Cancers

14 pages, 1201 KB

Open AccessArticle

Clinical Characteristics and Prognosis of Primary Central Nervous System Lymphoma: A Retrospective Analysis

by Shupeng Zhong, Linjun Zhao, Jin Chai, Lan Mi, Yan Xie, Lingyan Ping, Xiaopei Wang, Jun Zhu, Lijuan Deng and Yuqin Song

Cancers 2026, 18(3), 541; https://doi.org/10.3390/cancers18030541 - 6 Feb 2026

Viewed by 537

Abstract

Background: Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma characterized by a poor prognosis due to high relapse rates and a lack of standardized treatment. This study aimed to evaluate the impact of induction/consolidation therapy on long-term survival and to [...] Read more.

Background: Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma characterized by a poor prognosis due to high relapse rates and a lack of standardized treatment. This study aimed to evaluate the impact of induction/consolidation therapy on long-term survival and to provide extended follow-up data. Methods: In this retrospective analysis, 140 immunocompetent patients with diffuse large B-cell PCNSL (DLBCL-PCNSL) treated at two centers between 2014 and 2024 were enrolled. Treatment efficacy was assessed based on baseline characteristics, therapeutic regimens, and treatment response. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and prognostic factors were identified using multivariate Cox proportional hazards regression models. Results: With a median follow-up of 5.3 years (range: 0.1–11.0 years), the 2- and 5-year PFS rates were 50.4% (95% CI: 42.1–60.2) and 34.1% (95% CI: 25.5–45.0), respectively, while the corresponding OS rates were 85.3% (95% CI: 79.4–91.6) and 60.8% (95% CI: 52.0–71.1). No survival plateau was observed. Among patients, 94% received methotrexate-based induction therapy: 94 received rituximab–methotrexate–temozolomide (R-MT) and 17 received MT alone, with 2-year PFS rates of 57.7% and 39.7%, respectively. Overall, 75% of patients achieved remission (CR/CRu/PR) after induction, and among these, 55% underwent consolidation therapy, predominantly autologous stem cell transplantation (ASCT, 90%) or whole-brain radiotherapy (10%). Patients receiving ASCT exhibited superior survival outcomes compared to those who did not. Conclusions: R-MT induction combined with ASCT consolidation is associated with improved survival in PCNSL, although relapse risk remains substantial. Outcomes remain poor in refractory subgroups, highlighting the need for novel therapeutic strategies. Full article

(This article belongs to the Section Cancer Therapy)

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20 pages, 6989 KB

Open AccessArticle

FAM64A Potentiates Bladder Carcinoma Tumorigenesis and Metastasis Through PI3K/mTORC2/AKT Pathway Activation

by Tao Zhu, Cen Liufu, Cong Yin, Jinqing He, Junhua Luo, Bentao Shi and Yan Wang

Cancers 2026, 18(3), 540; https://doi.org/10.3390/cancers18030540 - 6 Feb 2026

Viewed by 504

Abstract

Background: FAM64A is highly expressed in various cancers (e.g., breast cancer, ovarian cancer), indicating that it promotes tumorigenesis and progression by facilitating epithelial–mesenchymal transition. In the genitourinary system, dihydrotestosterone promotes the expression of FAM64A by binding of the androgen receptor to the FAM64A [...] Read more.

Background: FAM64A is highly expressed in various cancers (e.g., breast cancer, ovarian cancer), indicating that it promotes tumorigenesis and progression by facilitating epithelial–mesenchymal transition. In the genitourinary system, dihydrotestosterone promotes the expression of FAM64A by binding of the androgen receptor to the FAM64A promoter, thereby enhancing the proliferation, migration, and cell cycle progression of androgen-dependent prostate cancer cell lines. However, its specific role in the initiation and progression of bladder cancer remains unclear. FAM64A overexpression has been observed in cancers such as breast and prostate; however, its role in bladder cancer (BLCA) is less understood. Muscle-invasive BLCA (MIBC) has a poor prognosis, with five-year survival rates below 50%. This study explores FAM64A’s molecular mechanisms and therapeutic potential in BLCA. Methods: FAM64A expression was analyzed using TCGA data and clinical BLCA tissues. Functional assays (CCK-8, wound-healing, Transwell) assessed proliferation, migration, and invasion following FAM64A modulation. Western blotting was used to evaluate EMT markers (Vimentin, Slug) and proteins involved in the PI3K/AKT pathway. Bioinformatics (TCGA/GTEx) identified FAM64A-correlated genes, followed by KEGG pathway analysis. Taselisib (PI3K/AKT inhibitor) validated pathway involvement. Results: FAM64A was upregulated in BLCA and correlated with advanced tumor stage, T-stage, and grade. Knockdown suppressed proliferation, migration, and invasion, while overexpression exacerbated these effects. FAM64A promoted G2/M progression (via Cyclin B1/Ki67) and EMT (via Vimentin/Slug). KEGG analysis linked FAM64A to the PI3K/mTORC2/AKT signaling pathway. Taselisib reversed FAM64A-induced EMT and malignant phenotypes. Conclusions: FAM64A drives BLCA progression via PI3K/mTORC2/AKT-mediated EMT, serving as a potential prognostic biomarker and therapeutic target for metastatic BLCA. Full article

(This article belongs to the Section Molecular Cancer Biology)

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16 pages, 671 KB

Open AccessArticle

Melanoma Presentations Before, During, and After the COVID-19 Pandemic: A Multicenter Cohort Study from North Rhine-Westphalia, Germany

by Thilo Gambichler, Carmen Colo, Sera Selina Weyer-Fahlbusch, Laura Susok, Stefanie Boms and Nessr Abu Rached

Cancers 2026, 18(3), 539; https://doi.org/10.3390/cancers18030539 - 6 Feb 2026

Viewed by 382

Abstract

Background: The COVID-19 pandemic disrupted access to routine dermatologic care and may have delayed melanoma diagnosis and management. Evidence on the post-pandemic period and on hospital-based referral cohorts remains limited. We assessed melanoma presentations before, during and after the pandemic in three skin [...] Read more.

Background: The COVID-19 pandemic disrupted access to routine dermatologic care and may have delayed melanoma diagnosis and management. Evidence on the post-pandemic period and on hospital-based referral cohorts remains limited. We assessed melanoma presentations before, during and after the pandemic in three skin cancer centers in North Rhine-Westphalia, Germany. Methods: We conducted a multicenter retrospective cohort study of inpatients with cutaneous melanoma grouped into Phase 1 (February 2017–February 2020), Phase 2 (March 2020–March 2023), and Phase 3 (April 2023–May 2024). The primary endpoint was Breslow tumor thickness (TT) among invasive melanomas, analyzed using multivariable log-linear regression adjusted for center, age, sex, anatomic site, and histologic subtype. Secondary endpoints included T category and AJCC stage distributions (including stage 0/Tis), macroscopic primary tumor specimen dimensions (area and volume; available cases), staging work-up and sentinel lymph node biopsy (SLNB) indicators, and exploratory laboratory parameters (LDH, S100, CRP) and dermal mitotic rate. Results: We included 2960 patients (Phase 1: 1162; Phase 2: 1251; Phase 3: 547). Median TT among invasive melanomas was 1.1 mm (IQR 0.6–2.3), 1.1 mm (0.5–2.4), and 1.0 mm (0.5–2.3) across phases (p = 0.037). In adjusted models among invasive tumors, TT did not increase (Phase 2 vs. Phase 1: 0.97, 95% CI 0.90–1.04; Phase 3 vs. Phase 1: 0.94, 0.86–1.03). AJCC stage 0 decreased from 7.7% and 6.1% to 2.0%; adjusted OR Phase 3 vs. Phase 1: 0.24 (95% CI 0.13–0.46). Within invasive tumors, the distribution of T categories (T1a–T4) and AJCC stages I–IV was similar across periods. Among cases with available macroscopic primary tumor specimen dimensions, median area and volume were higher during and after the pandemic (area p = 0.030; volume p = 0.042), but period effects attenuated in models adjusted for TT. Exploratory analyses suggested a higher proportion of elevated LDH and a lower proportion of elevated S100 across periods, while CRP and dermal mitotic rate showed no clear period shift. Conclusions: In this large melanoma inpatient cohort, the pandemic period was not associated with thicker invasive melanomas after covariate adjustment. However, a persistent reduction in stage 0/Tis presentations in the post-pandemic period suggests ongoing disruption or shifting of early detection and referral pathways. Exploratory increases in macroscopic tumor dimensions may point to changes not captured by thickness alone, but require cautious interpretation given missingness and potential documentation effects. Full article

(This article belongs to the Special Issue Advances in Cancer Data and Statistics: 2nd Edition)

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23 pages, 3562 KB

Open AccessArticle

Real-World Treatment Patterns and Survival in Patients with Advanced Non-Small Cell Lung Cancer: An Italian Retrospective Cohort Study

by Angelo Delmonte, Nicola Gentili, Andrea Roncadori, Roberta Maltoni, Valentina Danesi, Pooja Hindocha, Cátia Leal, Stavros Oikonomou, Marta Mella, Sarah Lay-Flurrie, Gabrielle Emanuel, Caroline Rault, Mrudula B. Glassberg, Adam Lee, Yong Yuan and Ilaria Massa

Cancers 2026, 18(3), 538; https://doi.org/10.3390/cancers18030538 - 6 Feb 2026

Cited by 1 | Viewed by 842

Abstract

Background: Treatment for advanced non-small-cell lung cancer (NSCLC) has evolved substantially over the past decade, necessitating evaluation of real-world treatment patterns and effectiveness before and after the introduction of newer therapies. Methods: This retrospective cohort study included adult patients initiating a non-curative first-line [...] Read more.

Background: Treatment for advanced non-small-cell lung cancer (NSCLC) has evolved substantially over the past decade, necessitating evaluation of real-world treatment patterns and effectiveness before and after the introduction of newer therapies. Methods: This retrospective cohort study included adult patients initiating a non-curative first-line therapy for advanced NSCLC between 2014 and 2021 at the IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST), with follow-up through 2022. Overall survival (OS) and real-world progression-free survival from the start date of the first line of therapy for advanced NSCLC were estimated using Kaplan–Meier methods. Results: Overall, 910 patients were included; at diagnosis, 83% had a de novo diagnosis and 17% had recurrent disease. During the study, 41% of patients received platinum-based chemotherapy alone; 22% received non-platinum-based chemotherapy alone; 21% received anti-programmed death (PD)-(ligand [L])1 immune checkpoint inhibitors (ICIs), alone or with chemotherapy; and 16% received targeted therapy (single-agent tyrosine kinase inhibitors) as first-line therapy for advanced disease. From 2014 to 2021, the proportion of patients receiving first-line anti-PD-(L)1 ICIs increased from 0% to 58% and the proportion of those receiving first-line platinum-based chemotherapy decreased from 65% to 6%. Median (95% CI) OS was 8.2 (7.5–9.2) months; the minimum-to-maximum range of median OS was 6.0–7.4 months from 2014 to 2017 and 8.4–15.9 months from 2018 to 2021. Median OS was numerically longer in patients with recurrent disease versus a de novo diagnosis, first-line targeted versus other therapy, high versus low PD-L1 expression, and non-squamous/other versus squamous histology. Conclusions: This study provides real-world data further supporting (i) the benefits of precision targeted therapy for patients with advanced NSCLC and actionable genomic alterations and (ii) the positive impact of immunotherapy approvals on the treatment paradigm for advanced NSCLC. Full article

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

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42 pages, 2328 KB

Open AccessReview

Extracellular Vesicles in Cancer: Mechanistic Insights and Clinical Applications

by Fahad A. Alhumaydhi and Shehwaz Anwar

Cancers 2026, 18(3), 537; https://doi.org/10.3390/cancers18030537 - 6 Feb 2026

Cited by 1 | Viewed by 869

Abstract

Extracellular vesicles (EVs) have emerged as important messengers in cell-to-cell communication, carrying biologically active molecules such as lipids, nucleic acids, and proteins that influence both normal physiology and disease. In cancer, EVs play complex and context-dependent roles, contributing to tumor growth, angiogenesis, immune [...] Read more.

Extracellular vesicles (EVs) have emerged as important messengers in cell-to-cell communication, carrying biologically active molecules such as lipids, nucleic acids, and proteins that influence both normal physiology and disease. In cancer, EVs play complex and context-dependent roles, contributing to tumor growth, angiogenesis, immune evasion, metastasis, and resistance to therapy, while in certain settings, they may also support antitumor immune responses. Increasing evidence shows that EVs released from tumor and stromal cells actively reshape the tumor microenvironment (TME) and participate in the formation of pre-metastatic niches, thereby facilitating cancer dissemination. Because EVs are stable, readily detectable in body fluids, and reflect the molecular characteristics of their cells of origin, they have attracted considerable interest as minimally invasive biomarkers for cancer diagnosis, prognosis, and treatment monitoring. In addition, their natural biocompatibility makes them attractive candidates for targeted drug delivery. This review summarizes current knowledge on EV biogenesis, cargo composition, and functional roles in cancer progression, with a particular focus on recent advances in their clinical applications. Key challenges related to EV isolation, characterization, and clinical translations are also discussed, highlighting future opportunities for integrating EV-based strategies into precision oncology. Full article

(This article belongs to the Special Issue The Future of Cancer Immunotherapy: Biomarkers, Tumor Microenvironment, and Precision Medicine)

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13 pages, 3297 KB

Open AccessArticle

Effect of a Real-Time Artificial Intelligence-Assisted Ultrasound System on BI-RADS C4 Breast Lesions Based on Breast Density

by Jeeyeon Lee, Won Hwa Kim, Jaeil Kim, Byeongju Kang, Joon Suk Moon, Hye Jung Kim, Soo Jung Lee, In Hee Lee and Ho Yong Park

Cancers 2026, 18(3), 536; https://doi.org/10.3390/cancers18030536 - 6 Feb 2026

Viewed by 653

Abstract

Background: Artificial intelligence-based computer-aided diagnosis (AI-CAD) systems are increasingly used in breast ultrasonography; however, their diagnostic performance may vary with breast density. Given that dense breasts are highly prevalent among Asian women, understanding this relationship is essential for optimizing AI-assisted imaging strategies. Therefore, [...] Read more.

Background: Artificial intelligence-based computer-aided diagnosis (AI-CAD) systems are increasingly used in breast ultrasonography; however, their diagnostic performance may vary with breast density. Given that dense breasts are highly prevalent among Asian women, understanding this relationship is essential for optimizing AI-assisted imaging strategies. Therefore, this study aims to evaluate the effect of breast density on the diagnostic accuracy of an AI-CAD ultrasound system in BI-RADS category 4 (C4) breast lesions. Methods: Overall, 110 consecutive BI-RADS C4 lesions were reviewed between January and December 2023. An AI-CAD ultrasound system automatically assigned BI-RADS categories and calculated the probability of malignancy (POM) using static ultrasound images. Histopathology served as the reference standard, with atypia and malignancy combined into a non-benign category. Diagnostic performance—including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy—was analyzed based on breast density (BI-RADS B–D), determined using AI-assisted mammography. Results: Overall, the sensitivity and NPV were 81.3% and 87.5%, respectively, while the specificity and PPV were lower at 53.8% and 41.9%. All diagnostic performance metrics improved with increasing breast density. In the density D category, sensitivity (92.3%), specificity (61.5%), NPV (96.0%), and accuracy (69.2%) were highest. Additionally, concordance between AI-assigned BI-RADS categories and histopathologic diagnoses increased with density (B: 50.0%, C: 57.5%, D: 67.3%). Across all density groups, non-benign lesions consistently demonstrated higher POM values. Conclusions: Breast density significantly affects the diagnostic performance of AI-CAD ultrasound in BI-RADS C4 lesions. The AI system demonstrates higher accuracy and concordance in dense breasts, suggesting more consistent lesion interpretation in high-density environments. These findings highlight the potential utility of AI-assisted ultrasound as a diagnostic adjunct, particularly for Asian women, who commonly have dense breast composition. Further multicenter, real-time validation studies are warranted to validate these findings. Full article

(This article belongs to the Special Issue Application of Ultrasound in Cancer Diagnosis and Treatment)

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25 pages, 26612 KB

Open AccessArticle

SAPCD2 Drives Bladder Cancer Progression by Stabilizing TANK and Engaging a CREB–PLAGL2 Feedback Loop to Sustain MAPK Signaling

by Yueqiang Peng, Hai Wang, Hualin Chen, Zhaoheng Jin, Yingjie Li, Lin Ma and Zhigang Ji

Cancers 2026, 18(3), 535; https://doi.org/10.3390/cancers18030535 - 6 Feb 2026

Viewed by 455

Abstract

Background: Bladder cancer (BCa) is a prevalent and aggressive malignancy characterized by high recurrence and metastasis rates. Despite advances in treatment, the prognosis for patients with advanced BCa remains poor. This study aimed to investigate the role of SAPCD2 in BCa progression [...] Read more.

Background: Bladder cancer (BCa) is a prevalent and aggressive malignancy characterized by high recurrence and metastasis rates. Despite advances in treatment, the prognosis for patients with advanced BCa remains poor. This study aimed to investigate the role of SAPCD2 in BCa progression and its potential as a therapeutic target. Methods: We performed a series of in vitro and in vivo experiments to assess the expression and function of SAPCD2 in BCa. The correlation between SAPCD2 expression and clinicopathological features was analyzed using tissue samples from BCa patients. Functional assays, including cell proliferation, migration, invasion, and metastasis tests, were conducted to evaluate the biological impact of SAPCD2. Mechanistic studies focused on the MAPK signaling pathway, TANK stabilization, and the interaction between SAPCD2 and the PLAGL2–CREB feedback loop. Results: Our results showed that SAPCD2 was significantly upregulated in BCa tissues and correlated with advanced clinicopathological features and poor prognosis. Overexpression of SAPCD2 promoted cell proliferation, migration, invasion, and metastasis, while its silencing led to the opposite effects. Mechanistically, SAPCD2 activated the MAPK signaling pathway by stabilizing TANK and preventing its degradation by SYVN1. Furthermore, we identified a positive feedback loop in which SAPCD2 enhanced PLAGL2 expression through CREB phosphorylation, further amplifying SAPCD2 expression and MAPK signaling. Conclusions: This study indicated that SAPCD2 could serve as a critical driver of BCa malignancy, emphasizing its role in sustaining oncogenic signaling through the SAPCD2–TANK–MAPK axis and the PLAGL2–SAPCD2–CREB feedback loop. Targeting this pathway may offer novel therapeutic strategies for treating aggressive BCa. Full article

(This article belongs to the Section Molecular Cancer Biology)

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14 pages, 1353 KB

Open AccessArticle

Operationalizing Next-Generation Sequencing in a Community-Based Academic Cancer Center: Workflow, Integration, and Impact

by Gayathri Moorthy, Annette Sereika, Bruce Brockstein, Megan Parilla, Mir B. Alikhan, Michael Bouma, Janardan Khandekar, Dyson Wake, Peter J. Hulick, Henry M. Dunnenberger, Linda Sabatini, Mathew Yang, Kathy A. Mangold, Erin Proctor, Nicholas Evans, Nicholas Miller, Donald L. Helseth, Jr., Darryck Maurer, Justin Brueck and Karen Kaul

Cancers 2026, 18(3), 534; https://doi.org/10.3390/cancers18030534 - 6 Feb 2026

Viewed by 504

Abstract

Background/Objectives: Prompt integration of molecular and clinical data into electronic medical records, with a sustainable workflow that supports clinicians in rendering genomics-guided care, is critical. We sought to expand the implementation of in-house NGS at our community-based academic cancer center to operationalize [...] Read more.

Background/Objectives: Prompt integration of molecular and clinical data into electronic medical records, with a sustainable workflow that supports clinicians in rendering genomics-guided care, is critical. We sought to expand the implementation of in-house NGS at our community-based academic cancer center to operationalize the utilization of molecular diagnostic studies to optimize cancer care for all patients, including those outside this study, through broader adoption and diffusion. Methods: In this prospective IRB-approved study, the Kellogg Cancer Genomic Initiative (KCGI), patients with advanced cancers underwent in-house NGS, including tumor mutational burden (TMB) and pharmacogenomics. In-house bioinformatics (Flype) was used for structured reporting and served as a molecular knowledgebase. A multidisciplinary molecular tumor board (MTB) was created to provide precision therapy recommendations. Results: In-house NGS, completed within 11 business days on average, was performed in 90% (251) of the 279 patients in the KCGI with advanced cancers. RNA and TMB analyses were successful in 89.2% and 86.5% of patients, respectively. A total of 54.2% of patients were identified as candidates for use of on- or off-label FDA-approved therapies, and 99.6% of patients who underwent pharmacogenomics testing had at least one gene alteration associated with medication dose adjustment/avoidance. An MTB was established to discuss these and other molecularly challenging cases continues to function as a consultative service that provides actionable recommendations. Conclusions: In this real-world trial, the utilization of in-house NGS with an adaptable bioinformatics pipeline and the establishment of an MTB enabled the refinement of institutional processes and created an environment that enhanced clinician interest in genomics and improved genomics-guided care for patients with advanced cancers. Full article

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

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16 pages, 701 KB

Open AccessReview

Cyclin-Dependent 4/6 Kinase Inhibitors for Treatment of HER2-Positive Breast Cancer: 2026 Update

by Ciara C. O’Sullivan

Cancers 2026, 18(3), 533; https://doi.org/10.3390/cancers18030533 - 6 Feb 2026

Viewed by 1147

Abstract

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i; palbociclib, ribociclib, abemaciclib, dalpiciclib) combined with endocrine therapy (ET) were a major advance in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) worldwide. Notably, clinical activity has also been [...] Read more.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i; palbociclib, ribociclib, abemaciclib, dalpiciclib) combined with endocrine therapy (ET) were a major advance in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) worldwide. Notably, clinical activity has also been observed in HR+HER2-positive (HER2+) MBC, with significant progression-free survival (PFS) benefits. Cyclin-dependent kinases 4/6 (CDK4/6) are downstream of HER2 and pathways driving resistance to HER2-targeted therapies. However, clinical development of CDK4/6i in HER2+ MBC slowed, given the advent of highly effective tyrosine-kinase inhibitors (TKIs) (i.e., tucatinib) and antibody–drug conjugates (ADCs) (i.e., trastuzumab deruxtecan), which currently dominate the treatment armamentarium. The observation that luminal disease defined by a predictive analysis of microarray 50 (PAM50) was independently associated with a significantly longer PFS versus nonluminal disease was important, with researchers inferring that intrinsic molecular subtypes could be used to identify patients most suitable for ET + CDK4/6i + HER2-targeted treatment. Subsequently, the phase III PATINA trial (which included patients with 1L HR+HER2+ MBC, treated with palbociclib vs. placebo with maintenance ET+ H[P]) noted a striking PFS improvement of >15 months in the palbociclib arm, renewing interest in CDK4/6i-based treatments for HR+HER2+ MBC. Herein, we review the development of CDK4/6i in HER2+ BC, discussing current challenges and potential future directions. Full article

(This article belongs to the Special Issue Advances in Invasive Breast Cancer: Treatment and Prognosis (2nd Edition))

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13 pages, 683 KB

Open AccessArticle

High Oncological Efficacy of BCG Maintenance Therapy for Primary High-Grade T1 Urothelial Carcinoma of the Bladder

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

Cancers 2026, 18(3), 532; https://doi.org/10.3390/cancers18030532 - 6 Feb 2026

Viewed by 586

Abstract

Background: In high-risk non-muscle-invasive bladder cancer (NMIBC), adjuvant therapies, such as intravesical Bacillus Calmette–Guérin (BCG) instillation, are widely employed; however, BCG treatment poses challenges due to potential adverse effects and ongoing supply limitations. This study aimed to evaluate treatment patterns, therapeutic efficacy, [...] Read more.

Background: In high-risk non-muscle-invasive bladder cancer (NMIBC), adjuvant therapies, such as intravesical Bacillus Calmette–Guérin (BCG) instillation, are widely employed; however, BCG treatment poses challenges due to potential adverse effects and ongoing supply limitations. This study aimed to evaluate treatment patterns, therapeutic efficacy, incidence of adverse events, and clinical predictors of recurrence and progression in patients with high-grade pT1 urothelial carcinoma (HG-T1 UC) of the bladder. Methods: This retrospective cohort study included 204 patients diagnosed with HG-pT1 UC who underwent transurethral resection of bladder tumor (TURBT) at Toho University Sakura Medical Center between 2010 and 2021. Clinical data encompassing treatment modalities (BCG or intravesical chemotherapy), complications, and oncological outcomes were collected. Recurrence-Free Survival (RFS), Progression-Free Survival, and Cancer-Specific Survival were analyzed using Kaplan–Meier analyses and multivariate regression models. Results: Maintenance BCG therapy was significantly associated with prolonged RFS compared to other treatments, including among ‘very high-risk’ patients. However, 52.4% of patients receiving BCG maintenance experienced adverse events, with dose reductions required in 59% of cases. Notably, recurrence rates did not significantly differ based on dose reduction or the total number of BCG instillations. Tumor multiplicity emerged as an independent risk factor for recurrence. Conclusions: Although maintenance BCG therapy remains essential for managing HG-T1 UC, especially in high-risk patients, treatment should be individualized due to concerns about tolerability and availability. The study results support the importance of personalized strategies based on risk stratification as outlined in clinical guidelines for preventing recurrence in NMIBC. Full article

(This article belongs to the Special Issue Multidisciplinary Approach to Bladder Cancer Treatment and Care)

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19 pages, 864 KB

Open AccessReview

FGFR2-Rearranged Biliary Tract Cancer: Biology, Resistance Mechanisms, and Emerging Therapeutic Strategies

by Xin Xin and Ruoyu Miao

Cancers 2026, 18(3), 531; https://doi.org/10.3390/cancers18030531 - 6 Feb 2026

Viewed by 742

Abstract

Fibroblast growth factor receptor 2 (FGFR2) rearrangements represent one of the most actionable molecular alterations in biliary tract cancer, particularly in intrahepatic cholangiocarcinoma (iCCA). Approximately 10–16% of iCCA cases harbor FGFR2 fusions or rearrangements, defining a distinct molecular subtype characterized by sensitivity to [...] Read more.

Fibroblast growth factor receptor 2 (FGFR2) rearrangements represent one of the most actionable molecular alterations in biliary tract cancer, particularly in intrahepatic cholangiocarcinoma (iCCA). Approximately 10–16% of iCCA cases harbor FGFR2 fusions or rearrangements, defining a distinct molecular subtype characterized by sensitivity to FGFR-targeted therapies. Selective FGFR tyrosine kinase inhibitors, including the reversible inhibitor pemigatinib and the irreversible inhibitor futibatinib, have demonstrated clinically meaningful response rates and durable disease control in patients with previously treated FGFR2-altered iCCA, leading to regulatory approvals and the incorporation of FGFR inhibition into contemporary treatment paradigms. However, the development of acquired resistance—most commonly driven by secondary kinase-domain mutations and activation of bypass signaling pathways—remains a major limitation to sustained therapeutic benefit. This review summarizes the biological basis of FGFR2 alterations, highlights current clinical evidence supporting FGFR inhibition, and discusses the evolving landscape of resistance mechanisms. We further examine emerging therapeutic strategies aimed at overcoming resistance, including next-generation FGFR inhibitors and rational combination approaches. In addition, we highlight the growing role of circulating tumor DNA as a noninvasive tool for longitudinal molecular monitoring and treatment guidance. Together, these insights underscore the central role of FGFR2-directed therapy in precision oncology for biliary tract cancer and provide a framework for optimizing and extending targeted treatment in this molecularly defined disease subset. Full article

(This article belongs to the Special Issue Proteomic and Oncogenic Biomarkers in Gastrointestinal Cancer)

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2 pages, 142 KB

Open AccessCorrection

Correction: Wu et al. WIP1 Inhibition by GSK2830371 Potentiates HDM201 Through Enhanced p53 Phosphorylation and Activation in Liver Adenocarcinoma Cells. Cancers 2021, 13, 3876

by Chiao-En Wu, Ahmed Khairallah Mahdi, Chen-Yang Huang, Chiao-Ping Chen, Yi-Ru Pan, John Wen-Cheng Chang, Jen-Shi Chen, Chun-Nan Yeh and John Lunec

Cancers 2026, 18(3), 530; https://doi.org/10.3390/cancers18030530 - 6 Feb 2026

Viewed by 282

Abstract

In the original publication [...] Full article

17 pages, 788 KB

Open AccessArticle

Age-Specific ADHD and Internalizing/Externalizing Comorbidity in Children with Neurofibromatosis Type 1: A Multi-Site Study

by Dan Liu, Pamela L. Wolters, Bonita P. Klein-Tasman, Karin S. Walsh, Jonathan M. Payne, Natalie Pride, Stephanie M. Morris and Yang Hou

Cancers 2026, 18(3), 529; https://doi.org/10.3390/cancers18030529 - 6 Feb 2026

Viewed by 621

Abstract

Objective: The current study tested (1) how ADHD symptoms and internalizing or externalizing problems covaried across ages 3–18 in children with neurofibromatosis type 1 (NF1), and (2) whether demographic and NF1-specific factors moderated the associations. Method: We analyzed integrated cross-sectional data [...] Read more.

Objective: The current study tested (1) how ADHD symptoms and internalizing or externalizing problems covaried across ages 3–18 in children with neurofibromatosis type 1 (NF1), and (2) whether demographic and NF1-specific factors moderated the associations. Method: We analyzed integrated cross-sectional data of 685 observations from 455 children and adolescents with NF1 (M_age = 9.79 years, SD = 3.88; 43% female) across six institutions in the United States and Australia. ADHD symptoms (inattention and hyperactivity/impulsivity) and internalizing/externalizing problems were assessed via parent-report measures. Time-varying effect modeling was employed to examine the age-specific associations between ADHD symptoms and internalizing/externalizing problems. Moderation analyses tested effects of sex, parental education, and NF1 inheritance mode (familial vs. sporadic). Results: Inattention and hyperactivity/impulsivity symptoms were associated with greater internalizing and externalizing problems across ages 3–17. Inattention links were similar across ages, while the hyperactivity/impulsivity-externalizing link was stronger in early childhood than during adolescence. NF1 inheritance mode significantly moderated the inattention-externalizing link, with stronger associations observed among children with familial NF1. Other moderators were nonsignificant. Conclusions: ADHD symptoms are robustly linked to internalizing and externalizing problems from childhood to middle adolescence in children with NF1, with familial NF1 emerging as a potentially elevated risk factor. Future longitudinal and experimental research is needed to inform integrated intervention approaches, especially for those with familial NF1. Full article

(This article belongs to the Special Issue Advances in Neurofibromatosis in Children, Adolescents, and Young Adults)

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12 pages, 1158 KB

Open AccessArticle

Symptomatic Pheochromocytoma: A Risk Model

by María Consuelo Muñoz, Beatriz Febrero, Miriam Abellán and José Manuel Rodríguez

Cancers 2026, 18(3), 528; https://doi.org/10.3390/cancers18030528 - 6 Feb 2026

Viewed by 342

Abstract

Background/Objectives: Pheochromocytoma (PHEO) is increasingly detected incidentally or through genetic screening; however, predictors of symptomatic presentation and its perioperative impact remain unclear. We aimed to quantify the prevalence of symptomatic PHEO, identify associated factors, compare perioperative outcomes, and develop a predictive nomogram. [...] Read more.

Background/Objectives: Pheochromocytoma (PHEO) is increasingly detected incidentally or through genetic screening; however, predictors of symptomatic presentation and its perioperative impact remain unclear. We aimed to quantify the prevalence of symptomatic PHEO, identify associated factors, compare perioperative outcomes, and develop a predictive nomogram. Methods: We retrospectively analyzed patients diagnosed and/or operated on for PHEO at a tertiary referral center between 1984 and 2021. Associations with symptomatic presentation were assessed using univariate and multivariable logistic regression analyses. A nomogram was constructed based on independent predictors and evaluated using receiver operating characteristic (ROC) analysis and the area under the curve (AUC). Results: Among 173 patients (mean age 44.4 ± 15.8 years; 53.2% women), 67.1% were symptomatic. In multivariable analysis, male sex (odds ratio [OR] 0.33; p = 0.023) and the presence of a germline mutation (OR 0.15; p = 0.004) were associated with a lower likelihood of symptoms, whereas a noradrenergic secretion profile was associated with a higher likelihood (OR 12.73; p = 0.02). Symptomatic patients had higher rates of intraoperative (OR 2.60; p = 0.032) and postoperative complications (OR 3.09; p = 0.04). The nomogram incorporating sex, genetic status, and noradrenergic profile demonstrated moderate discrimination (AUC 0.799; 95% confidence interval 0.722–0.877; p < 0.001). Conclusions: Symptomatic PHEO is associated with sex, genetic status, and noradrenergic secretion profile and is linked to increased perioperative morbidity. A simple nomogram based on readily available variables may help estimate individual risk and support perioperative management. Full article

(This article belongs to the Special Issue New Insights into Pheochromocytoma and Paraganglioma)

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13 pages, 1682 KB

Open AccessReview

Perioperative Immune-Checkpoint Inhibition in Renal Cell Carcinoma: Lessons Learned and Future Directions

by Adam Adika and Matthew Zibelman

Cancers 2026, 18(3), 527; https://doi.org/10.3390/cancers18030527 - 6 Feb 2026

Cited by 1 | Viewed by 618

Abstract

Background/Objectives: Localized renal cell carcinoma (RCC) unfortunately has a suboptimal rate of metastatic recurrence. Immune-checkpoint inhibition (ICI), commonly known as immunotherapy, is being increasingly utilized in the management of other localized cancers. The objective of this paper is to review the most [...] Read more.

Background/Objectives: Localized renal cell carcinoma (RCC) unfortunately has a suboptimal rate of metastatic recurrence. Immune-checkpoint inhibition (ICI), commonly known as immunotherapy, is being increasingly utilized in the management of other localized cancers. The objective of this paper is to review the most recent literature as it pertains to ICI in localized RCC, highlight major lessons learned across clinical trials, and then suggest new directions based on these lessons and on new technologies. Methods: English-language articles were identified in PubMed/Google Scholar/Scopus. Selection priority was placed on prospective clinical trials. Particular emphasis was placed on disease-free survival (DFS), overall survival (OS), and clinical trial design. Novel approaches to the diagnosis, risk stratification, and management of RCC were also queried. Results: The KEYNOTE-564 trial demonstrated DFS and OS benefits of adjuvant pembrolizumab in high-risk clear cell RCC. Although discordance exists with adjuvant ICI in the IMmotion-010 and CheckMate-914 trials, preliminary data from the RAMPART trial also reveal a DFS benefit for adjuvant durvalumab–tremelimumab. The PROSPER trial failed to show a benefit for perioperative nivolumab, but ongoing neoadjuvant/perioperative ICI trials show promise. Subtle differences in design exist across the mentioned trials and are arguably clinically significant. Several new diagnostic tools and technologies have been identified for use in RCC. Conclusions: By applying the lessons learned from the differences in clinal trial design, along with leveraging new diagnostic tools and technologies, there is great potential to more accurately stratify risk amongst patients with localized RCC and therefore better identify the patients who are most likely to benefit from perioperative ICI. Full article

(This article belongs to the Special Issue Advances in Locally Advanced and Metastatic Kidney Cancer (2nd Edition))

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2 pages, 445 KB

Open AccessCorrection

Correction: Golubovskaya et al. Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting FAK and P53 Complex. Cancers 2014, 6, 166–178

by Vita M. Golubovskaya, Baotran Ho, Jeffrey Conroy, Song Liu, Dan Wang and William G. Cance

Cancers 2026, 18(3), 526; https://doi.org/10.3390/cancers18030526 - 6 Feb 2026

Viewed by 234

Abstract

Error in Figure [...] Full article

(This article belongs to the Special Issue The p53 Pathway in Cancers)

15 pages, 776 KB

Open AccessReview

Liquid Biopsy for Early Pancreatic Cancer Detection: Why Has It Not Yet Worked?

by Kenji Takahashi, Yusuke Ono, Kenzui Taniue, Krushna C. Patra, Takuya Yamamoto, Mikihiro Fujiya and Yusuke Mizukami

Cancers 2026, 18(3), 525; https://doi.org/10.3390/cancers18030525 - 5 Feb 2026

Viewed by 713

Abstract

Despite extensive technological advances and an ever-growing body of literature, liquid biopsy has yet to achieve reliable early detection of pancreatic ductal adenocarcinoma (PDA). Numerous studies have investigated circulating tumor-derived components, including cell-free DNA (cfDNA), cell-free RNA (cfRNA), extracellular vesicles (EVs), and circulating [...] Read more.

Despite extensive technological advances and an ever-growing body of literature, liquid biopsy has yet to achieve reliable early detection of pancreatic ductal adenocarcinoma (PDA). Numerous studies have investigated circulating tumor-derived components, including cell-free DNA (cfDNA), cell-free RNA (cfRNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs), primarily using peripheral blood samples; however, their clinical utility for early-stage disease remains limited. The fundamental obstacles are biological rather than purely technical: early PDA and its precursor lesions, such as pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMN), are characterized by minimal tumor burden, low levels of nucleic acid shedding, and substantial background signals from non-neoplastic tissues. Increasing analytical complexity through multilayered liquid biopsy approaches, including analyses from pancreas-associated fluid, has not consistently translated into improved diagnostic performance and, in some cases, has amplified issues related to specificity, reproducibility, and interpretability. Moreover, molecular alterations detected in body fluids may reflect clonal expansion without inevitable malignant progression, raising concerns regarding overdiagnosis and clinical decision-making. Pre-analytical variability, lack of standardization, and limited access to tumor-adjacent fluids further hinder clinical implementation. Liquid biopsy should therefore be regarded as a complementary modality rather than a substitute for histopathological diagnosis, with its precise clinical role in early detection still ill-defined. In this review, we critically examine why liquid biopsy has not yet succeeded in early PDA detection, highlighting the key biological, technical, and clinical barriers that must be addressed to move the field beyond exploratory research toward meaningful clinical application. Full article

(This article belongs to the Special Issue Novel Diagnosis and Treatment Approaches in Pancreatic Cancer)

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13 pages, 1508 KB

Open AccessReview

A Narrative Review of European Registries for Skin Cancer: Where Are We and Where Should We Be?

by Alexander Katalinic, Karima Hammas, Lukasz Taraszkiewicz, Marieke Louwman, Joanna Julia Bartnicka, Giorgia Randi, Manola Bettio, Andreas Stang and Emanuele Crocetti

Cancers 2026, 18(3), 524; https://doi.org/10.3390/cancers18030524 - 5 Feb 2026

Viewed by 792

Abstract

Background: European population-based cancer registries (PBCRs) provide the foundation for monitoring skin cancer, yet registration practices and coverage vary, particularly for non-melanoma skin cancer (NMSC). Methods: We conducted a narrative review combining descriptive analyses of European Cancer Information System (ECIS) outputs [...] Read more.

Background: European population-based cancer registries (PBCRs) provide the foundation for monitoring skin cancer, yet registration practices and coverage vary, particularly for non-melanoma skin cancer (NMSC). Methods: We conducted a narrative review combining descriptive analyses of European Cancer Information System (ECIS) outputs with evidence from the European Network of Cancer Registries (ENCR) Working Group on NMSC and from national reports. A targeted PubMed search (2015–2025) assessed scientific usage of European registry data. Results: Nearly 200 PBCRs operate across about 40 European countries, with heterogeneous structures and timeliness. The ECIS estimated 101,500 incident cutaneous melanomas (CM) in the European Union in 2022. Long-term data from Nordic countries show a tenfold increase in CM incidence over the last six decades, with recent plateauing in younger cohorts. NMSC registration remains inconsistent: some countries record both cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), others record cSCC only, and several omit NMSC entirely. Consequently, Europe-wide NMSC figures are not available from the ECIS. Global estimates exclude BCC and understate the true burden, which is likely between 1 and 1.6 million incident cases annually in Europe. The PubMed search identified 538 European registry-based publications on skin cancer (2015–2025). Conclusions: Melanoma registration in Europe is robust, but NMSC remains under-registered. Priorities include harmonized definitions and counting rules, better integration of outpatient and pathology data, streamlined EU-level reporting, digital/AI-enabled case ascertainment, and sentinel regions to generate reliable NMSC estimates. Full article

(This article belongs to the Special Issue Skin Cancer Prevention: Strategies, Challenges and Future Directions)

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3 pages, 144 KB

Open AccessEditorial

How to Properly Diagnose and Treat Immune-Related Adverse Events During Immunotherapy in Patients with Cancer: Discussion Between Specialists

by Angioletta Lasagna and Paolo Sacchi

Cancers 2026, 18(3), 523; https://doi.org/10.3390/cancers18030523 - 5 Feb 2026

Viewed by 341

Abstract

Immune checkpoint inhibitors and other immune-based cancer therapies have profoundly transformed the treatment of solid and hematological malignancies, leading to durable responses and significant survival benefits in a growing number of patients [...] Full article

(This article belongs to the Special Issue How to Properly Diagnose and Treat Immune-Related Adverse Events during Immunotherapy in Patients with Cancer: Discussion between Specialists)

23 pages, 5410 KB

Open AccessReview

The Vesicular Intersection Layer: A Framework for Cross-Kingdom Extracellular Vesicle Signaling That May Connect Gut Dysbiosis to Skeletal Muscle Wasting in Colorectal Cancer Cachexia

by Young-Sool Hah, Seung-Jun Lee, Jeongyun Hwang and Seung-Jin Kwag

Cancers 2026, 18(3), 522; https://doi.org/10.3390/cancers18030522 - 5 Feb 2026

Viewed by 761

Abstract

Colorectal cancer (CRC) cachexia is a multifactorial, treatment-limiting syndrome characterized by progressive loss of skeletal muscle with or without loss of fat mass, accompanied by systemic inflammation, anorexia, metabolic dysregulation, and impaired treatment tolerance. Despite decades of work, cachexia remains clinically underdiagnosed and [...] Read more.

Colorectal cancer (CRC) cachexia is a multifactorial, treatment-limiting syndrome characterized by progressive loss of skeletal muscle with or without loss of fat mass, accompanied by systemic inflammation, anorexia, metabolic dysregulation, and impaired treatment tolerance. Despite decades of work, cachexia remains clinically underdiagnosed and therapeutically underserved, in part because canonical models treat tumor-derived factors and host inflammatory mediators as a largely ‘host-only’ network. In parallel, CRC is strongly linked to intestinal dysbiosis, barrier disruption, and microbial translocation. Extracellular vesicles (EVs)—host small EVs, tumor-derived EVs, and bacterial extracellular vesicles (including outer membrane vesicles)—may provide a mechanistically plausible, information-dense route by which these domains could be coupled. Here, we synthesize emerging evidence suggesting that cross-kingdom EV signaling may operate as a vesicular ecosystem spanning gut lumen, mucosa, circulation, and peripheral organs. We propose the “vesicular intersection layer” as a unifying framework for how heterogeneous EV cargos converge on shared host decoding hubs (e.g., pattern-recognition receptors and stress-response pathways) to potentially contribute to muscle catabolism. We critically evaluate what is known—and what remains unproven—about EV biogenesis, trafficking, and causal mechanisms in CRC cachexia, highlight methodological constraints in microbial EV isolation and attribution, and outline minimum evidentiary standards for cross-kingdom claims. Finally, we translate the framework into actionable hypotheses for EV-informed endotyping, biomarker development (including stool EV assays), and therapeutic strategies targeting shared signaling nodes (e.g., TLR4–p38) and endocrine mediators that are predominantly soluble but may be fractionally vesicle-associated (e.g., GDF15). By reframing CRC cachexia as an emergent property of tumor–host–microbiota vesicular communication, this review provides a roadmap for mechanistic studies and clinically tractable interventions. Full article

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

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18 pages, 1616 KB

Open AccessArticle

Oncologic and Surgical Outcomes After Short-Course Neoadjuvant CAPOX Plus Bevacizumab in High-Risk Colorectal Liver Metastases

by Yawen Dong, Madita Tschoegl, Florian Lehner, Jonas Santol, Francesca Notte, Mariel Gramberger, Mohammed Salem, Edanur Cenan, Rebecca Thonhauser, Thomas Hoblaj, Rosemarie Valenta, Birgit Gruenberger and Thomas Gruenberger

Cancers 2026, 18(3), 521; https://doi.org/10.3390/cancers18030521 - 5 Feb 2026

Viewed by 516

Abstract

Background: The optimal duration of neoadjuvant therapy for high-risk colorectal liver metastases (CRLM) remains debated. While prolonged chemotherapy may enhance response, it also increases toxicity and risks delaying potentially curative resection. These considerations have raised the question whether a short-course neoadjuvant strategy might [...] Read more.

Background: The optimal duration of neoadjuvant therapy for high-risk colorectal liver metastases (CRLM) remains debated. While prolonged chemotherapy may enhance response, it also increases toxicity and risks delaying potentially curative resection. These considerations have raised the question whether a short-course neoadjuvant strategy might achieve sufficient oncologic selection and response while minimizing treatment-related morbidity. Methods: Patients with synchronous or metachronous CRLM who received two cycles of neoadjuvant CAPOX plus bevacizumab followed by curative-intent liver resection treated between 2014 and 2024 at Health Network Vienna, Austria, were included. Clinicopathologic characteristics, treatment tolerability, response assessments (biochemical, radiologic, and pathologic), and survival outcomes were collected and analyzed. Results: A total of 57 patients were included (65% synchronous, 35% metachronous), with the rectum being the most frequent primary tumor site (45.6%). Most liver lesions were <5 cm (84.2%), and 47% had bilobar disease. Minor hepatectomy was performed in 65% of cases, predominantly via open surgery (72%). Grade ≥3 treatment-related adverse events occurred in 6 patients (10.6%), mainly neutropenia and diarrhea. Biochemically, 53.7% achieved >50% tumor marker reduction. Radiologic assessment showed partial response in 31.6% and complete response in 1.7%. Pathologic evaluation revealed TRG 3 as the most common finding (57.1%), followed by TRG 2 in 22.5%. Subgroup analyses demonstrated significantly improved OS and RFS in patients receiving adjuvant therapy and in those with tumors < 5 cm. Conclusion: A two-cycle, short-course regimen of CAPOX plus bevacizumab proved both effective and safe in high-risk CRLM, achieving meaningful biochemical, radiologic, and pathologic responses with acceptable toxicity. This abbreviated approach allowed delivery of neoadjuvant therapy while limiting cumulative treatment-related toxicity, supporting its feasibility as a neoadjuvant strategy in selected high-risk CRLM patients. Full article

(This article belongs to the Special Issue Multidisciplinary Treatment with Surgery and Chemotherapy of Liver Metastases from Colorectal Cancer)

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13 pages, 645 KB

Open AccessArticle

Characterization of Clinical Outcomes for Patients with Relapsed High-Risk Neuroblastoma After Autologous Stem Cell Transplant and External Beam Radiotherapy

by Mathew Lin, Jie Jane Chen, Rochelle Bagatell, Sherif G. Shaaban, Benjamin J. Lerman, Suzanne Shusterman, Myrsini Ioakeim-Ioannidou, Torunn I. Yock, Paul J. Catalano, Hesham Elhalawani, Kathryn E. Dusenbery, Kieuhoa T. Vo, Mary S. Huang, Alison M. Friedmann, Lisa R. Diller, Karen J. Marcus, Shannon M. MacDonald, Stephanie A. Terezakis, Steve E. Braunstein, Christine E. Hill-Kayser, Daphne A. Haas-Kogan, Steven G. DuBois and Kevin X. Liu Show full author list Hide full author list

Cancers 2026, 18(3), 520; https://doi.org/10.3390/cancers18030520 - 5 Feb 2026

Viewed by 666

Abstract

Background: Limited data inform the outcomes of patients with high-risk neuroblastoma (HR-NBL) who relapse after high-dose chemotherapy, autologous stem cell transplantation (ASCT), and external beam radiotherapy (EBRT). Methods: This is a multi-institutional retrospective study of 84 patients with HR-NBL diagnosed between 1997–2021 with [...] Read more.

Background: Limited data inform the outcomes of patients with high-risk neuroblastoma (HR-NBL) who relapse after high-dose chemotherapy, autologous stem cell transplantation (ASCT), and external beam radiotherapy (EBRT). Methods: This is a multi-institutional retrospective study of 84 patients with HR-NBL diagnosed between 1997–2021 with a first recurrence after definitive upfront treatment, including ≥1 ASCT and EBRT. Site(s) of first relapse were defined with relation to a patient’s primary tumor location. Progression-free survival (PFS) and overall survival (OS) outcomes were analyzed using Kaplan–Meier curves and log-rank tests. Cox proportional hazard models were used for univariate and multivariable analyses. Results: Twenty-four patients had local recurrences with or without distant relapses (LR) and 60 had distant relapses only. The LR cohort had higher rates of MYCN amplification (70% vs. 36%, p = 0.016). At relapse, the LR cohort had lower rates of additional radiotherapy (32% vs. 61%, p = 0.029) and higher rates of additional surgery (29% vs. 5%, p = 0.005), with similar rates of chemotherapy for both cohorts. With a median follow-up after first relapse of 1.53 years (range: 0.03–15.82), there were no significant differences in interval PFS and OS between the cohorts. After controlling for age at diagnosis and pattern of recurrence, time to interval relapse ≥ 2 years was a significant predictor of improved OS (HR: 0.50, 95% CI: 0.29–0.85, p = 0.011). Conclusions: Patients with relapsed HR-NBL have poor outcomes with median OS < 2 years. Time to relapse was a significant predictor of OS. Full article

(This article belongs to the Section Pediatric Oncology)

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16 pages, 672 KB

Open AccessArticle

Comparison of Pelvic Peritonectomy vs. Rectosigmoid Resection During Hudson Procedure for Advanced Ovarian Cancer: 6-Year Experience of an ESGO-Certified Center

by Dimitrios Zouzoulas, Panagiotis Tzitzis, Iliana Sofianou, Katerina Tzika, Kimon Chatzistamatiou, Vasilis Theodoulidis, Eleni Timotheadou, Grigoris Grimbizis and Dimitrios Tsolakidis

Cancers 2026, 18(3), 519; https://doi.org/10.3390/cancers18030519 - 5 Feb 2026

Viewed by 404

Abstract

(1) Background: Hudson first described the procedure that includes en-block removal of an ovarian tumor fixed in the pelvis with the whole pelvic peritoneum and invaded surrounding structures. However, sometimes pelvic peritonectomy (PP) with or without shaving of the bowel serosa is not [...] Read more.

(1) Background: Hudson first described the procedure that includes en-block removal of an ovarian tumor fixed in the pelvis with the whole pelvic peritoneum and invaded surrounding structures. However, sometimes pelvic peritonectomy (PP) with or without shaving of the bowel serosa is not enough to achieve complete cytoreduction, and en-block rectosigmoid resection (RR) is necessary. This study aims to investigate the impact of bowel surgery on survival rates and morbidity of patients with advanced ovarian cancer. (2) Methods: We retrospectively analyzed patients with advanced ovarian cancer with cul-de-sac involvement that underwent debulking surgery at the 1st Department of Obstetrics—Gynecology of “Papageorgiou” General Hospital, from 2017–2022. The primary outcomes were the survival rates and morbidity between PP and RR. (3) Results: A total of 93 patients met the inclusion criteria. Patients were categorized into two groups: Group A (34 patients) with RR and Group B (59 patients) with PP. There was no statistically significant difference in the majority of patients’ characteristics and oncological outcomes. On the other hand, patients with RR had a significantly higher surgical complexity score (SCS), peritoneal cancer index (PCI), ICU admission, rate of postoperative complications, longer surgery duration and hospital stay. When comparing the duration of surgery, the RR group has significantly higher operation time during primary compared to interval debulking surgery. Concerning survival rates, there was no significant difference in progression-free (PFS) (p = 0.22) and overall survival (OS) (p = 0.85) between the two groups, while residual disease and postoperative complications were identified as independent prognostic factors for PFS and OS; (4) Conclusions: The modified Hudson procedure with RR is a safe and reproductible technique, but when complete gross resection can be achieved with PP, this technique is preferred in order to avoid increased patient’s morbidity. Full article

(This article belongs to the Special Issue Advances in Ovarian Cancer Treatment: Past, Present and Future)

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12 pages, 641 KB

Open AccessReview

Notch2, a Key Player in Chronic Lymphocytic Leukemia: Mechanism, Microenvironment Interactions, and Therapeutic Implications

by Ramona Miserendino, Claudio Giacinto Atene, Mario Luppi, Roberto Marasca and Stefania Fiorcari

Cancers 2026, 18(3), 518; https://doi.org/10.3390/cancers18030518 - 5 Feb 2026

Viewed by 409

Abstract

Background/Objectives: Tissue niches, such as those in the spleen, bone marrow, and lymph nodes, are crucial for the survival and growth of leukemic cells in chronic lymphocytic leukemia (CLL). Methods: A growing amount of research over the last 20 years has [...] Read more.

Background/Objectives: Tissue niches, such as those in the spleen, bone marrow, and lymph nodes, are crucial for the survival and growth of leukemic cells in chronic lymphocytic leukemia (CLL). Methods: A growing amount of research over the last 20 years has shown how important the tumor microenvironment (TME) is to the pathophysiology, development, and resistance to treatment of CLL. This protective environment, which is made up of various cell types (including stromal and immune cells), extracellular matrix components, and soluble factors, supports CLL cells and encourages their survival, growth, and drug resistance. Even in the absence of mutations, Notch2 is functionally activated in the CLL system, in addition to the well-known Notch1. This occurs because leukemic cells aberrantly express the ligand Jagged1/2, which activates the Notch2 receptor on both stromal and CLL cells themselves. Notch2 activation on stromal cells leads to the triggering of the Wnt/β-catenin program in CLL cells, whereas the activation of Notch2 in CLL cells promotes the expression of Mcl-1, which confers drug tolerance (especially in cases with trisomy 12). Results: In addition to these mechanisms, Notch2 acts as a transcription factor that directly controls the expression of key targets, such as CD23 and Hes1, that are fundamental for B cell proliferation, differentiation, and survival in CLL. Conclusions: All of these circuits represent important therapeutic targets and help explain the cells’ dependence on their niche, the formation of proliferation centers, and resistance to modern targeted agents. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: From Genetics to Therapy)

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10 pages, 1141 KB

Open AccessArticle

Is Systematic Biopsy Mandatory in All MRI-Guided Fusion Prostate Biopsies? A Machine Learning Prediction Model

by Omer Longo, Gil Raviv and Miki Haifler

Cancers 2026, 18(3), 517; https://doi.org/10.3390/cancers18030517 - 4 Feb 2026

Viewed by 1037

Abstract

Objectives: To develop a prediction model able to accurately predict which patients will harbor higher risk prostate cancer in the systematic biopsy template compared to the targeted biopsy during MRI/US fusion biopsy. Methods: We included patients who underwent fusion biopsy. Clinical and radiographic [...] Read more.

Objectives: To develop a prediction model able to accurately predict which patients will harbor higher risk prostate cancer in the systematic biopsy template compared to the targeted biopsy during MRI/US fusion biopsy. Methods: We included patients who underwent fusion biopsy. Clinical and radiographic variables were collected from patients’ records. The outcome of the model was higher risk prostate cancer in the systematic compared with targeted biopsies. An extreme gradient boosting model was trained and tested. We evaluated variable importance and clinical benefit. Results: Five hundred and twenty-nine patients were included. Eighty-two (15.5%) patients had higher risk prostate cancer in the systematic biopsies. The area under the ROC curve and negative predictive value were 0.82 and 0.92, respectively. The four most important features for outcome prediction were prostate volume, PSAD, patient’s age, and PSA. The decision curve showed increased clinical benefit of our model at threshold probabilities of 0–0.5. Limitations include the retrospective design of the study and the lack of external validation of the model. Conclusions: We developed a prediction model able to accurately predict which patients must undergo systematic and targeted biopsy. This prediction model has the potential to help in the decision whether to perform SB and thus may lower the adverse event rate while keeping a high detection rate. Full article

(This article belongs to the Special Issue Advances in Quantitative Imaging, AI, and Novel Imaging Techniques for Precision Radiology in Prostate Cancer)

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16 pages, 1888 KB

Open AccessArticle

Differentiating Borderline from Malignant Ovarian-Adnexal Tumours: A Multimodal Predictive Approach Joining Clinical, Analytic, and MRI Parameters

by Lledó Cabedo, Carmen Sebastià, Meritxell Munmany, Adela Saco, Eduardo Gallardo, Olatz Sáenz de Argandoña, Gonzalo Peón, Josep Lluís Carrasco and Carlos Nicolau

Cancers 2026, 18(3), 516; https://doi.org/10.3390/cancers18030516 - 4 Feb 2026

Viewed by 570

Abstract

Objectives: To improve the differentiation of borderline ovarian-adnexal tumours (BOTs) from malignant ovarian-adnexal masses, most of which fall into the indeterminate O-RADS MRI 4 category, by developing a multimodal predictive model that integrates clinical, analytic, and MRI parameters. Methods: This retrospective, single-centre study [...] Read more.

Objectives: To improve the differentiation of borderline ovarian-adnexal tumours (BOTs) from malignant ovarian-adnexal masses, most of which fall into the indeterminate O-RADS MRI 4 category, by developing a multimodal predictive model that integrates clinical, analytic, and MRI parameters. Methods: This retrospective, single-centre study included 248 women who underwent standardised MRI for ovarian-adnexal mass characterisation between 2019 and 2024. Of these, 201 had true ovarian-adnexal masses (114 benign, 22 borderline, and 65 malignant), confirmed by histopathology or stability after ≥12-month follow-up. Forty-one clinical, laboratory, and imaging variables were initially assessed, and after a bivariate evaluation, 18 final predictors with clinical relevance were selected for model construction with thresholds learned from the data. A classification and regression tree (CART) model (“Full Model”) was applied as a second-stage tool after O-RADS MRI scoring, using 10-fold cross-validation to prevent overfitting. A pruned “Simplified Model” was also derived to enhance interpretability. Results: O-RADS MRI performed well at the extremes (scores 2–3 and 5) but showed limited discrimination between BOTs and malignancies within category 4 (PPV for borderline = 0.50). The decision-tree models significantly improved diagnostic performance, increasing overall accuracy from 0.856 with O-RADS MRI alone to 0.905 (Simplified Model) and 0.955 (Full Model). The PPV for BOTs within the intermediate O-RADS MRI 4 category increased from 0.49 with O-RADS MRI alone to 0.77 and 0.90 with the simplified and full models, respectively, while maintaining high accuracy for benign and malignant lesions. Conclusions: In this retrospective single-centre cohort, the addition of an interpretable rule-based predictive model as a second-line tool within O-RADS MRI category 4 was associated with improved discrimination between borderline and invasive malignant ovarian-adnexal tumours. These findings suggest that multimodal integration of clinical, laboratory, and MRI features may help refine risk stratification in indeterminate cases; however, external validation in prospective multicentre cohorts is required before clinical implementation. Full article

(This article belongs to the Special Issue Gynecological Cancer: Prevention, Diagnosis, Prognosis and Treatment)

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14 pages, 952 KB

Open AccessArticle

Prognostic Impact of Blood Tumor Mutational Burden in pMMR/MSS Metastatic Colorectal Cancer Assessed by FoundationOne^® Liquid CDx

by Benoist Chibaudel, Elisabeth Carola, Hamid Mekranter, Perrine Goyer, Arnaud Saget, Olivier Oberlin, Hélène Marijon, Hubert Richa, Ida Iurisci, Honorine Gervais, Nathalie Perez-Staub, Linda Dainese, Pascal Pujol, Hanah Lamallem, Clémentine Besnard, Sofya Latrache, Alain Toledano and Aimery de Gramont

Cancers 2026, 18(3), 515; https://doi.org/10.3390/cancers18030515 - 4 Feb 2026

Viewed by 496

Abstract

Background/Objectives: The prognostic significance of blood tumor mutational burden (bTMB) in metastatic colorectal cancer (mCRC) remains poorly defined. While tissue-based TMB has been associated with favorable outcomes in selected colorectal cancer subgroups, the clinical meaning of bTMB in real-world practice is unclear. This [...] Read more.

Background/Objectives: The prognostic significance of blood tumor mutational burden (bTMB) in metastatic colorectal cancer (mCRC) remains poorly defined. While tissue-based TMB has been associated with favorable outcomes in selected colorectal cancer subgroups, the clinical meaning of bTMB in real-world practice is unclear. This study evaluated the prognostic impact of bTMB measured through liquid biopsy in an unselected cohort of patients with mCRC. Methods: This monocentric, real-world study included 255 adult patients with pMMR/MSS mCRC who underwent routine comprehensive genomic profiling using the FoundationOne^® Liquid CDx assay. bTMB was quantified in mutations per megabase (mut/Mb), and patients were classified into bTMB-low and bTMB-high groups using the cohort median. The primary endpoint was overall survival (OS). Subgroup analyses, including stratification by RAS/BRAF mutation status, were descriptive. Results: The median bTMB was 5 mut/Mb. Patients in the bTMB-high group had an increased risk of death compared with those in the bTMB-low group (hazard ratio (HR) 1.88). The adverse prognostic effect for OS of high bTMB was more pronounced in patients with RAS mutant tumors (HR 2.32) than with RAS/BRAF wild-type tumors (HR 1.81), while no prognostic impact was observed in BRAF^V600E mutant tumors (HR 0.90). bTMB was strongly correlated with ctDNA fraction (p < 0.0001). Conclusions: In routine clinical practice, elevated bTMB is associated with poor prognosis in pMMR/MSS mCRC, particularly in RAS mutant tumors. These results contrast with prior tissue-based studies and indicate that bTMB may reflect tumor burden and aggressive disease biology rather than tumor immunogenicity. Prospective studies integrating bTMB with ctDNA fraction, tumor burden metrics, and longitudinal molecular dynamics are warranted to refine its clinical utility. Full article

(This article belongs to the Special Issue Oncogenetics of Colorectal Cancer (2nd Edition))

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21 pages, 622 KB

Open AccessReview

Advances and Emerging Techniques in Transarterial Chemoembolization for Hepatocellular Carcinoma

by Hunter L. Gazda, Phuoc-Hanh D. Le, Ankit Patel, Arjun Jha and Mina S. Makary

Cancers 2026, 18(3), 514; https://doi.org/10.3390/cancers18030514 - 4 Feb 2026

Viewed by 649

Abstract

HCC is the most common primary liver cancer and the third leading cause of cancer-related death overall [...] Full article

(This article belongs to the Special Issue Advances in the Treatment of Gastrointestinal (GI) Cancers)

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30 pages, 868 KB

Open AccessReview

Genome Instability and Somatic Mutagenesis in Autoimmune Diseases

by Sriram Vijayraghavan and Natalie Saini

Cancers 2026, 18(3), 513; https://doi.org/10.3390/cancers18030513 - 4 Feb 2026

Viewed by 1046

Abstract

The adaptive immune system plays a vital role in protecting individuals against invading pathogens primarily through its ability to discern self- versus non-self-antigens. Conditions leading to the breakdown of such immune surveillance can have devastating consequences, one of them being erroneous recognition and [...] Read more.

The adaptive immune system plays a vital role in protecting individuals against invading pathogens primarily through its ability to discern self- versus non-self-antigens. Conditions leading to the breakdown of such immune surveillance can have devastating consequences, one of them being erroneous recognition and immune response against self-antigens, resulting in autoimmunity. Autoimmune diseases (AID) are widespread and span multiple organ systems and cellular functions. Historically, the etiology of AID is multifarious and complex owing to a mix of genetic predisposition and environmental conditions. However, in recent years the study of somatic mutations has gained traction in understanding the basis of AID. Somatic mutations commonly result from elevated DNA damage and inefficient DNA repair and have been linked to cancer. Moreover, the hyper-inflammatory microenvironment is highly conducive to the accumulation of DNA damage in immune cells. Thus, understanding the mutational burden and landscape of somatic mutagenesis in the context of AID can illuminate the basis of disease development and progression. In this review, we summarize past and current research on genome instability in AID, focusing on the nexus between inflammation, immune response, DNA damage, and mutagenesis, and discuss the possible link between AID and cancer development. We provide examples of autoimmune disorders that have been studied from a mutational standpoint and outline results from key studies highlighting the extent of DNA damage and mutagenesis in cells from AID patients. Lastly, we provide our perspective on the key challenges and future directions to understand the role of somatic mutagenesis in autoimmunity and cancer. Full article

(This article belongs to the Special Issue Genome Instability and Human Cancer)

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Open AccessArticle

Characterisation of Bespoke Patient-Derived In Vitro Models of Ewing Sarcoma

by Elizabeth A. Roundhill, Elton J. R. Vasconcelos, John Davies and Susan A. Burchill

Cancers 2026, 18(3), 512; https://doi.org/10.3390/cancers18030512 - 4 Feb 2026

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Abstract

Background/Objectives: Preclinical models that accurately reflect Ewing sarcoma (ES) will enable the prioritisation of clinically active targeted agents from bench to clinic. To expedite this process, we have established and characterised patient-derived ES cultures (PDES) in vitro. Methods: Fluorescence in situ [...] Read more.

Background/Objectives: Preclinical models that accurately reflect Ewing sarcoma (ES) will enable the prioritisation of clinically active targeted agents from bench to clinic. To expedite this process, we have established and characterised patient-derived ES cultures (PDES) in vitro. Methods: Fluorescence in situ hybridisation, RT-PCR and western blotting were used to examine expression of the pathognomonic EWSR1 fusions. Activation or repression of EWSR1 fusion downstream targets and proliferation was examined by immunofluorescence and immunohistochemistry. Using next-generation sequencing, the DNA and transcriptomic profiles of PDES and cell lines were compared. The response of PDES and cell lines to standard-of-care chemotherapeutics, ionising radiation and investigational drugs was examined. Results: All PDES contain EWSR1 fusion DNA, consistent with a diagnosis of ES. EWSR1 fusion gene RNA and protein were detected in 70% and 21% of PDES, respectively. Markers of proliferation and expression of EWSR1 fusion target genes were consistent with the tumours from which PDES were derived (R² = 0.74, p < 0.0001) and the paediatric mesenchymal lineage (SBS5 and SBS1, ID1 and ID2). In contrast, the transcriptome of PDES was significantly different from that of cell lines. PDES had a significantly increased doubling time (p < 0.00001), decreased expression of Ki67 (p < 0.0001) and increased migration (p < 0.02) compared to cell lines. Consistent with the longer doubling time, PDES were more resistant to doxorubicin, etoposide and vincristine and ionising radiation (p < 0.0001) than cell lines. PDES were sensitive to mTKIs (cabozantinib, lenvatinib, and regorafenib), and trabectedin. The response of PDES to drugs in vitro reflects the clinical experience of patients. Conclusions: Models incorporating PDES cells may positively contribute to the preclinical pipeline. Full article

(This article belongs to the Section Cancer Drug Development)

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Cancers, Volume 18, Issue 3 (February-1 2026) – 193 articles

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