Cancers

15 pages, 1325 KB

Open AccessEditor’s ChoiceReview

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

by Jeffrey Molldrem and Dongxing Zha

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

Cited by 2 | Viewed by 7418

Abstract

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

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

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

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16 pages, 21457 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 3427

Abstract

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

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

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

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18 pages, 1512 KB

Open AccessEditor’s ChoiceReview

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

by Sandhya Dhiman, Vikram Dhillon and Suresh Kumar Balasubramanian

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

Cited by 3 | Viewed by 6272

Abstract

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

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

(This article belongs to the Section Cancer Therapy)

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55 pages, 1491 KB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 53 | Viewed by 28625

Abstract

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

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

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

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17 pages, 9029 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 7658

Abstract

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

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

(This article belongs to the Section Cancer Metastasis)

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15 pages, 646 KB

Open AccessEditor’s ChoiceReview

Copper and Colorectal Cancer

by Maciej Małyszko and Adam Przybyłkowski

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

Cited by 5 | Viewed by 5969

Abstract

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

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

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

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15 pages, 3900 KB

Open AccessEditor’s ChoiceSystematic Review

Predicting Biochemical Recurrence of Prostate Cancer Post-Prostatectomy Using Artificial Intelligence: A Systematic Review

by Jianliang Liu, Haoyue Zhang, Dixon T. S. Woon, Marlon Perera and Nathan Lawrentschuk

Cancers 2024, 16(21), 3596; https://doi.org/10.3390/cancers16213596 - 25 Oct 2024

Cited by 8 | Viewed by 3160

Abstract

Background/Objectives: Biochemical recurrence (BCR) after radical prostatectomy (RP) is a significant predictor of distal metastases and mortality in prostate cancer (PCa) patients. This systematic review aims to evaluate the accuracy of artificial intelligence (AI) in predicting BCR post-RP. Methods: Adhering to [...] Read more.

Background/Objectives: Biochemical recurrence (BCR) after radical prostatectomy (RP) is a significant predictor of distal metastases and mortality in prostate cancer (PCa) patients. This systematic review aims to evaluate the accuracy of artificial intelligence (AI) in predicting BCR post-RP. Methods: Adhering to PRISMA guidelines, a comprehensive literature search was conducted across Medline, Embase, Web of Science, and IEEE Xplore. Studies were included if they utilised AI to predict BCR in patients post-RP. Studies involving patients who underwent radiotherapy or salvage RP were excluded. This systematic review was registered on PROSPERO (International prospective register of systematic reviews) under the ID CRD42023482392. Results: After screening 9764 articles, 24 met the inclusion criteria. The included studies involved 27,216 patients, of whom 7267 developed BCR. AI algorithms developed using radiological parameters demonstrated higher predictive accuracy (median AUROC of 0.90) compared to algorithms based solely on pathological variables (median AUROC of 0.74) or clinicopathological variables (median AUROC of 0.81). According to the Prediction Model Risk of Bias Assessment Tool (PROBAST), the overall risk of bias was unclear in three studies due to ambiguous inclusion criteria and the exclusion of many patients because of missing follow-up data. In seven studies, the developed AI outperformed or was at least equivocal to traditional methods of BCR prediction. Conclusions: AI shows promise in predicting BCR post-RP, particularly when radiological data were used in its development. However, the significant variability in AI performance and study methodologies highlights the need for larger, standardised prospective studies with external validation prior to clinical application. Full article

(This article belongs to the Special Issue Artificial Intelligence in Cancer Research: Knowledge Representation and Data Perspectives)

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30 pages, 2989 KB

Open AccessEditor’s ChoiceReview

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

by Jagadeesh Rajaram and Yaswanth Kuthati

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

Cited by 7 | Viewed by 2501

Abstract

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

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

(This article belongs to the Topic Nanomaterials and Diseases)

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18 pages, 477 KB

Open AccessEditor’s ChoiceReview

Risk-Stratified Radiotherapy in Pediatric Cancer

by Rituraj Upadhyay and Arnold C. Paulino

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

Cited by 1 | Viewed by 3224

Abstract

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

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

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

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38 pages, 8614 KB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 12 | Viewed by 5584

Abstract

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

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

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

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15 pages, 1992 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 2389

Abstract

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

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

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

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18 pages, 3914 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 9 | Viewed by 3931

Abstract

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

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

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

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24 pages, 5399 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 3106

Abstract

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

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

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

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15 pages, 1268 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 4 | Viewed by 1812

Abstract

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

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

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

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23 pages, 1108 KB

Open AccessEditor’s ChoiceReview

Recent Advances in the Molecular Biology of Chronic Lymphocytic Leukemia: How to Define Prognosis and Guide Treatment

by Annalisa Arcari, Lucia Morello, Elena Borotti, Elena Ronda, Angela Rossi and Daniele Vallisa

Cancers 2024, 16(20), 3483; https://doi.org/10.3390/cancers16203483 - 14 Oct 2024

Cited by 4 | Viewed by 5946

Abstract

Chronic Lymphocytic Leukemia (CLL) is the most frequent type of leukemia in Western countries. In recent years, there have been important advances in the knowledge of molecular alterations that underlie the disease’s pathogenesis. Very heterogeneous prognostic subgroups have been identified by the mutational [...] Read more.

Chronic Lymphocytic Leukemia (CLL) is the most frequent type of leukemia in Western countries. In recent years, there have been important advances in the knowledge of molecular alterations that underlie the disease’s pathogenesis. Very heterogeneous prognostic subgroups have been identified by the mutational status of immunoglobulin heavy variable genes (IGVH), FISH analysis and molecular evaluation of TP53 mutations. Next-generation sequencing (NGS) technologies have provided a deeper characterization of the genomic and epigenomic landscape of CLL. New therapeutic targets have led to a progressive reduction of traditional chemoimmunotherapy in favor of specific biological agents. Furthermore, in the latest clinical trials, the minimal residual disease (MRD) has emerged as a potent marker of outcome and a guide to treatment duration. This review focuses on recent insights into the understanding of CLL biology. We also consider the translation of these findings into the development of risk-adapted and targeted therapeutic approaches. Full article

(This article belongs to the Special Issue Recent Advances in Genetic Studies on Leukemia)

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10 pages, 1838 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 2963

Abstract

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

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

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

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17 pages, 2928 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 5 | Viewed by 3007

Abstract

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

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

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

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18 pages, 1579 KB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 5 | Viewed by 4645

Abstract

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

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

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

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32 pages, 3865 KB

Open AccessEditor’s ChoiceReview

Mechanistic Insights on Microbiota-Mediated Development and Progression of Esophageal Cancer

by Kyaw Thu Moe and Kevin Shyong-Wei Tan

Cancers 2024, 16(19), 3305; https://doi.org/10.3390/cancers16193305 - 27 Sep 2024

Cited by 8 | Viewed by 3403

Abstract

Esophageal cancer (EC) is one of the most common malignant tumors worldwide, and its two major types, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), present a severe global public health problem with an increasing incidence and mortality. Established risk factors include [...] Read more.

Esophageal cancer (EC) is one of the most common malignant tumors worldwide, and its two major types, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), present a severe global public health problem with an increasing incidence and mortality. Established risk factors include smoking, alcohol consumption, and dietary habits, but recent research has highlighted the substantial role of oral microbiota in EC pathogenesis. This review explores the intricate relationship between the microbiome and esophageal carcinogenesis, focusing on the following eight significant mechanisms: chronic inflammation, microbial dysbiosis, production of carcinogenic metabolites, direct interaction with epithelial cells, epigenetic modifications, interaction with gastroesophageal reflux disease (GERD), metabolic changes, and angiogenesis. Certain harmful bacteria, such as Porphyromonas gingivalis and Fusobacterium nucleatum, are specifically implicated in sustaining irritation and tumor progression through pathways including NF-κB and NLRP3 inflammasome. Additionally, the review explores how microbial byproducts, including short-chain fatty acids (SCFAs) and reactive oxygen species (ROS), contribute to DNA harm and disease advancement. Furthermore, the impact of reflux on microbiota composition and its role in esophageal carcinogenesis is evaluated. By combining epidemiological data with mechanistic understanding, this review underscores the potential to target the microbiota–immune system interplay for novel therapeutic and diagnostic strategies to prevent and treat esophageal cancer. Full article

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

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32 pages, 6049 KB

Open AccessEditor’s ChoiceReview

Deep Learning for Image Analysis in the Diagnosis and Management of Esophageal Cancer

by Charalampos Theocharopoulos, Spyridon Davakis, Dimitrios C. Ziogas, Achilleas Theocharopoulos, Dimitra Foteinou, Adam Mylonakis, Ioannis Katsaros, Helen Gogas and Alexandros Charalabopoulos

Cancers 2024, 16(19), 3285; https://doi.org/10.3390/cancers16193285 - 26 Sep 2024

Cited by 5 | Viewed by 3852

Abstract

Esophageal cancer has a dismal prognosis and necessitates a multimodal and multidisciplinary approach from diagnosis to treatment. High-definition white-light endoscopy and histopathological confirmation remain the gold standard for the definitive diagnosis of premalignant and malignant lesions. Artificial intelligence using deep learning (DL) methods [...] Read more.

Esophageal cancer has a dismal prognosis and necessitates a multimodal and multidisciplinary approach from diagnosis to treatment. High-definition white-light endoscopy and histopathological confirmation remain the gold standard for the definitive diagnosis of premalignant and malignant lesions. Artificial intelligence using deep learning (DL) methods for image analysis constitutes a promising adjunct for the clinical endoscopist that could effectively decrease BE overdiagnosis and unnecessary surveillance, while also assisting in the timely detection of dysplastic BE and esophageal cancer. A plethora of studies published during the last five years have consistently reported highly accurate DL algorithms with comparable or superior performance compared to endoscopists. Recent efforts aim to expand DL utilization into further aspects of esophageal neoplasia management including histologic diagnosis, segmentation of gross tumor volume, pretreatment prediction and post-treatment evaluation of patient response to systemic therapy and operative guidance during minimally invasive esophagectomy. Our manuscript serves as an introduction to the growing literature of DL applications for image analysis in the management of esophageal neoplasia, concisely presenting all currently published studies. We also aim to guide the clinician across basic functional principles, evaluation metrics and limitations of DL for image recognition to facilitate the comprehension and critical evaluation of the presented studies. Full article

(This article belongs to the Special Issue Applications of Machine and Deep Learning in Thoracic Malignancies)

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12 pages, 2697 KB

Open AccessEditor’s ChoiceArticle

Complex Relationships between Diagnostics and Survival in Chronic Lymphocytic Leukemia in Denmark, Finland, Norway, and Sweden

by Kari Hemminki, Frantisek Zitricky, Asta Försti, Tuija Tapaninen, Akseli Hemminki, Gunnar Juliusson and Carsten Utoft Niemann

Cancers 2024, 16(18), 3229; https://doi.org/10.3390/cancers16183229 - 22 Sep 2024

Cited by 3 | Viewed by 2189

Abstract

Background: Chronic lymphocytic leukemia (CLL) is a common hematological malignancy with highly variable clinical presentation. Many patients never require any treatment but for the others, chemotherapy, immunochemotherapy, and newer targeted therapies have changed the treatment landscape. Diagnostic age influences the applied treatment, and [...] Read more.

Background: Chronic lymphocytic leukemia (CLL) is a common hematological malignancy with highly variable clinical presentation. Many patients never require any treatment but for the others, chemotherapy, immunochemotherapy, and newer targeted therapies have changed the treatment landscape. Diagnostic age influences the applied treatment, and we thus wanted to analyze age-specific survival trends through 50 years up to 2020s. Methods: We used 1- and 5-year relative survival from the NORDCAN database, with data from Denmark (DK), Finland (FI), Norway (NO), and Sweden (SE). Because of the variable presentation of CLL, we also considered incidence and mortality trends. For comparison, US SEER data were used. Results: The large age-specific survival differences in 1972–76 almost disappeared by 2017–21. While 5-year survival in younger patients exceeded 90%, for those diagnosed at age 80–89 years, survival reached 90% in DK and SE women, 80% in NO and SE men, but only 50% in FI. DK 5-year overall survival for men was 92.4%, and for women, it was 96.3%. These survival figures were higher than age-group-specific US survival data. Conclusions: The DK data are probably global top figures for national survival which could be achieved by boosting survival even among the oldest patients. The qualification to these figures and international comparisons is that survival needs to be considered in terms of incidence, which is high in DK and NO. Low survival of the FI 80–89-year-old patients, even in the first year after diagnosis, may suggest delayed diagnosis, which should call for a closer national scrutiny. Full article

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

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11 pages, 1443 KB

Open AccessEditor’s ChoiceArticle

Response Rates and Transplantation Impact in Patients with Relapsed Acute Promyelocytic Leukemia

by Alessandro Costa, Carmelo Gurnari, Emilia Scalzulli, Laura Cicconi, Luca Guarnera, Ida Carmosino, Raffaella Cerretti, Maria Laura Bisegna, Saveria Capria, Clara Minotti, Anna Paola Iori, Lorenzo Torrieri, Adriano Venditti, Alessandro Pulsoni, Maurizio Martelli, Maria Teresa Voso and Massimo Breccia

Cancers 2024, 16(18), 3214; https://doi.org/10.3390/cancers16183214 - 21 Sep 2024

Cited by 3 | Viewed by 2201

Abstract

Background: The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has radically improved the prognosis of acute promyelocytic leukemia (APL), with cure rates above 80%. While relapse occurs in less than 20% of cases, addressing this issue remains challenging. Identifying [...] Read more.

Background: The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has radically improved the prognosis of acute promyelocytic leukemia (APL), with cure rates above 80%. While relapse occurs in less than 20% of cases, addressing this issue remains challenging. Identifying effective salvage therapies for relapsed APL is crucial to improve patient outcomes. Methods: A retrospective analysis was performed on a multicentric cohort of 67 APL patients in first relapse, treated in three Italian hematology centers from June 1981 to November 2021. The overall survival (OS) and cumulative incidence of relapse (CIR) were calculated, and predictive factors were assessed using Cox regression models. Results: Overall, 61 patients (91%) received ATO ± ATRA (40.3%), chemo-based regimens (40.3%), or ATRA ± Gemtuzumab ozogamicin (GO) (10.4%). Complete remission (CR) was achieved in 98.2% of patients (molecular CR, n = 71.4%). With a median follow-up time of 54.5 months, the 5-year OS was 73% in the ATO ± ATRA group, 44% in the chemo-based group, and 29% in the ATRA ± GO group (p = 0.035). The 5-year OS rate was also higher for transplant recipients vs. non-recipients within the chemo-based cohort (50% vs. 33%, p = 0.017), but not in the ATO-based cohort (p = 0.12). ATO-based salvage therapy resulted in better OS in both univariate (p = 0.025) and multivariate analyses (p = 0.026). The 2-year CIR was higher in patients without molecular CR vs. patients in molecular CR (66% vs. 24%, p = 0.034). Molecular CR was a significant predictor of second relapse in both univariate (p = 0.035) and multivariate analyses (p = 0.036). Conclusions: Our findings support the efficacy of ATO-based therapies in first relapse of APL and confirm the achievement of molecular remission as an independent outcome predictor in both first and second APL relapse. Full article

(This article belongs to the Section Cancer Pathophysiology)

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21 pages, 2340 KB

Open AccessEditor’s ChoiceSystematic Review

Leucocyte Telomere Length and Lung Cancer Risk: A Systematic Review and Meta-Analysis of Prospective Studies

by Roberto Fabiani, Manuela Chiavarini, Patrizia Rosignoli and Irene Giacchetta

Cancers 2024, 16(18), 3218; https://doi.org/10.3390/cancers16183218 - 21 Sep 2024

Cited by 6 | Viewed by 2186

Abstract

Although numerous epidemiological studies are available, the relationship between leukocyte telomere length (LTL) and lung cancer risk is still controversial. This systematic review and meta-analysis, performed according to the PRISMA statement and MOOSE guidelines, aims to summarize the evidence and calculate the risk [...] Read more.

Although numerous epidemiological studies are available, the relationship between leukocyte telomere length (LTL) and lung cancer risk is still controversial. This systematic review and meta-analysis, performed according to the PRISMA statement and MOOSE guidelines, aims to summarize the evidence and calculate the risk of lung cancer associated with LTL. The literature search was performed on PubMed, Web of Science, and Scopus databases through May 2024. A random-effects model was used to calculate the pooled risk. Heterogeneity was assessed using I² and Cochran’s Q statistic. Begg’s and Egger’s tests were used to detect publication bias. Based on 8055 lung cancer cases and 854,653 controls (nine prospective studies), longer LTL was associated with a significant 42% increment in all types of lung cancer risk (OR 1.42, 95% CI 1.24–1.63). The effect was even more evident for adenocarcinomas (OR 1.98, 95% CI 1.69–2.31), while no association was observed for squamous cell carcinoma (OR 0.87, 95% CI 0.72–1.06). Significantly, no association was found for current smokers (OR 1.08, 95% CI 0.90–1.30), while it remained high for both never-smokers (OR 1.92, 95% CI 1.62–2.28) and former smokers (OR 1.34, 95% CI 1.11–1.62). No significant publication bias was evidenced. Longer LTL is associated with an increment in lung cancer risk particularly in never-smoker subjects. Full article

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

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33 pages, 6663 KB

Open AccessEditor’s ChoiceReview

Vitamin D in Cancer Prevention and Treatment: A Review of Epidemiological, Preclinical, and Cellular Studies

by Siva Dallavalasa, SubbaRao V. Tulimilli, Vidya G. Bettada, Medha Karnik, Chinnappa A. Uthaiah, Preethi G. Anantharaju, Suma M. Nataraj, Rajalakshmi Ramashetty, Olga A. Sukocheva, Edmund Tse, Paramahans V. Salimath and SubbaRao V. Madhunapantula

Cancers 2024, 16(18), 3211; https://doi.org/10.3390/cancers16183211 - 20 Sep 2024

Cited by 15 | Viewed by 15367

Abstract

Background: Inhibition of human carcinomas has previously been linked to vitamin D due to its effects on cancer cell proliferation, migration, angiogenesis, and apoptosis induction. The anticancer activity of vitamin D has been confirmed by several studies, which have shown that increased cancer [...] Read more.

Background: Inhibition of human carcinomas has previously been linked to vitamin D due to its effects on cancer cell proliferation, migration, angiogenesis, and apoptosis induction. The anticancer activity of vitamin D has been confirmed by several studies, which have shown that increased cancer incidence is associated with decreased vitamin D and that dietary supplementation of vitamin D slows down the growth of xenografted tumors in mice. Vitamin D inhibits the growth of cancer cells by the induction of apoptosis as well as by arresting the cells at the G0/G1 (or) G2/M phase of the cell cycle. Aim and Key Scientific Concepts of the Review: The purpose of this article is to thoroughly review the existing information and discuss and debate to conclude whether vitamin D could be used as an agent to prevent/treat cancers. The existing empirical data have demonstrated that vitamin D can also work in the absence of vitamin D receptors (VDRs), indicating the presence of multiple mechanisms of action for this sunshine vitamin. Polymorphism in the VDR is known to play a key role in tumor cell metastasis and drug resistance. Although there is evidence that vitamin D has both therapeutic and cancer-preventive properties, numerous uncertainties and concerns regarding its use in cancer treatment still exist. These include (a) increased calcium levels in individuals receiving therapeutic doses of vitamin D to suppress the growth of cancer cells; (b) hyperglycemia induction in certain vitamin D-treated study participants; (c) a dearth of evidence showing preventive or therapeutic benefits of cancer in clinical trials; (d) very weak support from proof-of-principle studies; and (e) the inability of vitamin D alone to treat advanced cancers. Addressing these concerns, more potent and less toxic vitamin D analogs have been created, and these are presently undergoing clinical trial evaluation. To provide key information regarding the functions of vitamin D and VDRs, this review provided details of significant advancements in the functional analysis of vitamin D and its analogs and VDR polymorphisms associated with cancers. Full article

(This article belongs to the Special Issue Emerging Trends in Global Cancer Epidemiology: 2nd Edition)

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16 pages, 4837 KB

Open AccessEditor’s ChoiceArticle

Cancer-Associated Fibroblast Proteins as Potential Targets against Colorectal Cancers

by Ruchi Shah, Katherine A. Johnson, Anna E. L. Lippert, Sean G. Kraus, Philip B. Emmerich, Cheri A. Pasch, Wei Zhang, Kristina A. Matkowskyj, Aaron M. LeBeau and Dustin A. Deming

Cancers 2024, 16(18), 3158; https://doi.org/10.3390/cancers16183158 - 14 Sep 2024

Cited by 11 | Viewed by 4256

Abstract

In colorectal cancer (CRC), attempts to identify cancer cell-specific markers to guide antibody-mediated therapeutics have failed to uncover markers that are both exclusive to cancer tissues and abundant across CRCs. Alternatively, cancer-associated fibroblasts (CAFs), which are abundant in the tumor microenvironment and upregulate [...] Read more.

In colorectal cancer (CRC), attempts to identify cancer cell-specific markers to guide antibody-mediated therapeutics have failed to uncover markers that are both exclusive to cancer tissues and abundant across CRCs. Alternatively, cancer-associated fibroblasts (CAFs), which are abundant in the tumor microenvironment and upregulate unique surface markers, are not found in healthy tissues. Here, we evaluated the expression patterns of CAF-associated proteins α-smooth muscle actin (αSMA), fibroblast activation protein (FAP), podoplanin (PDPN), matrix metalloproteinase-2 (MMP2), transgelin (TAGLN), and THY1. While αSMA and THY1 were abundant in cancer tissues, high abundance in normal tissues limited their targeting potential. FAP was present in 94.5% of primary and metastatic CRC tissues and absent in 93.7% of adjacent normal colon and liver tissues assessed. These results indicate that FAP is a promising target for antibody conjugates with potential for broad application in CRC. Co-expression analyses showed that CRCs simultaneously expressing high levels of PDPN, MMP2, and THY1 were enriched for immune-related signatures, indicating potential for antibody-mediated immune engagers. Overall, this work highlights the potential of CAF proteins to act as therapeutic targets for novel anticancer agents and become important therapeutic biomarkers. Full article

(This article belongs to the Section Molecular Cancer Biology)

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12 pages, 911 KB

Open AccessEditor’s ChoiceReview

The Role of Circulating Tumor DNA in Ovarian Cancer

by Anna Golara, Mateusz Kozłowski and Aneta Cymbaluk-Płoska

Cancers 2024, 16(18), 3117; https://doi.org/10.3390/cancers16183117 - 10 Sep 2024

Cited by 4 | Viewed by 2747

Abstract

Ovarian cancer is the deadliest of all gynecological diseases because its diagnosis and treatment still pose many problems. Surgical excision, hormone therapy, radiation, chemotherapy, or targeted therapy for eradicating the main tumor and halting the spread of metastases are among the treatment options [...] Read more.

Ovarian cancer is the deadliest of all gynecological diseases because its diagnosis and treatment still pose many problems. Surgical excision, hormone therapy, radiation, chemotherapy, or targeted therapy for eradicating the main tumor and halting the spread of metastases are among the treatment options available to individuals with ovarian cancer, depending on the disease’s stage. Tumor DNA that circulates in a patient’s bodily fluids has been studied recently as a possible novel biomarker for a number of cancers, as well as a means of quantifying tumor size and evaluating the efficacy of cancer therapy. The most significant alterations that we could find in the ctDNA of ovarian cancer patients—such as chromosomal instability, somatic mutations, and methylation—are discussed in this review. Additionally, we talk about the utility of ctDNA in diagnosis, prognosis, and therapy response prediction for these patients. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)

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17 pages, 295 KB

Open AccessEditor’s ChoicePerspective

Immunotherapy and Radiotherapy for Older Patients with Locally Advanced Non-Metastatic Non-Small-Cell Lung Cancer Who Are Not Candidates for or Decline Surgery and Chemotherapy: A Practical Proposal by the International Geriatric Radiotherapy Group

by Nam P. Nguyen, Brandi R. Page, Huan Giap, Zineb Dahbi, Vincent Vinh-Hung, Olena Gorobets, Mohammad Mohammadianpanah, Micaela Motta, Maurizio Portaluri, Meritxell Arenas, Marta Bonet, Pedro Carlos Lara, Lyndon Kim, Fabien Dutheil, Elena Natoli, Gokoulakrichenane Loganadane, David Lehrman, Satya Bose, Sarabjot Kaur, Sergio Calleja Blanco and Alexander Chi Show full author list Hide full author list

Cancers 2024, 16(17), 3112; https://doi.org/10.3390/cancers16173112 - 9 Sep 2024

Cited by 5 | Viewed by 2806

Abstract

The standard of care for locally advanced non-small-cell lung cancer (NSCLC) is either surgery combined with chemotherapy pre- or postoperatively or concurrent chemotherapy and radiotherapy. However, older and frail patients may not be candidates for surgery and chemotherapy due to the high mortality [...] Read more.

The standard of care for locally advanced non-small-cell lung cancer (NSCLC) is either surgery combined with chemotherapy pre- or postoperatively or concurrent chemotherapy and radiotherapy. However, older and frail patients may not be candidates for surgery and chemotherapy due to the high mortality risk and are frequently referred to radiotherapy alone, which is better tolerated but carries a high risk of disease recurrence. Recently, immunotherapy with immune checkpoint inhibitors (ICIs) may induce a high response rate among cancer patients with positive programmed death ligand 1 (PD-L1) expression. Immunotherapy is also well tolerated among older patients. Laboratory and clinical studies have reported synergy between radiotherapy and ICI. The combination of ICI and radiotherapy may improve local control and survival for NSCLC patients who are not candidates for surgery and chemotherapy or decline these two modalities. The International Geriatric Radiotherapy Group proposes a protocol combining radiotherapy and immunotherapy based on the presence or absence of PD-L1 to optimize the survival of those patients. Full article

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

43 pages, 1436 KB

Open AccessEditor’s ChoiceReview

Orally Ingested Micro- and Nano-Plastics: A Hidden Driver of Inflammatory Bowel Disease and Colorectal Cancer

by Annalisa Bruno, Melania Dovizio, Cristina Milillo, Eleonora Aruffo, Mirko Pesce, Marco Gatta, Piero Chiacchiaretta, Piero Di Carlo and Patrizia Ballerini

Cancers 2024, 16(17), 3079; https://doi.org/10.3390/cancers16173079 - 4 Sep 2024

Cited by 16 | Viewed by 13652

Abstract

Micro- and nano-plastics (MNPLs) can move along the food chain to higher-level organisms including humans. Three significant routes for MNPLs have been reported: ingestion, inhalation, and dermal contact. Accumulating evidence supports the intestinal toxicity of ingested MNPLs and their role as drivers for [...] Read more.

Micro- and nano-plastics (MNPLs) can move along the food chain to higher-level organisms including humans. Three significant routes for MNPLs have been reported: ingestion, inhalation, and dermal contact. Accumulating evidence supports the intestinal toxicity of ingested MNPLs and their role as drivers for increased incidence of colorectal cancer (CRC) in high-risk populations such as inflammatory bowel disease (IBD) patients. However, the mechanisms are largely unknown. In this review, by using the leading scientific publication databases (Web of Science, Google Scholar, Scopus, PubMed, and ScienceDirect), we explored the possible effects and related mechanisms of MNPL exposure on the gut epithelium in healthy conditions and IBD patients. The summarized evidence supports the idea that oral MNPL exposure may contribute to intestinal epithelial damage, thus promoting and sustaining the chronic development of intestinal inflammation, mainly in high-risk populations such as IBD patients. Colonic mucus layer disruption may further facilitate MNPL passage into the bloodstream, thus contributing to the toxic effects of MNPLs on different organ systems and platelet activation, which may, in turn, contribute to the chronic development of inflammation and CRC development. Further exploration of this threat to human health is warranted to reduce potential adverse effects and CRC risk. Full article

(This article belongs to the Special Issue Signaling Mechanisms Underlying Gastrointestinal Tract Tumorigenesis)

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19 pages, 2049 KB

Open AccessEditor’s ChoiceReview

TP53 Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications

by Chuqi Wang, Jordan Yong Ming Tan, Nishtha Chitkara and Shruti Bhatt

Cancers 2024, 16(17), 3069; https://doi.org/10.3390/cancers16173069 - 3 Sep 2024

Cited by 30 | Viewed by 14677

Abstract

Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range [...] Read more.

Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range of immune-based therapies, such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T, and hematopoietic stem cell transplantation (HSCT). This highlights the role of p53 mutations in driving immune evasion of tumor cells. In this review, we first summarize recent studies revealing mechanisms by which p53-mutant tumors evade immune surveillance from T cells, natural killer (NK) cells, and macrophages. We then review how these mutant tumor cells reshape the tumor microenvironment (TME), modulating bystander cells such as macrophages, neutrophils, and regulatory T (Treg) cells to foster immunosuppression. Additionally, we review clinical observations indicative of immune evasion associated with p53 loss or mutations. Finally, we discuss therapeutic strategies to enhance immune response in p53 wild-type (WT) or mutant tumors. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment in Cancer: Promises and Challenges)

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25 pages, 1386 KB

Open AccessEditor’s ChoiceReview

Aberrant SWI/SNF Complex Members Are Predominant in Rare Ovarian Malignancies—Therapeutic Vulnerabilities in Treatment-Resistant Subtypes

by Yue Ma, Natisha R. Field, Tao Xie, Sarina Briscas, Emily G. Kokinogoulis, Tali S. Skipper, Amani Alghalayini, Farhana A. Sarker, Nham Tran, Nikola A. Bowden, Kristie-Ann Dickson and Deborah J. Marsh

Cancers 2024, 16(17), 3068; https://doi.org/10.3390/cancers16173068 - 3 Sep 2024

Cited by 7 | Viewed by 6299

Abstract

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations [...] Read more.

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42–67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69–100% of SCCOHT cases and SMARCA2 silencing seen 86–100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade. Full article

(This article belongs to the Special Issue Rare Gynecological Cancers)

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15 pages, 1217 KB

Open AccessEditor’s ChoiceReview

Therapeutical Usefulness of PD-1/PD-L1 Inhibitors in Aggressive or Metastatic Pituitary Tumours

by Mariana Lopes-Pinto, Ema Lacerda-Nobre, Ana Luísa Silva and Pedro Marques

Cancers 2024, 16(17), 3033; https://doi.org/10.3390/cancers16173033 - 30 Aug 2024

Cited by 5 | Viewed by 1913

Abstract

Therapeutic options for pituitary neuroendocrine tumours (PitNETs) refractory to temozolomide are scarce. Immune checkpoint inhibitors (ICIs), particularly inhibitors of the programmed cell death-1 (PD-1) pathway and its ligand (PD-L1), have been experimentally used in aggressive or metastatic PitNETs. We aimed to study the [...] Read more.

Therapeutic options for pituitary neuroendocrine tumours (PitNETs) refractory to temozolomide are scarce. Immune checkpoint inhibitors (ICIs), particularly inhibitors of the programmed cell death-1 (PD-1) pathway and its ligand (PD-L1), have been experimentally used in aggressive or metastatic PitNETs. We aimed to study the therapeutic usefulness of anti-PD-1 drugs in patients with aggressive or metastatic PitNETs. Published cases and case series involving patients with PitNETs treated with PD-1/PD-L1 inhibitors were reviewed. Demographic data, clinical–pathological features, previous therapies, drug dosage and posology, and the best radiological and biochemical responses, as well as survival data, were evaluated. We identified 29 cases of aggressive (n = 13) or metastatic (n = 16) PitNETs treated with PD-1/PD-L1 inhibitors. The hypersecretion of adrenocorticotropic hormone (ACTH) was documented in eighteen cases (62.1%), seven were prolactinomas (24.1%), and four were non-functioning PitNETs. All patients underwent various therapies prior to using ICIs. Overall, a positive radiological response (i.e., partial/complete radiological response and stable disease) was observed in eighteen of twenty-nine cases (62.1%), of which ten and four were ACTH- and prolactin-secreting PitNETs, respectively. Hormonal levels reduced or stabilised after using ICIs in 11 of the 17 functioning PitNET cases with available data (64.7%). The median survival of patients treated with ICIs was 13 months, with a maximum of 42 months in two ACTH-secreting tumours. Among 29 patients with PitNETs treated with PD-1/PD-L1 inhibitors, the positive radiological and biochemical response rates were 62.1% and 64.7%, respectively. Altogether, these data suggest a promising role of ICIs in patients with aggressive or metastatic PitNETs refractory to other treatment modalities. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: From Diagnosis to Therapy)

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24 pages, 1710 KB

Open AccessEditor’s ChoiceReview

Recent Treatment Strategies and Molecular Pathways in Resistance Mechanisms of Antiangiogenic Therapies in Glioblastoma

by Md Ataur Rahman and Meser M. Ali

Cancers 2024, 16(17), 2975; https://doi.org/10.3390/cancers16172975 - 27 Aug 2024

Cited by 17 | Viewed by 5172

Abstract

Malignant gliomas present great difficulties in treatment, with little change over the past 30 years in the median survival time of 15 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic [...] Read more.

Malignant gliomas present great difficulties in treatment, with little change over the past 30 years in the median survival time of 15 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic treatments) or destroying formed tumor vasculature (vascular disrupting agents) show promise. This study summarizes the existing knowledge regarding the processes by which glioblastoma (GBM) tumors acquire resistance to antiangiogenic treatments. The discussion encompasses the activation of redundant proangiogenic pathways, heightened tumor cell invasion and metastasis, resistance induced by hypoxia, creation of vascular mimicry channels, and regulation of the tumor immune microenvironment. Subsequently, we explore potential strategies to overcome this resistance, such as combining antiangiogenic therapies with other treatment methods, personalizing treatments for each patient, focusing on new therapeutic targets, incorporating immunotherapy, and utilizing drug delivery systems based on nanoparticles. Additionally, we would like to discuss the limitations of existing methods and potential future directions to enhance the beneficial effects of antiangiogenic treatments for patients with GBM. Therefore, this review aims to enhance the research outcome for GBM and provide a more promising opportunity by thoroughly exploring the mechanisms of resistance and investigating novel therapeutic strategies. Full article

(This article belongs to the Special Issue Current Challenges and Opportunities in Treating Glioma)

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11 pages, 866 KB

Open AccessEditor’s ChoiceReview

Small Bowel Cancer in Crohn’s Disease

by Ilaria Faggiani, Ferdinando D’Amico, Federica Furfaro, Alessandra Zilli, Tommaso Lorenzo Parigi, Clelia Cicerone, Gionata Fiorino, Laurent Peyrin-Biroulet, Silvio Danese and Mariangela Allocca

Cancers 2024, 16(16), 2901; https://doi.org/10.3390/cancers16162901 - 21 Aug 2024

Cited by 5 | Viewed by 3026

Abstract

Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) that frequently affects the small bowel. Individuals diagnosed with CD are at increased risk of developing bowel cancer compared to the general population. Small bowel cancer is a rare but significant CD complication. [...] Read more.

Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) that frequently affects the small bowel. Individuals diagnosed with CD are at increased risk of developing bowel cancer compared to the general population. Small bowel cancer is a rare but significant CD complication. Adenocarcinoma represents the most prevalent of these neoplasms, followed by neuroendocrine tumors and sarcomas. The primary risk factors identified are being of the male sex, disease duration, previous surgical intervention, perianal disease, and chronic inflammation. The precise etiology remains unclear. Another crucial issue concerns the role of immunomodulators and advanced therapies. By inhibiting inflammation, these therapies can reduce the risk of cancer, which is often initiated by the inflammation–dysplasia–adenocarcinoma sequence. In accordance with the most recent guidelines, it is not necessary to conduct surveillance in patients with small bowel cancer among CD patients, as it is considered a rare disease. Nevertheless, it is of significant importance for gastroenterologists to be aware of this potential CD complication, as well as the patients who are most at risk of developing it. The purpose of this review is to provide a comprehensive overview of CD-SBC, focusing on epidemiology, etiopathogenesis, risk factors, diagnosis, and the role of advanced therapies in CD-SBC. Full article

(This article belongs to the Special Issue Cancer and Immunomediated Inflammatory Diseases (IMIDs))

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21 pages, 1614 KB

Open AccessEditor’s ChoiceReview

WFUMB Review Paper. Incidental Findings in Otherwise Healthy Subjects, How to Manage: Liver

by Roxana Șirli, Alina Popescu, Christian Jenssen, Kathleen Möller, Adrian Lim, Yi Dong, Ioan Sporea, Dieter Nürnberg, Marieke Petry and Christoph F. Dietrich

Cancers 2024, 16(16), 2908; https://doi.org/10.3390/cancers16162908 - 21 Aug 2024

Cited by 4 | Viewed by 5628

Abstract

An incidental focal liver lesion (IFLL) is defined as a hepatic lesion identified in a patient imaged for an unrelated reason. They are frequently encountered in daily practice, sometimes leading to unnecessary, invasive and potentially harmful follow-up investigations. The clinical presentation and the [...] Read more.

An incidental focal liver lesion (IFLL) is defined as a hepatic lesion identified in a patient imaged for an unrelated reason. They are frequently encountered in daily practice, sometimes leading to unnecessary, invasive and potentially harmful follow-up investigations. The clinical presentation and the imaging aspects play an important role in deciding if, and what further evaluation, is needed. In low-risk patients (i.e., without a history of malignant or chronic liver disease or related symptoms), especially in those younger than 40 years old, more than 95% of IFLLs are likely benign. Shear Wave liver Elastography (SWE) of the surrounding liver parenchyma should be considered to exclude liver cirrhosis and for further risk stratification. If an IFLL in a low-risk patient has a typical appearance on B-mode ultrasound of a benign lesion (e.g., simple cyst, calcification, focal fatty change, typical hemangioma), no further imaging is needed. Contrast-Enhanced Ultrasound (CEUS) should be considered as the first-line contrast imaging modality to differentiate benign from malignant IFLLs, since it has a similar accuracy to contrast-enhanced (CE)-MRI. On CEUS, hypoenhancement of a lesion in the late vascular phase is characteristic for malignancy. CE-CT should be avoided for characterizing probable benign FLL and reserved for staging once a lesion is proven malignant. In high-risk patients (i.e., with chronic liver disease or an oncological history), each IFLL should initially be considered as potentially malignant, and every effort should be made to confirm or exclude malignancy. US-guided biopsy should be considered in those with unresectable malignant lesions, particularly if the diagnosis remains unclear, or when a specific tissue diagnosis is needed. Full article

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

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26 pages, 1512 KB

Open AccessEditor’s ChoiceReview

Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment

by Nikolaos Vitorakis, Antonios N. Gargalionis, Kostas A. Papavassiliou, Christos Adamopoulos and Athanasios G. Papavassiliou

Cancers 2024, 16(16), 2876; https://doi.org/10.3390/cancers16162876 - 19 Aug 2024

Cited by 10 | Viewed by 8349

Abstract

Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells’ metabolism, inhibit drug [...] Read more.

Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells’ metabolism, inhibit drug delivery, enhance immune suppression mechanisms and finally develop resistance to chemotherapy and immunotherapy. New strategies target TME genetic alterations and specific pathways in cell populations of the TME. Complex molecular interactions develop between PDAC cells and TME cell populations including cancer-associated fibroblasts, myeloid-derived suppressor cells, pancreatic stellate cells, tumor-associated macrophages, tumor-associated neutrophils, and regulatory T cells. In the present review, we aim to fully explore the molecular landscape of the pancreatic cancer TME cell populations and discuss current TME targeting strategies to provide thoughts for further research and preclinical testing. Full article

(This article belongs to the Special Issue Clinical Applications of Molecular Subtyping of Pancreatic Cancer)

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29 pages, 5058 KB

Open AccessEditor’s ChoiceReview

Non-Small-Cell Lung Cancers (NSCLCs) Harboring RET Gene Fusion, from Their Discovery to the Advent of New Selective Potent RET Inhibitors: “Shadows and Fogs”

by Gianluca Spitaleri, Pamela Trillo Aliaga, Ilaria Attili, Ester Del Signore, Carla Corvaja, Gloria Pellizzari, Jalissa Katrini, Antonio Passaro and Filippo de Marinis

Cancers 2024, 16(16), 2877; https://doi.org/10.3390/cancers16162877 - 19 Aug 2024

Cited by 4 | Viewed by 6974

Abstract

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading [...] Read more.

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the ‘old’ multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events. Full article

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

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36 pages, 955 KB

Open AccessEditor’s ChoiceReview

The Genetic Analysis and Clinical Therapy in Lung Cancer: Current Advances and Future Directions

by Angela Rina, Debora Maffeo, Francesca Minnai, Martina Esposito, Maria Palmieri, Viola Bianca Serio, Diletta Rosati, Francesca Mari, Elisa Frullanti and Francesca Colombo

Cancers 2024, 16(16), 2882; https://doi.org/10.3390/cancers16162882 - 19 Aug 2024

Cited by 15 | Viewed by 12942

Abstract

Lung cancer, including both non-small cell lung cancer and small cell lung cancer, remains the leading cause of cancer-related mortality worldwide, representing 18% of the total cancer deaths in 2020. Many patients are identified already at an advanced stage with metastatic disease and [...] Read more.

Lung cancer, including both non-small cell lung cancer and small cell lung cancer, remains the leading cause of cancer-related mortality worldwide, representing 18% of the total cancer deaths in 2020. Many patients are identified already at an advanced stage with metastatic disease and have a worsening prognosis. Recent advances in the genetic understanding of lung cancer have opened new avenues for personalized treatments and targeted therapies. This review examines the latest discoveries in the genetics of lung cancer, discusses key biomarkers, and analyzes current clinical therapies based on this genetic information. It will conclude with a discussion of future prospects and potential research directions. Full article

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

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36 pages, 1910 KB

Open AccessEditor’s ChoiceReview

Unveiling the Dynamic Interplay between Cancer Stem Cells and the Tumor Microenvironment in Melanoma: Implications for Novel Therapeutic Strategies

by Patrizia Limonta, Raffaella Chiaramonte and Lavinia Casati

Cancers 2024, 16(16), 2861; https://doi.org/10.3390/cancers16162861 - 16 Aug 2024

Cited by 5 | Viewed by 3203

Abstract

Cutaneous melanoma still represents a significant health burden worldwide, being responsible for the majority of skin cancer deaths. Key advances in therapeutic strategies have significantly improved patient outcomes; however, most patients experience drug resistance and tumor relapse. Cancer stem cells (CSCs) are a [...] Read more.

Cutaneous melanoma still represents a significant health burden worldwide, being responsible for the majority of skin cancer deaths. Key advances in therapeutic strategies have significantly improved patient outcomes; however, most patients experience drug resistance and tumor relapse. Cancer stem cells (CSCs) are a small subpopulation of cells in different tumors, including melanoma, endowed with distinctive capacities of self-renewal and differentiation into bulk tumor cells. Melanoma CSCs are characterized by the expression of specific biomarkers and intracellular pathways; moreover, they play a pivotal role in tumor onset, progression and drug resistance. In recent years, great efforts have been made to dissect the molecular mechanisms underlying the protumor activities of melanoma CSCs to provide the basis for novel CSC-targeted therapies. Herein, we highlight the intricate crosstalk between melanoma CSCs and bystander cells in the tumor microenvironment (TME), including immune cells, endothelial cells and cancer-associated fibroblasts (CAFs), and its role in melanoma progression. Specifically, we discuss the peculiar capacities of melanoma CSCs to escape the host immune surveillance, to recruit immunosuppressive cells and to educate immune cells toward an immunosuppressive and protumor phenotype. We also address currently investigated CSC-targeted strategies that could pave the way for new promising therapeutic approaches for melanoma care. Full article

(This article belongs to the Collection Deciphering the Crosstalk between Tumor Cells and Their Microenvironment: From Molecular Aspects to Therapeutic Implications)

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14 pages, 696 KB

Open AccessEditor’s ChoiceReview

Early-Stage Non-Small Cell Lung Cancer: New Challenges with Immune Checkpoint Blockers and Targeted Therapies

by Pernelle Lavaud, Martina Bortolot, Lodovica Zullo, David O’Reilly, Jarushka Naidoo, Giannis Mountzios, Olaf Mercier, Lizza E. L. Hendriks and Jordi Remon

Cancers 2024, 16(16), 2779; https://doi.org/10.3390/cancers16162779 - 6 Aug 2024

Cited by 10 | Viewed by 6824

Abstract

The recent advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint blockers (ICBs) in early-stage non-small cell lung cancer (NSCLC) has dramatically modified treatment strategies by improving the prognosis in this setting. Osimertinib and alectinib, both TKIs, have shown significant improvements in outcomes [...] Read more.

The recent advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint blockers (ICBs) in early-stage non-small cell lung cancer (NSCLC) has dramatically modified treatment strategies by improving the prognosis in this setting. Osimertinib and alectinib, both TKIs, have shown significant improvements in outcomes for patients with resected EGFR- and ALK-positive NSCLC, respectively, changing the standard of care in these subgroups. More recently, the LAURA trial showed the efficacy of osimertinib after chemoradiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. Numerous trials are still ongoing to investigate neoadjuvant/perioperative TKIs in several oncogene-driven NSCLC. In addition, several ICBs have been tested and approved as adjuvant (atezolizumab and pembrolizumab), neoadjuvant (nivolumab), and perioperative treatments (pembrolizumab) for patients with resectable early-stage NSCLC. Despite these advances, many challenges remain regarding the use of TKIs and ICBs in this setting, including the optimal duration of adjuvant TKI or induction ICB therapy, the role of minimal residual disease to identify patients at high-risk of disease relapse and to guide adjuvant treatment decisions, and the role of adjuvant chemotherapy in resected oncogene-driven NSCLC. Furthermore, potential predictive biomarkers for efficacy are needed to eventually intensify the entire perioperative strategies. This review aims to summarize and discuss the available evidence, the ongoing trials, and the challenges associated with TKI- and ICB-based approaches in early-stage NSCLC. Full article

(This article belongs to the Special Issue New Advances in Lung Cancer: Diagnosis, Pathophysiology and Emerging Treatments. A Selection of Papers from the 4th Joint Meeting on Lung Cancer of the FHU OncoAge (Nice, France) and the MD Anderson Cancer Center (Houston, TX, USA))

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24 pages, 3685 KB

Open AccessEditor’s ChoiceReview

FUCA1: An Underexplored p53 Target Gene Linking Glycosylation and Cancer Progression

by Die Hu, Naoya Kobayashi and Rieko Ohki

Cancers 2024, 16(15), 2753; https://doi.org/10.3390/cancers16152753 - 2 Aug 2024

Cited by 8 | Viewed by 3345

Abstract

Cancer is a difficult-to-cure disease with high worldwide incidence and mortality, in large part due to drug resistance and disease relapse. Glycosylation, which is a common modification of cellular biomolecules, was discovered decades ago and has been of interest in cancer research due [...] Read more.

Cancer is a difficult-to-cure disease with high worldwide incidence and mortality, in large part due to drug resistance and disease relapse. Glycosylation, which is a common modification of cellular biomolecules, was discovered decades ago and has been of interest in cancer research due to its ability to influence cellular function and to promote carcinogenesis. A variety of glycosylation types and structures regulate the function of biomolecules and are potential targets for investigating and treating cancer. The link between glycosylation and carcinogenesis has been more recently revealed by the role of p53 in energy metabolism, including the p53 target gene alpha-L-fucosidase 1 (FUCA1), which plays an essential role in fucosylation. In this review, we summarize roles of glycan structures and glycosylation-related enzymes to cancer development. The interplay between glycosylation and tumor microenvironmental factors is also discussed, together with involvement of glycosylation in well-characterized cancer-promoting mechanisms, such as the epidermal growth factor receptor (EGFR), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and p53-mediated pathways. Glycan structures also modulate cell–matrix interactions, cell–cell adhesion as well as cell migration and settlement, dysfunction of which can contribute to cancer. Thus, further investigation of the mechanistic relationships among glycosylation, related enzymes and cancer progression may provide insights into potential novel cancer treatments. Full article

(This article belongs to the Section Molecular Cancer Biology)

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28 pages, 4230 KB

Open AccessEditor’s ChoiceReview

RNA-Independent Regulatory Functions of lncRNA in Complex Disease

by Michaela Kafida, Maria Karela and Antonis Giakountis

Cancers 2024, 16(15), 2728; https://doi.org/10.3390/cancers16152728 - 31 Jul 2024

Cited by 5 | Viewed by 3307

Abstract

During the metagenomics era, high-throughput sequencing efforts both in mice and humans indicate that non-coding RNAs (ncRNAs) constitute a significant fraction of the transcribed genome. During the past decades, the regulatory role of these non-coding transcripts along with their interactions with other molecules [...] Read more.

During the metagenomics era, high-throughput sequencing efforts both in mice and humans indicate that non-coding RNAs (ncRNAs) constitute a significant fraction of the transcribed genome. During the past decades, the regulatory role of these non-coding transcripts along with their interactions with other molecules have been extensively characterized. However, the study of long non-coding RNAs (lncRNAs), an ncRNA regulatory class with transcript lengths that exceed 200 nucleotides, revealed that certain non-coding transcripts are transcriptional “by-products”, while their loci exert their downstream regulatory functions through RNA-independent mechanisms. Such mechanisms include, but are not limited to, chromatin interactions and complex promoter-enhancer competition schemes that involve the underlying ncRNA locus with or without its nascent transcription, mediating significant or even exclusive roles in the regulation of downstream target genes in mammals. Interestingly, such RNA-independent mechanisms often drive pathological manifestations, including oncogenesis. In this review, we summarize selective examples of lncRNAs that regulate target genes independently of their produced transcripts. Full article

(This article belongs to the Special Issue State-of-the-Art Strategies for Non-Coding RNA Function Detection and Regulation in Cancer)

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20 pages, 642 KB

Open AccessEditor’s ChoiceReview

Artificial Intelligence in Detection, Management, and Prognosis of Bone Metastasis: A Systematic Review

by Giuseppe Francesco Papalia, Paolo Brigato, Luisana Sisca, Girolamo Maltese, Eliodoro Faiella, Domiziana Santucci, Francesco Pantano, Bruno Vincenzi, Giuseppe Tonini, Rocco Papalia and Vincenzo Denaro

Cancers 2024, 16(15), 2700; https://doi.org/10.3390/cancers16152700 - 29 Jul 2024

Cited by 15 | Viewed by 5814

Abstract

Background: Metastasis commonly occur in the bone tissue. Artificial intelligence (AI) has become increasingly prevalent in the medical sector as support in decision-making, diagnosis, and treatment processes. The objective of this systematic review was to assess the reliability of AI systems in clinical, [...] Read more.

Background: Metastasis commonly occur in the bone tissue. Artificial intelligence (AI) has become increasingly prevalent in the medical sector as support in decision-making, diagnosis, and treatment processes. The objective of this systematic review was to assess the reliability of AI systems in clinical, radiological, and pathological aspects of bone metastases. Methods: We included studies that evaluated the use of AI applications in patients affected by bone metastases. Two reviewers performed a digital search on 31 December 2023 on PubMed, Scopus, and Cochrane library and extracted authors, AI method, interest area, main modalities used, and main objectives from the included studies. Results: We included 59 studies that analyzed the contribution of computational intelligence in diagnosing or forecasting outcomes in patients with bone metastasis. Six studies were specific for spine metastasis. The study involved nuclear medicine (44.1%), clinical research (28.8%), radiology (20.4%), or molecular biology (6.8%). When a primary tumor was reported, prostate cancer was the most common, followed by lung, breast, and kidney. Conclusions: Appropriately trained AI models may be very useful in merging information to achieve an overall improved diagnostic accuracy and treatment for metastasis in the bone. Nevertheless, there are still concerns with the use of AI systems in medical settings. Ethical considerations and legal issues must be addressed to facilitate the safe and regulated adoption of AI technologies. The limitations of the study comprise a stronger emphasis on early detection rather than tumor management and prognosis as well as a high heterogeneity for type of tumor, AI technology and radiological techniques, pathology, or laboratory samples involved. Full article

(This article belongs to the Special Issue Artificial Intelligence and MRI Characterization of Tumors: 2nd Edition)

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35 pages, 2926 KB

Open AccessEditor’s ChoiceSystematic Review

Single-Domain Antibodies as Antibody–Drug Conjugates: From Promise to Practice—A Systematic Review

by Víctor Manuel Medina Pérez, Marta Baselga and Alberto J. Schuhmacher

Cancers 2024, 16(15), 2681; https://doi.org/10.3390/cancers16152681 - 27 Jul 2024

Cited by 16 | Viewed by 9332

Abstract

Background: Antibody–drug conjugates (ADCs) represent potent cancer therapies that deliver highly toxic drugs to tumor cells precisely, thus allowing for targeted treatment and significantly reducing off-target effects. Despite their effectiveness, ADCs can face limitations due to acquired resistance and potential side effects. Objectives: [...] Read more.

Background: Antibody–drug conjugates (ADCs) represent potent cancer therapies that deliver highly toxic drugs to tumor cells precisely, thus allowing for targeted treatment and significantly reducing off-target effects. Despite their effectiveness, ADCs can face limitations due to acquired resistance and potential side effects. Objectives: This study focuses on advances in various ADC components to improve both the efficacy and safety of these agents, and includes the analysis of several novel ADC formats. This work assesses whether the unique features of VHHs—such as their small size, enhanced tissue penetration, stability, and cost-effectiveness—make them a viable alternative to conventional antibodies for ADCs and reviews their current status in ADC development. Methods: Following PRISMA guidelines, this study focused on VHHs as components of ADCs, examining advancements and prospects from 1 January 2014 to 30 June 2024. Searches were conducted in PubMed, Cochrane Library, ScienceDirect and LILACS using specific terms related to ADCs and single-domain antibodies. Retrieved articles were rigorously evaluated, excluding duplicates and non-qualifying studies. The selected peer-reviewed articles were analyzed for quality and synthesized to highlight advancements, methods, payloads, and future directions in ADC research. Results: VHHs offer significant advantages for drug conjugation over conventional antibodies due to their smaller size and structure, which enhance tissue penetration and enable access to previously inaccessible epitopes. Their superior stability, solubility, and manufacturability facilitate cost-effective production and expand the range of targetable antigens. Additionally, some VHHs can naturally cross the blood–brain barrier or be easily modified to favor their penetration, making them promising for targeting brain tumors and metastases. Although no VHH–drug conjugates (nADC or nanoADC) are currently in the clinical arena, preclinical studies have explored various conjugation methods and linkers. Conclusions: While ADCs are transforming cancer treatment, their unique mechanisms and associated toxicities challenge traditional views on bioavailability and vary with different tumor types. Severe toxicities, often linked to compound instability, off-target effects, and nonspecific blood cell interactions, highlight the need for better understanding. Conversely, the rapid distribution, tumor penetration, and clearance of VHHs could be advantageous, potentially reducing toxicity by minimizing prolonged exposure. These attributes make single-domain antibodies strong candidates for the next generation of ADCs, potentially enhancing both efficacy and safety. Full article

(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)

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14 pages, 824 KB

Open AccessEditor’s ChoiceSystematic Review

Exposure to Light at Night and Risk of Cancer: A Systematic Review, Meta-Analysis, and Data Synthesis

by Samuel Ma, Yossef Alsabawi, Hashem B El-Serag and Aaron P Thrift

Cancers 2024, 16(15), 2653; https://doi.org/10.3390/cancers16152653 - 26 Jul 2024

Cited by 7 | Viewed by 4610

Abstract

Background: Emerging interest surrounds the role of environmental factors, notably exposure to light at night (LAN), as a potential cause of cancer. The aim of this study was to conduct a systematic review and, if possible, meta-analysis of observational studies on LAN and [...] Read more.

Background: Emerging interest surrounds the role of environmental factors, notably exposure to light at night (LAN), as a potential cause of cancer. The aim of this study was to conduct a systematic review and, if possible, meta-analysis of observational studies on LAN and cancer risk of multiple types. Methods: A systematic literature search in PubMed, Web of Science, and Embase, spanning from inception to May 2023, was conducted. Studies focusing on the association between LAN exposure and cancer risk in adult populations were included. We used random effects models to calculate pooled risk estimates (RR) and 95% confidence intervals (CI). We assessed study quality using the Risk of Bias in Non-randomized Studies of Interventions. Results: Among 8492 initially identified studies, 26 met the inclusion criteria (13 were case–control and 13 were cohort studies). These studies were published from 2001 to 2023 and assessed diverse cancer types in North America, Asia, Europe, and Australia. Except for breast cancer, there was a paucity of site-specific cancer studies. In the meta-analysis of 19 breast cancer studies, higher exposure to indoor (summary RR, 1.08; 95% CI 1.01–1.15) and outdoor (summary RR, 1.10; 95% CI, 1.04–1.15) LAN were associated with increased risk. After excluding one low-quality study, the results were unchanged. Conclusions: We found a positive association between LAN exposure and breast cancer risk in women. However, data are lacking for other cancer types, and further studies are required to better understand the role of LAN on cancer. Full article

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

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13 pages, 749 KB

Open AccessEditor’s ChoiceArticle

Adverse Events in Anti-PD-1-Treated Adjuvant and First-Line Advanced Melanoma Patients

by Daan Jan Willem Rauwerdink, Olivier van Not, Melissa de Meza, Remco van Doorn, Jos van der Hage, A. J. M. van den Eertwegh, John B. Haanen, Maureen J. B. Aarts, Franchette W. P. J. van den Berkmortel, Christiaan U. Blank, Marye J. Boers-Sonderen, Jan Willem B. de Groot, Geke A. P. Hospers, Djura Piersma, Rozemarijn S. van Rijn, A. M. Stevense-den Boer, Astrid A. M. van der Veldt, Gerard Vreugdenhil, Michel W. J. M. Wouters, Karijn P. M. Suijkerbuijk and Ellen Kapiteijn Show full author list Hide full author list

Cancers 2024, 16(15), 2656; https://doi.org/10.3390/cancers16152656 - 26 Jul 2024

Cited by 4 | Viewed by 2105

Abstract

Introduction: The difference in incidence and severity of anti-PD-1 therapy-related adverse events (irAEs) between adjuvant and advanced treated melanoma patients remains unclear, as no head-to-head studies have compared these groups. Methods: This multi-center cohort study analyzed melanoma patients treated with anti-PD-1 [...] Read more.

Introduction: The difference in incidence and severity of anti-PD-1 therapy-related adverse events (irAEs) between adjuvant and advanced treated melanoma patients remains unclear, as no head-to-head studies have compared these groups. Methods: This multi-center cohort study analyzed melanoma patients treated with anti-PD-1 in adjuvant or advanced settings between 2015 and 2021. Comorbidities and ECOG performance status were assessed before treatment, and grade III-IV irAEs were monitored during treatment. Univariate and multivariate regression analyses were conducted to identify factors associated with irAE development. Results: A total of 1465 advanced melanoma patients and 908 resected melanoma patients received anti-PD-1 therapy. Adjuvant-treated patients were younger, with a median age of 63 years compared to 69 years in the advanced group (p < 0.01), and had a better ECOG performance status (p < 0.01). Comorbidities were seen more frequently in advanced melanoma patients than in those receiving adjuvant treatment, 76% versus 68% (p < 0.01). Grade III-IV irAEs occurred in 214 (15%) advanced treated patients and in 119 (13%) adjuvant-treated patients. Multivariate analysis showed an increased risk of severe irAE development with the presence of any comorbidity (adjusted OR 1.22, 95% CI 1.02–1.44) and ECOG status greater than 1 (adjusted OR 2.00, 95% CI 1.20–3.32). Adjuvant therapy was not associated with an increased risk of irAE development compared to advanced treatment (adjusted OR 0.95, 95% CI 0.74–1.21) after correcting for comorbidities and ECOG performance score. Anti-PD-1 therapy was halted due to toxicity (any grade irAE) more often in the adjuvant setting than in the advanced setting, 20% versus 15% (p < 0.01). Conclusions: Higher ECOG performance status and presence of any comorbidity were independently associated with an increased risk of Grade III-IV irAE in adjuvant and advanced treated melanoma patients. Patients treated in the adjuvant setting did not have an increased risk of developing severe irAEs compared to advanced melanoma patients. These findings are of clinical significance in consulting patients for adjuvant anti-PD-1 treatment. Full article

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

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22 pages, 3302 KB

Open AccessEditor’s ChoiceArticle

VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma

by Natalia Muñoz Perez, Juliana M. Pensabene, Phillip M. Galbo, Jr., Negar Sadeghipour, Joanne Xiu, Kirsten Moziak, Rita M. Yazejian, Rachel L. Welch, W. Robert Bell, Soma Sengupta, Sonikpreet Aulakh, Charles G. Eberhart, David M. Loeb, Emad Eskandar, Deyou Zheng, Xingxing Zang and Allison M. Martin

Cancers 2024, 16(15), 2629; https://doi.org/10.3390/cancers16152629 - 24 Jul 2024

Cited by 3 | Viewed by 3143

Abstract

Background: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration [...] Read more.

Background: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. Methods: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. Results: Flow cytometry reveals a notable presence of CD45^hi/CD11b^hi macrophage-like and CD45^int/CD11b^int microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (T_regs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45^hi/CD11b^hi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor–cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA’s binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. Conclusions: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA–VSIG axis to enhance anti-tumor responses. Full article

(This article belongs to the Special Issue Challenges and New Strategies in the Management of Pediatric Brain Tumors)

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16 pages, 1514 KB

Open AccessEditor’s ChoiceArticle

Cobalt Serum Level as a Biomarker of Cause-Specific Survival among Prostate Cancer Patients

by Sandra Pietrzak, Wojciech Marciniak, Róża Derkacz, Milena Matuszczak, Adam Kiljańczyk, Piotr Baszuk, Marta Bryśkiewicz, Andrzej Sikorski, Jacek Gronwald, Marcin Słojewski, Cezary Cybulski, Adam Gołąb, Tomasz Huzarski, Tadeusz Dębniak, Marcin R. Lener, Anna Jakubowska, Tomasz Kluz, Marianna Soroka, Rodney J. Scott and Jan Lubiński

Cancers 2024, 16(15), 2618; https://doi.org/10.3390/cancers16152618 - 23 Jul 2024

Cited by 3 | Viewed by 2086

Abstract

Prostate cancer is the most common cancer diagnosed in men and the second leading cause of death in male cancer patients. The WHO suggests that cobalt is involved in the carcinogenesis of prostate cancer. There are, however, no studies associating cobalt levels and [...] Read more.

Prostate cancer is the most common cancer diagnosed in men and the second leading cause of death in male cancer patients. The WHO suggests that cobalt is involved in the carcinogenesis of prostate cancer. There are, however, no studies associating cobalt levels and prostate cancer patient survival. In this study, 261 Polish prostate cancer (n = 261) patients were recruited into a prospective cohort between 2009 and 2015. Serum cobalt levels were measured using ICP-MS after prostate cancer diagnosis and before treatment. All study participants were assigned into quartiles (QI-QIV) based on the distribution of serum cobalt levels among censored patients. Univariable and multivariable COX regression models were used to calculate hazard ratios (HRs) for each serum cobalt level quartile. We found a significant relationship between high serum cobalt levels and poor prostate cancer patient total survival (HR = 2.60; 95% CI: 1.17–5.82; p = 0.02). In relation to prostate cancer patients who died as a result of other non-cancer causes, the association with high levels of cobalt was even stronger (HR = 3.67; 95% CI: 1.03–13.00; p = 0.04). The impact of high serum cobalt levels on overall survival of prostate cancer-specific-related deaths was not statistically significant. Full article

(This article belongs to the Special Issue Feature Papers in Section "Cancer Biomarkers" in 2023–2024)

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13 pages, 11263 KB

Open AccessEditor’s ChoiceArticle

Unlocking the Potential Role of Decellularized Biological Scaffolds as a 3D Radiobiological Model for Low- and High-LET Irradiation

by Alexandra Charalampopoulou, Amelia Barcellini, Andrea Peloso, Alessandro Vanoli, Stefania Cesari, Antonia Icaro Cornaglia, Margarita Bistika, Stefania Croce, Lorenzo Cobianchi, Giovanni Battista Ivaldi, Laura Deborah Locati, Giuseppe Magro, Paola Tabarelli de Fatis, Marco Giuseppe Pullia, Ester Orlandi and Angelica Facoetti

Cancers 2024, 16(14), 2582; https://doi.org/10.3390/cancers16142582 - 18 Jul 2024

Cited by 4 | Viewed by 2355

Abstract

Introduction: Decellularized extracellular matrix (ECM) bioscaffolds have emerged as a promising three-dimensional (3D) model, but so far there are no data concerning their use in radiobiological studies. Material and Methods: We seeded two well-known radioresistant cell lines (HMV-II and PANC-1) in decellularized porcine [...] Read more.

Introduction: Decellularized extracellular matrix (ECM) bioscaffolds have emerged as a promising three-dimensional (3D) model, but so far there are no data concerning their use in radiobiological studies. Material and Methods: We seeded two well-known radioresistant cell lines (HMV-II and PANC-1) in decellularized porcine liver-derived scaffolds and irradiated them with both high- (Carbon Ions) and low- (Photons) Linear Energy Transfer (LET) radiation in order to test whether a natural 3D-bioscaffold might be a useful tool for radiobiological research and to achieve an evaluation that could be as near as possible to what happens in vivo. Results: Biological scaffolds provided a favorable 3D environment for cell proliferation and expansion. Cells did not show signs of dedifferentiation and retained their distinct phenotype coherently with their anatomopathological and clinical behaviors. The radiobiological response to high LET was higher for HMV-II and PANC-1 compared to the low LET. In particular, Carbon Ions reduced the melanogenesis in HMV-II and induced more cytopathic effects and the substantial cell deterioration of both cell lines compared to photons. Conclusions: In addition to offering a suitable 3D model for radiobiological research and an appropriate setting for preclinical oncological analysis, we can attest that bioscaffolds seemed cost-effective due to their ease of use, low maintenance requirements, and lack of complex technology Full article

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

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17 pages, 1234 KB

Open AccessEditor’s ChoiceArticle

The Prognostic Impact of HER2-Low and Menopausal Status in Triple-Negative Breast Cancer

by Woong Ki Park, Seok Jin Nam, Seok Won Kim, Jeong Eon Lee, Jonghan Yu, Se Kyung Lee, Jai Min Ryu and Byung Joo Chae

Cancers 2024, 16(14), 2566; https://doi.org/10.3390/cancers16142566 - 17 Jul 2024

Cited by 5 | Viewed by 3650

Abstract

TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data [...] Read more.

TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data on demographics, tumor characteristics, pathologic complete response (pCR) rates and disease-free survival (DFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed. The HER2-low group, compared to the HER2-0 group, showed significantly better DFS, DMFS, OS, BCSS (p = 0.0072, p = 0.0096, p = 0.0180, and p = 0.0001, respectively) with older age and higher rates of postmenopausal status (p < 0.0001). No significant differences in pCR rates were observed. Multivariate analyses identified HER2 status as a significant prognostic factor for DFS (p = 0.048), DMFS (p = 0.018), OS (p = 0.049), and BCSS (p = 0.008). Subgroup analysis revealed that these effects varied with menopausal status, showing more pronounced benefits in postmenopausal women. Our findings suggest that HER2-low TNBC patients exhibit a distinct clinical profile and improved survival compared to HER2-0 TNBC patients, especially in postmenopausal patients. Further research on estrogen and HER2 interaction is needed. Full article

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

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21 pages, 2092 KB

Open AccessEditor’s ChoiceReview

Imaging and Metabolic Diagnostic Methods in the Stage Assessment of Rectal Cancer

by Rafał Maksim, Angelika Buczyńska, Iwona Sidorkiewicz, Adam Jacek Krętowski and Ewa Sierko

Cancers 2024, 16(14), 2553; https://doi.org/10.3390/cancers16142553 - 16 Jul 2024

Cited by 7 | Viewed by 3024

Abstract

Rectal cancer (RC) is a prevalent malignancy with significant morbidity and mortality rates. The accurate staging of RC is crucial for optimal treatment planning and patient outcomes. This review aims to summarize the current literature on imaging and metabolic diagnostic methods used in [...] Read more.

Rectal cancer (RC) is a prevalent malignancy with significant morbidity and mortality rates. The accurate staging of RC is crucial for optimal treatment planning and patient outcomes. This review aims to summarize the current literature on imaging and metabolic diagnostic methods used in the stage assessment of RC. Various imaging modalities play a pivotal role in the initial evaluation and staging of RC. These include magnetic resonance imaging (MRI), computed tomography (CT), and endorectal ultrasound (ERUS). MRI has emerged as the gold standard for local staging due to its superior soft tissue resolution and ability to assess tumor invasion depth, lymph node involvement, and the presence of extramural vascular invasion. CT imaging provides valuable information about distant metastases and helps determine the feasibility of surgical resection. ERUS aids in assessing tumor depth, perirectal lymph nodes, and sphincter involvement. Understanding the strengths and limitations of each diagnostic modality is essential for accurate staging and treatment decisions in RC. Furthermore, the integration of multiple imaging and metabolic methods, such as PET/CT or PET/MRI, can enhance diagnostic accuracy and provide valuable prognostic information. Thus, a literature review was conducted to investigate and assess the effectiveness and accuracy of diagnostic methods, both imaging and metabolic, in the stage assessment of RC. Full article

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

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