Cancers

21 pages, 7124 KB

Open AccessEditor’s ChoiceReview

Novel Targets, Novel Treatments: The Changing Landscape of Non-Small Cell Lung Cancer

by Dorine de Jong, Jeeban P. Das, Hong Ma, Jacienta Pailey Valiplackal, Conor Prendergast, Tina Roa, Brian Braumuller, Aileen Deng, Laurent Dercle, Randy Yeh, Mary M. Salvatore and Kathleen M. Capaccione

Cancers 2023, 15(10), 2855; https://doi.org/10.3390/cancers15102855 - 21 May 2023

Cited by 37 | Viewed by 7107

Abstract

Treatment of non-small cell lung cancer (NSCLC) has undergone a paradigm shift. Once a disease with limited potential therapies, treatment options for patients have exploded with the availability of molecular testing to direct management and targeted therapies to treat tumors with specific driver [...] Read more.

Treatment of non-small cell lung cancer (NSCLC) has undergone a paradigm shift. Once a disease with limited potential therapies, treatment options for patients have exploded with the availability of molecular testing to direct management and targeted therapies to treat tumors with specific driver mutations. New in vitro diagnostics allow for the early and non-invasive detection of disease, and emerging in vivo imaging techniques allow for better detection and monitoring. The development of checkpoint inhibitor immunotherapy has arguably been the biggest advance in lung cancer treatment, given that the vast majority of NSCLC tumors can be treated with these therapies. Specific targeted therapies, including those against KRAS, EGFR, RTK, and others have also improved the outcomes for those individuals bearing an actionable mutation. New and emerging therapies, such as bispecific antibodies, CAR T cell therapy, and molecular targeted radiotherapy, offer promise to patients for whom none of the existing therapies have proved effective. In this review, we provide the most up-to-date survey to our knowledge regarding emerging diagnostic and therapeutic strategies for lung cancer to provide clinicians with a comprehensive reference of the options for treatment available now and those which are soon to come. Full article

(This article belongs to the Special Issue Lung Cancer - Molecular Insights and Targeted Therapies)

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32 pages, 907 KB

Open AccessEditor’s ChoiceReview

Beyond CTLA-4 and PD-1 Inhibition: Novel Immune Checkpoint Molecules for Melanoma Treatment

by Dimitrios C. Ziogas, Charalampos Theocharopoulos, Panagiotis-Petros Lialios, Dimitra Foteinou, Ioannis-Alexios Koumprentziotis, Georgios Xynos and Helen Gogas

Cancers 2023, 15(10), 2718; https://doi.org/10.3390/cancers15102718 - 11 May 2023

Cited by 59 | Viewed by 9992

Abstract

More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a [...] Read more.

More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a considerable proportion of patients do not respond or experience early relapse, due to multiple parameters that contribute to melanoma resistance. The expression of other immune checkpoints beyond the PD-1 and CTLA-4 molecules remains a major mechanism of immune evasion. The recent approval of anti-LAG-3 ICI, relatlimab, in combination with nivolumab for metastatic disease, has capitalized on the extensive research in the field and has highlighted the potential for further improvement of melanoma prognosis by synergistically blocking additional immune targets with new ICI-doublets, antibody–drug conjugates, or other novel modalities. Herein, we provide a comprehensive overview of presently published immune checkpoint molecules, including LAG-3, TIGIT, TIM-3, VISTA, IDO1/IDO2/TDO, CD27/CD70, CD39/73, HVEM/BTLA/CD160 and B7-H3. Beginning from their immunomodulatory properties as co-inhibitory or co-stimulatory receptors, we present all therapeutic modalities targeting these molecules that have been tested in melanoma treatment either in preclinical or clinical settings. Better understanding of the checkpoint-mediated crosstalk between melanoma and immune effector cells is essential for generating more effective strategies with augmented immune response. Full article

(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)

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27 pages, 4387 KB

Open AccessEditor’s ChoiceArticle

Development and Validation of Blood-Based Predictive Biomarkers for Response to PD-1/PD-L1 Checkpoint Inhibitors: Evidence of a Universal Systemic Core of 3D Immunogenetic Profiling across Multiple Oncological Indications

by Ewan Hunter, Matthew Salter, Ryan Powell, Ann Dring, Tarun Naithani, Maria Eleni Chatziioannou, Abel Gebregzabhar, Mutaz Issa, Jayne Green, Serene Ng, Chun Ren Lim, Cheah Soon Keat, Ang Tick Suan, Rakesh Raman, Ho Kean Fatt, Fabian Lee Wei Luen, Heba Alshaker, Dmitri Pchejetski, Dave Blum, Thomas Guiel, Robert Heaton, Jr., Jedd Levine and Alexandre Akoulitchev Show full author list Hide full author list

Cancers 2023, 15(10), 2696; https://doi.org/10.3390/cancers15102696 - 10 May 2023

Cited by 12 | Viewed by 6916

Abstract

Background: Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICIs) remain limited to only a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetic and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint [...] Read more.

Background: Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICIs) remain limited to only a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetic and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint pathways reveal a highly prevalent molecular profile predictive of response to PD-1/PD-L1 ICIs. A clinical blood test based on a set of eight (8) 3D genomic biomarkers has been developed and validated on the basis of an observational trial to predict response to ICI therapy. Methods: The predictive eight biomarker set is derived from prospective observational clinical trials, representing 280 treatments with Pembrolizumab, Atezolizumab, Durvalumab, Nivolumab, and Avelumab in a broad range of indications: melanoma, lung, hepatocellular, renal, breast, bladder, colon, head and neck, bone, brain, lymphoma, prostate, vulvar, and cervical cancers. Results: The 3D genomic eight biomarker panel for response to immune checkpoint therapy achieved a high accuracy of 85%, sensitivity of 93%, and specificity of 82%. Conclusions: This study demonstrates that a 3D genomic approach can be used to develop a predictive clinical assay for response to PD-1/PD-L1 checkpoint inhibition in cancer patients. Full article

(This article belongs to the Topic Biomarker Development and Application)

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12 pages, 1034 KB

Open AccessEditor’s ChoiceReview

HER2 Intratumoral Heterogeneity in Breast Cancer, an Evolving Concept

by Yanjun Hou, Hiroaki Nitta and Zaibo Li

Cancers 2023, 15(10), 2664; https://doi.org/10.3390/cancers15102664 - 9 May 2023

Cited by 54 | Viewed by 7269

Abstract

Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is associated with an adverse prognosis. The introduction of anti-HER2 targeted therapy has dramatically improved the clinical outcomes of patients with HER2-positive breast cancer. Unfortunately, a significant number of [...] Read more.

Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is associated with an adverse prognosis. The introduction of anti-HER2 targeted therapy has dramatically improved the clinical outcomes of patients with HER2-positive breast cancer. Unfortunately, a significant number of patients eventually relapse and develop distant metastasis. HER2 intratumoral heterogeneity (ITH) has been reported to be associated with poor prognosis in patients with anti-HER2 targeted therapies and was proposed to be a potential mechanism for anti-HER2 resistance. In this review, we described the current definition, common types of HER2 ITH in breast cancer, the challenge in interpretation of HER2 status in cases showing ITH and the clinical applications of anti-HER2 agents in breast cancer showing heterogeneous HER2 expression. Digital image analysis has emerged as an objective and reproducible scoring method and its role in the assessment of HER2 status with ITH remains to be demonstrated. Full article

(This article belongs to the Special Issue Biomarkers in Breast Cancer: Recent Advances and Challenges)

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12 pages, 272 KB

Open AccessEditor’s ChoiceReview

The Role of HER2 Status in the Biliary Tract Cancers

by Ruveyda Ayasun, Muhammet Ozer and Ilyas Sahin

Cancers 2023, 15(9), 2628; https://doi.org/10.3390/cancers15092628 - 5 May 2023

Cited by 16 | Viewed by 5614

Abstract

Despite recent advances, biliary tract cancer (BTC) is traditionally known as being hard to treat with a poor prognosis. Recent state-of-the-art genomic technologies such as next-generation sequencing (NGS) revolutionized cancer management and shed light on the genomic landscape of BTCs. There are ongoing [...] Read more.

Despite recent advances, biliary tract cancer (BTC) is traditionally known as being hard to treat with a poor prognosis. Recent state-of-the-art genomic technologies such as next-generation sequencing (NGS) revolutionized cancer management and shed light on the genomic landscape of BTCs. There are ongoing clinical trials to assess the efficacy of HER2-blocking antibodies or drug conjugates in BTCs with HER2 amplifications. However, HER2 amplifications may not be the sole eligibility factor for these clinical trials. In this review, we aimed to comprehensively examine the role of somatic HER2 alterations and amplifications in patient stratification and provide an overview of the current state of ongoing clinical trials. Full article

(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)

48 pages, 7853 KB

Open AccessEditor’s ChoiceReview

Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer

by Javad Alizadeh, Mahboubeh Kavoosi, Navjit Singh, Shahrokh Lorzadeh, Amir Ravandi, Biniam Kidane, Naseer Ahmed, Fatima Mraiche, Michael R. Mowat and Saeid Ghavami

Cancers 2023, 15(8), 2195; https://doi.org/10.3390/cancers15082195 - 7 Apr 2023

Cited by 39 | Viewed by 8122

Abstract

Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated [...] Read more.

Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated with metabolism in mammalian cells, acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. In addition, we discuss the impact of these metabolic pathways on autophagy in lung cancer. Full article

(This article belongs to the Special Issue Autophagy–EMT Interrelations: At the Core of Tumor Transformation)

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20 pages, 1020 KB

Open AccessEditor’s ChoiceReview

Detection and Molecular Characterization of Circulating Tumour Cells: Challenges for the Clinical Setting

by Areti Strati, Athina Markou, Evgenia Kyriakopoulou and Evi Lianidou

Cancers 2023, 15(7), 2185; https://doi.org/10.3390/cancers15072185 - 6 Apr 2023

Cited by 27 | Viewed by 5618

Abstract

Over the last decade, liquid biopsy has gained much attention as a powerful tool in personalized medicine since it enables monitoring cancer evolution and follow-up of cancer patients in real time. Through minimally invasive procedures, liquid biopsy provides important information through the analysis [...] Read more.

Over the last decade, liquid biopsy has gained much attention as a powerful tool in personalized medicine since it enables monitoring cancer evolution and follow-up of cancer patients in real time. Through minimally invasive procedures, liquid biopsy provides important information through the analysis of circulating tumour cells (CTCs) and circulating tumour-derived material, such as circulating tumour DNA (ctDNA), circulating miRNAs (cfmiRNAs) and extracellular vehicles (EVs). CTC analysis has already had an important impact on the prognosis, detection of minimal residual disease (MRD), treatment selection and monitoring of cancer patients. Numerous clinical trials nowadays include a liquid biopsy arm. CTC analysis is now an exponentially expanding field in almost all types of solid cancers. Functional studies, mainly based on CTC-derived cell-lines and CTC-derived explants (CDx), provide important insights into the metastatic process. The purpose of this review is to summarize the latest findings on the clinical significance of CTCs for the management of cancer patients, covering the last four years. This review focuses on providing a comprehensive overview of CTC analysis in breast, prostate and non-small-cell lung cancer. The unique potential of CTC single-cell analysis for understanding metastasis biology, and the importance of quality control and standardization of methodologies used in this field, is also discussed. Full article

(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)

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25 pages, 1410 KB

Open AccessEditor’s ChoiceReview

The Cell Biology of Metastatic Invasion in Pancreatic Cancer: Updates and Mechanistic Insights

by Vidhu B. Joshi, Omar L. Gutierrez Ruiz and Gina L. Razidlo

Cancers 2023, 15(7), 2169; https://doi.org/10.3390/cancers15072169 - 6 Apr 2023

Cited by 17 | Viewed by 6816

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality worldwide. This is largely due to the lack of routine screening protocols, an absence of symptoms in early-stage disease leading to late detection, and a paucity of effective treatment options. [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality worldwide. This is largely due to the lack of routine screening protocols, an absence of symptoms in early-stage disease leading to late detection, and a paucity of effective treatment options. Critically, the majority of patients either present with metastatic disease or rapidly develop metastatic disease. Thus, there is an urgent need to deepen our understanding of metastasis in PDAC. During metastasis, tumor cells escape from the primary tumor, enter the circulation, and travel to a distant site to form a secondary tumor. In order to accomplish this relatively rare event, tumor cells develop an enhanced ability to detach from the primary tumor, migrate into the surrounding matrix, and invade across the basement membrane. In addition, cancer cells interact with the various cell types and matrix proteins that comprise the tumor microenvironment, with some of these factors working to promote metastasis and others working to suppress it. In PDAC, many of these processes are not well understood. The purpose of this review is to highlight recent advances in the cell biology of the early steps of the metastatic cascade in pancreatic cancer. Specifically, we will examine the regulation of epithelial-to-mesenchymal transition (EMT) in PDAC and its requirement for metastasis, summarize our understanding of how PDAC cells invade and degrade the surrounding matrix, and discuss how migration and adhesion dynamics are regulated in PDAC to optimize cancer cell motility. In addition, the role of the tumor microenvironment in PDAC will also be discussed for each of these invasive processes. Full article

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

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58 pages, 2391 KB

Open AccessEditor’s ChoiceReview

DNA-Based Nanomaterials as Drug Delivery Platforms for Increasing the Effect of Drugs in Tumors

by Anastasiya N. Shishparenok, Vitalina V. Furman and Dmitry D. Zhdanov

Cancers 2023, 15(7), 2151; https://doi.org/10.3390/cancers15072151 - 5 Apr 2023

Cited by 33 | Viewed by 8427

Abstract

DNA nanotechnology has significantly advanced and might be used in biomedical applications, drug delivery, and cancer treatment during the past few decades. DNA nanomaterials are widely used in biomedical research involving biosensing, bioimaging, and drug delivery since they are remarkably addressable and biocompatible. [...] Read more.

DNA nanotechnology has significantly advanced and might be used in biomedical applications, drug delivery, and cancer treatment during the past few decades. DNA nanomaterials are widely used in biomedical research involving biosensing, bioimaging, and drug delivery since they are remarkably addressable and biocompatible. Gradually, modified nucleic acids have begun to be employed to construct multifunctional DNA nanostructures with a variety of architectural designs. Aptamers are single-stranded nucleic acids (both DNAs and RNAs) capable of self-pairing to acquire secondary structure and of specifically binding with the target. Diagnosis and tumor therapy are prospective fields in which aptamers can be applied. Many DNA nanomaterials with three-dimensional structures have been studied as drug delivery systems for different anticancer medications or gene therapy agents. Different chemical alterations can be employed to construct a wide range of modified DNA nanostructures. Chemically altered DNA-based nanomaterials are useful for drug delivery because of their improved stability and inclusion of functional groups. In this work, the most common oligonucleotide nanomaterials were reviewed as modern drug delivery systems in tumor cells. Full article

(This article belongs to the Special Issue Nanoplatforms Based Cancers Therapy 2.0)

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37 pages, 1753 KB

Open AccessEditor’s ChoiceReview

Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM)

by Satya Siva Kishan Yalamarty, Nina Filipczak, Xiang Li, Md Abdus Subhan, Farzana Parveen, Janaína Artem Ataide, Bharat Ashok Rajmalani and Vladimir P. Torchilin

Cancers 2023, 15(7), 2116; https://doi.org/10.3390/cancers15072116 - 1 Apr 2023

Cited by 174 | Viewed by 20813

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer that is difficult to treat due to its resistance to both radiation and chemotherapy. This resistance is largely due to the unique biology of GBM cells, which can evade the effects of [...] Read more.

Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer that is difficult to treat due to its resistance to both radiation and chemotherapy. This resistance is largely due to the unique biology of GBM cells, which can evade the effects of conventional treatments through mechanisms such as increased resistance to cell death and rapid regeneration of cancerous cells. Additionally, the blood–brain barrier makes it difficult for chemotherapy drugs to reach GBM cells, leading to reduced effectiveness. Despite these challenges, there are several treatment options available for GBM. The standard of care for newly diagnosed GBM patients involves surgical resection followed by concurrent chemoradiotherapy and adjuvant chemotherapy. Emerging treatments include immunotherapy, such as checkpoint inhibitors, and targeted therapies, such as bevacizumab, that attempt to attack specific vulnerabilities in GBM cells. Another promising approach is the use of tumor-treating fields, a type of electric field therapy that has been shown to slow the growth of GBM cells. Clinical trials are ongoing to evaluate the safety and efficacy of these and other innovative treatments for GBM, intending to improve with outcomes for patients. Full article

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14 pages, 3978 KB

Open AccessEditor’s ChoiceArticle

Pediatric Patients with Stage IV Rhabdomyosarcoma Significantly Benefit from Long-Term Maintenance Therapy: Results of the CWS-IV 2002 and the CWS DOK IV 2004-Trials

by Lars Tramsen, Konrad Bochennek, Monika Sparber-Sauer, Emilia Salzmann-Manrique, Monika Scheer, Tobias Dantonello, Arndt Borkhardt, Uta Dirksen, Anne Thorwarth, Jeanette Greiner, Martin Ebinger, Jadwiga Weclawek-Tompol, Ruth Ladenstein, Gustaf Ljungman, Erika Hallmen, Thomas Lehrnbecher, Ewa Koscielniak and Thomas Klingebiel

Cancers 2023, 15(7), 2050; https://doi.org/10.3390/cancers15072050 - 30 Mar 2023

Cited by 16 | Viewed by 6177

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, with survival rates of less than 30%. The HD CWS-96 trial showed [...] Read more.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, with survival rates of less than 30%. The HD CWS-96 trial showed an improved outcome for patients receiving maintenance therapy after completing intensive chemotherapy. Consequently, the international clinical trials CWS-IV 2002 and CWS DOK IV 2004 on metastatic disease of STS of the Cooperative Weichteilsarkom Studiengruppe (CWS) were designed in addition to the CWS-2002P trial for localized RMS disease. All patients received a multimodal intensive treatment regimen. To maintain remission, three options were compared: long-term maintenance therapy (LTMT) versus allogeneic hematopoietic stem cell transplantation (alloHSCT) versus high-dose chemotherapy (HDCT). A total of 176 pediatric patients with a histologically confirmed diagnosis of metastatic RMS or RMS-like tumor were included. A total of 89 patients receiving LTML showed a significantly better outcome, with an event-free survival (EFS) of 41% and an overall survival (OS) of 53%, than alloHSCT (n = 21, EFS 19%, p = 0.02, OS 24%, p = 0.002). The outcome of LTML was slightly improved compared to HDCT (n = 13, EFS 35%, OS 34%). In conclusion, our data suggest that in patients suffering from metastatic RMS, long-term maintenance therapy is a superior strategy in terms of EFS and OS compared to alloHSCT. EFS and OS of HDCT are similar in these strategies; however, the therapeutic burden of LTMT is much lower. Full article

(This article belongs to the Special Issue Rhabdomyosarcoma: Still Unresolved Questions but New Perspectives)

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30 pages, 1692 KB

Open AccessEditor’s ChoiceReview

The Glioma Immune Landscape: A Double-Edged Sword for Treatment Regimens

by Sukrit Mahajan, Mirko H. H. Schmidt and Ulrike Schumann

Cancers 2023, 15(7), 2024; https://doi.org/10.3390/cancers15072024 - 28 Mar 2023

Cited by 20 | Viewed by 5666

Abstract

Immune cells constitute a major part of the tumor microenvironment, thereby playing an important role in regulating tumor development. They interact with tumor cells, resulting in the suppression or promotion of glioma development. Therefore, in recent years, scientists have focused on immunotherapy that [...] Read more.

Immune cells constitute a major part of the tumor microenvironment, thereby playing an important role in regulating tumor development. They interact with tumor cells, resulting in the suppression or promotion of glioma development. Therefore, in recent years, scientists have focused on immunotherapy that involves enhancing the immune response to fight the battle against cancer more effectively. While it has shown success against different cancer types, immunotherapy faces major roadblocks in glioma treatment. These involve the blood brain barrier, tumor heterogeneity and an immunosuppressive glioma microenvironment, among other factors. Additionally, the interaction of the peripheral immune system with the central nervous system provides another challenge for immunotherapeutic regimens. For modulating different immune cell populations to counter glioma cells, it is important to expand our knowledge about their role within the glioma microenvironment; therefore, herein, we review the different immune cell populations found in the glioma microenvironment and navigate through the various shortcomings of current immunotherapies for glioma. We conclude by providing an insight into ongoing pre-clinical and clinical trials for glioma therapies. Full article

(This article belongs to the Special Issue The Development of Effective Therapy Targeting the Microenvironment of Cancer)

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20 pages, 576 KB

Open AccessEditor’s ChoiceArticle

Mathematical Model of Clonal Evolution Proposes a Personalised Multi-Modal Therapy for High-Risk Neuroblastoma

by Matteo Italia, Kenneth Y. Wertheim, Sabine Taschner-Mandl, Dawn Walker and Fabio Dercole

Cancers 2023, 15(7), 1986; https://doi.org/10.3390/cancers15071986 - 26 Mar 2023

Cited by 11 | Viewed by 4008

Abstract

Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid [...] Read more.

Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid COJEC) administers fixed doses of chemotherapeutic agents in eight two-week cycles. Perhaps because of differences in resistance, this standard regimen results in highly heterogeneous outcomes in different tumours. In this study, we formulated a mathematical model comprising ordinary differential equations. The equations describe the clonal evolution within a neuroblastoma tumour being treated with vincristine and cyclophosphamide, which are used in the rapid COJEC regimen, including genetically conferred and phenotypic drug resistance. The equations also describe the agents’ pharmacokinetics. We devised an optimisation algorithm to find the best chemotherapy schedules for tumours with different pre-treatment clonal compositions. The optimised chemotherapy schedules exploit the cytotoxic difference between the two drugs and intra-tumoural clonal competition to shrink the tumours as much as possible during induction chemotherapy and before surgical removal. They indicate that induction chemotherapy can be improved by finding and using personalised schedules. More broadly, we propose that the overall multi-modal therapy can be enhanced by employing targeted therapies against the mutations and oncogenic pathways enriched and activated by the chemotherapeutic agents. To translate the proposed personalised multi-modal therapy into clinical use, patient-specific model calibration and treatment optimisation are necessary. This entails a decision support system informed by emerging medical technologies such as multi-region sequencing and liquid biopsies. The results and tools presented in this paper could be the foundation of this decision support system. Full article

(This article belongs to the Special Issue Childhood Cancer in the Genomic Era: Experimental and Theoretical Approaches)

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15 pages, 2281 KB

Open AccessEditor’s ChoiceArticle

Immune Checkpoint and EMT-Related Molecules in Circulating Tumor Cells (CTCs) from Triple Negative Breast Cancer Patients and Their Clinical Impact

by Vasileios Vardas, Anastasios Tolios, Athina Christopoulou, Vassilis Georgoulias, Anastasia Xagara, Filippos Koinis, Athanasios Kotsakis and Galatea Kallergi

Cancers 2023, 15(7), 1974; https://doi.org/10.3390/cancers15071974 - 25 Mar 2023

Cited by 15 | Viewed by 2835

Abstract

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. There are few targeted therapies for these patients, leading to an unmet need for new biomarkers. The present study aimed to investigate the expression of PD-L1, CTLA-4, GLU, and VIM in [...] Read more.

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. There are few targeted therapies for these patients, leading to an unmet need for new biomarkers. The present study aimed to investigate the expression of PD-L1, CTLA-4, GLU, and VIM in CTCs of TNBC patients. Ninety-five patients were enrolled in this study: sixty-four TNBC and thirty-one luminal. Of these patients, 60 were in the early stage, while 35 had metastatic disease. Protein expression was identified by immunofluorescence staining experiments and VyCAP analysis. All the examined proteins were upregulated in TNBC patients. The expression of the GLU⁺VIM⁺CK⁺ phenotype was higher (50%) in metastatic TNBC compared to early TNBC patients (17%) (p = 0.005). Among all the BC patients, a significant correlation was found between PD-L1⁺CD45⁻CK⁺ and CTLA-4⁺CD45⁻CK⁺ phenotypes (Spearman test, p = 0.024), implying an important role of dual inhibition in BC. Finally, the phenotypes GLU⁺VIM⁺CK⁺ and PD-L1⁺CD45⁻CK⁺ were associated with shorter OS in TNBC patients (OS: log-rank p = 0.048, HR = 2.9, OS: log-rank p < 0.001, HR = 8.7, respectively). Thus, PD-L1, CTLA-4, GLU, and VIM constitute significant biomarkers in TNBC associated with patients’ outcome, providing new therapeutic targets for this difficult breast cancer subtype. Full article

(This article belongs to the Special Issue The Analysis of Circulating Tumor Cells (CTCs): New Insights into the Biology of Cancers)

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21 pages, 5153 KB

Open AccessEditor’s ChoiceArticle

From Head and Neck Tumour and Lymph Node Segmentation to Survival Prediction on PET/CT: An End-to-End Framework Featuring Uncertainty, Fairness, and Multi-Region Multi-Modal Radiomics

by Zohaib Salahuddin, Yi Chen, Xian Zhong, Henry C. Woodruff, Nastaran Mohammadian Rad, Shruti Atul Mali and Philippe Lambin

Cancers 2023, 15(7), 1932; https://doi.org/10.3390/cancers15071932 - 23 Mar 2023

Cited by 17 | Viewed by 4613

Abstract

Automatic delineation and detection of the primary tumour (GTVp) and lymph nodes (GTVn) using PET and CT in head and neck cancer and recurrence-free survival prediction can be useful for diagnosis and patient risk stratification. We used data from nine different centres, with [...] Read more.

Automatic delineation and detection of the primary tumour (GTVp) and lymph nodes (GTVn) using PET and CT in head and neck cancer and recurrence-free survival prediction can be useful for diagnosis and patient risk stratification. We used data from nine different centres, with 524 and 359 cases used for training and testing, respectively. We utilised posterior sampling of the weight space in the proposed segmentation model to estimate the uncertainty for false positive reduction. We explored the prognostic potential of radiomics features extracted from the predicted GTVp and GTVn in PET and CT for recurrence-free survival prediction and used SHAP analysis for explainability. We evaluated the bias of models with respect to age, gender, chemotherapy, HPV status, and lesion size. We achieved an aggregate Dice score of 0.774 and 0.760 on the test set for GTVp and GTVn, respectively. We observed a per image false positive reduction of 19.5% and 7.14% using the uncertainty threshold for GTVp and GTVn, respectively. Radiomics features extracted from GTVn in PET and from both GTVp and GTVn in CT are the most prognostic, and our model achieves a C-index of 0.672 on the test set. Our framework incorporates uncertainty estimation, fairness, and explainability, demonstrating the potential for accurate detection and risk stratification. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic, Predictive Biomarkers and New Targets for Treatment in Head and Neck Cancers)

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14 pages, 1976 KB

Open AccessEditor’s ChoiceArticle

Exact Probability Distribution for the ROC Area under Curve

by Joakim Ekström, Jim Åkerrén Ögren and Tobias Sjöblom

Cancers 2023, 15(6), 1788; https://doi.org/10.3390/cancers15061788 - 15 Mar 2023

Cited by 16 | Viewed by 2814

Abstract

The Receiver Operating Characteristic (ROC) is a de facto standard for determining the accuracy of in vitro diagnostic (IVD) medical devices, and thus the exactness in its probability distribution is crucial toward accurate statistical inference. We show the exact probability distribution of the [...] Read more.

The Receiver Operating Characteristic (ROC) is a de facto standard for determining the accuracy of in vitro diagnostic (IVD) medical devices, and thus the exactness in its probability distribution is crucial toward accurate statistical inference. We show the exact probability distribution of the ROC AUC-value, hence exact critical values and p-values are readily obtained. Because the exact calculations are computationally intense, we demonstrate a method of geometric interpolation, which is exact in a special case but generally an approximation, vastly increasing computational speeds. The method is illustrated through open access data, demonstrating superiority of 26 composite biomarkers relative to a predicate device. Especially under correction for testing of multiple hypotheses, traditional asymptotic approximations are encumbered by considerable imprecision, adversely affecting IVD device development. The ability to obtain exact p-values will allow more efficient IVD device development. Full article

(This article belongs to the Section Cancer Informatics and Big Data)

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18 pages, 3732 KB

Open AccessEditor’s ChoiceReview

Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer

by Éabha O’Sullivan, Anna Keogh, Brian Henderson, Stephen P. Finn, Steven G. Gray and Kathy Gately

Cancers 2023, 15(6), 1635; https://doi.org/10.3390/cancers15061635 - 7 Mar 2023

Cited by 59 | Viewed by 18140

Abstract

Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in [...] Read more.

Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in NSCLC and is associated with a more aggressive clinical phenotype, highlighting the need for KRAS-targeted therapy. Once considered undruggable due to its smooth shallow surface, a breakthrough showed that the activated G12C-mutated KRAS isozyme can be directly inhibited via a newly identified switch II pocket. This discovery led to the development of a new class of selective small-molecule inhibitors against the KRAS G12C isoform. Sotorasib and adagrasib are approved in locally advanced or metastatic NSCLC patients who have received at least one prior systemic therapy. Currently, there are at least twelve KRAS G12C inhibitors being tested in clinical trials, either as a single agent or in combination. In this study, KRAS mutation prevalence, subtypes, rates of occurrence in treatment-resistant invasive mucinous adenocarcinomas (IMAs), and novel drug delivery options are reviewed. Additionally, the current status of KRAS inhibitors, multiple resistance mechanisms that limit efficacy, and their use in combination treatment strategies and novel multitargeted approaches in NSCLC are discussed. Full article

(This article belongs to the Special Issue Update in Lung Cancer Molecular Pathology: Technological Advances and Clinical Practice)

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85 pages, 4243 KB

Open AccessEditor’s ChoiceReview

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

by Katarzyna Starska-Kowarska

Cancers 2023, 15(6), 1642; https://doi.org/10.3390/cancers15061642 - 7 Mar 2023

Cited by 28 | Viewed by 11819

Abstract

Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive and heterogeneous groups of human neoplasms. HNSCC is characterized by high morbidity, accounting for 3% of all cancers, and high mortality with ~1.5% of all cancer deaths. It was the [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive and heterogeneous groups of human neoplasms. HNSCC is characterized by high morbidity, accounting for 3% of all cancers, and high mortality with ~1.5% of all cancer deaths. It was the most common cancer worldwide in 2020, according to the latest GLOBOCAN data, representing the seventh most prevalent human malignancy. Despite great advances in surgical techniques and the application of modern combinations and cytotoxic therapies, HNSCC remains a leading cause of death worldwide with a low overall survival rate not exceeding 40–60% of the patient population. The most common causes of death in patients are its frequent nodal metastases and local neoplastic recurrences, as well as the relatively low response to treatment and severe drug resistance. Much evidence suggests that the tumour microenvironment (TME), tumour infiltrating lymphocytes (TILs) and circulating various subpopulations of immunocompetent cells, such regulatory T cells (CD4⁺CD25⁺Foxp3⁺T_regs), cytotoxic CD3⁺CD8⁺ T cells (CTLs) and CD3⁺CD4⁺ T helper type 1/2/9/17 (Th₁/Th₂/Th₉/Th₁₇) lymphocytes, T follicular helper cells (T_fh) and CD56^dim/CD16^bright activated natural killer cells (NK), carcinoma-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (N1/N2 TANs), as well as tumour-associated macrophages (M1/M2 phenotype TAMs) can affect initiation, progression and spread of HNSCC and determine the response to immunotherapy. Rapid advances in the field of immuno-oncology and the constantly growing knowledge of the immunosuppressive mechanisms and effects of tumour cancer have allowed for the use of effective and personalized immunotherapy as a first-line therapeutic procedure or an essential component of a combination therapy for primary, relapsed and metastatic HNSCC. This review presents the latest reports and molecular studies regarding the anti-tumour role of selected subpopulations of immunocompetent cells in the pathogenesis of HNSCC, including HPV^+ve (HPV⁺) and HPV^−ve (HPV⁻) tumours. The article focuses on the crucial regulatory mechanisms of pro- and anti-tumour activity, key genetic or epigenetic changes that favour tumour immune escape, and the strategies that the tumour employs to avoid recognition by immunocompetent cells, as well as resistance mechanisms to T and NK cell-based immunotherapy in HNSCC. The present review also provides an overview of the pre- and clinical early trials (I/II phase) and phase-III clinical trials published in this arena, which highlight the unprecedented effectiveness and limitations of immunotherapy in HNSCC, and the emerging issues facing the field of HNSCC immuno-oncology. Full article

(This article belongs to the Special Issue Molecular Signatures in Head and Neck Cancer)

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35 pages, 1829 KB

Open AccessEditor’s ChoiceReview

Immunotargeting of Cancer Stem Cells

by Ayse Sedef Köseer, Simona Di Gaetano, Claudia Arndt, Michael Bachmann and Anna Dubrovska

Cancers 2023, 15(5), 1608; https://doi.org/10.3390/cancers15051608 - 5 Mar 2023

Cited by 20 | Viewed by 5653

Abstract

The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and [...] Read more.

The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and normal stem cells share many important signaling mechanisms for their maintenance and survival. Furthermore, the efficacy of this therapy is opposed by tumor heterogeneity and CSC plasticity. While there have been considerable efforts to target CSC populations by the chemical inhibition of the developmental pathways such as Notch, Hedgehog (Hh), and Wnt/β-catenin, noticeably fewer attempts were focused on the stimulation of the immune response by CSC-specific antigens, including cell-surface targets. Cancer immunotherapies are based on triggering the anti-tumor immune response by specific activation and targeted redirecting of immune cells toward tumor cells. This review is focused on CSC-directed immunotherapeutic approaches such as bispecific antibodies and antibody-drug candidates, CSC-targeted cellular immunotherapies, and immune-based vaccines. We discuss the strategies to improve the safety and efficacy of the different immunotherapeutic approaches and describe the current state of their clinical development. Full article

(This article belongs to the Special Issue Cancer Stem Cells and Targeted Therapy)

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20 pages, 4420 KB

Open AccessEditor’s ChoiceSystematic Review

A Systematic Review of High-Dose Methotrexate for Adults with Primary Central Nervous System Lymphoma

by Gabriela Villanueva, Martin Guscott, Paula Schaiquevich, Claudia Sampor, Ryan Combs, Nicolás Tentoni, Miriam Hwang, Jennifer Lowe and Scott Howard

Cancers 2023, 15(5), 1459; https://doi.org/10.3390/cancers15051459 - 25 Feb 2023

Cited by 18 | Viewed by 5458

Abstract

Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma that is confined within the CNS. Due to its ability to cross the blood–brain barrier, high-dose methotrexate (HDMTX) is the backbone for induction chemotherapy. This systematic review was conducted to observe [...] Read more.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma that is confined within the CNS. Due to its ability to cross the blood–brain barrier, high-dose methotrexate (HDMTX) is the backbone for induction chemotherapy. This systematic review was conducted to observe outcomes among different HDMTX doses (low, <3 g/m²; intermediate, 3–4.9 g/m²; high, ≥5 g/m²) and regimens used in the treatment of PCNSL. A PubMed search resulted in 26 articles reporting clinical trials using HDMTX for PCNSL, from which 35 treatment cohorts were identified for analysis. The median dose of HDMTX used for induction was 3.5 g/m² (interquartile range IQR, 3–3.5); the intermediate dose was most frequently used in the studies examined (24 cohorts, 69%). Five cohorts used HDMTX monotherapy, 19 cohorts used HDMTX + polychemotherapy, and 11 cohorts used HDMTX + rituximab ± polychemotherapy. Pooled overall response rate (ORR) estimates for low, intermediate, and high dose HDMTX cohorts were 71%, 76%, and 76%, respectively. Pooled 2-year progression-free survival (PFS) estimates for low, intermediate, and high HDMTX dose cohorts were 50%, 51%, and 55%, respectively. Regimens that included rituximab showed a tendency to have higher ORR and 2-year PFS than those that did not include rituximab. These findings indicate that current protocols utilizing 3–4 g/m² of HDMTX in combination with rituximab provide therapeutic efficacy in PCNSL. Full article

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

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23 pages, 370 KB

Open AccessEditor’s ChoiceReview

Bispecific T-Cell Engagers Therapies in Solid Tumors: Focusing on Prostate Cancer

by Diana C. Simão, Kevin K. Zarrabi, José L. Mendes, Ricardo Luz, Jorge A. Garcia, William K. Kelly and Pedro C. Barata

Cancers 2023, 15(5), 1412; https://doi.org/10.3390/cancers15051412 - 23 Feb 2023

Cited by 39 | Viewed by 9993

Abstract

Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering [...] Read more.

Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering responses. Similarly, many tumors’ immune microenvironment allows them to become evasive, leading to resistance and, thus, limiting the durability of responses. To overcome this limitation, new T-cell redirecting strategies such as bispecific T-cell engager (BiTE) have become attractive and promising immunotherapies. Our review provides a comprehensive perspective of the current evidence of BiTE therapies in solid tumors. Considering that immunotherapy has shown modest results in advanced prostate cancer to date, we review the biologic rationale and promising results of BiTE therapy in this clinical setting and discuss potential tumor-associated antigens that may be integrated into BiTE construct designs. Our review also aims to evaluate the advances of BiTE therapies in prostate cancer, illustrate the major obstacles and underlying limitations, and discuss directions for future research. Full article

(This article belongs to the Collection Urological Cancer 2023-2025)

16 pages, 1929 KB

Open AccessEditor’s ChoiceReview

Unlocking the Resistance to Anti-HER2 Treatments in Breast Cancer: The Issue of HER2 Spatial Distribution

by Federica Giugliano, Ambra Carnevale Schianca, Chiara Corti, Mariia Ivanova, Nadia Bianco, Silvia Dellapasqua, Carmen Criscitiello, Nicola Fusco, Giuseppe Curigliano and Elisabetta Munzone

Cancers 2023, 15(5), 1385; https://doi.org/10.3390/cancers15051385 - 22 Feb 2023

Cited by 18 | Viewed by 6509

Abstract

Approximately 15% of breast cancers are classified as HER2-positive, with an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein. Up to 30% of HER2-positive breast cancers shows heterogeneity in HER2 expression and different patterns of spatial distribution, i.e., the [...] Read more.

Approximately 15% of breast cancers are classified as HER2-positive, with an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein. Up to 30% of HER2-positive breast cancers shows heterogeneity in HER2 expression and different patterns of spatial distribution, i.e., the variability in the distribution and expression of the HER2 protein within a single tumour. Spatial heterogeneity may potentially affect treatment, response, assessment of HER2 status and consequently, may impact on the best treatment strategy. Understanding this feature can help clinicians to predict response to HER2-targeted therapies and patient outcomes, and to fine tune treatment decisions. This review summarizes the available evidence on HER2 heterogeneity and spatial distribution and how this may affect current available treatment choices, exploring possible opportunities for overcoming this issue, such as novel pharmacological agents, belonging to the group of antibody–drug conjugates. Full article

(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)

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14 pages, 1198 KB

Open AccessEditor’s ChoiceReview

The Gut-Prostate Axis: A New Perspective of Prostate Cancer Biology through the Gut Microbiome

by Kazutoshi Fujita, Makoto Matsushita, Marco A. De Velasco, Koji Hatano, Takafumi Minami, Norio Nonomura and Hirotsugu Uemura

Cancers 2023, 15(5), 1375; https://doi.org/10.3390/cancers15051375 - 21 Feb 2023

Cited by 38 | Viewed by 7827

Abstract

Obesity and a high-fat diet are risk factors associated with prostate cancer, and lifestyle, especially diet, impacts the gut microbiome. The gut microbiome plays important roles in the development of several diseases, such as Alzheimer’s disease, rheumatoid arthritis, and colon cancer. The analysis [...] Read more.

Obesity and a high-fat diet are risk factors associated with prostate cancer, and lifestyle, especially diet, impacts the gut microbiome. The gut microbiome plays important roles in the development of several diseases, such as Alzheimer’s disease, rheumatoid arthritis, and colon cancer. The analysis of feces from patients with prostate cancer by 16S rRNA sequencing has uncovered various associations between altered gut microbiomes and prostate cancer. Gut dysbiosis caused by the leakage of gut bacterial metabolites, such as short-chain fatty acids and lipopolysaccharide results in prostate cancer growth. Gut microbiota also play a role in the metabolism of androgen which could affect castration-resistant prostate cancer. Moreover, men with high-risk prostate cancer share a specific gut microbiome and treatments such as androgen-deprivation therapy alter the gut microbiome in a manner that favors prostate cancer growth. Thus, implementing interventions aiming to modify lifestyle or altering the gut microbiome with prebiotics or probiotics may curtail the development of prostate cancer. From this perspective, the “Gut–Prostate Axis” plays a fundamental bidirectional role in prostate cancer biology and should be considered when screening and treating prostate cancer patients. Full article

(This article belongs to the Special Issue Metastatic Prostate Cancer: Interaction with Tumors and Their Microenvironments)

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23 pages, 1809 KB

Open AccessEditor’s ChoiceReview

Downstream Targets of VHL/HIF-α Signaling in Renal Clear Cell Carcinoma Progression: Mechanisms and Therapeutic Relevance

by Sonia Mazumder, Paul J. Higgins and Rohan Samarakoon

Cancers 2023, 15(4), 1316; https://doi.org/10.3390/cancers15041316 - 19 Feb 2023

Cited by 57 | Viewed by 12051

Abstract

The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several [...] Read more.

The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several types of tumors including ccRCC. Normally, the Hypoxia Inducible Factor alpha (HIF-α) subunits of the HIF heterodimeric transcription factor complex are regulated by oxygen-dependent prolyl-hydroxylation, VHL-mediated ubiquitination and proteasomal degradation. Loss of pVHL function results in elevated levels of HIF-α due to increased stability, leading to RCC progression. While HIF-1α acts as a tumor suppressor, HIF-2α promotes oncogenic potential by driving tumor progression and metastasis through activation of hypoxia-sensitive signaling pathways and overexpression of HIF-2α target genes. One strategy to suppress ccRCC aggressiveness is directed at inhibition of HIF-2α and the associated molecular pathways leading to cell proliferation, angiogenesis, and metastasis. Indeed, clinical and pre-clinical data demonstrated the effectiveness of HIF-2α targeted therapy in attenuating ccRCC progression. This review focuses on the signaling pathways and the involved genes (cyclin D, c-Myc, VEGF-a, EGFR, TGF-α, GLUT-1) that confer oncogenic potential downstream of the VHL-HIF-2α signaling axis in ccRCC. Discussed as well are current treatment options (including receptor tyrosine kinase inhibitors such as sunitinib), the medical challenges (high prevalence of metastasis at the time of diagnosis, refractory nature of advanced disease to current treatment options), scientific challenges and future directions. Full article

(This article belongs to the Special Issue Cancers Driven by HIF)

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12 pages, 1341 KB

Open AccessEditor’s ChoiceReview

Mechanisms of Resistance to Antibody–Drug Conjugates

by Rachel Occhiogrosso Abelman, Bogang Wu, Laura M. Spring, Leif W. Ellisen and Aditya Bardia

Cancers 2023, 15(4), 1278; https://doi.org/10.3390/cancers15041278 - 17 Feb 2023

Cited by 90 | Viewed by 11268

Abstract

Antibody–drug conjugates (ADCs), with antibodies targeted against specific antigens linked to cytotoxic payloads, offer the opportunity for a more specific delivery of chemotherapy and other bioactive payloads to minimize side effects. First approved in the setting of HER2+ breast cancer, more recent ADCs [...] Read more.

Antibody–drug conjugates (ADCs), with antibodies targeted against specific antigens linked to cytotoxic payloads, offer the opportunity for a more specific delivery of chemotherapy and other bioactive payloads to minimize side effects. First approved in the setting of HER2+ breast cancer, more recent ADCs have been developed for triple-negative breast cancer (TNBC) and, most recently, hormone receptor-positive (HR+) breast cancer. While antibody–drug conjugates have compared favorably against traditional chemotherapy in some settings, patients eventually progress on these therapies and require a change in treatment. Mechanisms to explain the resistance to ADCs are highly sought after, in hopes of developing next-line treatment options and expanding the therapeutic windows of existing therapies. These resistance mechanisms are categorized as follows: change in antigen expression, change in ADC processing and resistance, and efflux of the ADC payload. This paper reviews the recently published literature on these mechanisms as well as potential options to overcome these barriers. Full article

(This article belongs to the Special Issue Resistance in Breast Cancer)

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12 pages, 293 KB

Open AccessEditor’s ChoiceReview

Evolving Treatment Landscape of HER2-mutant Non-Small Cell Lung Cancer: Trastuzumab Deruxtecan and Beyond

by Ioannis A. Vathiotis, Dimitrios Bafaloukos, Konstantinos N. Syrigos and George Samonis

Cancers 2023, 15(4), 1286; https://doi.org/10.3390/cancers15041286 - 17 Feb 2023

Cited by 16 | Viewed by 5537

Abstract

Successful targeting of HER2-activating mutations in DESTINY-Lung02 phase II study has led to the approval of the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) as second-line treatment in patients with non-small cell lung cancer (NSCLC). Despite the impressive results, several matters need to [...] Read more.

Successful targeting of HER2-activating mutations in DESTINY-Lung02 phase II study has led to the approval of the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) as second-line treatment in patients with non-small cell lung cancer (NSCLC). Despite the impressive results, several matters need to be addressed, including the clinical activity of T-DXd in patients with disease in the central nervous system as well as the role of T-DXd in the context of HER2 overexpression. Additionally, data regarding novel agents used to target HER2 continue to accumulate. This review highlights the challenges and unanswered questions that have emerged after the approval of T-DXd in patients with HER2-mutant NSCLC. Full article

(This article belongs to the Special Issue World Lung Cancer Awareness Month)

12 pages, 862 KB

Open AccessEditor’s ChoiceReview

CAR-T Therapy in GBM: Current Challenges and Avenues for Improvement

by Ayush Pant and Michael Lim

Cancers 2023, 15(4), 1249; https://doi.org/10.3390/cancers15041249 - 16 Feb 2023

Cited by 28 | Viewed by 5664

Abstract

Completed clinical trials of CAR-T cells in glioblastoma (GBM) have revealed key challenges that limit their efficacy. These include incomplete antigen coverage, downregulation of target antigen in response to therapy, exposure to immunosuppressive cells and cytokines in the tumor microenvironment and exhaustion of [...] Read more.

Completed clinical trials of CAR-T cells in glioblastoma (GBM) have revealed key challenges that limit their efficacy. These include incomplete antigen coverage, downregulation of target antigen in response to therapy, exposure to immunosuppressive cells and cytokines in the tumor microenvironment and exhaustion of CAR-T cells. To overcome these challenges, CAR-T cells have been modified to maximize effector function and resist immunosuppression in the tumor while limiting toxicities to the host. Adoption of these novel CAR-T strategies in GBM can overcome the “cold tumor” phenotype of GBM and trigger an inflammatory cascade that maximizes tumor clearance and minimizes CAR-T dysfunction. To achieve this, understanding and harnessing the antigenic, metabolic and immunological composition of GBM is crucial. Here we review the findings from completed clinical trials of CAR-T cells in GBM as well as novel strategies that could improve CAR-T survival and function in the tumor. Full article

(This article belongs to the Collection Treatment of Glioma)

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21 pages, 2645 KB

Open AccessEditor’s ChoiceReview

NKG2A Immune Checkpoint in Vδ2 T Cells: Emerging Application in Cancer Immunotherapy

by Valentina Cazzetta, Delphine Depierreux, Francesco Colucci, Joanna Mikulak and Domenico Mavilio

Cancers 2023, 15(4), 1264; https://doi.org/10.3390/cancers15041264 - 16 Feb 2023

Cited by 12 | Viewed by 5886

Abstract

Immune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the [...] Read more.

Immune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. Current challenges associated with the enhancement of ICI effects are increasing the fraction of responding patients through personalized combinations of multiple ICIs and overcoming acquired resistance. This requires a complete overview of the anti-tumor immune response, which depends on a complex interplay between innate and adaptive immune cells with the tumor microenvironment. The NKG2A was revealed to be a key immune checkpoint for both Natural Killer (NK) cells and T cells. Monalizumab, a humanized anti-NKG2A antibody, enhances NK cell activity against various tumor cells and rescues CD8 αβ T cell function in combination with PD-1/PD-L1 blockade. In this review, we discuss the potential for targeting NKG2A expressed on tumor-sensing human γδ T cells, mostly on the specific Vδ2 T cell subset, in order to emphasize its importance and potential in the development of new ICI-based therapeutic approaches. Full article

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

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8 pages, 2264 KB

Open AccessEditor’s ChoiceArticle

Radical Prostatectomy without Prior Biopsy in Patients with High Suspicion of Prostate Cancer Based on Multiparametric Magnetic Resonance Imaging and Prostate-Specific Membrane Antigen Positron Emission Tomography: A Prospective Cohort Study

by Michael Chaloupka, Maria Apfelbeck, Nikolaos Pyrgidis, Julian Marcon, Philipp Weinhold and Christian G. Stief

Cancers 2023, 15(4), 1266; https://doi.org/10.3390/cancers15041266 - 16 Feb 2023

Cited by 16 | Viewed by 2953

Abstract

Modern risk stratification of prostate cancer (PCa) allows for prediction of advanced disease with a high level of certainty. We aimed to evaluate a prospective series of patients undergoing radical prostatectomy without prior biopsy based solely on clinical criteria and imaging results. The [...] Read more.

Modern risk stratification of prostate cancer (PCa) allows for prediction of advanced disease with a high level of certainty. We aimed to evaluate a prospective series of patients undergoing radical prostatectomy without prior biopsy based solely on clinical criteria and imaging results. The patients were divided into three groups. Group 1 included 27 patients with: (i) suspicious digital rectal examination, (ii) PSA ≥ 10 ng/mL, (iii) PI-RADS 4/5 on mpMRI, and (iv) high suspicion of PCa on PSMA-PET. Group 2 included six patients who fulfilled criteria i, ii, and iii but did not undergo PSMA-PET imaging. Group 3 included 17 patients with at least one clinical (i or ii) and one imaging (iii or iv) criterion. All of the patients were diagnosed with PCa. Comparison of Group 1 and 2 versus Group 3 showed a significantly higher ratio of locally advanced PCa for Groups 1 and 2 compared to Group 3 (60.6% versus 11.8%, p = 0.005, respectively). Similarly, these patients displayed a significantly higher ratio of aggressive PCa (ISUP grade > 2: 66.7% versus 23.5%, p = 0.027, respectively) and tumor infiltration (median tumor infiltration: 32.5% vs. 15%, p = 0.001, respectively) in the final specimen compared to Group 3. In conclusion, we have shown that radical prostatectomy without prior biopsy is safe in terms of the diagnosis of clinically significant PCa when proper preoperative risk stratification involving mpMRI and PSMA-PET imaging is applied. Full article

(This article belongs to the Section Cancer Therapy)

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28 pages, 1165 KB

Open AccessEditor’s ChoiceReview

Hypoxia, a Targetable Culprit to Counter Pancreatic Cancer Resistance to Therapy

by Raefa Abou Khouzam, Jean-Marie Lehn, Hemma Mayr, Pierre-Alain Clavien, Michael Bradley Wallace, Michel Ducreux, Perparim Limani and Salem Chouaib

Cancers 2023, 15(4), 1235; https://doi.org/10.3390/cancers15041235 - 15 Feb 2023

Cited by 16 | Viewed by 5733

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it is a disease of dismal prognosis. While immunotherapy has revolutionized the treatment of various solid tumors, it has achieved little success in PDAC. Hypoxia within the stroma-rich tumor microenvironment [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it is a disease of dismal prognosis. While immunotherapy has revolutionized the treatment of various solid tumors, it has achieved little success in PDAC. Hypoxia within the stroma-rich tumor microenvironment is associated with resistance to therapies and promotes angiogenesis, giving rise to a chaotic and leaky vasculature that is inefficient at shuttling oxygen and nutrients. Hypoxia and its downstream effectors have been implicated in immune resistance and could be contributing to the lack of response to immunotherapy experienced by patients with PDAC. Paradoxically, increasing evidence has shown hypoxia to augment genomic instability and mutagenesis in cancer, suggesting that hypoxic tumor cells could have increased production of neoantigens that can potentially enable their clearance by cytotoxic immune cells. Strategies aimed at relieving this condition have been on the rise, and one such approach opts for normalizing the tumor vasculature to reverse hypoxia and its downstream support of tumor pathogenesis. An important consideration for the successful implementation of such strategies in the clinic is that not all PDACs are equally hypoxic, therefore hypoxia-detection approaches should be integrated to enable optimal patient selection for achieving improved patient outcomes. Full article

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

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25 pages, 775 KB

Open AccessEditor’s ChoiceReview

Radiomics Applications in Head and Neck Tumor Imaging: A Narrative Review

by Mario Tortora, Laura Gemini, Alessandra Scaravilli, Lorenzo Ugga, Andrea Ponsiglione, Arnaldo Stanzione, Felice D’Arco, Gennaro D’Anna and Renato Cuocolo

Cancers 2023, 15(4), 1174; https://doi.org/10.3390/cancers15041174 - 12 Feb 2023

Cited by 37 | Viewed by 5295

Abstract

Recent advances in machine learning and artificial intelligence technology have ensured automated evaluation of medical images. As a result, quantifiable diagnostic and prognostic biomarkers have been created. We discuss radiomics applications for the head and neck region in this paper. Molecular characterization, categorization, [...] Read more.

Recent advances in machine learning and artificial intelligence technology have ensured automated evaluation of medical images. As a result, quantifiable diagnostic and prognostic biomarkers have been created. We discuss radiomics applications for the head and neck region in this paper. Molecular characterization, categorization, prognosis and therapy recommendation are given special consideration. In a narrative manner, we outline the fundamental technological principles, the overall idea and usual workflow of radiomic analysis and what seem to be the present and potential challenges in normal clinical practice. Clinical oncology intends for all of this to ensure informed decision support for personalized and useful cancer treatment. Head and neck cancers present a unique set of diagnostic and therapeutic challenges. These challenges are brought on by the complicated anatomy and heterogeneity of the area under investigation. Radiomics has the potential to address these barriers. Future research must be interdisciplinary and focus on the study of certain oncologic functions and outcomes, with external validation and multi-institutional cooperation in order to achieve this. Full article

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27 pages, 471 KB

Open AccessEditor’s ChoiceReview

CAR-Based Immunotherapy of Solid Tumours—A Survey of the Emerging Targets

by John Maher and David M. Davies

Cancers 2023, 15(4), 1171; https://doi.org/10.3390/cancers15041171 - 11 Feb 2023

Cited by 20 | Viewed by 8004

Abstract

Immunotherapy with CAR T-cells has revolutionised the treatment of B-cell and plasma cell-derived cancers. However, solid tumours present a much greater challenge for treatment using CAR-engineered immune cells. In a partner review, we have surveyed data generated in clinical trials in which patients [...] Read more.

Immunotherapy with CAR T-cells has revolutionised the treatment of B-cell and plasma cell-derived cancers. However, solid tumours present a much greater challenge for treatment using CAR-engineered immune cells. In a partner review, we have surveyed data generated in clinical trials in which patients with solid tumours that expressed any of 30 discrete targets were treated with CAR-based immunotherapy. That exercise confirms that efficacy of this approach falls well behind that seen in haematological malignancies, while significant toxic events have also been reported. Here, we consider approximately 60 additional candidates for which such clinical data are not available yet, but where pre-clinical data have provided support for their advancement to clinical evaluation as CAR target antigens. Full article

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31 pages, 1969 KB

Open AccessEditor’s ChoiceReview

Mitochondrial Metabolism in Pancreatic Ductal Adenocarcinoma: From Mechanism-Based Perspectives to Therapy

by Hafiza Padinharayil, Vikrant Rai and Alex George

Cancers 2023, 15(4), 1070; https://doi.org/10.3390/cancers15041070 - 8 Feb 2023

Cited by 12 | Viewed by 5017

Abstract

Pancreatic ductal adenocarcinoma (PDAC), the fourteenth most common malignancy, is a major contributor to cancer-related death with the utmost case fatality rate among all malignancies. Functional mitochondria, regardless of their complex ecosystem relative to normal cells, are essential in PDAC progression. Tumor cells’ [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC), the fourteenth most common malignancy, is a major contributor to cancer-related death with the utmost case fatality rate among all malignancies. Functional mitochondria, regardless of their complex ecosystem relative to normal cells, are essential in PDAC progression. Tumor cells’ potential to produce ATP as energy, despite retaining the redox potential optimum, and allocating materials for biosynthetic activities that are crucial for cell growth, survival, and proliferation, are assisted by mitochondria. The polyclonal tumor cells with different metabolic profiles may add to carcinogenesis through inter-metabolic coupling. Cancer cells frequently possess alterations in the mitochondrial genome, although they do not hinder metabolism; alternatively, they change bioenergetics. This can further impart retrograde signaling, educate cell signaling, epigenetic modifications, chromatin structures, and transcription machinery, and ultimately satisfy cancer cellular and nuclear demands. To maximize the tumor microenvironment (TME), tumor cells remodel nearby stromal cells and extracellular matrix. These changes initiate polyclonality, which is crucial for growth, stress response, and metastasis. Here, we evaluate all the intrinsic and extrinsic pathways drawn by mitochondria in carcinogenesis, emphasizing the perspectives of mitochondrial metabolism in PDAC progression and treatment. Full article

(This article belongs to the Special Issue Mitochondria and Metabolism of Pancreatic Adenocarcinoma Cells)

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23 pages, 3095 KB

Open AccessEditor’s ChoiceReview

Aquaporins and Ion Channels as Dual Targets in the Design of Novel Glioblastoma Therapeutics to Limit Invasiveness

by Alanah Varricchio and Andrea J. Yool

Cancers 2023, 15(3), 849; https://doi.org/10.3390/cancers15030849 - 30 Jan 2023

Cited by 7 | Viewed by 4918

Abstract

Current therapies for Glioblastoma multiforme (GBM) focus on eradicating primary tumors using radiotherapy, chemotherapy and surgical resection, but have limited success in controlling the invasive spread of glioma cells into a healthy brain, the major factor driving short survival times for patients post-diagnosis. [...] Read more.

Current therapies for Glioblastoma multiforme (GBM) focus on eradicating primary tumors using radiotherapy, chemotherapy and surgical resection, but have limited success in controlling the invasive spread of glioma cells into a healthy brain, the major factor driving short survival times for patients post-diagnosis. Transcriptomic analyses of GBM biopsies reveal clusters of membrane signaling proteins that in combination serve as robust prognostic indicators, including aquaporins and ion channels, which are upregulated in GBM and implicated in enhanced glioblastoma motility. Accumulating evidence supports our proposal that the concurrent pharmacological targeting of selected subclasses of aquaporins and ion channels could impede glioblastoma invasiveness by impairing key cellular motility pathways. Optimal sets of channels to be selected as targets for combined therapies could be tailored to the GBM cancer subtype, taking advantage of differences in patterns of expression between channels that are characteristic of GBM subtypes, as well as distinguishing them from non-cancerous brain cells such as neurons and glia. Focusing agents on a unique channel fingerprint in GBM would further allow combined agents to be administered at near threshold doses, potentially reducing off-target toxicity. Adjunct therapies which confine GBM tumors to their primary sites during clinical treatments would offer profound advantages for treatment efficacy. Full article

(This article belongs to the Special Issue The Emerging Role of Ion Channels in Brain Cancer: Mechanisms of Action and Therapeutic Targets)

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44 pages, 1995 KB

Open AccessEditor’s ChoiceReview

Gut Microbiota in Colorectal Cancer: Biological Role and Therapeutic Opportunities

by Himani Pandey, Daryl W. T. Tang, Sunny H. Wong and Devi Lal

Cancers 2023, 15(3), 866; https://doi.org/10.3390/cancers15030866 - 30 Jan 2023

Cited by 105 | Viewed by 13377

Abstract

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. While CRC is thought to be an interplay between genetic and environmental factors, several lines of evidence suggest the involvement of gut microbiota in promoting inflammation and tumor progression. Gut microbiota refer [...] Read more.

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. While CRC is thought to be an interplay between genetic and environmental factors, several lines of evidence suggest the involvement of gut microbiota in promoting inflammation and tumor progression. Gut microbiota refer to the ~40 trillion microorganisms that inhabit the human gut. Advances in next-generation sequencing technologies and metagenomics have provided new insights into the gut microbial ecology and have helped in linking gut microbiota to CRC. Many studies carried out in humans and animal models have emphasized the role of certain gut bacteria, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli, in the onset and progression of CRC. Metagenomic studies have opened up new avenues for the application of gut microbiota in the diagnosis, prevention, and treatment of CRC. This review article summarizes the role of gut microbiota in CRC development and its use as a biomarker to predict the disease and its potential therapeutic applications. Full article

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13 pages, 1717 KB

Open AccessEditor’s ChoiceArticle

Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection

by Dmitri Pchejetski, Ewan Hunter, Mehrnoush Dezfouli, Matthew Salter, Ryan Powell, Jayne Green, Tarun Naithani, Christina Koutsothanasi, Heba Alshaker, Jiten Jaipuria, Martin J. Connor, David Eldred-Evans, Francesca Fiorentino, Hashim Ahmed, Alexandre Akoulitchev and Mathias Winkler

Cancers 2023, 15(3), 821; https://doi.org/10.3390/cancers15030821 - 29 Jan 2023

Cited by 11 | Viewed by 24249

Abstract

Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of [...] Read more.

Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of any prostate cancer, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with PCa. We have recently identified circulating chromosome conformation signatures (CCSs, Episwitch^® PCa test) allowing PCa detection and risk stratification in line with standards of clinical PCa staging. The purpose of this study was to determine whether combining the Episwitch PCa test with the PSA test will increase its diagnostic accuracy. Methods: n = 109 whole blood samples of men enrolled in the PROSTAGRAM screening pilot study and n = 38 samples of patients with established PCa diagnosis and cancer-negative controls from Imperial College NHS Trust were used. Samples were tested for PSA, and the presence of CCSs in the loci encoding for of DAPK1, HSD3B2, SRD5A3, MMP1, and miRNA98 associated with high-risk PCa identified in our previous work. Results: PSA > 3 ng/mL alone showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. EpiSwitch alone showed a PPV of 0.91 and a NPV of 0.32. Combining PSA and Episwitch tests has significantly increased the PPV to 0.81 although reducing the NPV to 0.78. Furthermore, integrating PSA, as a continuous variable (rather than a dichotomised 3 ng/mL cut-off), with EpiSwitch in a new multivariant stratification model, Prostate Screening EpiSwitch (PSE) test, has yielded a remarkable combined PPV of 0.93 and NPV of 0.95 when tested on the independent combined cohort. Conclusions: Our results demonstrate that combining the standard PSA readout with circulating chromosome conformations (PSE test) allows for significantly enhanced PSA PPV and overall accuracy for PCa detection. The PSE test is accurate, rapid, minimally invasive, and inexpensive, suggesting significant screening diagnostic potential to minimise unnecessary referrals for expensive and invasive MRI and/or biopsy testing. Further extended prospective blinded validation of the new combined signature in a screening cohort with low cancer prevalence would be the recommended step for PSE adoption in PCa screening. Full article

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

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13 pages, 1181 KB

Open AccessEditor’s ChoiceReview

CAR-T Cell Therapy and the Gut Microbiota

by Sahana Asokan, Nyssa Cullin, Christoph K. Stein-Thoeringer and Eran Elinav

Cancers 2023, 15(3), 794; https://doi.org/10.3390/cancers15030794 - 28 Jan 2023

Cited by 24 | Viewed by 8889

Abstract

Chimeric antigen receptor (CAR) - T cell cancer therapy has yielded promising results in treating hematologic malignancies in clinical studies, and a growing number of CAR-T regimens are approved for clinical usage. While the therapy is considered of great potential in expanding the [...] Read more.

Chimeric antigen receptor (CAR) - T cell cancer therapy has yielded promising results in treating hematologic malignancies in clinical studies, and a growing number of CAR-T regimens are approved for clinical usage. While the therapy is considered of great potential in expanding the cancer immunotherapy arsenal, more than half of patients receiving CAR-T infusions do not respond, while others develop significant adverse effects, collectively indicating a need for optimization of CAR-T treatment to the individual. The microbiota is increasingly suggested as a major modulator of immunotherapy responsiveness. Studying causal microbiota roles possibly contributing to CAR-T therapy efficacy, adverse effects reduction, and prediction of patient responsiveness constitutes an exciting area of active research. Herein, we discuss the latest developments implicating human microbiota involvement in CAR-T therapy, while highlighting challenges and promises in harnessing the microbiota as a predictor and modifier of CAR-T treatment towards optimized efficacy and minimization of treatment-related adverse effects. Full article

(This article belongs to the Special Issue CAR T-cell Therapy for Lymphoma Research)

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29 pages, 1727 KB

Open AccessEditor’s ChoiceReview

Current Status and Future Prospects for Esophageal Cancer

by Mahdi Sheikh, Gholamreza Roshandel, Valerie McCormack and Reza Malekzadeh

Cancers 2023, 15(3), 765; https://doi.org/10.3390/cancers15030765 - 26 Jan 2023

Cited by 182 | Viewed by 18906

Abstract

Esophageal cancer (EC) is the ninth most common cancer and the sixth leading cause of cancer deaths worldwide. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two main histological subtypes with distinct epidemiological and clinical features. While the global incidence [...] Read more.

Esophageal cancer (EC) is the ninth most common cancer and the sixth leading cause of cancer deaths worldwide. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two main histological subtypes with distinct epidemiological and clinical features. While the global incidence of ESCC is declining, the incidence of EAC is increasing in many countries. Decades of epidemiologic research have identified distinct environmental exposures for ESCC and EAC subtypes. Recent advances in understanding the genomic aspects of EC have advanced our understanding of EC causes and led to using specific genomic alterations in EC tumors as biomarkers for early diagnosis, treatment, and prognosis of this cancer. Nevertheless, the prognosis of EC is still poor, with a five-year survival rate of less than 20%. Currently, there are significant challenges for early detection and secondary prevention for both ESCC and EAC subtypes, but Cytosponge™ is shifting this position for EAC. Primary prevention remains the preferred strategy for reducing the global burden of EC. In this review, we will summarize recent advances, current status, and future prospects of the studies related to epidemiology, time trends, environmental risk factors, prevention, early diagnosis, and treatment for both EC subtypes. Full article

(This article belongs to the Special Issue Current Status and Future Prospects for Oesophageal Cancer)

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15 pages, 787 KB

Open AccessEditor’s ChoiceReview

Tumor Infiltrating Lymphocytes across Breast Cancer Subtypes: Current Issues for Biomarker Assessment

by Carmine Valenza, Beatrice Taurelli Salimbeni, Celeste Santoro, Dario Trapani, Gabriele Antonarelli and Giuseppe Curigliano

Cancers 2023, 15(3), 767; https://doi.org/10.3390/cancers15030767 - 26 Jan 2023

Cited by 53 | Viewed by 5949

Abstract

Tumor-infiltrating lymphocytes (TILs) represent a surrogate biomarker of anti-tumor, lymphocyte-mediated immunity. In early, triple-negative breast cancer, TILs have level 1B of evidence to predict clinical outcomes. TILs represent a promising biomarker to select patients who can experience a better prognosis with de-intensified cancer [...] Read more.

Tumor-infiltrating lymphocytes (TILs) represent a surrogate biomarker of anti-tumor, lymphocyte-mediated immunity. In early, triple-negative breast cancer, TILs have level 1B of evidence to predict clinical outcomes. TILs represent a promising biomarker to select patients who can experience a better prognosis with de-intensified cancer treatments and derive larger benefits from immune checkpoint inhibitors. However, the assessment and the validation of TILs as a biomarker require a prospective and rigorous demonstration of its clinical validity and utility, provided reproducible analytical performance. With pending data about the prospective validation of TILs’ clinical validity to modulate treatments in early breast cancer, this review summarizes the most important current issues and future challenges related to the implementation of TILs assessments across all breast cancer subtypes and their potential integration into clinical practice. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Multidisciplinary Approaches and Predictive Biomarkers)

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31 pages, 974 KB

Open AccessEditor’s ChoiceReview

Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy

by Marianna Sirico, Alberto D’Angelo, Caterina Gianni, Chiara Casadei, Filippo Merloni and Ugo De Giorgi

Cancers 2023, 15(3), 703; https://doi.org/10.3390/cancers15030703 - 23 Jan 2023

Cited by 77 | Viewed by 8219

Abstract

The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of the rapamycin (mTOR) axis is a key signal transduction system that links oncogenes and multiple receptor classes which are involved in many essential cellular functions. Aberrant PI3K signalling is one of the most [...] Read more.

The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of the rapamycin (mTOR) axis is a key signal transduction system that links oncogenes and multiple receptor classes which are involved in many essential cellular functions. Aberrant PI3K signalling is one of the most commonly mutated pathways in cancer. Consequently, more than 40 compounds targeting key components of this signalling network have been tested in clinical trials among various types of cancer. As the oncogenic activation of the PI3K/AKT/mTOR pathway often occurs alongside mutations in other signalling networks, combination therapy should be considered. In this review, we highlight recent advances in the knowledge of the PI3K pathway and discuss the current state and future challenges of targeting this pathway in clinical practice. Full article

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

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17 pages, 920 KB

Open AccessEditor’s ChoiceArticle

Safety and Feasibility of Radiation Therapy Combined with CDK 4/6 Inhibitors in the Management of Advanced Breast Cancer

by Marcin Kubeczko, Dorota Gabryś, Marzena Gawkowska, Anna Polakiewicz-Gilowska, Alexander J. Cortez, Aleksandra Krzywon, Grzegorz Woźniak, Tomasz Latusek, Aleksandra Leśniak, Katarzyna Świderska, Marta Mianowska-Malec, Barbara Łanoszka, Konstanty Chomik, Mateusz Gajek, Anna Michalik, Elżbieta Nowicka, Rafał Tarnawski, Tomasz Rutkowski and Michał Jarząb

Cancers 2023, 15(3), 690; https://doi.org/10.3390/cancers15030690 - 22 Jan 2023

Cited by 20 | Viewed by 6738

Abstract

The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast [...] Read more.

The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast cancer patients (pts) treated with CDK4/6i was performed, and 100 pts also received RT. Forty-six pts received 63 RT courses concurrently and fifty-four sequentially before CDK4/6i initiation (76 RT courses). Neutropenia was common (79%) and more frequent during and after concurrent RT than sequential RT (86% vs. 76%); however, CDK4/6i dose reduction rates were similar. In patients treated with CDK4/6i alone, the dose reduction rate was 42% (79 pts) versus 38% with combined therapy, and 5% discontinued treatment due to toxicity in the combined group. The risk of CDK4/6i dose reduction was correlated with neutropenia grade, RT performed within the first two CDK4/6i cycles, and more than one concurrent RT; a tendency was observed in concurrent bone irradiation. However, on multivariate regression analysis, only ECOG 1 performance status and severe neutropenia at the beginning of the second cycle were found to be associated with a higher risk of CDK4/6i dose reduction. This largest single-center experience published to date confirmed the acceptable safety profile of the CDK4/6i and RT combination without a significantly increased toxicity compared with CDK4/6i alone. However, one might delay RT for the first two CDK4/6i cycles, when myelotoxic AE are most common. Full article

(This article belongs to the Special Issue Radiation Therapy for Breast Cancer: Recent Advances and Challenges)

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25 pages, 1287 KB

Open AccessEditor’s ChoiceReview

Treatment Strategies for Non-Small Cell Lung Cancer with Common EGFR Mutations: A Review of the History of EGFR TKIs Approval and Emerging Data

by Julian A. Marin-Acevedo, Bruna Pellini, ErinMarie O. Kimbrough, J. Kevin Hicks and Alberto Chiappori

Cancers 2023, 15(3), 629; https://doi.org/10.3390/cancers15030629 - 19 Jan 2023

Cited by 33 | Viewed by 11654

Abstract

The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR-mutant NSCLC [...] Read more.

The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR-mutant NSCLC in the first-line setting, therapy selection after progression on EGFR TKIs remains complex. Multiple groups are investigating novel therapies and drug combinations to determine the optimal therapy and treatment sequence for these patients. In this review, we summarize the landmark trials and history of the approval of EGFR TKIs, their efficacy and tolerability, and the role of these therapies in patients with central nervous system metastasis. We also briefly discuss the mechanisms of resistance to EGFR TKIs, ongoing attempts to overcome resistance and improve outcomes, and finalize by offering treatment sequencing recommendations. Full article

(This article belongs to the Special Issue Lung Cancer - Molecular Insights and Targeted Therapies)

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22 pages, 2233 KB

Open AccessEditor’s ChoiceReview

MicroRNAs in the Pathogenesis, Prognostication and Prediction of Treatment Resistance in Soft Tissue Sarcomas

by Andrea York Tiang Teo, Vivian Yujing Lim and Valerie Shiwen Yang

Cancers 2023, 15(3), 577; https://doi.org/10.3390/cancers15030577 - 18 Jan 2023

Cited by 9 | Viewed by 6742

Abstract

Soft tissue sarcomas are highly aggressive malignant neoplasms of mesenchymal origin, accounting for less than 1% of adult cancers, but comprising over 20% of paediatric solid tumours. In locally advanced, unresectable, or metastatic disease, outcomes from even the first line of systemic treatment [...] Read more.

Soft tissue sarcomas are highly aggressive malignant neoplasms of mesenchymal origin, accounting for less than 1% of adult cancers, but comprising over 20% of paediatric solid tumours. In locally advanced, unresectable, or metastatic disease, outcomes from even the first line of systemic treatment are invariably poor. MicroRNAs (miRNAs), which are short non-coding RNA molecules, target and modulate multiple dysregulated target genes and/or signalling pathways within cancer cells. Accordingly, miRNAs demonstrate great promise for their utility in diagnosing, prognosticating and improving treatment for soft tissue sarcomas. This review aims to provide an updated discussion on the known roles of specific miRNAs in the pathogenesis of sarcomas, and their potential use in prognosticating outcomes and prediction of therapeutic resistance. Full article

(This article belongs to the Topic Soft Tissue Sarcomas: Treatment and Management)

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19 pages, 1305 KB

Open AccessEditor’s ChoiceReview

Mass Spectrometry-Based Proteomics Workflows in Cancer Research: The Relevance of Choosing the Right Steps

by Paula Carrillo-Rodriguez, Frode Selheim and Maria Hernandez-Valladares

Cancers 2023, 15(2), 555; https://doi.org/10.3390/cancers15020555 - 16 Jan 2023

Cited by 29 | Viewed by 12984

Abstract

The qualitative and quantitative evaluation of proteome changes that condition cancer development can be achieved with liquid chromatography–mass spectrometry (LC-MS). LC-MS-based proteomics strategies are carried out according to predesigned workflows that comprise several steps such as sample selection, sample processing including labeling, MS [...] Read more.

The qualitative and quantitative evaluation of proteome changes that condition cancer development can be achieved with liquid chromatography–mass spectrometry (LC-MS). LC-MS-based proteomics strategies are carried out according to predesigned workflows that comprise several steps such as sample selection, sample processing including labeling, MS acquisition methods, statistical treatment, and bioinformatics to understand the biological meaning of the findings and set predictive classifiers. As the choice of best options might not be straightforward, we herein review and assess past and current proteomics approaches for the discovery of new cancer biomarkers. Moreover, we review major bioinformatics tools for interpreting and visualizing proteomics results and suggest the most popular machine learning techniques for the selection of predictive biomarkers. Finally, we consider the approximation of proteomics strategies for clinical diagnosis and prognosis by discussing current barriers and proposals to circumvent them. Full article

(This article belongs to the Special Issue Application of Proteomics in Cancers)

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18 pages, 1714 KB

Open AccessEditor’s ChoiceReview

Mechanisms of Acquired Resistance and Tolerance to EGFR Targeted Therapy in Non-Small Cell Lung Cancer

by Houssein Chhouri, David Alexandre and Luca Grumolato

Cancers 2023, 15(2), 504; https://doi.org/10.3390/cancers15020504 - 13 Jan 2023

Cited by 63 | Viewed by 13950

Abstract

Non-small cell lung cancers (NSCLC) harboring activating mutations of the epidermal growth factor receptor (EGFR) are treated with specific tyrosine kinase inhibitors (EGFR-TKIs) of this receptor, resulting in clinically responses that can generally last several months. Unfortunately, EGFR-targeted therapy also favors the emergence [...] Read more.

Non-small cell lung cancers (NSCLC) harboring activating mutations of the epidermal growth factor receptor (EGFR) are treated with specific tyrosine kinase inhibitors (EGFR-TKIs) of this receptor, resulting in clinically responses that can generally last several months. Unfortunately, EGFR-targeted therapy also favors the emergence of drug tolerant or resistant cells, ultimately resulting in tumor relapse. Recently, cellular barcoding strategies have arisen as a powerful tool to investigate the clonal evolution of these subpopulations in response to anti-cancer drugs. In this review, we provide an overview of the currently available treatment options for NSCLC, focusing on EGFR targeted therapy, and discuss the common mechanisms of resistance to EGFR-TKIs. We also review the characteristics of drug-tolerant persister (DTP) cells and the mechanistic basis of drug tolerance in EGFR-mutant NSCLC. Lastly, we address how cellular barcoding can be applied to investigate the response and the behavior of DTP cells upon EGFR-TKI treatment. Full article

(This article belongs to the Special Issue Mechanisms of Acquired Resistance to Targeted Therapy)

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21 pages, 1058 KB

Open AccessEditor’s ChoiceReview

Obesity and Cancer: A Current Overview of Epidemiology, Pathogenesis, Outcomes, and Management

by Sukanya Pati, Wadeed Irfan, Ahmad Jameel, Shahid Ahmed and Rabia K. Shahid

Cancers 2023, 15(2), 485; https://doi.org/10.3390/cancers15020485 - 12 Jan 2023

Cited by 431 | Viewed by 32442

Abstract

Background: Obesity or excess body fat is a major global health challenge that has not only been associated with diabetes mellitus and cardiovascular disease but is also a major risk factor for the development of and mortality related to a subgroup of cancer. [...] Read more.

Background: Obesity or excess body fat is a major global health challenge that has not only been associated with diabetes mellitus and cardiovascular disease but is also a major risk factor for the development of and mortality related to a subgroup of cancer. This review focuses on epidemiology, the relationship between obesity and the risk associated with the development and recurrence of cancer and the management of obesity. Methods: A literature search using PubMed and Google Scholar was performed and the keywords ‘obesity’ and cancer’ were used. The search was limited to research papers published in English prior to September 2022 and focused on studies that investigated epidemiology, the pathogenesis of cancer, cancer incidence and the risk of recurrence, and the management of obesity. Results: About 4–8% of all cancers are attributed to obesity. Obesity is a risk factor for several major cancers, including post-menopausal breast, colorectal, endometrial, kidney, esophageal, pancreatic, liver, and gallbladder cancer. Excess body fat results in an approximately 17% increased risk of cancer-specific mortality. The relationship between obesity and the risk associated with the development of cancer and its recurrence is not fully understood and involves altered fatty acid metabolism, extracellular matrix remodeling, the secretion of adipokines and anabolic and sex hormones, immune dysregulation, and chronic inflammation. Obesity may also increase treatment-related adverse effects and influence treatment decisions regarding specific types of cancer therapy. Structured exercise in combination with dietary support and behavior therapy are effective interventions. Treatment with glucagon-like peptide-1 analogues and bariatric surgery result in more rapid weight loss and can be considered in selected cancer survivors. Conclusions: Obesity increases cancer risk and mortality. Weight-reducing strategies in obesity-associated cancers are important interventions as a key component of cancer care. Future studies are warranted to further elucidate the complex relationship between obesity and cancer with the identification of targets for effective interventions. Full article

(This article belongs to the Special Issue Environmental Carcinogenesis)

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13 pages, 521 KB

Open AccessEditor’s ChoiceReview

Metastatic Prostate Cancer—A Review of Current Treatment Options and Promising New Approaches

by Philip Posdzich, Christopher Darr, Thomas Hilser, Milan Wahl, Ken Herrmann, Boris Hadaschik and Viktor Grünwald

Cancers 2023, 15(2), 461; https://doi.org/10.3390/cancers15020461 - 11 Jan 2023

Cited by 103 | Viewed by 11555

Abstract

Androgen deprivation therapy (ADT) alone has been the standard of care for many years in men with metastatic prostate cancer. Due to the limited survival under this monotherapy, many new treatment options have been developed in the last few years. Regarding hormone-sensitive prostate [...] Read more.

Androgen deprivation therapy (ADT) alone has been the standard of care for many years in men with metastatic prostate cancer. Due to the limited survival under this monotherapy, many new treatment options have been developed in the last few years. Regarding hormone-sensitive prostate cancer, combination therapies of two or three agents of ADT, androgen receptor signaling inhibitors (ARSI) and chemotherapy have been established and led to a significant benefit in overall survival. Additionally, in patients with metastatic castration-resistant prostate cancer, there are many new therapeutic approaches. Chemotherapy alone has been the standard of care in this situation. In the last years, some new therapeutic options have been developed, which led to an improved survival after progression under chemotherapy. These therapies include ARSI, PARP inhibitors and Lu-PSMA radioligand therapy. The use of a bispecific T-cell engager (BiTE) in this setting is a new promising therapeutic approach, which has not been established as standard of care yet. The role of immunotherapy in prostate cancer is still under investigation. Overall, many new treatment options make prostate cancer therapy a challenging and promising field. Full article

(This article belongs to the Special Issue Novel Therapeutics for Genitourinary Tumors)

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44 pages, 1344 KB

Open AccessEditor’s ChoiceReview

DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities

by María Ovejero-Sánchez, Rogelio González-Sarmiento and Ana Belén Herrero

Cancers 2023, 15(2), 448; https://doi.org/10.3390/cancers15020448 - 10 Jan 2023

Cited by 20 | Viewed by 7225

Abstract

The DNA damage response (DDR), a set of signaling pathways for DNA damage detection and repair, maintains genomic stability when cells are exposed to endogenous or exogenous DNA-damaging agents. Alterations in these pathways are strongly associated with cancer development, including ovarian cancer (OC), [...] Read more.

The DNA damage response (DDR), a set of signaling pathways for DNA damage detection and repair, maintains genomic stability when cells are exposed to endogenous or exogenous DNA-damaging agents. Alterations in these pathways are strongly associated with cancer development, including ovarian cancer (OC), the most lethal gynecologic malignancy. In OC, failures in the DDR have been related not only to the onset but also to progression and chemoresistance. It is known that approximately half of the most frequent subtype, high-grade serous carcinoma (HGSC), exhibit defects in DNA double-strand break (DSB) repair by homologous recombination (HR), and current evidence indicates that probably all HGSCs harbor a defect in at least one DDR pathway. These defects are not restricted to HGSCs; mutations in ARID1A, which are present in 30% of endometrioid OCs and 50% of clear cell (CC) carcinomas, have also been found to confer deficiencies in DNA repair. Moreover, DDR alterations have been described in a variable percentage of the different OC subtypes. Here, we overview the main DNA repair pathways involved in the maintenance of genome stability and their deregulation in OC. We also recapitulate the preclinical and clinical data supporting the potential of targeting the DDR to fight the disease. Full article

(This article belongs to the Special Issue Innovations in Diagnosis, Prognostic Evaluation, and Therapeutic Management of Gynecologic Tumors)

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25 pages, 1780 KB

Open AccessEditor’s ChoiceReview

The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited

by Kevin Dzobo, Dimakatso A. Senthebane and Collet Dandara

Cancers 2023, 15(2), 376; https://doi.org/10.3390/cancers15020376 - 6 Jan 2023

Cited by 99 | Viewed by 15575

Abstract

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, [...] Read more.

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation. Full article

(This article belongs to the Special Issue Concepts to Improve Targeted Radionuclide Therapy in Cancer: Ligand Design Optimization and Application of Emerging Radionuclides and Combination Therapies)

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25 pages, 7771 KB

Open AccessEditor’s ChoiceReview

Risk Assessment and Pancreatic Cancer: Diagnostic Management and Artificial Intelligence

by Vincenza Granata, Roberta Fusco, Sergio Venanzio Setola, Roberta Galdiero, Nicola Maggialetti, Lucrezia Silvestro, Mario De Bellis, Elena Di Girolamo, Giulia Grazzini, Giuditta Chiti, Maria Chiara Brunese, Andrea Belli, Renato Patrone, Raffaele Palaia, Antonio Avallone, Antonella Petrillo and Francesco Izzo

Cancers 2023, 15(2), 351; https://doi.org/10.3390/cancers15020351 - 5 Jan 2023

Cited by 17 | Viewed by 5213

Abstract

Pancreatic cancer (PC) is one of the deadliest cancers, and it is responsible for a number of deaths almost equal to its incidence. The high mortality rate is correlated with several explanations; the main one is the late disease stage at which the [...] Read more.

Pancreatic cancer (PC) is one of the deadliest cancers, and it is responsible for a number of deaths almost equal to its incidence. The high mortality rate is correlated with several explanations; the main one is the late disease stage at which the majority of patients are diagnosed. Since surgical resection has been recognised as the only curative treatment, a PC diagnosis at the initial stage is believed the main tool to improve survival. Therefore, patient stratification according to familial and genetic risk and the creation of screening protocol by using minimally invasive diagnostic tools would be appropriate. Pancreatic cystic neoplasms (PCNs) are subsets of lesions which deserve special management to avoid overtreatment. The current PC screening programs are based on the annual employment of magnetic resonance imaging with cholangiopancreatography sequences (MR/MRCP) and/or endoscopic ultrasonography (EUS). For patients unfit for MRI, computed tomography (CT) could be proposed, although CT results in lower detection rates, compared to MRI, for small lesions. The actual major limit is the incapacity to detect and characterize the pancreatic intraepithelial neoplasia (PanIN) by EUS and MR/MRCP. The possibility of utilizing artificial intelligence models to evaluate higher-risk patients could favour the diagnosis of these entities, although more data are needed to support the real utility of these applications in the field of screening. For these motives, it would be appropriate to realize screening programs in research settings. Full article

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

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