DLBCL

by Adolfo E. Diaz Duque, Pedro S. S. M. Ferrari, Purushoth Ethiraj, Carine Jaafar, Zhijun Qiu, Kenneth Holder, Mathew J. Butler, Gabriela Huelgas-Morales, Anand Karnad, Patricia L. M. Dahia and Ricardo C. T. Aguiar

Cancers 2024, 16(22), 3857; https://doi.org/10.3390/cancers16223857 - 18 Nov 2024

Cited by 1 | Viewed by 1906

Abstract

Background: Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. The standard-of-care immunochemotherapy, R-CHOP, cures only about 60% of DLBCL patients. Improving this cure rate will likely require the effective translation of basic biology knowledge into clinical activities. We previously [...] Read more.

Background: Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. The standard-of-care immunochemotherapy, R-CHOP, cures only about 60% of DLBCL patients. Improving this cure rate will likely require the effective translation of basic biology knowledge into clinical activities. We previously identified the cyclic-AMP/phosphodiesterase 4 (PDE4) axis as an important modulator of lymphomagenic processes. We also showed that the FDA-approved PDE4 inhibitor roflumilast can suppress B-cell receptor (BCR) signals, phosphoinositide 3-kinase (PI3K) activity and angiogenesis. These data suggested that combining roflumilast with R-CHOP may be beneficial in DLBCL. Methods: We conducted a single-center, single-arm, open-label, phase 1 study of roflumilast in combination with the standard of care, R-CHOP (Ro+R-CHOP), in pathologically proven, treatment-naïve, high-risk DLBCL patients. Results: Ro+R-CHOP was safe, and at a median follow-up time of 44 months, 70% of patients were alive and disease free (median OS not reached, PFS 44% (95% CI, 21–92). In this pilot series, we found that the addition of roflumilast suppressed PI3K activity in peripheral blood mononuclear cells, and VEGF-A secretion in the urine. We also encountered preliminary evidence to suggest that the Ro+R-CHOP combination may be particularly beneficial to patients diagnosed with high-risk genetic subtypes of DLBCL, namely MCD and A53. Conclusions: These initial findings suggest that roflumilast may be an alternative agent able to inhibit BCR/PI3K activity and angiogenesis in DLBCL, and that the testing of Ro+R-CHOP in a larger series of genetically characterized tumors is warranted. This study was registered at ClinicalTrials.gov, number NCT03458546. Full article

(This article belongs to the Special Issue PI3K Pathway in Cancer)

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21 pages, 1704 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Landscape of FOXM1 in Triple-Negative Breast Cancer and Aggressive Solid Cancers

by Sayra Dilmac, Zuhal Hamurcu and Bulent Ozpolat

Cancers 2024, 16(22), 3823; https://doi.org/10.3390/cancers16223823 - 14 Nov 2024

Cited by 4 | Viewed by 3302

Abstract

Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer, lacking common treatment targets such as estrogen (ER), progesterone (PR), and HER2 receptors. This subtype is associated with significant heterogeneity, chemoresistance, early recurrence, metastasis, and poor patient survival. FOXM1 [...] Read more.

Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer, lacking common treatment targets such as estrogen (ER), progesterone (PR), and HER2 receptors. This subtype is associated with significant heterogeneity, chemoresistance, early recurrence, metastasis, and poor patient survival. FOXM1 is a cancer-promoting transcription factor that plays a critical role in TNBC and other highly aggressive cancers by driving cell proliferation, invasion, metastasis, and drug resistance. In TNBC, mutations in the TP53 gene—detected in approximately 80% of patients—lead to the overexpression of FOXM1, making it a promising therapeutic target. Beyond TNBC, FOXM1 is implicated in other solid cancers, such as brain (glioblastoma), lung, and pancreatic cancers, and is considered an Achilles’ heel of aggressive cancers. Despite its potential as a therapeutic target, there are currently no FDA-approved FOXM1 inhibitors, and none have advanced to clinical trials. This review explores the role of FOXM1 in cancer progression and highlights the current status of efforts to develop effective FOXM1 inhibitors. Full article

(This article belongs to the Collection Targeting Solid Tumors)

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17 pages, 2527 KiB

Open AccessEditor’s ChoiceReview

Tracing Quiescent Cancer Cells In Vivo

by Moon Jong Kim

Cancers 2024, 16(22), 3822; https://doi.org/10.3390/cancers16223822 - 14 Nov 2024

Cited by 4 | Viewed by 2256

Abstract

QCCs have long gained significant interest as potential “seeds” for recurrent cancers. Clinical evidence suggests that a subset of cancer cells exits the cell cycle and enters a quiescent state following anti-cancer treatment. These microscopic-residual QCCs are extremely challenging to trace and detect [...] Read more.

QCCs have long gained significant interest as potential “seeds” for recurrent cancers. Clinical evidence suggests that a subset of cancer cells exits the cell cycle and enters a quiescent state following anti-cancer treatment. These microscopic-residual QCCs are extremely challenging to trace and detect within patients. Additionally, QCCs resist conventional anti-cancer therapies due to the lack of cell activity. Notably, upon the unknown environmental cues in unknown time points, sometimes decades later, QCCs can reactivate, triggering cancer relapse at primary or secondary sites. Currently, no targeted therapies or diagnostic tools exist for QCCs, and their molecular regulatory mechanisms remain largely unknown. The major challenge in understanding QCCs lies in the limited availability of human-relevant pre-clinical models that trace and collect QCCs in vivo. This review provides an overview of existing QCC tracing systems and analyzes their limitations. It also cautiously proposes potential improvements for tracing QCCs in vivo based on recent advancements in QCC studies and lineage-tracing techniques. Developing human-relevant and easily accessible in vivo tracing systems will be a crucial step in advancing QCC diagnostics and therapeutic strategies. Full article

(This article belongs to the Special Issue Cancer Cells Fostered Microenvironment in Metastasis)

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24 pages, 2009 KiB

Open AccessEditor’s ChoiceReview

Harnessing Bacterial Agents to Modulate the Tumor Microenvironment and Enhance Cancer Immunotherapy

by Christina James Thomas, Kaylee Delgado, Kamlesh Sawant, Jacob Roy, Udit Gupta, Carly Shaw Song, Rayansh Poojary, Paul de Figueiredo and Jianxun Song

Cancers 2024, 16(22), 3810; https://doi.org/10.3390/cancers16223810 - 13 Nov 2024

Cited by 7 | Viewed by 3666

Abstract

Cancer immunotherapy has revolutionized cancer treatment by leveraging the immune system to attack tumors. However, its effectiveness is often hindered by the immunosuppressive tumor microenvironment (TME), where a complex interplay of tumor, stromal, and immune cells undermines antitumor responses and allows tumors to [...] Read more.

Cancer immunotherapy has revolutionized cancer treatment by leveraging the immune system to attack tumors. However, its effectiveness is often hindered by the immunosuppressive tumor microenvironment (TME), where a complex interplay of tumor, stromal, and immune cells undermines antitumor responses and allows tumors to evade immune detection. This review explores innovative strategies to modify the TME and enhance immunotherapy outcomes, focusing on the therapeutic potential of engineered bacteria. These bacteria exploit the unique characteristics of the TME, such as abnormal vasculature and immune suppression, to selectively accumulate in tumors. Genetically modified bacteria can deliver therapeutic agents, including immune checkpoint inhibitors and cytokines, directly to tumor sites. This review highlights how bacterial therapeutics can target critical immune cells within the TME, such as myeloid-derived suppressor cells and tumor-associated macrophages, thereby promoting antitumor immunity. The combination of bacterial therapies with immune checkpoint inhibitors or adoptive cell transfer presents a promising strategy to counteract immune suppression. Continued research in this area could position bacterial agents as a powerful new modality to reshape the TME and enhance the efficacy of cancer immunotherapy, particularly for tumors resistant to conventional treatments. Full article

(This article belongs to the Topic Gut Microbiota and Cancer)

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15 pages, 1325 KiB

Open AccessEditor’s ChoiceReview

Unlocking Intracellular Oncology Targets: The Unique Role of Antibody-Based T-Cell Receptor Mimic (TCRm) Therapeutics in T-Cell Engagers (TCEs) and Antibody-Drug Conjugates (ADCs)

by Jeffrey Molldrem and Dongxing Zha

Cancers 2024, 16(22), 3776; https://doi.org/10.3390/cancers16223776 - 8 Nov 2024

Cited by 1 | Viewed by 4648

Abstract

Effectively targeting intracellular tumor-associated proteins presents a formidable challenge in oncology, as they are traditionally considered inaccessible to conventional antibody-based therapies and CAR-T cell therapies. However, recent advancements in antibody engineering have revolutionized this field, offering promising new strategies to combat cancer. This [...] Read more.

Effectively targeting intracellular tumor-associated proteins presents a formidable challenge in oncology, as they are traditionally considered inaccessible to conventional antibody-based therapies and CAR-T cell therapies. However, recent advancements in antibody engineering have revolutionized this field, offering promising new strategies to combat cancer. This review focuses on the innovative use of T-cell receptor mimic (TCRm) antibodies within the therapeutic frameworks of T-cell engagers (TCE) and antibody-drug conjugates (ADCs). TCRm antibodies, designed to recognize peptide-MHC complexes rather than cell surface proteins, integrate the capacity of T-cells to reach intracellular targets with the unique strengths of antibodies. When incorporated into T-cell engaging therapeutics, TCRms redirect T cells to cancer cells, facilitating direct cytotoxicity. In ADCs, TCRm antibodies deliver cytotoxic agents with highly specific targeting to cancer cells, sparing healthy tissues. Together, these antibody-based strategies represent a significant leap forward in oncology, opening new avenues for the treatment of cancers previously deemed untreatable, with other potential applications in autoimmune diseases. This review discusses the mechanisms, clinical advancements, and future prospects of these cutting-edge therapies, highlighting their potential to transform the landscape of cancer treatment. Full article

(This article belongs to the Collection The Development of Anti-cancer Agents)

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16 pages, 21457 KiB

Open AccessEditor’s ChoiceArticle

Virtual Tumor Mapping: A New Standard for Surgeon–Pathologist Collaboration in Treating Oral Squamous Cell Carcinoma

by Adam Michcik, Maksym Jopek, Rafał Pęksa, Piotr Choma, Łukasz Garbacewicz, Adam Polcyn, Tomasz Wach, Maciej Sikora and Barbara Drogoszewska

Cancers 2024, 16(22), 3761; https://doi.org/10.3390/cancers16223761 - 7 Nov 2024

Cited by 1 | Viewed by 1349

Abstract

Background: The histopathological assessment is critical in the comprehensive treatment process for patients diagnosed with oral squamous cell carcinoma (OSCC). A detailed and precise specimen characterization is essential to facilitate effective surgeon–pathologist communication. Methods: In response to this need, a user-friendly virtual communication [...] Read more.

Background: The histopathological assessment is critical in the comprehensive treatment process for patients diagnosed with oral squamous cell carcinoma (OSCC). A detailed and precise specimen characterization is essential to facilitate effective surgeon–pathologist communication. Methods: In response to this need, a user-friendly virtual communication protocol utilizing a 3D scanner has been developed. This study involved 50 patients with OSCC, whose resected tumors were directly scanned in the operating room and subsequently annotated and characterized using available software. Results: The direct application of annotations and descriptions onto the virtual tumor specimens significantly enhanced the quantity and accuracy of information conveyed to the pathologist. Conclusions: The proposed solution’s repeatability and standardized approach make integration into routine clinical practice feasible, thereby establishing a potential new standard in the field. Full article

(This article belongs to the Special Issue Recent Studies on Oral Cancer: Diagnostic Technologies, Pathology, and Surgery)

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18 pages, 1512 KiB

Open AccessEditor’s ChoiceReview

Targeting Menin in Acute Myeloid Leukemia: Therapeutic Advances and Future Directions

by Sandhya Dhiman, Vikram Dhillon and Suresh Kumar Balasubramanian

Cancers 2024, 16(22), 3743; https://doi.org/10.3390/cancers16223743 - 6 Nov 2024

Cited by 3 | Viewed by 3904

Abstract

Germline mutations in the MEN1 gene encoding menin protein cause multiple endocrine neoplasia type 1 (MEN1) syndrome. Recent evidence suggests that inhibiting the interaction of menin with its crucial oncogenic protein partners represents a promising therapeutic strategy to AML. Menin plays a critical [...] Read more.

Germline mutations in the MEN1 gene encoding menin protein cause multiple endocrine neoplasia type 1 (MEN1) syndrome. Recent evidence suggests that inhibiting the interaction of menin with its crucial oncogenic protein partners represents a promising therapeutic strategy to AML. Menin plays a critical role in lysine methyltransferase 2A (KMT2A)-gene-rearranged and NPM1-m acute leukemias, both associated with adverse outcomes with current standard therapies, especially in the relapsed/refractory setting. Disrupting the menin–KMT2A interaction affects the proleukemogenic HOX/MEIS transcription program. This disruption leads to the differentiation of KMT2Ar and NPM1-m AML cells. Small molecular inhibitors of the menin–KMT2A interaction target the central cavity of MEN1 to inhibit the MEN1-KMT2A interaction and could target a similar transcriptional dependency in other leukemia subsets, broadening their therapeutic potential. These agents, both as monotherapies and in combination with synergistic drugs, are undergoing preclinical and clinical evaluation with promising early results. With the growing literature around menin inhibitors in AML, we discussed the biology of menin, its mechanism of action, its interacting partners in leukemia, possible inhibitors, their implications, synergistic drugs, and future therapeutic strategies in this review. Full article

(This article belongs to the Section Cancer Therapy)

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55 pages, 1491 KiB

Open AccessEditor’s ChoiceReview

Microplastics in the Human Body: Exposure, Detection, and Risk of Carcinogenesis: A State-of-the-Art Review

by Eliasz Dzierżyński, Piotr J. Gawlik, Damian Puźniak, Wojciech Flieger, Katarzyna Jóźwik, Grzegorz Teresiński, Alicja Forma, Paulina Wdowiak, Jacek Baj and Jolanta Flieger

Cancers 2024, 16(21), 3703; https://doi.org/10.3390/cancers16213703 - 1 Nov 2024

Cited by 30 | Viewed by 17280

Abstract

Background: Humans cannot avoid plastic exposure due to its ubiquitous presence in the natural environment. The waste generated is poorly biodegradable and exists in the form of MPs, which can enter the human body primarily through the digestive tract, respiratory tract, or damaged [...] Read more.

Background: Humans cannot avoid plastic exposure due to its ubiquitous presence in the natural environment. The waste generated is poorly biodegradable and exists in the form of MPs, which can enter the human body primarily through the digestive tract, respiratory tract, or damaged skin and accumulate in various tissues by crossing biological membrane barriers. There is an increasing amount of research on the health effects of MPs. Most literature reports focus on the impact of plastics on the respiratory, digestive, reproductive, hormonal, nervous, and immune systems, as well as the metabolic effects of MPs accumulation leading to epidemics of obesity, diabetes, hypertension, and non-alcoholic fatty liver disease. MPs, as xenobiotics, undergo ADMET processes in the body, i.e., absorption, distribution, metabolism, and excretion, which are not fully understood. Of particular concern are the carcinogenic chemicals added to plastics during manufacturing or adsorbed from the environment, such as chlorinated paraffins, phthalates, phenols, and bisphenols, which can be released when absorbed by the body. The continuous increase in NMP exposure has accelerated during the SARS-CoV-2 pandemic when there was a need to use single-use plastic products in daily life. Therefore, there is an urgent need to diagnose problems related to the health effects of MP exposure and detection. Methods: We collected eligible publications mainly from PubMed published between 2017 and 2024. Results: In this review, we summarize the current knowledge on potential sources and routes of exposure, translocation pathways, identification methods, and carcinogenic potential confirmed by in vitro and in vivo studies. Additionally, we discuss the limitations of studies such as contamination during sample preparation and instrumental limitations constraints affecting imaging quality and MPs detection sensitivity. Conclusions: The assessment of MP content in samples should be performed according to the appropriate procedure and analytical technique to ensure Quality and Control (QA/QC). It was confirmed that MPs can be absorbed and accumulated in distant tissues, leading to an inflammatory response and initiation of signaling pathways responsible for malignant transformation. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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17 pages, 9029 KiB

Open AccessEditor’s ChoiceArticle

Genome-Wide CRISPR Screen Identifies Genes Involved in Metastasis of Pancreatic Ductal Adenocarcinoma

by Risky Oktriani, Anna Chiara Pirona, Lili Kalmár, Ariani S. Rahadian, Beiping Miao, Andrea S. Bauer, Jörg D. Hoheisel, Michael Boettcher and Haoqi Du

Cancers 2024, 16(21), 3684; https://doi.org/10.3390/cancers16213684 - 31 Oct 2024

Cited by 2 | Viewed by 2248

Abstract

Background/Objectives: Early and aggressive metastasis is a major feature of pancreatic ductal adenocarcinoma. Understanding the processes underlying metastasis is crucial for making a difference to disease outcome. Towards these ends, we looked in a comprehensive manner for genes that are metastasis-specific. Methods [...] Read more.

Background/Objectives: Early and aggressive metastasis is a major feature of pancreatic ductal adenocarcinoma. Understanding the processes underlying metastasis is crucial for making a difference to disease outcome. Towards these ends, we looked in a comprehensive manner for genes that are metastasis-specific. Methods: A genome-wide CRISPR-Cas9 gene knockout screen with 259,900 single guide RNA constructs was performed on pancreatic cancer cell lines with very high or very low metastatic capacity, respectively. Functional aspects of some of the identified genes were analysed in vitro. The injection of tumour cells with or without a gene knockout into mice was used to confirm the effect on metastasis. Results: The knockout of 590 genes—and, with higher analysis stringency, 67 genes—affected the viability of metastatic cells substantially, while these genes were not vital to non-metastasizing cells. Further evaluations identified different molecular processes related to this observation. One of the genes was MYBL2, encoding for a well-known transcription factor involved in the regulation of cell survival, proliferation, and differentiation in cancer tissues. In our metastasis-focussed study, no novel functional activity was detected for MYBL2, however. Instead, a metastasis-specific transformation of its genetic interaction with FOXM1 was observed. The interaction was synergistic in cells of low metastatic capacity, while there was a strong switch to a buffering mode in metastatic cells. In vivo analyses confirmed the strong effect of MYBL2 on metastasis. Conclusions: The genes found to be critical for the viability of metastatic cells form a basis for further investigations of the processes responsible for triggering and driving metastasis. As shown for MYBL2, unexpected processes of regulating metastasis might also be involved. Full article

(This article belongs to the Section Cancer Metastasis)

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15 pages, 646 KiB

Open AccessEditor’s ChoiceReview

Copper and Colorectal Cancer

by Maciej Małyszko and Adam Przybyłkowski

Cancers 2024, 16(21), 3691; https://doi.org/10.3390/cancers16213691 - 31 Oct 2024

Cited by 2 | Viewed by 2701

Abstract

Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30–40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is [...] Read more.

Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30–40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is crucial for mitochondrial respiration, pigmentation, iron transport, antioxidant defense, hormone production, and extracellular matrix biosynthesis. Copper deficiency, often caused by mutations in the ATP7A gene, results in Menkes disease, an X-linked recessive disorder. On the contrary, Wilson disease is characterized by toxic copper accumulation. Cuproptosis, a unique form of cell death regulated by copper, is a subtype of necrosis induced by enhanced mitochondrial metabolism and intracellular copper accumulation. This process can reduce the malignant potential of tumor cells by inhibiting glucose metabolism. Therapeutically, copper and its complexes have shown efficacy in malignancy treatments. The disruption of copper homeostasis and excessive cuproplasia are significant in colorectal cancer development and metastasis. Therefore, manipulating copper status presents a potential therapeutic target for colorectal cancer, using copper chelators to inhibit copper formation or copper ion carriers to promote cuproptosis. This review highlights the role of copper in human physiology and pathology, emphasizing its impact on colorectal cancer and potential therapeutic strategies. Future AI-based approaches are anticipated to accelerate the development of new compounds targeting cuproptosis and copper disruption in colorectal cancer. Full article

(This article belongs to the Special Issue Advancing Horizons in Colorectal Surgery: Innovative Approaches and Outcomes)

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30 pages, 2989 KiB

Open AccessEditor’s ChoiceReview

Metal Peroxide Nanoparticles for Modulating the Tumor Microenvironment: Current Status and Recent Prospects

by Jagadeesh Rajaram and Yaswanth Kuthati

Cancers 2024, 16(21), 3581; https://doi.org/10.3390/cancers16213581 - 24 Oct 2024

Cited by 3 | Viewed by 1932

Abstract

Background: The significant expansion of nanobiotechnology and nanomedicine has led to the development of innovative and effective techniques to combat various pathogens, demonstrating promising results with fewer adverse effects. Metal peroxide nanoparticles stand out among the crucial yet often overlooked types of nanomaterials, [...] Read more.

Background: The significant expansion of nanobiotechnology and nanomedicine has led to the development of innovative and effective techniques to combat various pathogens, demonstrating promising results with fewer adverse effects. Metal peroxide nanoparticles stand out among the crucial yet often overlooked types of nanomaterials, including metals. These nanoparticles are key in producing oxygen (O₂) and hydrogen peroxide (H₂O₂) through simple chemical reactions, which are vital in treating various diseases. These compounds play a crucial role in boosting the effectiveness of different treatment methods and also possess unique properties due to the addition of metal ions. Methods: This review discusses and analyzes some of the most common metal peroxide nanoparticles, including copper peroxide (CuO₂), calcium peroxide (CaO₂), magnesium peroxide (MgO₂), zinc peroxide (ZnO₂), barium peroxide (BaO₂), and titanium peroxide (TiOx) nanosystems. These nanosystems, characterized by their greater potential and treatment efficiency, are primarily needed in nanomedicine to combat various harmful pathogens. Researchers have extensively studied the effects of these peroxides in various treatments, such as catalytic nanotherapeutics, photodynamic therapy, radiation therapy, and some combination therapies. The tumor microenvironment (TME) is particularly unique, making the impact of nanomedicine less effective or even null. The presence of high levels of reactive oxygen species (ROS), hypoxia, low pH, and high glutathione levels makes them competitive against nanomedicine. Controlling the TME is a promising approach to combating cancer. Results: Metal peroxides with low biodegradability, toxicity, and side effects could reduce their effectiveness in treating the TME. It is important to consider the distribution of metal peroxides to effectively target cancer cells while avoiding harm to nearby normal cells. As a result, modifying the surface of metal peroxides is a key strategy to enhance their delivery to the TME, thereby improving their therapeutic benefits. Conclusions: This review discussed the various aspects of the TME and the importance of modifying the surface of metal peroxides to enhance their therapeutic advantages against cancer, as well as address safety concerns. Additionally, this review covered the current challenges in translating basic research findings into clinical applications of therapies based on metal peroxide nanoparticles. Full article

(This article belongs to the Topic Nanomaterials and Diseases)

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18 pages, 477 KiB

Open AccessEditor’s ChoiceReview

Risk-Stratified Radiotherapy in Pediatric Cancer

by Rituraj Upadhyay and Arnold C. Paulino

Cancers 2024, 16(20), 3530; https://doi.org/10.3390/cancers16203530 - 18 Oct 2024

Cited by 1 | Viewed by 2488

Abstract

While the cure rate of cancer in children has markedly improved in the last few decades, late effects continue to be a problem in survivors. Radiotherapy, which is a major component of treatment in many cancers, is one of the major agents responsible [...] Read more.

While the cure rate of cancer in children has markedly improved in the last few decades, late effects continue to be a problem in survivors. Radiotherapy, which is a major component of treatment in many cancers, is one of the major agents responsible for late toxicity. In the past decade, radiotherapy has been omitted in patients achieving excellent response to chemotherapy, such as in Hodgkin lymphoma and some Wilms tumors with lung metastases. Likewise, response to chemotherapy has been used to determine whether lower doses of radiation can be delivered in intracranial germinoma and pediatric nasopharyngeal carcinoma. Molecular subtyping in medulloblastoma is currently being employed, and in WNT-pathway M0 tumors, the reduction in radiotherapy dose to the craniospinal axis and tumor bed is currently being investigated. Finally, dose escalation was recently evaluated in patients with rhabdomyosarcoma > 5 cm who do not achieve a complete response to initial 9 weeks of chemotherapy as well as for unresectable Ewing sarcoma patients to improve local control. Full article

(This article belongs to the Special Issue Personalized Radiotherapy in Cancer Care)

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38 pages, 8614 KiB

Open AccessEditor’s ChoiceReview

Enhancing Lymphoma Diagnosis, Treatment, and Follow-Up Using ¹⁸F-FDG PET/CT Imaging: Contribution of Artificial Intelligence and Radiomics Analysis

by Setareh Hasanabadi, Seyed Mahmud Reza Aghamiri, Ahmad Ali Abin, Hamid Abdollahi, Hossein Arabi and Habib Zaidi

Cancers 2024, 16(20), 3511; https://doi.org/10.3390/cancers16203511 - 17 Oct 2024

Cited by 9 | Viewed by 3618

Abstract

Lymphoma, encompassing a wide spectrum of immune system malignancies, presents significant complexities in its early detection, management, and prognosis assessment since it can mimic post-infectious/inflammatory diseases. The heterogeneous nature of lymphoma makes it challenging to definitively pinpoint valuable biomarkers for predicting tumor biology [...] Read more.

Lymphoma, encompassing a wide spectrum of immune system malignancies, presents significant complexities in its early detection, management, and prognosis assessment since it can mimic post-infectious/inflammatory diseases. The heterogeneous nature of lymphoma makes it challenging to definitively pinpoint valuable biomarkers for predicting tumor biology and selecting the most effective treatment strategies. Although molecular imaging modalities, such as positron emission tomography/computed tomography (PET/CT), specifically ¹⁸F-FDG PET/CT, hold significant importance in the diagnosis of lymphoma, prognostication, and assessment of treatment response, they still face significant challenges. Over the past few years, radiomics and artificial intelligence (AI) have surfaced as valuable tools for detecting subtle features within medical images that may not be easily discerned by visual assessment. The rapid expansion of AI and its application in medicine/radiomics is opening up new opportunities in the nuclear medicine field. Radiomics and AI capabilities seem to hold promise across various clinical scenarios related to lymphoma. Nevertheless, the need for more extensive prospective trials is evident to substantiate their reliability and standardize their applications. This review aims to provide a comprehensive perspective on the current literature regarding the application of AI and radiomics applied/extracted on/from ¹⁸F-FDG PET/CT in the management of lymphoma patients. Full article

(This article belongs to the Special Issue PET/CT in Cancers Outcomes Prediction)

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15 pages, 1992 KiB

Open AccessEditor’s ChoiceArticle

Effect of Fluorescence Lymph Node Mapping on Improving Diagnostic Values of CT D3 Lymph Node Staging for Right-Sided Colon Cancer

by Gyung Mo Son, Tae Un Kim, Mi Sook Yun, ChangYeop Kim, In Young Lee, Su Bum Park, Dong-Hoon Shin and Gi Won Ha

Cancers 2024, 16(20), 3496; https://doi.org/10.3390/cancers16203496 - 16 Oct 2024

Cited by 3 | Viewed by 1457

Abstract

Background/Objectives: This study evaluated the impact of fluorescence lymph node mapping (FLNM) using indocyanine green (ICG) on the diagnostic accuracy of preoperative computed tomography (CT) in right-sided colon cancer. Methods: A total of 218 patients who underwent laparoscopic right hemicolectomy with D3 lymph [...] Read more.

Background/Objectives: This study evaluated the impact of fluorescence lymph node mapping (FLNM) using indocyanine green (ICG) on the diagnostic accuracy of preoperative computed tomography (CT) in right-sided colon cancer. Methods: A total of 218 patients who underwent laparoscopic right hemicolectomy with D3 lymph node dissection (LND) were analyzed: 86 patients in the FLNM group and 132 in the conventional surgery group. The FLNM technique allowed for enhanced intraoperative visualization of lymph node (LN) and more precise dissection, improving the identification of metastatic LNs. The diagnostic value of preoperative CT staging was assessed in both the FLNM and control groups by calculating the apparent prevalence, true prevalence, sensitivity, specificity, positive predictive value (PPV), negative predictive value, positive likelihood ratio (PLR), negative likelihood ratio, false positive and false negative proportions, and accuracy. Results: FLNM increased the accuracy of CT staging for detecting D3 LN metastasis in advanced cancer cases, with a higher PPV, PLR, and accuracy. In the FLNM group, the false-positive rate was significantly reduced, and the specificity was higher compared to the control group. Multivariate analysis identified FLNM as an independent factor associated with improved D3 LN metastasis detection. These findings suggest that incorporating FLNM into surgical procedures enhances the diagnostic value of preoperative CT by improving the precision of LND, particularly in patients with advanced colon cancer. Conclusions: The use of FLNM for D3 LND enhances the diagnostic accuracy of cN staging in right-sided colon cancer by improving surgical precision. Full article

(This article belongs to the Special Issue The Surgical Management of Colorectal Cancer)

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15 pages, 1268 KiB

Open AccessEditor’s ChoiceArticle

Multiparametric Approach to the Colorectal Cancer Phenotypes Integrating Morphofunctional Assessment and Computer Tomography

by Patricia Guirado-Peláez, Rocío Fernández-Jiménez, Francisco José Sánchez-Torralvo, Fernanda Mucarzel Suárez-Arana, Fiorella Ximena Palmas-Candia, Isabel Vegas-Aguilar, María del Mar Amaya-Campos, Gema Martínez Tamés, Virginia Soria-Utrilla, Francisco Tinahones-Madueño, José Manuel García-Almeida, Rosa Burgos-Peláez and Gabriel Olveira

Cancers 2024, 16(20), 3493; https://doi.org/10.3390/cancers16203493 - 15 Oct 2024

Cited by 3 | Viewed by 1532

Abstract

(1) Background: Accurate body composition assessment in CCR patients is crucial due to the high prevalence of malnutrition, sarcopenia, and cachexia affecting survival. This study evaluates the correlation between body composition assessed by CT imaging as a reference technique, BIVA, nutritional ultrasound, and [...] Read more.

(1) Background: Accurate body composition assessment in CCR patients is crucial due to the high prevalence of malnutrition, sarcopenia, and cachexia affecting survival. This study evaluates the correlation between body composition assessed by CT imaging as a reference technique, BIVA, nutritional ultrasound, and handgrip strength in CCR patients. (2) Methods: This retrospective study included CCR patients assessed by the Endocrinology and Nutrition Services of Virgen de la Victoria in Malaga and Vall d’Hebron in Barcelona from October 2018 to July 2023. Assessments included anthropometry, BIVA, NU, HGS, and AI-assisted CT analysis at the L3 level for body composition. Pearson’s analysis determined the correlation of CT-derived variables with BIVA, NU, and HGS. (3) Results: A total of 267 CCR patients (mean age 68.2 ± 10.9 years, 61.8% men) were studied. Significant gender differences were found in body composition and strength. CT-SMI showed strong correlations with body cell mass (r = 0.65), rectus femoris cross-sectional area (r = 0.56), and handgrip strength (r = 0.55), with a Cronbach’s alpha of 0.789. CT-based adipose tissue measurements showed significant correlations with fat mass (r = 0.56), BMI (r = 0.78), A-SAT (r = 0.49), and L-SAT (r = 0.66). Regression analysis indicated a high predictive power for CT-SMI, explaining approximately 80% of its variance (R² = 0.796). (4) Conclusions: Comprehensive screening of colorectal cancer patients through BIVA, NU, HGS, and CT optimizes the results of the evaluation. These methods complement each other in assessing muscle mass, fat distribution, and nutritional status in CCR. When CT is unavailable or bedside assessment is needed, HGS, BIVA, and NU provide an accurate assessment of body composition. Full article

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

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24 pages, 5399 KiB

Open AccessEditor’s ChoiceArticle

Whole Exome Sequencing of Intracranial Epidermoid Cysts Reveals Immune-Associated Mechanistic and Potential Targets

by Shruthi Kondaboina, Oscar Parrish, Carolina Angelica Parada and Manuel Ferreira, Jr.

Cancers 2024, 16(20), 3487; https://doi.org/10.3390/cancers16203487 - 15 Oct 2024

Cited by 2 | Viewed by 1848

Abstract

Background/Objectives: Intracranial Epidermoid Cysts (IECs) are rare intracranial tumors primarily treated through surgery. Cyst adherence complicates complete removal, leading to high rates of tumor progression after subtotal resection. The molecular drivers of IEC remain unknown. Consequently, advances in treatment have fallen short. Tumor [...] Read more.

Background/Objectives: Intracranial Epidermoid Cysts (IECs) are rare intracranial tumors primarily treated through surgery. Cyst adherence complicates complete removal, leading to high rates of tumor progression after subtotal resection. The molecular drivers of IEC remain unknown. Consequently, advances in treatment have fallen short. Tumor genetic profiling has revealed potential targets for drug development, including FDA-approved options and reshaping treatment. The genetic landscape of IECs has not been explored. We applied Whole Exome Sequencing (WES) to IECs to gain insights into the mechanisms of oncogenesis and identify potential therapeutic targets. Methods: We performed WES on tumor tissue and matched blood samples, when available. Following GATK best practices, we conducted read processing, quality control, somatic variant calling, and copy-number inference. Data analyses and visualization were conducted in R. Results: Top altered genes are associated with the immune system and tumor microenvironment, suggesting a mechanism of immune evasion. Gene and pathway enrichment revealed a high mutation burden in genes associated with Extracellular Matrix (ECM) and PI3K-AKT-mTOR cascades. Recurrent and deleterious alterations in NOTCH2 and USP8 were identified in 50% and 30% of the cohort, respectively. Frequent amplifications in deubiquitinases and beta-defensins strengthened the involvement of immune mechanisms for oncogenic transformation. Conclusions: Top altered genes and recurrent mutations may play a role in shaping the microenvironment and modulating immune evasion in IECs. USP8 and NOTCH2 may serve as clinically relevant target for IECs. Finally, we present evidence that the crosstalk between the PI3K-Akt-mTOR and ECM signaling pathways may play a role in modulating the immune escape mechanism in IECs. Full article

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

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18 pages, 3914 KiB

Open AccessEditor’s ChoiceArticle

Overcoming Irinotecan Resistance by Targeting Its Downstream Signaling Pathways in Colon Cancer

by Shashank Saurav, Sourajeet Karfa, Trung Vu, Zhipeng Liu, Arunima Datta, Upender Manne, Temesgen Samuel and Pran K. Datta

Cancers 2024, 16(20), 3491; https://doi.org/10.3390/cancers16203491 - 15 Oct 2024

Cited by 4 | Viewed by 3000

Abstract

Among the most popular chemotherapeutic agents, irinotecan, regarded as a prodrug belonging to the camptothecin family that inhibits topoisomerase I, is widely used to treat metastatic colorectal cancer (CRC). Although immunotherapy is promising for several cancer types, only microsatellite-instable (~7%) and not microsatellite-stable [...] Read more.

Among the most popular chemotherapeutic agents, irinotecan, regarded as a prodrug belonging to the camptothecin family that inhibits topoisomerase I, is widely used to treat metastatic colorectal cancer (CRC). Although immunotherapy is promising for several cancer types, only microsatellite-instable (~7%) and not microsatellite-stable CRCs are responsive to it. Therefore, it is important to investigate the mechanism of irinotecan function to identify cellular proteins and/or pathways that could be targeted for combination therapy. Here, we have determined the effect of irinotecan treatment on the expression/activation of tumor suppressor genes (including p15^Ink4b, p21^Cip1, p27^Kip1, and p53) and oncogenes (including OPN, IL8, PD-L1, NF-κB, ISG15, Cyclin D1, and c-Myc) using qRT-PCR, Western blotting, immunofluorescence (IF), and RNA sequencing of tumor specimens. We employed stable knockdown, neutralizing antibodies (Abs), and inhibitors of OPN, p53, and NF-κB to establish downstream signaling and sensitivity/resistance to the cytotoxic activities of irinotecan. Suppression of secretory OPN and NF-κB sensitized colon cancer cells to irinotecan. p53 inhibition or knockdown was not sufficient to block or potentiate SN38-regulated signaling, suggesting p53-independent effects. Irinotecan treatment inhibited tumor growth in syngeneic mice. Analyses of allograft tumors from irinotecan-treated mice validated the cell culture results. RNA-seq data suggested that irinotecan-mediated activation of NF-κB signaling modulated immune and inflammatory genes in mice, which may compromise drug efficacy and promote resistance. In sum, these results suggest that, for CRCs, targeting OPN, NF-κB, PD-L1, and/or ISG15 signaling may provide a potential strategy to overcome resistance to irinotecan-based chemotherapy. Full article

(This article belongs to the Special Issue Overcoming Chemoresistance in Cancer: Identifying Biomarkers and Novel Targets)

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10 pages, 1838 KiB

Open AccessEditor’s ChoiceArticle

Examination of Sarcopenia with Obesity as a Prognostic Factor in Patients with Colorectal Cancer Using the Psoas Muscle Mass Index

by Kengo Haruna, Soichiro Minami, Norikatsu Miyoshi, Shiki Fujino, Rie Mizumoto, Yuki Toyoda, Rie Hayashi, Shinya Kato, Mitsunobu Takeda, Yuki Sekido, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Hirofumi Yamamoto, Yuichiro Doki and Hidetoshi Eguchi

Cancers 2024, 16(19), 3429; https://doi.org/10.3390/cancers16193429 - 9 Oct 2024

Cited by 2 | Viewed by 1906

Abstract

Background: Sarcopenia, the age-related loss of muscle mass, is a negative prognostic factor in gastrointestinal cancer. Sarcopenia combined with visceral obesity (sarcopenic obesity) is associated with poor outcomes. We explored the influence of obesity and other factors on the prognosis of patients [...] Read more.

Background: Sarcopenia, the age-related loss of muscle mass, is a negative prognostic factor in gastrointestinal cancer. Sarcopenia combined with visceral obesity (sarcopenic obesity) is associated with poor outcomes. We explored the influence of obesity and other factors on the prognosis of patients with colorectal cancer diagnosed with sarcopenia. Methods: We enrolled 211 patients with colorectal cancer diagnosed with preoperative sarcopenic obesity who underwent radical resection at Osaka University Hospital between January 2009 and January 2012. Muscle mass was assessed using the psoas muscle mass index. Obesity was evaluated by measuring the visceral fat area in the umbilical region. Patients were categorized into two groups: sarcopenia with obesity (SO) and sarcopenia without obesity (non-SO). Overall survival, cancer-specific survival, and cancer-related relapse-free survival (CRRFS) were compared between the two groups. Patient characteristics, including age, sex, body mass index, serum albumin, C-reactive protein, tumor markers, prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and geriatric nutritional risk index (GNRI), were also analyzed. Results: CRRFS was significantly shorter in the SO group than in the non-SO group (p = 0.028). PNI, mGPS, and GNRI were not identified as significant prognostic factors for CRRFS. Multivariate analysis highlighted sarcopenic obesity, elevated carcinoembryonic antigen levels, and unfavorable histological types as significant predictors of poor CRRFS outcomes. Conclusions: Sarcopenic obesity is an independent predictor of poor prognosis in patients with CRC. Thus, interventions aimed at increasing muscle mass and reducing visceral fat could potentially improve the prognosis of these patients. Full article

(This article belongs to the Special Issue Obesity and Cancers)

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17 pages, 2928 KiB

Open AccessEditor’s ChoiceArticle

A Novel Chimeric Oncolytic Virus Mediates a Multifaceted Cellular Immune Response in a Syngeneic B16 Melanoma Model

by Sonja Glauß, Victoria Neumeyer, Lorenz Hanesch, Janina Marek, Nina Hartmann, Gabriela M. Wiedemann and Jennifer Altomonte

Cancers 2024, 16(19), 3405; https://doi.org/10.3390/cancers16193405 - 6 Oct 2024

Cited by 3 | Viewed by 2126

Abstract

Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo [...] Read more.

Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo tumor models. While OVs are known to mediate systemic anti-tumor immune responses, the detailed characterization of local and systemic immune responses to fusogenic oncolytic virotherapy remains unexplored. Methods and Results: We analyzed immune cell compartments in the spleen, blood, tumor-draining lymph nodes (TDLNs), and tumors over the course of VSV-NDV therapy in a bilateral syngeneic melanoma mouse model. Our results revealed significant local infiltration and activation of T lymphocytes in tumors and globally in the blood and spleen. Notably, in vivo CD8⁺ T cell depletion led to complete abrogation of the tumor response, highlighting the crucial role of T cells in promoting the therapeutic effects of oncolytic VSV-NDV. In vitro co-culture experiments enabled the interrogation of human immune cell responses to VSV-NDV-mediated oncolysis. Human peripheral blood mononuclear cells (PBMCs) were efficiently stimulated by exposure to VSV-NDV-infected cancer cells, which recapitulates the in vivo murine findings. Conclusions: Taken together, these data characterize a broad anti-tumor immune cell response to oncolytic VSV-NDV therapy and suggest that CD8⁺ T cells play a decisive role in therapeutic outcome, which supports the further development of this chimeric vector as a multimechanistic immunotherapy for solid cancers. Full article

(This article belongs to the Special Issue Oncolytic Viruses as an Emerging Aspect of Immune Oncology)

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18 pages, 1579 KiB

Open AccessEditor’s ChoiceReview

The Tumor Microenvironment as a Therapeutic Target in Cutaneous T Cell Lymphoma

by Louis Boafo Kwantwi, Steven T. Rosen and Christiane Querfeld

Cancers 2024, 16(19), 3368; https://doi.org/10.3390/cancers16193368 - 1 Oct 2024

Cited by 2 | Viewed by 2619

Abstract

Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas, with mycosis fungoides and Sézary syndrome being the two common subtypes. Despite the substantial improvement in early-stage diagnosis and treatments, some patients still progress to the advanced stage with an elusive [...] Read more.

Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas, with mycosis fungoides and Sézary syndrome being the two common subtypes. Despite the substantial improvement in early-stage diagnosis and treatments, some patients still progress to the advanced stage with an elusive underpinning mechanism. While this unsubstantiated disease mechanism coupled with diverse clinical outcomes poses challenges in disease management, emerging evidence has implicated the tumor microenvironment in the disease process, thus revealing a promising therapeutic potential of targeting the tumor microenvironment. Notably, malignant T cells can shape their microenvironment to dampen antitumor immunity, leading to Th2-dominated responses that promote tumor progression. This is largely orchestrated by alterations in cytokines expression patterns, genetic dysregulations, inhibitory effects of immune checkpoint molecules, and immunosuppressive cells. Herein, the recent insights into the determining factors in the CTCL tumor microenvironment that support their progression have been highlighted. Also, recent advances in strategies to target the CTCL tumor micromovement with the rationale of improving treatment efficacy have been discussed. Full article

(This article belongs to the Special Issue Cutaneous Lymphomas: From Pathology to Treatment)

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