Cancers

13 pages, 1190 KB

Open AccessArticle

Carbon Ion Radiotherapy for Retroperitoneal Sarcoma: A Single-Institution Study

by Reiko Imai, Tsukasa Yonemoto, Nobuhito Araki, Hirotoshi Takiyama, Hiroaki Ikawa, Shigeru Yamada and Hitoshi Ishikawa

Cancers 2025, 17(20), 3395; https://doi.org/10.3390/cancers17203395 - 21 Oct 2025

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Abstract

Background/Objectives: Surgery remains the mainstay of treatment for retroperitoneal sarcoma (RPS); however, definitive therapeutic strategies for patients with insufficient surgical margins and unresectable disease owing to locally advanced RPS remain unclear. Carbon ion radiotherapy (CIRT) has been employed in patients with unresectable RPS. [...] Read more.

Background/Objectives: Surgery remains the mainstay of treatment for retroperitoneal sarcoma (RPS); however, definitive therapeutic strategies for patients with insufficient surgical margins and unresectable disease owing to locally advanced RPS remain unclear. Carbon ion radiotherapy (CIRT) has been employed in patients with unresectable RPS. This study aimed to evaluate the effectiveness of CIRT in this patient population. Methods: A retrospective analysis was conducted in 76 patients with unresectable RPS treated with CIRT. Of these, 95% had a confirmed prognosis until 2022. In 74 patients, the prescribed relative biological effectiveness dose was 70.4 Gy, delivered in 16 fractions over 4 weeks. Respiratory gating was used, and spot scanning irradiation has been performed in all patients since 2016. Results: The 3- and 5-year overall survival rates for the entire cohort were 68.3% and 49.4%, respectively, with a median overall survival time of 58.1 months. The 3- and 5-year local control rates were 79.0% and 72.0%, respectively. Among 47 naïve patients with treatment-naïve tumors, the 3- and 5-year abdominal recurrence-free survival rates were 51.1% and 29.1%, respectively. Late adverse events of grade 3 or higher occurred in 4 (5.2%) patients. Conclusions: CIRT represents a definitive treatment option for patients with unresectable RPS. In the future, multicenter studies should be conducted to evaluate the effectiveness of CIRT for RPS in larger patient cohorts. Full article

(This article belongs to the Special Issue Radiotherapy for Sarcoma)

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18 pages, 2025 KB

Open AccessArticle

A Priori Prediction of Neoadjuvant Chemotherapy Response in Breast Cancer Using Deep Features from Pre-Treatment MRI and CT

by Deok Hyun Jang, Laurentius O. Osapoetra, Lakshmanan Sannachi, Belinda Curpen, Ana Pejović-Milić and Gregory J. Czarnota

Cancers 2025, 17(20), 3394; https://doi.org/10.3390/cancers17203394 - 21 Oct 2025

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Abstract

Background: Response to neoadjuvant chemotherapy (NAC) is a key prognostic indicator in breast cancer, yet current assessment relies on postoperative pathology. This study investigated the use of deep features derived from pre-treatment MRI and CT scans, in conjunction with clinical variables, to [...] Read more.

Background: Response to neoadjuvant chemotherapy (NAC) is a key prognostic indicator in breast cancer, yet current assessment relies on postoperative pathology. This study investigated the use of deep features derived from pre-treatment MRI and CT scans, in conjunction with clinical variables, to predict treatment response a priori. Methods: Two response endpoints were analyzed: pathologic complete response (pCR) versus non-pCR, and responders versus non-responders, with response defined as a reduction in tumor size of at least 30%. Intratumoral and peritumoral segmentations were generated on contrast-enhanced T1-weighted (CE-T1) and T2-weighted MRI, as well as contrast-enhanced CT images of tumors. Deep features were extracted from these regions using ResNet10, ResNet18, ResNet34, and ResNet50 architectures pre-trained with MedicalNet. Handcrafted radiomic features were also extracted for comparison. Feature selection was conducted with minimum redundancy maximum relevance (mRMR) followed by recursive feature elimination (RFE), and classification was performed using XGBoost across ten independent data partitions. Results: A total of 177 patients were analyzed in this study. ResNet34-derived features achieved the highest overall classification performance under both criteria, outperforming handcrafted features and deep features from other ResNet architectures. For distinguishing pCR from non-pCR, ResNet34 achieved a balanced accuracy of 81.6%, whereas handcrafted radiomics achieved 77.9%. For distinguishing responders from non-responders, ResNet34 achieved a balanced accuracy of 73.5%, compared with 70.2% for handcrafted radiomics. Conclusions: Deep features extracted from routinely acquired MRI and CT, when combined with clinical information, improve the prediction of NAC response in breast cancer. This multimodal framework demonstrates the value of deep learning-based approaches as a complement to handcrafted radiomics and provides a basis for more individualized treatment strategies. Full article

(This article belongs to the Special Issue CT/MRI/PET in Cancer)

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15 pages, 1175 KB

Open AccessArticle

The Impact of Local Ablative Therapies as Bridging Treatment on Overall Survival Following Liver Transplantation in Patients with HCC

by Laura Schwenk, Felix Dondorf, Oliver Rohland, Aladdin Ali-Deeb, Utz Settmacher and Falk Rauchfuß

Cancers 2025, 17(20), 3393; https://doi.org/10.3390/cancers17203393 - 21 Oct 2025

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Abstract

Background: The use of neoadjuvant therapies in patients with hepatocellular carcinoma prior to liver transplantation has gained increasing popularity in recent years. To date, there are only limited data investigating the impact of neoadjuvant therapy on post-transplant survival. Methods: In this retrospective study, [...] Read more.

Background: The use of neoadjuvant therapies in patients with hepatocellular carcinoma prior to liver transplantation has gained increasing popularity in recent years. To date, there are only limited data investigating the impact of neoadjuvant therapy on post-transplant survival. Methods: In this retrospective study, we evaluated patients with hepatocellular carcinoma who underwent deceased donor or living donor liver transplantation at Jena University Hospital between 2019 and 2023. Comprehensive clinical and pathological variables were systematically analyzed, including correlations between neoadjuvant therapy use, tumor burden and overall survival. Survival outcomes were estimated using the Kaplan–Meier method. Results: A total of 107 patients were included in the analysis, of whom 90 received neoadjuvant therapy prior to transplantation. Treatment modalities comprised SIRT, TACE, liver resection and combined SIRT and TACE. The 1-, 3-, and 5-year OS rates following transplantation were 93.5%, 82.2%, and 79.4%, respectively. Recurrence-free survival at 1, 3, and 5 years was 91.6%, 85.0%, and 83.2%, respectively. Among the various neoadjuvant strategies, SIRT and TACE yielded the highest OS rates. Patients listed outside the transplantation criteria (Milan, UCSF, up-to-seven) at the time of initial diagnosis who underwent SIRT had significantly better OS than those outside the criteria who underwent TACE. In contrast, among patients within the Milan, UCSF and up-to-seven criteria, TACE was associated with superior OS compared with SIRT. Conclusion: The use of neoadjuvant therapies confers a significant survival benefit following liver transplantation in patients with HCC. TACE appears to be most suitable for patients listed within established transplantation criteria, who consequently have a lower tumor burden. In contrast, SIRT is more beneficial for patients with a higher tumor burden and those beyond standard transplantation criteria. A limitation of our study, however, is that the included SIRT cohort comprised only 24 patients, and TACE was preferentially performed in patients with a lower tumor burden, which means that a selection bias cannot be fully excluded. Overall, further studies are required to define the optimal bridging strategies. Full article

(This article belongs to the Special Issue Surgical Treatment of Hepatocellular Carcinoma)

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10 pages, 664 KB

Open AccessReview

The Central Anatomical Question: Treatment of Lymphoma Within Border-Zone Anatomical Sites Adjacent to the Central Nervous System

by Candace Marsters, Chai Phua, Maria MacDonald, Gabriel Boldt and Seth Climans

Cancers 2025, 17(20), 3392; https://doi.org/10.3390/cancers17203392 - 21 Oct 2025

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Abstract

Lymphomas involving the central nervous system (CNS) have worse outcomes, including both primary and secondary CNS lymphomas, which are associated with poorer overall survival outcomes. The World Health Organization classifies CNS lymphoma as arising from the brain, leptomeninges, and spinal cord, but this [...] Read more.

Lymphomas involving the central nervous system (CNS) have worse outcomes, including both primary and secondary CNS lymphomas, which are associated with poorer overall survival outcomes. The World Health Organization classifies CNS lymphoma as arising from the brain, leptomeninges, and spinal cord, but this simplified CNS anatomical definition fails to incorporate areas of ambiguity that can be clinically relevant for treatment decision making. In this article, we review the anatomical boundaries of CNS lymphoma within select border-zone biological structures located at the CNS borders in order to gain a consensus working definition of CNS disease boundaries. We review anatomical localizations with border-zone CNS boundaries, including the dura, cavernous sinus, circumventricular organs, pituitary gland, and cranial nerves. Though some portions of the eye would be considered CNS and others extra-CNS, recommendations for this structure are outside the scope of this review. Through this review, we examine the impact of lymphomatous invasion on select CNS-bordering anatomical structures, aiming to better define treatment categorization as CNS or extra-CNS, with a focus on B cell lymphoma types. Full article

(This article belongs to the Special Issue Primary Central Nervous System Lymphoma: A Challenging Disease)

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15 pages, 354 KB

Open AccessArticle

The Effectiveness of ¡Salud!, por la Vida, an Educational Intervention to Increase Colorectal Cancer Screening in Puerto Rico

by Josheili Llavona-Ortiz, Maria E. Fernández, Ileska M. Valencia-Torres, Francisco J. Muñoz-Torres, Marievelisse Soto-Salgado, Yara Sánchez-Cabrera and Vivian Colón-López

Cancers 2025, 17(20), 3391; https://doi.org/10.3390/cancers17203391 - 21 Oct 2025

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Abstract

Background/Objectives: Colorectal cancer (CRC) is the leading cancer-related death in Puerto Rico (PR). Yet CRC screening (CRCS) rates remain low. We developed ¡Salud!, por la Vida, an educational intervention aiming to increase CRCS among age-eligible adults living in PR. Methods: [...] Read more.

Background/Objectives: Colorectal cancer (CRC) is the leading cancer-related death in Puerto Rico (PR). Yet CRC screening (CRCS) rates remain low. We developed ¡Salud!, por la Vida, an educational intervention aiming to increase CRCS among age-eligible adults living in PR. Methods: We conducted a cluster randomized controlled trial among adults 50–75 years old at Federally Qualified Health Clinics in PR. Participants could not have a history of CRC nor be currently adherent to CRCS guidelines for a fecal occult blood test (FOBT) or fecal immunochemical test (FIT) (within last year) or colonoscopy (within last 5–10 years). Out of 445 randomized participants, 355 completed the study procedures (Control: 277; Intervention: 78) and were included in the main analysis. Participants in the intervention arm completed baseline and follow-up questionnaires alongside the educational intervention (at baseline) and two reminder calls (before follow-up) within a four-month period. Control arm participants only completed baseline and follow-up questionnaires within the same period. All participants were followed up to assess CRCS completion. Results: Post-trial screening rates were significantly higher in the intervention group: FOBT/FIT (55% vs. 39%, p = 0.02), colonoscopy (10% vs. 3%, p = 0.02), and any CRCS (60% vs. 41%, p < 0.01). Compared to controls, those in the intervention group showed a 48% higher probability of undergoing any CRCS (RR = 1.48, 95%CI: 1.17, 1.86), were 1.4 times more likely to complete a FOBT/FIT (RR = 1.40, 95%CI: 1.09, 1.80), and were over 3 times more likely to undergo a colonoscopy (RR = 3.16, 95%CI: 1.26, 7.91). Conclusions: The findings underscore the efficacy of the intervention in increasing CRCS uptake, potentially preventing late-stage detection and reducing CRC mortality in PR. Full article

(This article belongs to the Special Issue Cancer Screening and Primary Care)

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10 pages, 621 KB

Open AccessArticle

Evaluation of a Novel Tapered Tip EUS-FNB Needle: A UK Multicentre Study

by Darragh Storan, John Leeds, Arif Hussenbux, Mohamed Elseragy, Ruridh Allen, Tareq El Menabawey, Aaron McGowan, Matthew T. Huggett, Umair Kamran, Bidour Awadelkarim, Beate Haugk, Kofi Oppong and Manu Nayar

Cancers 2025, 17(20), 3390; https://doi.org/10.3390/cancers17203390 - 21 Oct 2025

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Abstract

Introduction: A new core biopsy needle with a novel tapered stylet tip has been introduced for endoscopic ultrasound-guided fine needle biopsy (EUS-FNB). The tapered point stylet is purported to improve ease of puncture, leading to improved tissue acquisition and accuracy. However, there [...] Read more.

Introduction: A new core biopsy needle with a novel tapered stylet tip has been introduced for endoscopic ultrasound-guided fine needle biopsy (EUS-FNB). The tapered point stylet is purported to improve ease of puncture, leading to improved tissue acquisition and accuracy. However, there are no data available in the published literature. The aim of this study was to compare the diagnostic performance of the tapered stylet needle with conventional end-cutting FNB needles for tissue acquisition from solid lesions. Methods: Patients who underwent EUS-FNB of a solid lesion using the tapered stylet FNB needle across four tertiary hepatopancreaticobiliary centres in the UK were included in the study. Demographic, clinical, and performance outcomes were included in the analysis. Diagnostic performance was compared with a similar cohort of patients who underwent EUS-FNB using standard end-cutting FNB needles with a blunt-tipped stylet. The primary outcome was accuracy for the diagnosis of malignancy. Results: A total of 270 patients were included for analysis; 129 patients (48%) had sampling with the novel tapered stylet tip needle, among which 50% were female, the median age was 69, 74% had pancreatic lesions, and 80% had a final diagnosis of malignancy; 141 control cases (52%) were included for comparison, among which 48% were female, the median age was 68, 67% had pancreatic lesions, and 72% had a final diagnosis of malignancy. The tapered stylet needle demonstrated a sensitivity of 90% and an NPV of 72% for the diagnosis of malignancy compared with 88% and 77% for controls (p = 0.147). The overall diagnostic accuracy of the tapered stylet needle was 92.2% compared with 91.5% for controls (p = 0.634). Conclusions: The novel tapered tip stylet FNB needle demonstrated comparable sensitivity, NPV, and diagnostic accuracy to conventional FNB needles. This is the first and largest study reporting results for this new needle. However, further large comparative studies are warranted to validate our results and to determine if the tapered stylet offers an advantage over the conventional design. Full article

(This article belongs to the Special Issue New Advances in Oncology Research and Practice)

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18 pages, 4021 KB

Open AccessArticle

A Novel Allosteric Inhibitor Targeting IMPDH at Y233 Overcomes Resistance to Tyrosine Kinase Inhibitors in Lymphoma

by Nagarajan Pattabiraman, Cosimo Lobello, David Rushmore, Luca Mologni, Mariusz Wasik and Johnvesly Basappa

Cancers 2025, 17(20), 3389; https://doi.org/10.3390/cancers17203389 - 21 Oct 2025

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Abstract

Background/Objective: Oncogenic tyrosine kinases (TKs) such as ALK and SRC promote cancer progression, but their effects on metabolic enzymes are still not well understood. This study examines how TK signaling regulates inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, and [...] Read more.

Background/Objective: Oncogenic tyrosine kinases (TKs) such as ALK and SRC promote cancer progression, but their effects on metabolic enzymes are still not well understood. This study examines how TK signaling regulates inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, and assesses its potential as a therapeutic target. Methods: Phosphoproteomic screening and in vitro kinase assays were used to identify phosphorylation sites on IMPDH2. Lipid-binding assays explored the role of phosphatidylinositol 3-phosphate (PI3P) in IMPDH2 regulation. Structure-based virtual screening discovered small-molecule allosteric inhibitors, which were tested in lymphoma cell models, including ALK and BTK-inhibitor resistant lines. Results: Here, we identify Inosine monophosphate dehydrogenase-2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, as a novel substrate of ALK and SRC. We show that phosphorylation at the conserved Y233 residue within the allosteric domain enhances IMPDH2 activity, linking TK signaling to metabolic reprogramming in cancer cells. We further identify PI3P as a natural lipid inhibitor that binds IMPDH2 and suppresses its enzymatic function. Using structure-based virtual screening, we developed Comp-10, a first-in-class allosteric IMPDH inhibitor. Unlike classical active-site inhibitors such as mycophenolic acid (MPA), Comp-10 decreases IMPDH1/2 protein levels, blocks filament (rod/ring) formation, and inhibits the growth of ALK and BTK inhibitor-resistant lymphoma cells. Comp-10 acts post-transcriptionally and avoids compensatory IMPDH upregulation observed with MPA (rod/ring) formation, and inhibited growth in TKI-resistant lymphoma cells. Notably, Comp-10 avoided the compensatory IMPDH upregulation observed with MPA. Conclusion: These findings uncover a novel TK–IMPDH2 signaling axis and provide mechanistic and therapeutic insight into the allosteric regulation of IMPDH2. Comp-10 represents a promising therapeutic candidate for targeting metabolic vulnerabilities in tyrosine kinase driven cancers. Full article

(This article belongs to the Section Molecular Cancer Biology)

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19 pages, 8646 KB

Open AccessArticle

Impact of Diagnostic Confidence, Perceived Difficulty, and Clinical Experience in Facial Melanoma Detection: Results from a European Multicentric Teledermoscopic Study

by Alessandra Cartocci, Alessio Luschi, Sofia Lo Conte, Elisa Cinotti, Francesca Farnetani, Aimilios Lallas, John Paoli, Caterina Longo, Elvira Moscarella, Danica Tiodorovic, Ignazio Stanganelli, Mariano Suppa, Emi Dika, Iris Zalaudek, Maria Antonietta Pizzichetta, Jean Luc Perrot, Imma Savarese, Magdalena Żychowska, Giovanni Rubegni, Mario Fruschelli, Ernesto Iadanza, Gabriele Cevenini and Linda Tognetti Show full author list Hide full author list

Cancers 2025, 17(20), 3388; https://doi.org/10.3390/cancers17203388 - 21 Oct 2025

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Abstract

Background: Diagnosing facial melanoma, specifically lentigo maligna (LM) and lentigo maligna melanoma (LMM), is a daily clinical challenge, particularly for small or traumatized lesions. LM and LMM are part of the broader group of atypical pigmented facial lesions (aPFLs), which also includes benign [...] Read more.

Background: Diagnosing facial melanoma, specifically lentigo maligna (LM) and lentigo maligna melanoma (LMM), is a daily clinical challenge, particularly for small or traumatized lesions. LM and LMM are part of the broader group of atypical pigmented facial lesions (aPFLs), which also includes benign look-alikes such as solar lentigo (SL), atypical nevi (AN), seborrheic keratosis (SK), and seborrheic-lichenoid keratosis (SLK), as well as pigmented actinic keratosis (PAK), a potentially premalignant keratinocytic lesion. Standard dermoscopy with handheld devices is the most widely used diagnostic tool in dermatology, but its accuracy heavily depends on the clinician’s experience and the perceived difficulty of the case. As a result, many benign aPFLs are excised for histological analysis, often leading to aesthetic concerns. Reflectance confocal microscopy (RCM) can reduce the need for biopsies, but it is limited to specialized centers and requires skilled operators. Aims: This study aimed to assess the impact of personal skill, diagnostic confidence, and perceived difficulty on the diagnostic accuracy and management in the differential dermoscopic diagnosis of aPFLs. Methods: A total of 1197 aPFLs dermoscopic images were examined on a teledermoscopic web platform by 155 dermatologists and residents with 4 skill levels (<1, 1–4, 5–8, >8 years). They were asked to give a diagnosis, to estimate their confidence and rate the case, and choose a management strategy: “follow-up”, “RCM” or “biopsy”. Diagnostic accuracy was examined according to the personal skill level, confidence level, and rating in three settings: (I) all seven diagnoses, (II) LM vs. PAK vs. fully benign aPFLs, (III) malignant vs benign aPFLs. The same analyses were performed for management decisions. Results: The diagnostic confidence has a certain impact on the diagnostic accuracy, both in terms of multi-class diagnosis of six aPFLs in diagnostic (setting 1) and in benign vs malignant (setting 3) or benign vs. malignant/premalignant discrimination (setting 2). The perceived difficulty influences the management of benign lesions, with easy ratings predominantly matching with “follow-up” decision in benign cases, but not that of malignant lesions assigned to “biopsy”. The experience level had an impact on the perception of the number of real easy cases and had no to minimal impact on the average diagnostic accuracy of aPFLs. It, however, has an impact on the management strategy and specifically in terms of error reduction, namely the lowest rates of missed malignant cases after 8 years of experience and the lowest rates of inappropriate biopsies of benign lesions after 1 year of experience. Conclusions: The noninvasive diagnosis and management of aPFLs rest on a daily challenge. Highlighting which specific subgroups of lesions need attention and second-level examination (RCM) or biopsy can help detect early malignant cases, and, in parallel, reduce the rate of unnecessary removal of benign lesions. Full article

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

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26 pages, 1154 KB

Open AccessReview

AI-Based Characterization of Breast Cancer in Mammography and Tomosynthesis: A Review of Radiomics and Deep Learning for Subtyping, Staging, and Prognosis

by Ana M. Mota

Cancers 2025, 17(20), 3387; https://doi.org/10.3390/cancers17203387 - 21 Oct 2025

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Abstract

Background: Biopsy remains the gold standard for characterizing breast cancer, but it is invasive, costly, and may not fully capture tumor heterogeneity. Advances in artificial intelligence (AI) now allow for the extraction of biological and clinical information from medical images, raising the [...] Read more.

Background: Biopsy remains the gold standard for characterizing breast cancer, but it is invasive, costly, and may not fully capture tumor heterogeneity. Advances in artificial intelligence (AI) now allow for the extraction of biological and clinical information from medical images, raising the possibility of using imaging as a non-invasive alternative. Methods: A semi-systematic review was conducted to identify AI-based approaches applied to mammography (MM) and breast tomosynthesis (BT) for tumor subtyping, staging, and prognosis. A PubMed search retrieved 1091 articles, of which 81 studies met inclusion criteria (63 MM, 18 BT). Studies were analyzed by clinical target, modality, AI pipeline, number of cases, dataset type, and performance metrics (AUC, accuracy, or C-index). Results: Most studies focused on tumor subtyping, particularly receptor status and molecular classification. Contrast-enhanced spectral mammography (CESM) was frequently used in radiomics pipelines, while end-to-end deep learning (DL) approaches were increasingly applied to MM. Deep models achieved strong performance for ER/PR and HER2 status prediction, especially in large datasets. Fewer studies addressed staging or prognosis, but promising results were obtained for axillary lymph node (ALN) metastasis and pathological complete response (pCR). Multimodal and longitudinal approaches—especially those combining MM or BT with MRI or ultrasound—show improved accuracy but remain rare. Public datasets were used in only a minority of studies, limiting reproducibility. Conclusions: AI models can predict key tumor characteristics directly from MM and BT, showing promise as non-invasive tools to complement or even replace biopsy. However, challenges remain in terms of generalizability, external validation, and clinical integration. Future work should prioritize standardized annotations, larger multicentric datasets, and integration of histological or transcriptomic validation to ensure robustness and real-world applicability. Full article

(This article belongs to the Special Issue Advances in Breast Cancer Imaging: From Detection to Personalized Diagnosis)

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26 pages, 2438 KB

Open AccessReview

Exosomes in HPV-Associated Cancers: From Biomarkers to Engineered Therapeutics

by Muharrem Okan Cakir, Melis Selek, Betul Yilmaz, Mustafa Ozdogan and G. Hossein Ashrafi

Cancers 2025, 17(20), 3386; https://doi.org/10.3390/cancers17203386 - 21 Oct 2025

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Abstract

Background/Objectives: Human papillomavirus (HPV) is the main causative agent of cervical cancer and contributes to a significant proportion of other anogenital and oropharyngeal malignancies. The need for better biomarkers and therapeutic approaches in HPV-associated cancers has drawn attention to exosomes, small extracellular vesicles [...] Read more.

Background/Objectives: Human papillomavirus (HPV) is the main causative agent of cervical cancer and contributes to a significant proportion of other anogenital and oropharyngeal malignancies. The need for better biomarkers and therapeutic approaches in HPV-associated cancers has drawn attention to exosomes, small extracellular vesicles known for their stability, biomolecule transport capabilities, and role in cell-to-cell communication. Methods: This review comprehensively evaluates recent literature on the diagnostic, prognostic, and therapeutic applications of small extracellular vesicles, particularly exosomes, in HPV-related cancers. It analyzes findings on exosomal nucleic acids, proteins, and long non-coding RNAs, as well as engineered exosome-based therapies. Results: Exosomal miRNAs (e.g., miR-204-5p, miR-99a-5p, miR-21), proteins (e.g., glycolytic enzymes, HSP90), and lncRNAs (e.g., HOTAIR, DLEU1) have emerged as promising biomarkers for disease detection and monitoring. Exosomal cargo actively participates in HPV-related tumor progression. For example, miRNAs such as miR-21 and miR-146a modulate immune cell polarization and inflammatory signaling, while lncRNAs like HOTAIR promote oncogenic transcriptional programs. Exosomal proteins including HSP90 and ANXA1 facilitate extracellular matrix remodeling and immune evasion, thereby influencing tumor growth and metastasis. In HPV-positive head and neck and cervical cancers, exosomal cargo reflects HPV status, tumor progression, and treatment response. Therapeutic studies demonstrate the utility of exosomes in vaccine delivery, immune modulation, and drug delivery systems, including the use of PROTACs. However, clinical translation faces barriers including isolation protocol standardization, biomarker validation, and scalable production. Conclusions: Exosomes hold great promise for integration into diagnostic and therapeutic workflows for HPV-related cancers. Future research should focus on resolving standardization issues, validating biomarkers in diverse cohorts, and optimizing engineered exosome platforms for targeted therapy. Full article

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

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10 pages, 234 KB

Open AccessArticle

Index Cancer Density Is a Stronger Predictor of Pelvic Lymph Node Invasion than Percentage of Biopsy-Positive Cores in EAU High-Risk Prostate Cancer: Clinical Impact in 254 Patients Treated and Staged with Robot-Assisted Radical Prostatectomy

by Maria Angela Cerruto, Antonio Benito Porcaro, Alberto Bianchi, Alessandro Tafuri, Andrea Panunzio, Rosella Orlando, Francesca Montanaro, Alberto Baielli, Francesco Artoni, Andrea Franceschini, Lorenzo De Bon, Alessandro Veccia, Riccardo Rizzetto, Matteo Brunelli, Vincenzo De Marco, Filippo Migliorini, Salvatore Siracusano, Riccardo Giuseppe Bertolo and Alessandro Antonelli

Cancers 2025, 17(20), 3385; https://doi.org/10.3390/cancers17203385 - 21 Oct 2025

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Abstract

Objectives: To evaluate the density percentage of biopsy-positive cores (BPCs) relative to prostate volume, defined as Id-BPC, compared with BPCs as a predictor of pelvic lymph node invasion (PLNI) in EAU high-risk prostate cancer (PCa) treated and staged with robot-assisted radical prostatectomy (RARP). [...] Read more.

Objectives: To evaluate the density percentage of biopsy-positive cores (BPCs) relative to prostate volume, defined as Id-BPC, compared with BPCs as a predictor of pelvic lymph node invasion (PLNI) in EAU high-risk prostate cancer (PCa) treated and staged with robot-assisted radical prostatectomy (RARP). Methods: Overall, 254 EAU high-risk patients were treated with RARP between January 2013 and December 2021. Results: Overall, PLNI was detected in 23.2% of patients who were more likely to present with standard adverse clinical features; likewise, on multivariate models, PLNI was independently predicted by both BPC and Id-BPC with the latter showing a stronger association (OR = 1.926; 95% CI: 1.246–2.977; p = 0.003) than the former (OR = 1.028; 95% CI: 1.014–1.042; p < 0.0001); moreover, when cancer density was categorized at Id-BPC ≥ 1.0 versus < 1.0, the prediction was even stronger (OR = 3.535; 95% CI: 1.551–8.054; p = 0.003). Conclusions: In the investigated population, Id-BPC was a stronger predictor of PLNI than BPC; accordingly, as Id-BPC increased, patients were more likely to have PLNI; equivalently, subjects presenting with Id-BPC less than one were 3.5 times less likely to have PLNI. This information has implications for clinical practice as well as for computing nomograms or patterns of artificial intelligence networks. Full article

(This article belongs to the Special Issue Robot-Assisted Radical Prostatectomy for Urologic Cancer: State of the Art)

2 pages, 1409 KB

Open AccessCorrection

Correction: Miyajima, Y.; Kawakami, T. Treatment Selection for Patients with HER2-Negative Metastatic Gastric Cancer Expressing Claudin 18.2 and PD-L1. Cancers 2025, 17, 1120

by Yusuke Miyajima and Takeshi Kawakami

Cancers 2025, 17(20), 3384; https://doi.org/10.3390/cancers17203384 - 21 Oct 2025

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Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Developments in the Management of Gastrointestinal Malignancies)

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20 pages, 2387 KB

Open AccessArticle

Prognostic Value of Dynamic Changes in Immune-Inflammatory and Tumor Biomarkers Following Chemoradiotherapy in Locally Advanced Rectal Cancer

by Mahmoud Al-Masri, Yasmin Safi, Mohammad Almasri, Ramiz Kardan, Daliana Mustafa, Osama Alayyan, Bilal Kahalah and Rama AlMasri

Cancers 2025, 17(20), 3383; https://doi.org/10.3390/cancers17203383 - 20 Oct 2025

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Abstract

Background: The prognostic utility of inflammatory and tumor biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and carcinoembryonic antigen (CEA), in rectal cancer has been increasingly studied, but results remain inconsistent. This study evaluates the prognostic significance of pre- and post-chemoradiotherapy (CRT) levels [...] Read more.

Background: The prognostic utility of inflammatory and tumor biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and carcinoembryonic antigen (CEA), in rectal cancer has been increasingly studied, but results remain inconsistent. This study evaluates the prognostic significance of pre- and post-chemoradiotherapy (CRT) levels and dynamic changes in NLR, PLR, and CEA for predicting overall survival (OS) and disease-free survival (DFS) in locally advanced rectal cancer (LARC). Methods: This retrospective study included 261 LARC patients treated with neoadjuvant CRT followed by curative surgery. Pre- and post-CRT NLR, PLR, and CEA were collected. Survival analyses were performed using Kaplan–Meier curves and Cox proportional hazards models. ROC curves assessed predictive performance, and patients were stratified by cut-offs and biomarker changes (delta values). Results: The cohort had a mean age of 55.5 years; 55.9% were male, and 93.5% had clinical stage III disease. Post-CRT NLR (HR: 1.05, p = 0.007) and CEA (HR: 1.00, p < 0.001) were independently associated with OS, while post-CRT CEA and AJCC stage III were predictors of DFS (HR: 4.12, p = 0.009). ROC analysis showed improved accuracy when combining NLR (AUC = 0.66) and CEA (AUC = 0.70), yielding a combined AUC of 0.84 for OS. Patients with decreases in both NLR and CEA had the most favorable outcomes, whereas increases in both markers indicated poor prognosis (OS p < 0.0001; DFS p = 0.00019). Conclusions: Post-CRT levels and dynamic changes in NLR and CEA are independent prognostic markers in rectal cancer. Their combined assessment enhances survival prediction and may guide personalized postoperative surveillance and treatment strategies. Full article

(This article belongs to the Special Issue Biomarkers for Therapy Response in Gastrointestinal Malignancies: Predicting Outcomes and Personalizing Care)

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15 pages, 979 KB

Open AccessArticle

Visceral Pleural Invasion as a Determinant of Surgical Strategy in Non–Small Cell Lung Cancer: A Multicenter Study

by Wakako Nagase, Yujin Kudo, Takuya Nagashima, Takahiro Mimae, Yoshihisa Shimada, Masaru Hagiwara, Masatoshi Kakihana, Tatsuo Ohira, Yoshihiro Miyata, Hiroyuki Ito, Morihito Okada and Norihiko Ikeda

Cancers 2025, 17(20), 3382; https://doi.org/10.3390/cancers17203382 - 20 Oct 2025

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Abstract

Background: Visceral pleural invasion (VPI) has traditionally been regarded as a negative prognostic indicator in non-small-cell lung cancer (NSCLC). However, with the increasing adoption of sublobar resection for small-sized NSCLC, the clinical significance of VPI is being fundamentally reassessed. Specifically, it remains uncertain [...] Read more.

Background: Visceral pleural invasion (VPI) has traditionally been regarded as a negative prognostic indicator in non-small-cell lung cancer (NSCLC). However, with the increasing adoption of sublobar resection for small-sized NSCLC, the clinical significance of VPI is being fundamentally reassessed. Specifically, it remains uncertain whether VPI is indicative of tumor size or represents distinct metastatic behavior. Methods: We conducted a retrospective comprehensive multicenter study involving 2464 patients with pathologically confirmed NSCLC ≤ 3 cm who underwent complete resection at three Japanese institutions. The prevalence, metastatic patterns, and prognostic impact of VPI were systematically evaluated, with particular focus on histological growth patterns. Results: VPI was identified in 370 patients (15%). Notably, VPI-positive tumors demonstrated a doubled incidence of lymph node metastasis (31% vs. 15%, p < 0.001) and a distinct metastatic profile characterized by preferential hilar spread (#12, 16.9%) and an increased risk of skip N2 metastasis (4.0% vs. 2.0%). Five-year recurrence-free survival was significantly reduced in the VPI group (33.7% vs. 50.6%, respectively). Conversely, adenocarcinomas with lepidic characteristics demonstrated a minimal risk of VPI or nodal metastasis, with incidences of 2% and 1%, respectively. This finding highlights the heterogeneity in the biological aggressiveness of small-sized NSCLC. Conclusions: Our findings suggest that VPI is not merely a histopathological descriptor but also acts as a clinically significant indicator of aggressive metastatic behavior, potentially enhancing surgical and staging approaches beyond just considering tumor size. With the increasing adoption of sublobar resection for small-sized NSCLC, recognizing that VPI appears to be associated with predominant hilar involvement and an elevated risk of skip N2 metastasis may help refine decisions on the extent of lung and lymph node resection. Full article

(This article belongs to the Special Issue Surgical Management of Non-Small Cell Lung Cancer)

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20 pages, 701 KB

Open AccessArticle

Familial Non-Medullary Thyroid Carcinoma: Distinct Clinicopathological Features and Prognostic Implications in a Large Cohort of 46,572 Patients

by Cho Rok Lee, Jin Kyong Kim, Joon Ho, Sang-Wook Kang, Jandee Lee, Jong Ju Jeong, Kee-Hyun Nam and Woong Youn Chung

Cancers 2025, 17(20), 3381; https://doi.org/10.3390/cancers17203381 - 20 Oct 2025

Viewed by 309

Abstract

Background: The incidence of thyroid cancer has rapidly increased worldwide, and familial aggregation of the disease has been increasingly recognized. This study aimed to evaluate the prevalence, clinicopathological characteristics, and long-term outcomes of familial non-medullary thyroid cancer (FNMTC) in a large institutional cohort. [...] Read more.

Background: The incidence of thyroid cancer has rapidly increased worldwide, and familial aggregation of the disease has been increasingly recognized. This study aimed to evaluate the prevalence, clinicopathological characteristics, and long-term outcomes of familial non-medullary thyroid cancer (FNMTC) in a large institutional cohort. Methods: Patients with non-medullary thyroid cancer (NMTC) who had undergone surgery were classified as sporadic NMTC (SNMTC) or FNMTC based on family history. Clinicopathological features at diagnosis and surgery were compared, and prognostic outcomes were analyzed in patients with follow-up data. Results: Among the 46,572 NMTC patients, 3829 (8.2%) had FNMTC, and 42,743 (91.8%) had SNMTC. FNMTC was more prevalent in women and occurred at a younger age. Its proportion increased over time, peaking in the 35–59 age group. FNMTC showed higher rates of bilaterality (23.5% vs. 17.5%, p < 0.001), multifocality (39.0% vs. 30.5%, p < 0.001), and central lymph node metastasis (41.5% vs. 38.8%, p = 0.001), despite smaller tumors (0.9 ± 0.7 cm vs. 1.0 ± 0.9 cm, p < 0.001). Recurrence rates were similar between the two groups (1.9% vs. 2.3%, p = 0.1), but overall survival was higher in the FNMTC group (99.6% vs. 98.6%, p < 0.001). Family history, extracapsular extension, lymph node metastasis, and tumor size independently predicted recurrence. Family history significantly impacted recurrence-free survival in the intermediate-to-high-risk group (HR = 1.65, p < 0.001) but not in low-risk patients. Conclusions: FNMTC represents a distinct NMTC subset with more extensive local disease but favorable survival, warranting risk-adapted management, particularly for intermediate-to-high-risk patients. Full article

(This article belongs to the Section Cancer Therapy)

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28 pages, 1015 KB

Open AccessReview

Multicentric and Multifocal Breast Tumors—Narrative Literature Review

by Mircea-Octavian Poenaru, Mihaela Amza, Cristian-Valentin Toma, Fernanda-Ecaterina Augustin, Irina Pacu, Giorgia Zampieri, Liana Ples, Romina-Marina Sima and Andrei-Sebastian Diaconescu

Cancers 2025, 17(20), 3380; https://doi.org/10.3390/cancers17203380 - 20 Oct 2025

Viewed by 556

Abstract

Background: Multifocal (MF) and multicentric (MC) breast cancers, defined by the presence of multiple synchronous tumor foci within the same breast, present important diagnostic, therapeutic, and prognostic challenges. Historically considered a contraindication for breast-conserving therapy (BCT), advances in imaging, surgical techniques, and adjuvant [...] Read more.

Background: Multifocal (MF) and multicentric (MC) breast cancers, defined by the presence of multiple synchronous tumor foci within the same breast, present important diagnostic, therapeutic, and prognostic challenges. Historically considered a contraindication for breast-conserving therapy (BCT), advances in imaging, surgical techniques, and adjuvant therapy have reshaped management strategies. Methods: A narrative literature review was conducted through PubMed, Web of Science, and Scopus, prioritizing ISI-indexed articles published within the last 10–15 years. More than 55 relevant studies, including systematic reviews, meta-analyses, and large cohorts, were analyzed to evaluate epidemiology, pathological features, imaging modalities, treatment outcomes, and prognosis of MF/MC breast cancers. Results: The reported incidence of MF/MC breast cancers ranges from 10% to 24%, increasing when MRI or whole-organ pathology is applied. MRI can detect otherwise occult additional foci in up to 30% of patients, improving staging accuracy but raising concerns of overdiagnosis. MF/MC presentation is strongly associated with lobular histology, younger age at diagnosis, and higher rates of axillary involvement—nodal positivity is observed in up to 45% of MF/MC cases versus 28% in unifocal tumors. Pathological analyses demonstrate frequent clonal origin of MF lesions, whereas MC lesions may represent independent primaries, occasionally with receptor heterogeneity that alters systemic therapy selection. From a prognostic perspective, older series suggested shorter breast cancer-specific survival (e.g., median 154 vs. 204 months for MF/MC vs. unifocal disease), and higher local recurrence with BCT. However, contemporary analyses, including a 2022 meta-analysis of 15,703 patients, demonstrated no significant difference in overall or disease-free survival once adjusted for tumor size and nodal status. Local recurrence remains slightly higher with BCT in MF/MC (5.6% vs. 4.2%), but outcomes are equivalent to mastectomy when radiotherapy is appropriately delivered. Five-year survival in early-stage MF/MC exceeds 90% with guideline-concordant multimodal therapy. Conclusions: MF/MC breast cancers represent a biologically heterogeneous entity. Optimal outcomes rely on precise imaging, complete excision, tailored systemic therapy, and multidisciplinary management, with increasing acceptance of breast conservation in selected patients. Full article

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

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14 pages, 2631 KB

Open AccessFeature PaperArticle

Impact of UV Exposure and Incidence of Merkel Cell Carcinoma Between 1990 and 2018 in Austria

by Boban M. Erovic, Alois Schmalwieser, Rudolf Seemann, Florian Schwabel, Stefan Grasl, Stefan Janik and Matthaeus C. Grasl

Cancers 2025, 17(20), 3379; https://doi.org/10.3390/cancers17203379 - 20 Oct 2025

Viewed by 243

Abstract

Background: The purpose of this study was to report on (i) patients’ demographics and (ii) Austrian UV data, and (iii) to examine a possible association between UV exposure and the onset of disease in Austria between 1990 and 2018. Methods: We included all [...] Read more.

Background: The purpose of this study was to report on (i) patients’ demographics and (ii) Austrian UV data, and (iii) to examine a possible association between UV exposure and the onset of disease in Austria between 1990 and 2018. Methods: We included all patients diagnosed with MCC and their clinical and demographic data to compare with UV radiation. Results: A total of 538 cases were identified, and the incidence (per 100,000/y) increased from 0.013 to 0.43. The MCC incidence was significantly higher in West Austria (mean incidence 0.269 ± 0.04) compared to East Austria (0.180 ± 0.02 p = 0.005). Notably, the mean and maximum UV radiation values were higher in the western (p < 0.001) compared to the eastern part of Austria. The sum (p = 0.033; r: 0.503) and mean (p = 0.019; r: 0.546) UV values correlated significantly with the MCC incidence. Conclusions: The incidence of MCC increased significantly, and higher UV radiation levels in western Austria compared to the east were associated with a correspondingly higher MCC incidence, suggesting a contributing role of UV radiation in general. Full article

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

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16 pages, 830 KB

Open AccessReview

Colony-Stimulating Factor 3 Receptor Mutations and Variants in Hematological Malignancies

by Clifford Liongue, Tarindhi Ratnayake and Alister C. Ward

Cancers 2025, 17(20), 3378; https://doi.org/10.3390/cancers17203378 - 20 Oct 2025

Viewed by 375

Abstract

Colony-stimulating factor 3 (CSF3), additionally called granulocyte colony-stimulating factor (G-CSF), is the major cytokine regulating neutrophil production and also impacting their function. The actions of this cytokine are mediated through its unique receptor, the colony-stimulating factor 3 receptor (CSF3R). Several classes of pathogenic [...] Read more.

Colony-stimulating factor 3 (CSF3), additionally called granulocyte colony-stimulating factor (G-CSF), is the major cytokine regulating neutrophil production and also impacting their function. The actions of this cytokine are mediated through its unique receptor, the colony-stimulating factor 3 receptor (CSF3R). Several classes of pathogenic mutations in the CSF3R gene have been identified that have distinct biological properties and clinical impacts. This review provides an overview of CSF3R, the various pathogenic CSF3R mutations/variants and their biological effects. It also details the diseases to which they contribute, notably including chronic neutrophilic leukemia (CNL) and other myeloproliferative neoplasms (MPNs), myelodysplastic neoplasms (MDS), combined MDS/MPN disorders such as atypical chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML), as well as acute myeloid leukemia (AML) and lymphoid malignancies. Full article

(This article belongs to the Special Issue Aberrant Cytokine Receptor Signaling in Hematological Cancers and Proliferative Disorders)

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15 pages, 564 KB

Open AccessReview

Immune Checkpoint Therapy for Thymic Carcinoma

by Jinhui Li, Fuling Mao, Hongyu Liu and Jun Chen

Cancers 2025, 17(20), 3377; https://doi.org/10.3390/cancers17203377 - 20 Oct 2025

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Abstract

Thymic carcinoma (TC) is a rare, aggressive cancer that originates from thymus’s epithelial cells. It distinguishes itself from other thymic epithelial tumors with its unique pathological structure, clinical behavior, and immune characteristics. Immune checkpoint inhibitors (ICIs) targeting the Programmed cell death protein 1/Programmed [...] Read more.

Thymic carcinoma (TC) is a rare, aggressive cancer that originates from thymus’s epithelial cells. It distinguishes itself from other thymic epithelial tumors with its unique pathological structure, clinical behavior, and immune characteristics. Immune checkpoint inhibitors (ICIs) targeting the Programmed cell death protein 1/Programmed cell death protein ligand 1 (PD-1/PD-L1) pathway have shown promise in advanced TC, potentially benefiting from frequent PD-L1 overexpression and abundant CD8⁺ tumor-infiltrating lymphocytes (TILs), despite typically low tumor mutational burden (TMB). While ICI monotherapy can achieve disease control in some patients, its overall efficacy is limited and it is associated with a distinct profile of immune-related adverse events (irAEs) which occur less often than in thymomas. The predictive value of biomarkers—particularly PD-L1 expression—remains uncertain, underscoring the importance of consistent assessment criteria. In this review, we summarize evidence on ICI monotherapy as well as combination approaches that incorporate anti-angiogenic agents, chemotherapy, or dual checkpoint blockade. Emerging therapeutic targets—such as CD70, TIM-3, and B7-H4—are also considered in the context of their potential clinical relevance. Finally, we discuss future directions aimed at improving efficacy, extending response durability, and reducing treatment-related toxicity through biomarker-based patient selection and tailored therapeutic strategies. Full article

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

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Open AccessArticle

Molecular Testing and Surgical Outcomes in Bethesda III and IV Thyroid Nodules: A Retrospective Cohort Study

by Alexandra E. Payne, Layla Gobeil, Marc P. Pusztaszeri, Isabelle Bannister, Saruchi Bandargal, Sabrina Daniela da Silva and Veronique-Isabelle Forest

Cancers 2025, 17(20), 3376; https://doi.org/10.3390/cancers17203376 - 20 Oct 2025

Viewed by 510

Abstract

Background: Bethesda III and IV thyroid nodules, which fall under the category of indeterminate cytology, pose challenges in clinical decision-making due to their ambiguous risk of malignancy. Molecular testing has been increasingly employed to aid risk stratification and optimize the extent of [...] Read more.

Background: Bethesda III and IV thyroid nodules, which fall under the category of indeterminate cytology, pose challenges in clinical decision-making due to their ambiguous risk of malignancy. Molecular testing has been increasingly employed to aid risk stratification and optimize the extent of surgical intervention. Methods: A retrospective review of 410 patients with Bethesda III and IV thyroid nodules who underwent thyroid surgery at McGill University teaching hospitals between January 2016 and April 2022. Patients were grouped based on whether or not they underwent preoperative molecular testing. Data were collected on demographic variables, histopathologic diagnosis, mutation profiles, and surgical outcomes. The primary outcome was to assess for concordance between surgical intervention and final pathology in both groups, with a focus on identifying optimal versus suboptimal management. Optimal management is defined as surgery appropriate to the aggressiveness of disease, meaning a hemi-thyroidectomy for a non-aggressive malignancy, total thyroidectomy for an aggressive malignancy, and no surgery for a benign nodule. Furthermore, suboptimal management includes unnecessary surgery or incorrect surgery for the level of aggressivity of the nodule. Results: Among the 410 patients, 203 underwent molecular testing, while 207 did not. Of those who underwent molecular testing, 117 had Bethesda III nodules and 86 had Bethesda IV nodules. In the non-tested group, 129 and 78 patients had Bethesda III and IV nodules, respectively. Optimal surgical intervention was achieved in 67.5% of patients who underwent molecular testing, compared with 25.1% in those who did not (p < 0.001). Subgroup analysis revealed that 61.5% of Bethesda III nodules with molecular testing received optimal care versus 21.0% of those without testing. In the Bethesda IV cohort, optimal surgery was achieved in 75.6% with testing versus 32.1% without. Among the suboptimally managed patients, 70.1% (155/221) were from the group that did not undergo molecular testing. In addition, molecular testing identified aggressive mutations such as BRAF V600E and TERT promoter mutations more frequently in Bethesda III nodules, while RAS-like mutations, associated with indolent behavior, predominated in Bethesda IV nodules. Conclusions: In this study, molecular testing significantly improved risk stratification and the likelihood of optimal surgical management in patients with Bethesda III and IV thyroid nodules. Incorporating molecular diagnostics into the standard preoperative workflow may enhance patient care, reduce unnecessary surgeries, and optimize the extent of surgery. Future studies should evaluate the cost-effectiveness and broader implementation of molecular testing in diverse healthcare settings. Full article

(This article belongs to the Special Issue Classification, Risk Assessment and Clinical Management of Malignant Thyroid Nodules: 2nd Edition)

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19 pages, 314 KB

Open AccessArticle

Stifled Motivation, Systemic Neglect: A Cross-Sectional Analysis of Inactivity in Post-Chemotherapy Cancer Survivors in the Middle East and North Africa Region

by Mariem Gaddour, Maha Ammar, Leila Ben Fatma, Halil İbrahim Ceylan, Ines Loubiri, Nedra El Feni, Sonia Jemni, Luca Puce, Nicola Luigi Bragazzi and Ismail Dergaa

Cancers 2025, 17(20), 3375; https://doi.org/10.3390/cancers17203375 - 19 Oct 2025

Viewed by 357

Abstract

Background: Physical activity provides substantial survival and quality-of-life benefits for cancer survivors, yet participation remains suboptimal globally, particularly in the Middle East and North Africa (MENA) regions. This study represents the first comprehensive examination of physical activity barriers and facilitators among Tunisian cancer [...] Read more.

Background: Physical activity provides substantial survival and quality-of-life benefits for cancer survivors, yet participation remains suboptimal globally, particularly in the Middle East and North Africa (MENA) regions. This study represents the first comprehensive examination of physical activity barriers and facilitators among Tunisian cancer survivors. Methods: This cross-sectional study recruited 120 cancer survivors ≥3 months post-chemotherapy completion from University Hospital Farhat Hached, Sousse, Tunisia (October–December 2024). Participants completed validated questionnaires via structured telephone interviews: the International Physical Activity Questionnaire Short Form (IPAQ-SF), the Physical Activity Barriers After Cancer scale (PABAC), the Fatigue Assessment Scale (FAS), and the Patient Activation Measure (PAM-13). Statistical analyses included descriptive statistics, receiver operating characteristic (ROC) analysis, correlation analyses, and multivariable regression modeling with Bonferroni correction for multiple comparisons. Results: Participants (mean age 51.89 ± 10.2 years, 73.9% female) demonstrated significant physical activity declines post-chemotherapy: moderate activity decreased from 31.1% to 1.7% (p < 0.001), median intensity declined from 297 to 44 MET-min/week (p < 0.001). Mean PABAC score was 29.72 ± 5.13, with cognitive barriers predominating (2.85 ± 0.58). Fatigue was universal (100%), with 21% reporting severe fatigue (FAS ≥ 35). Only 26.1% received exercise guidance from healthcare professionals. PABAC demonstrated excellent predictive performance for physical inactivity (AUC = 0.805, 95%CI: 0.724–0.887). Independent predictors of higher barriers included fatigue severity (β = 0.466, p < 0.001), low patient activation (β = −0.091, p = 0.010), and advanced cancer stage (β = 1.932, p = 0.008). Conclusions: Tunisian cancer survivors experience substantial, multidimensional barriers to physical activity, with inadequate healthcare guidance representing a critical system-level gap. Findings support the development of culturally adapted, multidisciplinary interventions that target modifiable cognitive and symptom-related barriers, while enhancing patient activation and healthcare provider engagement. Full article

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

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Open AccessReview

Multidisciplinary Perspective of Spread Through Air Spaces in Lung Cancer: A Narrative Review

by Riccardo Orlandi, Lorenzo Bramati, Maria C. Andrisani, Giorgio A. Croci, Claudia Bareggi, Simona Castiglioni, Francesca Romboni, Sara Franzi and Davide Tosi

Cancers 2025, 17(20), 3374; https://doi.org/10.3390/cancers17203374 - 19 Oct 2025

Viewed by 471

Abstract

Spread Through Air Spaces (STAS) is an emerging pattern of tumor invasion in lung cancer, first recognized by the World Health Organization in 2015. This narrative review examines STAS from a multidisciplinary perspective, integrating pathologic, radiologic, oncologic, and surgical points of view, together [...] Read more.

Spread Through Air Spaces (STAS) is an emerging pattern of tumor invasion in lung cancer, first recognized by the World Health Organization in 2015. This narrative review examines STAS from a multidisciplinary perspective, integrating pathologic, radiologic, oncologic, and surgical points of view, together with molecular biology to assess its clinical significance, diagnostic challenges, and therapeutic implications. Pathologically, STAS is characterized by tumor cells floating beyond the main tumor, contributing to recurrence and poor prognosis. Radiologic advancements suggest potential imaging markers for STAS, such as spiculation, the absence of an air bronchogram, solid tumor components, as well as high fluorodeoxyglucose uptake, though definitive preoperative identification remains challenging. Oncologic studies link STAS to aggressive tumor behavior and lympho-vascular invasion, suggesting a role for adjuvant chemotherapy even in the earliest stages of disease; furthermore, specific molecular alterations have been discovered, including EGFR wild-type status and ALK/ROS1 rearrangements together with high Ki-67 expression, tumor necrosis, and alterations in cell adhesion proteins like E-cadherin. Surgical aspects highlight the increased risk of recurrence following limited resection, raising concerns about optimal surgical strategies. The debate over STAS as a true invasion mechanism versus an artifact from surgical handling underscores the need for standardized pathological evaluation. This review aims to refine STAS detection, integrate it into multidisciplinary treatment decision-making, and assess its potential as a staging criterion in lung cancer management. Full article

(This article belongs to the Special Issue Surgical Management of Non-Small Cell Lung Cancer)

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36 pages, 3191 KB

Open AccessReview

The Interplay Between lncRNAs–microRNAs Network Dysregulation and Cellular Hallmarks of Thyroid Cancer

by Maryam Hejazi, Ramin Heshmat, Gita Shafiee, Bagher Larijani, Amir Ali Mokhtarzadeh, Vida Ebrahimi and Seyed Mohammad Tavangar

Cancers 2025, 17(20), 3373; https://doi.org/10.3390/cancers17203373 - 18 Oct 2025

Viewed by 345

Abstract

Background/Objectives: Thyroid cancer (TC) is the most common type of endocrine neoplasm and is increasing in incidence, particularly papillary thyroid carcinoma (PTC). Early-stage disease has a favorable prognosis; however, advanced forms, such as anaplastic thyroid carcinoma, complicate treatment. Long non-coding RNAs (lncRNAs), [...] Read more.

Background/Objectives: Thyroid cancer (TC) is the most common type of endocrine neoplasm and is increasing in incidence, particularly papillary thyroid carcinoma (PTC). Early-stage disease has a favorable prognosis; however, advanced forms, such as anaplastic thyroid carcinoma, complicate treatment. Long non-coding RNAs (lncRNAs), longer than 200 nucleotides and non-coding, together with microRNAs, have emerged as major regulators of TC pathogenesis. This review summarizes data on how dysregulated lncRNAs influence the hallmarks of cancer in thyroid malignancies. Methods: We reviewed the literature on the role of lncRNAs and microRNAs in TC, focusing on their functions as competing endogenous RNAs (ceRNAs), regulators of PI3K/AKT and Wnt/β-catenin pathways, and controllers of epigenetic alterations. Results: Dysregulated lncRNAs contribute to hallmarks including sustained growth, evading suppressors, resisting death, replicative immortality, angiogenesis, invasion, metabolic reprogramming, immune evasion, genomic instability, and tumor-promoting inflammation. ceRNA mechanisms amplify immune evasion by regulating checkpoint proteins and cytokines, altering immune cell activity. Altered lncRNA profiles correlate with aggressiveness, metastasis, and prognosis. Notable lncRNAs, such as H19, MALAT1, and DOCK9-AS2, dysregulate oncogenic pathways and represent potential biomarkers. Conclusions: Advances in therapeutics suggest inhibiting oncogenic lncRNAs or restoring tumor-suppressive lncRNAs via RNA interference, antisense oligonucleotides, or CRISPR/Cas9 editing. New technologies, including single-cell RNA sequencing and spatial transcriptomics, will improve understanding of heterogeneous lncRNA–microRNA networks in TC and support precision medicine. LncRNAs signify both molecular drivers and clinical targets for thyroid cancer. Full article

(This article belongs to the Special Issue MicroRNA and Cancer Immunology)

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21 pages, 1112 KB

Open AccessReview

Novel Molecular Insights and Evolution of Less Toxic Therapeutic Strategies in Burkitt Lymphoma

by Coen J. Lap and Kieron Dunleavy

Cancers 2025, 17(20), 3372; https://doi.org/10.3390/cancers17203372 - 18 Oct 2025

Viewed by 648

Abstract

Burkitt lymphoma (BL) is a rare, aggressive B-cell lymphoma that is characterized by rapid tumor proliferation and frequent extra-nodal involvement. While prompt diagnosis and initiation of highly intensive chemotherapy results in cure rates over 90% in children and adolescents, outcomes in adults are [...] Read more.

Burkitt lymphoma (BL) is a rare, aggressive B-cell lymphoma that is characterized by rapid tumor proliferation and frequent extra-nodal involvement. While prompt diagnosis and initiation of highly intensive chemotherapy results in cure rates over 90% in children and adolescents, outcomes in adults are more modest, as comorbidities and advancing age may compromise treatment tolerability. In recent years, intermediate-intensity regimens have been developed for BL. These are highly effective in patients of all ages and associated with significantly less treatment-related toxicity compared to traditional high-dose chemotherapy. This was demonstrated in a recent randomized study of dose-intensive R-CODOX-M/R-IVAC compared to the reduced-intensity DA-EPOCH-R regimen, which was associated with equivalent outcomes but with significantly fewer side effects. Regardless of the chemotherapy platform, CNS involvement at baseline predicts a significantly inferior outcome, and the development of an optimal approach for these patients is an area of unmet need in BL therapeutics. Patients with relapsed or refractory disease following frontline therapy have very short survival times, as currently available salvage options are largely ineffective. In this regard, novel agents such as anti-CD19 CAR-T cells and bi-specific antibodies are under development in BL. It is hoped that progress in novel drug development, alongside improved understanding of BL biology, to further elucidate its genetic and epigenetic vulnerabilities, will lead to improved outcomes for patients in the future. Full article

(This article belongs to the Special Issue Burkitt Lymphoma: From Pathogenesis to Current Treatments)

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13 pages, 299 KB

Open AccessArticle

Ovarian Cancer in the Era of Precision Surgery and Targeted Therapies

by Yagmur Sisman, Tim Svenstrup Poulsen, Tine Henrichsen Schnack, Claus Høgdall and Estrid Høgdall

Cancers 2025, 17(20), 3371; https://doi.org/10.3390/cancers17203371 - 18 Oct 2025

Viewed by 301

Abstract

Background: High-grade serous ovarian cancer (HGSC) is the most common and aggressive subtype of ovarian cancer. Despite initial response to platinum-based chemotherapy, most patients relapse. Cytoreductive surgery at relapse has been shown to improve survival in selected patients, but the biological mechanisms underlying [...] Read more.

Background: High-grade serous ovarian cancer (HGSC) is the most common and aggressive subtype of ovarian cancer. Despite initial response to platinum-based chemotherapy, most patients relapse. Cytoreductive surgery at relapse has been shown to improve survival in selected patients, but the biological mechanisms underlying recurrence and resistance remain unclear. This study aimed to investigate whether the mutational profile of HGSC changes from diagnosis to relapse, and to evaluate treatment patterns and survival outcomes in a cohort undergoing cytoreductive surgery. Methods: Sixteen patients with HGSC who underwent cytoreductive surgery at both diagnosis and relapse were included. Matched tumor tissue samples (n = 32) were collected and sequenced using a 501-gene cancer panel. Only pathogenic or likely pathogenic variants were registered. Clinical data, treatment history, and survival outcomes were obtained from medical records, with a median follow-up of 63 months. Results: All patients harbored pathogenic or likely pathogenic mutations, most frequently in TP53 (88%) and BRCA1/2 (38%). The mutational landscape was largely stable, with 15 of 16 patients (94%) showing no mutational changes between diagnosis and relapse. One patient acquired a NOTCH2 mutation at relapse. Complete resection was achieved in 88% of relapse surgeries. Median time to first relapse was 32 months, and overall survival was prolonged, with 87.5% of patients alive at last follow-up. BRCA mutated patients showed longer time to relapse, and overall follow-up compared to BRCA wild-type cases. Conclusions: The somatic mutational profile of HGSC remains remarkably stable from diagnosis to relapse. Clinically, this stability suggests that repeat mutational sequencing at relapse is unlikely to yield new actionable findings and may have limited value in guiding treatment decisions. Instead, resistance mechanisms likely arise from epigenetic or non-genetic changes, underscoring the need for future research in these areas and the continued importance of optimal surgical management in selected patients. Full article

(This article belongs to the Special Issue Novel Approaches in the Management of Gynecological Cancers)

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15 pages, 1034 KB

Open AccessArticle

Beyond Morphology: Quantitative MR Relaxometry in Pulmonary Lesion Classification

by Markus Graf, Alexander W. Marka, Andreas Wachter, Tristan Lemke, Nicolas Lenhart, Teresa Schredl, Jonathan Stelter, Kilian Weiss, Marcus Makowski, Dimitrios C. Karampinos, Daniela Pfeiffer, Gregor S. Zimmermann, Seyer Safi, Hans Hoffmann, Keno Bressem, Lisa Adams and Sebastian Ziegelmayer

Cancers 2025, 17(20), 3370; https://doi.org/10.3390/cancers17203370 - 18 Oct 2025

Viewed by 310

Abstract

Background/Objectives: Lung nodules present a common diagnostic challenge, particularly when benign and malignant lesions exhibit similar imaging characteristics. Standard evaluation relies on computed tomography (CT), positron emission tomography (PET), or biopsy, all of which have limitations. Quantitative magnetic resonance (MR) relaxometry using [...] Read more.

Background/Objectives: Lung nodules present a common diagnostic challenge, particularly when benign and malignant lesions exhibit similar imaging characteristics. Standard evaluation relies on computed tomography (CT), positron emission tomography (PET), or biopsy, all of which have limitations. Quantitative magnetic resonance (MR) relaxometry using native longitudinal relaxation time (T1) and transverse relaxation time (T2) mapping offers a radiation-free alternative reflecting tissue-specific differences. Methods: This prospective, single-center study included 64 patients with 76 histologically or radiologically confirmed lung lesions (25 primary lung cancers, 28 metastases, 9 granulomas, and 14 pneumonic infiltrates). The patients underwent T1 and T2 mapping at 3T. Two independent readers quantified the mean values for each lesion. The pre-specified primary endpoints were (1) benign versus malignant and (2) primary lung cancer versus pulmonary metastases. Results: Significant differences in T1 and T2 values were observed across lesion types. Benign lesions exhibited high T2 values (mean 213.6 ms) and low T1 values (mean 836.6 ms), whereas malignant tumors exhibited lower T2 values (~77–78 ms) and higher T1 values (~1460–1504 ms, p < 0.001). Binary classification yielded 95.7% accuracy (sensitivity 93.8% for malignant, specificity 100% for benign) in an internal 70/30 hold-out validation (no external dataset), with consistent performance confirmed by patient-level and nested cross-validation (balanced accuracy ≈ 0.92–0.94). However, malignant subtypes could not be reliably distinguished (p > 0.05), and multiclass accuracy was 60.9%. Conclusions: Quantitative MR relaxometry allows accurate, radiation-free differentiation of benign and malignant lung lesions and may help reduce unnecessary invasive procedures. Full article

(This article belongs to the Special Issue The Development and Application of Imaging Biomarkers in Cancer)

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14 pages, 737 KB

Open AccessArticle

Primary Versus Secondary Non-Urothelial Tumors Involving the Bladder: A 10-Year Analysis of Clinicopathologic Profiles and Adverse Feature Burden

by Alexei Croitor, Vlad Dema, Alin Cumpanas, Razvan Bardan, Diana Herman, Mihail Nanu and Sorin Dema

Cancers 2025, 17(20), 3369; https://doi.org/10.3390/cancers17203369 - 18 Oct 2025

Viewed by 314

Abstract

Background and Objectives: Non-urothelial bladder tumors and secondary bladder involvement from extravesical primaries are uncommon but clinically challenging. We compared clinicopathologic patterns between primary non-urothelial tumors and secondaries, and explored correlates of adverse pathologic features to inform diagnostic triage and surgical planning. Methods: [...] Read more.

Background and Objectives: Non-urothelial bladder tumors and secondary bladder involvement from extravesical primaries are uncommon but clinically challenging. We compared clinicopathologic patterns between primary non-urothelial tumors and secondaries, and explored correlates of adverse pathologic features to inform diagnostic triage and surgical planning. Methods: We performed a single-center retrospective cohort (2014–2024) of consecutive bladder lesions meeting WHO 2022 criteria and AJCC 8th staging. Eligible cases were primary non-urothelial malignancies (squamous cell carcinoma (SCC), adenocarcinoma (ADK), small-cell/neuroendocrine (NEC), sarcomatoid) or secondary bladder involvement (colorectal, prostate, cervix, ovary, uterus, breast). Outcomes included advanced pT (≥pT3), lympho–vascular invasion (LVI), perineural invasion (PNI), nodal metastasis, margin status, and composite adverse events. Results: Of 235 analyzable cases, 59 were primary and 176 were secondary. Age and sex distributions were similar. Secondaries had a higher adverse burden: advanced pT 56.8% vs. 23.7%, LVI 47.2% vs. 27.1%, PNI 40.3% vs. 22.0%, node-positive 11.9% vs. 0%, and any adverse 65.3% vs. 33.9% (all significant). Histology composition differed (p < 10⁻⁶): secondaries were ADK-dominant (59.1%), whereas primaries were enriched for SCC (38.5%), sarcomatoid (28.8%), and NEC (21.2%). Among secondaries, prostate origin showed the most ominous profile (advanced pT 97.5%, PNI 77.5%, positive margins 64.7%); colorectal cases combined high advanced pT (70.2%) with lower margin positivity (27.6%). Adverse-feature count correlated with pT (ρ = 0.586). Conclusions: Secondary bladder involvement carries substantially higher adverse-pathology rates than primary non-urothelial tumors, with origin-specific risk gradients (prostate > colorectal ≳ cervix). Rigorous origin adjudication and a margin-focused, anatomy-adapted surgical strategy may improve outcomes; prospective outcome-linked validation is warranted. Full article

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

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26 pages, 875 KB

Open AccessReview

Digital Serious Games for Cancer Education and Behavioural Change: A Scoping Review of Evidence Across Patients, Professionals, and the Public

by Guangyan Si, Gillian Prue, Stephanie Craig, Tara Anderson and Gary Mitchell

Cancers 2025, 17(20), 3368; https://doi.org/10.3390/cancers17203368 - 18 Oct 2025

Viewed by 509

Abstract

Background/Objectives: Gamification and game-based learning (GBL) have recently emerged as fresh and appealing ways of health education, and they have been shown to perform better in knowledge acquisition than traditional teaching approaches. Digital serious games are developing as innovative tools for cancer education [...] Read more.

Background/Objectives: Gamification and game-based learning (GBL) have recently emerged as fresh and appealing ways of health education, and they have been shown to perform better in knowledge acquisition than traditional teaching approaches. Digital serious games are developing as innovative tools for cancer education and behaviour change, yet no review has systematically synthesized their use across key populations. This scoping review aimed to map evidence on serious games for cancer prevention, care, and survivorship among the public, patients, and healthcare professionals, framed through the Capability, Opportunity, Motivation-Behaviour (COM-B) model. Methods: Following Joanna Briggs Institute methodology, we searched Web of Science, MEDLINE, CINAHL, and PsycINFO. Eligible studies evaluated a serious game with a cancer focus and reported outcomes on knowledge, awareness, engagement, education, or behaviour. Data extraction and synthesis followed the PRISMA-ScR checklist. Results: Thirty-five studies met the inclusion criteria, covering diverse cancers, populations, and platforms. Most reported improvements in knowledge, engagement, self-efficacy, and communication. However, heterogeneity in study design and limited assessment of long-term behaviour change constrained comparability. Conclusions: Digital serious games show promise for enhancing cancer literacy and supporting behavioural outcomes across patients, professionals, and the public. By integrating multiple perspectives, this review highlights opportunities for theory-driven design, robust evaluation, and implementation strategies to maximize their impact in cancer education and awareness. Full article

(This article belongs to the Special Issue Nursing and Supportive Care for Cancer Survivors)

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17 pages, 2583 KB

Open AccessReview

Navigating Therapeutic Landscapes in Urothelial Cancer: From Chemotherapy to Precision Immuno-Oncology

by Takatoshi Somoto, Takanobu Utsumi, Rino Ikeda, Naoki Ishitsuka, Takahide Noro, Yuta Suzuki, Shota Iijima, Yuka Sugizaki, Ryo Oka, Takumi Endo, Naoto Kamiya and Hiroyoshi Suzuki

Cancers 2025, 17(20), 3367; https://doi.org/10.3390/cancers17203367 - 18 Oct 2025

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Abstract

Background/Objectives: The therapeutic landscape of advanced or metastatic urothelial carcinoma (UC) has shifted from platinum chemotherapy to precision immuno-oncology. Immune checkpoint inhibitors (ICIs)—pembrolizumab, nivolumab, and avelumab—show efficacy across platinum-refractory, maintenance, and adjuvant settings, yet benefit is limited to subsets, underscoring the need for [...] Read more.

Background/Objectives: The therapeutic landscape of advanced or metastatic urothelial carcinoma (UC) has shifted from platinum chemotherapy to precision immuno-oncology. Immune checkpoint inhibitors (ICIs)—pembrolizumab, nivolumab, and avelumab—show efficacy across platinum-refractory, maintenance, and adjuvant settings, yet benefit is limited to subsets, underscoring the need for biomarkers. Antibody–drug conjugates (ADCs), notably enfortumab vedotin(EV), and targeted agents such as FGFR inhibitors further expand options. This review synthesizes current evidence and emerging paradigms to guide combinations and sequencing. Methods: We performed a narrative synthesis of peer-reviewed trials (emphasizing pivotal phase III studies), key translational investigations, and contemporary guidelines on ICIs, ADCs, HER2-directed therapies, FGFR inhibitors, molecular subtyping, and genomic profiling in UC, integrating efficacy signals, biomarker associations, and practical implications for sequencing. Results: ICIs now occupy multiple settings, but heterogeneous benefit highlights the importance of molecularly informed selection. EV alone and with pembrolizumab has produced unprecedented first-line activity, prompting a strategic shift. Molecular subtyping and genomic profiling delineate phenotypes with variable immune responsiveness and targetable vulnerabilities, enabling rational combinations and refined sequencing. Ongoing trials are evaluating next-generation ADCs, HER2-directed approaches, and dual checkpoint blockade to achieve durable, personalized disease control. Conclusions: Management of locally advanced or metastatic UC is converging on precision immuno-oncology, wherein biomarker-driven selection, molecular subtyping, and thoughtful sequencing of ICIs, ADCs, and targeted agents are central to optimizing outcomes. Active trials and translational advances are expected to refine personalized strategies and embed molecular guidance into routine care. Full article

(This article belongs to the Special Issue State-of-the-Art Treatment on Chemotherapy and Immunotherapy for Urological Cancer)

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29 pages, 1625 KB

Open AccessReview

Finding the Sweet Spot for the Treatment of B Cell Malignancies

by Valerie R. Wiersma

Cancers 2025, 17(20), 3366; https://doi.org/10.3390/cancers17203366 - 18 Oct 2025

Viewed by 391

Abstract

The glycan profile of cells comprises a high variety of sugar moieties that are attached to proteins (glycoproteins) and lipids (glycolipids) via a process called ‘glycosylation’. Cancer cells commonly carry aberrant glycans, which may be of interest for cancer diagnosis, prognosis, as well [...] Read more.

The glycan profile of cells comprises a high variety of sugar moieties that are attached to proteins (glycoproteins) and lipids (glycolipids) via a process called ‘glycosylation’. Cancer cells commonly carry aberrant glycans, which may be of interest for cancer diagnosis, prognosis, as well as the development of novel therapeutic strategies. This review focuses on the differential glycosylation patterns on malignant B cells, including both B cell lymphoma and leukemia. Well-known aberrant glycan profiles on malignant B cells include acquired high mannose N-glycans in the B cell receptor (BCR) of follicular lymphoma (FL), and increased expression of the glycosphingolipid Gb3/CD77 on Burkitt’s lymphoma (BL). These structures can be exploited for therapy by using lectins that specifically recognize these patterns with intrinsic cytotoxic activity or in a drug-conjugate format. Furthermore, immunotherapy can be improved by modulating glycans, especially sialic acids. Targeting glycans for immunotherapy is also of interest for chimeric antigen receptor (CAR) T cell therapy, a relatively novel therapy that has been quite effective in various B cell malignancies. Thus, the glycan profile of malignant B cells harbors many opportunities for therapeutic targeting. It is anticipated that further in-depth glycan profiling will open up many more opportunities for the treatment of B cell malignancies. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in The Netherlands)

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