Cancers

22 pages, 323 KiB

Open AccessEditor’s ChoiceReview

Advances in Molecular Understanding of Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis: Towards Precision Medicine

by Hammad Tashkandi and Ismail Elbaz Younes

Cancers 2024, 16(9), 1679; https://doi.org/10.3390/cancers16091679 - 26 Apr 2024

Viewed by 2097

Abstract

Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of [...] Read more.

Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of the molecular pathogenesis of these diseases, with the discovery of key mutations in the JAK2, CALR, and MPL genes being pivotal. This review provides a comprehensive update on the molecular landscape of PV, ET, and PMF, highlighting the diagnostic, prognostic, and therapeutic implications of these genetic findings. We delve into the challenges of diagnosing and treating patients with prognostic mutations, clonal evolution, and the impact of emerging technologies like next-generation sequencing and single-cell genomics on the field. The future of MPN management lies in leveraging these molecular insights to develop personalized treatment strategies, aiming for precision medicine that optimizes outcomes for patients. This article synthesizes current knowledge on molecular diagnostics in MPNs, underscoring the critical role of genetic profiling in enhancing patient care and pointing towards future research directions that promise to further refine our approach to these complex disorders. Full article

(This article belongs to the Special Issue Molecular and Genetic Diagnosis and Targeted Therapy of Myeloproliferative Neoplasms)

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24 pages, 879 KiB

Open AccessEditor’s ChoiceReview

An Updated Review of Management of Resectable Stage III NSCLC in the Era of Neoadjuvant Immunotherapy

by Saurav Verma, Daniel Breadner, Abhenil Mittal, David A. Palma, Rahul Nayak, Jacques Raphael and Mark Vincent

Cancers 2024, 16(7), 1302; https://doi.org/10.3390/cancers16071302 - 27 Mar 2024

Cited by 2 | Viewed by 2196

Abstract

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the [...] Read more.

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space. Full article

(This article belongs to the Special Issue Treatment of Lung Cancer)

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12 pages, 473 KiB

Open AccessEditor’s ChoiceArticle

Comparing R-Bendamustine vs. R-CHOP Plus Maintenance Therapy as First-Line Systemic Treatment in Follicular Lymphoma: A Multicenter Retrospective GELTAMO Study

by Mariana Bastos-Oreiro, Antonio Gutierrez, Almudena Cabero, Javier López, Paola Villafuerte, Ana Jiménez-Ubieto, Raquel de Oña, Adolfo De la Fuente, Belén Navarro, Javier Peñalver, Pilar Martínez, Carmen Alonso, María Infante, Raúl Córdoba, Blanca Perez-Montero, Jaime Pérez de Oteyza, Sonia González de Villambrosio, Paula Fernández-Caldas, Raquel del Campo, Daniel García Belmonte, Javier Diaz-Gálvez, Antonio Salar and Juan-Manuel Sancho Show full author list Hide full author list

Cancers 2024, 16(7), 1285; https://doi.org/10.3390/cancers16071285 - 26 Mar 2024

Viewed by 1671

Abstract

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the [...] Read more.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the same approach after R-B therapy is still being determined. This retrospective analysis compared 476 FL patients from 17 GELTAMO centers who received R-based regimens followed by rituximab maintenance therapy for untreated advanced-stage FL. The complete response rate at the end of induction was higher with R-B and relapses were more frequent with R-CHOP. During induction, cytopenias were significantly more frequent with R-CHOP and so was the use of colony-stimulating factors. During maintenance therapy, R-B showed more neutropenia and infectious toxicity. After a median follow-up of 81 months (95% CI: 77–86), the 6-year rates of progression-free survival (PFS) were 79% (95% CI: 72–86) for R-bendamustine vs. 67% (95% CI: 61–73) for R-CHOP (p = 0.046), and 6-year overall survival (OS) values were 91% (95% CI: 86–96) for R-B vs. 91% (95% CI: 87–94) for R-CHOP (p = 0.49). In conclusion, R-B followed by rituximab maintenance therapy in patients with previously untreated FL resulted in significantly longer PFS than R-CHOP, with older patients also benefiting from this treatment without further toxicity. Adverse events during maintenance were more frequent with R-B without impacting mortality. Full article

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

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28 pages, 6424 KiB

Open AccessEditor’s ChoiceArticle

Transforming Growth Factor Beta 2 (TGFB2) mRNA Levels, in Conjunction with Interferon-Gamma Receptor Activation of Interferon Regulatory Factor 5 (IRF5) and Expression of CD276/B7-H3, Are Therapeutically Targetable Negative Prognostic Markers in Low-Grade Gliomas

by Vuong Trieu, Anthony E. Maida and Sanjive Qazi

Cancers 2024, 16(6), 1202; https://doi.org/10.3390/cancers16061202 - 19 Mar 2024

Viewed by 1911

Abstract

LGG tumors are characterized by a low infiltration of immune cells, requiring therapeutic interventions to boost the immune response. We conducted a study analyzing mRNA expression datasets from the UCSC Xena web platform. To screen for upregulated genes, we sought to compare normal [...] Read more.

LGG tumors are characterized by a low infiltration of immune cells, requiring therapeutic interventions to boost the immune response. We conducted a study analyzing mRNA expression datasets from the UCSC Xena web platform. To screen for upregulated genes, we sought to compare normal brain tissue with LGG tumor samples. We also used cBioportal to determine the relationship between mRNA expression levels of 513 LGG patients and their overall survival (OS) outcomes. Three tumor-associated macrophage (TAM) markers, MSR1/CD204, CD86, and CD68, exhibited a 6-fold (p < 0.0001), 8.9-fold (p < 0.0001), and 15.6-fold increase in mRNA expression levels, respectively, in LGG tumors. In addition, both TGFB1 (4.1-fold increase, p < 0.0001) and TGFB2 (2.2-fold increase, p < 0.0001) ligands were also upregulated in these tumors compared to normal brain tissue, suggesting that TGFB ligands are pivotal in establishing an immunosuppressive, angiogenic, and pro-tumorigenic TME in gliomas mediated through TAMs. In addition, mRNA upregulation of interferon-gamma receptors, IFNGR1 and IFNGR2, and the downstream signaling molecules STAT1, IRF1, and IRF5, pointed to an essential role for IFN-γ mediated remodeling of the TME. Interestingly, the mRNA expression of a tumor-associated antigen, CD276/B7-H3, showed a significant (p < 0.0001) 4.03-fold increase in tumor tissue, giving further insights into the roles of macrophages and tumor cells in supporting the immunosuppressive TME. Multivariate Cox proportional hazards models investigating the interaction of TGFB2 and activation of IFNGR2, STAT1, IRF1, or IRF5 showed that the prognostic impact of high mRNA levels (25th percentile cut-off) of TGFB2 was independent of IFNGR2, STAT1, IRF1, or IRF5 mRNA levels (TGFB2^high HR (95% CI) = 4.07 (2.35–7.06), 6 (3.62–10.11), 4.38 (2.67–7.17), and 4.48 (2.82–7.12) for models with IFNGR2, STAT1, IRF1, or IRF5, respectively) and age at diagnosis. Patients with high levels of TGFB2 and IFNGR2 were over-represented by LGG patients with isocitrate dehydrogenase wild-type (IDHwt) mutation status. The prognostic impact of high levels of TGFB2 and IDH wild-type observed by the increases in hazard ratios for TGFB2 (HR (95% CI range) = 2.02 (1.05–3.89)) and IDH wild-type (HR (95% CI range) = 4.44 (1.9–10.4)) were independent predictors of survival, suggesting that risk stratification of patients identifies LGG patients with IDH wild-type and high levels of TGFB2 in the design of clinical trials. Furthermore, we have additional IRF5 and CD276/B7-H3 as prognostic markers that can also be targeted for combination therapies with TGFB2 inhibitors. In support of these findings, we demonstrated that low levels of gene methylation in TGFB2, IFNGR2, IRF1, IRF5, STAT1, and CD276 were associated with significantly worse overall survival (OS) outcomes. This suggests that potential mechanisms to increase the expression of these prognostic markers occur via the action of demethylation enzymes. Full article

(This article belongs to the Special Issue Past, Present, and Future Strategies in the Treatment and Management of Gliomas)

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28 pages, 2428 KiB

Open AccessEditor’s ChoiceReview

Epigenetic Mechanisms in Latent Epstein-Barr Virus Infection and Associated Cancers

by Atharva S. Torne and Erle S. Robertson

Cancers 2024, 16(5), 991; https://doi.org/10.3390/cancers16050991 - 29 Feb 2024

Viewed by 1847

Abstract

The Epstein–Barr Virus (EBV) is a double-stranded DNA-based human tumor virus that was first isolated in 1964 from lymphoma biopsies. Since its initial discovery, EBV has been identified as a major contributor to numerous cancers and chronic autoimmune disorders. The virus is particularly [...] Read more.

The Epstein–Barr Virus (EBV) is a double-stranded DNA-based human tumor virus that was first isolated in 1964 from lymphoma biopsies. Since its initial discovery, EBV has been identified as a major contributor to numerous cancers and chronic autoimmune disorders. The virus is particularly efficient at infecting B-cells but can also infect epithelial cells, utilizing an array of epigenetic strategies to establish long-term latent infection. The association with histone modifications, alteration of DNA methylation patterns in host and viral genomes, and microRNA targeting of host cell factors are core epigenetic strategies that drive interactions between host and virus, which are necessary for viral persistence and progression of EBV-associated diseases. Therefore, understanding epigenetic regulation and its role in post-entry viral dynamics is an elusive area of EBV research. Here, we present current outlooks of EBV epigenetic regulation as it pertains to viral interactions with its host during latent infection and its propensity to induce tumorigenesis. We review the important epigenetic regulators of EBV latency and explore how the strategies involved during latent infection drive differential epigenetic profiles and host-virus interactions in EBV-associated cancers. Full article

(This article belongs to the Special Issue Epstein–Barr Virus (EBV) Associated Cancers)

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30 pages, 2609 KiB

Open AccessEditor’s ChoiceReview

Impact of Complex Apoptotic Signaling Pathways on Cancer Cell Sensitivity to Therapy

by Ryungsa Kim, Takanori Kin and William T. Beck

Cancers 2024, 16(5), 984; https://doi.org/10.3390/cancers16050984 - 28 Feb 2024

Cited by 2 | Viewed by 2011

Abstract

Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the c-Jun/activator protein 1 (AP-1)/p53 [...] Read more.

Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the c-Jun/activator protein 1 (AP-1)/p53 signaling pathway leading to apoptotic death is altered. Cancer cells treated with anticancer drugs undergo c-Jun/AP-1–mediated apoptotic death and are involved in c-Jun N-terminal kinase activation and growth arrest- and DNA damage-inducible gene 153 (Gadd153)/CCAAT/enhancer-binding protein homologous protein pathway induction, regardless of the p53 genotype. Gadd153 induction is associated with mitochondrial membrane permeabilization after anticancer drug treatment and involves a coupled endoplasmic reticulum stress response. The induction of apoptosis by anticancer drugs is mediated by the intrinsic pathway (cytochrome c, Cyt c) and subsequent activation of the caspase cascade via proapoptotic genes (e.g., Bax and Bcl-xS) and their interactions. Anticancer drug-induced apoptosis involves caspase-dependent and caspase-independent pathways and occurs via intrinsic and extrinsic pathways. The targeting of antiapoptotic genes such as Bcl-2 enhances anticancer drug efficacy. The modulation of apoptotic signaling by Bcl-xS transduction increases the sensitivity of multidrug resistance-related protein-overexpressing epidermoid carcinoma cells to anticancer drugs. The significance of autophagy in cancer therapy remains to be elucidated. In this review, we summarize current knowledge of cancer cell death-related signaling pathways and their alterations during anticancer drug treatment and discuss potential strategies to enhance treatment efficacy. Full article

(This article belongs to the Special Issue Feature Review for Cancer Therapy)

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23 pages, 25758 KiB

Open AccessEditor’s ChoiceArticle

Molecular, Metabolic, and Subcellular Mapping of the Tumor Immune Microenvironment via 3D Targeted and Non-Targeted Multiplex Multi-Omics Analyses

by Sammy Ferri-Borgogno, Jared K. Burks, Erin H. Seeley, Trevor D. McKee, Danielle L. Stolley, Akshay V. Basi, Javier A. Gomez, Basant T. Gamal, Shamini Ayyadhury, Barrett C. Lawson, Melinda S. Yates, Michael J. Birrer, Karen H. Lu and Samuel C. Mok

Cancers 2024, 16(5), 846; https://doi.org/10.3390/cancers16050846 - 20 Feb 2024

Cited by 1 | Viewed by 7428

Abstract

Most platforms used for the molecular reconstruction of the tumor–immune microenvironment (TIME) of a solid tumor fail to explore the spatial context of the three-dimensional (3D) space of the tumor at a single-cell resolution, and thus lack information about cell–cell or cell–extracellular matrix [...] Read more.

Most platforms used for the molecular reconstruction of the tumor–immune microenvironment (TIME) of a solid tumor fail to explore the spatial context of the three-dimensional (3D) space of the tumor at a single-cell resolution, and thus lack information about cell–cell or cell–extracellular matrix (ECM) interactions. To address this issue, a pipeline which integrated multiplex spatially resolved multi-omics platforms was developed to identify crosstalk signaling networks among various cell types and the ECM in the 3D TIME of two FFPE (formalin-fixed paraffin embedded) gynecologic tumor samples. These platforms include non-targeted mass spectrometry imaging (glycans, metabolites, and peptides) and Stereo-seq (spatial transcriptomics) and targeted seqIF (IHC proteomics). The spatially resolved imaging data in a two- and three-dimensional space demonstrated various cellular neighborhoods in both samples. The collection of spatially resolved analytes in a voxel (3D pixel) across serial sections of the tissue was also demonstrated. Data collected from this analytical pipeline were used to construct spatial 3D maps with single-cell resolution, which revealed cell identity, activation, and energized status. These maps will provide not only insights into the molecular basis of spatial cell heterogeneity in the TIME, but also novel predictive biomarkers and therapeutic targets, which can improve patient survival rates. Full article

(This article belongs to the Section Tumor Microenvironment)

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17 pages, 704 KiB

Open AccessEditor’s ChoiceReview

Variant Allele Frequency Analysis of Circulating Tumor DNA as a Promising Tool in Assessing the Effectiveness of Treatment in Non-Small Cell Lung Carcinoma Patients

by Natalia Galant, Marcin Nicoś, Barbara Kuźnar-Kamińska and Paweł Krawczyk

Cancers 2024, 16(4), 782; https://doi.org/10.3390/cancers16040782 - 14 Feb 2024

Viewed by 5589

Abstract

Despite the different possible paths of treatment, lung cancer remains one of the leading causes of death in oncological patients. New tools guiding the therapeutic process are under scientific investigation, and one of the promising indicators of the effectiveness of therapy in patients [...] Read more.

Despite the different possible paths of treatment, lung cancer remains one of the leading causes of death in oncological patients. New tools guiding the therapeutic process are under scientific investigation, and one of the promising indicators of the effectiveness of therapy in patients with NSCLC is variant allele frequency (VAF) analysis. VAF is a metric characterized as the measurement of the specific variant allele proportion within a genomic locus, and it can be determined using methods based on NGS or PCR. It can be assessed using not only tissue samples but also ctDNA (circulating tumor DNA) isolated from liquid biopsy. The non-invasive characteristic of liquid biopsy enables a more frequent collection of material and increases the potential of VAF analysis in monitoring therapy. Several studies have been performed on patients with NSCLC to evaluate the possibility of VAF usage. The research carried out so far demonstrates that the evaluation of VAF dynamics may be useful in monitoring tumor progression, remission, and recurrence during or after treatment. Moreover, the use of VAF analysis appears to be beneficial in making treatment decisions. However, several issues require better understanding and standardization before VAF testing can be implemented in clinical practice. In this review, we discuss the difficulties in the application of ctDNA VAF analysis in clinical routine, discussing the diagnostic and methodological challenges in VAF measurement in liquid biopsy. We highlight the possible applications of VAF-based measurements that are under consideration in clinical trials in the monitoring of personalized treatments for patients with NSCLC. Full article

(This article belongs to the Special Issue Novel Biomarkers in Non-small Cell Lung Cancer (NSCLC))

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12 pages, 1197 KiB

Open AccessEditor’s ChoiceArticle

Improved Accuracy and Sensitivity in Diagnosis and Staging of Lung Cancer with Systematic and Combined Endobronchial and Endoscopic Ultrasound (EBUS-EUS): Experience from a Tertiary Center

by Abdenor Badaoui, Marion De Wergifosse, Benoit Rondelet, Pierre H. Deprez, Claudia Stanciu-Pop, Laurent Bairy, Philippe Eucher, Monique Delos, Sebahat Ocak, Cédric Gillain, Fabrice Duplaquet and Lionel Pirard

Cancers 2024, 16(4), 728; https://doi.org/10.3390/cancers16040728 - 9 Feb 2024

Viewed by 1755

Abstract

Background: Combined endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided tissue acquisition (EUS-TA) are accurate procedures for the diagnosis and staging of mediastinal lymph nodes (MLNs) in lung cancer. However, the respective contribution of separate and combined procedures in diagnosis and staging [...] Read more.

Background: Combined endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided tissue acquisition (EUS-TA) are accurate procedures for the diagnosis and staging of mediastinal lymph nodes (MLNs) in lung cancer. However, the respective contribution of separate and combined procedures in diagnosis and staging has not been fully studied. The aim of this study was to assess their respective performances. Methods: Patients with suspected malignant MLNs in lung cancer or recurrence identified by PET-CT who underwent combined EBUS-TBNA and EUS-TA were retrospectively reviewed. Results: A total of 141 patients underwent both procedures. Correct diagnosis was obtained in 82% with EBUS-TBNA, 91% with EUS-TA, and 94% with the combined procedure. The overall sensitivity, specificity, and positive and negative predictive values (PPV and NPV) of EBUS-TBNA, EUS-TA, and the combined procedure for diagnosing malignancy were [75%, 100%, 100%, 58%], [87%, 100%, 100%, 75%], and [93%, 100%, 100%, 80%], respectively, with a significantly better sensitivity of the combined procedure (p < 0.0001). Staging (82/141 patients) was correctly assessed in 74% with EBUS-TBNA, 68% with EUS-TA, and 85% with the combined procedure. The overall sensitivity, specificity, PPV, and NPV of EBUS-TBNA, EUS-TA, and the combined procedure for lung cancer staging were [62%, 100%, 100%, 55%], [54%, 100%, 100%, 50%], and [79%, 100%, 100%, 68%], respectively, significantly better in terms of sensitivity for the combined procedure (p < 0.001). Conclusion: The combined EBUS-EUS approach in lung cancer patients showed better accuracy and sensitivity in diagnosis and staging when compared with EBUS-TBNA and EUS-TA alone. Full article

(This article belongs to the Special Issue Pulmonary Oncology Research)

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12 pages, 248 KiB

Open AccessEditor’s ChoiceReview

Oligometastasis of Gastric Cancer: A Review

by Itaru Yasufuku, Hiroshi Tsuchiya, Seito Fujibayashi, Naoki Okumura, Yuki Sengoku, Masahiro Fukada, Ryuichi Asai, Yuta Sato, Jesse Yu Tajima, Shigeru Kiyama, Takazumi Kato, Yoshihiro Tanaka, Katsutoshi Murase and Nobuhisa Matsuhashi

Cancers 2024, 16(3), 673; https://doi.org/10.3390/cancers16030673 - 5 Feb 2024

Cited by 2 | Viewed by 1938

Abstract

The concept of oligometastasis is not yet fully established in the field of gastric cancer. However, metastatic lesions that are localized, technically resectable at diagnosis, present a certain response to preoperative chemotherapy, and present favorable survival outcomes with local treatments, sometimes in combination [...] Read more.

The concept of oligometastasis is not yet fully established in the field of gastric cancer. However, metastatic lesions that are localized, technically resectable at diagnosis, present a certain response to preoperative chemotherapy, and present favorable survival outcomes with local treatments, sometimes in combination with chemotherapy, are recognized as oligometastasis in the field of gastric cancer. Oligometastasis is noted in European Society for Medical Oncology guidelines and Japanese gastric cancer treatment guidelines, and local treatment is mentioned as one of the pivotal treatment options for oligometastasis. Solitary liver metastasis or a small number of liver metastases; retroperitoneal lymph node metastasis, especially localized para-aortic lymph node metastasis; localized peritoneal dissemination; and Krukenberg tumor are representative types of oligometastasis in gastric cancer. The AIO-FLOT3 trial prospectively evaluated the efficacy of multimodal treatments for gastric cancer with oligometastasis, including surgical resection of primary and metastatic lesions combined with chemotherapy, confirming favorable survival outcomes. Two phase 3 studies are ongoing to investigate the efficacy of surgical resection combined with perioperative chemotherapy compared with palliative chemotherapy. Thus far, the evidence suggests that multimodal treatment for oligometastasis of gastric cancer is promising. Full article

(This article belongs to the Special Issue New Insights into Oligo-Recurrence of Various Cancers)

17 pages, 727 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Immunomodulation in Gastric Cancer

by Venu Akkanapally, Xue-Feng Bai and Sujit Basu

Cancers 2024, 16(3), 560; https://doi.org/10.3390/cancers16030560 - 28 Jan 2024

Cited by 2 | Viewed by 2751

Abstract

Gastric carcinoma, being one of the most prevalent types of solid tumors, has emerged as the third leading cause of death worldwide. The symptoms of gastric cancer (GC) are typically complex, which makes early detection challenging. Immune checkpoint inhibition has become the new [...] Read more.

Gastric carcinoma, being one of the most prevalent types of solid tumors, has emerged as the third leading cause of death worldwide. The symptoms of gastric cancer (GC) are typically complex, which makes early detection challenging. Immune checkpoint inhibition has become the new standard targeted therapy for advanced or metastatic GC. It is currently being explored in various combinations, both with and without chemotherapy, across multiple therapies in clinical trials. Immunotherapy can stimulate immune responses in GC patients, leading to the destruction of cancer cells. Compared with traditional therapies, immunotherapy has shown strong effectiveness with tolerable toxicity levels. Hence, this innovative approach to the treatment of advanced GC has gained popularity. In this review, we have outlined the recent advancements in immunotherapy for advanced GC, including immune checkpoint inhibitors, cancer vaccines, vascular endothelial growth factor-A inhibitors, and chimeric antigen receptor T-cell therapy. Our current emphasis is on examining the immunotherapies presently employed in clinical settings, addressing the existing challenges associated with these therapeutic approaches, and exploring promising strategies to overcome their limitations. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment in Gastric Cancers)

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15 pages, 1017 KiB

Open AccessEditor’s ChoiceArticle

Severe Acute Kidney Injury in Hospitalized Cancer Patients: Epidemiology and Predictive Model of Renal Replacement Therapy and In-Hospital Mortality

by Roberto Calças Marques, Marina Reis, Gonçalo Pimenta, Inês Sala, Teresa Chuva, Inês Coelho, Hugo Ferreira, Ana Paiva and José Maximino Costa

Cancers 2024, 16(3), 561; https://doi.org/10.3390/cancers16030561 - 28 Jan 2024

Cited by 2 | Viewed by 1470

Abstract

Background: Acute kidney injury (AKI) is a common complication among cancer patients, often leading to longer hospital stays, discontinuation of cancer treatment, and a poor prognosis. This study aims to provide insight into the incidence of severe AKI in this population and identify [...] Read more.

Background: Acute kidney injury (AKI) is a common complication among cancer patients, often leading to longer hospital stays, discontinuation of cancer treatment, and a poor prognosis. This study aims to provide insight into the incidence of severe AKI in this population and identify the risk factors associated with renal replacement therapy (RRT) and in-hospital mortality. Methods: This retrospective cohort study included 3201 patients with cancer and severe AKI admitted to a Comprehensive Cancer Center between January 1995 and July 2023. Severe AKI was defined according to the KDIGO guidelines as grade ≥ 2 AKI with nephrological in-hospital follow-up. Data were analyzed in two timelines: Period A (1995–2010) and Period B (2011–2023). Results: A total of 3201 patients (1% of all hospitalized cases) were included, with a mean age of 62.5 ± 17.2 years. Solid tumors represented 75% of all neoplasms, showing an increasing tendency, while hematological cancer decreased. Obstructive AKI declined, whereas the incidence of sepsis-associated, prerenal, and drug-induced AKI increased. Overall, 20% of patients required RRT, and 26.4% died during hospitalization. A predictive model for RRT (AUC 0.833 [95% CI 0.817–0.848]) identified sepsis and hematological cancer as risk factors and prerenal and obstructive AKI as protective factors. A similar model for overall in-hospital mortality (AUC 0.731 [95% CI 0.71–0.752]) revealed invasive mechanical ventilation (IMV), sepsis, and RRT as risk factors and obstructive AKI as a protective factor. The model for hemato-oncological patients’ mortality (AUC 0.832 [95% CI 0.803–0.861]) included IMV, sepsis, hematopoietic stem cell transplantation, and drug-induced AKI. Mortality risk point score models were derived from these analyses. Conclusions: This study addresses the demographic and clinical features of cancer patients with severe AKI. The development of predictive models for RRT and in-hospital mortality, along with risk point scores, may play a role in the management of this population. Full article

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

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26 pages, 1978 KiB

Open AccessEditor’s ChoiceReview

Is Immunotherapy Beneficial in Patients with Oncogene-Addicted Non-Small Cell Lung Cancers? A Narrative Review

by David John McMahon, Ronan McLaughlin and Jarushka Naidoo

Cancers 2024, 16(3), 527; https://doi.org/10.3390/cancers16030527 - 26 Jan 2024

Cited by 1 | Viewed by 3315

Abstract

Over the past 20 years, there has been a paradigm shift in the care of patients with non-small cell lung cancer (NSCLC), who now have a range of systemic treatment options including targeted therapy, chemotherapy, immunotherapy (ICI), and antibody–drug conjugates (ADCs). A proportion [...] Read more.

Over the past 20 years, there has been a paradigm shift in the care of patients with non-small cell lung cancer (NSCLC), who now have a range of systemic treatment options including targeted therapy, chemotherapy, immunotherapy (ICI), and antibody–drug conjugates (ADCs). A proportion of these cancers have single identifiable alterations in oncogenes that drive their proliferation and cancer progression, known as “oncogene-addiction”. These “driver alterations” are identified in approximately two thirds of patients with lung adenocarcinomas, via next generation sequencing or other orthogonal tests. It was noted in the early clinical development of ICIs that patients with oncogene-addicted NSCLC may have differential responses to ICI. The toxicity signal for patients with oncogene-addicted NSCLC when treated with ICIs also seemed to differ depending on the alteration present and the specific targeted agent used. Developing a greater understanding of the underlying reasons for these clinical observations has become an important area of research in NSCLC. In this review, we analyze the efficacy and safety of ICI according to specific mutations, and consider possible future directions to mitigate safety concerns and improve the outcomes for patients with oncogene-addicted NSCLC. Full article

(This article belongs to the Special Issue Discovery, Development and Application of Innovative Approaches to Cancer Therapy)

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20 pages, 2370 KiB

Open AccessEditor’s ChoiceReview

Antibody–Drug Conjugates: The Dynamic Evolution from Conventional to Next-Generation Constructs

by Virginia Metrangolo and Lars H. Engelholm

Cancers 2024, 16(2), 447; https://doi.org/10.3390/cancers16020447 - 20 Jan 2024

Cited by 6 | Viewed by 10408

Abstract

Introduced almost two decades ago, ADCs have marked a breakthrough in the targeted therapy era, providing clinical benefits to many cancer patients. While the inherent complexity of this class of drugs has challenged their development and broad application, the experience gained from years [...] Read more.

Introduced almost two decades ago, ADCs have marked a breakthrough in the targeted therapy era, providing clinical benefits to many cancer patients. While the inherent complexity of this class of drugs has challenged their development and broad application, the experience gained from years of trials and errors and recent advances in construct design and delivery have led to an increased number of ADCs approved or in late clinical development in only five years. Target and payload diversification, along with novel conjugation and linker technologies, are at the forefront of next-generation ADC development, renewing hopes to broaden the scope of these targeted drugs to difficult-to-treat cancers and beyond. This review highlights recent trends in the ADC field, focusing on construct design and mechanism of action and their implications on ADCs’ therapeutic profile. The evolution from conventional to innovative ADC formats will be illustrated, along with some of the current hurdles, including toxicity and drug resistance. Future directions to improve the design of next-generation ADCs will also be presented. Full article

(This article belongs to the Special Issue Innovation in Antibody-Drug Conjugates (ADCs))

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13 pages, 1188 KiB

Open AccessEditor’s ChoiceArticle

Elasticity Values as a Predictive Modality for Response to Neoadjuvant Chemotherapy in Breast Cancer

by Min Ji Kim, Na Lae Eun, Sung Gwe Ahn, Jee Hung Kim, Ji Hyun Youk, Eun Ju Son, Joon Jeong, Yoon Jin Cha and Soong June Bae

Cancers 2024, 16(2), 377; https://doi.org/10.3390/cancers16020377 - 16 Jan 2024

Cited by 1 | Viewed by 1135

Abstract

Shear-wave elastography (SWE) is an effective tool in discriminating malignant lesions of breast and axillary lymph node metastasis in patients with breast cancer. However, the association between the baseline elasticity value of breast cancer and the treatment response of neoadjuvant chemotherapy is yet [...] Read more.

Shear-wave elastography (SWE) is an effective tool in discriminating malignant lesions of breast and axillary lymph node metastasis in patients with breast cancer. However, the association between the baseline elasticity value of breast cancer and the treatment response of neoadjuvant chemotherapy is yet to be elucidated. Baseline SWE measured mean stiffness (E-mean) and maximum stiffness (E-max) in 830 patients who underwent neoadjuvant chemotherapy and surgery from January 2012 to December 2022. Association of elasticity values with breast pCR (defined as ypTis/T0), pCR (defined as ypTis/T0, N0), and tumor-infiltrating lymphocytes (TILs) was analyzed. Of 830 patients, 356 (42.9%) achieved breast pCR, and 324 (39.0%) achieved pCR. The patients with low elasticity values had higher breast pCR and pCR rates than those with high elasticity values. A low E-mean (adjusted odds ratio (OR): 0.620; 95% confidence interval (CI): 0.437 to 0.878; p = 0.007) and low E-max (adjusted OR: 0.701; 95% CI: 0.494 to 0.996; p = 0.047) were independent predictive factors for breast pCR. Low elasticity values were significantly correlated with high TILs. Pretreatment elasticity values measured using SWE were significantly associated with treatment response and inversely correlated with TILs, particularly in HR+HER2- breast cancer and TNBC. Full article

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

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21 pages, 1305 KiB

Open AccessEditor’s ChoiceReview

17q Gain in Neuroblastoma: A Review of Clinical and Biological Implications

by Vid Mlakar, Isabelle Dupanloup, Fanny Gonzales, Danai Papangelopoulou, Marc Ansari and Fabienne Gumy-Pause

Cancers 2024, 16(2), 338; https://doi.org/10.3390/cancers16020338 - 12 Jan 2024

Cited by 2 | Viewed by 2005

Abstract

Neuroblastoma (NB) is the most frequent extracranial solid childhood tumor. Despite advances in the understanding and treatment of this disease, the prognosis in cases of high-risk NB is still poor. 17q gain has been shown to be the most frequent genomic alteration in [...] Read more.

Neuroblastoma (NB) is the most frequent extracranial solid childhood tumor. Despite advances in the understanding and treatment of this disease, the prognosis in cases of high-risk NB is still poor. 17q gain has been shown to be the most frequent genomic alteration in NB. However, the significance of this remains unclear because of its high frequency and association with other genetic modifications, particularly segmental chromosomal aberrations, 1p and 11q deletions, and MYCN amplification, all of which are also associated with a poor clinical prognosis. This work reviewed the evidence on the clinical and biological significance of 17q gain. It strongly supports the significance of 17q gain in the development of NB and its importance as a clinically relevant marker. However, it is crucial to distinguish between whole and partial chromosome 17q gains. The most important breakpoints appear to be at 17q12 and 17q21. The former distinguishes between whole and partial chromosome 17q gain; the latter is a site of IGF2BP1 and NME1 genes that appear to be the main oncogenes responsible for the functional effects of 17q gain. Full article

(This article belongs to the Special Issue Advances in Genomics and Molecular Pathology of Rare Cancers—Focus on Diverse Populations)

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21 pages, 4413 KiB

Open AccessEditor’s ChoiceArticle

Preclinical Evaluation of Novel Folate Receptor 1-Directed CAR T Cells for Ovarian Cancer

by Julie Daigre, Manuel Martinez-Osuna, Maria Bethke, Larissa Steiner, Vera Dittmer, Katrin Krischer, Cathrin Bleilevens, Janina Brauner, Jens Kopatz, Matthias David Grundmann, Paurush Praveen, Dominik Eckardt, Andreas Bosio and Christoph Herbel

Cancers 2024, 16(2), 333; https://doi.org/10.3390/cancers16020333 - 12 Jan 2024

Cited by 2 | Viewed by 3022

Abstract

Treatment options for ovarian cancer patients are limited, and a high unmet clinical need remains for targeted and long-lasting, efficient drugs. Genetically modified T cells expressing chimeric antigen receptors (CAR), are promising new drugs that can be directed towards a defined target and [...] Read more.

Treatment options for ovarian cancer patients are limited, and a high unmet clinical need remains for targeted and long-lasting, efficient drugs. Genetically modified T cells expressing chimeric antigen receptors (CAR), are promising new drugs that can be directed towards a defined target and have shown efficient, as well as persisting, anti-tumor responses in many patients. We sought to develop novel CAR T cells targeting ovarian cancer and to assess these candidates preclinically. First, we identified potential CAR targets on ovarian cancer samples. We confirmed high and consistent expressions of the tumor-associated antigen FOLR1 on primary ovarian cancer samples. Subsequently, we designed a series of CAR T cell candidates against the identified target and demonstrated their functionality against ovarian cancer cell lines in vitro and in an in vivo xenograft model. Finally, we performed additional in vitro assays recapitulating immune suppressive mechanisms present in solid tumors and developed a process for the automated manufacturing of our CAR T cell candidate. These findings demonstrate the feasibility of anti-FOLR1 CAR T cells for ovarian cancer and potentially other FOLR1-expressing tumors. Full article

(This article belongs to the Special Issue Innovative Immunotherapies: CAR-T Cell Therapy for Cancers)

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17 pages, 3360 KiB

Open AccessEditor’s ChoiceArticle

Cell-Free DNA as a Biomarker at Diagnosis and Follow-Up in 256 B and T-Cell Lymphomas

by Ramón Diez-Feijóo, Marcio Andrade-Campos, Joan Gibert, Blanca Sánchez-González, Lierni Fernández-Ibarrondo, Concepción Fernández-Rodríguez, Nieves Garcia-Gisbert, Laura Camacho, Marta Lafuente, Ivonne Vázquez, Luis Colomo, Antonio Salar and Beatriz Bellosillo

Cancers 2024, 16(2), 321; https://doi.org/10.3390/cancers16020321 - 11 Jan 2024

Viewed by 1210

Abstract

Background: Cell-free DNA (cfDNA) analysis has become a promising tool for the diagnosis, prognosis, and monitoring of lymphoma cases. Until now, research in this area has mainly focused on aggressive lymphomas, with scanty information from other lymphoma subtypes. Methods: We selected 256 patients [...] Read more.

Background: Cell-free DNA (cfDNA) analysis has become a promising tool for the diagnosis, prognosis, and monitoring of lymphoma cases. Until now, research in this area has mainly focused on aggressive lymphomas, with scanty information from other lymphoma subtypes. Methods: We selected 256 patients diagnosed with lymphomas, including a large variety of B-cell and T-cell non-Hodgkin and Hodgkin lymphomas, and quantified cfDNA from plasma at the time of diagnosis. We further selected 49 large B-cell lymphomas (LBCL) and analyzed cfDNA levels at diagnosis (pre-therapy) and after therapy. In addition, we performed NGS on cfDNA and tissue in this cohort of LBCL. Results: Lymphoma patients showed a statistically significant higher cfDNA concentration than healthy controls (mean 53.0 ng/mL vs. 5.6 ng/mL, p < 0.001). The cfDNA concentration was correlated with lymphoma subtype, lactate dehydrogenase, the International Prognostic Index (IPI) score, Ann Arbor (AA), and B-symptoms. In 49 LBCL cases, the cfDNA concentration decreased after therapy in cases who achieved complete response (CR) and increased in non-responders. The median cfDNA at diagnosis of patients who achieved CR and later relapsed was higher (81.5 ng/mL) compared with levels of those who did not (38.6 ng/mL). A concordance of 84% was observed between NGS results in tumor and cfDNA samples. Higher VAF in cfDNA is correlated with advanced stage and bulky disease. Conclusions: cfDNA analysis can be easily performed in almost all lymphoma cases. The cfDNA concentration correlated with the characteristics of the aggressiveness of the lymphomas and, in LBCL, with the response achieved after therapy. These results support the utility of cfDNA analysis as a complementary tool in the management of lymphoma patients. Full article

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

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23 pages, 2492 KiB

Open AccessEditor’s ChoiceReview

MASLD and the Development of HCC: Pathogenesis and Therapeutic Challenges

by Anju G. S. Phoolchund and Salim I. Khakoo

Cancers 2024, 16(2), 259; https://doi.org/10.3390/cancers16020259 - 6 Jan 2024

Cited by 5 | Viewed by 3441

Abstract

Metabolic-dysfunction-associated steatotic liver disease (MASLD, previously known as non-alcoholic fatty liver disease (NAFLD)) represents a rapidly increasing cause of chronic liver disease and hepatocellular carcinoma (HCC), mirroring increasing rates of obesity and metabolic syndrome in the Western world. MASLD-HCC can develop at an [...] Read more.

Metabolic-dysfunction-associated steatotic liver disease (MASLD, previously known as non-alcoholic fatty liver disease (NAFLD)) represents a rapidly increasing cause of chronic liver disease and hepatocellular carcinoma (HCC), mirroring increasing rates of obesity and metabolic syndrome in the Western world. MASLD-HCC can develop at an earlier stage of fibrosis compared to other causes of chronic liver disease, presenting challenges in how to risk-stratify patients to set up effective screening programmes. Therapeutic decision making for MASLD-HCC is also complicated by medical comorbidities and disease presentation at a later stage. The response to treatment, particularly immune checkpoint inhibitors, may vary by the aetiology of the disease, and, in the future, patient stratification will be key to optimizing the therapeutic pathways. Full article

(This article belongs to the Special Issue Molecular Landscape in Liver, Pancreas and Gastrointestinal Tumors)

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13 pages, 4698 KiB

Open AccessEditor’s ChoiceArticle

Ninjurin 2, a Cell Adhesion Molecule and a Target of p53, Modulates Wild-Type p53 in Growth Suppression and Mutant p53 in Growth Promotion

by Jin Zhang, Xiangmudong Kong, Hee Jung Yang, Shakur Mohibi, Christopher August Lucchesi, Weici Zhang and Xinbin Chen

Cancers 2024, 16(1), 229; https://doi.org/10.3390/cancers16010229 - 4 Jan 2024

Cited by 1 | Viewed by 1962

Abstract

The nerve injury-induced protein 1 (NINJ1) and NINJ2 constitute a family of homophilic adhesion molecules and are involved in nerve regeneration. Previously, we showed that NINJ1 and p53 are mutually regulated and the NINJ1-p53 loop plays a critical role in p53-dependent tumor suppression. [...] Read more.

The nerve injury-induced protein 1 (NINJ1) and NINJ2 constitute a family of homophilic adhesion molecules and are involved in nerve regeneration. Previously, we showed that NINJ1 and p53 are mutually regulated and the NINJ1-p53 loop plays a critical role in p53-dependent tumor suppression. However, the biology of NINJ2 has not been well-explored. By using multiple in vitro cell lines and genetically engineered mouse embryo fibroblasts (MEFs), we showed that NINJ2 is induced by DNA damage in a p53-dependent manner. Moreover, we found that the loss of NINJ2 promotes p53 expression via mRNA translation and leads to growth suppression in wild-type p53-expressing MCF7 and Molt4 cells and premature senescence in MEFs in a wild-type p53-dependent manner. Interestingly, NINJ2 also regulates mutant p53 expression, and the loss of NINJ2 promotes cell growth and migration in mutant p53-expressing MIA-PaCa2 cells. Together, these data indicate that the mutual regulation between NINJ2 and p53 represents a negative feedback loop, and the NINJ2-p53 loop has opposing functions in wild-type p53-dependent growth suppression and mutant p53-dependent growth promotion. Full article

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

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12 pages, 895 KiB

Open AccessEditor’s ChoiceArticle

Artificial Intelligence and Panendoscopy—Automatic Detection of Clinically Relevant Lesions in Multibrand Device-Assisted Enteroscopy

by Francisco Mendes, Miguel Mascarenhas, Tiago Ribeiro, João Afonso, Pedro Cardoso, Miguel Martins, Hélder Cardoso, Patrícia Andrade, João P. S. Ferreira, Miguel Mascarenhas Saraiva and Guilherme Macedo

Cancers 2024, 16(1), 208; https://doi.org/10.3390/cancers16010208 - 1 Jan 2024

Cited by 1 | Viewed by 1299

Abstract

Device-assisted enteroscopy (DAE) is capable of evaluating the entire gastrointestinal tract, identifying multiple lesions. Nevertheless, DAE’s diagnostic yield is suboptimal. Convolutional neural networks (CNN) are multi-layer architecture artificial intelligence models suitable for image analysis, but there is a lack of studies about their [...] Read more.

Device-assisted enteroscopy (DAE) is capable of evaluating the entire gastrointestinal tract, identifying multiple lesions. Nevertheless, DAE’s diagnostic yield is suboptimal. Convolutional neural networks (CNN) are multi-layer architecture artificial intelligence models suitable for image analysis, but there is a lack of studies about their application in DAE. Our group aimed to develop a multidevice CNN for panendoscopic detection of clinically relevant lesions during DAE. In total, 338 exams performed in two specialized centers were retrospectively evaluated, with 152 single-balloon enteroscopies (Fujifilm®, Porto, Portugal), 172 double-balloon enteroscopies (Olympus^®, Porto, Portugal) and 14 motorized spiral enteroscopies (Olympus^®, Porto, Portugal); then, 40,655 images were divided in a training dataset (90% of the images, n = 36,599) and testing dataset (10% of the images, n = 4066) used to evaluate the model. The CNN’s output was compared to an expert consensus classification. The model was evaluated by its sensitivity, specificity, positive (PPV) and negative predictive values (NPV), accuracy and area under the precision recall curve (AUC-PR). The CNN had an 88.9% sensitivity, 98.9% specificity, 95.8% PPV, 97.1% NPV, 96.8% accuracy and an AUC-PR of 0.97. Our group developed the first multidevice CNN for panendoscopic detection of clinically relevant lesions during DAE. The development of accurate deep learning models is of utmost importance for increasing the diagnostic yield of DAE-based panendoscopy. Full article

(This article belongs to the Topic Deep Learning for Medical Image Analysis and Medical Natural Language Processing)

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13 pages, 4255 KiB

Open AccessEditor’s ChoiceArticle

Development and Validation of an Explainable Radiomics Model to Predict High-Aggressive Prostate Cancer: A Multicenter Radiomics Study Based on Biparametric MRI

by Giulia Nicoletti, Simone Mazzetti, Giovanni Maimone, Valentina Cignini, Renato Cuocolo, Riccardo Faletti, Marco Gatti, Massimo Imbriaco, Nicola Longo, Andrea Ponsiglione, Filippo Russo, Alessandro Serafini, Arnaldo Stanzione, Daniele Regge and Valentina Giannini

Cancers 2024, 16(1), 203; https://doi.org/10.3390/cancers16010203 - 1 Jan 2024

Cited by 1 | Viewed by 2040

Abstract

In the last years, several studies demonstrated that low-aggressive (Grade Group (GG) ≤ 2) and high-aggressive (GG ≥ 3) prostate cancers (PCas) have different prognoses and mortality. Therefore, the aim of this study was to develop and externally validate a radiomic model to [...] Read more.

In the last years, several studies demonstrated that low-aggressive (Grade Group (GG) ≤ 2) and high-aggressive (GG ≥ 3) prostate cancers (PCas) have different prognoses and mortality. Therefore, the aim of this study was to develop and externally validate a radiomic model to noninvasively classify low-aggressive and high-aggressive PCas based on biparametric magnetic resonance imaging (bpMRI). To this end, 283 patients were retrospectively enrolled from four centers. Features were extracted from apparent diffusion coefficient (ADC) maps and T2-weighted (T2w) sequences. A cross-validation (CV) strategy was adopted to assess the robustness of several classifiers using two out of the four centers. Then, the best classifier was externally validated using the other two centers. An explanation for the final radiomics signature was provided through Shapley additive explanation (SHAP) values and partial dependence plots (PDP). The best combination was a naïve Bayes classifier trained with ten features that reached promising results, i.e., an area under the receiver operating characteristic (ROC) curve (AUC) of 0.75 and 0.73 in the construction and external validation set, respectively. The findings of our work suggest that our radiomics model could help distinguish between low- and high-aggressive PCa. This noninvasive approach, if further validated and integrated into a clinical decision support system able to automatically detect PCa, could help clinicians managing men with suspicion of PCa. Full article

(This article belongs to the Special Issue MRI in Prostate Cancer)

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12 pages, 2770 KiB

Open AccessEditor’s ChoiceArticle

The National Burden of Colorectal Cancer in the United States from 1990 to 2019

by Saqr Alsakarneh, Fouad Jaber, Azizullah Beran, Mohammad Aldiabat, Yazan Abboud, Noor Hassan, Mohamed Abdallah, Thaer Abdelfattah, Laith Numan, Wendell Clarkston, Mohammad Bilal and Aasma Shaukat

Cancers 2024, 16(1), 205; https://doi.org/10.3390/cancers16010205 - 1 Jan 2024

Cited by 3 | Viewed by 2382

Abstract

CRC accounts for approximately a tenth of all cancer cases and deaths in the US. Due to large differences in demographics among the different states, we aim to determine trends in the CRC epidemiology and across different states, age groups, and genders. CRC [...] Read more.

CRC accounts for approximately a tenth of all cancer cases and deaths in the US. Due to large differences in demographics among the different states, we aim to determine trends in the CRC epidemiology and across different states, age groups, and genders. CRC rates, age-adjusted to the standard US population, were obtained from the GBD 2019 database. Time trends were estimated as annual percentage change (APC). A pairwise comparison was conducted between age- and gender-specific trends using the tests of parallelism and coincidence. Age-specific trends were also assessed in two age subgroups: younger adults aged 15–49 years and older adults aged 50–74 years. We also analyzed the prevalence, incidence, mortality, and DALYs in the US between 1990 and 2019. A total of 5.53 million patients were diagnosed with CRC in the US between 1990 and 2019. Overall, CRC incidence rates have significantly increased in younger adults (11.1 per 100,000 persons) and decreased in older adults (136.8 per 100,000 persons) (AAPC = 1.2 vs. −0.6; AAPC difference = 1.8, p < 0.001). Age-specific trends were neither identical (p < 0.001) nor parallel (p < 0.001), suggesting that CRC incidence rates are different and increasing at a greater rate in younger adults compared to older adults. However, for both men and women (49.4 and 35.2 per 100,000 persons), incidence rates have decreased over the past three decades at the same rate (AAPC = −0.5 vs. −0.5; AAPC difference = 0, p = 0.1). Geographically, the southern states had the highest mortality rates with Mississippi having the highest rate of 20.1 cases per 100,000 population in 2019. Massachusetts, New York, and the District of Colombia had the greatest decreases in mortality over the study period (−42.1%, −41.4%, and −40.9%). Decreased mortality was found in all states except Mississippi, where the mortality of CRC increased over the study period (+1.5%). This research provides crucial insights for policymakers to tailor resource allocation, emphasizing the dynamic nature of CRC burden across states and age groups, ultimately informing targeted strategies for prevention and intervention. Full article

(This article belongs to the Special Issue Clinical Epidemiology and Risk Prediction for Gastrointestinal Cancers)

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13 pages, 1189 KiB

Open AccessEditor’s ChoiceArticle

Validation of Inflammatory Prognostic Biomarkers in Pleural Mesothelioma

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

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

Cited by 1 | Viewed by 1656

Abstract

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

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

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

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33 pages, 1918 KiB

Open AccessEditor’s ChoiceReview

Promises and Pitfalls of Next-Generation Treg Adoptive Immunotherapy

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

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

Cited by 1 | Viewed by 2076

Abstract

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

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

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

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20 pages, 1599 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 1 | Viewed by 1896

Abstract

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

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

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

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22 pages, 563 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 1 | Viewed by 1400

Abstract

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

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

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

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19 pages, 5749 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Viewed by 2174

Abstract

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

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

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

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18 pages, 1560 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Targeting of Glioblastoma and the Interactions with Its Microenvironment

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

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

Cited by 3 | Viewed by 1625

Abstract

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

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

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

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18 pages, 1106 KiB

Open AccessEditor’s ChoiceReview

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

by Sherise Rogers, Angel Charles and Ryan M. Thomas

Cancers 2023, 15(24), 5708; https://doi.org/10.3390/cancers15245708 - 5 Dec 2023

Cited by 1 | Viewed by 1610

Abstract

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

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

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

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22 pages, 7073 KiB

Open AccessEditor’s ChoiceArticle

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

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

Cancers 2023, 15(24), 5711; https://doi.org/10.3390/cancers15245711 - 5 Dec 2023

Viewed by 1264

Abstract

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

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

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

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16 pages, 1190 KiB

Open AccessEditor’s ChoiceArticle

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

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

Cancers 2023, 15(23), 5693; https://doi.org/10.3390/cancers15235693 - 2 Dec 2023

Cited by 1 | Viewed by 1247

Abstract

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

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

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

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22 pages, 11501 KiB

Open AccessEditor’s ChoiceArticle

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

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

Cancers 2023, 15(23), 5686; https://doi.org/10.3390/cancers15235686 - 1 Dec 2023

Viewed by 1637

Abstract

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

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

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

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20 pages, 2725 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Viewed by 2199

Abstract

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

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

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

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14 pages, 6258 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 1328

Abstract

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

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

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

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13 pages, 1544 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 1 | Viewed by 1377

Abstract

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

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

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

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20 pages, 7360 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 1547

Abstract

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

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

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

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15 pages, 1894 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Viewed by 1768

Abstract

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

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

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

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13 pages, 1805 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 1444

Abstract

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

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

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

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11 pages, 1576 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Viewed by 1270

Abstract

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

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

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

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15 pages, 1433 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 1451

Abstract

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

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

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

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15 pages, 1056 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 1097

Abstract

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

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

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

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34 pages, 1963 KiB

Open AccessEditor’s ChoiceSystematic Review

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

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

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

Cited by 2 | Viewed by 1854

Abstract

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

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

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

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21 pages, 11726 KiB

Open AccessEditor’s ChoiceReview

Hepatocellular Carcinoma: Surveillance, Diagnosis, Evaluation and Management

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

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

Cited by 6 | Viewed by 2206

Abstract

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

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

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

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16 pages, 318 KiB

Open AccessEditor’s ChoiceReview

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

by Edward Young, Louisa Edwards and Rajvinder Singh

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

Cited by 5 | Viewed by 1869

Abstract

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

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

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

16 pages, 2199 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 2813

Abstract

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

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

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

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25 pages, 3586 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 1741

Abstract

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

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

(This article belongs to the Section Cancer Biomarkers)

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21 pages, 2132 KiB

Open AccessEditor’s ChoiceArticle

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

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

Cancers 2023, 15(19), 4892; https://doi.org/10.3390/cancers15194892 - 9 Oct 2023

Cited by 3 | Viewed by 1027

Abstract

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

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

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

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14 pages, 281 KiB

Open AccessEditor’s ChoiceReview

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

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

Cancers 2023, 15(19), 4875; https://doi.org/10.3390/cancers15194875 - 7 Oct 2023

Viewed by 2017

Abstract

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

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

(This article belongs to the Section Cancer Biomarkers)

15 pages, 17662 KiB

Open AccessEditor’s ChoiceArticle

Molecular Characterization of Primary Mediastinal Large B-Cell Lymphomas

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

Cancers 2023, 15(19), 4866; https://doi.org/10.3390/cancers15194866 - 6 Oct 2023

Cited by 2 | Viewed by 1743

Abstract

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

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

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