Cancers

Editorial

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7 pages, 214 KiB

Open AccessEditorial

Learning from Other Tumors: Pathways for Progress and Overcoming Challenges in Cholangiocarcinoma

by Giulia Tesini, Chiara Braconi, Lorenza Rimassa and Rocio I. R. Macias

Cancers 2025, 17(1), 156; https://doi.org/10.3390/cancers17010156 - 6 Jan 2025

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Abstract

Cholangiocarcinoma (CCA) is a group of complex and heterogeneous tumors originating from the epithelial cells of bile ducts that can occur in intrahepatic, perihilar, or distal localizations [...] Full article

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3 pages, 155 KiB

Open AccessEditorial

Beyond Primary HER2 Expression: Trastuzumab Deruxtecan’s Efficacy in Brain Metastasis

by Glori Das, Stephen T. C. Wong and Hong Zhao

Cancers 2024, 16(20), 3525; https://doi.org/10.3390/cancers16203525 - 18 Oct 2024

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Abstract

This commentary focuses on the DESTINY-Breast12 study, published in Nature Medicine on 13 September 2024, which evaluates the efficacy of Trastuzumab deruxtecan (T-DXd) in treating HER2-positive advanced breast cancer, including those with brain metastases. We emphasize the broadened clinical potential of T-DXd in [...] Read more.

This commentary focuses on the DESTINY-Breast12 study, published in Nature Medicine on 13 September 2024, which evaluates the efficacy of Trastuzumab deruxtecan (T-DXd) in treating HER2-positive advanced breast cancer, including those with brain metastases. We emphasize the broadened clinical potential of T-DXd in treating brain metastases from tumors originally classified as HER2-null or HER2-low, extending beyond its current use for breast cancer. This expanded application of T-DXd could provide new hope to patients dealing with challenging brain metastases, addressing an urgent need for effective treatment options. Full article

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Research

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16 pages, 940 KiB

Open AccessArticle

Elastography Enhances the Diagnostic Performance of Conventional Ultrasonography in Differentiating Benign from Malignant Superficial Lymphadenopathies

by Novella Pugliese, Marco Picardi, Claudia Giordano, Annamaria Vincenzi, Rosaria Cappiello, Massimo Mascolo and Fabrizio Pane

Cancers 2025, 17(9), 1480; https://doi.org/10.3390/cancers17091480 (registering DOI) - 28 Apr 2025

Abstract

Background/Objectives: Lymph node (LN) evaluation is critical in diagnosing, staging, and managing various diseases, particularly lymphoma and metastatic cancer. Although conventional ultrasound (US) is widely used for this purpose, its limitations in reliably differentiating between benign and malignant LNs persist. Ultrasound elastography (US-E), [...] Read more.

Background/Objectives: Lymph node (LN) evaluation is critical in diagnosing, staging, and managing various diseases, particularly lymphoma and metastatic cancer. Although conventional ultrasound (US) is widely used for this purpose, its limitations in reliably differentiating between benign and malignant LNs persist. Ultrasound elastography (US-E), which evaluates tissue stiffness, has emerged as a promising adjunct to improve diagnostic accuracy. This study aims to evaluate the diagnostic performance of conventional US, power Doppler US, and strain elastography (SE) in distinguishing malignant from benign superficial lymph nodes. Methods: In this prospective study, 214 consecutive patients referred for US of enlarged LNs were enrolled. Conventional B-mode US, power Doppler, and SE were performed, and the strain ratio (SR) was calculated as a measure of LN stiffness. Histopathological examination was used as the reference standard. Diagnostic accuracy was assessed using receiver operating characteristic (ROC) analysis, and multivariable logistic regression models were applied to determine the independent predictive role of SR. Results: Among the 214 LNs (one for each patient), 74 (34.6%) were benign and 140 (65.4%) were malignant. The SR showed a significant association with malignancy (p < 0.001). For hematological malignancies, SR demonstrated high sensitivity (79–85%) and specificity (81–96%), with an overall area under the curve (AUC) of 0.91. Multivariable analysis confirmed that SR was an independent predictor of malignancy (continuous and dichotomous), with a 14% gain in predictive accuracy when treated as a continuous variable (p < 0.0001). Conclusions: US-E, particularly SR, is a valuable tool in the differentiation of benign and malignant superficial LNs. SR provides significant diagnostic value, especially in hematological neoplasms like Hodgkin lymphoma, and can serve as an independent predictor of malignancy. This technique, when used in combination with conventional US features, offers enhanced diagnostic performance for LN evaluation. Full article

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10 pages, 1800 KiB

Open AccessArticle

Impact of Bowel Cleansing on Polyp and Adenoma Detection Rate: Post-Hoc Analysis of a Randomized Clinical Trial

by Maida Marcello, Vassallo Roberto, Alessandro Vitello, Zullo Angelo, Venezia Ludovica and Facciorusso Antonio

Cancers 2025, 17(9), 1421; https://doi.org/10.3390/cancers17091421 - 24 Apr 2025

Abstract

Objectives: To assess the impact of bowel cleansing quality on polyp detection rate (PDR) and adenoma detection rate (ADR) and explore predictors of lesion detection rate in patients undergoing colonoscopy. Methods: This is a post-hoc analysis of a multicenter randomized controlled trial (RCT) [...] Read more.

Objectives: To assess the impact of bowel cleansing quality on polyp detection rate (PDR) and adenoma detection rate (ADR) and explore predictors of lesion detection rate in patients undergoing colonoscopy. Methods: This is a post-hoc analysis of a multicenter randomized controlled trial (RCT) comparing 1L polyethylene glycol plus ascorbate (1L PEG+ASC) vs. 4L PEG as bowel preparation for colonoscopy. Results: PDR was significantly higher (35.6% vs. 18.5%, p = 0.013), and ADR was higher even if not significantly (25.6% vs. 16.7%, p = 0.153) in patients with Boston Bowel Preparation Scale (BBPS) ≥6 over BBPS <6. Comparing patients with BBPS = 9 over BBPS = 7–8, no significant differences were found in PDR (34.5% vs. 38.4%, p = 0.483) nor ADR (24.1% vs. 27.2%, p = 0.553). At multivariable regression analysis, older age (OR = 1.042, 95%CI = 1.021–1.063; p < 0.001), shorter intubation time (OR = 0.891, 95%CI = 0.816–0.972; p = 0.010), higher withdrawal time (OR = 1.171, 95%CI = 1.094–1.253; p < 0.001) and full consumption of the first dose (OR = 8.368, 95%CI = 1.025–68.331; p = 0.047) were independently associated with ADR. Conclusions: This post-hoc analysis of a RCT showed that excellent cleansing (BBPS = 9) over high-quality cleansing (BBPS = 7–8) does not significantly improve PDR or ADR. Neither cleansing success nor preparation types were independently associated with ADR. Compliance with bowel preparation, timing of colonoscopy and withdrawal time are key elements for adequate ADR with potential implications for reducing interval colorectal cancer. Full article

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18 pages, 12086 KiB

Open AccessArticle

Temporal Validation of an FDG-PET-Radiomic Model for Distant-Relapse-Free-Survival After Radio-Chemotherapy for Pancreatic Adenocarcinoma

by Monica Maria Vincenzi, Martina Mori, Paolo Passoni, Roberta Tummineri, Najla Slim, Martina Midulla, Gabriele Palazzo, Alfonso Belardo, Emiliano Spezi, Maria Picchio, Michele Reni, Arturo Chiti, Antonella del Vecchio, Claudio Fiorino and Nadia Gisella Di Muzio

Cancers 2025, 17(6), 1036; https://doi.org/10.3390/cancers17061036 - 20 Mar 2025

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Abstract

Background/Objectives: Pancreatic cancer is a very aggressive disease with a poor prognosis, even when diagnosed at an early stage. This study aimed to validate and refine a radiomic-based [¹⁸F]FDG-PET model to predict distant relapse-free survival (DRFS) in patients with unresectable [...] Read more.

Background/Objectives: Pancreatic cancer is a very aggressive disease with a poor prognosis, even when diagnosed at an early stage. This study aimed to validate and refine a radiomic-based [¹⁸F]FDG-PET model to predict distant relapse-free survival (DRFS) in patients with unresectable locally advanced pancreatic cancer (LAPC). Methods: A Cox regression model incorporating two radiomic features (RFs) and cancer stage (III vs. IV) was temporally validated using a larger cohort (215 patients treated between 2005–2022). Patients received concurrent chemoradiotherapy with capecitabine and hypo-fractionated Intensity Modulated Radiotherapy (IMRT). Data were split into training (145 patients, 2005–2017) and validation (70 patients, 2017–2022) groups. Seventy-eight RFs were extracted, harmonized, and analyzed using machine learning to develop refined models. Results: The model incorporating Statistical-Percentile10, Morphological-ComShift, and stage demonstrated moderate predictive accuracy (training: C-index = 0.632; validation: C-index = 0.590). When simplified to include only Statistical-Percentile10, performance improved slightly in the validation group (C-index = 0.601). Adding GLSZM3D-grayLevelVariance to Statistical-Percentile10, while excluding Morphological-ComShift, further enhanced accuracy (training: C-index = 0.654; validation: C-index = 0.623). Despite these refinements, all versions showed similar moderate ability to stratify patients into risk classes. Conclusions: [¹⁸F]FDG-PET radiomic features are robust predictors of DRFS after chemoradiotherapy in LAPC. Despite moderate performance, these models hold promise for patient risk stratification. Further validation with external cohorts is ongoing. Full article

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24 pages, 7947 KiB

Open AccessArticle

Apatinib Degrades PD-L1 and Reconstitutes Colon Cancer Microenvironment via the Regulation of Myoferlin

by Chunyi Gao, Lu Chen, Lingying Zhao, Yongcheng Su, Miaomiao Ma, Wenqing Zhang, Xiaoting Hong, Li Xiao, Beibei Xu and Tianhui Hu

Cancers 2025, 17(3), 524; https://doi.org/10.3390/cancers17030524 - 5 Feb 2025

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Abstract

Background: For most colorectal cancer (CRC) patients, expanding the benefits of immunotherapy, particularly through blocking programmed cell death-1 (PD-1) and its ligand (PD-L1), is crucial, especially in cases with limited response to neoadjuvant therapy. This study investigates the role of Myoferlin (MYOF) as [...] Read more.

Background: For most colorectal cancer (CRC) patients, expanding the benefits of immunotherapy, particularly through blocking programmed cell death-1 (PD-1) and its ligand (PD-L1), is crucial, especially in cases with limited response to neoadjuvant therapy. This study investigates the role of Myoferlin (MYOF) as a novel target in CRC immunotherapy. Methods: Human CRC cell lines (RKO, HCT116), normal intestinal epithelial cells (HIEC-6), and the murine CRC cell line MC38 were used to study the effects of apatinib and MYOF in CRC cells. RNA sequencing, the CPTAC and TCGA databases, and other molecular and cellular methods were applied to disclose the mechanisms involved. A series of mouse models were established to assess the effects of apatinib and MYOF knockdown on tumor progression, immune cell infiltration, and immune checkpoint protein response. Results: We found that MYOF is overexpressed in CRC and linked to immune cell infiltration and checkpoint expression. Suppression of MYOF expression significantly inhibited CRC cell proliferation and migration, as well as reduced PD-L1 protein levels. Integrative analysis showed that apatinib modulates MYOF expression via VEGFR2, resulting in decreased PD-L1 expression, increased CD8+ T cell infiltration, and reduced pro-tumor M2 macrophages. Animal experiments further revealed that apatinib treatment or MYOF knockdown enhanced the efficacy of immune checkpoint blockade (ICB) in CRC. Conclusions: These findings highlight novel antitumor mechanisms of MYOF and suggest that combining apatinib with ICB therapy may improve CRC treatment outcomes, offering a promising strategy to enhance immune responses. Full article

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15 pages, 1077 KiB

Open AccessArticle

A Novel Nomogram for Estimating a High-Risk Result in the EndoPredict^® Test for Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Carcinoma

by Víctor Macarrón, Itsaso Losantos-García, Alberto Peláez-García, Laura Yébenes, Alberto Berjón, Laura Frías, Covadonga Martí, Pilar Zamora, José Ignacio Sánchez-Méndez and David Hardisson

Cancers 2025, 17(2), 273; https://doi.org/10.3390/cancers17020273 - 16 Jan 2025

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Abstract

Background/Objectives: The EndoPredict^® assay has been widely used in recent years to estimate the risk of distant recurrence and the absolute chemotherapy benefit for patients with estrogen (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, there are no well-defined [...] Read more.

Background/Objectives: The EndoPredict^® assay has been widely used in recent years to estimate the risk of distant recurrence and the absolute chemotherapy benefit for patients with estrogen (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, there are no well-defined criteria for selecting patients who may benefit from the test. The aim of this study was to develop a novel nomogram to estimate the probability of obtaining a high-risk EndoPredict^® result in clinical practice. Methods: The study cohort comprised 348 cases of T1-3/N0-1a/M0 ER-positive/HER2-negative breast carcinoma. A multivariate analysis was conducted using a training cohort (n = 270) based on clinicopathological features that demonstrated a statistically significant correlation with the EndoPredict^® result in a univariate analysis. The predictive model was subsequently represented as a nomogram to estimate the probability of obtaining a high-risk result in the EndoPredict^® assay. The predictive model was then validated using a separate validation cohort (n = 78). Results: The clinicopathological features incorporated into the nomogram included tumor size, tumor grade, sentinel lymph node status, pN stage, and Ki67. The internal validation of the model yielded an area under the curve (AUC) of 0.803 (95% CI = 0.751, 0.855) in the receiver operating characteristic (ROC) curve for the training cohort, with an optimal sensitivity and specificity at a threshold of 0.536. The external validation yielded an AUC of 0.789 (95% CI = 0.689, 0.890) in its ROC curve, with optimal sensitivity and specificity achieved at a threshold of 0.393. Conclusions: This study presents, for the first time, the development of a clinically accessible nomogram designed to estimate the probability of obtaining a high-risk result in the EndoPredict^® assay. The use of easily available clinicopathological features allows for the optimization of patient selection for the EndoPredict^® assay, ensuring that those who would most benefit from undergoing the test are identified. Full article

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10 pages, 553 KiB

Open AccessArticle

Treatment of Established Chemotherapy-Induced Neuropathy with N-Palmitoylethanolamide: A Randomized, Double-Blind Phase II Pilot Study

by Mellar P. Davis, Angela Ulrich, Rebecca Segal, Vinay Gudena, Kathryn J. Ruddy, Stacy D’Andre, Karthik V. Giridhar, Vamsi K. Vasireddy, Rajiv Agarwal, Abdel-Ghani Azzouqa, Paul Novotny, Shaylene McCue, Brent Bauer and Charles L. Loprinzi

Cancers 2024, 16(24), 4244; https://doi.org/10.3390/cancers16244244 - 20 Dec 2024

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Abstract

Background: Chemotherapy-induced peripheral neuropathy (CIPN) from oxaliplatin and taxane drugs is a bothersome toxicity. Palmitoylethanolamide (PEA) has been reported to improve myelinated nerve fiber function in patients experiencing painful CIPN. We conducted a double-blind, placebo-controlled, randomized trial of PEA in patients with established [...] Read more.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) from oxaliplatin and taxane drugs is a bothersome toxicity. Palmitoylethanolamide (PEA) has been reported to improve myelinated nerve fiber function in patients experiencing painful CIPN. We conducted a double-blind, placebo-controlled, randomized trial of PEA in patients with established CIPN. Methods: Eligible patients were adults who had pain, numbness, tingling, or other symptoms of CIPN for at least three months following completion of paclitaxel, oxaliplatin, or cisplatin-based chemotherapy. Study patients were randomized to one of the two treatment groups (PEA versus placebo, both administered either once or twice daily). The CIPN20 questionnaire was assessed weekly. Results: A total of 17 males and 71 females participated in the study; most had neuropathy from paclitaxel. Most (85%) finished 8 weeks of treatment. There was no suggestion that either of the PEA arms did any better than the combined placebo arms. There was no signal of significant toxicity differences between the three study arms. Quality of life outcome measures were similar between the study arms, as were cognitive function evaluations. Discussion: PEA failed to improve established CIPN. Future trials might explore whether PEA may be effective in preventing CIPN or cognitive changes based on data that suggest it may be helpful in this situation. Conclusions: PEA failed to improve established chemotherapy-induced neuropathy. Full article

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11 pages, 557 KiB

Open AccessArticle

Bayesan Model to Predict R Status After Neoadjuvant Therapy in Pancreatic Cancer

by Isabella Frigerio, Quoc Riccardo Bao, Elisa Bannone, Alessandro Giardino, Gaya Spolverato, Giulia Lorenzoni, Filippo Scopelliti, Roberto Girelli, Guido Martignoni, Paolo Regi, Danila Azzolina, Dario Gregori and Giovanni Butturini

Cancers 2024, 16(23), 4106; https://doi.org/10.3390/cancers16234106 - 7 Dec 2024

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Abstract

Objective: To build a Bayesian approach-based model to predict the success of surgical exploration post-neoadjuvant treatment. Background: Pancreatic cancer (PDAC) is best treated with radical surgery and chemotherapy, offering the greatest chance of survival. Surgery after neoadjuvant treatment (NAT) is indicated in the [...] Read more.

Objective: To build a Bayesian approach-based model to predict the success of surgical exploration post-neoadjuvant treatment. Background: Pancreatic cancer (PDAC) is best treated with radical surgery and chemotherapy, offering the greatest chance of survival. Surgery after neoadjuvant treatment (NAT) is indicated in the absence of progression, knowing the limits in accurately predicting resectability with traditional radiology. R Status being a pathological parameter, it can be assessed only after surgery. Method: Patients successfully resected for histologically confirmed PDAC after NAT for BR and LA disease were included, with attention to the predictors of R status from the existing literature. The Bayesian logistic regression model was estimated for predicting the R1 status. The area under curve (AUC) of the average posterior probability of R1 was calculated and results were reported considering the 95% posterior credible intervals for the odds ratios, along with the probability of direction. Results: The final model demonstrated a commendable AUC value of 0.72, indicating good performance. The likelihood of positive margins was associated with older age, higher ASA score, the presence of venous and/or arterial involvement at preoperative radiology, tumor location within the pancreatic body, a lack of tumor size reduction post-NAT, and the persistence of an elevated Ca19.9 value. Conclusions: A Bayesian approach using only preoperative items is firstly used with good performance to predict R Status in pancreatic cancer patients who underwent resection after neoadjuvant therapy. Full article

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22 pages, 7953 KiB

Open AccessArticle

Proteomic Analysis Identifies Multiple Mechanisms of 5-Fluorouracil-Induced Gut Mucositis in Mice

by Sergey M. Ivanov, Victor G. Zgoda, Valeria A. Isakova, Lyubov S. Trukhanova, Vladimir V. Poroikov and Alexander A. Shtil

Cancers 2024, 16(23), 4025; https://doi.org/10.3390/cancers16234025 - 30 Nov 2024

Cited by 1 | Viewed by 1076

Abstract

Background/Objectives. Damage of the gastrointestinal mucosa is a major side effect of the anticancer drug 5-fluorouracil (5-FU). Insight into the molecular pathogenesis of 5-FU-induced gut mucositis is expected to justify the strategies of prophylaxis. Methods. We analyzed intestinal specimens obtained from Balb/c mice [...] Read more.

Background/Objectives. Damage of the gastrointestinal mucosa is a major side effect of the anticancer drug 5-fluorouracil (5-FU). Insight into the molecular pathogenesis of 5-FU-induced gut mucositis is expected to justify the strategies of prophylaxis. Methods. We analyzed intestinal specimens obtained from Balb/c mice treated with 70 mg/kg 5-FU daily for up to 6 days. Results. Manifestations of mucositis in the ileum and the colon included diarrhea, weight loss, and morphological lesions. The proteomic analysis revealed dozens of differentially expressed proteins governed by a set of master regulator proteins that regulated downstream pathways culminating in the complexes of specific transcription factors. Among the most important mechanisms of 5-FU-induced gut damage predicted by bioinformatics tools was stimulation of insulin-like growth factor 1 concomitant with inhibition of insulin receptor substrate 1, suggesting an involvement of the insulin pathway. Furthermore, the levels of 14-3-3γ protein and epinephrin B2 tyrosine kinase were interpreted as key inhibitory effects of 5-FU. These changes were detectable in the ileum as well as in the colon, pointing to the commonality of 5-FU responses across the gut. Conclusion. These results demonstrated a hierarchical network of gut injury mechanisms differentially regulated in the course of the emergence of 5-FU-induced mucositis. Full article

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Review

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41 pages, 2291 KiB

Open AccessReview

Understanding Merkel Cell Carcinoma: Pathogenic Signaling, Extracellular Matrix Dynamics, and Novel Treatment Approaches

by Maria Konstantaraki, Aikaterini Berdiaki, Monica Neagu, Sabina Zurac, Konstantinos Krasagakis and Dragana Nikitovic

Cancers 2025, 17(7), 1212; https://doi.org/10.3390/cancers17071212 - 2 Apr 2025

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Abstract

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer, driven by either Merkel cell polyomavirus (MCPyV) integration or ultraviolet (UV)-induced mutations. In MCPyV-positive tumors, viral T antigens inactivate tumor suppressors pRb and p53, while virus-negative MCCs harbor UV-induced mutations that [...] Read more.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer, driven by either Merkel cell polyomavirus (MCPyV) integration or ultraviolet (UV)-induced mutations. In MCPyV-positive tumors, viral T antigens inactivate tumor suppressors pRb and p53, while virus-negative MCCs harbor UV-induced mutations that activate similar oncogenic pathways. Key signaling cascades, including PI3K/AKT/mTOR and MAPK, support tumor proliferation, survival, and resistance to apoptosis. Histologically, MCC consists of small round blue cells with neuroendocrine features, high mitotic rate, and necrosis. The tumor microenvironment (TME) plays a central role in disease progression and immune escape. It comprises a mix of tumor-associated macrophages, regulatory and cytotoxic T cells, and elevated expression of immune checkpoint molecules such as PD-L1, contributing to an immunosuppressive niche. The extracellular matrix (ECM) within the TME is rich in proteoglycans, collagens, and matrix metalloproteinases (MMPs), facilitating tumor cell adhesion, invasion, and interaction with stromal and immune cells. ECM remodeling and integrin-mediated signaling further promote immune evasion and therapy resistance. Although immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in treating MCC, resistance remains a major hurdle. Therapeutic strategies that concurrently target the TME—through inhibition of ECM components, MMPs, or integrin signaling—may enhance immune responses and improve clinical outcomes. Full article

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23 pages, 7017 KiB

Open AccessReview

Hot Spots in Urogenital Basic Cancer Research and Clinics

by Claudia Manini, Gorka Larrinaga, Javier C. Angulo and José I. López

Cancers 2025, 17(7), 1173; https://doi.org/10.3390/cancers17071173 - 31 Mar 2025

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Abstract

Urogenital cancer is very common in the male population of Western countries, a problem of major concern for public health systems, and a frequent test subject for oncological research. In this narrative, we identify the main hot topics for clinics and the basic [...] Read more.

Urogenital cancer is very common in the male population of Western countries, a problem of major concern for public health systems, and a frequent test subject for oncological research. In this narrative, we identify the main hot topics for clinics and the basic science of urological cancer in the last few years (from 2021 onwards), considering the information given in the abstracts of almost 300 original articles published in outstanding journals of pathology, urology, and basic science. Once defined, for the top ten list of hot topics (the 2022 WHO update on the classification of urinary and male genital tumors, new entities in kidney cancer, urinary cancer-omics, update on the Gleason grading system, targeted therapies and other novel therapies in renal cancer, news on non-muscle invasive urothelial carcinoma, artificial intelligence in urologic cancer, intratumor heterogeneity influence in therapeutic failures in urologic neoplasms, intratumor microbiome and its influence in urologic tumor aggressiveness, and ecological principles and mathematics applied to urogenital cancer study), each issue is independently reviewed in an attempt to put together the most relevant updates and/or useful features accompanied by selected illustrations. This review article addresses some of the most interesting and current hot spots in urogenital basic cancer research and clinics and is mainly aimed toward clinicians, including pathologists, urologists, and oncologists. Readers are invited to explore each topic for further, more detailed information, in addition to the references provided. Full article

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20 pages, 721 KiB

Open AccessReview

Beyond Telomeres: Unveiling the Extratelomeric Functions of TERT in B-Cell Malignancies

by Silvia Giunco, Maria Raffaella Petrara, Stefano Indraccolo, Vincenzo Ciminale and Anita De Rossi

Cancers 2025, 17(7), 1165; https://doi.org/10.3390/cancers17071165 - 30 Mar 2025

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Abstract

The reactivation of telomerase enables cancer cells to maintain the telomere length, bypassing replicative senescence and achieving cellular immortality. In addition to its canonical role in telomere maintenance, accumulating evidence highlights telomere-length-independent functions of TERT, the catalytic subunit of telomerase. These extratelomeric functions [...] Read more.

The reactivation of telomerase enables cancer cells to maintain the telomere length, bypassing replicative senescence and achieving cellular immortality. In addition to its canonical role in telomere maintenance, accumulating evidence highlights telomere-length-independent functions of TERT, the catalytic subunit of telomerase. These extratelomeric functions involve the regulation of signaling pathways and transcriptional networks, creating feed-forward loops that promote cancer cell proliferation, resistance to apoptosis, and disease progression. This review explores the complex mechanisms by which TERT modulates key signaling pathways, such as NF-κB, AKT, and MYC, highlighting its role in driving autonomous cancer cell growth and resistance to therapy in B-cell malignancies. Furthermore, we discuss the therapeutic potential of targeting TERT’s extratelomeric functions. Unlike telomere-directed approaches, which may require prolonged treatment to achieve effective telomere erosion, inhibiting TERT’s extratelomeric functions offers the prospect of rapid tumor-specific effects. This strategy could complement existing chemotherapeutic regimens, providing an innovative and effective approach to managing B-cell malignancies. Full article

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21 pages, 992 KiB

Open AccessReview

The Current Role of Circulating Cell-Free DNA in the Management of Hepatocellular Carcinoma

by Alkistis Papatheodoridi, Vasileios Lekakis, Antonios Chatzigeorgiou and George Papatheodoridis

Cancers 2025, 17(6), 1042; https://doi.org/10.3390/cancers17061042 - 20 Mar 2025

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Abstract

Circulating cell-free DNA (cfDNA) has emerged as a compelling candidate of liquid biopsy markers for the diagnosis and prognosis of several cancers. We systematically reviewed data on the role of cfDNA markers in the diagnosis, prognosis and treatment of hepatocellular carcinoma (HCC). Early [...] Read more.

Circulating cell-free DNA (cfDNA) has emerged as a compelling candidate of liquid biopsy markers for the diagnosis and prognosis of several cancers. We systematically reviewed data on the role of cfDNA markers in the diagnosis, prognosis and treatment of hepatocellular carcinoma (HCC). Early studies suggested that levels of circulating cfDNA, mitochondrial DNA and cfDNA integrity are higher in patients with HCC than chronic liver diseases. In subsequent studies, methylation changes in circulating tumor DNA (ctDNA) as well as cfDNA fragmentation patterns and circulating nucleosomes were found to offer high sensitivity (>60%) and excellent specificity (>90%) for HCC diagnosis. The predictive role of cfDNA markers and ctDNA has been assessed in a few studies including untreated patients with HCC providing promising results for prediction of survival. However, port-hepatectomy detection of cfDNA/ctDNA markers or copy number variation indicators of cfDNA seem to reflect minimum residual disease and thus a high risk for HCC recurrence. The same markers can be useful for prediction after transarterial chemoembolization, radiofrequency ablation, radiotherapy and even systemic therapies. In conclusion, cfDNA markers can be useful in HCC surveillance, improving early diagnosis rates, as well as for monitoring treatment effectiveness and minimal residual disease post-treatment. Full article

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17 pages, 5324 KiB

Open AccessReview

Melanoma Arising in Tattoos: A Case Series and Scoping Review of the Literature

by Marco Brusasco, Sofia Spagnolini, Laura Mazzoni, Serena Magi, Giuseppe Scarcella and Ignazio Stanganelli

Cancers 2025, 17(5), 767; https://doi.org/10.3390/cancers17050767 - 24 Feb 2025

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Abstract

Background/Objectives: The prevalence of tattoos has risen globally in recent decades, ranging from 10% to 29%. Although rare, melanomas arising within tattoos are challenging for dermatologists due to the complexities in clinical and dermoscopic evaluation. In this article, we report two cases of [...] Read more.

Background/Objectives: The prevalence of tattoos has risen globally in recent decades, ranging from 10% to 29%. Although rare, melanomas arising within tattoos are challenging for dermatologists due to the complexities in clinical and dermoscopic evaluation. In this article, we report two cases of melanoma on tattoos, review the reported cases in the literature, and examine the role of reflectance confocal microscopy (RCM) in improving the diagnosis of melanoma on tattooed skin. Methods: We conducted a systematic literature search on Medline/Pubmed for the period from the inception of the databases to 31 October 2024, using the Mesh major topics ‘melanoma’ AND ‘tattoo’ OR ‘tattoo skin tumor’. Out of the 268 citations identified by our search, 37 studies met the eligibility criteria. Results: In total, 43 cases of melanoma arising on tattooed skin were identified, to which we add our 2 cases, bringing the total to 45. The most common locations were the upper limbs (53%) and trunk (38%), predominantly arisen on black and blue tattoos. Of 40 cases with known depth of invasion, 4 were in situ and 36 invasive, with a mean Breslow thickness of 2.7 mm. Seven patients had a positive sentinel lymph node. Of 16 cases with an available horizontal diameter, 12 melanomas had a diameter of ≥1 cm. Conclusions: The limited cases of ‘’melanoma on tattoos” reported in the literature suggest a coincidental association rather than a direct causal link. Nevertheless, increased awareness among patients and tattoo artists about potential risks and preventive measures may enhance the management of melanocytic lesions in tattooed individuals. Lastly, integrating reflectance confocal microscopy with dermoscopy increases the overall diagnostic accuracy for melanoma, enhancing the identification of pigmented and non-pigmented skin lesions. Full article

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26 pages, 971 KiB

Open AccessReview

The Emerging Role of CD8⁺ T Cells in Shaping Treatment Outcomes of Patients with MDS and AML

by Athanasios Tasis, Theodoros Spyropoulos and Ioannis Mitroulis

Cancers 2025, 17(5), 749; https://doi.org/10.3390/cancers17050749 - 22 Feb 2025

Viewed by 714

Abstract

CD8⁺ T cells are critical players in anti-tumor immunity against solid tumors, targeted by immunotherapies. Emerging evidence suggests that CD8⁺ T cells also play a crucial role in anti-tumor responses and determining treatment outcomes in hematologic malignancies like myelodysplastic neoplasms (MDS) [...] Read more.

CD8⁺ T cells are critical players in anti-tumor immunity against solid tumors, targeted by immunotherapies. Emerging evidence suggests that CD8⁺ T cells also play a crucial role in anti-tumor responses and determining treatment outcomes in hematologic malignancies like myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). In this review, we focus on the implication of CD8⁺ T cells in the treatment response of patients with MDS and AML. First, we review reported studies of aberrant functionality and clonality of CD8⁺ T cells in MDS and AML, often driven by the immunosuppressive bone marrow microenvironment, which can hinder effective antitumor immunity. Additionally, we discuss the potential use of CD8⁺ T cell subpopulations, including memory and senescent-like subsets, as predictive biomarkers for treatment response to a variety of treatment regimens, such as hypomethylating agents, which is the standard of care for patients with higher-risk MDS, and chemotherapy which is the main treatment of patients with AML. Understanding the multifaceted role of CD8⁺ T cells and their interaction with malignant cells in MDS and AML will provide useful insights into their potential as prognostic/predictive biomarkers, but also uncover alternative approaches to novel treatment strategies that could reshape the therapeutic landscape, thus improving treatment efficacy, aiding in overcoming treatment resistance and improving patient survival in these challenging myeloid neoplasms. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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19 pages, 7912 KiB

Open AccessReview

Cancer Risk in IBD Patients Treated with JAK Inhibitors: Reassuring Evidence from Trials and Real-World Data

by Pierluigi Puca, Angelo Del Gaudio, Jacopo Iaccarino, Valentina Blasi, Gaetano Coppola, Lucrezia Laterza, Loris Riccardo Lopetuso, Stefania Colantuono, Antonio Gasbarrini, Franco Scaldaferri and Alfredo Papa

Cancers 2025, 17(5), 735; https://doi.org/10.3390/cancers17050735 - 21 Feb 2025

Viewed by 974

Abstract

The advent of Janus kinase (JAK) inhibitors, including tofacitinib, filgotinib, and upadacitinib, has significantly widened the therapeutic options for patients with inflammatory bowel disease (IBD). These agents offer the advantage of oral administration and have demonstrated efficacy in inducing and maintaining remission. However, [...] Read more.

The advent of Janus kinase (JAK) inhibitors, including tofacitinib, filgotinib, and upadacitinib, has significantly widened the therapeutic options for patients with inflammatory bowel disease (IBD). These agents offer the advantage of oral administration and have demonstrated efficacy in inducing and maintaining remission. However, concerns regarding their safety have emerged, particularly concerning cardiovascular and infectious complications, which appear more pronounced in patients with pre-existing risk factors such as older age, smoking, or comorbidities. While these risks are better understood, the potential association between JAK inhibitors and malignancies remains a subject of ongoing investigation. Current data from randomised controlled trials, pooled and integrated analyses, and real-world studies provide conflicting evidence regarding cancer risk. Notably, studies in patients with rheumatologic diseases treated with JAK inhibitors have contributed additional insights into long-term safety outcomes. Despite the uncertainty surrounding malignancy risks, it is likely that predisposing factors, including older age, smoking history, and long-standing IBD with chronic inflammation, play a more substantial role in cancer development than JAK inhibitor therapy alone. This paper reviews safety data from clinical trials, meta-analyses, and observational studies, focusing on cancer risk in patients treated with JAK inhibitors for IBD. We also review evidence from rheumatology studies, highlighting the need for individualised risk assessment and close monitoring to optimise the safety profile of these medications in clinical practice. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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21 pages, 1003 KiB

Open AccessReview

Recent Advances in Pineoblastoma Research: Molecular Classification, Modelling and Targetable Vulnerabilities

by Zhe Jiang, Michelle S. Allkanjari, Philip E. D. Chung, Hanna Tran, Ronak Ghanbari-Azarnier, Dong-Yu Wang, Daniel J. Lin, Jung Yeon Min, Yaacov Ben-David and Eldad Zacksenhaus

Cancers 2025, 17(5), 720; https://doi.org/10.3390/cancers17050720 - 20 Feb 2025

Viewed by 1247

Abstract

Pineoblastoma (PB) is a rare yet lethal pediatric brain cancer of the pineal gland, a small endocrine organ that secretes melatonin to regulate the circadian rhythm. For PB patients ≤5 years of age, the overall survival rate is approximately 15%; metastatic PB is [...] Read more.

Pineoblastoma (PB) is a rare yet lethal pediatric brain cancer of the pineal gland, a small endocrine organ that secretes melatonin to regulate the circadian rhythm. For PB patients ≤5 years of age, the overall survival rate is approximately 15%; metastatic PB is incurable. Standard treatment, including surgical resection, radiation, and systemic chemotherapy, improves survival but compromises neurocognitive function. A better understanding of the disease and the generation of preclinical models may enable re-evaluation of previous clinical trials, development of precision therapeutic strategies and improve patient outcome. Over the past 5 years, PB has been recognized to include several major subtypes driven by (i) loss of microRNA processing factors DICER and DROSHA characterized by a relatively good prognosis; (ii) loss of the retinoblastoma tumor suppressor RB1; and (iii) amplification or induction of the cMYC protooncogene, with the latter two subtypes exhibiting exceedingly poor prognosis. Recently, mouse models for the major PB subtypes (RB1-, DICER1- and DROSHA-) except MYC- have been established. This progress, including better understanding of the disease, cell of origin, tumor progression, role of autophagy, and targetable vulnerabilities, holds promise for novel therapeutic strategies to combat each subtype of this lethal childhood malignancy. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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42 pages, 2072 KiB

Open AccessReview

Threading the Needle: Navigating Novel Immunotherapeutics in Pancreatic Ductal Adenocarcinoma

by Tarik Demir, Carolyn Moloney and Devalingam Mahalingam

Cancers 2025, 17(5), 715; https://doi.org/10.3390/cancers17050715 - 20 Feb 2025

Viewed by 870

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a poor prognosis. Currently, chemotherapy is the only option for most patients with advanced-stage PDAC. Further, conventional immunotherapies and targeted therapies improve survival outcomes only in rare PDAC patient subgroups. To date, combinatory immunotherapeutic [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a poor prognosis. Currently, chemotherapy is the only option for most patients with advanced-stage PDAC. Further, conventional immunotherapies and targeted therapies improve survival outcomes only in rare PDAC patient subgroups. To date, combinatory immunotherapeutic strategies to overcome the immune-hostile PDAC tumor microenvironment (TME) have resulted in limited efficacy in clinical studies. However, efforts are ongoing to develop new treatment strategies for patients with PDAC with the evolving knowledge of the TME, molecular characterization, and immune resistance mechanisms. Further, the growing arsenal of various immunotherapeutic agents, including novel classes of immune checkpoint inhibitors and oncolytic, chimeric antigen receptor T cell, and vaccine therapies, reinforces these efforts. This review will focus on the place of immunotherapy and future possible strategies in PDAC. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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25 pages, 1334 KiB

Open AccessReview

A Perspective on Therapeutic Targeting Against Ubiquitin Ligases to Stabilize Tumor Suppressor Proteins

by Ishaar P. Ganesan and Hiroaki Kiyokawa

Cancers 2025, 17(4), 626; https://doi.org/10.3390/cancers17040626 - 13 Feb 2025

Viewed by 793

Abstract

The loss of functions of tumor suppressor (TS) genes plays a key role in not only tumor initiation but also tumor progression leading to poor prognosis. While therapeutic inhibition of oncogene-encoded kinases has shown clinical success, restoring TS functions remains challenging due to [...] Read more.

The loss of functions of tumor suppressor (TS) genes plays a key role in not only tumor initiation but also tumor progression leading to poor prognosis. While therapeutic inhibition of oncogene-encoded kinases has shown clinical success, restoring TS functions remains challenging due to conceptual and technical limitations. E3 ubiquitin ligases that ubiquitinate TS proteins for accelerated degradation in cancers emerge as promising therapeutic targets. Unlike proteasomal inhibitors with a broad spectrum, inhibitors of an E3 ligase would offer superior selectivity and efficacy in enhancing expression of its substrate TS proteins as far as the TS proteins retain wild-type structures. Recent advances in developing E3 inhibitors, including MDM2 inhibitors, highlight their potential and ultimately guide the framework to establish E3 inhibition as effective strategies to treat specific types of cancers. This review explores E3 ligases that negatively regulate bona fide TS proteins, the developmental status of E3 inhibitors, and their promise and pitfalls as therapeutic agents for anti-cancer precision medicine. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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26 pages, 3054 KiB

Open AccessReview

Metabolic Singularities in Microsatellite-Stable Colorectal Cancer: Identifying Key Players in Immunosuppression to Improve the Immunotherapy Response

by Teresa Gorría, Marina Sierra-Boada, Mariam Rojas, Carolina Figueras, Silvia Marin, Sergio Madurga, Marta Cascante and Joan Maurel

Cancers 2025, 17(3), 498; https://doi.org/10.3390/cancers17030498 - 2 Feb 2025

Viewed by 1338

Abstract

Although immune checkpoint inhibitor (ICI) therapy is currently the standard of care in microsatellite-unstable (MSI) metastatic colorectal cancer (CRC), ICI therapy, alone or in combination with other therapies, is not a treatment approach in microsatellite-stable (MSS) CRC, which is present in 95% of [...] Read more.

Although immune checkpoint inhibitor (ICI) therapy is currently the standard of care in microsatellite-unstable (MSI) metastatic colorectal cancer (CRC), ICI therapy, alone or in combination with other therapies, is not a treatment approach in microsatellite-stable (MSS) CRC, which is present in 95% of patients. In this review, we focus on metabolic singularities—at the transcriptomic (either bulk or single cell), proteomic, and post-translational modification levels—that induce immunosuppression in cancer and specifically in MSS CRC. First, we evaluate the current efficacy of ICIs in limited and metastatic disease in MSS CRC. Second, we discuss the latest findings on the potential biomarkers for evaluating ICI efficacy in MSS CRC using strict REMARK criteria. Third, we review the current evidence on metabolic patterns in CRC tumors and immune cell metabolism to advance our understanding of metabolic crosstalk and to pave the way for the development of combination strategies to enhance ICI efficacy. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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Graphical abstract

37 pages, 2658 KiB

Open AccessReview

Long Non-Coding RNAs in Ovarian Cancer: Mechanistic Insights and Clinical Applications

by Sneha Basu, Revathy Nadhan and Danny N. Dhanasekaran

Cancers 2025, 17(3), 472; https://doi.org/10.3390/cancers17030472 - 30 Jan 2025

Viewed by 1099

Abstract

Background/Objectives: Ovarian cancer is a leading cause of gynecological cancer mortality worldwide, often diagnosed at advanced stages due to vague symptoms and the lack of effective early detection methods. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancer biology, influencing cellular [...] Read more.

Background/Objectives: Ovarian cancer is a leading cause of gynecological cancer mortality worldwide, often diagnosed at advanced stages due to vague symptoms and the lack of effective early detection methods. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancer biology, influencing cellular processes such as proliferation, apoptosis, and chemoresistance. This review explores the multifaceted roles of lncRNAs in ovarian cancer pathogenesis and their potential as biomarkers and therapeutic targets. Methods: A comprehensive literature review was conducted to analyze the structural and functional characteristics of lncRNAs and their contributions to ovarian cancer biology. This includes their regulatory mechanisms, interactions with signaling pathways, and implications for therapeutic resistance. Advanced bioinformatics and omics approaches were also evaluated for their potential in lncRNA research. Results: The review highlights the dual role of lncRNAs as oncogenes and tumor suppressors, modulating processes such as cell proliferation, invasion, and angiogenesis. Specific lncRNAs, such as HOTAIR and GAS5, demonstrate significant potential as diagnostic biomarkers and therapeutic targets. Emerging technologies, such as single-cell sequencing, provide valuable insights into the tumor microenvironment and the heterogeneity of lncRNA expression. Conclusions: LncRNAs hold transformative potential in advancing ovarian cancer diagnosis, prognosis, and treatment. Targeting lncRNAs or their associated pathways offers promising strategies to overcome therapy resistance and enhance personalized medicine. Continued research integrating omics and bioinformatics will be essential to unlock the full clinical potential of lncRNAs in ovarian cancer management. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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19 pages, 3682 KiB

Open AccessReview

Activation of Genes by Nuclear Receptor/Specificity Protein (Sp) Interactions in Cancer

by Stephen Safe, Evan Farkas, Amanuel E. Hailemariam, Arafat Rahman Oany, Gargi Sivaram and Wai Ning Tiffany Tsui

Cancers 2025, 17(2), 284; https://doi.org/10.3390/cancers17020284 - 17 Jan 2025

Cited by 1 | Viewed by 868

Abstract

The human nuclear receptor (NR) superfamily consists of 48 genes that are ligand-activated transcription factors that play a key role in maintaining cellular homeostasis and in pathophysiology. NRs are important drug targets for both cancer and non-cancer endpoints as ligands for these receptors [...] Read more.

The human nuclear receptor (NR) superfamily consists of 48 genes that are ligand-activated transcription factors that play a key role in maintaining cellular homeostasis and in pathophysiology. NRs are important drug targets for both cancer and non-cancer endpoints as ligands for these receptors can act as agonists, antagonists or inverse agonists to modulate gene expression. With two exceptions, the classical mechanism of action of NRs involves their interactions as monomers, dimers or heterodimers with their cognate response elements (cis-elements) in target gene promoters. Several studies showed that a number of NR-regulated genes did not directly bind their corresponding cis-elements and promoter analysis identified that NR-responsive gene promoters contained GC-rich sequences that bind specificity protein 1 (Sp1), Sp3 and Sp4 transcription factors (TFs). This review is focused on identifying an important sub-set of Sp-regulated genes that are indirectly coregulated through interactions with NRs. Subsequent studies showed that many NRs directly bind Sp1 (or Sp3 and Sp4), the NR/Sp complexes bind GC-rich sites to regulate gene expression and the NR acts as a ligand-modulated nuclear cofactor. In addition, several reports show that NR-responsive genes contain cis-elements that bind both Sp TFs and NRs, and mutation of either cis-element results in loss of NR-responsive (inducible and/or basal). Regulation of these genes involves interactions between DNA-bound Sp TFs with proximal or distal DNA-bound NRs, and, in some cases, other nuclear cofactors are required for gene expression. Thus, many NR-responsive genes are regulated by NR/Sp complexes, and these genes can be targeted by ligands that target NRs and also by drugs that induce degradation of Sp1, Sp3 and Sp4. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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17 pages, 902 KiB

Open AccessReview

Chronic Lymphocytic Leukemia Care and Beyond: Navigating the Needs of Long-Term Survivors

by Stefano Molica and David Allsup

Cancers 2025, 17(1), 119; https://doi.org/10.3390/cancers17010119 - 2 Jan 2025

Cited by 1 | Viewed by 1585

Abstract

Chronic lymphocytic leukemia (CLL) treatment has undergone a significant evolution with a shift from historical chemotherapeutic regimens to targeted therapies such as Bruton tyrosine kinase (BTK) and BCL-2 inhibitors. These advancements have been associated with a notable improvement in survival rates with a [...] Read more.

Chronic lymphocytic leukemia (CLL) treatment has undergone a significant evolution with a shift from historical chemotherapeutic regimens to targeted therapies such as Bruton tyrosine kinase (BTK) and BCL-2 inhibitors. These advancements have been associated with a notable improvement in survival rates with a transformation of CLL into a chronic and manageable condition for most persons with this disease. However, as a consequence of improved outcomes, long-term CLL survivors now face emergent challenges which include a risk of infections, cardiovascular complications, and secondary malignancies. In this changed scenario, holistic models of care are essential to address emergent health risks. Such models of care for CLL patients require a multidisciplinary approach that integrates CLL treatment with the proactive management of frailty, comorbidities, and psychosocial well-being to enhance both survival and quality of life (QoL). CLL predominantly affects older persons, many of whom present with concurrent frailty and comorbidities that may complicate CLL treatment and impact QoL. Comprehensive geriatric assessments (GA) may play a critical role in the identification of persons at a heightened risk of treatment-related toxicity and may help guide rational therapy selection, particularly in very frail persons. In addition to the assessment of hematological responses, the prospective assessment of patient-reported outcomes (PROs) and frailty metrics may offer a more nuanced understanding of the global treatment benefits. A survivorship-focused care model is crucial to address the multifaceted needs of CLL patients with the extension of patient care into the broader domain of long-term health maintenance with associated improvements in QoL. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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19 pages, 1067 KiB

Open AccessReview

Connexin-43 in Cancer: Above and Beyond Gap Junctions!

by Shishir Paunikar and Luca Tamagnone

Cancers 2024, 16(24), 4191; https://doi.org/10.3390/cancers16244191 - 16 Dec 2024

Cited by 1 | Viewed by 1281

Abstract

Connexin-43 (Cx43) is the most characterized gap junction protein, primarily involved in the Gap Junctional Intercellular Communication (GJIC) between adjacent cells to facilitate molecule exchange and the formation of a signaling network. It is increasingly evident that the importance of Cx43 is not [...] Read more.

Connexin-43 (Cx43) is the most characterized gap junction protein, primarily involved in the Gap Junctional Intercellular Communication (GJIC) between adjacent cells to facilitate molecule exchange and the formation of a signaling network. It is increasingly evident that the importance of Cx43 is not only limited to its GJIC function, but rather includes its role in connecting the intracellular and extracellular environment by forming membrane hemichannels, as well as its intracellular signaling function mediated by its C-terminal tail (Cx43-CT). Notably, Cx43 has been implicated in a variety of cancers, with earlier notions suggesting a tumor-suppressor function, whereas new studies shed light on its pro-tumorigenic role. Moreover, apart from GJIC-based activities, the relevance of the non-canonical functions of Cx43 in tumor progression is being actively studied. This review provides an analysis of the current research on the pro-tumorigenic roles of Cx43, with a focus on Cx43-CT interactions and the function of hemichannels in cancer progression. A better understanding of the multifaceted functions of Cx43 in cancer biology could foster its recognition as a pivotal target for the development of innovative therapeutic strategies. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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33 pages, 2408 KiB

Open AccessReview

Interleukin-6 Modulation in Ovarian Cancer Necessitates a Targeted Strategy: From the Approved to Emerging Therapies

by Hina Amer, Nirmala C. Kampan, Catherine Itsiopoulos, Katie L. Flanagan, Clare L. Scott, Apriliana E. R. Kartikasari and Magdalena Plebanski

Cancers 2024, 16(24), 4187; https://doi.org/10.3390/cancers16244187 - 16 Dec 2024

Cited by 1 | Viewed by 1538

Abstract

Despite significant advances in treatments, ovarian cancer (OC) remains one of the most prevalent and lethal gynecological cancers in women. The frequent detection at the advanced stages has contributed to low survival rates, resistance to various treatments, and disease recurrence. Thus, a more [...] Read more.

Despite significant advances in treatments, ovarian cancer (OC) remains one of the most prevalent and lethal gynecological cancers in women. The frequent detection at the advanced stages has contributed to low survival rates, resistance to various treatments, and disease recurrence. Thus, a more effective approach is warranted to combat OC. The cytokine Interleukin-6 (IL6) has been implicated in various stages of OC development. High IL6 levels are also correlated with a lower survival rate in OC patients. In this current review, we summarized the pivotal roles of IL6 in OC, including the initiation, development, invasion, metastasis, and drug resistance mechanisms. This article systematically highlights how targeting IL6 improves OC outcomes by altering various cancer processes and reports the ongoing clinical trials that would further shape the IL6-based targeted therapies. This review also suggests how combining IL6-targeted therapies with other therapeutic strategies could further enhance their efficacy to combat OC. Full article

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10 pages, 889 KiB

Open AccessReview

Hepcidin Is a Valuable Therapeutic Target for Colorectal Cancer

by Rachele Frascatani, Marco Colella and Giovanni Monteleone

Cancers 2024, 16(23), 4068; https://doi.org/10.3390/cancers16234068 - 5 Dec 2024

Viewed by 1329

Abstract

Colorectal cancer (CRC) is one of the most frequent neoplasms and a major cause of cancer death worldwide. Despite recent advances in treatment approaches, the prognosis of advanced CRC remains poor, thus indicating the necessity of more effective treatments for CRC patients. CRC [...] Read more.

Colorectal cancer (CRC) is one of the most frequent neoplasms and a major cause of cancer death worldwide. Despite recent advances in treatment approaches, the prognosis of advanced CRC remains poor, thus indicating the necessity of more effective treatments for CRC patients. CRC cells produce high levels of hepcidin, a peptide hormone that binds to the membrane-bound ferroportin and promotes its internalization and degradation, thus sequestering iron into the cancer cells with the downstream effect of enhancing tumor growth. Additionally, CRC cell-expressed hepcidin prolongs cell survival and, by targeting both CD8+ T cells and myeloid cells, restrains the induction of an efficient immune response against tumor antigens. The greatest expression of hepcidin is found in patients with metastatic CRC, and CRC patients with high hepcidin content have a worse survival rate than those with low hepcidin content. In the present article, we review the data supporting the prominent role of hepcidin in colon tumorigenesis and discuss how hepcidin inhibitors can help treat CRC patients in the metastatic setting with particular regard to the impact of hepcidin modulation on immunotherapeutic outcomes. Full article

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13 pages, 1588 KiB

Open AccessCommentary

Mimicking the Complexity of Solid Tumors: How Spheroids Could Advance Cancer Preclinical Transformative Approaches

by Sylvia Mangani, Spyros Kremmydas and Nikos K. Karamanos

Cancers 2025, 17(7), 1161; https://doi.org/10.3390/cancers17071161 - 30 Mar 2025

Viewed by 790

Abstract

Traditional 2D cell culture models present significant limitations in replicating the intricate architecture and microenvironment of in vivo solid tumors, which are essential for accurately studying cancer initiation, growth, progression, and metastasis. This underscores the need for the development of advanced preclinical models [...] Read more.

Traditional 2D cell culture models present significant limitations in replicating the intricate architecture and microenvironment of in vivo solid tumors, which are essential for accurately studying cancer initiation, growth, progression, and metastasis. This underscores the need for the development of advanced preclinical models to accelerate research outcomes. Emerging 3D cell culture systems, particularly spheroid models, provide a more realistic representation of solid tumor properties by capturing the complex interactions occurring within the tumor microenvironment, including the extracellular matrix dynamics that influence cancer progression. Among solid tumors, breast cancer remains the most frequently diagnosed cancer among women globally and a leading cause of cancer-related mortality. Here we emphasize the value of breast cancer cell-derived spheroids in revealing differential molecular characteristics and understanding cancer cell properties during the early stages of invasion into adjacent tissues. Conclusively, this study underscores the urgent need to adopt 3D cell culture platforms, given their significant contributions to advanced cancer research and pharmaceutical targeting. This may well offer a transformative approach for preclinical studies and enhance our ability to test therapeutic efficiency in conditions that closely mimic the growth and progression of in vivo solid tumors. Full article

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26 pages, 961 KiB

Open AccessSystematic Review

Surgical Outcomes in Stage IV Pancreatic Cancer with Liver Metastasis Current Evidence and Future Directions: A Systematic Review and Meta-Analysis of Surgical Resection

by Noah Clements, Jeremy Gaskins and Robert C. G. Martin II

Cancers 2025, 17(4), 688; https://doi.org/10.3390/cancers17040688 - 18 Feb 2025

Cited by 1 | Viewed by 976

Abstract

Background/Objectives: There is increasing evidence that a subset of patients with stage IV pancreatic ductal adenocarcinoma (PDAC) and liver-only metastasis may benefit from surgical resection of both the primary tumor and metastatic lesions. Methods: A meta-analysis and systematic review were conducted in patients [...] Read more.

Background/Objectives: There is increasing evidence that a subset of patients with stage IV pancreatic ductal adenocarcinoma (PDAC) and liver-only metastasis may benefit from surgical resection of both the primary tumor and metastatic lesions. Methods: A meta-analysis and systematic review were conducted in patients with stage IV PDAC and hepatic-only metastasis. A comprehensive literature search (January 2015–June 2023) was performed using PubMed with keywords including “pancreatic cancer”, “oligometastatic”, and “surgery”. Results: Sixteen articles were included in the final review and characterized based on patient selection factors and prognostic indicators. Seven studies reported hazard ratios (HRs) or Kaplan–Meier curves for survival in synchronous resected cohorts versus chemotherapy/palliation alone, which indicated a statistically significant survival benefit in the resection cohorts (pooled HR: 0.41, 95% CI: 0.31–0.53, p < 0.01). Prognostic indicators for synchronous and metachronous resection included lower pre-operative CA19-9, negative margin status of the primary tumor, moderate-to-well-differentiated tumors (grades I–II), and receiving pre-operative chemotherapy. Conclusions: Surgical/ablation selection factors are evolving, with priorities on (1) response to induction chemotherapy, (2) ability to achieve R0 resection, and (3) minimally invasive approaches remaining critical to optimal patient selection. Standardized radiologic and tumor marker evaluation and response to neoadjuvant therapy and optimizing performance status are critical to improved outcomes. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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6 pages, 317 KiB

Open AccessCommentary

Updates and Future Directions for the Nottingham Research Programme on Primary Breast Cancer in Older Women

by Ruth Mary Parks and Kwok-Leung Cheung

Cancers 2025, 17(3), 346; https://doi.org/10.3390/cancers17030346 - 21 Jan 2025

Viewed by 776

Abstract

The global population is ageing and the risk of breast cancer increases with age. Therefore, we can expect an increase in the number of cases of breast cancer worldwide in the next 20 years. Currently, there are few age-specific guidelines for the management [...] Read more.

The global population is ageing and the risk of breast cancer increases with age. Therefore, we can expect an increase in the number of cases of breast cancer worldwide in the next 20 years. Currently, there are few age-specific guidelines for the management of breast cancer in older women. The International Society of Geriatric Oncology and European Society of Breast Cancer guidelines on this topic were last updated in 2021 and provide some recommendations, although it is worth noting that, generally, the level of evidence pertaining to older women is low. The Nottingham research team on older women with primary breast cancer is working on three main aims in this cohort: (1) understand the unique biological differences between breast cancer in older compared to younger women, (2) explore the unique psycho-social factors that may be present in this population and differ from those found in younger women, as well as how this may influence treatment decisions, and (3) the cost-effectiveness of various treatment strategies in this cohort. This paper will outline key studies published by the Nottingham team in these areas to gather data and highlight future directions for the research group. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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14 pages, 244 KiB

Open AccessOpinion

Prevention and Treatment of Venous Thromboembolism Associated with Amivantamab-Based Therapies in Patients with Lung Cancer—Provisional Clinical Opinion Based on Existing Clinical Practice Guidelines

by Florian Moik, Gudrun Absenger, Robert Wurm, Maximilian J. Hochmair and Cihan Ay

Cancers 2025, 17(2), 259; https://doi.org/10.3390/cancers17020259 - 14 Jan 2025

Viewed by 1482

Abstract

Improved efficacy has been shown for amivantamab and amivantamab-based combination therapies in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) compared to established treatment options in clinical trials. However, a high risk of venous thromboembolism (VTE) was observed in [...] Read more.

Improved efficacy has been shown for amivantamab and amivantamab-based combination therapies in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) compared to established treatment options in clinical trials. However, a high risk of venous thromboembolism (VTE) was observed in patients treated with amivantamab-based therapies, with considerable differences in VTE risk according to the line of systemic treatment, concomitant treatment with lazertinib, and intravenous vs. subcutaneous amivantamab administration. Based on early reports of high VTE rates, prophylactic anticoagulation has been implemented in ongoing clinical trials for the first 4 months of amivantamab–lazertinib therapy. However, open questions remain concerning the type, dosing, and duration of primary pharmacological thromboprophylaxis in patients treated with amivantamab-based therapies. Therefore, the aim of this clinical opinion piece is to provide provisional guidance on how to mitigate VTE risk in patients treated with amivantamab-based therapies following existing clinical practice guidelines on primary thromboprophylaxis and treatment of VTE in ambulatory patients with cancer. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

13 pages, 709 KiB

Open AccessCommentary

A Landscape of Cancer Initiation and Cancer Stem Cells

by Masaharu Seno

Cancers 2025, 17(2), 203; https://doi.org/10.3390/cancers17020203 - 9 Jan 2025

Cited by 1 | Viewed by 1431

Abstract

Exposure to radiation and chemicals, oncogenic viruses, microbiomes, and inflammation are the major events of cancer initiation. DNA damage and chromosomal aberrations are classically considered the main causes of cancer. The recent idea of epigenetics is broadening the concept, including the suggestion that [...] Read more.

Exposure to radiation and chemicals, oncogenic viruses, microbiomes, and inflammation are the major events of cancer initiation. DNA damage and chromosomal aberrations are classically considered the main causes of cancer. The recent idea of epigenetics is broadening the concept, including the suggestion that oncogenic virus infection disrupts various intracellular signaling cascades. Chronic inflammation was proposed as the origin of cancer in the 19th century, and the molecular level of events has been made clear with scientific development. Much knowledge of cancer initiation has become available for integration into research. Simultaneously, the presence of cancer stem cells has been identified and characterized. However, the point of shift from normal to malignant still appears obscure even when taking cancer stem cells into consideration. From these points of view, the advent of cancer stem cells and cancer initiation are briefly discussed as the points of shift from normal to malignant in this paper. Full article

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9 pages, 431 KiB

Open AccessCommentary

Beyond the Horizon: Rethinking Prostate Cancer Treatment Through Innovation and Alternative Strategies

by Siddhant Bhoir and Arrigo De Benedetti

Cancers 2025, 17(1), 75; https://doi.org/10.3390/cancers17010075 - 29 Dec 2024

Viewed by 1221

Abstract

For nearly a century, fundamental observations that prostate cancer (PCa) cells nearly always require AR stimulation for sustained proliferation have led to a unidirectional quest to abrogate such a pathway. Similarly focused have been efforts to understand AR-driven processes in the context of [...] Read more.

For nearly a century, fundamental observations that prostate cancer (PCa) cells nearly always require AR stimulation for sustained proliferation have led to a unidirectional quest to abrogate such a pathway. Similarly focused have been efforts to understand AR-driven processes in the context of elevated expression of its target genes, and much less so on products that become overexpressed when AR signaling is suppressed. Treatment with ARSI results in an increased expression of the TLK1B splice variant via a ‘translational’ derepression driven by the compensatory mTOR activation and consequent activation of the TLK1 > NEK1 > ATR > Chk1 and NEK1 > YAP axes. In due course, this results first in a pro-survival quiescence and then adaptation to ADT and CRPC progression. This constitutes a novel liability for PCa that we have targeted for several years and novel approaches. Full article

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10 pages, 3002 KiB

Open AccessCommentary

IDH2 Inhibitors Gain a Wildcard Status in the Cancer Therapeutics Competition

by Roberto Piva, Nariman Gharari, Maria Labrador and Sylvie Mader

Cancers 2024, 16(19), 3280; https://doi.org/10.3390/cancers16193280 - 26 Sep 2024

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Abstract

The metabolic reprogramming characteristic of cancer cells, including the Warburg effect, has long been recognized as a hallmark of malignancy. This commentary explores three recent investigations focusing on the role of wild-type IDH2 in cancer and immune cell function. The first publication identifies [...] Read more.

The metabolic reprogramming characteristic of cancer cells, including the Warburg effect, has long been recognized as a hallmark of malignancy. This commentary explores three recent investigations focusing on the role of wild-type IDH2 in cancer and immune cell function. The first publication identifies wild-type IDH2 as a crucial factor in the survival of triple-negative breast cancer (TNBC) cells, with its inhibition leading to disrupted energy metabolism, reduced tumor growth, and enhanced apoptosis. The second analysis examines the role of IDH2 in CD8+ T cells, revealing that its inhibition promotes the differentiation of memory T cells, thereby enhancing the efficacy of cell-based immunotherapies like CAR T cells. A third investigation supports these findings, demonstrating that IDH2 inhibition in CAR T cells reduces exhaustion, enhances memory T cell formation, and improves anti-tumor efficacy. Collectively, these reports highlight wild-type IDH2 as a promising therapeutic target, with potential applications as a two-edged sword in both cancer treatment and immunotherapy. The development of specific wild-type IDH2 inhibitors could offer new avenues for therapy, particularly in tumors reliant on IDH2 activity as well as in enhancing the effectiveness of CAR T cell therapies. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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