Cancers

19 pages, 6210 KB

Open AccessArticle

Nestin as a Vascular Marker of Angiogenesis in Non-Melanoma Skin Cancer

by Katarzyna Nowogrodzka, Maciej Tota, Aleksandra Piotrowska, Andrzej Bieniek, Piotr Dzięgiel and Alina Jankowska-Konsur

Cancers 2026, 18(9), 1495; https://doi.org/10.3390/cancers18091495 - 6 May 2026

Viewed by 825

Abstract

Background: Angiogenesis is critical for tumor progression. Microvessel density (MVD) is commonly assessed using CD31 and CD34, which detect both mature and newly formed vessels and therefore cannot distinguish active neoangiogenesis from stable, quiescent vasculature. Nestin, an intermediate filament protein expressed preferentially in [...] Read more.

Background: Angiogenesis is critical for tumor progression. Microvessel density (MVD) is commonly assessed using CD31 and CD34, which detect both mature and newly formed vessels and therefore cannot distinguish active neoangiogenesis from stable, quiescent vasculature. Nestin, an intermediate filament protein expressed preferentially in proliferating endothelial cells, has been proposed as a complementary marker of active angiogenesis and has been investigated in several solid tumor types, including pancreatic, colorectal, and breast carcinomas. However, no studies have quantitatively compared nestin-positive MVD across AK, BCC, and SCC using standardized methods. Methods: Immunohistochemistry for nestin, CD31, and CD34 was performed on 118 patient samples collected in 2015–2019 and diagnosed with AK, BCC, or SCC. MVD was quantified by averaging vessel counts in three representative “hot spot” areas. Results: Nestin-positive MVD was significantly lower in patients with AK compared to patients with BCC and SCC (p < 0.001). The mean MVD of nestin-positive vessels was significantly lower in AK than in BCC and SCC (p < 0.0001). In all three groups, nestin-positive MVD demonstrated a strong, positive correlation with both CD34 and CD31. Conclusions: Nestin-positive MVD was significantly elevated in BCC and SCC compared to AK lesions and demonstrated strong correlations with standard angiogenic markers. These findings suggest that nestin may warrant further investigation as a complementary marker of angiogenesis in non-melanoma skin cancer. Whether nestin-positive MVD offers independent diagnostic or prognostic value in this context remains to be determined in larger, prospective, multicentre studies. Full article

(This article belongs to the Special Issue Histopathology and Pathogenesis of Skin Cancer)

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15 pages, 813 KB

Open AccessSystematic Review

HDR Endorectal/Endoluminal Brachytherapy Boost in Rectal Organ Preservation: A Systematic Review and Meta-Analysis

by Yuanjie Cao, Chen Li, Baozhong Zhang and Jie Chen

Cancers 2026, 18(9), 1494; https://doi.org/10.3390/cancers18091494 - 6 May 2026

Viewed by 639

Abstract

Background and purpose: Organ-preservation strategies are increasingly being incorporated into rectal cancer management, but the role of HDR endorectal/endoluminal brachytherapy boost remains less well defined than that of broader non-operative treatment pathways. Existing literature is frequently mixed with contact X-ray brachytherapy series, neoadjuvant [...] Read more.

Background and purpose: Organ-preservation strategies are increasingly being incorporated into rectal cancer management, but the role of HDR endorectal/endoluminal brachytherapy boost remains less well defined than that of broader non-operative treatment pathways. Existing literature is frequently mixed with contact X-ray brachytherapy series, neoadjuvant protocols with planned surgery, or heterogeneous watch-and-wait cohorts, limiting the interpretation of this specific strategy. Materials and methods: We performed a PROSPERO-registered systematic review and meta-analysis of studies evaluating definitive-intent external beam radiotherapy (EBRT), with or without chemotherapy, followed by HDR endorectal/endoluminal brachytherapy boost in histologically confirmed rectal adenocarcinoma managed without planned surgery. Pooled analyses were performed for clinical complete response (cCR) and late grade ≥3 gastrointestinal (GI) toxicity. Regrowth/local failure outcomes were synthesized descriptively because of heterogeneity in endpoint definitions, denominator selection, and follow-up structure. Results: Six studies were included in the quantitative evidence base, with one additional small feasibility report summarized narratively. The pooled cCR proportion was 69.2% (95% confidence interval [CI], 43.7–86.6). The pooled proportion of late grade ≥3 GI toxicity was 18.1% (95% CI, 10.9–28.6). Reported regrowth/local failure outcomes were not suitable for formal pooling because of inconsistent definitions, differing denominator structures, and non-uniform follow-up frameworks across studies. Conclusion: Current evidence suggests that EBRT plus HDR endorectal/endoluminal brachytherapy boost may represent a selective organ-preservation strategy for carefully chosen patients with rectal adenocarcinoma, particularly where surgery is not feasible or not desired. Its broader clinical use remains limited not only by the small size of the evidence base, but also by fragmented endpoint definitions, inconsistent denominator reporting, and insufficiently standardized durable local-control outcomes. These findings support cautious interpretation of the current evidence and highlight priorities for future prospective studies in rectal cancer management. Full article

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

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20 pages, 1378 KB

Open AccessReview

Prospects of Chimeric Antigen Receptor T-Cell Therapy in Myelofibrosis: From Immunopathogenesis to Therapeutic Strategies

by Lulu Kong, Chunling Fu, Lianggui Song, Wenxiao Wang, Mengchu Ji, Fei Li, Xiaofeng Shi and Wei Chen

Cancers 2026, 18(9), 1493; https://doi.org/10.3390/cancers18091493 - 6 May 2026

Viewed by 1675

Abstract

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal hematopoietic dysregulation, amplification of chronic inflammation, and progressive remodeling of the bone marrow fibrotic niche, clinically manifesting as bone marrow failure, splenomegaly, and systemic inflammatory symptoms. Although Janus kinase (JAK) inhibitors can alleviate symptom [...] Read more.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal hematopoietic dysregulation, amplification of chronic inflammation, and progressive remodeling of the bone marrow fibrotic niche, clinically manifesting as bone marrow failure, splenomegaly, and systemic inflammatory symptoms. Although Janus kinase (JAK) inhibitors can alleviate symptom burden and reduce spleen size, they have limited capacity to eradicate malignant clones or reverse fibrosis. Allogeneic hematopoietic stem cell transplantation remains the only potentially curative option; however, its application is constrained by advanced age, comorbidities, unavailable donor, and transplant-related risks. Therefore, the development of disease-modifying therapeutic strategies has become a central focus in MF research. Chimeric antigen receptor T (CAR-T)-cell therapy has demonstrated robust efficacy across various hematologic malignancies. Its application in MF holds the potential not only to selectively eliminate malignant hematopoietic clones but also to modulate the immunosuppressive and profibrotic microenvironment through advanced cellular engineering, thereby enabling a dual therapeutic paradigm involving both clonal control and microenvironmental reprogramming. In this context, potential targets and pathways include CD123, myeloproliferative leukemia protein (MPL), fibroblast activation protein (FAP), the TGF-β signaling axis, the CXCR4–CXCL12 niche-regulatory axis, and molecules associated with myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Future strategies may optimize both efficacy and safety through combinatorial approaches, including integration with JAK inhibitors, development of armored CAR-T constructs, and bridging to hematopoietic stem cell transplantation. Collectively, CAR-T-cell therapy offers a promising avenue for shifting MF management from symptomatic control toward true disease modification. Full article

(This article belongs to the Special Issue Novel Advances in the Molecular Understanding of Myeloproliferative Neoplasms (MPNs))

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18 pages, 6684 KB

Open AccessArticle

Diagnostic Utility of Endoscopic Features and Endoscopic Ultrasonography for Ulcerative Colitis-Associated Neoplasia: A Retrospective Study on the Role of Endoscopic Submucosal Dissection as a Total Biopsy

by Saki Yoshida, Yoriaki Komeda, Masashi Kono, Kohei Handa, Tomoyuki Nagai, Satoru Hagiwara, Shunsuke Omoto, Mamoru Takenaka, Hiroshi Kashida, George Tribonias, Koji Daito, Junichiro Kawamura and Masatoshi Kudo

Cancers 2026, 18(9), 1492; https://doi.org/10.3390/cancers18091492 - 6 May 2026

Viewed by 633

Abstract

Background/Objectives: Ulcerative colitis (UC)-associated neoplasia (UCAN) often presents as flat lesions with indistinct margins, and biopsy sensitivity is limited. Therefore, we evaluated endoscopic criteria to distinguish UCAN from sporadic neoplasia, assessing the accuracy of endoscopic ultrasonography (EUS) for invasion depth and the role [...] Read more.

Background/Objectives: Ulcerative colitis (UC)-associated neoplasia (UCAN) often presents as flat lesions with indistinct margins, and biopsy sensitivity is limited. Therefore, we evaluated endoscopic criteria to distinguish UCAN from sporadic neoplasia, assessing the accuracy of endoscopic ultrasonography (EUS) for invasion depth and the role of endoscopic submucosal dissection (ESD) as a “total biopsy.” Methods: We reviewed 212 endoscopically treated neoplastic lesions in UC-affected mucosa (April 2016–January 2025). We compared preoperative diagnoses using macroscopic type, pit pattern, and the Japan Narrow-Band Imaging Expert Team classification with final histology. We compared depth estimates with pathology in 10 UCAN-suspected lesions undergoing EUS. Lesions < 2 cm underwent conventional endoscopic resection, whereas those ≥ 2 cm underwent ESD. Results: No UCAN was found in 189 lesions < 2 cm. Among 23 ESD lesions, 8 suspected sporadic lesions were non-UCAN. Of 15 UCAN-suspected lesions, 8 were UCAN, 6 sporadic, and 1 inflammatory. For positive T1b or deeper invasion, the sensitivity, specificity, positive and negative predictive values, and overall accuracy of EUS were 50.0%, 100%, 100%, 88.9%, and 90.0%, respectively. EUS depth assessment agreed with pathology in 9/10 cases; nine lesions were T1a or shallower, and one was T1b. Third-layer thickening occurred in two lesions—both UCAN—including the T1b cancer. In ESD cases, redness and a VI pit pattern were independent predictors of UCAN. Conclusions: EUS-based depth assessment is useful for determining optimal treatment strategies. Beyond therapy, ESD enables comprehensive histologic assessment of the entire lesion, functioning as a total biopsy to guide management while preserving bowel function. Full article

(This article belongs to the Special Issue IBD-Associated Cancer)

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15 pages, 2711 KB

Open AccessSystematic Review

The Self-Perpetuating Cycle of Psychological Distress and Clinical Outcomes in Head and Neck Oncology

by Ankita Chakrawal, Aashruti Pathania, Ruhi Dixit and Manoj Pandey

Cancers 2026, 18(9), 1491; https://doi.org/10.3390/cancers18091491 - 6 May 2026

Viewed by 966

Abstract

Background: Head and neck cancer (HNC) presents unique challenges due to impairments in vital functions and appearance. This narrative synthesis of systematic review synthesizes evidence on the prevalence and predictors of distress in HNC and proposes a Multifactorial Cycle of Distress to explain [...] Read more.

Background: Head and neck cancer (HNC) presents unique challenges due to impairments in vital functions and appearance. This narrative synthesis of systematic review synthesizes evidence on the prevalence and predictors of distress in HNC and proposes a Multifactorial Cycle of Distress to explain how psychological burdens compromise clinical outcomes. Methods: A systematic search of PubMed and Scopus was conducted (up to June 2025). From 342 articles, 32 were included, covering HNC patients with quantitative or qualitative distress assessments related to quality of life (QoL) and survival. Results: Distress prevalence ranged from 23–47%, with 30% of survivors experiencing persistent symptoms long-term. Key predictors included advanced tumor stage, radiotherapy-induced side effects, and pre-treatment depression, which increased distress risk 2- to 3-fold. Notably, distress was associated with a 25% reduction in radiotherapy completion and a 55% increased risk of mortality. Additionally, 71% of patients experienced decision regret, further impacting outcomes. Psychosocial interventions, including cognitive-behavioral therapy and mindfulness, showed potential in reducing anxiety by 15–20%. Conclusions: Distress in HNC functions as a self-perpetuating cycle where physical morbidity triggers psychological barriers that directly impair treatment adherence and survival. Routine screening using tools like the Distress Thermometer or DIC-2 and integrated multidisciplinary care are essential to break this cycle and improve patient and caregiver well-being. Full article

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

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21 pages, 1410 KB

Open AccessSystematic Review

A Mapping of Operative Heterogeneity in Robotic Splenic Flexure Cancer Surgery, Focusing on Vascular Ligation and Reconstructive Strategy

by Mohit Satish Gupta, Georgios Kyriakopoulos, Sina Hossaini, Mick Harper, Gerald David, Guglielmo Piozzi, Filippos Sagias, John Conti and Jim Khan

Cancers 2026, 18(9), 1490; https://doi.org/10.3390/cancers18091490 - 6 May 2026

Viewed by 614

Abstract

Background: Splenic flexure cancers represent a small but anatomically complex subset of colorectal malignancies, characterised by variable vascular supply and lymphatic drainage. This has led to ongoing uncertainty regarding the optimal extent of resection and level of vascular ligation. With increasing adoption of [...] Read more.

Background: Splenic flexure cancers represent a small but anatomically complex subset of colorectal malignancies, characterised by variable vascular supply and lymphatic drainage. This has led to ongoing uncertainty regarding the optimal extent of resection and level of vascular ligation. With increasing adoption of robotic surgery, a range of operative approaches has been described, although these remain inconsistently reported and poorly synthesised. Aim: We aimed to map operative heterogeneity in robotic splenic flexure cancer surgery, focusing on resection extent, vascular ligation, reconstruction strategy, and technical configuration. Methods: A structured scoping review was performed in accordance with PRISMA-ScR guidelines. MEDLINE (PubMed) and Embase (Ovid) were searched from inception to January 2026. Studies reporting robotic resection for primary splenic flexure colon cancer with extractable operative detail were included. Data were synthesised descriptively and grouped into three tiers based on study design: comparative cohorts, case series, and technical reports. Results: Sixteen studies comprising 97 robotic resections were included. Three were comparative cohort studies; two were case series, and eleven were single-case technical reports. Comparative studies consistently described a flexure-directed segmental resection with preservation of the inferior mesenteric artery and division of the left colic artery. In contrast, there was greater variability in management of the middle colic branches and inferior mesenteric vein. Reconstruction strategy differed across tiers, with extracorporeal anastomosis more commonly reported in comparative cohorts, while intracorporeal techniques were frequently described in technical series. Anastomotic configuration, specimen extraction, and use of indocyanine green fluorescence varied widely. Terminology relating to complete mesocolic excision and D2/D3 lymphadenectomy was inconsistent and often poorly defined. Conclusions: Robotic splenic flexure surgery shows broad agreement in overall resection strategy but considerable variability in vascular control, reconstruction, and technical execution. This likely reflects differences in reporting rather than clear differences in oncological intent. A more consistent and structured operative description is needed to allow meaningful comparison and to support the development of evidence-based approaches in this technically demanding area. Full article

(This article belongs to the Special Issue Surgical Treatment of Abdominal Tumors)

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25 pages, 7356 KB

Open AccessArticle

Single-Cell and Spatial Transcriptomics Reveals Selenoproteins Shape Immunosuppressive Microenvironment and Therapeutic Outcomes in Glioma

by Xiaowei Zhang, Na Zhang, Yuqing Zhong, Siqi Ou, Guitao Wu, Taohui Ouyang and Kejun He

Cancers 2026, 18(9), 1489; https://doi.org/10.3390/cancers18091489 - 6 May 2026

Viewed by 898

Abstract

Background: Gliomas exhibit substantial intratumoral heterogeneity, which limits prognostic precision and therapeutic efficacy. Selenoproteins are key regulators of redox homeostasis, but their role in glioma progression remains insufficiently defined. This study aimed to characterize glioma cells with high selenoprotein activity and to determine [...] Read more.

Background: Gliomas exhibit substantial intratumoral heterogeneity, which limits prognostic precision and therapeutic efficacy. Selenoproteins are key regulators of redox homeostasis, but their role in glioma progression remains insufficiently defined. This study aimed to characterize glioma cells with high selenoprotein activity and to determine their biological and clinical significance. Methods: We performed integrated multi-omic analyses combining bulk transcriptomic, single-cell transcriptomic, and spatial transcriptomic data to identify and characterize glioma cell states associated with elevated selenoprotein expression. Functional validation was conducted using SELENOS knockdown assays to evaluate effects on glioma proliferation, invasion, tumor growth, macrophage recruitment, CSF1 expression, and macrophage polarization. Results: We identified a malignant glioma cell state, termed SehighMali, characterized by elevated selenoprotein expression and distinct metabolic and immunological features. SehighMali cells showed enhanced oxidative phosphorylation, MYC-associated transcription, and DNA repair activity, and preferentially engaged in immunosuppressive crosstalk with myeloid cells through the CSF1–CSF1R axis. Spatial analyses demonstrated enrichment of SehighMali cells in tumor cores and close colocalization with immunosuppressive myeloid populations. Across bulk cohorts, higher SehighMali abundance was associated with aggressive molecular features, poor clinical outcomes, and a predicted temozolomide-resistant phenotype. SELENOS knockdown suppressed glioma proliferation, invasion, and tumor growth, reduced macrophage recruitment, decreased CSF1 expression, and promoted macrophage polarization toward a pro-inflammatory phenotype. Conclusions: These findings define a selenoprotein-driven malignant glioma state associated with immune evasion and therapeutic vulnerability. They further identify SELENOS as a potential therapeutic target and provide insight into how selenoprotein-related programs contribute to glioma progression. Full article

(This article belongs to the Special Issue Single-Cell Biology of Cancer)

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Graphical abstract

2 pages, 143 KB

Open AccessCorrection

Correction: Chitoran et al. A Systematic Review and Meta-Analysis on Opioid Management of Dyspnea in Cancer Patients. Cancers 2025, 17, 1368

by Elena Chitoran, Vlad Rotaru, Giuseppe Gullo, Daniela Viorica Mosoiu and Laurentiu Simion

Cancers 2026, 18(9), 1488; https://doi.org/10.3390/cancers18091488 - 6 May 2026

Viewed by 448

Abstract

Following publication of this article [...] Full article

(This article belongs to the Special Issue Integrating Palliative Care in Oncology)

3 pages, 165 KB

Open AccessEditorial

Commentary on “Shifting Paradigm: Utilization and Outcomes with Neoadjuvant Chemotherapy for cT4 and cN2 Colon Cancers”

by Carlo Alberto Schena, Luigi Marano, Sergio Alfieri and Fausto Rosa

Cancers 2026, 18(9), 1487; https://doi.org/10.3390/cancers18091487 - 6 May 2026

Viewed by 574

Abstract

We find the article by Hartley et al [...] Full article

(This article belongs to the Section Cancer Therapy)

23 pages, 4564 KB

Open AccessReview

Breast Cancer-Associated Venous Thromboembolism: Risk Factors, Mechanisms, and Clinical Management

by Panlin Xie, Yunbo Luo, Lingmi Hou, Jia Xu and Qun Yi

Cancers 2026, 18(9), 1486; https://doi.org/10.3390/cancers18091486 - 5 May 2026

Viewed by 1551

Abstract

Venous thromboembolism (VTE) is a clinically significant complication in patients with breast cancer (BC) and may disrupt treatment continuity while contributing to adverse outcomes. Although BC is generally regarded as a relatively low-risk malignancy for VTE compared with several other cancer types, its [...] Read more.

Venous thromboembolism (VTE) is a clinically significant complication in patients with breast cancer (BC) and may disrupt treatment continuity while contributing to adverse outcomes. Although BC is generally regarded as a relatively low-risk malignancy for VTE compared with several other cancer types, its high incidence and the increasing use of multimodal therapies have resulted in a growing clinical burden of breast cancer-associated VTE. This review summarizes the epidemiological features, risk factors, biological mechanisms, and advances in the prevention and management of breast cancer-associated VTE. Current evidence indicates that patients with cancer have an approximately 4- to 7-fold higher risk of VTE than the general population, with the risk in BC being particularly pronounced during the first 3–6 months after diagnosis. Older age, metabolic comorbidities, advanced disease, and exposure to multiple anticancer therapies have all been associated with an increased risk of VTE. Mechanistically, tissue factor, procoagulant extracellular vesicles, neutrophil extracellular traps, and inflammatory signaling pathways may contribute to breast cancer-associated VTE by promoting coagulation activation and endothelial dysfunction, while also linking thrombosis to immune evasion and Smetastatic progression. Improved identification of high-risk patients, optimization of dynamic risk assessment, and the implementation of individualized prophylactic and anticoagulant strategies may help improve outcomes in patients with BC. Full article

(This article belongs to the Section Molecular Cancer Biology)

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25 pages, 1804 KB

Open AccessArticle

Artificial Intelligence-Assisted Colposcopy: Deep Learning Multi-Class Segmentation of Anatomical Structures and Pathological Findings for Cervical Cancer Screening

by Marcin Jurczak, Łukasz Charzewski, Beata Goźlińska, Paweł Albrycht, Kacper Kobus, Artur Ludwin, Zoulikha Jabiry-Zieniewicz, Sylwester Kominek, Grzegorz Basiński, Bartosz Korzeb and Barbara Ewa Suchońska

Cancers 2026, 18(9), 1485; https://doi.org/10.3390/cancers18091485 - 5 May 2026

Viewed by 1318

Abstract

Background: Accurate colposcopy assessment is essential for detection of cervical precancerous lesions. However, the diagnostic performance depends heavily on the examiner’s experience and subjective interpretation. Recent advances in artificial intelligence offer new opportunities for automated image analysis. In particular, deep learning models [...] Read more.

Background: Accurate colposcopy assessment is essential for detection of cervical precancerous lesions. However, the diagnostic performance depends heavily on the examiner’s experience and subjective interpretation. Recent advances in artificial intelligence offer new opportunities for automated image analysis. In particular, deep learning models have shown promise for colposcopy image analysis intended for precancer screening. However, their limited interpretability restricts their translational value in clinical gynecology. This study leverages a custom dataset of expert-annotated digital colposcopic images to quantify the diagnostic strengths of these architectures. Methods: A comparative analysis was provided of the well-established convolutional neural network YOLOv11 and the modern transformer-based RF-DETR architecture, both of which were trained for the segmentation of 10 distinct classes. Target objects included anatomical structures, medical instruments and colposcopic findings. Results: Our results demonstrate that the YOLO architecture provides better performance for anatomical structures, whereas the RF-DERT reaches higher scores for colposcopy findings. These findings demonstrate transformer architecture superiority in more nuanced segmentation of clinically relevant findings, providing an interesting framework for computer-aided decision support systems in colposcopy. Conclusions: Both YOLOv11 and RF-DETR enable effective segmentation of colposcopic images, with performance dependent on class size and characteristics. Best results were achieved for large anatomical structures, while small and underrepresented findings remained challenging due to class imbalance. YOLO offers greater stability and efficiency, whereas RF-DETR performs better on more complex cases. Limitations include data imbalance, variable image quality, and annotation inconsistencies; future work should address these issues to improve generalization. Full article

(This article belongs to the Collection Artificial Intelligence in Oncology)

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14 pages, 966 KB

Open AccessArticle

Can Artificial Intelligence Interpret Pulmonary Function Tests and Predict Prolonged Air Leaks After Lung Resection

by Omar Zahra, Alexander Pohlman, Ayham Odeh, Mohammad Alhusseini, James Lubawski, Julia M. Coughlin, Wissam Raad, Amit Goyal and Zaid M. Abdelsattar

Cancers 2026, 18(9), 1484; https://doi.org/10.3390/cancers18091484 - 5 May 2026

Viewed by 897

Abstract

Background/Objectives: Preoperative pulmonary function tests (PFTs) contain numerous physiologic parameters, yet surgeons typically rely on forced expiratory volume in one second (FEV₁) and diffusing capacity of the lung for carbon monoxide (DLCO) to assess surgical risk. This study aimed to evaluate [...] Read more.

Background/Objectives: Preoperative pulmonary function tests (PFTs) contain numerous physiologic parameters, yet surgeons typically rely on forced expiratory volume in one second (FEV₁) and diffusing capacity of the lung for carbon monoxide (DLCO) to assess surgical risk. This study aimed to evaluate whether artificial intelligence (AI) could utilize more PFT data to predict the occurrence of prolonged air leak (PAL) following lung resection. Methods: An optical character recognition (OCR) model was used to extract structured data from PFT reports. These data were combined with clinical and demographic features from our institutional Society of Thoracic Surgeons General Thoracic Surgery Database (STS-GTSD) between 2016 and 2023. A feature selection algorithm was used to select the most predictive features, and a neural network was trained and tested on an internal validation cohort to predict PAL. Model performance was compared to previously published models. Results: There were 410 patients undergoing lung resection who had PFTs successfully digitized by the OCR system. A total of 76 available PFT features were extracted per patient. The final AI model included 10 key input variables, including three PFTs and seven clinical variables. On validation, the model achieved a specificity of 73%, sensitivity of 60%, overall accuracy of 72%, and an area under the curve of 0.74. This performance exceeded most existing PAL prediction models. Conclusions: AI-driven models using structured PFT and clinical data can enhance prediction of prolonged air leak after lung resection and outperform conventional regression-based models. Further research may focus on external validation and integration into clinical workflows. Full article

(This article belongs to the Special Issue Artificial Intelligence (AI), Robotics, and Cancer Surgery)

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15 pages, 1298 KB

Open AccessArticle

Association of Age with Outcomes in Adrenocortical Carcinoma: A Combined Cancer Registry and Multi-Omic Analysis

by Lindsay F. Remer, Rachyl M. Shanker, Thomas J. Meyer, John I. Lew and Naris Nilubol

Cancers 2026, 18(9), 1483; https://doi.org/10.3390/cancers18091483 - 5 May 2026

Viewed by 833

Abstract

Background: Given the higher incidence of adrenocortical carcinoma in peri-menopausal women, this study investigates the associations between sex, age, and ACC prognosis. Methods: We analyzed the National Cancer Database (NCDB) for adult patients with ACC (n = 2384) from 2004 to 2022. [...] Read more.

Background: Given the higher incidence of adrenocortical carcinoma in peri-menopausal women, this study investigates the associations between sex, age, and ACC prognosis. Methods: We analyzed the National Cancer Database (NCDB) for adult patients with ACC (n = 2384) from 2004 to 2022. Overall survival (OS) was the primary endpoint. Patients were stratified by sex and menopausal status (pre- and post-menopausal age of ≤45 and ≥55, respectively). Data from The Cancer Genome Atlas (TCGA) cohort (n = 92) were analyzed to examine clinical characteristics, genetics, transcriptomics, and methylation profiles of primary ACC samples by age group. Results: The analysis of the NCDB cohort revealed that younger men and pre-menopausal women had significantly longer OS compared to older groups. However, age was the only independent variable associated with OS. Using 50 years as the optimal age cutoff, we found no differences in clinical characteristics, rates of pathogenic driver mutations, methylation or gene expression profiles, or enriched molecular pathways in the TCGA ACC cohort by age group. Conclusions: While age ≥50 years is an independent factor associated with shorter OS in ACC, no differences in clinical characteristics or multi-omic profiles were observed by age. These findings suggest that age-related prognosis may be influenced by other factors such as microenvironmental changes or epigenetics. Full article

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

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23 pages, 3965 KB

Open AccessArticle

Contribution of Risk Factors, Including Polygenic Score, to the Multifactorial Risk Assessment for the Implementation of Personalized Breast Cancer Screening: Insights from the PERSPECTIVE: Integration and Implementation Project

by Xin Yang, Juliet A. Usher-Smith, Kristina M. Blackmore, Jennifer D. Brooks, Kathleen A. Bell, Tim Carver, Amy Chang, Jocelyne Chiquette, Douglas F. Easton, Andrea Eisen, Laurence Eloy, Samantha Fienberg, Yann Joly, Raymond H. Kim, Bartha M. Knoppers, Laurence Lambert-Côté, Hermann Nabi, Nora Pashayan, Penny Soucy, Tracy L. Stockley, Annie Turgeon, Meghan J. Walker, Michael Wolfson, Michel Dorval, Anna M. Chiarelli, Antonis C. Antoniou and Jacques Simard Show full author list Hide full author list

Cancers 2026, 18(9), 1482; https://doi.org/10.3390/cancers18091482 - 5 May 2026

Viewed by 1095

Abstract

Background/Objectives: Risk-based breast cancer (BC) screening can provide tailored recommendations based on individual risk. We aimed to identify key predictors for BC risk stratification to inform implementation in screening programs. Methods: We estimated 10-year BC risks using BOADICEA v.6 (CanRisk) in 3753 women [...] Read more.

Background/Objectives: Risk-based breast cancer (BC) screening can provide tailored recommendations based on individual risk. We aimed to identify key predictors for BC risk stratification to inform implementation in screening programs. Methods: We estimated 10-year BC risks using BOADICEA v.6 (CanRisk) in 3753 women aged 40–70 with no cancer history from the PERSPECTIVE I&I cohort. The primary endpoint was risk reclassification, assessed as the proportion of women whose assigned 10-year risk category changed when using different risk factor combinations against a full multifactorial model including questionnaire-based risk factors (QRFs), polygenic score (PGS), mammographic density (MD), and pedigree-structured first- and second-degree family history (FH) of breast, ovarian, pancreatic and prostate cancer, including both affected and unaffected relatives. Relative risk thresholds were set as <1.5 (average), 1.5–2.7 (higher-than-average), and ≥2.7 (high), equivalent to the remaining lifetime risk categories of <15%, 15–25% and ≥25% for women aged 30 (the anchor) to age 80. We quantified individual-level reclassification flows by direction and magnitude. Results: Excluding PGS from risk calculations led to the highest overall reclassification. Using only the BC status in first- and second-degree relatives produced comparable risk classification to that of the full FH data that included breast, ovarian, prostate and pancreatic cancer (reclassification = 0.5%). However, collecting only affected relatives led to overestimation of risk. Excluding either PGS, MD or FH resulted in a greater proportion of reclassification among younger women. Adding the PGS to risk factors already collected in provincial screening programs reduced reclassification from 23% to ~13%. Conclusions: PGS, MD, QRFs and FH of BC in affected and unaffected first- and second-degree relatives are key for refining risk stratification. These findings provide real-world evidence on how incorporating different sets of risk factors, both those routinely collected in screening programs and those requiring additional data collection, affect individual-level risk classification amongst a population-based cohort, and how the impacts differ across age groups. While risk classification reflects model-based changes in estimated risk categories rather than direct evidence of mis-screening or clinical outcomes, comparison with the current eligibility criteria used to identify women at higher-than-average risk highlights the potential clinical value of a multifactorial risk assessment approach in ensuring more appropriate screening strategies. Full article

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

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11 pages, 241 KB

Open AccessArticle

Risk Stratification of Indeterminate Thyroid Nodules (TIR3A vs. TIR3B): Impact of NIFTP Reclassification in a Surgical Cohort

by Pietro De Luca, Giulia Chiappino, Luca de Campora, Anna Sambito, Angelo Camaioni and Claudio Viti

Cancers 2026, 18(9), 1481; https://doi.org/10.3390/cancers18091481 - 5 May 2026

Viewed by 815

Abstract

Background: Indeterminate thyroid nodules classified as TIR3 according to the SIAPEC-IAP classification represent a heterogeneous group with variable malignancy risk, complicating clinical management. The reclassification of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has further influenced risk estimates. Methods: We conducted [...] Read more.

Background: Indeterminate thyroid nodules classified as TIR3 according to the SIAPEC-IAP classification represent a heterogeneous group with variable malignancy risk, complicating clinical management. The reclassification of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has further influenced risk estimates. Methods: We conducted a retrospective single-center study including adult patients who underwent ultrasound-guided fine-needle aspiration cytology followed by thyroid surgery between January 2016 and September 2025. Cytological diagnoses were classified according to the SIAPEC-IAP system and correlated with final histology. Ultrasound risk stratification was performed according to EU-TIRADS criteria. Risk of malignancy (ROM) and cytology–histology concordance were assessed, including the impact of NIFTP reclassification. Results: A total of 228 patients were included, with an overall malignancy rate of 27.6%. TIR3A nodules showed a significantly lower ROM than TIR3B (15.6% vs. 48.7%), decreasing to 12.5% and 41.4%, respectively, after exclusion of NIFTP. Cytology–histology agreement was substantial (κ = 0.72). Ultrasound features associated with malignancy included microcalcifications, irregular margins, taller-than-wide shape, and EU-TIRADS ≥4. The BRAF V600E mutation was significantly associated with malignant histology. Conclusions: TIR3A and TIR3B nodules exhibit markedly different malignant potential and should not be managed as a homogeneous group. NIFTP significantly modifies malignancy risk estimates and represents an important source of potential overtreatment. Integration of cytological subclassification with ultrasound and molecular findings improves preoperative risk stratification and supports personalized management of indeterminate thyroid nodules. Full article

(This article belongs to the Special Issue Targeted Therapy in Head and Neck Cancer)

9 pages, 386 KB

Open AccessArticle

Role of Maximum Standardized Uptake Volume in Predicting Tumor Spread Through Air Spaces in Stage IA Lung Cancers Smaller than 2 cm

by Massimiliano Bassi, Beatrice Zacchini, Rita Vaz Sousa, Angelina Pernazza, Paolo Graziano, Silvia De Maria, Silvia Albano, Camilla Poggi, Marco Anile, Tiziano De Giacomo, Federico Venuta and Daniele Diso

Cancers 2026, 18(9), 1480; https://doi.org/10.3390/cancers18091480 - 5 May 2026

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Abstract

Objective: Recent guidelines suggest sublobar resection as a viable option for peripheral lung cancer smaller than 2 cm. However, the presence of Spread through Air Spaces (STAS) is a well-known poor prognostic factor in early-stage lung cancer treated with sublobar resections. The aim [...] Read more.

Objective: Recent guidelines suggest sublobar resection as a viable option for peripheral lung cancer smaller than 2 cm. However, the presence of Spread through Air Spaces (STAS) is a well-known poor prognostic factor in early-stage lung cancer treated with sublobar resections. The aim of this study is to analyze the potential correlation between STAS and maximum standardized uptake volume (SUVmax) in this subset of patients to help define the optimal resection. Methods: A retrospective monocentric study was performed including patients diagnosed with stage IA lung cancer undergoing surgical resection. Patients were divided into two groups according to the presence/absence of STAS. As further investigation, we also separately analyzed the subgroup of patients with a peripheral nodule smaller than 2 cm. A p-value ≤ 0.05 was considered statistically significant. Results: The study cohort consists of 121 patients, 76 (62.8%) male, with a mean age of 74.2 ± 8.8 years. STAS was observed in 67 (55.4%) cases. The STAS-positive group showed a higher SUVmax value compared to the STAS-negative one (mean 5.5 ± 4.4 vs. 3.9 ± 3.0; p-value 0.007) with an AUC of 0.65 and an optimum SUVmax cut-off value of 3.0. Moreover, patients with SUVmax ≥ 3 showed a 77% increase in risk of having STAS (RR = 1.77; 95%CI = 1.21–2.59, p-value 0.014). This association was confirmed also in the subgroup of patients with nodules ≤ 2 cm (mean SUVmax 5.3 ± 4.6 vs. 3.6 ± 2.7; p value = 0.014). Conclusions: In our study, an SUVmax ≥ 3 in preoperative 18-FDG-PET is associated with the presence of STAS in stage IA lung cancer and peripheral cancer smaller than 2 cm. These findings, integrated with other clinical and radiological data, may guide surgeons to optimize the surgical strategy. Full article

(This article belongs to the Section Cancer Therapy)

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19 pages, 2671 KB

Open AccessArticle

Tumor-Suppressive microRNA Therapy Inhibits Growth of Glioblastoma Multiforme Xenografts

by Ezgi Biltekin, Sayra Dilmac, Nermin Kahraman, Ogun Ali Gul, Yasemin M. Akay, Zhihui Wang, Metin Akay and Bulent Ozpolat

Cancers 2026, 18(9), 1479; https://doi.org/10.3390/cancers18091479 - 4 May 2026

Cited by 1 | Viewed by 1089

Abstract

Glioblastoma multiforme (GBM) is defined by rapid progression, high invasiveness, and a poor prognosis, with a median survival of only ≅13 months despite current treatments. Its marked genetic heterogeneity, high mutational burden, and cancer stem cell population make GBM exceptionally difficult to treat, [...] Read more.

Glioblastoma multiforme (GBM) is defined by rapid progression, high invasiveness, and a poor prognosis, with a median survival of only ≅13 months despite current treatments. Its marked genetic heterogeneity, high mutational burden, and cancer stem cell population make GBM exceptionally difficult to treat, highlighting the urgent need for more effective, multitargeted therapies. Non-coding RNAs, particularly tumor suppressor microRNAs (miRNAs), have gained attention for suppressing key oncogenic processes that drive tumorigenesis, metastasis, and drug resistance, positioning them as promising tools for targeting multiple oncogenic pathways. We recently found that FOXM1/AXL-eEF2K collaboratively drive GBM cell proliferation, survival, and invasion through the formation of a signaling hub complex. In this study, we employed miRNA prediction algorithms to identify a specific miRNA, in vitro functional assays and in vivo GBM flank model to target GBM tumorigenesis by distrupting the FOXM1/AXL-eEF2K signaling hub. Our results indicated that FOXM1, AXL, and eEF2K are overexpressed in GBM patient tumors. To target the FOXM1/AXL-eEF2K signaling hub, we identified miR-449b-5p, miR-329-3p, and miR-518c as potential co-inhibitors of FOXM1/AXL-eEF2K and suppressors of cell proliferation, migration–invasion, and spheroid formation. Furthermore, the combination of miR-449b-5p, miR-329-3p, and miR-518c treatments with temozolomide led to synergistic enhancements in cell proliferation suppression and the induction of apoptosis and ferroptosis. More importantly, in vivo miR-329-3p treatment led to remarkable suppression of GBM tumor xenografts. These findings indicate that miR-329-3p-based tumor suppressor therapy may offer a multitargeted approach for GBM treatment. Full article

(This article belongs to the Special Issue Advances in Targeted Therapies in Cancer (2nd Edition))

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24 pages, 1488 KB

Open AccessArticle

Investigating the Prognostic Value of Pretreatment Body Composition in Women with Ovarian Cancer: Impact on Clinical Outcomes

by Sarah Benna-Doyle, Erin Laing, Brenton J. Baguley, Nicholas Hardcastle, Gavin Abbott and Nicole Kiss

Cancers 2026, 18(9), 1478; https://doi.org/10.3390/cancers18091478 - 4 May 2026

Cited by 1 | Viewed by 981 | Correction

Abstract

Background/Objectives: In ovarian cancer, the association between low muscle mass and outcomes is unclear, despite well-established evidence in other cancer diagnoses. Overall body composition may have greater prognostic value. This study aimed to investigate associations between body composition and clinical outcomes. Methods: Retrospective [...] Read more.

Background/Objectives: In ovarian cancer, the association between low muscle mass and outcomes is unclear, despite well-established evidence in other cancer diagnoses. Overall body composition may have greater prognostic value. This study aimed to investigate associations between body composition and clinical outcomes. Methods: Retrospective study of women diagnosed with ovarian cancer between August 2020 and March 2024. Clinical characteristics were extracted from medical records. Body composition phenotypes (low skeletal muscle index [SMI], low skeletal muscle density [SMD], high subcutaneous [SATI], visceral [VATI] and total adipose tissue index [TATI]) were assessed from pre-treatment CT images. Logistic regression, chi-squared, Fisher’s exact tests, and Mann–Whitney U tests were used to assess associations between body composition phenotypes, patient characteristics and study outcomes. Cox proportional hazards models were fitted to examine associations with survival. Results: Ninety-nine patients [mean (SD) age 61 (12.7) years, 80% stage III/IV] were included. Overall, 67 (67%) women had low SMI, 57 (57%) low SMD, and 49 (49%) high TATI. Thirty-seven (37%) women had low SMI and low SMD, 23 (23%) low SMI with high TATI, and 33 (33%) low SMD with high TATI. Post-menopausal status was associated with higher VAT (p = 0.004). Low SMI or low SMD co-occurring with high adiposity was associated with a 1.91–2.03 and 2.15–2.49 higher hazard mortality. There was insufficient or weak evidence of an association between body composition and other treatment outcomes. Conclusion: These findings suggest additive effects when phenotypes co-occur. In ovarian cancer, singular assessments may be an oversimplification. Future studies should continue to consider co-occurring phenotypes to adequately capture risk. Full article

(This article belongs to the Special Issue Nutrition in Survivors with Advanced Cancer: The Role of Appetite, Muscle Wasting, Obesity, and Altered Body Composition)

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16 pages, 4408 KB

Open AccessArticle

T-Cell Clonal Expansion in Peripheral Blood Following Interventional Radiology Procedures for Metastatic Liver Cancer

by Chenyang Zhan, Anita Karimi, Leila Haghani, Brett Marinelli, Wei Tian, Etay Ziv, Hooman Yarmohammadi, Erica S. Alexander, Vlasios S. Sotirchos, Ken Zhao, James W. Smithy, Alexander N. Shoushtari, David A. Scheinberg and Joseph P. Erinjeri

Cancers 2026, 18(9), 1477; https://doi.org/10.3390/cancers18091477 - 4 May 2026

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Abstract

Background: Interventional radiology (IR) procedures may induce anti-tumor immune responses, with subsequent clonal expansion of specific T-cells recognizing tumor antigens. This exploratory study aims to investigate the clonal expansion of T-cells in the peripheral blood after interventional radiology procedures for metastatic liver cancer. [...] Read more.

Background: Interventional radiology (IR) procedures may induce anti-tumor immune responses, with subsequent clonal expansion of specific T-cells recognizing tumor antigens. This exploratory study aims to investigate the clonal expansion of T-cells in the peripheral blood after interventional radiology procedures for metastatic liver cancer. Methods: This prospective study included 16 patients with metastatic liver cancer undergoing IR procedures (13 embolizations and 3 ablations). Biopsy samples were collected prior to the procedure, and peripheral blood samples were obtained both pre- and post-procedure. Bulk T-cell receptor (TCR) sequencing was conducted to assess T-cell clonality dynamics and to evaluate the impact of procedures on the T-cell repertoire. Results: The overall clonality of the T-cell repertoire in the peripheral blood did not demonstrate significant variations following IR procedures (p = 0.27–0.77). A subset of patients exhibited limited T-cell clonal expansion in peripheral blood one month after IR procedures, with more than 10 T-cell clonotypes expanding in 43% of patients. Most clonal expansions decreased in frequency by three months; however, 3 patients displayed persistently expanding T-cell clonotypes in peripheral blood ≥ 3 months following IR procedures. Conclusions: IR procedures do not alter the overall clonality of the T-cell repertoire but may promote the expansion of a limited number of clonotypes. This study demonstrates that it is feasible to detect and longitudinally track expanding T-cell clonotypes following IR liver-directed therapy. Further studies are needed to determine whether these expanding clonotypes contribute to systemic anti-tumor immunity. Full article

(This article belongs to the Section Cancer Therapy)

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22 pages, 513 KB

Open AccessReview

Evolving Paradigms in Cancer Pain Management: From Opioid-Centric Care to Multimodal and Personalized Strategies

by Isabella Barrios, Sara A. Thomas, Yesenia L. Hernandez, Ana Pagan, Emily Munoz, Kamilah Cespedes and Saurabh Aggarwal

Cancers 2026, 18(9), 1476; https://doi.org/10.3390/cancers18091476 - 3 May 2026

Viewed by 1926

Abstract

Background/Objectives: Cancer-related pain remains one of the most prevalent and distressing symptoms across the disease trajectory, significantly impairing function and quality of life. Although opioids are central to managing moderate to severe pain, their limitations, including adverse effects, dependence risk, and societal concerns, [...] Read more.

Background/Objectives: Cancer-related pain remains one of the most prevalent and distressing symptoms across the disease trajectory, significantly impairing function and quality of life. Although opioids are central to managing moderate to severe pain, their limitations, including adverse effects, dependence risk, and societal concerns, highlight the need for more individualized and comprehensive strategies. This review aims to synthesize current approaches to cancer pain management within a palliative care framework, emphasizing multimodal, mechanism-based, and patient-centered care. Methods: A narrative review was conducted using literature searches of PubMed, Scopus, and Google Scholar. Articles published between 2010 and 2026, with emphasis on recent literature (2020–2026), were included. Search terms included combinations of “cancer pain,” “palliative care,” “multimodal analgesia,” “opioids,” “adjuvant analgesics,” and “neuropathic pain.” Peer-reviewed studies, clinical guidelines, systematic reviews, and meta-analyses relevant to cancer pain mechanisms and management were considered. Results: Cancer pain is heterogeneous, arising from tumor progression and treatment-related injury, and includes neuropathic, visceral, and somatic components. Effective management requires mechanism-based assessment and multimodal strategies. Adjuvant analgesics, such as antidepressants, anticonvulsants, corticosteroids, and topical agents, enhance pain control and reduce opioid reliance. Non-pharmacological interventions and early integration of palliative care further improve symptom management and quality of life. Emerging therapies, including cannabinoid-based treatments and gene-targeted approaches, show promise but require further clinical validation. Conclusions: A multidisciplinary, patient-centered approach that integrates pharmacologic and non-pharmacologic strategies is essential for optimizing cancer pain management. Advancing toward personalized and multimodal care models may improve outcomes, reduce opioid-related risks, and enhance quality of life for patients with cancer. Full article

(This article belongs to the Special Issue Pain and Palliative Care in Patients with Cancers)

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19 pages, 4825 KB

Open AccessArticle

Hypofractionated Gamma Knife Radiosurgery for Large Brain Metastases in Surgery-Ineligible Patients: Outcomes of a Uniform 5-Fraction Regimen

by Juhee Jeon, Yukyeng Byeon, Gung Ju Kim, Yoohyun Kwon, Suhmi Chung, Do Hee Lee, Sang Woo Song, Young Hyun Cho, Chang-Ki Hong, Seok Ho Hong, Jeong-Hoon Kim and Young-Hoon Kim

Cancers 2026, 18(9), 1475; https://doi.org/10.3390/cancers18091475 - 3 May 2026

Viewed by 1244

Abstract

Background: Surgical resection remains the standard treatment for large brain metastases (LBMs), but many patients are not surgical candidates due to poor performance status or uncontrolled systemic disease. Gamma Knife-based hypofractionated stereotactic radiotherapy (GKRS) has emerged as a potential alternative; however, its clinical [...] Read more.

Background: Surgical resection remains the standard treatment for large brain metastases (LBMs), but many patients are not surgical candidates due to poor performance status or uncontrolled systemic disease. Gamma Knife-based hypofractionated stereotactic radiotherapy (GKRS) has emerged as a potential alternative; however, its clinical role in this population remains insufficiently defined. We evaluated whether a uniform daily 5-fraction GKRS provides effective and safe local treatment for surgery-ineligible LBMs. Methods: We retrospectively analyzed 100 patients with LBMs (>14 cm³) who underwent primary hypofractionated GKRS using a uniform daily 5-fraction schedule. Forty-six patients were male; the median age was 60 years. The median Karnofsky Performance Status (KPS) was 70 (60–100); a total of 47 patients (47%) had pre-GKRS neurological deficits. The most common primary sites were lung (41), breast (24), and kidney (14). The median tumor volume was 22.0 cm³ (14–70 cm³), and the marginal dose was 35.2 Gy (50% isodose line) in 5 fractions. The primary endpoints included local tumor control (LTC), intracranial progression-free survival (PFS), and overall survival (OS). Radiation necrosis (RN) was assessed as a key safety outcome. Results: At a median follow-up of 18 months, the overall LTC rate was 74%, with 1-, 2-, and 3-year rates of 73%, 65%, and 60%, respectively. Median PFS and OS were 7.5 and 16.3 months. Higher pre-treatment KPS and absence of neurological deficits were independently associated with improved OS (p = 0.003 and 0.025, respectively). RN occurred in 16% of patients, with 9% developing symptoms; all symptomatic cases were effectively managed with corticosteroids or bevacizumab. Most tumors demonstrated substantial volumetric reduction, with a median decrease of 80% and 30% achieving near-complete response (>95%). Conclusions: A uniform daily 5-fraction hypofractionated GKRS provides effective local control with acceptable toxicity in patients with LBMs. These findings support its role as a feasible local treatment option in selected patients who are not candidates for surgery. Integration with systemic therapies and prospective validation are warranted to refine patient selection and optimize outcomes. Full article

(This article belongs to the Special Issue Brain Metastases: From Mechanisms to Treatment)

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26 pages, 2088 KB

Open AccessReview

Amino Acid-Driven Mitochondrial Metabolic Rewiring Controls Antitumor Immunity

by Suji Ham, Min-Jeong Jo, Kwon-Ho Song and Bo-Hyun Choi

Cancers 2026, 18(9), 1474; https://doi.org/10.3390/cancers18091474 - 3 May 2026

Viewed by 1194

Abstract

Amino acids are essential nutrients for both tumor growth and immune cell function. Cancer cells actively deplete intracellular and extracellular amino acid pools, and limited amino acid availability in the tumor microenvironment (TME) reinforces immunosuppression. Mitochondria are not merely adenosine triphosphate-producing organelles. Amino [...] Read more.

Amino acids are essential nutrients for both tumor growth and immune cell function. Cancer cells actively deplete intracellular and extracellular amino acid pools, and limited amino acid availability in the tumor microenvironment (TME) reinforces immunosuppression. Mitochondria are not merely adenosine triphosphate-producing organelles. Amino acid metabolism within mitochondria contributes to tumor progression and influences immune cell fate and effector function. These effects are mediated through biosynthetic precursor generation for lipid, nucleotide, and polyamine synthesis, maintenance redox homeostasis through glutathione and NAD⁺ metabolism, and regulation of gene expression through aryl hydrocarbon receptor signaling. In this review, we discuss four major mitochondrial amino acid metabolic pathways: glutamine-driven anaplerosis, serine/glycine-dependent one-carbon metabolism, arginine–ornithine metabolism, and tryptophan–kynurenine metabolism. We examine how these pathways are rewired in cancer cells, how they influence immune cell function through direct or mitochondria-associated mechanisms, and how such metabolic reprogramming promotes tumor progression while impairing antitumor immunity. Finally, we consider therapeutic strategies to improve cancer immunotherapy by targeting amino acid metabolism, including mitochondrial metabolic enzymes. This review may help guide the development of more effective metabolic biomarkers and mitochondria-based therapeutic strategies for cancer immunotherapy. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism in Cancer Immune Responses)

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16 pages, 21410 KB

Open AccessArticle

Glycosylated Chitosan Inhibits Pancreatic Cancer Metastasis by Blocking the Caveolin Signaling Pathway

by Yong Li, Jacob Paul Adams, Jingxuan Yang, Abigael P. Williams, Min Li, Joanne Tuohy and Wei R. Chen

Cancers 2026, 18(9), 1473; https://doi.org/10.3390/cancers18091473 - 3 May 2026

Cited by 1 | Viewed by 1240

Abstract

Background and Objectives: Pancreatic cancer is highly metastatic, and metastasis is the main cause of cancer-related deaths. Therefore, finding methods to inhibit pancreatic cancer metastasis has important clinical value. Methods: N-dihydrogalactochitosan (GC) is an immunostimulant that can enhance the anti-tumor immune response [...] Read more.

Background and Objectives: Pancreatic cancer is highly metastatic, and metastasis is the main cause of cancer-related deaths. Therefore, finding methods to inhibit pancreatic cancer metastasis has important clinical value. Methods: N-dihydrogalactochitosan (GC) is an immunostimulant that can enhance the anti-tumor immune response to inhibit metastasis in combination with photothermal therapy. Results: Here, we found that GC can inhibit the migration of pancreatic cancer cells through interactions with caveolin-1 (Cav-1). The fluorescence of GC-FITC on the cell surface overlaps with Cav-1-Red, is enhanced by adCav-1, and is weakened by siCav-1, indicating that the localization of GC depends on Cav-1. GC inhibits the migration of malignant cells by blocking the signal transduction of Cav-1 and its downstream molecules. In an orthotopic pancreatic tumor model, GC can inhibit tumor metastasis in tumor-bearing mice. Conclusions: These results demonstrate GC’s capacity to act as a partner in pancreatic cancer therapy and indicate future directions for metastatic cancer therapy. Full article

(This article belongs to the Special Issue Cancer Inhibitory Receptors: Targeting Tumor Microenvironment Therapeutically)

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19 pages, 2454 KB

Open AccessArticle

Sex-Specific Trends in Thyroid Cancer Incidence and Histological Patterns in Northern Tunisia: A Population-Based Study with Implications for Cancer Control and Prevention

by Hyem Khiari, Soumaya Henchiri, Ismail Dergaa, Halil İbrahim Ceylan, Valentina Stefanica, Saida Sakhri, Semia Zarraa, Hajer Ben Mansour, Yoser Zenzri, Houssem Dziri, Nadia Ben Mansour, Najet Mahjoub, Raul Ioan Muntean and Mohamed Hsairi

Cancers 2026, 18(9), 1472; https://doi.org/10.3390/cancers18091472 - 3 May 2026

Viewed by 1305

Abstract

Background: Thyroid cancer (TC) represents the most common endocrine malignancy worldwide, with incidence increasing rapidly across diverse geographic regions. However, population-based evidence from North Africa remains limited, and comprehensive longitudinal analyses examining sex-specific incidence patterns, histological subtypes, and trends in tumor extension are [...] Read more.

Background: Thyroid cancer (TC) represents the most common endocrine malignancy worldwide, with incidence increasing rapidly across diverse geographic regions. However, population-based evidence from North Africa remains limited, and comprehensive longitudinal analyses examining sex-specific incidence patterns, histological subtypes, and trends in tumor extension are lacking in Tunisia. Aim: This study aimed to (i) quantify TC incidence trends by sex and age group, (ii) characterize histological subtype-specific temporal patterns and tumor extension at diagnosis in northern Tunisia between 2000 and 2018, and (iii) to address projections in incidence by sex until 2040. Methods: A retrospective, population-based registry study was conducted using data from the Northern Tunisia Cancer Registry (NTCR), covering 11 governorates with a population of 5,233,700 in 2018. All primary invasive TC cases diagnosed between 2000 and 2018 were included (n = 3639). Age-standardized incidence rates (ASIRs) were calculated using the WHO standard population. Temporal trends were assessed using Joinpoint regression to estimate average annual percentage change (AAPC) with 95% confidence intervals. Projections of TC incidence to 2040 were generated using Bayesian autoregressive age–period–cohort models. Results: TC incidence increased significantly between 2000 and 2018, with overall ASIR rising from 2.8 to 5.0 per 100,000 person-years (AAPC = 3.8%, p < 0.001). In males, ASIR increased from 0.9 to 2.4 (AAPC = 3.0%, p < 0.001), while in females it rose from 3.7 to 7.8 (AAPC = 4.3%, 95% CI: 3.0–5.7; p < 0.001). The increase was predominantly driven by papillary thyroid carcinoma (PTC) (AAPC = 6.4% in males; 5.8% in females; both p < 0.001), whereas follicular thyroid carcinoma (FTC) remained stable. Notably, the proportion of metastatic cases decreased significantly in females (AAPC = −7.2%, p = 0.033), and the proportion of regionally advanced disease decreased in males (AAPC = −5.0%, p = 0.034). Conclusions: This population-based study demonstrates a sustained rise in TC incidence in northern Tunisia, disproportionately affecting women and largely driven by papillary histology. The concurrent increase in TC incidence alongside a reduction in regional and metastatic extension at diagnosis occurred. These findings have important implications for cancer prevention and control, highlighting the need for risk-adapted screening strategies and rationalized diagnostic practices. Full article

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

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16 pages, 1467 KB

Open AccessArticle

Histologic Transformation in Follicular Lymphoma: Real-World Outcomes with Rituximab vs. Obinutuzumab-Based Combinations

by Dor Shpitzer, Chava Perry, Tamir Shragai, Guy Melamed, Mitchell R. Smith, Roy Vitkon, Hillel Alapi and Irit Avivi

Cancers 2026, 18(9), 1471; https://doi.org/10.3390/cancers18091471 - 3 May 2026

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Abstract

Background/Objectives: The survival of patients experiencing transformation of follicular lymphoma (tFL) is generally inferior to that of their non-transformed FL counterparts. While rituximab (R) has been shown to reduce transformation rates, data on Obinutuzumab (O), a third generation anti-CD20 monoclonal antibody, are [...] Read more.

Background/Objectives: The survival of patients experiencing transformation of follicular lymphoma (tFL) is generally inferior to that of their non-transformed FL counterparts. While rituximab (R) has been shown to reduce transformation rates, data on Obinutuzumab (O), a third generation anti-CD20 monoclonal antibody, are limited. Methods: This retrospective study analyzed risk factors for tFL and evaluated outcomes following transformation in 1145 consecutive patients with FL (2010–2023). Results: Over a median follow-up of 70 months, 9% (n = 103) of FL patients developed tFL, with a median time of 36 months from FL diagnosis to transformation. In multivariate analysis, O-based, compared to R-based regimens and maintenance therapy (compared to no maintenance), were independently associated with reduced risk of histologic transformation (HR 0.40, 95% CI 0.19–0.90, p = 0.026 and HR 0.42, 95% CI 0.23–0.77, p = 0.005, respectively). Transformed FL was associated with shorter overall survival (OS) from FL diagnosis compared to non-transformed FL (median not reached, p < 0.001), while prior exposure to anti-FL chemoimmunotherapy predicted shorter OS following transformation (median 34.6 months vs. not reached, p = 0.001). Multivariate analysis confirmed prior exposure to anti-FL therapy (HR 5.27, p < 0.001), male sex (HR 2.36, p = 0.014), and age over 65 (HR 2.54, p = 0.019) to be associated with shorter OS among patients with tFL. Conclusions: These findings, although requiring further validation, suggest that O-based regimens may reduce the risk of transformation and support prior studies demonstrating adverse survival outcomes in previously treated tFL patients. Full article

(This article belongs to the Section Cancer Pathophysiology)

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21 pages, 2089 KB

Open AccessArticle

External Beam Radiation Therapy for Pheochromocytoma and Non-Head and Neck Paraganglioma: A Single-Institution Experience and Systematic Review

by Katherine S. Jin, Mandy Wan, Kari Chau, Catelina Nguyen, Scott Jackson, Tanaya Kollipara, Evans Whitaker and Erqi L. Pollom

Cancers 2026, 18(9), 1470; https://doi.org/10.3390/cancers18091470 - 2 May 2026

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Abstract

Background/Objectives: Paragangliomas (PGLs) and pheochromocytomas (PCCs) are rare neuroendocrine tumors. While external beam radiation therapy (EBRT), particularly stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT), is established for head and neck PGLs (HNPGLs), its efficacy for non-head and neck PGLs (non-HNPGLs) [...] Read more.

Background/Objectives: Paragangliomas (PGLs) and pheochromocytomas (PCCs) are rare neuroendocrine tumors. While external beam radiation therapy (EBRT), particularly stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT), is established for head and neck PGLs (HNPGLs), its efficacy for non-head and neck PGLs (non-HNPGLs) and PCCs is less defined. We aimed to compare treatment outcomes of EBRT across these anatomic sites. Methods: We retrospectively reviewed patients with confirmed PGL or PCC treated with EBRT at a single institution between 1998 and 2025. Treated lesions were classified as non-HNPGL or HNPGL based on the radiation treatment field. Outcomes included local control (LC), distant progression-free survival (dPFS), overall survival (OS), symptomatic/biochemical response, and toxicity. We also conducted a systematic review examining EBRT for non-HNPGLs and PCCs following PRISMA guidelines. Results: We included 74 patients with 129 lesions who were treated with EBRT, with 62 HNPGL lesions and 67 non-HNPGL lesions. Of the non-HNPGL lesions, 50.7% (34/67) received SRS/SBRT with a median BED₁₀ of 50.8 Gy (range, 35.7–112.5). 5-year LC rate for non-HNPGL lesions was 95.3%, compared to 100% for HNPGL lesions, with 78% of lesions achieving symptomatic control. For non-HNPGL patients, median dPFS and OS were 37.6 and 131 months, respectively. There were no acute or late G ≥ 3 toxicities. Our systematic review (61 studies, 183 patients) showed LC and symptomatic improvement ranges of 76–100% and 76–94%, respectively. Conclusions: EBRT, including SRS and SBRT, provides excellent local control and symptomatic relief for both non-HNPGLs and HNPGLs. It represents a safe, effective treatment option for these rare tumors regardless of anatomic location. Full article

(This article belongs to the Special Issue Stereotactic Body Radiation and Stereotactic Ablative Radiotherapy Therapy for Cancers—2nd Edition)

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18 pages, 6482 KB

Open AccessArticle

Impact of Blood Type and Administration Timing on Therapeutic Outcomes of Immune Checkpoint Inhibitors for Patients with Lung Cancer in the Chinese Alpine Region

by Meiling Zhang, Xin Zhang, Tie Lin, Bao Liu, Jingwei Hao, Ziyi Gao, Xiaoli Li and Meng Wang

Cancers 2026, 18(9), 1469; https://doi.org/10.3390/cancers18091469 - 2 May 2026

Viewed by 1101

Abstract

Background: Although immune function and tumor biology follow circadian rhythms, it is unclear whether optimizing the timing of immunotherapy can enhance clinical outcomes. This study evaluated the association between time-of-day administration of immune checkpoint inhibitors (ICIs) and treatment efficacy, and explored whether blood [...] Read more.

Background: Although immune function and tumor biology follow circadian rhythms, it is unclear whether optimizing the timing of immunotherapy can enhance clinical outcomes. This study evaluated the association between time-of-day administration of immune checkpoint inhibitors (ICIs) and treatment efficacy, and explored whether blood type modifies ICI response in Chinese lung cancer patients living in an alpine region. Methods: We performed a retrospective analysis of 1247 Chinese lung cancer patients treated with first-line chemoimmunotherapy between January 2016 and March 2021 at Harbin Medical University Cancer Hospital (Cohort 1, n = 839) and the Fourth Affiliated Hospital of Harbin Medical University (Cohort 2, n = 408). Primary endpoints were overall survival (OS) and progression-free survival (PFS) estimated by the Kaplan–Meier method. Secondary endpoints included immune-related adverse events (irAEs), disease control rate (DCR), and objective response rate (ORR). Results: Patients treated before 13:00 had superior outcomes compared with those treated later, with longer mOS (34.3 vs. 22.0 months, p < 0.0001) and mPFS (16.7 vs. 12.7 months, p < 0.001). The ORR was significantly higher in the before 13:00 group of Cohort 1 (64.4% vs. 55%, p = 0.005). Additionally, blood type O was associated with a higher irAEs rate (35.6% vs. 20.1%, p < 0.01) and longer mOS (34.5 vs. 23.1 months, p < 0.0001) than non-O types. Conclusions: Time-of-day administration and blood type may influence ICI efficacy, supporting circadian-informed and patient-tailored immunotherapy. These findings support incorporating circadian timing and patient-specific factors into cancer immunotherapy strategies. Full article

(This article belongs to the Topic The Tumor Microenvironment, Immuno-Oncology, and Immune Checkpoint: Implications for Current and Emergent Immunotherapies, 2nd Edition)

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14 pages, 503 KB

Open AccessArticle

Itraconazole in the Treatment of Aberrantly Active Hedgehog and/or PI3K Recurrent Ovarian Cancer

by Cynthia S. E. Hendrikse, Noortje Voeten, Phyllis van der Ploeg, Huberdina P. M. Smedts, Hans M. Westgeest, Steven Bosch, Roy I. Lalisang, Birgit E. P. J. Vriens, Anna M. J. Thijs, Sandrina Lambrechts, Ruud L. M. Bekkers and Jurgen M. J. Piek

Cancers 2026, 18(9), 1468; https://doi.org/10.3390/cancers18091468 - 2 May 2026

Viewed by 1148

Abstract

Background: Treatment options for recurrent ovarian cancer (OC) are limited, leading to poor prognosis. Targeting tumor-promoting signaling transduction pathways (STPs), such as Hedgehog (HH) and Phosphoinositide-3-kinase (PI3K) STPs, might be an option for treatment. This study evaluates the efficacy of itraconazole as a [...] Read more.

Background: Treatment options for recurrent ovarian cancer (OC) are limited, leading to poor prognosis. Targeting tumor-promoting signaling transduction pathways (STPs), such as Hedgehog (HH) and Phosphoinositide-3-kinase (PI3K) STPs, might be an option for treatment. This study evaluates the efficacy of itraconazole as a targeted treatment in HH and/or PI3K active recurrent OC. Methods: We assessed HH and PI3K STP activity in recurrent OC patients. If activity was aberrantly high in either STP, patients received itraconazole treatment, which has been shown to inhibit both HH and PI3K pathways. The primary objective is to compare progression-free survival (PFS) on itraconazole therapy (PFS2) to the PFS on therapy prior to enrolment (PFS1). A PFS2/PFS1 ≥ 1.0 was considered successful. Secondary objectives included side effects, best overall response, one-year survival, and CA125 levels, though this was not a secondary endpoint. Results: Of sixteen patients with successful STP analysis, 93% were eligible for itraconazole therapy. Nine patients started treatment, with a mean duration of 55 days. None achieved a PFS2/PFS1 ratio ≥ 1.0 (mean 0.26, range 0.1–0.7). One patient had radiologically stable disease, while the others experienced disease progression. Side effects were mostly limited to grade 1–2, including fatigue, nausea, dysgeusia, dyspnea, cough, vertigo, and edema. No grade ≥ 3 adverse effects were linked to treatment. One-year survival was 22%. CA125 levels did not correlate with the treatment outcome, but increased rapidly after ceasing treatment. Conclusions: Itraconazole monotherapy for recurrent HH and/or PI3K aberrantly active OC is an ineffective treatment. While CA125 did not correlate with treatment outcome, the rapid increase in CA125 after therapy cessation suggests tumor inhibitory effects. Full article

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

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23 pages, 6403 KB

Open AccessArticle

Extracellular Enolase-1 Promotes CAF-Associated Stromal Reprogramming via the Plasmin/TGF-β Axis in Multiple Myeloma

by I-Che Chung, Tung-Yueh Chuang, Yu-Tung Ko, Mao-Lin Chen, Po-Yang Hsu, Wei-Ching Huang and Ta-Tung Yuan

Cancers 2026, 18(9), 1467; https://doi.org/10.3390/cancers18091467 - 2 May 2026

Cited by 1 | Viewed by 1091

Abstract

Background: Stromal remodeling in the tumor microenvironment contributes to multiple myeloma (MM) progression and drug resistance, but the extracellular mediators that drive these changes remain incompletely defined. Extracellular enolase-1 (ENO1), including membrane-associated and secreted forms, has been implicated in tumor progression; however, [...] Read more.

Background: Stromal remodeling in the tumor microenvironment contributes to multiple myeloma (MM) progression and drug resistance, but the extracellular mediators that drive these changes remain incompletely defined. Extracellular enolase-1 (ENO1), including membrane-associated and secreted forms, has been implicated in tumor progression; however, its role in cancer-associated fibroblast (CAF)-associated stromal reprogramming in MM is unclear. Methods: The effects of extracellular ENO1 on stromal activation and tumor-supportive functions were examined in MM using MM–bone marrow stromal cell (BMSC) co-cultures, lactate production and viability assays, immunoblotting, cytokine analyses, and a subcutaneous xenograft model of bortezomib (BTZ)-resistant MM in male 6–7-week-old NOD.Cg-Prkdc^scid Il2rg^tm1Vst/Vst (NPG) mice. HuL001, an anti-ENO1 monoclonal antibody, was used to evaluate the therapeutic relevance of extracellular ENO1 targeting. Results: Extracellular ENO1 promoted fibroblast activation protein expression through plasmin-mediated transforming growth factor-β (TGF-β) activation and induced a CAF-associated stromal phenotype marked by enhanced glycolytic activity and increased secretion of tumor-promoting cytokines in MM-BMSC co-cultures. HuL001 suppressed these ENO1-driven effects. HuL001-pretreated stromal cells also exhibited reduced tumor-supportive activity in a BTZ-resistant MM xenograft model. In addition, HuL001 combined with lenalidomide overcame BTZ resistance in MM. Conclusions: Extracellular ENO1 drives CAF-associated stromal reprogramming in the MM microenvironment through the ENO1/plasminogen/plasmin/TGF-β axis. Therapeutic targeting of extracellular ENO1 with HuL001 may disrupt these tumor-supportive stromal activities and help overcome drug resistance in MM. Full article

(This article belongs to the Section Cancer Therapy)

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16 pages, 9946 KB

Open AccessArticle

Histone Deacetylase-2 Expression in Colorectal Cancer: An Immunohistochemical Study and Its Clinicopathological Significance

by Nikolaos Garmpis, Afroditi Nonni, Dimitrios Dimitroulis, Eleni I. Effraimidou, Anna Garmpi, Miltiadis-Panagiotis Papandroudis, Konstantinos Kontzoglou and Christos Damaskos

Cancers 2026, 18(9), 1466; https://doi.org/10.3390/cancers18091466 - 2 May 2026

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Abstract

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality and is characterized by substantial molecular heterogeneity, including epigenetic dysregulation. Histone acetylation, regulated by histone acetyltransferases and histone deacetylases (HDAC), has been implicated in CRC development and progression. The aim of [...] Read more.

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality and is characterized by substantial molecular heterogeneity, including epigenetic dysregulation. Histone acetylation, regulated by histone acetyltransferases and histone deacetylases (HDAC), has been implicated in CRC development and progression. The aim of the present study was to evaluate HDAC-2 expression in CRC and investigate its association with clinicopathological parameters and patient outcomes. Methods: In this retrospective study, tumor tissue samples from 77 patients with CRC and documented recurrence were examined. HDAC-2 expression was assessed by immunohistochemistry and classified as low or high using a semi-quantitative scoring system. Associations with clinicopathological parameters and survival outcomes (disease-free survival, DFS; overall survival, OS) were analyzed. Results: High HDAC-2 expression was associated with younger patient age and earlier disease recurrence, while its association with overall survival was borderline. Conclusions: HDAC-2 expression may have clinicopathological relevance in CRC, particularly in relation to recurrence-related outcomes, although larger studies are needed to confirm its prognostic significance. Full article

(This article belongs to the Special Issue Perspectives on the Efficacy and Biomarkers of Immunotherapy and Targeted Therapy for Patients with Colorectal Cancer)

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Cancers, Volume 18, Issue 9 (May-1 2026) – 176 articles

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