Cancers

18 pages, 788 KB

Open AccessSystematic Review

The Use of Radiotherapy in Leptomeningeal Carcinomatosis: A Systematic Review and Random-Effects Proportions Meta-Analysis

by Pamela Ochoa-Lantigua, Mauricio Moreno-Bejarano, Cayetana Guarderas-Arias, José Bueno-Miño and Jose E. Leon-Rojas

Cancers 2026, 18(4), 547; https://doi.org/10.3390/cancers18040547 (registering DOI) - 7 Feb 2026

Abstract

Objective: Leptomeningeal carcinomatosis (LMC) is a rare but devastating complication of advanced cancer, particularly in patients with breast and lung malignancies. This systematic review provides a descriptive synthesis of radiotherapy approaches used in patients with leptomeningeal metastases, with a quantitative proportions meta-analysis [...] Read more.

Objective: Leptomeningeal carcinomatosis (LMC) is a rare but devastating complication of advanced cancer, particularly in patients with breast and lung malignancies. This systematic review provides a descriptive synthesis of radiotherapy approaches used in patients with leptomeningeal metastases, with a quantitative proportions meta-analysis focused on treatment-related toxicity. Materials and methods: A systematic search was conducted in PubMed, Scopus, and the virtual health library (BVS) databases following PRISMA 2020 guidelines. Studies including patients diagnosed with LMC and treated with RT were selected. Outcomes included overall survival (OS), adverse events (toxicities), and functional response. Results: A total of 39 studies comprising 2822 patients were included; the most frequent primary tumors were lung (n = 1337) and breast (n = 990) cancers. The mean time from cancer diagnosis to LMC was 22.4 months. Radiotherapy regimens included whole-brain radiotherapy (WBRT, n = 1054), craniospinal irradiation (CSI, n = 148), and focal RT (n = 27); RT was administered alone or in combination with systemic treatments. Toxicity was reported in 462 patients, primarily fatigue (n = 115), nausea/vomiting (n = 72), and hematological events (notably in CSI). The pooled toxicity prevalence was 50.8% (95% CI, 26.1–75.4; I² = 96.1; p < 0.0001) for all RT modalities, and 31.6% (95%CI, 15.0–50.8; I² = 90.7; p < 0.0001) for WBRT. CSI toxicity estimates were based on a limited number of studies and did not reach statistical significance, and should therefore be interpreted as exploratory. Mean OS from LMC diagnosis was 18.2 weeks; OS by treatment was 21.5 weeks and 20.3 weeks, for RT by itself and combined, respectively. Conclusions: LMC predominantly affects patients with advanced-stage lung and breast cancers and presents with variable clinical timelines and functional impairment. Radiotherapy represents a frequently utilized and clinically important component of the palliative management of leptomeningeal disease, particularly for symptom control and neurological stabilization, rather than a treatment associated with superior survival outcomes. Prognosis is more closely linked to patient-specific factors than to treatment type. Radiotherapy toxicity is prevalent; however, most are categorized as type 1 toxicities with insignificant to little damaging effects on patients. Full article

(This article belongs to the Special Issue Radiotherapy for the Management of Brain Metastases)

15 pages, 2627 KB

Open AccessReview

The Structure, Pathogenesis, and Inhibition of the p53-MDM2 Pathway

by Amanda L. Brown, Xiaoying Lian and Qian Wang

Cancers 2026, 18(4), 546; https://doi.org/10.3390/cancers18040546 (registering DOI) - 7 Feb 2026

Abstract

The p53 tumor suppressor protein plays a central role in maintaining genomic stability by regulating cell cycle arrest, apoptosis, and DNA repair under cellular stress. Mouse double minute 2 (MDM2), an E3 ubiquitin ligase, negatively regulates p53 via direct binding and proteasomal degradation. [...] Read more.

The p53 tumor suppressor protein plays a central role in maintaining genomic stability by regulating cell cycle arrest, apoptosis, and DNA repair under cellular stress. Mouse double minute 2 (MDM2), an E3 ubiquitin ligase, negatively regulates p53 via direct binding and proteasomal degradation. Overexpression or amplification of MDM2 can disrupt this pathway and promote tumorigenesis, even in cancers with wild-type p53. This review outlines the structural features of MDM2, particularly its N-terminal hydrophobic pocket and C-terminal RING domain, and their roles in p53 regulation. We further examine the pathological effects of MDM2 dysregulation and SNPs linked to increased cancer risk. Recent progress in small molecule MDM2 inhibitors is discussed, with a focus on non-covalent agents such as rhein-derived anthraquinone analogs, including AQ-101, which demonstrate promising anti-cancer activity with reduced toxicity. These findings support the continued development of non-covalent MDM2 inhibitors as a novel therapeutic approach for cancers involving both wild-type and mutant p53. Full article

(This article belongs to the Section Molecular Cancer Biology)

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14 pages, 481 KB

Open AccessReview

The Impact of the Number of Neoadjuvant Chemotherapy Cycles on Outcomes in Advanced Ovarian Cancer: A Narrative Review

by Ana Carla Franco Ubinha, Camila Musa Honorato, Marcelo Henrique dos Santos, Luis Pires de Melo Filho, Luciano Ipólito Branquinho, Adhemar Longatto-Filho and Ricardo Dos Reis

Cancers 2026, 18(4), 545; https://doi.org/10.3390/cancers18040545 (registering DOI) - 7 Feb 2026

Abstract

Although standard chemotherapy for three to four cycles followed by surgery is considered safe and effective in the management of advanced ovarian cancer, the impact of extending treatment beyond this period remains uncertain. Some authors suggest that the number of neoadjuvant chemotherapy cycles [...] Read more.

Although standard chemotherapy for three to four cycles followed by surgery is considered safe and effective in the management of advanced ovarian cancer, the impact of extending treatment beyond this period remains uncertain. Some authors suggest that the number of neoadjuvant chemotherapy cycles does not directly affect prognosis and may reflect a confounding bias. Others, however, indicate that a prolonged exposure to chemotherapy can promote the selection of resistant tumor clones, negatively influencing patient survival and disease progression. This review aims to summarize the current evidence on the topic, evaluating the effect of prolonged chemotherapy on surgical cytoreduction and survival. To achieve this, we conducted an analysis of the English-language literature available in PubMed, focusing on treatment duration, achievement of complete surgical resection, survival outcomes, and prognostic factors. Full article

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

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14 pages, 489 KB

Open AccessArticle

Using AI to Design and Develop Online Educational Modules to Enhance Lung Cancer Screening Uptake Among High-Risk Individuals

by Fang Lei, Hua Zhao, Feifei Huang and Edris Farhadi

Cancers 2026, 18(4), 544; https://doi.org/10.3390/cancers18040544 (registering DOI) - 7 Feb 2026

Abstract

Background: Despite clear evidence supporting low-dose computed tomography (LDCT) for lung cancer screening, the participation rate among eligible high-risk individuals remains low. Educational interventions that address gaps in knowledge, attitude, and beliefs may improve screening uptake. Objective: This study describes the systematic use [...] Read more.

Background: Despite clear evidence supporting low-dose computed tomography (LDCT) for lung cancer screening, the participation rate among eligible high-risk individuals remains low. Educational interventions that address gaps in knowledge, attitude, and beliefs may improve screening uptake. Objective: This study describes the systematic use of artificial intelligence to design and develop a series of online educational modules aimed at improving knowledge, attitudes, and beliefs toward lung cancer screening among high-risk individuals. Methods: Guided by the Health Belief Model and principles of digital health education, five interactive online modules were developed by artificial intelligence technology to address key topics: (1) lung cancer epidemiology, etiology, signs, and symptoms; (2) lung cancer treatment and care; (3) lung cancer prevention methods; (4) screening guidelines, benefits, and risks; and (5) screening procedures and results interpretation. The design process included literature review, individual cognitive interviews, expert consultation, and pilot testing among target users. Qualitative individual interviews were conducted with 12 high-risk individuals. Content validity was evaluated by an expert panel (n = 7) using a content validity index (CVI), and pilot usability testing was conducted with 25 high-risk individuals. Results: All five modules achieved high content validity (I-CVI range = 0.90–1.00; S-CVI = 0.96). Usability and satisfaction testing showed that participants rated the modules as clear, engaging, and relevant (mean System Usability Scale score = 88/100, mean satisfaction score = 18.32/20). Participants demonstrated significant improvements in knowledge (p < 0.001), lung cancer stigma (p < 0.001), and health beliefs (p < 0.001) after module completion. Of the 22 participants who completed the 3-month follow-up (88%), 13 (59.1%) reported obtaining LDCT screening. Conclusions: The developed online modules demonstrated strong content validity and usability, indicating their feasibility for use in future intervention studies to promote lung cancer screening knowledge, attitude, beliefs, and participation among high-risk individuals. Full article

(This article belongs to the Special Issue Artificial Intelligence and Machine Learning in Lung Cancer)

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16 pages, 1987 KB

Open AccessArticle

Radiation Dose to Swallowing Muscles and Post-Radiotherapy Laryngeal Penetration or Aspiration in Head and Neck Squamous Cell Carcinoma

by Thong Chotchutipan, Peesit Leelasawatsuk, Tiraya Phuengtrakul, Jinnatham Apichato, Kemmapon Chumchuen and Jidapa Bridhikitti

Cancers 2026, 18(4), 543; https://doi.org/10.3390/cancers18040543 (registering DOI) - 7 Feb 2026

Abstract

Background/Objectives: Radiation-induced dysphagia can cause life-threatening complications including aspiration pneumonia. Consequently, studies have attempted to limit the radiation dose to the swallowing muscles to prevent radiation-induced dysphagia. However, data identifying the specific swallowing muscles associated with post-radiation dysphagia are lacking. Therefore, this case–control [...] Read more.

Background/Objectives: Radiation-induced dysphagia can cause life-threatening complications including aspiration pneumonia. Consequently, studies have attempted to limit the radiation dose to the swallowing muscles to prevent radiation-induced dysphagia. However, data identifying the specific swallowing muscles associated with post-radiation dysphagia are lacking. Therefore, this case–control study aimed to identify the swallowing muscles whose radiotherapy-related damage is likely to cause radiation-induced dysphagia. Methods: This retrospective study included 53 patients with head and neck cancer who received definitive radiotherapy and underwent post-radiotherapy swallowing function evaluation using videofluoroscopy or fiberoptic endoscopic evaluation of swallowing at least 3 months post-radiotherapy. Twenty-two patients with a Penetration-Aspiration Scale score ≥ 3 were defined as having laryngeal penetration or aspiration. Twenty-two controls matched for age and tumor site were selected using propensity score matching. The primary exposure variable was radiation dose to the swallowing muscles, including the floor of the mouth, thyrohyoid, posterior digastric/stylohyoid, longitudinal pharynx, hyoglossus, styloglossus, genioglossus, and intrinsic tongue muscles. A LASSO regression model was used to select the most predictive dosimetric parameter. Results: The percentage of genioglossus muscle receiving a radiation dose ≥70 Gy (GGS V70) was the only dosimetric variable predictive of radiation-induced dysphagia. After adjusting for the clinical variables, GGS V70 demonstrated a significant association with post-radiotherapy laryngeal penetration or aspiration (p = 0.003), with an adjusted odds ratio of 1.06 for each increasing radiation dose unit of GGS V70. Conclusions: The genioglossus muscle might be associated with radiation-induced dysphagia and, therefore, should be further investigated in prospective studies. Full article

(This article belongs to the Special Issue Radiotherapy for Head and Neck Squamous Cell Carcinoma (2nd Edition))

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16 pages, 5086 KB

Open AccessArticle

12-Hydroxyheptadecatrienoic Acid Predicts Hepatocellular Carcinoma Development During Nucleos(t)ide Analogue Therapy

by Hiroko Ikenaga, Ritsuzo Kozuka, Kirara Inoue, Tsutomu Matsubara, Naoshi Odagiri, Kanako Yoshida, Kohei Kotani, Etsushi Kawamura, Atsushi Hagihara, Hideki Fujii, Masaru Enomoto and Sawako Uchida-Kobayashi

Cancers 2026, 18(4), 542; https://doi.org/10.3390/cancers18040542 (registering DOI) - 7 Feb 2026

Abstract

Background/Objectives: Alterations in polyunsaturated fatty acid (PUFA) metabolites have been linked to the development of hepatocellular carcinoma (HCC). However, the association between PUFA metabolites and HCC development during nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B virus infection remains unclear. [...] Read more.

Background/Objectives: Alterations in polyunsaturated fatty acid (PUFA) metabolites have been linked to the development of hepatocellular carcinoma (HCC). However, the association between PUFA metabolites and HCC development during nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B virus infection remains unclear. Methods: This study enrolled 195 NUC-naïve patients who received NUC therapy. Associations between metabolic factors—especially PUFA metabolites—and HCC development during NUC therapy were evaluated. Baseline serum concentrations of 158 PUFA metabolites were quantified using targeted lipidomic analysis. Results: Nineteen patients developed HCC during the follow-up period. The cumulative incidences of HCC at 5 and 10 years were 7.7% and 12.4%, respectively. Variable importance in projection analysis identified 12-hydroxyheptadecatrienoic acid (12-HHT) as the top-ranked metabolite differentiating patients with and without HCC development. Furthermore, 14 metabolites were significantly associated with HCC development based on the log-rank test with 12-HHT being the most significant predictor. The cumulative incidences of HCC at 5 and 10 years were 13.7% and 24.7%, respectively, in patients with 12-HHT concentration ≤ 3.82 ng/mL compared with 3.3% at both time points in those with 12-HHT concentration > 3.82 ng/mL (p < 0.001). In multivariate analysis, low 12-HHT concentration (≤3.82 ng/mL; p = 0.027; hazard ratio [HR], 4.28; 95% confidence interval [CI], 1.18–15.55) and a fibrosis-4 index ≥ 4.08 (p = 0.005; HR, 5.19; 95% CI, 1.64–16.41) were significantly associated with HCC development during NUC therapy. Conclusions: Pre-treatment 12-HHT represents a novel predictive biomarker for HCC development during NUC therapy. Full article

(This article belongs to the Collection Primary Liver Cancer)

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15 pages, 2354 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

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)

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

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, 609 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

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)

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

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

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

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

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

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

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

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

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

Abstract

In the original publication [...] Full article

17 pages, 841 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

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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