Cancers

37 pages, 1614 KB

Open AccessReview

Targeting the Epigenetic–Immune Axes in Hematologic Malignancies

by Ravina Pandita and Evan F. Lind

Cancers 2026, 18(18), 2985; https://doi.org/10.3390/cancers18182985 - 15 Sep 2026

Despite significant advances in treatment for several hematologic malignancies, treatment resistance and relapse remain major challenges. Immune escape is recognized as a key mechanism that can lead to tumor evasion and treatment resistance in blood cancers. Among the various drivers of immune evasion, [...] Read more.

Despite significant advances in treatment for several hematologic malignancies, treatment resistance and relapse remain major challenges. Immune escape is recognized as a key mechanism that can lead to tumor evasion and treatment resistance in blood cancers. Among the various drivers of immune evasion, epigenetic dysregulation is a recurrent and central feature in these malignancies. Although epigenetic targeting therapies have shown benefit in blood cancers, relapse still occurs, indicating the need for improved therapies. This review focuses on epigenetic mechanisms causing immune evasion in blood cancers and discusses emerging therapies that focus on combining epigenetic modulators with immunotherapies to improve anti-tumor immunity. We focus on how epigenetic mechanisms, including DNA methylation, histone modification and chromatin remodeling, influence tumor cells or immune cell subsets including T cells, NK cells and macrophages to promote tumor growth. We then discuss immunomodulatory effects of epigenetic therapies including DNA methyltransferase inhibitors and histone deacetylase inhibitors and how they can restore immune cell function and limit tumor growth and progression. Finally, we highlight the potential of combining epigenetics with different immunotherapies including adoptive cell therapy and immune checkpoint blockade, while discussing their current limitations and suggesting ways to overcome this therapy resistance. A deeper understanding of the immune–epigenetic axis in blood cancers may facilitate the development of effective therapies that will benefit patients with hematologic malignancies. Full article

(This article belongs to the Special Issue Epigenetic Regulation in Hematologic Malignancies)

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19 pages, 5664 KB

Open AccessReview

Brachytherapy-Integrated Hyperthermia for Pelvic Malignancies: Clinical Evidence, Technical Platforms, Thermal Dosimetry, and Translational Barriers

by Yuanjie Cao, Ronglan Cui, Chen Li, Youheng Tan, Qingxin Wang, Wei Wang, Jaeho Cho and Jie Chen

Cancers 2026, 18(18), 2984; https://doi.org/10.3390/cancers18182984 - 15 Sep 2026

Abstract

Brachytherapy-integrated hyperthermia combines implant-based radiation delivery with localized heating, but the evidence spans heterogeneous diseases, devices, temperature measurements, and study designs. We conducted a systematic search-based evidence map with revision-stage record reconciliation, human adjudication, report-to-study linkage, and design-matched clinical appraisal. Of 8189 unique [...] Read more.

Brachytherapy-integrated hyperthermia combines implant-based radiation delivery with localized heating, but the evidence spans heterogeneous diseases, devices, temperature measurements, and study designs. We conducted a systematic search-based evidence map with revision-stage record reconciliation, human adjudication, report-to-study linkage, and design-matched clinical appraisal. Of 8189 unique records screened in the original search, 2178 candidate or uncertain records underwent documented revision-stage human adjudication. During acceptance-stage revision, all 3919 records originally assigned to the machine exclusion stratum also received a primary human title/abstract re-screen decision; 3916 exclusions were confirmed and three boundary records were reclassified. The final unified worklist comprised 285 records. Ninety-two verified/supporting report units were adjudicated (15 direct clinical, 34 technical/platform, 24 supporting, and 19 excluded). The 15 core clinical reports represented 14 independent studies and generated 17 appraisal records using RoB 2, ROBINS-I, and JBI tools. Two randomised phase III trials did not show improved disease control or survival with added hyperthermia; both were judged to raise some concerns for risk of bias, and both had important thermal intervention limitations. One non-randomised cervical comparison was at serious risk of bias from confounding by indication. Uncontrolled prostate, anal, gynaecologic, and mixed pelvic series supported procedural feasibility but not causal efficacy. Two predefined supplemental saturation batches added no new eligible evidence in any family or domain. The evidence supports standardised multipoint thermometry, measurement-anchored spatial reconstruction, coupled planning, platform qualification, and disease-specific trials only after thermal fidelity gates are passed. Full article

(This article belongs to the Section Cancer Therapy)

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20 pages, 927 KB

Open AccessArticle

Pathological Complete Response and Residual Disease Patterns After Neoadjuvant Chemoradiotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma: Clinical and Laboratory Associations

by Azer Gökmen and Erdoğan Şeyran

Cancers 2026, 18(18), 2983; https://doi.org/10.3390/cancers18182983 - 15 Sep 2026

Abstract

Background: Pathological response after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma may differ between the primary tumor and regional lymph nodes. We evaluated pretreatment factors associated with pathological complete response (pCR) and the anatomical distribution of residual disease after esophagectomy. Methods: This retrospective [...] Read more.

Background: Pathological response after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma may differ between the primary tumor and regional lymph nodes. We evaluated pretreatment factors associated with pathological complete response (pCR) and the anatomical distribution of residual disease after esophagectomy. Methods: This retrospective single-center cohort included 100 patients treated with neoadjuvant chemoradiotherapy followed by esophagectomy. pCR was defined as ypT0N0. Associations with pCR were evaluated using logistic regression. Results: Among 99 response-evaluable patients, 59 achieved pCR (59.6%; 95% CI, 49.7–68.7%). Of 40 patients with non-pCR, residual disease involved only the primary tumor in 26 (65%), both primary and nodal compartments in 10 (25%), and only regional lymph nodes despite complete primary tumor regression in 4 (10%). Overall, 14 patients with non-pCR (35%) had residual nodal disease. In an exploratory adjusted analysis that could not account for baseline cT and cN categories, lower pretreatment lactate dehydrogenase (OR per 10 U/L increase, 0.93; 95% CI, 0.86–0.99; p = 0.026) and female sex (OR, 2.72; 95% CI, 1.02–7.24; p = 0.045) were associated with pCR. Conclusions: Response was heterogeneous across primary tumor and nodal compartments. Primary tumor regression did not invariably indicate nodal clearance, supporting compartment-specific response assessment. The lactate dehydrogenase and sex associations may reflect residual confounding by baseline disease extent and require external validation. Full article

(This article belongs to the Special Issue Advances in Clinical Therapy and Prognosis of Gastrointestinal Cancer)

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34 pages, 4467 KB

Open AccessReview

Biomimetic Nanocarriers for Glioblastoma Therapy: Translational Advances and Strategic Challenges

by Bhawana Jain, Sunita Sanwaria, Arti Hadap, I Made Joni, Renny Febrida, Rovina Ruslami, Irwan Purnama, Deoraj Singh and Camellia Panatarani

Cancers 2026, 18(18), 2982; https://doi.org/10.3390/cancers18182982 - 15 Sep 2026

Abstract

Glioblastoma (GBM) is the most aggressive and common type of brain tumor, characterized by rapid growth and infiltration, as well as high resistance to conventional treatments. Given the persistent challenge posed by the bloodbrain barrier (BBB) to effective drug delivery, a shift in [...] Read more.

Glioblastoma (GBM) is the most aggressive and common type of brain tumor, characterized by rapid growth and infiltration, as well as high resistance to conventional treatments. Given the persistent challenge posed by the bloodbrain barrier (BBB) to effective drug delivery, a shift in therapeutic strategies is required. Biomimetic nanocarriers (BNCs) represent a promising approach for the targeted treatment of malignant brain tumors. By replicating biological structures and functions, BNCs enhance drug stability, facilitate penetration across the BBB, and promote tumor-specific targeting while minimizing the risk of systemic toxicity. These nanocarriers can be engineered using a wide variety of biomaterials, including cell membranes, liposomes, and polymeric systems. Recent preclinical and early clinical studies suggest that BNCs provide a viable method to increase drug bioavailability and therapeutic activity. However, several translational challenges remain, including formulation stability, immunogenicity, regulatory acceptability, and large-scale manufacturing. This review discusses recent advances in BNCs for GBM treatment, drug-targeting strategies, and the structural hurdles that limit their clinical translation. Furthermore, we examine emerging multimodal approaches that integrate BNCs with immunotherapy and gene therapy to enhance personalized GBM treatment. Full article

(This article belongs to the Topic Advanced Nanotechnology in Drug Delivery Systems)

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21 pages, 2945 KB

Open AccessArticle

Prognostic Value of Masseter Muscle Index, Masseter Radiodensity, and the Global Immune-Nutrition-Inflammation Index in Laryngeal Carcinoma Treated with Definitive Radiotherapy

by Mehmet Kızılkaya, Timur Koca and Aylin Fidan Korcum

Cancers 2026, 18(18), 2981; https://doi.org/10.3390/cancers18182981 - 15 Sep 2026

Abstract

Background: This retrospective study evaluated pretreatment masseter muscle index (MMI), masseter radiodensity (HUAC), and Global Immune–Nutrition–Inflammation Index (GINI) as prognostic markers in patients with laryngeal squamous cell carcinoma treated with definitive radiotherapy. Methods: MMI and HUAC were measured on simulation computed tomography, and [...] Read more.

Background: This retrospective study evaluated pretreatment masseter muscle index (MMI), masseter radiodensity (HUAC), and Global Immune–Nutrition–Inflammation Index (GINI) as prognostic markers in patients with laryngeal squamous cell carcinoma treated with definitive radiotherapy. Methods: MMI and HUAC were measured on simulation computed tomography, and GINI was calculated from pretreatment laboratory values. Biomarkers were analyzed continuously using Firth penalized Cox models adjusted for age, performance status, tumor site, and T and N categories. Nonlinearity was assessed using restricted cubic splines. Joint models and multiple imputation assessed robustness. HUAC associations were assessed over time. Exploratory cutoffs were derived using censoring-aware three-year time-dependent receiver operating characteristic analysis, with radiotherapy initiation as time zero. Results: Among 146 patients, 30 died and 48 experienced progression or death; GINI was available in 116. Each standard-deviation decrease in MMI was associated with worse overall survival (OS; adjusted hazard ratio 1.92, 95% confidence interval 1.21–3.05; p = 0.002) and progression-free survival (PFS; 1.91, 1.35–2.71; p < 0.001). These associations weakened after further adjustment for body mass index and concurrent systemic therapy. GINI findings were not robust in adjusted, joint, and missing-data analyses. Lower HUAC showed an exploratory association with poorer outcomes later in follow-up, based on few late events. Three-year OS/PFS estimates were 92.5%/81.1% versus 68.9%/59.5% for MMI > 2.830 versus ≤2.830 cm²/m², and 90.2%/81.9% versus 45.1%/38.0% for GINI < 139.67 versus ≥139.67. The GINI cutoff was unstable, with a 95% bootstrap interval of 20.104–180.985. Conclusions: Lower MMI showed the most consistent prognostic association. This initial evaluation of GINI in laryngeal cancer supports further investigation of its prognostic potential. HUAC findings and cohort-derived cutoffs remain exploratory and require external validation. Full article

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

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17 pages, 3613 KB

Open AccessArticle

Structure–Function Analysis of Individual Reversion Variants of the Engineered Mpp46Aa1 (PS2Aa1) N65 Protein

by Natalia A. Bravo-Granados, Nohora Juliana Rueda-Forero, Lydia Visser and Miguel O. Suárez-Barrera

Cancers 2026, 18(18), 2980; https://doi.org/10.3390/cancers18182980 - 15 Sep 2026

Abstract

Background: Mpp46Aa1 (formerly PS2Aa1) is a β-pore-forming protein produced by Bacillus thuringiensis that exhibits selective cytotoxicity against cancer cells. Protein engineering has generated variants with improved antitumor activity, including the N65 variant, which contains three amino acid substitutions. Objective: In this study, three [...] Read more.

Background: Mpp46Aa1 (formerly PS2Aa1) is a β-pore-forming protein produced by Bacillus thuringiensis that exhibits selective cytotoxicity against cancer cells. Protein engineering has generated variants with improved antitumor activity, including the N65 variant, which contains three amino acid substitutions. Objective: In this study, three individual reversion variants of N65 were generated by site-directed mutagenesis to determine the contribution of each substitution to cytotoxicity, selectivity, and cell death mechanisms in the colorectal cancer cell lines SW480 and SW620 and the non-tumorigenic colonic epithelial cell line NCM460. Methods: Recombinant proteins were purified and evaluated using AlamarBlue viability assays, Annexin V/Cy3 staining, caspase-3/7 and caspase-9 activation assays, and JC-1 mitochondrial membrane potential analysis. Results: The reversion variants differentially affected the biological activity of N65. Among them, the D34N variant exhibited low IC₅₀ values against both colorectal cancer cell lines, while maintaining selectivity towards non-cancerous cells. D34N also induced phosphatidylserine externalization, activation of caspase-3/7 and caspase-9, and mitochondrial membrane depolarization, indicating activation of the intrinsic apoptotic pathway. Structural analyses revealed that the reverted residues modified local interaction networks, suggesting that these positions may influence CD59 recognition and contribute to cellular selectivity. Conclusions: These findings demonstrate that the three substitutions present in N65 contribute unequally to its biological activity and identify residue 34 as a key determinant of Mpp46Aa1 cytotoxicity. This study provides structural and functional insights that support the rational engineering of parasporins with enhanced antitumor selectivity. Full article

(This article belongs to the Special Issue A New Road for Cancer Drug Discovery)

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16 pages, 919 KB

Open AccessPerspective

Eco-Evolutionary Thinking in Metastatic Breast Cancer: A Clinician’s Primer on Why Tumors Outsmart Us and How to Fight Back Smarter

by Aixa Elena Soyano, Renee Brady-Nicholls, Hatem H. Soliman, Robert A. Gatenby, Mark Robertson-Tessi and Dana Ataya

Cancers 2026, 18(18), 2979; https://doi.org/10.3390/cancers18182979 - 15 Sep 2026

Abstract

Metastatic breast cancer (MBC) remains incurable because of tumor evolution. Despite advances in targeted therapies—CDK4/6 inhibitors, PIK3 inhibitors, HER2-directed agents, and antibody–drug conjugates—median overall survival is modest, with resistance emerging in nearly all patients. From an evolutionary perspective, standard continuous maximum tolerated dose [...] Read more.

Metastatic breast cancer (MBC) remains incurable because of tumor evolution. Despite advances in targeted therapies—CDK4/6 inhibitors, PIK3 inhibitors, HER2-directed agents, and antibody–drug conjugates—median overall survival is modest, with resistance emerging in nearly all patients. From an evolutionary perspective, standard continuous maximum tolerated dose (MTD) therapy may create intense selective pressure that reduces treatment-sensitive cells and, in some incurable and resistance-prone settings, could permit competitive release of resistant clones. While MTD remains the guideline-endorsed standard of care in many metastatic settings and has produced substantial survival gains, the eco-evolutionary framework highlights a potential trade-off rather than a categorical failure of MTD. Cancer is not just a genetic disease but an evolving ecosystem where cell populations compete for limited resources. Resistant cells typically carry a fitness cost—slower growth in the absence of treatment—creating an exploitable vulnerability. By preserving treatment-sensitive cells through dose modulation or treatment holidays (adaptive therapy), we can harness competitive suppression to control resistant populations and prolong disease control, potentially doubling time to progression compared to continuous MTD. This primer translates these ideas into plain language for clinical trial application. We explain four core eco-evolutionary principles every breast oncologist should know, review emerging evidence from adaptive therapy trials in breast and other cancers, and discuss practical implementation strategies to incorporate into future trials. The goal is not cure through eradication, but long-term control through evolutionary management. These evolution-informed strategies may, in selected contexts, help delay resistance and prolong disease control, and represent a complementary framework that warrants prospective testing. Full article

(This article belongs to the Section Cancer Therapy)

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25 pages, 2972 KB

Open AccessReview

Non-Invasive Assessment of Tertiary Lymphoid Structure in Hepatocellular Carcinoma Based on Multi-Parameter Imaging: From Tumor Immunobiology to Immunotherapy Benefit Prediction

by Dan Liu, Qian Li, Feng Che, Qin Wang, Tong Zhang, Wei Ren, Liping Deng, Bin Song, Yi Wei, Hehan Tang, Jing Zhu and Yuan Yuan

Cancers 2026, 18(18), 2978; https://doi.org/10.3390/cancers18182978 - 15 Sep 2026

Abstract

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates within the intratumoral and peritumoral microenvironment. In hepatocellular carcinoma (HCC), the presence of TLSs was closely associated with immunotherapy response and prognostic outcomes. However, TLSs exhibit pronounced spatial heterogeneity within tumors and biopsy, being invasive [...] Read more.

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates within the intratumoral and peritumoral microenvironment. In hepatocellular carcinoma (HCC), the presence of TLSs was closely associated with immunotherapy response and prognostic outcomes. However, TLSs exhibit pronounced spatial heterogeneity within tumors and biopsy, being invasive and prone to sampling bias, may cause inaccurate assessments. Multi-parametric imaging techniques based on computed tomography (CT)/magnetic resonance imaging (MRI)CT/MRICT/MRI with the aid of artificial intelligence (AI) algorithms could effectively integrate anatomical structures with functional metabolic information, quantifying and visualizing key pathological molecular features of tumor treatment response across multiple dimensions. This review summarizes the biological characteristics and clinical significance of TLSs in hepatocellular carcinoma. Furthermore, it focuses on the latest advances in non-invasive TLS assessment using multi-parametric imaging techniques, integrating these technologies with large-scale artificial intelligence models to explore their application value in prognosis prediction and immunotherapy benefit evaluation. Full article

(This article belongs to the Special Issue State-of-the-Art Imaging Advances and Translational Applications in Liver Cancer)

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15 pages, 2437 KB

Open AccessArticle

TIGIT⁺ CD4⁺ T Cell Enrichment in Colorectal Liver Metastases Is Associated with Shorter Survival

by Janusz von Renesse, Jakob Langsdorf, Elisabeth Kalb, Carolin Beer, David Digomann, Loreen Natusch Bufe, Daniela E. Aust, Jürgen Weitz, Lena Seifert and Adrian M. Seifert

Cancers 2026, 18(18), 2977; https://doi.org/10.3390/cancers18182977 - 15 Sep 2026

Abstract

Background/Objectives: The immune microenvironment of colorectal cancer liver metastases (CRCLM) differs from that of primary colorectal tumors and may influence responses to immunotherapy. We aimed to characterize T cell subsets and checkpoint receptor expression in CRCLM and explore associations with overall survival. Methods: [...] Read more.

Background/Objectives: The immune microenvironment of colorectal cancer liver metastases (CRCLM) differs from that of primary colorectal tumors and may influence responses to immunotherapy. We aimed to characterize T cell subsets and checkpoint receptor expression in CRCLM and explore associations with overall survival. Methods: We performed flow cytometric profiling of matched peripheral blood, non-tumor liver tissue, and CRCLM specimens from 17 patients undergoing hepatic metastasectomy. A separate cohort of 19 patients was studied using ex vivo expanded TILs. Kaplan–Meier/log-rank analyses were complemented by Cox models using dichotomized and continuous marker values, median-cut-off and permutation sensitivity analyses, and post hoc clinical covariate comparisons. Results: CRCLM showed relative enrichment of CD4⁺ T cells and depletion of CD8⁺ T cells. In the fresh cohort, 16 patients (12 deaths) were evaluable for CRCLM TIGIT⁺ CD4⁺ cells. The optimized split was associated with shorter survival for the high group (HR 5.26, 95% CI 1.54–17.94; log-rank p = 0.0036). The median-cut-off analysis showed the same direction (HR 3.17, 95% CI 0.92–11.00; p = 0.0551), as did the continuous model (HR 1.69 per 10-percentage-point increase, 95% CI 0.82–3.45; p = 0.153). In the expanded cohort, the optimized high-versus-low HR was 17.47 (95% CI 3.23–94.59; p < 0.001), and the continuous HR was directionally concordant (HR 2.68, 95% CI 0.96–7.51; p = 0.060). Clinical characteristics were balanced between optimized low and high groups. Conclusions: TIGIT⁺ CD4⁺ T cell enrichment showed an exploratory association with shorter survival in CRCLM and represents a promising candidate for further prognostic and functional investigation. The separate expanded cohort provided complementary evidence supporting this observation. Full article

(This article belongs to the Special Issue Immune Cells Within the Tumor Microenvironment)

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13 pages, 1177 KB

Open AccessArticle

Welfare Regimes and Out-of-Pocket Healthcare Spending in the Last Year of Life Among Cancer Decedents in Europe and Israel

by Aviad Tur-Sinai and Netta Bentur

Cancers 2026, 18(18), 2976; https://doi.org/10.3390/cancers18182976 - 15 Sep 2026

Abstract

Background/Objectives: Out-of-pocket (OOP) healthcare spending can remain substantial near the end of life even in countries with broad health coverage, yet less is known about whether these expenditures follow broader welfare-regime patterns. This study examined OOP healthcare expenditure among cancer decedents and assessed [...] Read more.

Background/Objectives: Out-of-pocket (OOP) healthcare spending can remain substantial near the end of life even in countries with broad health coverage, yet less is known about whether these expenditures follow broader welfare-regime patterns. This study examined OOP healthcare expenditure among cancer decedents and assessed whether welfare-regime differences persisted after adjustment for individual demographic and socioeconomic characteristics. Methods: We analyzed Survey of Health, Ageing and Retirement in Europe (SHARE) End-of-Life data for 1950 cancer decedents aged 50 years and older from 14 countries including Israel, classified into Continental, Social Democratic, Mediterranean, and East European welfare regimes. Logistic regression examined the likelihood of OOP expenditure, and linear regression examined expenditure magnitude, adjusting for gender, age, education, household economic capacity, and supplemental health insurance. Results: Overall, 58.0% of cancer decedents incurred OOP healthcare expenditure during their final year of life. Compared with the Continental regime, adjusted odds were higher in the Social Democratic regime (OR = 1.841) and lower in the Mediterranean (OR = 0.480) and East European (OR = 0.731) regimes. Social Democratic and East European regimes were also associated with lower expenditure levels than the Continental regime, whereas the Mediterranean regime did not differ significantly. Supplemental health insurance was associated with lower odds of OOP expenditure, while education was inversely associated with expenditure magnitude. Conclusions: OOP healthcare spending among cancer decedents varies systematically across welfare-regime contexts. Macro-institutional arrangements governing healthcare financing and social protection appear to be associated with household exposure to healthcare costs beyond individual socioeconomic characteristics. Full article

(This article belongs to the Special Issue Health Economic and Policy Issues Regarding Cancer)

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9 pages, 230 KB

Open AccessArticle

Optimizing Tissue Preparation for Molecular Testing in Thyroid Tumors: A Retrospective Analysis of 177 Cases from a High-Volume Japanese Center

by Mitsuyoshi Hirokawa, Miyoko Higuchi, Ayana Suzuki, Minoru Kihara and Takashi Akamizu

Cancers 2026, 18(18), 2975; https://doi.org/10.3390/cancers18182975 - 15 Sep 2026

Abstract

Background/Objectives: Reliable molecular testing is essential for selecting targeted therapies for thyroid tumors; however, assay performance can be affected by pre-analytical tissue conditions. This retrospective, single-center study evaluated real-world formalin-fixed, paraffin-embedded (FFPE) specimens to identify pathology practices associated with successful companion diagnostic [...] Read more.

Background/Objectives: Reliable molecular testing is essential for selecting targeted therapies for thyroid tumors; however, assay performance can be affected by pre-analytical tissue conditions. This retrospective, single-center study evaluated real-world formalin-fixed, paraffin-embedded (FFPE) specimens to identify pathology practices associated with successful companion diagnostic testing using the next-generation sequencing (NGS)-based Oncomine Dx assay and the polymerase chain reaction (PCR)-based BRAF3 assay widely used in routine clinical care in Japan. Methods: We retrospectively analyzed 177 cases with thyroid tumors tested at a high-volume thyroid center in Japan between 2022 and 2026. Results: All 79 specimens analyzed using the BRAF3 assay yielded successful test results, including specimens fixed in unbuffered formalin and archival blocks stored for up to 27 years. In contrast, the Oncomine Dx assay was successful in 93 of 98 specimens (94.9%), with all five failures occurring in specimens fixed in unbuffered formalin. DNA failure was more common than RNA failure. All five Oncomine Dx failures occurred in archived tissue blocks stored for 3–9 years, all of which had been fixed in unbuffered formalin. The BRAF3 test had a shorter turnaround time and was more frequently used in rapidly progressive tumors, such as anaplastic thyroid carcinoma. Conclusions: The NGS-based Oncomine Dx assay showed reduced success in samples stored long-term or in unbuffered specimens, whereas RNA preservation was high. In contrast, the PCR-based BRAF3 assay remained highly reliable even in long-stored archival blocks. Because fixative type and storage duration were confounded in this cohort, the independent effects of these variables could not be determined. The study’s findings provide practical real-world insights into how specimen handling, fixation, and storage conditions may influence the reliability of genomic diagnostics in routine practice. Full article

(This article belongs to the Special Issue Integrating Molecular and Conventional Diagnostics in Thyroid Nodule Management: Implications for Cancer Diagnosis and Treatment)

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Graphical abstract

51 pages, 1809 KB

Open AccessReview

From Donor to Discovery and Diagnosis: A Comprehensive 2026 Review of International Biobanking Guidelines Underpinning Molecular Pathology-Driven Cancer Diagnostics, with a Practical Roadmap for Establishing a New Biobank

by Andreea-Adriana Neamțu, Robert Barna, Alon Vigdorovits, Iulian-Andrei Hotinceanu, Mihaela-Mirela Muresan, Andrei-Vasile Pascalau and Ovidiu-Laurean Pop

Cancers 2026, 18(18), 2974; https://doi.org/10.3390/cancers18182974 - 14 Sep 2026

Abstract

Molecular pathology-driven oncologic diagnostics—genomic profiling, transcriptomics, proteomics, and, increasingly, artificial intelligence applied to tissue and liquid biopsy—can only be as accurate as the biospecimens on which they are performed. Biobanks are the infrastructures that secure this foundation, linking donors, biological samples, and data [...] Read more.

Molecular pathology-driven oncologic diagnostics—genomic profiling, transcriptomics, proteomics, and, increasingly, artificial intelligence applied to tissue and liquid biopsy—can only be as accurate as the biospecimens on which they are performed. Biobanks are the infrastructures that secure this foundation, linking donors, biological samples, and data to discovery and, through the pathology interface, back to diagnosis. Their scientific and diagnostic value, however, is determined less by the number of specimens stored than by the rigor of the guidelines under which those specimens are collected, processed, annotated, governed, and shared. The normative landscape has changed considerably in the last three years: the ISBER Best Practices reached their fifth edition (2023), the NCI Best Practices were comprehensively revised (2026), the Standard PREanalytical Code (SPREC) was updated to version 4.0 (2024/2025), MIABIS Core reached version 3.0 (2024), the 2024 revision of the Declaration of Helsinki explicitly anchored biobank governance to the Declaration of Taipei, the European Health Data Space Regulation (EU) 2025/327 entered into force, and ISO 20387—the accreditation standard for biobanks—is undergoing its first full revision. This review synthesizes the current (2026) status of international biobanking standards, ethical and legal frameworks, pre-analytical and quality management requirements, data and interoperability standards, and sustainability models, drawing on more than 200 sources with emphasis on the 2023–2026 literature. Standards are presented not as an inventory but as an operational system, organized along the biobanking workflow from donor consent to sample distribution and impact tracking. On this basis, we propose a phased, guideline-anchored roadmap and a start-up checklist to help new teams establish a real-world biobank—particularly hospital-integrated biobanks in settings without a mature national biobanking infrastructure—and we review comprehensively the financial, operational, regulatory, and societal challenges that determine whether a new biobank thrives or stalls. Particular attention is given to the specimen classes and quality controls on which molecular tumor diagnostics depend—FFPE tissue and its sequencing artifacts, fresh-frozen tissue, liquid biopsy analytes, and DV200-gated derivative quality—and to the interface between research biobanking and the accredited diagnostic laboratory, which is set out explicitly because the two are governed by different standards. We further provide explicit, endpoint-specific operational control of warm and cold ischemia, a quality-control framework for advanced patient-derived models (xenografts and organoids) and their interface with dedicated model cores, an explicit statement of the evidence underlying the practical recommendations, and a dedicated limitations section. The review is intended as a reference piece for biobankers, pathologists, clinician-researchers, quality managers, and institutional decision-makers building the biobanks on which the coming decade of precision oncology will depend. Full article

(This article belongs to the Special Issue Molecular Pathology-Driven Approaches to Improve Cancer Diagnostic Accuracy)

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17 pages, 679 KB

Open AccessArticle

A Scoring System Contributing to the Detection of Radiation Pneumonitis in Elderly Patients with Lung Cancer—Results of the POLCAR Trial

by Dirk Rades, Inga Zwaan, Elisa Marie Groh, Cansu Delikanli, Daphne Schepers-von Ohlen, Laura Doehring, Sabine Bohnet, Charlotte Kristiansen, Hanne Falk Grauslund, Christian Felix Schulz and Stefan Janssen

Cancers 2026, 18(18), 2973; https://doi.org/10.3390/cancers18182973 - 14 Sep 2026

Abstract

Background/Objectives: A symptom-based scoring system (0–9 points) for the identification of radiation pneumonitis was previously evaluated in lung cancer patients without age restrictions. A threshold of five points appeared optimal to detect pneumonitis. Since elderly patients have a higher pneumonitis risk, this threshold [...] Read more.

Background/Objectives: A symptom-based scoring system (0–9 points) for the identification of radiation pneumonitis was previously evaluated in lung cancer patients without age restrictions. A threshold of five points appeared optimal to detect pneumonitis. Since elderly patients have a higher pneumonitis risk, this threshold may not be valid for this group. The POLCAR trial evaluated performance and threshold selection in elderly patients. Methods: Diagnostic discrimination was assessed by receiver operating characteristic analysis. The areas under the curve (AUCs) and a null hypothesis that AUC equaled 0.7 were evaluated. Youden indices were used to identify candidate thresholds. In addition, the change from baseline and patient satisfaction were assessed. The dissatisfaction rate should be <20%. Results: Thirty new patients, plus 31 patients from another prospective trial with an almost identical design, qualified for analyses. The AUC for the pneumonitis score was 0.85 (95% confidence interval: 0.73–0.97). The highest Youden index (0.535) was observed for a threshold of four points. A threshold of five points led to a similar Youden index, a lower sensitivity, and higher specificity. An increase from the baseline by two points had a Youden index of 0.566 and a sensitivity of 100%, while an increase by three points had a Youden index of 0.550 and a specificity of 92.5%. Statistically superior discrimination for the change-from-baseline approach was not observed. The dissatisfaction rate was 5.4%. Conclusions: The scoring system showed good discrimination and high acceptance by patients. A threshold of four points appeared appropriate use in routine screening for the early detection of pneumonitis, whereas the change from baseline was considered useful as an exploratory tool when baseline data were available. Since only eight pneumonitis events occurred, threshold estimates require external validation. Full article

(This article belongs to the Special Issue Recent Advances and Emerging Directions in Lung Cancer Radiotherapy)

29 pages, 1369 KB

Open AccessSystematic Review

Fertility-Sparing Treatment of Endometrial Cancer and Atypical Endometrial Hyperplasia by Molecular Classification: A Systematic Review and Meta-Analysis Accounting for Outcome-Assessment Timing and Follow-Up Duration

by Abeer Alatawi, Saleem Almaser, Malak Alanazi, Amirah Alatawi and Seongmin Kim

Cancers 2026, 18(18), 2972; https://doi.org/10.3390/cancers18182972 - 14 Sep 2026

Abstract

Background/Objectives: Molecular classification (POLE-mutated, mismatch-repair–deficient [MMRd], no-specific-molecular-profile [NSMP], p53-abnormal [p53abn]) is used to stratify women receiving fertility-sparing treatment (FST) for early endometrial carcinoma or atypical hyperplasia, but reported subtype differences are inconsistent. We estimated subtype-specific complete response (CR) and post-CR recurrence and [...] Read more.

Background/Objectives: Molecular classification (POLE-mutated, mismatch-repair–deficient [MMRd], no-specific-molecular-profile [NSMP], p53-abnormal [p53abn]) is used to stratify women receiving fertility-sparing treatment (FST) for early endometrial carcinoma or atypical hyperplasia, but reported subtype differences are inconsistent. We estimated subtype-specific complete response (CR) and post-CR recurrence and examined how outcome-assessment timing (fixed early timepoint versus best response) and follow-up duration affect subtype comparisons. Methods: PubMed and Embase (January 2015–August 2025) were searched; overlapping reports were consolidated; proportions were pooled with binomial–normal generalised linear mixed models; late response among early non-responders was analysed in paired cohorts; recurrence was meta-regressed on follow-up; risk of bias (QUIPS) and certainty (GRADE) were assessed. Results: Twenty reports yielded 15 cohorts (10 primary). Best CR was 85% (95% CI 70–93) for POLE, 71% (57–83) for MMRd, and 85% (77–91) for NSMP. In six paired cohorts, CR rose from the early timepoint to best response in every subtype (MMRd 44→77%, NSMP 57→90%); 55% of MMRd and 76% of NSMP early non-responders later achieved CR, and within-cohort best CR was lower for MMRd than NSMP (odds ratio [OR] 0.36, 0.17–0.79). Recurrence after CR was 34% (23–46) for MMRd, 30% (17–49) for NSMP, and 19% (4–57; 0–100% across cohorts) for POLE. NSMP recurrence tended to rise with follow-up in an exploratory study-level analysis (OR 1.02/month; p = 0.06, dependent on the few long-follow-up cohorts), whereas MMRd recurrence did not (adjusted OR vs. NSMP 1.7, 0.9–3.3). p53abn tumours (n = 28) showed variable CR (17/24) and recurrence in 9/17. Occult p53abn or MMRd tumours affected 17% (12–24%; range 7–47%) of conventionally selected candidates. Certainty was low or very low. Conclusions: Subtype comparisons in FST depend on when outcomes are assessed and how long patients are followed. Molecular classification is prognostic, not predictive; its principal value is to identify occult higher-risk tumours and to calibrate counselling and surveillance, not to justify de-escalation. Full article

(This article belongs to the Topic Biomarker Development and Application, 2nd Edition)

22 pages, 2269 KB

Open AccessSystematic Review

Immune Checkpoint Inhibitor Combinations in Advanced Ovarian Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

by Boram Choi, Youn Jin Choi and Keun Ho Lee

Cancers 2026, 18(18), 2971; https://doi.org/10.3390/cancers18182971 - 14 Sep 2026

Abstract

Background/Objectives: Immune checkpoint inhibitors (ICIs) have shown limited efficacy in the treatment of ovarian cancer when used alone. This systematic review and meta-analysis evaluated the impact of different combination partners on ICI efficacy. Methods: PubMed, Embase, CENTRAL, and Web of Science were searched [...] Read more.

Background/Objectives: Immune checkpoint inhibitors (ICIs) have shown limited efficacy in the treatment of ovarian cancer when used alone. This systematic review and meta-analysis evaluated the impact of different combination partners on ICI efficacy. Methods: PubMed, Embase, CENTRAL, and Web of Science were searched until March 2026 for phase III randomized controlled trials (RCTs) of anti-PD-1/PD-L1 combination regimens. Nine fully published trials (N = 7381) were included in the primary analyses; an ICI monotherapy trial and two conference-abstract-only trials were considered in sensitivity analyses. Hazard ratios (HRs) were pooled using random-effects models with pre-specified subgroup analyses by combination partner. Evidence certainty was assessed using GRADE. Results: Overall, ICI combination therapy significantly improved progression-free survival (PFS) (HR 0.83, 95% confidence interval (CI) 0.73–0.93; I² = 55.8%; p = 0.007). Bevacizumab plus ICI significantly improved progression-free survival (PFS) (k = 4; HR 0.83, 95% CI 0.74–0.93 [Wald-type]; GRADE: Moderate). PARP inhibitor plus ICI also showed a Wald-type PFS improvement (k = 3; HR 0.78, 95% CI 0.63–0.96 [Wald-type]; GRADE: Low), but this was not robust to Hartung–Knapp–Sidik–Jonkman (HKSJ) adjustment or inclusion of abstract-only trials (SA5: k = 5; HR 0.85, 95% CI 0.67–1.09; I² = 90.1%). Chemotherapy plus ICI (two avelumab trials) showed no benefit (k = 2; HR 0.96, 95% CI 0.66–1.38). KEYNOTE-B96 demonstrated the first significant overall survival (OS) benefit with an ICI regimen (HR 0.82, 95% CI 0.69–0.97). Funnel plot assessment showed no asymmetry; Egger’s test was not formally applied, as the pre-specified threshold of ten trials was not met (descriptive p = 0.81). Conclusions: ICI combination therapy improved PFS in advanced ovarian cancer, in contrast to earlier syntheses pooling monotherapy and combination regimens. The benefit was most consistent for bevacizumab-based regimens (GRADE: Moderate); the PARP inhibitor–based benefit was less robust (Low), and chemotherapy combinations offered no advantage (Very low). Subgroup differences were not statistically significant and remain exploratory; a partner-specific, biomarker-guided approach is warranted. Full article

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

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15 pages, 462 KB

Open AccessSystematic Review

Epidemiology of Non-Melanoma Skin Cancer in Europe over the Last Decade: A Systematic Review

by Andrzej Ciborek, Hanna Krauss, Zuzanna Chęcińska-Maciejewska, Dariusz Kowalczyk and Jolanta Jaworek

Cancers 2026, 18(18), 2970; https://doi.org/10.3390/cancers18182970 - 14 Sep 2026

Abstract

Background: Non-melanoma skin cancer (NMSC), principally basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), is incompletely captured by cancer surveillance. Objective: To synthesize European epidemiological evidence, with Poland considered in this context. Methods: PubMed/MEDLINE, Scopus, and Web of Science were searched [...] Read more.

Background: Non-melanoma skin cancer (NMSC), principally basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), is incompletely captured by cancer surveillance. Objective: To synthesize European epidemiological evidence, with Poland considered in this context. Methods: PubMed/MEDLINE, Scopus, and Web of Science were searched for publications dated 1 January 2015–31 March 2026, supplemented by registry resources and reference-list searching. Additional eligibility checks during manuscript revision continued until 30 August 2026. The publication-date criterion was distinct from the observation periods of source data. Source-level methodological appraisal informed a descriptive synthesis. Results: The consolidated selection record comprised 198 records, 165 screened records, 61 full-text assessments, 37 full-text exclusions, and 24 included sources. Several registry-based studies reported increasing BCC or cSCC incidence in defined populations. Model-based age-standardized trends varied by geography, sex, age, and observation period. These results do not establish a uniform European increase. Polish estimates were affected by histological aggregation and incomplete ascertainment. Selected pandemic-period studies reported fewer diagnoses or changes in the treated case mix; these findings do not establish a Europe-wide decline in biological incidence or subsequent rebound. Conclusions: NMSC creates a substantial and incompletely measured European burden. Histology-specific registration, explicit multiple-primary counting rules, and improved outpatient capture are priorities for interpreting trends and planning care. Full article

(This article belongs to the Special Issue Non-Melanoma Skin Cancer: A Growing Problem in the Elderly Population)

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24 pages, 6585 KB

Open AccessArticle

Increasing H3K9 Methylation Level Reduces the Proliferation of Leukemic Stem Cells

by Barbara Walter, Polina Zjablovskaja, Sara Montserrat-Vazquez, Eva Mejia-Ramirez, Laia Solé-Castilla, Javier Lozano-Bartolome, Miroslava Kari Adamcová, Meritxell Alberich-Jorda, Chang Sun, Qin Peng, Michael Lübbert, Amanda Amoah, Liam MacPhee, Melika Bakharzi, Florian Kuchenbauer, Arefeh Rouhi, Jasson Villarreal-Hernandez, Montserrat Arnan-Sangerman and Maria Carolina Florian

Cancers 2026, 18(18), 2969; https://doi.org/10.3390/cancers18182969 - 14 Sep 2026

Abstract

Background/Objectives: Genetic and epigenetic alterations accumulate throughout life in hematopoietic stem and progenitor cells (HSPCs), leading to an increased risk of age-related hematological malignancies, such as acute myeloid leukemia (AML). While a few epigenetic drugs have entered clinical practice, studies focusing on [...] Read more.

Background/Objectives: Genetic and epigenetic alterations accumulate throughout life in hematopoietic stem and progenitor cells (HSPCs), leading to an increased risk of age-related hematological malignancies, such as acute myeloid leukemia (AML). While a few epigenetic drugs have entered clinical practice, studies focusing on histone post-translational modifications (PTMs) altered in AML remain limited. Methods: Here, we used murine HSPCs, murine AML mouse models, human leukemic cell lines, and leukemic patient samples to investigate whether targeting the methylation of histone 3 at lysine 9 (H3K9 methylation) affects HSPCs upon aging and leukemogenesis and might represent a possible target. Results: Our data show that H3K9 methylation changes upon aging in HSPCs and is linked to a pre-malignant phenotype. Low levels of H3K9 methylation in leukemic cells are required to maintain proliferative capacities in vitro. Increasing H3K9 methylation reduces the leukemogenesis of both young and aged murine and patient-derived leukemic cells. Conclusions: Thus, H3K9 methylation might be a potential and selective therapeutic target in AML patients. Full article

(This article belongs to the Special Issue Blood Stem Cell and Hematological Malignancies (Second Edition))

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3 pages, 144 KB

Open AccessEditorial

Neuroendocrine Tumors Have Outgrown the Orphan-Disease Framework: Building an Evidence Base for a Changing Field

by Aman Chauhan and Jaydira Del Rivero

Cancers 2026, 18(18), 2968; https://doi.org/10.3390/cancers18182968 - 14 Sep 2026

Abstract

For decades, one word shaped the story of neuroendocrine cancer: Rare [...] Full article

(This article belongs to the Special Issue Current Updates and Future Directions in Neuroendocrine Neoplasms (NENs): Understanding Biology, Diagnosis, Management and Research Efforts in NENs (2nd Edition))

16 pages, 45901 KB

Open AccessArticle

Beyond Morphology: Molecular Evidence Supporting a Clonal Relationship Between Pancreatic Undifferentiated Carcinoma with Osteoclast-like Giant Cells (UCOGC) and Conventional Pancreatic Ductal Adenocarcinoma (PDAC)

by Esmeralda Celia Marginean, Dilshad Dhaliwal, Kevin E. Fisher, Sonalben Italiya and Alis Dema

Cancers 2026, 18(18), 2967; https://doi.org/10.3390/cancers18182967 - 14 Sep 2026

Abstract

Background: Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) is a rare pancreatic malignancy with striking morphology. Its prognosis appears more heterogeneous than its high-grade histology would suggest. Larger clinicopathologic and population-based studies suggest that UCOGC may behave more favorably than conventional PDAC. However, [...] Read more.

Background: Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) is a rare pancreatic malignancy with striking morphology. Its prognosis appears more heterogeneous than its high-grade histology would suggest. Larger clinicopathologic and population-based studies suggest that UCOGC may behave more favorably than conventional PDAC. However, the prognostic impact of an associated PDAC component remains unresolved. Methods: Six cases of pancreatic UCOGC, diagnosed between 2019 and 2024, were retrospectively identified and selected for immunohistochemical and molecular analysis. We retrieved available clinical, radiologic, and follow-up data from electronic medical records. We performed targeted next-generation sequencing on individually macro-dissected UCOGC and PDAC components. Results: The cohort included four females and two males, with a median age of 68.5 years. All tumors were associated with conventional PDAC, and, in this series, only two cases were correctly diagnosed at biopsy; others were interpreted as PDAC or sarcomatoid carcinoma, with a definitive UCOGC diagnosis made only at resection. Immunoreactivity for cytokeratin was observed in the epithelial component, while the undifferentiated and giant cell components showed vimentin and CD68 immunoreactivity, respectively. NGS revealed co-mutations in TP53 and KRAS in 4 cases. Pathogenic mutations in APC, BRCA2, BRAF, GNAS, PIK3CA, RB1, SMAD4, and CDKN2A/B loss were also detected. concordant pathogenic variants Paired analysis of macro-dissected components from the same tumor (n = 4) demonstrated concordant pathogenic variants, providing supportive evidence of a shared clonal relationship. Two patients received neoadjuvant chemotherapy, and systemic therapy was administered in five patients. Three patients were alive during the last follow-up, including two long-term survivors. Conclusions: Pancreatic UCOGC shares key genetic alterations with PDAC, and paired molecular analysis provides supportive evidence of a shared clonal relationship between the UCOGC and ductal components. The variable clinical outcomes observed in this small series are descriptive and hypothesis-generating and require validation in larger cohorts. Full article

(This article belongs to the Section Cancer Pathophysiology)

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