Cancers

15 pages, 3594 KiB

Open AccessEditor’s ChoiceArticle

Identification of GB3 as a Novel Biomarker of Tumor-Derived Vasculature in Neuroblastoma Using a Stiffness-Based Model

by Aranzazu Villasante, Josep Corominas, Clara Alcon, Andrea Garcia-Lizarribar, Jaume Mora, Monica Lopez-Fanarraga and Josep Samitier

Cancers 2024, 16(5), 1060; https://doi.org/10.3390/cancers16051060 - 5 Mar 2024

Cited by 1 | Viewed by 2325

Abstract

Neuroblastoma (NB) is a childhood cancer in sympathetic nervous system cells. NB exhibits cellular heterogeneity, with adrenergic and mesenchymal states displaying distinct tumorigenic potentials. NB is highly vascularized, and blood vessels can form through various mechanisms, including endothelial transdifferentiation, leading to the development [...] Read more.

Neuroblastoma (NB) is a childhood cancer in sympathetic nervous system cells. NB exhibits cellular heterogeneity, with adrenergic and mesenchymal states displaying distinct tumorigenic potentials. NB is highly vascularized, and blood vessels can form through various mechanisms, including endothelial transdifferentiation, leading to the development of tumor-derived endothelial cells (TECs) associated with chemoresistance. We lack specific biomarkers for TECs. Therefore, identifying new TEC biomarkers is vital for effective NB therapies. A stiffness-based platform simulating human arterial and venous stiffness was developed to study NB TECs in vitro. Adrenergic cells cultured on arterial-like stiffness transdifferentiated into TECs, while mesenchymal state cells did not. The TECs derived from adrenergic cells served as a model to explore new biomarkers, with a particular focus on GB3, a glycosphingolipid receptor implicated in angiogenesis, metastasis, and drug resistance. Notably, the TECs unequivocally expressed GB3, validating its novelty as a marker. To explore targeted therapeutic interventions, nanoparticles functionalized with the non-toxic subunit B of the Shiga toxin were generated, because they demonstrated a robust affinity for GB3-positive cells. Our results demonstrate the value of the stiffness-based platform as a predictive tool for assessing NB aggressiveness, the discovery of new biomarkers, and the evaluation of the effectiveness of targeted therapeutic strategies. Full article

(This article belongs to the Section Cancer Biomarkers)

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15 pages, 2164 KiB

Open AccessEditor’s ChoiceArticle

High HER2 Intratumoral Heterogeneity Is a Predictive Factor for Poor Prognosis in Early-Stage and Locally Advanced HER2-Positive Breast Cancer

by Tomonori Tanei, Shigeto Seno, Yoshiaki Sota, Takaaki Hatano, Yuri Kitahara, Kaori Abe, Nanae Masunaga, Masami Tsukabe, Tetsuhiro Yoshinami, Tomohiro Miyake, Masafumi Shimoda, Hideo Matsuda and Kenzo Shimazu

Cancers 2024, 16(5), 1062; https://doi.org/10.3390/cancers16051062 - 5 Mar 2024

Cited by 8 | Viewed by 3912

Abstract

Purpose: Breast cancer tumors frequently have intratumoral heterogeneity (ITH). Tumors with high ITH cause therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically [...] Read more.

Purpose: Breast cancer tumors frequently have intratumoral heterogeneity (ITH). Tumors with high ITH cause therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically related to a poor prognosis for HER2-targeted adjuvant therapy resistance in primary breast cancers. Methods: This study included patients with primary breast cancer (n = 251) treated with adjuvant HER2-targeted therapies. HER2 heterogeneity was manifested by the shape of HER2 fluorescence in situ hybridization amplification (FISH) distributed histograms with the HER2 gene copy number within a tumor sample. Each tumor was classified into a biphasic grade graph (high heterogeneity [HH]) group or a monophasic grade graph (low heterogeneity [LH]) group based on heterogeneity. Both groups were evaluated for disease-free survival (DFS) and overall survival (OS) for a median of ten years of annual follow-up. Results: Of 251 patients with HER2-positive breast cancer, 46 (18.3%) and 205 (81.7%) were classified into the HH and LH groups, respectively. The HH group had more distant metastases and a poorer prognosis than the LH group (DFS: p < 0.001 (HH:63% vs. LH:91% at 10 years) and for the OS: p = 0.012 (HH:78% vs. LH:95% at 10 years). Conclusions: High HER2 heterogeneity is a poor prognostic factor in patients with HER2-positive breast cancer. A novel approach to heterogeneity, which is manifested by the shape of HER2 FISH distributions, might be clinically useful in the prognosis prediction of patients after HER2 adjuvant therapy. Full article

(This article belongs to the Section Molecular Cancer Biology)

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19 pages, 1200 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment

by William H. Gmeiner

Cancers 2024, 16(5), 1029; https://doi.org/10.3390/cancers16051029 - 2 Mar 2024

Cited by 24 | Viewed by 11705

Abstract

Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual [...] Read more.

Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual tumor mutational profiles. Activating mutations in the RAS/RAF/MAPK pathway downstream of EGFR signaling have, until recently, limited the use of EGFR-targeted therapies for mCRC; however, the development of anti-RAS and anti-RAF therapies together with improved strategies to limit compensatory signaling pathways is resulting in improved survival rates in several highly lethal mCRC sub-types (e.g., BRAF-mutant). The use of fluoropyrimidine (FP)-based chemotherapy regimens to treat mCRC continues to evolve contributing to improved long-term survival. Future advances in chemotherapy for mCRC will need to position development relative to the advances made in precision oncology. Full article

(This article belongs to the Special Issue Novel Strategies in the Prevention/Treatment of Colorectal Cancer)

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28 pages, 2428 KiB

Open AccessEditor’s ChoiceReview

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

by Atharva S. Torne and Erle S. Robertson

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

Cited by 14 | Viewed by 5924

Abstract

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

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

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

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24 pages, 404 KiB

Open AccessEditor’s ChoiceReview

Risk Factors and Innovations in Risk Assessment for Melanoma, Basal Cell Carcinoma, and Squamous Cell Carcinoma

by K. Wunderlich, M. Suppa, S. Gandini, J. Lipski, J. M. White and V. Del Marmol

Cancers 2024, 16(5), 1016; https://doi.org/10.3390/cancers16051016 - 29 Feb 2024

Cited by 26 | Viewed by 6251

Abstract

Skin cancer is the most frequently diagnosed cancer globally and is preventable. Various risk factors contribute to different types of skin cancer, including melanoma, basal cell carcinoma, and squamous cell carcinoma. These risk factors encompass both extrinsic, such as UV exposure and behavioral [...] Read more.

Skin cancer is the most frequently diagnosed cancer globally and is preventable. Various risk factors contribute to different types of skin cancer, including melanoma, basal cell carcinoma, and squamous cell carcinoma. These risk factors encompass both extrinsic, such as UV exposure and behavioral components, and intrinsic factors, especially involving genetic predisposition. However, the specific risk factors vary among the skin cancer types, highlighting the importance of precise knowledge to facilitate appropriate early diagnosis and treatment for at-risk individuals. Better understanding of the individual risk factors has led to the development of risk scores, allowing the identification of individuals at particularly high risk. These advances contribute to improved prevention strategies, emphasizing the commitment to mitigating the impact of skin cancer. Full article

(This article belongs to the Special Issue Skin Cancer: Recent Advances in Diagnosis, Treatment, and Prevention)

30 pages, 2609 KiB

Open AccessEditor’s ChoiceReview

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

by Ryungsa Kim, Takanori Kin and William T. Beck

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

Cited by 23 | Viewed by 7313

Abstract

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

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

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

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14 pages, 2047 KiB

Open AccessEditor’s ChoiceArticle

Anti-PD-1 Therapy in Advanced Pediatric Malignancies in Nationwide Study: Good Outcome in Skin Melanoma and Hodgkin Lymphoma

by Agata Marjańska, Katarzyna Pawińska-Wąsikowska, Aleksandra Wieczorek, Monika Drogosiewicz, Bożenna Dembowska-Bagińska, Katarzyna Bobeff, Wojciech Młynarski, Katarzyna Adamczewska-Wawrzynowicz, Jacek Wachowiak, Małgorzata A. Krawczyk, Ninela Irga-Jaworska, Jadwiga Węcławek-Tompol, Krzysztof Kałwak, Małgorzata Sawicka-Żukowska, Maryna Krawczuk-Rybak, Anna Raciborska, Agnieszka Mizia-Malarz, Agata Sobocińska-Mirska, Paweł Łaguna, Walentyna Balwierz and Jan Styczyński Show full author list Hide full author list

Cancers 2024, 16(5), 968; https://doi.org/10.3390/cancers16050968 - 28 Feb 2024

Cited by 3 | Viewed by 2684

Abstract

Background/aim: The role of immune checkpoint inhibitors (ICIs; anti-PD1) in the treatment of childhood cancers is still evolving. The aim of this nationwide retrospective study was to assess the safety and effectiveness of ICIs used in a group of 42 patients, with a [...] Read more.

Background/aim: The role of immune checkpoint inhibitors (ICIs; anti-PD1) in the treatment of childhood cancers is still evolving. The aim of this nationwide retrospective study was to assess the safety and effectiveness of ICIs used in a group of 42 patients, with a median age of 13.6 years, with various types of advanced malignancies treated in pediatric oncology centers in Poland between 2015 and 2023. Results: The indications for treatment with anti-PD1 were as follows: Hodgkin lymphoma (11); malignant skin melanoma (9); neuroblastoma (8); and other malignancies (14). At the end of follow-up, complete remission (CR) was observed in 37.7% (15/42) of children and disease stabilization in 9.5% (4/42), with a mean survival 3.6 (95% CI = 2.6–4.6) years. The best survival (OS = 1.0) was observed in the group of patients with Hodgkin lymphoma. For malignant melanoma of the skin, neuroblastoma, and other rare malignancies, the estimated 3-year OS values were, respectively, 0.78, 0.33, and 0.25 (p = 0.002). The best progression-free survival value (0.78) was observed in the group with malignant melanoma. Significantly better effects of immunotherapy were confirmed in patients ≥ 14 years of age and good overall performance ECOG status. Severe adverse events were observed in 30.9% (13/42) patients. Full article

(This article belongs to the Special Issue Targeted Therapy of Pediatric Cancer)

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13 pages, 2431 KiB

Open AccessEditor’s ChoiceArticle

Assessing the New 2020 ESGO/ESTRO/ESP Endometrial Cancer Risk Molecular Categorization System for Predicting Survival and Recurrence

by Yung-Taek Ouh, Yoonji Oh, Jinwon Joo, Joo Hyun Woo, Hye Jin Han, Hyun Woong Cho, Jae Kwan Lee, Yikyeong Chun, Myoung-nam Lim and Jin Hwa Hong

Cancers 2024, 16(5), 965; https://doi.org/10.3390/cancers16050965 - 27 Feb 2024

Cited by 4 | Viewed by 3376

Abstract

This study aimed to evaluate the efficacy of the 2020 European Society of Gynecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) guidelines for endometrial cancer (EC). Additionally, a novel risk category incorporating clinicopathological and molecular factors was introduced. The predictive [...] Read more.

This study aimed to evaluate the efficacy of the 2020 European Society of Gynecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) guidelines for endometrial cancer (EC). Additionally, a novel risk category incorporating clinicopathological and molecular factors was introduced. The predictive value of this new category for recurrence and survival in Korean patients with EC was assessed, and comparisons were made with the 2013 and 2016 European Society of Medical Oncology (ESMO) risk classifications. Patients with EC were categorized into the POLE-mutated (POLEmut), mismatch repair-deficient (MMRd), p53-aberrant (P53abn), and nonspecific molecular profile (NSMP) subtypes. Recurrence, survival, and adjuvant therapy were assessed according to each classification. Notably, patients with the POLEmut subtype showed no relapse, while patients with the P53abn subtype exhibited higher recurrence (31.8%) and mortality rates (31.8%). Regarding adjuvant therapy, 33.3% of low-risk patients were overtreated according to the 2020 ESGO/ESTRO/ESP guidelines. Overall and progression-free survival differed significantly across molecular classifications, with the POLEmut subtype showing the best and the P53abn subtype showing the worst outcomes. The 2020 ESGO molecular classification system demonstrated practical utility and significantly influenced survival outcomes. Immunohistochemistry for TP53 and MMR, along with POLE sequencing, facilitated substantial patient reclassification, underscoring the clinical relevance of molecular risk categories in EC management. Full article

(This article belongs to the Special Issue Endometrial Cancer: Old Questions and New Perspectives (Volume II))

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17 pages, 3156 KiB

Open AccessEditor’s ChoiceSystematic Review

The Efficacy and Safety of Immune Checkpoint Inhibitors in Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis

by Obada Ababneh, Alina Ghazou, Mohmmad Alawajneh, Saleh Alhaj Mohammad, Abdullah Bani-Hani, Nasr Alrabadi and Aditya Shreenivas

Cancers 2024, 16(5), 900; https://doi.org/10.3390/cancers16050900 - 23 Feb 2024

Cited by 7 | Viewed by 3955

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of different malignancies. However, their efficacy in advanced adrenocortical carcinoma (ACC) remains uncertain. Thus, we conducted a systematic review and meta-analysis to summarize the efficacy and tolerability of ICIs in patients with advanced ACC. We [...] Read more.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of different malignancies. However, their efficacy in advanced adrenocortical carcinoma (ACC) remains uncertain. Thus, we conducted a systematic review and meta-analysis to summarize the efficacy and tolerability of ICIs in patients with advanced ACC. We searched PubMed, Scopus, and CENTRAL for studies that used ICIs in ACC. Studies with more than five patients were included in the meta-analysis of the objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and grade 3/4 adverse events. Twenty studies with 23 treatment arms and 250 patients were included. Single-agent anti-PD1 or anti-PD-L1 treatment was utilized in 13 treatment arms, whereas an anti-PD1 or anti-PD-L1 and anti-CTLA4 combination was used in 4 treatment arms. Other anti-PD1- or anti-PD-L1-based combinations were used in five treatment arms. The ORR was 14% (95% CI = 10–19%, I² = 0%), and the DCR was 43% (95% CI = 37–50%, I² = 13%). The combination anti-PD1- or anti-PD-L1-based treatment strategies did not correlate with higher responses compared with monotherapy. The median OS was 13.9 months (95% CI = 7.85–23.05), and the median PFS was 2.8 months (95% CI = 1.8–5.4). ICIs have a modest efficacy in advanced ACC but a good OS. Further studies are needed to investigate predictive biomarkers for ICI response and to compare ICI-based strategies with the current standard of care. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors for Urologic Cancers)

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11 pages, 468 KiB

Open AccessEditor’s ChoiceArticle

Fear of Recurrence in Advanced Cancer Patients: Sociodemographic, Clinical, and Psychological Correlates

by Caterina Calderon, Marina Gustems, Rocio Galán-Moral, Maria M. Muñoz-Sánchez, Lorena Ostios-García and Paula Jiménez-Fonseca

Cancers 2024, 16(5), 909; https://doi.org/10.3390/cancers16050909 - 23 Feb 2024

Cited by 9 | Viewed by 2999

Abstract

Fear of cancer recurrence significantly impacts advanced cancer patients, prompting emotional distress and increased healthcare utilization. This present study aims to analyze the fear of recurrence among patients with advanced cancer undergoing systemic treatment and its relationship with sociodemographic, clinical, and psychological factors. [...] Read more.

Fear of cancer recurrence significantly impacts advanced cancer patients, prompting emotional distress and increased healthcare utilization. This present study aims to analyze the fear of recurrence among patients with advanced cancer undergoing systemic treatment and its relationship with sociodemographic, clinical, and psychological factors. A multicenter cross-sectional study was conducted in 15 oncology departments across Spain, involving patients with locally advanced, unresectable, or metastatic cancer eligible for systemic treatment. Participants provided demographic information and completed instruments such as the Cancer Worry Scale, Brief Symptom Inventory, Mishel Uncertainty in Illness Scale, and the Duke–UNC-11 Functional Social Support Questionnaire (DUFSSQ). A total of 1195 participants participated: median age 66, 56% male, mostly metastatic cancers (80%), and common tumor sites. Two fear groups emerged: 28% low and 72% high levels of fear. High fear was associated with being female, being younger, lower levels of education, and worse survival estimates. High fear correlated with more depression, anxiety, somatic symptoms, uncertainty, and stronger social support. Multivariate analyses indicated that younger patients, those with shorter survival estimates, higher depression and anxiety scores, more uncertainty, and stronger social support had a greater likelihood of experiencing fear of recurrence, while the opposite was true for older patients. This study underscores distinct fear of recurrence profiles in advanced cancer patients, emphasizing the need for targeted interventions and support. Future research should delve deeper into understanding their repercussions for improving patient care and well-being. Full article

(This article belongs to the Special Issue Integrating Palliative Care in Oncology)

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23 pages, 25758 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 15 | Viewed by 13226

Abstract

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

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

(This article belongs to the Section Tumor Microenvironment)

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24 pages, 11226 KiB

Open AccessEditor’s ChoiceArticle

Identification of a Gene Signature That Predicts Dependence upon YAP/TAZ-TEAD

by Ryan Kanai, Emily Norton, Patrick Stern, Richard O. Hynes and John M. Lamar

Cancers 2024, 16(5), 852; https://doi.org/10.3390/cancers16050852 - 20 Feb 2024

Cited by 2 | Viewed by 3210

Abstract

Targeted therapies are effective cancer treatments when accompanied by accurate diagnostic tests that can help identify patients that will respond to those therapies. The YAP/TAZ-TEAD axis is activated and plays a causal role in several cancer types, and TEAD inhibitors are currently in [...] Read more.

Targeted therapies are effective cancer treatments when accompanied by accurate diagnostic tests that can help identify patients that will respond to those therapies. The YAP/TAZ-TEAD axis is activated and plays a causal role in several cancer types, and TEAD inhibitors are currently in early-phase clinical trials in cancer patients. However, a lack of a reliable way to identify tumors with YAP/TAZ-TEAD activation for most cancer types makes it difficult to determine which tumors will be susceptible to TEAD inhibitors. Here, we used a combination of RNA-seq and bioinformatic analysis of metastatic melanoma cells to develop a YAP/TAZ gene signature. We found that the genes in this signature are TEAD-dependent in several melanoma cell lines, and that their expression strongly correlates with YAP/TAZ activation in human melanomas. Using DepMap dependency data, we found that this YAP/TAZ signature was predictive of melanoma cell dependence upon YAP/TAZ or TEADs. Importantly, this was not limited to melanoma because this signature was also predictive when tested on a panel of over 1000 cancer cell lines representing numerous distinct cancer types. Our results suggest that YAP/TAZ gene signatures like ours may be effective tools to predict tumor cell dependence upon YAP/TAZ-TEAD, and thus potentially provide a means to identify patients likely to benefit from TEAD inhibitors. Full article

(This article belongs to the Special Issue New Insights on the Hippo-YAP/TAZ-TEAD Pathway and Its Roles in Cancer)

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21 pages, 3530 KiB

Open AccessEditor’s ChoiceArticle

Identification of Tissue miRNA Signatures for Pancreatic Ductal Adenocarcinoma

by Carlo Caputo, Michela Falco, Anna Grimaldi, Angela Lombardi, Chiara Carmen Miceli, Mariateresa Cocule, Marco Montella, Luca Pompella, Giuseppe Tirino, Severo Campione, Chiara Tammaro, Antonio Cossu, Grazia Fenu Pintori, Margherita Maioli, Donatella Coradduzza, Giovanni Savarese, Antonio Fico, Alessandro Ottaiano, Giovanni Conzo, Madhura S. Tathode, Fortunato Ciardiello, Michele Caraglia, Ferdinando De Vita and Gabriella Misso Show full author list Hide full author list

Cancers 2024, 16(4), 824; https://doi.org/10.3390/cancers16040824 - 18 Feb 2024

Cited by 3 | Viewed by 3472

Abstract

Pancreatic ductal adenocarcinoma (PDAC), a neoplasm of the gastrointestinal tract, is the most common pancreatic malignancy (90%) and the fourth highest cause of cancer mortality worldwide. Surgery intervention is currently the only strategy able to offer an advantage in terms of overall survival, [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC), a neoplasm of the gastrointestinal tract, is the most common pancreatic malignancy (90%) and the fourth highest cause of cancer mortality worldwide. Surgery intervention is currently the only strategy able to offer an advantage in terms of overall survival, but prognosis remains poor even for operated patients. Therefore, the development of robust biomarkers for early diagnosis and prognostic stratification in clinical practice is urgently needed. In this work, we investigated deregulated microRNAs (miRNAs) in tissues from PDAC patients with high (G3) or low (G2) histological grade and with (N+) or without (N−) lymph node metastases. miRNA expression profiling was performed by a comprehensive PCR array and subsequent validation by RT-qPCR. The results showed a significant increase in miR-1-3p, miR-31-5p, and miR-205-5p expression in G3 compared to G2 patients (** p < 0.01; *** p < 0.001; *** p < 0.001). miR-518d-3p upregulation and miR-215-5p downregulation were observed in N+ compared to N− patients. A statistical analysis performed using OncomiR program showed the significant involvement (p < 0.05) of two miRNAs (miR-31 and miR-205) in the histological grade of PDAC patients. Also, an expression analysis in PDAC patients showed that miR-31 and miR-205 had the highest expression at grade 3 compared with normal and other tumor grades. Overall, survival plots confirmed that the overexpression of miR-31 and miR-205 was significantly correlated with decreased survival in TCGA PDAC clinical samples. A KEGG pathway analysis showed that all three miRNAs are involved in the regulation of multiple pathways, including the Hippo signaling, adherens junction and microRNAs in cancer, along with several target genes. Based on in silico analysis and experimental validation, our study suggests the potential role of miR-1-3p, miR-31-5p, and miR-205-5p as useful clinical biomarkers and putative therapeutic targets in PDAC, which should be further investigated to determine the specific molecular processes affected by their aberrant expression. Full article

(This article belongs to the Special Issue Hallmark Properties and Behind-the-Scenes Role of Non-coding RNAs in Gastrointestinal Cancers’ Onset, Progression and Metastasis)

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23 pages, 5097 KiB

Open AccessEditor’s ChoiceArticle

Transduction Efficiency of Zika Virus E Protein Pseudotyped HIV-1gfp and Its Oncolytic Activity Tested in Primary Glioblastoma Cell Cultures

by Jan Patrick Formanski, Hai Dang Ngo, Vivien Grunwald, Celine Pöhlking, Jana Sue Jonas, Dominik Wohlers, Birco Schwalbe and Michael Schreiber

Cancers 2024, 16(4), 814; https://doi.org/10.3390/cancers16040814 - 17 Feb 2024

Viewed by 2823

Abstract

The development of new tools against glioblastoma multiforme (GBM), the most aggressive and common cancer originating in the brain, remains of utmost importance. Lentiviral vectors (LVs) are among the tools of future concepts, and pseudotyping offers the possibility of tailoring LVs to efficiently [...] Read more.

The development of new tools against glioblastoma multiforme (GBM), the most aggressive and common cancer originating in the brain, remains of utmost importance. Lentiviral vectors (LVs) are among the tools of future concepts, and pseudotyping offers the possibility of tailoring LVs to efficiently transduce and inactivate GBM tumor cells. Zika virus (ZIKV) has a specificity for GBM cells, leaving healthy brain cells unharmed, which makes it a prime candidate for the development of LVs with a ZIKV coat. Here, primary GBM cell cultures were transduced with different LVs encased with ZIKV envelope variants. LVs were generated by using the pNLgfpAM plasmid, which produces the lentiviral, HIV-1-based, core particle with GFP (green fluorescent protein) as a reporter (HIVgfp). Using five different GBM primary cell cultures and three laboratory-adapted GBM cell lines, we showed that ZIKV/HIVgfp achieved a 4–6 times higher transduction efficiency compared to the commonly used VSV/HIVgfp. Transduced GBM cell cultures were monitored over a period of 9 days to identify GFP+ cells to study the oncolytic effect due to ZIKV/HIVgfp entry. Tests of GBM tumor specificity by transduction of GBM tumor and normal brain cells showed a high specificity for GBM cells. Full article

(This article belongs to the Special Issue Feature Papers in Section "Methods and Technologies Development")

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22 pages, 5602 KiB

Open AccessEditor’s ChoiceReview

Tissue-Based Diagnostic Biomarkers of Aggressive Variant Prostate Cancer: A Narrative Review

by Olga Kouroukli, Vasiliki Bravou, Konstantinos Giannitsas and Vasiliki Tzelepi

Cancers 2024, 16(4), 805; https://doi.org/10.3390/cancers16040805 - 16 Feb 2024

Viewed by 2502

Abstract

Prostate cancer (PC) is a common malignancy among elderly men, characterized by great heterogeneity in its clinical course, ranging from an indolent to a highly aggressive disease. The aggressive variant of prostate cancer (AVPC) clinically shows an atypical pattern of disease progression, similar [...] Read more.

Prostate cancer (PC) is a common malignancy among elderly men, characterized by great heterogeneity in its clinical course, ranging from an indolent to a highly aggressive disease. The aggressive variant of prostate cancer (AVPC) clinically shows an atypical pattern of disease progression, similar to that of small cell PC (SCPC), and also shares the chemo-responsiveness of SCPC. The term AVPC does not describe a specific histologic subtype of PC but rather the group of tumors that, irrespective of morphology, show an aggressive clinical course, dictated by androgen receptor (AR) indifference. AR indifference represents an adaptive response to androgen deprivation therapy (ADT), driven by epithelial plasticity, an inherent ability of tumor cells to adapt to their environment by changing their phenotypic characteristics in a bi-directional way. The molecular profile of AVPC entails combined alterations in the tumor suppressor genes retinoblastoma protein 1 (RB1), tumor protein 53 (TP53), and phosphatase and tensin homolog (PTEN). The understanding of the biologic heterogeneity of castration-resistant PC (CRPC) and the need to identify the subset of patients that would potentially benefit from specific therapies necessitate the development of prognostic and predictive biomarkers. This review aims to discuss the possible pathophysiologic mechanisms of AVPC development and the potential use of emerging tissue-based biomarkers in clinical practice. Full article

(This article belongs to the Section Cancer Pathophysiology)

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21 pages, 10757 KiB

Open AccessEditor’s ChoiceReview

Next-Generation HER2-Targeted Antibody–Drug Conjugates in Breast Cancer

by Brittney S. Zimmerman and Francisco J. Esteva

Cancers 2024, 16(4), 800; https://doi.org/10.3390/cancers16040800 - 16 Feb 2024

Cited by 13 | Viewed by 16160

Abstract

Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20% of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease. Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted monoclonal antibodies such as [...] Read more.

Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20% of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease. Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted monoclonal antibodies such as trastuzumab and pertuzumab. The HER2-targeted antibody–drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) represent a novel class of therapeutics in breast cancer. These drugs augment monoclonal antibodies with a cytotoxic payload, which is attached by a linker, forming the basic structure of an ADC. Novel combinations and sequential approaches are under investigation to overcome resistance to T-DM1 and T-DXd. Furthermore, the landscape of HER2-targeted therapy is rapidly advancing with the development of ADCs designed to attack cancer cells with greater precision and reduced toxicity. This review provides an updated summary of the current state of HER2-targeted ADCs as well as a detailed review of investigational agents on the horizon. Clinical trials are crucial in determining the optimal dosing regimens, understanding resistance mechanisms, and identifying patient populations that would derive the most benefit from these treatments. These novel ADCs are at the forefront of a new era in targeted cancer therapy, holding the potential to improve outcomes for patients with HER2-positive and HER2-Low breast cancer. Full article

(This article belongs to the Special Issue Her2-Positive Cancers and Antibody-Based Treatment: State of the Art and Future Developments (Volume II))

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11 pages, 1915 KiB

Open AccessEditor’s ChoiceArticle

ATOH1, TFAP2B, and CEACAM6 as Immunohistochemical Markers to Distinguish Merkel Cell Carcinoma and Small Cell Lung Cancer

by Serena M. Vilasi, Jannett Nguyen, Catherine J. Wang, Lingling Miao, Kenneth Daily, Mary Eid, Joon Seon Song, Hong Jiang, Kris Ylaya, Klaus J. Busam, Maria R. Gaiser, Stephen M. Hewitt and Isaac Brownell

Cancers 2024, 16(4), 788; https://doi.org/10.3390/cancers16040788 - 15 Feb 2024

Cited by 3 | Viewed by 2401

Abstract

Merkel cell carcinoma (MCC) and small cell lung cancer (SCLC) can be histologically similar. Immunohistochemistry (IHC) for cytokeratin 20 (CK20) and thyroid transcription factor 1 (TTF-1) are commonly used to differentiate MCC from SCLC; however, these markers have limited sensitivity and specificity. To [...] Read more.

Merkel cell carcinoma (MCC) and small cell lung cancer (SCLC) can be histologically similar. Immunohistochemistry (IHC) for cytokeratin 20 (CK20) and thyroid transcription factor 1 (TTF-1) are commonly used to differentiate MCC from SCLC; however, these markers have limited sensitivity and specificity. To identify new diagnostic markers, we performed differential gene expression analysis on transcriptome data from MCC and SCLC tumors. Candidate markers included atonal BHLH transcription factor 1 (ATOH1) and transcription factor AP-2β (TFAP2B) for MCC, as well as carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) for SCLC. Immunostaining for CK20, TTF-1, and new candidate markers was performed on 43 MCC and 59 SCLC samples. All three MCC markers were sensitive and specific, with CK20 and ATOH1 staining 43/43 (100%) MCC and 0/59 (0%) SCLC cases and TFAP2B staining 40/43 (93%) MCC and 0/59 (0%) SCLC cases. TTF-1 stained 47/59 (80%) SCLC and 1/43 (2%) MCC cases. CEACAM6 stained 49/59 (83%) SCLC and 0/43 (0%) MCC cases. Combining CEACAM6 and TTF-1 increased SCLC detection sensitivity to 93% and specificity to 98%. These data suggest that ATOH1, TFAP2B, and CEACAM6 should be explored as markers to differentiate MCC and SCLC. Full article

(This article belongs to the Special Issue Skin Cancer: Recent Advances in Diagnosis, Treatment, and Prevention)

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21 pages, 3137 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) Samples from Advanced Non-Small Cell Lung Cancer for Whole Genome, Whole Exome and Comprehensive Panel Sequencing

by David Fielding, Vanessa Lakis, Andrew J. Dalley, Haarika Chittoory, Felicity Newell, Lambros T. Koufariotis, Ann-Marie Patch, Stephen Kazakoff, Farzad Bashirzadeh, Jung Hwa Son, Kimberley Ryan, Daniel Steinfort, Jonathan P. Williamson, Michael Bint, Carl Pahoff, Phan Tien Nguyen, Scott Twaddell, David Arnold, Christopher Grainge, Andrew Pattison, David Fairbairn, Shailendra Gune, Jemma Christie, Oliver Holmes, Conrad Leonard, Scott Wood, John V. Pearson, Sunil R. Lakhani, Nicola Waddell, Peter T. Simpson and Katia Nones Show full author list Hide full author list

Cancers 2024, 16(4), 785; https://doi.org/10.3390/cancers16040785 - 15 Feb 2024

Cited by 1 | Viewed by 2909

Abstract

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is often the only source of tumor tissue from patients with advanced, inoperable lung cancer. EBUS-TBNA aspirates are used for the diagnosis, staging, and genomic testing to inform therapy options. Here we extracted DNA and RNA from [...] Read more.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is often the only source of tumor tissue from patients with advanced, inoperable lung cancer. EBUS-TBNA aspirates are used for the diagnosis, staging, and genomic testing to inform therapy options. Here we extracted DNA and RNA from 220 EBUS-TBNA aspirates to evaluate their suitability for whole genome (WGS), whole exome (WES), and comprehensive panel sequencing. For a subset of 40 cases, the same nucleic acid extraction was sequenced using WGS, WES, and the TruSight Oncology 500 assay. Genomic features were compared between sequencing platforms and compared with those reported by clinical testing. A total of 204 aspirates (92.7%) had sufficient DNA (100 ng) for comprehensive panel sequencing, and 109 aspirates (49.5%) had sufficient material for WGS. Comprehensive sequencing platforms detected all seven clinically reported tier 1 actionable mutations, an additional three (7%) tier 1 mutations, six (15%) tier 2–3 mutations, and biomarkers of potential immunotherapy benefit (tumor mutation burden and microsatellite instability). As expected, WGS was more suited for the detection and discovery of emerging novel biomarkers of treatment response. WGS could be performed in half of all EBUS-TBNA aspirates, which points to the enormous potential of EBUS-TBNA as source material for large, well-curated discovery-based studies for novel and more effective predictors of treatment response. Comprehensive panel sequencing is possible in the vast majority of fresh EBUS-TBNA aspirates and enhances the detection of actionable mutations over current clinical testing. Full article

(This article belongs to the Special Issue Genetic, Epigenetic, and Epitranscriptomic Changes in Lung Cancer)

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13 pages, 15593 KiB

Open AccessEditor’s ChoiceArticle

The Immunomodulatory Effects of Fluorescein-Mediated Sonodynamic Treatment Lead to Systemic and Intratumoral Depletion of Myeloid-Derived Suppressor Cells in a Preclinical Malignant Glioma Model

by Serena Pellegatta, Nicoletta Corradino, Manuela Zingarelli, Edoardo Porto, Matteo Gionso, Arianna Berlendis, Gianni Durando, Martina Maffezzini, Silvia Musio, Domenico Aquino, Francesco DiMeco and Francesco Prada

Cancers 2024, 16(4), 792; https://doi.org/10.3390/cancers16040792 - 15 Feb 2024

Cited by 5 | Viewed by 2109

Abstract

Fluorescein-mediated sonodynamic therapy (FL-SDT) is an extremely promising approach for glioma treatment, resulting from the combination of low-intensity focused ultrasound (FUS) with a sonosensitizer. In the present study, we evaluated the efficacy and immunomodulation of SDT with fluorescein as the sonosensitizer in immunocompetent [...] Read more.

Fluorescein-mediated sonodynamic therapy (FL-SDT) is an extremely promising approach for glioma treatment, resulting from the combination of low-intensity focused ultrasound (FUS) with a sonosensitizer. In the present study, we evaluated the efficacy and immunomodulation of SDT with fluorescein as the sonosensitizer in immunocompetent GL261 glioma mice for the first time. In vitro studies demonstrated that the exposure of GL261 cells to FL-SDT induced immunogenic cell death and relevant upregulation of MHC class I, CD80 and CD86 expression. In vivo studies were then performed to treat GL261 glioma-bearing mice with FL-SDT, fluorescein alone, or FUS alone. Perturbation of the glioma-associated macrophage subset within the immune microenvironment was induced by all the treatments. Notably, a relevant depletion of myeloid-derived suppressor cells (MDSCs) and concomitant robust infiltration of CD8+ T cells were observed in the SDT-FL-treated mice, resulting in a significant radiological delay in glioma progression and a consequent improvement in survival. Tumor control and improved survival were also observed in mice treated with FL alone (median survival 41.5 days, p > 0.0001 compared to untreated mice), reflecting considerable modulation of the immune microenvironment. Interestingly, a high circulating lymphocyte-to-monocyte ratio and a very low proportion of MDSCs were predictive of better survival in FL- and FL-SDT-treated mice than in untreated and FUS-treated mice, in which elevated monocyte and MDSC frequencies correlated with worse survival. The immunostimulatory potential of FL-SDT treatment and the profound modulation of most immunosuppressive components within the microenvironment encouraged the exploration of the combination of FL-SDT with immunotherapeutic strategies. Full article

(This article belongs to the Special Issue Sonodynamic Cancer Therapy)

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17 pages, 704 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 5 | Viewed by 7846

Abstract

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

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

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

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17 pages, 4839 KiB

Open AccessEditor’s ChoiceArticle

Drug Response of Patient-Derived Lung Cancer Cells Predicts Clinical Outcomes of Targeted Therapy

by Sunshin Kim, Youngjoo Lee, Bo Ram Song, Hanna Sim, Eun Hye Kang, Mihwa Hwang, Namhee Yu, Sehwa Hong, Charny Park, Beung-Chul Ahn, Eun Jin Lim, Kum Hui Hwang, Seog-Yun Park, Jin-Ho Choi, Geon Kook Lee and Ji-Youn Han

Cancers 2024, 16(4), 778; https://doi.org/10.3390/cancers16040778 - 14 Feb 2024

Cited by 1 | Viewed by 2733

Abstract

Intratumor heterogeneity leads to different responses to targeted therapies, even within patients whose tumors harbor identical driver oncogenes. This study examined clinical outcomes according to a patient-derived cell (PDC)-based drug sensitivity test in lung cancer patients treated with targeted therapies. From 487 lung [...] Read more.

Intratumor heterogeneity leads to different responses to targeted therapies, even within patients whose tumors harbor identical driver oncogenes. This study examined clinical outcomes according to a patient-derived cell (PDC)-based drug sensitivity test in lung cancer patients treated with targeted therapies. From 487 lung cancers, 397 PDCs were established with a success rate of 82%. In 139 PDCs from advanced non-small-cell lung cancer (NSCLC) patients receiving targeted therapies, the standardized area under the curve (AUC) values for the drugs was significantly correlated with their tumor response (p = 0.002). Among 59 chemo-naive EGFR/ALK-positive NSCLC patients, the PDC non-responders showed a significantly inferior response rate (RR) and progression-free survival (PFS) for the targeted drugs than the PDC responders (RR, 25% vs. 78%, p = 0.011; median PFS, 3.4 months [95% confidence interval (CI), 2.8–4.1] vs. 11.8 months [95% CI, 6.5–17.0], p < 0.001). Of 25 EGFR-positive NSCLC patients re-challenged with EGFR inhibitors, the PDC responder showed a higher RR than the PDC non-responder (42% vs. 15%). Four patients with wild-type EGFR or uncommon EGFR-mutant NSCLC were treated with EGFR inhibitors based on their favorable PDC response to EGFR inhibitors, and two patients showed dramatic responses. Therefore, the PDC-based drug sensitivity test results were significantly associated with clinical outcomes in patients with EGFR- or ALK-positive NSCLC. It may be helpful for predicting individual heterogenous clinical outcomes beyond genomic alterations. Full article

(This article belongs to the Special Issue Tumor Models and Drug Targeting In Vitro (Volume II))

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21 pages, 855 KiB

Open AccessEditor’s ChoiceReview

The Microbiome Modulates the Immune System to Influence Cancer Therapy

by Ruchi Roy and Sunil Kumar Singh

Cancers 2024, 16(4), 779; https://doi.org/10.3390/cancers16040779 - 14 Feb 2024

Cited by 9 | Viewed by 5838

Abstract

The gut microbiota composition can affect the tumor microenvironment and its interaction with the immune system, thereby having implications for treatment predictions. This article reviews the studies available to better understand how the gut microbiome helps the immune system fight cancer. To describe [...] Read more.

The gut microbiota composition can affect the tumor microenvironment and its interaction with the immune system, thereby having implications for treatment predictions. This article reviews the studies available to better understand how the gut microbiome helps the immune system fight cancer. To describe this fact, different mechanisms and approaches utilizing probiotics to improve advancements in cancer treatment will be discussed. Moreover, not only calorie intake but also the variety and quality of diet can influence cancer patients’ immunotherapy treatment because dietary patterns can impair immunological activities either by stimulating or suppressing innate and adaptive immunity. Therefore, it is interesting and critical to understand gut microbiome composition as a biomarker to predict cancer immunotherapy outcomes and responses. Here, more emphasis will be given to the recent development in immunotherapies utilizing microbiota to improve cancer therapies, which is beneficial for cancer patients. Full article

(This article belongs to the Special Issue Cancer Therapy: Where We Are and Where We Need to Go)

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14 pages, 1677 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Landscape of BRAF Variant Classes, Clonalities, and Co-Mutations in Metastatic Colorectal Cancer Using ctDNA Profiling

by Benny Johnson, Van Morris, Xuemei Wang, Arvind Dasari, Kanwal Raghav, John Paul Shen, Michael S. Lee, Ryan Huey, Christine Parseghian, Jason Willis, Robert Wolff, Leylah M. Drusbosky, Michael J. Overman and Scott Kopetz

Cancers 2024, 16(4), 737; https://doi.org/10.3390/cancers16040737 - 9 Feb 2024

Cited by 1 | Viewed by 2746

Abstract

Although V600E accounts for the majority of the BRAF mutations in metastatic colorectal cancer (mCRC), non-V600 BRAF variants have been shown in recent years to represent a distinct molecular subtype. This study provides a comprehensive profile of BRAF variants in mCRC using a [...] Read more.

Although V600E accounts for the majority of the BRAF mutations in metastatic colorectal cancer (mCRC), non-V600 BRAF variants have been shown in recent years to represent a distinct molecular subtype. This study provides a comprehensive profile of BRAF variants in mCRC using a large genomic database of circulating tumor DNA (ctDNA) and analyzing clinical outcomes in a cohort of patients with atypical (non-V600) BRAF variants (aBRAF; class II, class III, unclassified). Overall, 1733 out of 14,742 mCRC patients in the ctDNA cohort had at least one BRAF variant. Patients with atypical BRAF variants tended to be younger and male. In contrast to BRAF^V600E, BRAF class II and III variants and their co-occurrence with KRAS/NRAS mutations were increased at baseline and especially with those patients predicted to have prior anti-EGFR exposure. Our clinical cohort included 38 patients with atypical BRAF mCRC treated at a large academic referral center. While there were no survival differences between atypical BRAF classes, concurrent RAS mutations or liver involvement was associated with poorer prognosis. Notably, patients younger than 50 years of age had extremely poor survival. In these patients, the high-frequency KRAS/NRAS co-mutation and its correlation with poorer prognosis underlines the urgent need for novel therapeutic strategies. This study represents one of the most comprehensive characterizations to date of atypical BRAF variants, utilizing both ctDNA and clinical cohorts. Full article

(This article belongs to the Collection Factors Regulating Cancer Cell Growth, Migration, Invasion, and Apoptosis)

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12 pages, 1197 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 3593

Abstract

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

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

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

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18 pages, 4831 KiB

Open AccessEditor’s ChoiceArticle

Global Burden of Pancreatic Cancer Attributable to High Body-Mass Index in 204 Countries and Territories, 1990–2019

by Irena Ilic and Milena Ilic

Cancers 2024, 16(4), 719; https://doi.org/10.3390/cancers16040719 - 8 Feb 2024

Cited by 3 | Viewed by 3152

Abstract

(1) Background: This study aimed to assess the global burden of pancreatic cancer attributable to a high BMI in 1990–2019. (2) Methods: An ecological study was carried out. Data about deaths and Disability-Adjusted Life Years (DALYs) for pancreatic cancer were extracted from the [...] Read more.

(1) Background: This study aimed to assess the global burden of pancreatic cancer attributable to a high BMI in 1990–2019. (2) Methods: An ecological study was carried out. Data about deaths and Disability-Adjusted Life Years (DALYs) for pancreatic cancer were extracted from the Global Burden of Disease (GBD) study. The age-standardized rates (ASRs, per 100,000) were presented. In order to determine trends of pancreatic cancer burden, joinpoint regression analysis was used to calculate the average annual percent change (AAPC). (3) Results: The highest ASRs of DALYs of pancreatic cancer were found in the United Arab Emirates (47.5 per 100,000), followed by countries with about 25.0 per 100,000 (such as Hungary, Czechia, and Montenegro). From 1990 to 2019, the ASRs of deaths and DALYs of pancreatic cancer attributable to a high BMI significantly increased (p < 0.001) for both sexes in all ages, and across all SDI quintiles and all GBD regions. The highest fraction of DALYs attributable to a high BMI was found in the United States of America and China (equally about 15.0%), followed by the Russian Federation, India, Germany, and Brazil (about 5.0%, equally). (4) Conclusions: Further analytical epidemiological studies are necessary to elucidate the relationship between pancreatic cancer and a high BMI. Full article

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

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12 pages, 243 KiB

Open AccessEditor’s ChoiceArticle

Extrahepatic Malignancies Are the Leading Cause of Death in Patients with Chronic Hepatitis B without Cirrhosis: A Large Population-Based Cohort Study

by Young Eun Chon, Sung Jun Park, Man Young Park, Yeonjung Ha, Joo Ho Lee, Kwan Sik Lee, Eileen L. Yoon and Dae Won Jun

Cancers 2024, 16(4), 711; https://doi.org/10.3390/cancers16040711 - 7 Feb 2024

Cited by 2 | Viewed by 1813

Abstract

(1) Background: Accurate statistics on the causes of death in patients with chronic hepatitis B (CHB) are lacking. We investigated mortality rates and causes of death over time. (2) Methods: Data on patients newly diagnosed with CHB from 2007 to 2010 (cohort 1, [...] Read more.

(1) Background: Accurate statistics on the causes of death in patients with chronic hepatitis B (CHB) are lacking. We investigated mortality rates and causes of death over time. (2) Methods: Data on patients newly diagnosed with CHB from 2007 to 2010 (cohort 1, n = 223,424) and 2012 to 2015 (cohort 2, n = 177,966) were retrieved from the Korean National Health Insurance Service. Mortality data were obtained from Statistics Korea. The causes of death were classified as liver-related (hepatic decompensation or hepatocellular carcinoma [HCC]) or extrahepatic (cardiovascular-related, cerebrovascular-related, or extrahepatic malignancy-related). (3) Results: Over a 10-year follow-up period of 223,424 patients (cohort 1) with CHB, the overall mortality was 1.54 per 100 person-years. The mortality associated with HCC was the highest (0.65 per 100 person-years), followed by mortality related to extrahepatic malignancies (0.26 per 100 person-years), and cardio/cerebrovascular diseases (0.18 per 100 person-years). In the non-cirrhotic CHB (87.4%), 70% (11,198/15,996) of patients died due to non-liver-related causes over ten years. The 10-year overall mortality was 0.86 per 100 person-years. Among these, mortality due to extrahepatic malignancies had the highest rate (0.23 per 100 person-years), followed by mortality related to HCC (0.20 per 100 person-years), and cardio/cerebrovascular diseases (0.16 per 100 person-years). The 5-year mortality associated with extrahepatic malignancies increased from 0.36 per 100 person-years (cohort 1) to 0.40 per 100 person-years (cohort 2). (4) Conclusions: Mortality related to HCC decreased, whereas mortality related to extrahepatic malignancies increased in the antiviral era. Extrahepatic malignancies were the leading cause of death among patients with CHB without cirrhosis. Full article

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

12 pages, 2196 KiB

Open AccessEditor’s ChoiceArticle

Hepatoblastoma Relapse—Findings from the German HB99 Trial and the German Liver Tumor Registry

by Rebecca Maxwell, Beate Häberle, Roland Kappler, Dietrich von Schweinitz, Mark Rassner, Julia von Frowein and Irene Schmid

Cancers 2024, 16(4), 696; https://doi.org/10.3390/cancers16040696 - 6 Feb 2024

Cited by 1 | Viewed by 2480

Abstract

Survival rates for HB patients have improved; however, outcomes for patients who relapse remain poor. A retrospective review of information gathered for the HB99 study and the German Liver Tumor Registry identified 25 relapse patients (6.9%, 25/362). The median time from initial diagnosis [...] Read more.

Survival rates for HB patients have improved; however, outcomes for patients who relapse remain poor. A retrospective review of information gathered for the HB99 study and the German Liver Tumor Registry identified 25 relapse patients (6.9%, 25/362). The median time from initial diagnosis to first relapse was 13 months (range: 5–66 months). Two patients relapsed >36 months after initial diagnosis. A total of 68% (17/25) of relapses were metastatic, 24% local, and 8% combined. 67% of local relapses were alive at the last follow-up, in contrast to 53% of metastatic and 0% of combined relapses. At the last follow-up, 73% (8/11) of patients with lung relapses were still alive (0/4 with peritoneal, 1/2 with CNS involvement). A total of 20% of the patients had AFP-negative relapses, 64% of the relapse patients achieved a second complete remission, 69% were still in complete second remission at the last follow-up (median FU of 66 months), and 83% (5/6) of irinotecan-naïve patients who received relapse treatment including irinotecan were in second complete remission at the last follow-up. The 3-year overall survival/event-free survival from relapse was 63%/48% respectively. There is a good chance that HB patients will achieve a second remission despite a first relapse. However, patients who suffer further relapses tend to have a poorer prognosis. Full article

(This article belongs to the Special Issue Hepatoblastoma and Pediatric Liver Tumors (Volume II))

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12 pages, 248 KiB

Open AccessEditor’s ChoiceReview

Oligometastasis of Gastric Cancer: A Review

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

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

Cited by 11 | Viewed by 4594

Abstract

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

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

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

23 pages, 1652 KiB

Open AccessEditor’s ChoiceReview

Management of Hepatocellular Carcinoma in 2024: The Multidisciplinary Paradigm in an Evolving Treatment Landscape

by Emily Kinsey and Hannah M. Lee

Cancers 2024, 16(3), 666; https://doi.org/10.3390/cancers16030666 - 4 Feb 2024

Cited by 44 | Viewed by 11787

Abstract

Liver cancer is the third most common cause of cancer-related deaths worldwide, and hepatocellular carcinoma (HCC) makes up the majority of liver cancer cases. Despite the stabilization of incidence rates in recent years due to effective viral hepatitis treatments, as well as improved [...] Read more.

Liver cancer is the third most common cause of cancer-related deaths worldwide, and hepatocellular carcinoma (HCC) makes up the majority of liver cancer cases. Despite the stabilization of incidence rates in recent years due to effective viral hepatitis treatments, as well as improved outcomes from early detection and treatment advances, the burden of HCC is anticipated to rise again due to increasing rates of metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease. The treatment landscape is evolving and requires a multidisciplinary approach, often involving multi-modal treatments that include surgical resection, transplantation, local regional therapies, and systemic treatments. The optimal approach to the care of the HCC patient requires a multidisciplinary team involving hepatology, medical oncology, diagnostic and interventional radiology, radiation oncology, and surgery. In order to determine which approach is best, an individualized treatment plan should consider the patient’s liver function, functional status, comorbidities, cancer stage, and preferences. In this review, we provide an overview of the current treatment options and key trials that have revolutionized the management of HCC. We also discuss evolving treatment paradigms for the future. Full article

(This article belongs to the Special Issue New Insights on Therapy in Hepatocellular Carcinoma)

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29 pages, 3322 KiB

Open AccessEditor’s ChoiceReview

Chimeric Antigen Receptor T Cell and Chimeric Antigen Receptor NK Cell Therapy in Pediatric and Adult High-Grade Glioma—Recent Advances

by Adrian Kowalczyk, Julia Zarychta, Anna Marszołek, Joanna Zawitkowska and Monika Lejman

Cancers 2024, 16(3), 623; https://doi.org/10.3390/cancers16030623 - 31 Jan 2024

Cited by 7 | Viewed by 3856

Abstract

High-grade gliomas (HGG) account for approximately 10% of central nervous system (CNS) tumors in children and 25% of CNS tumors in adults. Despite their rare occurrence, HGG are a significant clinical problem. The standard therapeutic procedure in both pediatric and adult patients with [...] Read more.

High-grade gliomas (HGG) account for approximately 10% of central nervous system (CNS) tumors in children and 25% of CNS tumors in adults. Despite their rare occurrence, HGG are a significant clinical problem. The standard therapeutic procedure in both pediatric and adult patients with HGG is the surgical resection of the tumor combined with chemotherapy and radiotherapy. Despite intensive treatment, the 5-year overall survival in pediatric patients is below 20–30%. This rate is even lower for the most common HGG in adults (glioblastoma), at less than 5%. It is, therefore, essential to search for new therapeutic methods that can extend the survival rate. One of the therapeutic options is the use of immune cells (T lymphocytes/natural killer (NK) cells) expressing a chimeric antigen receptor (CAR). The objective of the following review is to present the latest results of preclinical and clinical studies evaluating the efficacy of CAR-T and CAR-NK cells in HGG therapy. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))

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17 pages, 727 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Immunomodulation in Gastric Cancer

by Venu Akkanapally, Xue-Feng Bai and Sujit Basu

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

Cited by 12 | Viewed by 5885

Abstract

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

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

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

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15 pages, 1017 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 5 | Viewed by 2861

Abstract

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

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

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

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20 pages, 8148 KiB

Open AccessEditor’s ChoiceReview

Therapies for the Treatment of Advanced/Metastatic Estrogen Receptor-Positive Breast Cancer: Current Situation and Future Directions

by Rohan Kalyan Rej, Joyeeta Roy and Srinivasa Rao Allu

Cancers 2024, 16(3), 552; https://doi.org/10.3390/cancers16030552 - 27 Jan 2024

Cited by 20 | Viewed by 7083

Abstract

The hormone receptor-positive (HR+) type is the most frequently identified subtype of breast cancer. HR+ breast cancer has a more positive prognosis when compared to other subtypes, such as human epidermal growth factor protein 2-positive disorder and triple-negative disease. The advancement in treatment [...] Read more.

The hormone receptor-positive (HR+) type is the most frequently identified subtype of breast cancer. HR+ breast cancer has a more positive prognosis when compared to other subtypes, such as human epidermal growth factor protein 2-positive disorder and triple-negative disease. The advancement in treatment outcomes for advanced HR+ breast cancer has been considerably elevated due to the discovery of cyclin-dependent kinase 4/6 inhibitors and their combination effects with endocrine therapy. However, despite the considerable effectiveness of tamoxifen, a selective estrogen receptor modulator (SERMs), and aromatase inhibitors (AI), the issue of treatment resistance still presents a significant challenge for HR+ breast cancer. As a result, there is a focus on exploring new therapeutic strategies such as targeted protein degradation and covalent inhibition for targeting ERα. This article discusses the latest progress in treatments like oral selective ER degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), proteolysis targeting chimera (PROTAC) degraders, and combinations of CDK4/6 inhibitors with endocrine therapy. The focus is specifically on those compounds that have transitioned into phases of clinical development. Full article

(This article belongs to the Special Issue Breast Cancer and Hormone-Related Therapy)

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26 pages, 1978 KiB

Open AccessEditor’s ChoiceReview

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

by David John McMahon, Ronan McLaughlin and Jarushka Naidoo

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

Cited by 5 | Viewed by 5099

Abstract

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

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

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

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34 pages, 574 KiB

Open AccessEditor’s ChoiceReview

Molecular Mechanisms of Prostate Cancer Development in the Precision Medicine Era: A Comprehensive Review

by Shigekatsu Maekawa, Ryo Takata and Wataru Obara

Cancers 2024, 16(3), 523; https://doi.org/10.3390/cancers16030523 - 25 Jan 2024

Cited by 13 | Viewed by 7435

Abstract

The progression of prostate cancer (PCa) relies on the activation of the androgen receptor (AR) by androgens. Despite efforts to block this pathway through androgen deprivation therapy, resistance can occur through several mechanisms, including the abnormal activation of AR, resulting in castration-resistant PCa [...] Read more.

The progression of prostate cancer (PCa) relies on the activation of the androgen receptor (AR) by androgens. Despite efforts to block this pathway through androgen deprivation therapy, resistance can occur through several mechanisms, including the abnormal activation of AR, resulting in castration-resistant PCa following the introduction of treatment. Mutations, amplifications, and splicing variants in AR-related genes have garnered attention in this regard. Furthermore, recent large-scale next-generation sequencing analysis has revealed the critical roles of AR and AR-related genes, as well as the DNA repair, PI3K, and cell cycle pathways, in the onset and progression of PCa. Moreover, research on epigenomics and microRNA has increasingly become popular; however, it has not translated into the development of effective therapeutic strategies. Additionally, treatments targeting homologous recombination repair mutations and the PI3K/Akt pathway have been developed and are increasingly accessible, and multiple clinical trials have investigated the efficacy of immune checkpoint inhibitors. In this comprehensive review, we outline the status of PCa research in genomics and briefly explore potential future developments in the field of epigenetic modifications and microRNAs. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Prostate Cancer Development)

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30 pages, 1847 KiB

Open AccessEditor’s ChoiceReview

Exploring Novel Frontiers: Leveraging STAT3 Signaling for Advanced Cancer Therapeutics

by Taiwo Adesoye, Debasish Tripathy, Kelly K. Hunt and Khandan Keyomarsi

Cancers 2024, 16(3), 492; https://doi.org/10.3390/cancers16030492 - 24 Jan 2024

Cited by 8 | Viewed by 4241

Abstract

Signal Transducer and Activator of Transcription 3 (STAT3) plays a significant role in diverse physiologic processes, including cell proliferation, differentiation, angiogenesis, and survival. STAT3 activation via phosphorylation of tyrosine and serine residues is a complex and tightly regulated process initiated by upstream signaling [...] Read more.

Signal Transducer and Activator of Transcription 3 (STAT3) plays a significant role in diverse physiologic processes, including cell proliferation, differentiation, angiogenesis, and survival. STAT3 activation via phosphorylation of tyrosine and serine residues is a complex and tightly regulated process initiated by upstream signaling pathways with ligand binding to receptor and non-receptor-linked kinases. Through downstream deregulation of target genes, aberrations in STAT3 activation are implicated in tumorigenesis, metastasis, and recurrence in multiple cancers. While there have been extensive efforts to develop direct and indirect STAT3 inhibitors using novel drugs as a therapeutic strategy, direct clinical application remains in evolution. In this review, we outline the mechanisms of STAT3 activation, the resulting downstream effects in physiologic and malignant settings, and therapeutic strategies for targeting STAT3. We also summarize the pre-clinical and clinical evidence of novel drug therapies targeting STAT3 and discuss the challenges of establishing their therapeutic efficacy in the current clinical landscape. Full article

(This article belongs to the Special Issue Targeting STATs for Anti-cancer Therapy)

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19 pages, 1233 KiB

Open AccessEditor’s ChoiceReview

The Aryl Hydrocarbon Receptor: Impact on the Tumor Immune Microenvironment and Modulation as a Potential Therapy

by Brian D. Griffith and Timothy L. Frankel

Cancers 2024, 16(3), 472; https://doi.org/10.3390/cancers16030472 - 23 Jan 2024

Cited by 9 | Viewed by 4532

Abstract

The aryl hydrocarbon receptor (AhR) is a ubiquitous nuclear receptor with a broad range of functions, both in tumor cells and immune cells within the tumor microenvironment (TME). Activation of AhR has been shown to have a carcinogenic effect in a variety of [...] Read more.

The aryl hydrocarbon receptor (AhR) is a ubiquitous nuclear receptor with a broad range of functions, both in tumor cells and immune cells within the tumor microenvironment (TME). Activation of AhR has been shown to have a carcinogenic effect in a variety of organs, through induction of cellular proliferation and migration, promotion of epithelial-to-mesenchymal transition, and inhibition of apoptosis, among other functions. However, the impact on immune cell function is more complicated, with both pro- and anti-tumorigenic roles identified. Although targeting AhR in cancer has shown significant promise in pre-clinical studies, there has been limited efficacy in phase III clinical trials to date. With the contrasting roles of AhR activation on immune cell polarization, understanding the impact of AhR activation on the tumor immune microenvironment is necessary to guide therapies targeting the AhR. This review article summarizes the state of knowledge of AhR activation on the TME, limitations of current findings, and the potential for modulation of the AhR as a cancer therapy. Full article

(This article belongs to the Special Issue Microenvironment and Cancer Progression 2.0)

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20 pages, 2370 KiB

Open AccessEditor’s ChoiceReview

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

by Virginia Metrangolo and Lars H. Engelholm

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

Cited by 32 | Viewed by 18191

Abstract

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

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

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

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13 pages, 1188 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 1988

Abstract

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

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

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

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21 pages, 4413 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 8 | Viewed by 6357

Abstract

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

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

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

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20 pages, 1305 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 4 | Viewed by 4564

Abstract

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

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

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

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17 pages, 3360 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 1 | Viewed by 2800

Abstract

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

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

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

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30 pages, 1765 KiB

Open AccessEditor’s ChoiceReview

Immune Escape Strategies in Head and Neck Cancer: Evade, Resist, Inhibit, Recruit

by Kourtney L. Kostecki, Mari Iida, Bridget E. Crossman, Ravi Salgia, Paul M. Harari, Justine Y. Bruce and Deric L. Wheeler

Cancers 2024, 16(2), 312; https://doi.org/10.3390/cancers16020312 - 11 Jan 2024

Cited by 9 | Viewed by 5146

Abstract

Head and neck cancers (HNCs) arise from the mucosal lining of the aerodigestive tract and are often associated with alcohol use, tobacco use, and/or human papillomavirus (HPV) infection. Over 600,000 new cases of HNC are diagnosed each year, making it the sixth most [...] Read more.

Head and neck cancers (HNCs) arise from the mucosal lining of the aerodigestive tract and are often associated with alcohol use, tobacco use, and/or human papillomavirus (HPV) infection. Over 600,000 new cases of HNC are diagnosed each year, making it the sixth most common cancer worldwide. Historically, treatments have included surgery, radiation, and chemotherapy, and while these treatments are still the backbone of current therapy, several immunotherapies have recently been approved by the Food and Drug Administration (FDA) for use in HNC. The role of the immune system in tumorigenesis and cancer progression has been explored since the early 20th century, eventually coalescing into the current three-phase model of cancer immunoediting. During each of the three phases—elimination, equilibrium, and escape—cancer cells develop and utilize multiple strategies to either reach or remain in the final phase, escape, at which point the tumor is able to grow and metastasize with little to no detrimental interference from the immune system. In this review, we summarize the many strategies used by HNC to escape the immune system, which include ways to evade immune detection, resist immune cell attacks, inhibit immune cell functions, and recruit pro-tumor immune cells. Full article

(This article belongs to the Special Issue Head and Neck Cancers—Novel Approaches and Future Outlook)

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21 pages, 2492 KiB

Open AccessEditor’s ChoiceReview

MASLD and the Development of HCC: Pathogenesis and Therapeutic Challenges

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

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

Cited by 40 | Viewed by 8439

Abstract

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

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

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

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13 pages, 4698 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 2 | Viewed by 3486

Abstract

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

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

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

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13 pages, 4255 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 8 | Viewed by 3559

Abstract

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

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

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

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12 pages, 895 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 2247

Abstract

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

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

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

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12 pages, 2770 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 12 | Viewed by 5027

Abstract

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

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

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

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13 pages, 1189 KiB

Open AccessEditor’s ChoiceArticle

Validation of Inflammatory Prognostic Biomarkers in Pleural Mesothelioma

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

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

Cited by 2 | Viewed by 2495

Abstract

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

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

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

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33 pages, 1918 KiB

Open AccessEditor’s ChoiceReview

Promises and Pitfalls of Next-Generation Treg Adoptive Immunotherapy

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

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

Cited by 5 | Viewed by 4148

Abstract

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

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

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

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