Cancers

16 pages, 623 KB

Open AccessArticle

Primary Radiotherapy Versus Surgery in Early-Stage Endometrial Cancer Among High-Risk Surgical Patients: A Retrospective Comparative Study

by Lucia Gómez-Lavin Fernández, Sergi Fernández-González, Dina Najjari-Jamal, Lola Marti Cardona, Marc Juarez Lozano, Marc Barahona, Marta Gil Martin, Beatriz Pardo Burdalo, Andrea Slocker Escarpa, Milica Stefanovic, Cristina Gutiérrez Miguelez and Jordi Ponce Sebastià

Cancers 2026, 18(11), 1858; https://doi.org/10.3390/cancers18111858 - 5 Jun 2026

Viewed by 567

Abstract

Background/Objectives: Surgery is the standard treatment for early-stage endometrial cancer (EC); however, some patients are medically inoperable due to comorbidities or morbid obesity. Definitive image-guided brachytherapy (BT) with or without external beam radiotherapy (EBRT) is a curative alternative, although comparative data with surgery [...] Read more.

Background/Objectives: Surgery is the standard treatment for early-stage endometrial cancer (EC); however, some patients are medically inoperable due to comorbidities or morbid obesity. Definitive image-guided brachytherapy (BT) with or without external beam radiotherapy (EBRT) is a curative alternative, although comparative data with surgery remains limited. This study compared cancer-specific survival (CSS) at 2 and 5 years in high-risk surgical patients with early-stage EC (FIGO 2009 I–II), treated with definitive radiotherapy or surgery. Secondary endpoints included overall survival (OS), recurrence-free survival (RFS), disease-free survival (DFS), and toxicity. Methods: Retrospective comparative study including 72 patients treated between 2011 and 2023: 36 medically inoperable treated with BT +/− EBRT and 36 matched undergoing surgery. Survival outcomes were estimated using Kaplan–Meier methods and compared using log-rank tests. Results: Median age was 74 years and mean BMI was 38.1 kg/m²; 75% were morbidly obese, with endometrioid carcinoma being the predominant histology (88.9%). Five-year CSS was 97.2% in the radiotherapy group versus 91.7% in the surgery group (p = 0.39). Five-year RFS was identical in both groups (86.1%), with recurrence rates of 13.9%. Five-year OS was lower in the radiotherapy group (66.7% vs. 77.8%; p = 0.3), without statistical significance. Grade ≥3 radiotherapy-related toxicity occurred in 19.4%, whereas severe surgical complications occurred in 8.3%. Conclusions: Definitive BT ± EBRT is an effective and well-tolerated curative option for medically inoperable early-stage EC, with survival and recurrence outcomes comparable to surgery, supporting its role as a valid therapeutic alternative in high-risk surgical patients. Full article

(This article belongs to the Special Issue Endometrial Cancer Therapy: Foundations and Future Directions)

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27 pages, 2607 KB

Open AccessReview

Computer Vision for Predicting the Efficacy of Neoadjuvant Therapy in Breast Cancer

by Daria Sitnikova, Alexey Fayzullin, Fedor Chistov, Peter Timashev and Nikita Savelov

Cancers 2026, 18(11), 1857; https://doi.org/10.3390/cancers18111857 - 5 Jun 2026

Viewed by 557

Abstract

Neoadjuvant therapy (NAT) is a standard component of breast cancer treatment, yet response rates vary substantially across patients. Accurate prediction of pathological complete response remains an unmet clinical need to improve patient selection for NAT. This review summarizes current approaches of using computer [...] Read more.

Neoadjuvant therapy (NAT) is a standard component of breast cancer treatment, yet response rates vary substantially across patients. Accurate prediction of pathological complete response remains an unmet clinical need to improve patient selection for NAT. This review summarizes current approaches of using computer vision to predict breast cancer response to NAT from histopathological slides. We examined studies employing computer vision and machine learning models on hematoxylin and eosin and immunohistochemically stained whole-slide images, focusing on morphological features of tumor cells, stroma and tumor-infiltrating lymphocytes associated with pathological complete response. Key morphological predictors of therapy resistance included low tumor cell density with cord-like patterns, necrosis, predominance of collagenous and fibroblast-rich stroma and tumor vascularization, while therapy sensitivity was associated with high nuclear staining intensity, high tumor cell density and lymphocyte infiltration. We highlighted the advantages of incorporating multimodal data to enhance predictive performance. Our analysis demonstrates that computer vision models can detect subtle morphological patterns that may be difficult for pathologists to evaluate, providing valuable insights for personalized therapy planning in breast cancer. Further development of cross-modal, interpretable artificial intelligence solutions may improve prediction accuracy and deepen our understanding of tumor biology relevant to NAT response. Full article

(This article belongs to the Topic Artificial Intelligence in Computational Pathology for Cancer Diagnosis)

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26 pages, 22689 KB

Open AccessPerspective

AI-Driven Design of High Affinity Biomolecule–Drug Conjugates for Gynecological Cancer Therapy: An Up-to-Date Narrative Review

by Pankaj Garg, David Horne, Ravi Salgia and Sharad S. Singhal

Cancers 2026, 18(11), 1856; https://doi.org/10.3390/cancers18111856 - 5 Jun 2026

Viewed by 758

Abstract

Background: Gynecological cancers include collections of cancers with diverse cellular and molecular characteristics that often develop drug resistance, making them treatment-resistant. Biomolecule–drug conjugates (BDCs), especially antibody–drug conjugates (ADCs), have revolutionized the targeted therapy of cancer; however, the creation of these entities has so [...] Read more.

Background: Gynecological cancers include collections of cancers with diverse cellular and molecular characteristics that often develop drug resistance, making them treatment-resistant. Biomolecule–drug conjugates (BDCs), especially antibody–drug conjugates (ADCs), have revolutionized the targeted therapy of cancer; however, the creation of these entities has so far been achieved by empirical, resource-intensive design methods. Objective: The aim of this review is to critically analyze how AI can be used for the rational design and optimization of high-affinity BDCs for gynecological cancer treatment. Methods and discussion: Recent advances in machine learning (ML)- and deep learning (DL)-based methods to predict biomolecule-target binding affinity, structural compatibility, linker stability, payload selection, trafficking in the cell, and biomolecule resistance mechanisms are summarized. The review also explores the possibilities for incorporation of structural, chemical, biological, and multi-omics data to enhance specificity, efficacy, and safety of conjugates. Besides antibody-based systems, AI-assisted design approaches with peptides, aptamers, and hybrid biomolecular systems are also included. This review also highlights parameters and experimental/numerical validation restrictions related to data quality, interpretability of models, regulatory aspects, etc. Conclusions: AI-based conjugate engineering is increasingly moving BDC development from a largely ‘trial and error’ approach to a more predictive and data-driven approach. While there are still challenges to be addressed in terms of translations and validations, the potential of AI approaches in the field of precision oncology and the development of more personalized treatment is promising in the context of gynecological cancers. Full article

(This article belongs to the Section Cancer Drug Development)

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16 pages, 3006 KB

Open AccessArticle

CX3CR1-Dependent Macrophages Drive Ovarian Cancer Progression Through MMP-2 and TGF-β Production

by Yuko Tanizaki-Horiuchi, Yuko Ishida, Aya Kobayashi, Tamaki Yahata, Yumi Kuninaka, Saori Toujima, Mizuho Nosaka, Reiko Matsuki, Akihiko Kimura, Mika Mizoguchi, Naofumi Mukaida, Kazuhiko Ino and Toshikazu Kondo

Cancers 2026, 18(11), 1855; https://doi.org/10.3390/cancers18111855 - 5 Jun 2026

Viewed by 662

Abstract

Background: Epithelial ovarian cancer (EOC) is characterized by aggressive peritoneal dissemination and an immunosuppressive tumor microenvironment in which tumor-associated macrophages (TAMs) play a central role. Chemokine signaling pathways regulate macrophage recruitment and function; however, the contribution of the CX3CL1–CX3CR1 axis to ovarian cancer [...] Read more.

Background: Epithelial ovarian cancer (EOC) is characterized by aggressive peritoneal dissemination and an immunosuppressive tumor microenvironment in which tumor-associated macrophages (TAMs) play a central role. Chemokine signaling pathways regulate macrophage recruitment and function; however, the contribution of the CX3CL1–CX3CR1 axis to ovarian cancer progression and TAM-mediated effector mechanisms remains unclarified. This study aimed to clarify the role of CX3CL1–CX3CR1 signaling in ovarian cancer progression, focusing on macrophage-derived pro-tumorigenic factors. Methods: CX3CL1 and CX3CR1 expression was examined in human EOC and healthy ovarian tissues by real-time polymerase chain reaction and immunohistochemistry. Functional effects of CX3CL1 on ovarian cancer cells were evaluated via migration and proliferation assays in the murine ID8 cell line. An intraperitoneal syngeneic ovarian cancer model was established by injecting ID8 cells into wild-type and Cx3cr1-deficient mice. Tumor burden, ascites formation, survival, macrophage infiltration, and expression levels of matrix metalloprotease-2 (MMP-2) and transforming growth factor-β (TGF-β) were assessed by histological, immunohistochemical, and molecular analyses. Results: CX3CL1 and CX3CR1 expression was significantly upregulated in human EOC tissues and associated with marked macrophage infiltration. CX3CL1 stimulation enhanced migration, but not proliferation, of ID8 cells. Cx3cr1 deficiency significantly suppressed intraperitoneal tumor growth, reduced ascitic fluid volume, and prolonged survival. This was accompanied by reduced CX3CR1⁺ TAM accumulation and decreased MMP-2 and TGF-β expression, which were predominantly produced by infiltrating macrophages. Conclusions: The CX3CL1–CX3CR1 axis promotes ovarian cancer progression by recruiting MMP-2- and TGF-β-producing macrophages. Targeting CX3CR1-dependent TAM functions may represent a therapeutic strategy for limiting peritoneal dissemination in ovarian cancer. Full article

(This article belongs to the Section Cancer Pathophysiology)

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12 pages, 483 KB

Open AccessReview

Allostatic Load as a Measure of Cumulative Physiological Stress in Cancer: Implications for Prehabilitation in Head and Neck Cancers—A Narrative Review

by Mariusz Kiszka, Anna Skotny, Magdalena Kanicka, Emilia Burnejko-Jaśkiewicz, Szczepan Barnaś, Piotr Barnaś, Marcin Łaśko and Dorota Kamińska

Cancers 2026, 18(11), 1854; https://doi.org/10.3390/cancers18111854 - 5 Jun 2026

Viewed by 786

Abstract

Allostatic load (AL) is a multisystemic indicator of the cumulative “wear and tear” on the body caused by chronic stress. In oncology, high AL is associated with a poorer prognosis, a higher number of postoperative complications, and lower treatment tolerance. Patients with head [...] Read more.

Allostatic load (AL) is a multisystemic indicator of the cumulative “wear and tear” on the body caused by chronic stress. In oncology, high AL is associated with a poorer prognosis, a higher number of postoperative complications, and lower treatment tolerance. Patients with head and neck cancer (HNC)—due to frequent smoking, alcohol abuse, low socioeconomic status, and high psychological and functional burden—belong to a group particularly vulnerable to high AL; however, its role in this population remains poorly understood. This narrative review includes publications from 2015 to 2026 from the PubMed/MEDLINE, Embase, and Scopus databases. We analyzed original studies, systematic reviews, and narrative reviews concerning AL in oncology, prehabilitation, and HNC. Additionally, we employed the snowballing method and included studies from key research groups. The results reveal a clear research gap—the lack of direct studies evaluating AL in HNC patients. In other cancers (breast, colorectal, lung), high AL is an independent risk factor for complications, longer hospital stays, and poorer survival. Multimodal prehabilitation (exercise, nutritional, and psychological support) shows potential for reducing AL, but no prospective studies evaluating this effect have been conducted in the HNC population. Assessment of AL may serve as a valuable tool for preoperative risk stratification and monitoring the effects of prehabilitation in patients with head and neck cancer. Prospective cohort and randomized trials are needed to integrate AL into precision medicine for this patient group. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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3 pages, 1102 KB

Open AccessCorrection

Correction: Kim et al. Identification of GREM-1 and GAS6 as Specific Biomarkers for Cancer-Associated Fibroblasts Derived from Patients with Non-Small-Cell Lung Cancer. Cancers 2025, 17, 2858

by Bo-Guen Kim, Kyunghee Park, Mina Hwang, Hyewon Lee, Kyung-Mi Park, Junsu Choe, Sun Hye Shin, Byeong-Ho Jeong, Kyungjong Lee, Junghee Lee, Yeong Jeong Jeon, Jong Ho Cho, Hong Kwan Kim, Woong-Yang Park and Sang-Won Um

Cancers 2026, 18(11), 1853; https://doi.org/10.3390/cancers18111853 - 5 Jun 2026

Viewed by 473

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Predictive Biomarkers for Lung Cancer)

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20 pages, 540 KB

Open AccessReview

Targeting Circulating Tumor Cells in Pancreatic Ductal Adenocarcinoma: Rationale, Current Evidence, and a CEACAM6 CAR-T Strategy

by Marcin Piejko, Karolina Bak, Joanna Wierciak, Hanna Plutecka, Natalia Wilczynska-Zawal, Malgorzata Osmola, Kamil Rapacz, Jacek Kijowski, Patrycja Mensah-Glanowska, Antoni Szczepanik and Marek Sierzega

Cancers 2026, 18(11), 1852; https://doi.org/10.3390/cancers18111852 - 5 Jun 2026

Viewed by 948

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits high post-resection relapse and early systemic dissemination rates. The level of circulating tumor cells (CTCs) correlates with early metastatic failure, motivating CTC interception strategies. Methods: In this hypothesis-driven review, we synthesized the contemporary evidence on [...] Read more.

Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits high post-resection relapse and early systemic dissemination rates. The level of circulating tumor cells (CTCs) correlates with early metastatic failure, motivating CTC interception strategies. Methods: In this hypothesis-driven review, we synthesized the contemporary evidence on PDAC staging and therapy, CTC detection (including portal versus peripheral sampling), and circulating tumor DNA (ctDNA)-based minimal residual disease (MRD), and evaluated the translational rationale for CTC-targeted adoptive immunotherapy focusing on CEACAM6 and CAR-T cells. Results: Prospective studies report higher portal versus peripheral CTC yields and stronger associations with relapse; tumor-informed ctDNA positivity in peri-operative and surveillance windows predicts shorter disease-free survival. CEACAM6 is overexpressed in PDAC and linked to invasion and metastasis, supporting antigen selection. However, target overexpression alone does not establish clinical suitability for adoptive cell transfer. Consequently, its therapeutic implementation must contend with assay heterogeneity, on-target/off-tumor risks, and the lack of interventional outcome data in PDAC, all of which remain key hurdles. Conclusions: CTC-targeting is biologically plausible and operationally measurable in PDAC. Consequently, a CEACAM6-directed CAR-T approach is proposed as a potential strategy for the interception of minimal residual disease (MRD). Randomized and biomarker-selected trials with composite MRD-clearance endpoints (CTC < LOQ and ctDNA-negative) may be justified to validate this interventional hypothesis. Full article

(This article belongs to the Special Issue Feature Papers in Section “Methods and Technologies Development” in 2026)

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14 pages, 473 KB

Open AccessArticle

Cervical Lymph Node Metastasis Patterns and Diagnostic Accuracy of Preoperative Staging in Oral Squamous Cell Carcinoma

by Michael-Tobias Neuhaus, Giulia Weniger, Efthymios Papazacharias, Fabian Fenske, Philipp Jehn, Fritjof Lentge, Philippe Korn, Nils-Claudius Gellrich and Rüdiger Zimmerer

Cancers 2026, 18(11), 1851; https://doi.org/10.3390/cancers18111851 - 5 Jun 2026

Cited by 1 | Viewed by 913

Abstract

Background: Reliable assessment of cervical lymph node metastases remains a key challenge in the management of oral squamous cell carcinoma (OSCC). While elective ipsilateral neck dissection (ND) is widely accepted, the benefit of contralateral ND and the influence of tumor site on [...] Read more.

Background: Reliable assessment of cervical lymph node metastases remains a key challenge in the management of oral squamous cell carcinoma (OSCC). While elective ipsilateral neck dissection (ND) is widely accepted, the benefit of contralateral ND and the influence of tumor site on metastatic risk remain incompletely defined. This study aimed to evaluate patterns of lymphatic metastases, the diagnostic accuracy of preoperative staging, and the therapeutic relevance of ipsilateral and contralateral ND. Methods: A retrospective single-center cohort study was conducted including 287 patients with histologically confirmed OSCC treated between 2013 and 2019. Patterns of lymph node metastases were analyzed with respect to tumor localization and clinicopathological factors. Multivariate binary logistic regression was performed to identify predictors of cervical lymph node metastases. The diagnostic accuracy of preoperative staging was evaluated using histopathological findings as the reference standard. Results: Tumor localization and histopathological grading significantly influenced the occurrence of lymph node metastases. OSCC of the maxilla demonstrated a significantly lower observed rate of cervical and occult metastases compared with other tumor sites. Occult metastases were detected in 16.9% of primary tumor cases, with only two contralateral occult metastases observed. The calculated number needed to treat (NNT) was 6 for ipsilateral elective ND and 74 for contralateral elective ND. Preoperative staging showed limited diagnostic accuracy, with a negative predictive value of 0.83 and a positive predictive value of 0.65. Conclusions: Elective ipsilateral ND remains an essential component in the surgical management of OSCC due to the considerable rate of occult metastases and the limited reliability of preoperative staging. In contrast, the benefit of contralateral elective ND appears limited in patients without midline-crossing tumors. Maxillary OSCC and well-differentiated tumors demonstrated a significantly lower metastatic risk, supporting a more individualized risk-adapted approach to neck dissection in selected cases. Full article

(This article belongs to the Section Cancer Metastasis)

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30 pages, 26500 KB

Open AccessReview

FLASH Radiotherapy and Organelle-Targeted Radiosensitization in Glioblastoma: A Conceptual and Translational Review

by Xielin Tang, Xiaoyi Wang, Kui Xiao, Bingcheng Zhu, Fa Lin and Liangxue Zhou

Cancers 2026, 18(11), 1850; https://doi.org/10.3390/cancers18111850 - 5 Jun 2026

Viewed by 719

Abstract

Radiotherapy remains a central component of standard treatment for glioblastoma (GBM), yet recurrence is common because GBM radioresistance is reinforced by enhanced DNA damage repair, glioma stem cells (GSCs), hypoxia, extracellular matrix remodeling, and an immunosuppressive tumor microenvironment. FLASH radiotherapy (FLASH-RT), delivered at [...] Read more.

Radiotherapy remains a central component of standard treatment for glioblastoma (GBM), yet recurrence is common because GBM radioresistance is reinforced by enhanced DNA damage repair, glioma stem cells (GSCs), hypoxia, extracellular matrix remodeling, and an immunosuppressive tumor microenvironment. FLASH radiotherapy (FLASH-RT), delivered at ultra-high dose rates, has shown reproducible normal-tissue-sparing effects in preclinical models, including the brain. In GBM models, however, available evidence indicates that FLASH-RT generally preserves tumor control at levels comparable to conventional radiotherapy rather than providing clearly superior eradication of hypoxic or stem-like tumor compartments. In parallel, endoplasmic reticulum (ER)-targeted interventions have emerged as a candidate strategy for disturbing tumor proteostasis, modulating unfolded protein response (UPR) signaling, impairing synthesis of repair-associated proteins, and promoting immunogenic cell death. This narrative review summarizes representative mechanisms of GBM radioresistance, appraises the opportunities and limitations of FLASH-RT in intracranial disease, and explains why ER targeting is discussed here as a lead but unproven biological axis for radiosensitization. We further compare ER-directed approaches with mitochondrial-, lysosomal-, and delivery-enabled radiosensitization strategies, and outline the translational variables that would determine clinical testability, including beam modality, blood–brain barrier heterogeneity, pharmacokinetics, treatment sequencing, and biomarker development. In this review, “physical precision” refers primarily to dose-rate-driven ultra-rapid delivery and the possibility of widening the normal-tissue therapeutic window under FLASH conditions, rather than to a universal depth–dose advantage shared by all FLASH platforms. Direct experimental evidence for combining FLASH-RT with ER-targeted therapy in GBM is currently lacking. We therefore present this model as a hypothesis-generating conceptual and translational framework for future preclinical testing rather than as an established therapeutic advance. Full article

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

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11 pages, 324 KB

Open AccessArticle

Clinical Outcome in Elderly Patients (Aged ≥ 65 Years) Treated with Chemotherapy for Advanced Soft Tissue Sarcomas: A Tokai Musculoskeletal Oncology Consortium Study

by Tomoki Nakamura, Satoshi Tsukushi, Akihito Nagano, Tomohisa Sakai, Hisaki Aiba, Junji Wasa, Kozo Hosono, Yoji Shido, Yuya Izubuchi, Tetsuo Shimoyama, Katsuhisa Kawanami, Eiji Kozawa, Masahiro Hasegawa and Yoshihiro Nishida

Cancers 2026, 18(11), 1849; https://doi.org/10.3390/cancers18111849 - 4 Jun 2026

Viewed by 525

Abstract

Background/Objectives: Chemotherapy is recommended for patients with advanced soft tissue sarcoma (STS). However, chemotherapy is less aggressive in elderly patients than in younger patients owing to comorbidities and other health problems. This multicenter study aimed to examine the outcomes of elderly patients [...] Read more.

Background/Objectives: Chemotherapy is recommended for patients with advanced soft tissue sarcoma (STS). However, chemotherapy is less aggressive in elderly patients than in younger patients owing to comorbidities and other health problems. This multicenter study aimed to examine the outcomes of elderly patients treated with chemotherapy for advanced STS. Methods: The study cohort included 60 men and 71 women with a mean age of 73 years. The mean follow-up duration was 22.9 months. Results: As first-line treatment, the doxorubicin-containing regimen was the most frequently used. Dose reduction was more frequent in patients aged ≥ 75 years than in those aged ≤ 74 years. Complete response occurred in two patients and partial response in eight patients. The objective response rate was 8.2%. The 1- and 2-year survival rates after first-line chemotherapy were 61.8% and 40.2%, respectively. The median survival time was 19 months. In multivariate analysis, patients with performance status (PS) 2 or 3 had poorer survival than those with PS 0 or 1. The median survival times for patients with PS 0 or 1 and PS 2 or 3 were 22.1 and 4.3 months, respectively. Among 131 patients, no fatal adverse events occurred, although chemotherapy was discontinued due to adverse events in 28 patients. Conclusions: Chemotherapy for advanced STS in elderly patients may be effective in those with good PS, although it should be considered to evaluate the benefits and risks of cytotoxic chemotherapy. Full article

(This article belongs to the Special Issue Recent Updates and Future Perspectives on Anti-Cancer Agents)

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15 pages, 815 KB

Open AccessArticle

Clinical Characteristics and Survival Outcomes in a Cohort of Pediatric Rhabdomyosarcoma Patients: The Impact of Risk-Adapted Therapy

by Yanhua Li, Yangyang Jiao, Xuelian Liao, Jingbo Shao, Ting Zhang, Can Huang, Jingwei Yang and Shayi Jiang

Cancers 2026, 18(11), 1848; https://doi.org/10.3390/cancers18111848 - 4 Jun 2026

Viewed by 594

Abstract

Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, with survival dependent on risk stratification and multimodal therapy. This single-center study explored the clinical characteristics, treatment outcomes and prognostic factors of pediatric RMS to optimize local management. Methods: Data of RMS [...] Read more.

Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, with survival dependent on risk stratification and multimodal therapy. This single-center study explored the clinical characteristics, treatment outcomes and prognostic factors of pediatric RMS to optimize local management. Methods: Data of RMS patients treated at Shanghai Children’s Hospital from 2011 to 2024 were analyzed to estimate event-free survival (EFS) and overall survival (OS), and factors associated with survival. Patients received the Rs-99 (pre-2019) regimen or a modified Rs-2018 (post-2019) regimen. Results: A total of 76 RMS patients were identified. The 5-year EFS and OS for the entire cohort were 71.1% (95% CI, 62.3% to 83.3%) and 72.4% (95% CI, 64.0% to 84.5%), respectively. No statistically significant differences were observed in EFS and OS between the Rs-2018 and Rs-99 regimens. Univariate survival analysis indicated that metastasis was associated with prognosis: the 5-year EFS and OS of patients with metastatic disease were 35.0% (95% CI, 18.3% to 57.6%) and 40.0% (95% CI, 27.3% to 75.3%), while both the 5-year EFS and OS of patients with localized disease reached 83.9% (95% CI, 69.3% to 93.6%). Primary tumor resection status was a key prognostic factor for patients with localized disease, with a 5-year EFS of 100% for R0 resection and 46.7% (95% CI, 25.2% to 74.0%) for R2 resection. For patients with localized disease, EFS was comparable between those who underwent delayed primary excision (DPE) and upfront resection. Conclusions: Outcomes for patients with metastatic RMS remain poor. For those with localized disease, primary tumor resection status correlates with improved EFS and OS; additionally, DPE represents a feasible therapeutic option for localized RMS involving complex anatomical sites. Full article

(This article belongs to the Special Issue Rare Tumors in Children: Trends in Diagnosis, Treatment and Prevention (2nd Edition))

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17 pages, 1093 KB

Open AccessArticle

Molecular Subtype-Associated Response to Cyclophosphamide–Epirubicin–Cisplatin Regimen in Recurrent or Metastatic Adenoid Cystic Carcinoma: A Retrospective Single-Center Study

by Wenbo Tang, Jiuli Zhou, Wei Zhao, Fengjuan Lin, Liqiong Xue and Ye Guo

Cancers 2026, 18(11), 1847; https://doi.org/10.3390/cancers18111847 - 4 Jun 2026

Viewed by 445

Abstract

Background/Objectives: Recurrent or metastatic adenoid cystic carcinoma (R/M ACC) has no standard systemic therapy. VEGFR-targeting tyrosine kinase inhibitors (TKIs) are commonly used first-line, though no international standard exists; cisplatin-based chemotherapy is an alternative. We retrospectively reviewed the cyclophosphamide–epirubicin–cisplatin (CEP) regimen to determine whether [...] Read more.

Background/Objectives: Recurrent or metastatic adenoid cystic carcinoma (R/M ACC) has no standard systemic therapy. VEGFR-targeting tyrosine kinase inhibitors (TKIs) are commonly used first-line, though no international standard exists; cisplatin-based chemotherapy is an alternative. We retrospectively reviewed the cyclophosphamide–epirubicin–cisplatin (CEP) regimen to determine whether prior TKI exposure compromises subsequent chemotherapy efficacy. Methods: We studied 31 patients given CEP for progressive R/M ACC (2018–2023). Tumor response was assessed by RECIST 1.1. Molecular subtype was determined by c-MYC/p63 immunohistochemistry (ACC-I, c-MYC-positive/p63-negative; ACC-II, p63-positive/c-MYC-low or negative). Multivariable models used Firth’s penalized likelihood Cox regression. Next-generation sequencing (NGS) was available in 21 of 31 patients. Results: Thirty-one patients were enrolled (median age 48; 17 [54.8%] with prior TKI). At median follow-up of 22.6 months, the objective response rate (ORR) was 19.4%, disease control rate 71.0%, median progression-free survival (PFS) 5.3 months, and median overall survival (OS) 10.3 months. Prior TKI did not lower efficacy: ORR 17.6% vs. 21.4%, PFS hazard ratio 0.76 (p = 0.519). All six partial responses occurred in ACC-I tumors (35.3% vs. 0% in ACC-II, p = 0.021). In the NGS subset (5 PIK3CA-mutant), PIK3CA mutation (OS HR 6.19, p = 0.024) and bone metastasis (OS HR 5.84, p = 0.027) remained associated with shorter OS after adjustment. No treatment-related deaths occurred. Conclusions: CEP is active in R/M ACC, and prior TKI exposure did not appear to reduce efficacy. Higher response rates in ACC-I tumors and the apparent PIK3CA-related survival deficit are exploratory observations that need prospective testing before they can guide treatment. Full article

(This article belongs to the Special Issue Head and Neck Cancer Therapies: Current and Innovative Options)

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18 pages, 1464 KB

Open AccessReview

Endoscopic Diagnosis of Chronic Atrophic Gastritis and Early Gastric Cancer: From Basics to Advanced Imaging

by Matthew Banks and David Graham

Cancers 2026, 18(11), 1846; https://doi.org/10.3390/cancers18111846 - 4 Jun 2026

Cited by 1 | Viewed by 3488

Abstract

Chronic atrophic gastritis (CAG) is the principal precursor lesion for gastric adenocarcinoma and represents a key target for endoscopic surveillance and early intervention. Although the global age-standardised incidence of gastric cancer has declined over recent decades, the absolute number of cases continues to [...] Read more.

Chronic atrophic gastritis (CAG) is the principal precursor lesion for gastric adenocarcinoma and represents a key target for endoscopic surveillance and early intervention. Although the global age-standardised incidence of gastric cancer has declined over recent decades, the absolute number of cases continues to rise because of population ageing and increasing incidence in younger individuals. The prognosis remains poor in advanced disease, whereas early gastric cancer (EGC) detected at a mucosal stage is associated with excellent long-term survival and may be curable with endoscopic resection. Consequently, high-quality endoscopic detection of premalignant gastric lesions is essential to reduce gastric cancer mortality. This review summarises current concepts in the endoscopic diagnosis of CAG, gastric intestinal metaplasia (GIM), and EGC, from conventional white-light endoscopy through to advanced imaging and artificial intelligence (AI)-assisted systems. Fundamental principles of high-quality oesophagogastroduodenoscopy are discussed, including adequate inspection time, systematic mucosal assessment, mucosal cleansing, and standardised photo-documentation. Characteristic endoscopic appearances of normal gastric mucosa, atrophy, and intestinal metaplasia are reviewed, alongside established staging systems including the Kimura–Takemoto and EGGIM classifications. The role of image-enhanced endoscopy is examined in detail, including narrow-band imaging, linked colour imaging, texture and colour enhancement imaging, and magnification optical enhancement. These modalities improve visualisation of pit patterns, microvascular architecture, and hallmark features of intestinal metaplasia such as the light blue crest sign, substantially increasing diagnostic sensitivity and specificity compared with conventional white light imaging alone. Advanced imaging combined with magnification also enhances the detection and characterisation of EGC. Emerging evidence regarding AI-assisted endoscopy demonstrates promising diagnostic accuracy for CAG, GIM, and early neoplasia, with improved lesion detection and reduced miss rates in several studies. However, limitations relating to external validation, generalisability, and integration into routine practice remain. Continued advances in optical imaging, structured training, and AI-supported diagnostics are likely to play an increasingly important role in improving early gastric cancer detection and surveillance outcomes worldwide. Full article

(This article belongs to the Special Issue Screening and Surveillance of Gastrointestinal and Pancreatic Cancers)

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17 pages, 1015 KB

Open AccessReview

Basic and Clinical Evidence for Perioperative Immunotherapy in Resectable HNSCC

by Shota Sakaue, Michihisa Kono, Takumi Kumai, Takahiro Inoue, Hisataka Ominato and Miki Takahara

Cancers 2026, 18(11), 1845; https://doi.org/10.3390/cancers18111845 - 4 Jun 2026

Viewed by 749

Abstract

Background: Perioperative immunotherapy has emerged as a promising strategy for improving outcomes in patients with resectable head and neck squamous cell carcinoma (HNSCC). However, its biological rationale, clinical evidence, and optimal implementation remain incompletely defined. Methods: We conducted a narrative review [...] Read more.

Background: Perioperative immunotherapy has emerged as a promising strategy for improving outcomes in patients with resectable head and neck squamous cell carcinoma (HNSCC). However, its biological rationale, clinical evidence, and optimal implementation remain incompletely defined. Methods: We conducted a narrative review of the current literature, integrating preclinical and clinical evidence on perioperative immune checkpoint inhibitor (ICI) therapy in resectable HNSCC, with particular attention to the immunological impact of surgery, tumor-draining lymph nodes, and treatment sequencing. Results: Neoadjuvant immunotherapy exploits the presence of intact tumor antigen and preserved lymphatic architecture, enabling broad T-cell priming, clonal expansion, and systemic immune memory formation. In contrast, adjuvant immunotherapy primarily targets residual microscopic disease and relies on preexisting tumor-reactive T cells, suggesting that these strategies are biologically distinct. Early-phase clinical trials have demonstrated the safety and feasibility of perioperative ICIs, with evidence of pathological responses. Recent phase III trials, including KEYNOTE-689 and NIVOPOSTOP, have provided practice-relevant evidence supporting the integration of ICIs into perioperative treatment, demonstrating improved event-free survival and clinical outcomes in selected populations. Several challenges remain, including optimal patient selection, lack of validated biomarkers, and treatment sequencing after perioperative ICI exposure. Conclusions: Perioperative immunotherapy represents a promising practice-relevant strategy in resectable HNSCC. Further studies are required to refine patient selection, develop predictive biomarkers, and optimize treatment sequencing to maximize clinical benefit. Full article

(This article belongs to the Special Issue Current Progress in the Clinical Management and Basic Science of Head and Neck Cancer: 2nd Edition)

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20 pages, 997 KB

Open AccessReview

Pan-RAS Inhibitors: Expanding Therapeutic Potential and Evading Resistance

by Sindhu Ramesh, Junwei Wang, Chung-Hui Huang, Austin M. Moore, Khalda Fadlalla, Kristy L. Berry, Yulia Y. Maxuitenko, Xi Chen, Adam B. Keeton, Bassel El-Rayes, Donald J. Buchsbaum, Karim I. Budhwani, Gang Zhou, Amit K. Mitra and Gary A. Piazza

Cancers 2026, 18(11), 1844; https://doi.org/10.3390/cancers18111844 - 4 Jun 2026

Cited by 1 | Viewed by 1833

Abstract

Approximately 30% of all human cancers are driven by mutations in RAS genes, KRAS, HRAS, and NRAS, resulting in the constitutive activation of RAS proteins and stimulation of MAPK/AKT signaling. Non-mutant, i.e., wild-type (WT) RAS can also become activated through mechanisms [...] Read more.

Approximately 30% of all human cancers are driven by mutations in RAS genes, KRAS, HRAS, and NRAS, resulting in the constitutive activation of RAS proteins and stimulation of MAPK/AKT signaling. Non-mutant, i.e., wild-type (WT) RAS can also become activated through mechanisms such as gene amplification or excessive stimulation by mutated or overexpressed receptor tyrosine kinases (e.g., EGFR), thereby promoting cancer progression. Mutant or activated RAS contributes to multiple hallmarks of cancer, including unchecked cellular proliferation, reprogrammed cellular metabolism, immunosuppression, and metastasis. Hence, RAS is of immense clinical importance, with hundreds of laboratories studying various aspects of RAS biology or developing RAS inhibitors. There is perhaps no greater unmet medical need in oncology than the need for a broadly efficacious but safe inhibitor of mutant and activated RAS. Mutant-specific KRAS G12C inhibitors have shown promising therapeutic efficacy, leading to FDA approval of sotorasib and adagrasib, although their use is limited to patients with the relatively rare G12C KRAS mutation. Mutant-specific KRAS inhibitors are also susceptible to adaptive resistance, in part, due to secondary RAS mutations, and compensatory signaling from WT RAS isozymes. A pan-RAS inhibitor capable of blocking all RAS isozymes, regardless of the underlying mutation, offers the potential for broader efficacy and capacity to avert resistance. While just a few years ago, pan-RAS inhibitors were predicted to be severely toxic or even fatal, the apparent safety profile of RMC-6236 (daraxonrasib), a pan-RAS inhibitor currently in clinical trials, suggests otherwise. Indeed, pan-RAS inhibitors are now considered by many in the RAS field to be the most promising class in development. In this review, we summarize the evolution and current status of pan-RAS and pan-KRAS inhibitors in preclinical and clinical development and highlight emerging human-relevant tumor models that are advancing preclinical evaluation. Full article

(This article belongs to the Special Issue Ras Signaling and Inhibitors: Strategies to Escape Resistance)

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17 pages, 3197 KB

Open AccessArticle

Targeting SIK2 with GRN-300 Potentiates Paclitaxel Efficacy in Triple-Negative Breast Cancer

by Marc A. Pina, Rumeysa Ozyurt, Weiqun Mao, Hailing Yang, Janice M. Santiago-O’Farrill, Zhen Lu and Robert C. Bast

Cancers 2026, 18(11), 1843; https://doi.org/10.3390/cancers18111843 - 4 Jun 2026

Viewed by 623

Abstract

Background/Objectives. Breast cancer is the most frequently diagnosed cancer worldwide, with approximately 15% classified as Triple-Negative Breast Cancer (TNBC). TNBC is characterized by the absence of estrogen receptor (ER) and progesterone receptor (PR), and the lack of HER2 overexpression, limiting use of targeted [...] Read more.

Background/Objectives. Breast cancer is the most frequently diagnosed cancer worldwide, with approximately 15% classified as Triple-Negative Breast Cancer (TNBC). TNBC is characterized by the absence of estrogen receptor (ER) and progesterone receptor (PR), and the lack of HER2 overexpression, limiting use of targeted therapies. Current TNBC treatment relies heavily on chemotherapy, most commonly taxanes including paclitaxel that stabilize microtubules, disrupt chromosome separation and induce apoptosis. TNBCs frequently develop chemoresistance after multiple treatment cycles, highlighting a critical unmet need for novel therapeutic strategies. This study addresses this challenge by targeting salt-inducible kinase 2 (SIK2), which is overexpressed in 85% of TNBCs compared to normal breast tissue. Methodes. In collaboration with Arrien Pharmaceuticals and Greenfire Biologics, we developed ARN-3261/GRN-300, a novel orally bioavailable SIK2 inhibitor and evaluated its ability to sensitize TNBC cells to paclitaxel in vitro and in vivo. Results. GRN-300 demonstrated strong synergy with paclitaxel in all eight TNBC cell lines tested, as indicated by favorable combination indices. In xenograft models, the combination therapy significantly enhanced tumor growth inhibition and prolonged survival compared to either agent alone. Mechanistic studies showed that GRN-300 disrupts the anaphase-promoting complex/cyclosome (APC/C) pathway by downregulating key mitotic regulators, including CDC27, CDK1, and PLK1, thereby potentiating G2/M cell cycle arrest and apoptosis. Conclusions. Together, these findings establish GRN-300 as a promising therapeutic agent that enhances paclitaxel efficacy through complementary disruption of mitotic regulatory pathways, providing strong preclinical rationale for clinical development in TNBC. Full article

(This article belongs to the Special Issue Innovative Therapeutics for Breast Cancer: Advancing Clinical and Translational Research)

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30 pages, 799 KB

Open AccessSystematic Review

Cryoablation in Early-Stage Breast Cancer: A Systematic Review of Efficacy, Safety and Oncologic Outcomes

by Sandra Maria Tsoti, Vasileios Kalles, Aristotelis Nikitaras, Ioannis Papapanagiotou and Nikolaos Michalopoulos

Cancers 2026, 18(11), 1842; https://doi.org/10.3390/cancers18111842 - 4 Jun 2026

Viewed by 882

Abstract

Background: Cryoablation is a minimally invasive technique that is being investigated as an alternative to surgery for early-stage breast cancer. Its potential advantages include outpatient treatment under local anaesthesia, favourable cosmetic outcomes, and possible immunologic synergy. However, its oncologic efficacy and long-term effectiveness [...] Read more.

Background: Cryoablation is a minimally invasive technique that is being investigated as an alternative to surgery for early-stage breast cancer. Its potential advantages include outpatient treatment under local anaesthesia, favourable cosmetic outcomes, and possible immunologic synergy. However, its oncologic efficacy and long-term effectiveness are yet to be determined. Methods: We conducted a systematic review in accordance with PRISMA 2020 and the Cochrane Handbook, registered on PROSPERO (CRD420251137549). Databases searched were PubMed/MEDLINE, Scopus, and CENTRAL, from inception to August 2025. Eligible studies included women with unifocal, node-negative invasive ductal carcinoma ≤ 2 cm treated with percutaneous cryoablation. Outcomes of interest were residual disease, ipsilateral breast tumour recurrence, procedural and late complications, and cosmetic or patient-reported outcomes. Results: From 1074 records, 15 unique studies (17 reports) were included, comprising cryoablation-only studies (n = 7), treat-and-resect studies (n = 6), and comparative studies versus surgery (n = 2). Studies containing overlapping pathology validation and comparative components were classified within a single category to avoid duplication. Across treat-and-resect cohorts, complete tumour necrosis was reported in 88–95% of cases, with residual invasive carcinoma (RIC) ranging from 5% to 12%. In cryoablation-only cohorts, IBTR rates ranged from 0% to 4.3%, with follow-up durations spanning 2 months to 8 years. The largest study (ICE3, n = 194) reported a 5-year recurrence rate of 4.3%. Procedural complications were infrequent and self-limiting, most commonly bruising, oedema, or superficial frostbite. No major adverse events were reported. Validated quality-of-life instruments reported high patient satisfaction, with favourable results in selected comparative domains. Most included studies were of moderate methodological quality. Conclusions: Cryoablation appears technically feasible, safe, and cosmetically favourable in well-selected low-risk early-stage breast cancers. Oncologic outcomes are encouraging, with reported local recurrence rates in carefully selected low-risk populations being low, although direct comparison with breast-conserving surgery remains limited by the small number of comparative studies and substantial heterogeneity across the evidence base. Rigorous multicentre randomised trials with long-term follow-up and validated patient-reported outcomes are needed before cryoablation can be considered for routine clinical adoption. Full article

(This article belongs to the Special Issue Minimally Invasive and Innovative Approaches in Breast Cancer Surgery: Techniques and Outcomes)

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20 pages, 1486 KB

Open AccessArticle

SNP-Based Chromosomal Microarray Analysis in the Era of Optical Genome Mapping: An Enriched Case-Series Evaluating Copy-Neutral Events

by Alexander R. Marr, Patrick R. Gonzales and Shivani Golem

Cancers 2026, 18(11), 1841; https://doi.org/10.3390/cancers18111841 - 4 Jun 2026

Viewed by 628

Abstract

Background/Objectives: Chromosomal microarray analysis (CMA) is an essential tool in modern cytogenetics for detecting copy number alterations and copy-neutral loss of heterozygosity (CN-LOH). As optical genome mapping (OGM) emerges as a potential replacement for traditional cytogenetic methods, the extent to which CMA remains [...] Read more.

Background/Objectives: Chromosomal microarray analysis (CMA) is an essential tool in modern cytogenetics for detecting copy number alterations and copy-neutral loss of heterozygosity (CN-LOH). As optical genome mapping (OGM) emerges as a potential replacement for traditional cytogenetic methods, the extent to which CMA remains necessary in routine diagnostic workflows remains to be elucidated. Methods: We retrospectively reviewed 53 primary neoplastic cases, selected from a larger cohort of 327 hematologic malignancy specimens, in which CMA identified one or more CN-LOH events. Event size, genomic content, and correlation with next-generation sequencing (NGS) findings were assessed. A separate cohort of newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL) was analyzed to evaluate disease-specific CN-LOH frequency. Results: Nearly half of CN-LOH events detected were <25 Mb, below the current detection threshold of OGM inferred from published benchmarks and validated workflows. Many encompassed clinically relevant genes, including FLT3, JAK2, TET2, TP53, and RUNX1. Additionally, two-thirds of cases harbored pathogenic or likely pathogenic variants by NGS within the corresponding CN-LOH regions, further underscoring the clinical value of detecting these copy-neutral events. In contrast, CN-LOH was uncommon in B-ALL, and most alterations identified by CMA would be detectable by OGM. Many of these patients also harbored complex structural rearrangements that required multiple conventional assays for full characterization; these could be resolved by OGM in a single analysis. Conclusions: Our findings indicate that although OGM excels at resolving complex structural variants, CMA remains essential for detecting copy-neutral events. Until OGM achieves improved sensitivity for CN-LOH, an integrated approach utilizing conventional cytogenetics, CMA, NGS, and OGM provides the most reliable framework for comprehensive genomic assessment across cancer types. Full article

(This article belongs to the Section Cancer Pathophysiology)

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18 pages, 2222 KB

Open AccessReview

Liquid Biopsy Biomarkers for Predicting and Monitoring Immunotherapy Response in Lung Cancer

by Viola Bianca Serio, Tommaso Regoli, Elisa Frullanti and Maria Palmieri

Cancers 2026, 18(11), 1840; https://doi.org/10.3390/cancers18111840 - 4 Jun 2026

Viewed by 908

Abstract

Background: While Immune Checkpoint Inhibitors (ICIs) have significantly improved outcomes in lung cancer (LC), clinical responses remain heterogeneous. Static tissue biomarkers, like PD-L1, and tumor mutational burden (TMB) are limited by intratumoral heterogeneity and the inability to track temporal changes. This review [...] Read more.

Background: While Immune Checkpoint Inhibitors (ICIs) have significantly improved outcomes in lung cancer (LC), clinical responses remain heterogeneous. Static tissue biomarkers, like PD-L1, and tumor mutational burden (TMB) are limited by intratumoral heterogeneity and the inability to track temporal changes. This review aims to evaluate the current state and future potential of liquid biopsy as a dynamic tool for patient selection, treatment monitoring, and the identification of resistance mechanisms in LC immunotherapy. Methods: A literature search was conducted in the PubMed database up to March 2026. We identified 65 eligible publications, including clinical trials, observational studies, and systematic reviews, focusing on liquid biopsy analytes such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, and soluble immune mediators. Results: Liquid biopsy provides a “pooled” representation of the total tumor burden, overcoming the spatial limitations of tissue biopsy. Key findings include that dynamic changes in ctDNA and bTMB can predict molecular progression weeks before radiological assessment; blood-based PD-L1 monitoring (soluble, exosomal, or on CTCs) correlates with survival outcomes and offers a real-time readout of immune checkpoint activity; novel markers like tumor-macrophage fusion (TMF) cells and cytokine signatures provide unique insights into the systemic immune microenvironment. Conclusions: Liquid biopsy is evolving from a complementary diagnostic tool into a central pillar of precision immuno-oncology. Although technical standardization remains a challenge, the integration of multi-omic blood-based biomarkers represents the future of personalized lung cancer management. Full article

(This article belongs to the Special Issue Liquid Biopsy for Lung Cancer Treatment (2nd Edition))

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25 pages, 2670 KB

Open AccessReview

Alternative Splicing of the NF-Y Subunit, NF-YA, in Neuroblastoma Phenotype Heterogeneity

by Ilaria Martelli, Lucia Anna-Maria Cappabianca, Maddalena Sbaffone, Antonietta Rosella Farina and Andrew Reay Mackay

Cancers 2026, 18(11), 1839; https://doi.org/10.3390/cancers18111839 - 4 Jun 2026

Viewed by 799

Abstract

Neuroblastomas (NBs) are aggressive, therapy-resistant embryonal tumors of neural crest origin, which despite low mutational burdens exhibit high intra-tumoral heterogeneity characterized by adrenergic, noradrenergic, mesenchymal and cancer stem cell (CSC)-like subpopulations. These phenotypes exhibit interconverting plasticity that reflect both stage of transformation during [...] Read more.

Neuroblastomas (NBs) are aggressive, therapy-resistant embryonal tumors of neural crest origin, which despite low mutational burdens exhibit high intra-tumoral heterogeneity characterized by adrenergic, noradrenergic, mesenchymal and cancer stem cell (CSC)-like subpopulations. These phenotypes exhibit interconverting plasticity that reflect both stage of transformation during sympathoadrenal development and conditions within the tumor microenvironment. Chemotherapeutic agents promote adrenergic-to-mesenchymal conversion in NBs, which underpins drug resistance, post-therapeutic relapse, metastatic progression, and the plateauing of responses to advances in multimodal therapy. Improved understanding of the molecular mechanisms that regulate NB phenotypic plasticity is essential for identifying novel prognostic markers and potential therapeutic targets. In this article, following introductions into NB, molecular regulation of NB phenotypic plasticity, and the NF-Y transcription factor and its role in development and differentiation, we focus on alternative NF-YAl, NF-YAs and NF-YAx splicing of the NF-Y subunit, NF-YA, and the potential influence that different NF-YA isoforms have on NF-Y function and the NF-Y-transcription factor networks that impact NB cell phenotypes. Particular attention is paid to the novel extra short-form NF-YAx isoform, originally detected as the exclusive NF-YA isoform in a non-MYCN amplified advanced stage 3 NB. This isoform is also induced by doxorubicin in non-Myc amplified SH-SY5Y NB cells and is involved in doxorubicin cytotoxicity. Despite high cytotoxicity, however, NF-YAx selects a resistant subpopulation with mesenchymal/neural crest stem cell-like identity, unveiling a doxorubicin-induced NF-YAx-dependent resistance mechanism, with potential to influence post-therapeutic relapse and disease progression. Therefore, evaluating alternative NF-YA splicing, and especially NF-YAx expression, in advanced stage and post-therapeutic relapsed NBs, may be of both prognostic and therapeutic significance. Full article

(This article belongs to the Special Issue Advances in Cellular Heterogeneity and Plasticity in the Tumor Microenvironment)

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10 pages, 767 KB

Open AccessArticle

Pulmonary Embolism in Patients with Lung Cancer: Incidence and Performance of Prognostic Markers

by Francesco Tannura, Andrea Sbrana, Antonio Chella, Francesco Pistelli, Laura Carrozzi, Alessandro Celi and Roberta Pancani

Cancers 2026, 18(11), 1838; https://doi.org/10.3390/cancers18111838 - 4 Jun 2026

Viewed by 629

Abstract

Background: The incidence of cancer-associated thromboembolism has been extensively investigated, but mostly in heterogeneous cancer populations. Prognostic risk assessment is crucial in pulmonary embolism, but the accuracy of the commonly used tools remains uncertain in patients with cancer. Methods: We retrospectively included outpatients [...] Read more.

Background: The incidence of cancer-associated thromboembolism has been extensively investigated, but mostly in heterogeneous cancer populations. Prognostic risk assessment is crucial in pulmonary embolism, but the accuracy of the commonly used tools remains uncertain in patients with cancer. Methods: We retrospectively included outpatients with consecutive lung cancer attending the Pulmonary Unit in Pisa from July 2019 to June 2021. The study population was the subgroup of patients who developed at least one episode of pulmonary embolism. For all patients, clinical data within 72 h of pulmonary embolism diagnosis, Khorana Risk Score, and overall survival time were collected. Results: A total of 512 patients with lung cancer attended the clinic; 40 patients developed pulmonary embolism (cumulative incidence of 7.81%). Eight patients (20%) died within a month, and twenty-two patients (55%) died within 6 months. Troponin, N-terminal pro-brain-type natriuretic peptide and shock index were significantly different between survivors and non-survivors (p < 0.05). Pulmonary artery diameter and the right to left ventricle index were not significantly different between survivors and non-survivors. Patients’ survival significantly decreased with the increase in Khorana Risk Score. Conclusions: Compared to previous studies, a higher incidence of pulmonary embolism in lung cancer was detected by our study. The prognosis of patients with lung cancer with pulmonary embolism seemed to be influenced more by the natural history of cancer than by the severity of pulmonary embolism. Khorana Risk Score might be considered as a prognostic tool in patients with lung cancer and may be used in the prognostic work-up for lung cancer-associated thromboembolism after a prospective validation. Full article

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

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Graphical abstract

39 pages, 3083 KB

Open AccessReview

Redefining the Treatment Landscape of Advanced Endometrial Cancer in the Era of Immunotherapy and Precision Oncology

by Martina Cassaniti, Ilaria Morelli, Anna Chiara Boschi, Simona Scodes, Giuseppe Comerci, Claudia Casanova and Stefano Tamberi

Cancers 2026, 18(11), 1837; https://doi.org/10.3390/cancers18111837 - 4 Jun 2026

Viewed by 1246

Abstract

The therapeutic landscape of advanced and recurrent endometrial cancer (EC) has evolved substantially in recent years due to the integration of molecular classification and novel systemic therapies. This review summarizes current treatment strategies in advanced EC, focusing on immunotherapy, targeted therapies, and molecularly [...] Read more.

The therapeutic landscape of advanced and recurrent endometrial cancer (EC) has evolved substantially in recent years due to the integration of molecular classification and novel systemic therapies. This review summarizes current treatment strategies in advanced EC, focusing on immunotherapy, targeted therapies, and molecularly guided approaches. Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment, particularly in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) tumors, where durable clinical benefit has been observed. Recent phase III trials demonstrated that the addition of ICIs to platinum-based chemotherapy significantly improves progression-free survival in the first-line setting, especially in dMMR disease, with more modest but clinically meaningful benefit in mismatch repair-proficient (pMMR) tumors. In the post-platinum setting, combinations such as pembrolizumab plus lenvatinib have expanded treatment options for pMMR patients, despite increased toxicity. Advances in molecular profiling, including the ProMisE classification, are increasingly guiding treatment personalization. Emerging therapies, including PARP inhibitors and antibody–drug conjugates targeting HER2 and Trop-2, are showing promising activity. Despite these advances, challenges remain regarding resistance mechanisms, optimal treatment sequencing, and predictive biomarkers beyond MMR status. Full article

(This article belongs to the Special Issue Feature Review for Cancer Therapy: 2nd Edition)

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12 pages, 1412 KB

Open AccessArticle

Clinical Characteristics and Management of Immune Checkpoint Inhibitor-Associated Sicca Syndrome

by Meridith L. Balbach and Douglas B. Johnson

Cancers 2026, 18(11), 1836; https://doi.org/10.3390/cancers18111836 - 4 Jun 2026

Viewed by 648

Abstract

Background: Immune checkpoint inhibitors (ICIs) can induce a sicca-like syndrome that differs from primary Sjögren’s disease in both immunopathogenesis and clinical phenotype. Despite growing recognition of this entity, data describing real-world management and outcomes, particularly in the context of ICI discontinuation and [...] Read more.

Background: Immune checkpoint inhibitors (ICIs) can induce a sicca-like syndrome that differs from primary Sjögren’s disease in both immunopathogenesis and clinical phenotype. Despite growing recognition of this entity, data describing real-world management and outcomes, particularly in the context of ICI discontinuation and rechallenge, remain limited. Methods: Patients with new onset of sicca syndrome or exacerbation of previous symptoms following ICI therapy were retrospectively identified and assessed. Results: Fifty-nine patients with diverse malignancies (including melanoma, gastrointestinal, genitourinary, etc.) and sicca syndrome following treatment with ICIs (most often pembrolizumab or nivolumab +/− ipilimumab) were evaluated. Acute-onset dry mouth, primarily CTCAE v6.0 grades 1 (n = 24, 40.7%) and 2 (n = 34, 57.6%), occurred at a median of 104 days after ICI initiation, sometimes with associated dry eye (n = 8, 13.6%). Most were managed conservatively with behavioral modification and over-the-counter therapies alone (n = 37, 62.7%) while others received sialagogues (n = 9, 15.3%), dexamethasone oral rinse (n = 11, 18.6%), and/or systemic corticosteroids (n = 16, 27.1%). Additional management strategies included de-escalation to ICI monotherapy (n = 5, 8.5%) or discontinued ICI (n = 6, 10.2%). Half of patients treated with corticosteroids demonstrated subjective improvement in symptoms while 75% improved following ICI discontinuation. Four patients underwent rechallenge after a median interruption of 564 days; all (n = 4) demonstrated sicca recurrence. Conclusions: In this largest cohort to date of ICI-associated sicca syndrome, we confirm frequent improvement with steroids and/or supportive care and suggest a greater than previously appreciated risk of recurrence with rechallenge. Full article

(This article belongs to the Special Issue Immune-Related Adverse Events in Cancer Immunotherapy)

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23 pages, 5892 KB

Open AccessArticle

Deep Learning-Based Synthetic Contrast-Enhanced Breast MRI for Monitoring Response to Neoadjuvant Therapy

by Suleeporn Sujichantararat, Debosmita Biswas, Anum S. Kazerouni, Edric D. Tsang, Aditi Sathe, Daniel S. Hippe, Vivian Y. Park, Maggie Chung, Jennifer M. Specht, Suzanne M. Dintzis, Habib Rahbar, James H. Holmes, Wei Huang and Savannah C. Partridge

Cancers 2026, 18(11), 1835; https://doi.org/10.3390/cancers18111835 - 4 Jun 2026

Viewed by 960

Abstract

Background/Objectives: Contrast-enhanced (CE) breast MRI is highly sensitive for evaluating breast cancer extent and response to neoadjuvant therapy (NAT) but requires intravenous administration of gadolinium-based contrast agents (GBCA), increasing cost, time, patient discomfort, and health concerns. This study explored the feasibility of [...] Read more.

Background/Objectives: Contrast-enhanced (CE) breast MRI is highly sensitive for evaluating breast cancer extent and response to neoadjuvant therapy (NAT) but requires intravenous administration of gadolinium-based contrast agents (GBCA), increasing cost, time, patient discomfort, and health concerns. This study explored the feasibility of reducing GBCA use in treatment monitoring using a deep learning (DL) model to synthesize CE-MRI from non-contrast MRI. Methods: This IRB-approved retrospective pilot study evaluated women with breast cancer enrolled in an ongoing trial using serial MRI to monitor NAT prior to surgery. A pre-trained DL model was used to synthesize CE-MRI from T1-, T2-, and diffusion-weighted MRI. Changes in tumor volume at early (post-1-cycle NAT) and mid-treatment were measured on synthetic and acquired CE-MRI. Performance for predicting residual cancer burden (RCB) class 0/1 was evaluated using AUC and compared with DeLong’s test. Results: 27 women were included in the study (median age, 47 years [range = 28–75]); 14 (52%) achieved RCB class 0 and six (22%) achieved class 1. Synthetic CE-MRI-derived tumor volumes showed strong correlation with those from acquired CE-MRI at pre-treatment (

ρ

= 0.92, p < 0.001) and early treatment (

ρ

= 0.83, p < 0.001), but lower agreement at mid-treatment (

ρ

= 0.57, p = 0.002). Change in tumor volume on synthetic CE-MRI was numerically similar to acquired CE-MRI for predicting RCB class 0/1 vs. 2/3 at both early (AUC = 0.84 vs. 0.86, p = 0.83) and mid-treatment (AUC = 0.73 vs. 0.75, p = 0.80). Conclusions: Synthetic CE-MRI demonstrates preliminary feasibility as a non-contrast surrogate for predicting favorable outcomes (RCB class 0/1) in this pilot study, but inconsistencies in tumor volume measurement vs. acquired CE-MRI warrant further model refinement and validation. Full article

(This article belongs to the Special Issue Imaging and Liquid Biopsy Biomarkers for Cancer Diagnosis and Treatment (2nd Edition))

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6 pages, 191 KB

Open AccessEditorial

Recent Advances in Basic and Clinical Colorectal Cancer Research

by Seiichi Shinji and Tomio Arai

Cancers 2026, 18(11), 1834; https://doi.org/10.3390/cancers18111834 - 3 Jun 2026

Viewed by 491

Abstract

Colorectal cancer remains the third most commonly diagnosed malignancy and the second leading cause of cancer-related death worldwide [...] Full article

(This article belongs to the Special Issue Recent Advances in Basic and Clinical Colorectal Cancer Research)

21 pages, 3873 KB

Open AccessArticle

Development of Genetically Modified ARH-77 Feeder Cells for Efficient Expansion of Natural Killer Cells with Potent Anti-Tumor Activity

by Yu-Jin Lim, Bryan Marr, Safa Ghaziasgar, Cheol-Jung Kim, Yeon-Ju Baek, Geun-Seop Kim, Je-Jung Lee, Yu-Jin Park, Yurim An, Seung-Hwan Lee and Sang-Ki Kim

Cancers 2026, 18(11), 1833; https://doi.org/10.3390/cancers18111833 - 3 Jun 2026

Viewed by 782

Abstract

Background/Objectives: Adoptive transfer of allogeneic natural killer (NK) cells represents a promising off-the-shelf immunotherapy for cancer, offering advantages in safety and availability over autologous T cell therapies. However, generating therapeutically sufficient NK cell numbers remains challenging due to their low frequency in blood [...] Read more.

Background/Objectives: Adoptive transfer of allogeneic natural killer (NK) cells represents a promising off-the-shelf immunotherapy for cancer, offering advantages in safety and availability over autologous T cell therapies. However, generating therapeutically sufficient NK cell numbers remains challenging due to their low frequency in blood sources. Engineered feeder cell co-cultures have enabled substantial expansions of NK cells to clinically relevant doses. Methods: We evaluated the plasma cell leukemia-derived ARH-77 cell line as a feeder for ex vivo NK cell expansion from healthy donor peripheral blood mononuclear cells (PBMCs). Unmodified ARH-77 was compared to K562, followed by engineering both lines to co-express B7-H6 (NKp30 ligand), CD137L (4-1BBL), IL-15, and IL-15Rα via sequential lentiviral transduction. PBMCs were co-cultured with irradiated feeders in cytokine-supplemented (IL-2, IL-21, and later IL-15) RPMI-1640 or DMEM/F-12 medium for up to 28 days. Expansion (fold change in CD3⁻CD56⁺ cells), purity, surface receptor expression, and cytotoxicity (against K562 targets) were quantified. Results: Unmodified ARH-77 supported significantly greater NK cell expansion than K562 (model-estimated 681-fold vs. 155-fold at week 4 in RPMI; p = 0.0018), with higher purity but comparable cytotoxicity and receptor profiles. Engineered ARH-77 cells achieved robust expansion in RPMI, comparable to that of engineered K562 cells. In optimized DMEM/F-12 medium, engineered ARH-77 drove superior expansion (up to model-estimated 101,241-fold; 95% CI 46,771–219,146 at week 4), significantly outperforming engineered K562 (4.4-fold greater; 95% CI 1.01 to 18.54; p = 0.0479) while maintaining high purity and equivalent cytotoxicity. Substantial inter-donor variability influenced expansion magnitude, though relative feeder performance remained consistent across donors. Conclusions: Genetically modified ARH-77 feeder cells provide a potent platform for large-scale ex vivo expansion of functional NK cells. Full article

(This article belongs to the Special Issue Cytokine and Growth Factor Signaling at the Interface between Immune Cells and Cancer)

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21 pages, 8713 KB

Open AccessReview

The Dual Role of Ferroptosis in Cancer: Molecular Mechanisms, Microenvironment Crosstalk, and Precision Therapeutics

by Yu Zhu, Meijia Chen, Jianglong Chen, Junjie Wang, Rujie Zhou, Yunfei Cui and Guang Li

Cancers 2026, 18(11), 1832; https://doi.org/10.3390/cancers18111832 - 3 Jun 2026

Viewed by 934

Abstract

Ferroptosis, an iron-dependent and lipid peroxidation-driven form of regulated cell death, has emerged as a “versatile player” in oncology. It exerts a dual, context-dependent role in cancer, acting as both a potent tumor suppressor and a facilitator of tumor progression and therapeutic resistance. [...] Read more.

Ferroptosis, an iron-dependent and lipid peroxidation-driven form of regulated cell death, has emerged as a “versatile player” in oncology. It exerts a dual, context-dependent role in cancer, acting as both a potent tumor suppressor and a facilitator of tumor progression and therapeutic resistance. This review systematically delineates the core molecular regulatory networks of ferroptosis, highlighting the intricate balance between its execution mechanisms—driven by polyunsaturated fatty acid (PUFA) oxidation, iron catalysis, and mitochondrial dysfunction—and the robust endogenous defense systems, including the GSH-GPX4, FSP1/DHODH-CoQ10, and GCH1-BH4 axes. We deeply explore the dichotomous nature of ferroptosis in tumorigenesis: while classical tumor suppressors like p53 and CDKN2A harness ferroptosis to halt tumor growth, cancer cells can hijack lipid metabolic reprogramming and specific enzymes (e.g., iPLA2β) to evade cell death and promote distant metastasis. Furthermore, we dissect the multidimensional crosstalk between ferroptosis and the tumor microenvironment (TME), emphasizing its bidirectional immunoregulatory effects. Although CD8+ T cell-derived IFN-γ can sensitize tumor cells to ferroptosis and amplify anti-tumor immunity, aberrant ferroptotic activation can paradoxically foster an immunosuppressive niche. Finally, we summarize the latest translational strategies using small-molecule inducers and synergistic combination therapies, emphasizing that biomarker-guided patient stratification remains the ultimate paradigm for overcoming resistance and realizing precision ferroptosis-targeted cancer therapy. Full article

(This article belongs to the Special Issue The Role of Ferroptosis in Cancer (2nd Edition))

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9 pages, 290 KB

Open AccessArticle

Higher Cumulative Cytarabine Consolidation Improves Survival in Older Adults with Acute Myeloid Leukemia

by Todd William Mudd, Kendall Diebold, Sravanti Rangaraju, Aditi Sharma, Kimo Bachiashvili, Pankit Vachhani, Manuel R. Espinoza-Gutarra, Razan Mohty, Ravi Bhatia, Jorge Cortes and Omer Jamy

Cancers 2026, 18(11), 1831; https://doi.org/10.3390/cancers18111831 - 3 Jun 2026

Viewed by 902

Abstract

Background: Post-remission cytarabine consolidation is a cornerstone of therapy for acute myeloid leukemia (AML), but the optimal dosing strategy in older adults (≥60 years) remains unclear. High-dose cytarabine (HiDAC) is often avoided due to toxicity concerns, and data guiding cumulative dosing are [...] Read more.

Background: Post-remission cytarabine consolidation is a cornerstone of therapy for acute myeloid leukemia (AML), but the optimal dosing strategy in older adults (≥60 years) remains unclear. High-dose cytarabine (HiDAC) is often avoided due to toxicity concerns, and data guiding cumulative dosing are limited. Methods: We conducted a single-center retrospective cohort study of 111 patients aged ≥60 years with AML who achieved complete remission after standard 7 + 3 induction and received at least one cycle of cytarabine consolidation between 2012 and 2024. A 90-day landmark analysis excluded early relapses or deaths. Results: The median age was 65 years; 41% proceeded to allogeneic hematopoietic stem cell transplantation (allo-SCT). Cytarabine consolidation was well tolerated, with no neurotoxicity and only one instance of reversible nephrotoxicity. Patients were stratified by median cumulative cytarabine dose into low-intensity (<18 g/m², LIC) and high-intensity (≥18 g/m², HIC) groups. HIC was associated with improved overall survival compared with LIC (median OS: 31 vs. 13 months, p = 0.02), particularly among non-transplanted patients (25 vs. 7 months, p = 0.01). On multivariable analysis, HIC (HR 0.71, 95% CI 0.51–0.82, p = 0.01) and allo-SCT (HR 0.58, 95% CI 0.44–0.79, p = 0.03) independently predicted superior survival. Conclusions: Higher cumulative cytarabine consolidation is safe, feasible, and associated with improved survival in older AML patients, especially among patients ineligible for transplant. Prospective studies are warranted to define the optimal dosing strategy in this population. Full article

(This article belongs to the Special Issue Lymphoid and Myeloid Leukemias—Current Progress in Biology and Treatment)

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10 pages, 224 KB

Open AccessReview

Current Clinical Utility of Gene Expression Panels in Primary Cutaneous Melanoma

by Taylor L. Garza, Jae Hwan Choi, Michelle McGee, Edmond Box, Timothy Nywening, Andreas Karachristos, Abraham Schwarzberg, Mayer Fishman and Richard Jacobson

Cancers 2026, 18(11), 1830; https://doi.org/10.3390/cancers18111830 - 3 Jun 2026

Viewed by 622

Abstract

Roughly 100,000 new cases of melanoma are diagnosed yearly in the United States, the majority of which are early-stage disease with excellent prognosis. However, a subset of patients harbors clinically occult aggressive biology that can go undetected on standard clinicopathologic analyses. Gene expression [...] Read more.

Roughly 100,000 new cases of melanoma are diagnosed yearly in the United States, the majority of which are early-stage disease with excellent prognosis. However, a subset of patients harbors clinically occult aggressive biology that can go undetected on standard clinicopathologic analyses. Gene expression profiling (GEP) assays have emerged as molecular adjuncts to risk stratification, aiming to improve sentinel lymph node biopsy (SLNB) decision-making and surveillance planning. Two commercial tests are widely available: the 31-gene expression profile (31-GEP, DecisionDx-Melanoma, Castle Biosciences) and the clinicopathologic gene expression profile (CP-GEP, Merlin, SkylineDx). This review summarizes the current evidence for each assay regarding their performance and utility, with a focus on potentially actionable use cases, limitations, and the practical context in which these tools are most valuable. Full article

(This article belongs to the Section Cancer Informatics and Big Data)

14 pages, 692 KB

Open AccessSystematic Review

The Prognostic Value of Clinical and Pathological Response to Neoadjuvant Therapy in Metastatic Renal Cell Carcinoma Undergoing Cytoreductive Nephrectomy: A Systematic Review and Clinical Implications

by Daria Chernysheva, Pedro Hernandez-Peñalver, Pablo Maroto, Joan Palou, Alberto Breda and Oscar Rodriguez-Faba

Cancers 2026, 18(11), 1829; https://doi.org/10.3390/cancers18111829 - 2 Jun 2026

Viewed by 443

Abstract

Background: In the immunotherapy era, cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is increasingly performed after neoadjuvant immune checkpoint inhibitor (ICI)-based therapy. Examination of the nephrectomy specimen may capture the depth of treatment-induced tumor clearance more accurately than size-based radiological criteria [...] Read more.

Background: In the immunotherapy era, cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is increasingly performed after neoadjuvant immune checkpoint inhibitor (ICI)-based therapy. Examination of the nephrectomy specimen may capture the depth of treatment-induced tumor clearance more accurately than size-based radiological criteria alone. However, pathological reporting is highly heterogeneous across studies: residual viable tumor (RVT), necrosis, pT stage, and binary downstaging have all been used, limiting reproducible cross-study comparison. We aimed to characterize this heterogeneity, assess its implications for evidence synthesis, and propose a pragmatic framework for qualitative interpretation. Methods: PRISMA-compliant systematic review of studies reporting pathological response and oncological outcomes in mRCC patients undergoing CN after neoadjuvant systemic therapy (PROSPERO CRD420251154068). A qualitative synthesis was performed. A three-category Pathological Response Category (PRC) framework is proposed to harmonize heterogeneous metrics. Results: Seven retrospective studies (n = 408) were included. Pathological reporting metrics were inconsistent across all studies, preventing formal meta-analysis. Nevertheless, across cohorts reporting survival outcomes, deeper pathological response was directionally associated with more favorable oncologic outcomes. A discordance between radiological and pathological response was observed, including near-complete tumor clearance in patients classified as radiologically stable, reflecting the non-size-based mechanisms of ICI-induced tumor killing. Conclusions: The central finding of this review is not that pathological response predicts survival—which is expected—but that current pathological reporting in the mRCC surgical setting is too heterogeneous to quantify the frequency, depth, or prognostic significance of that response in a reproducible way. Prospective adoption of standardized pathological reporting protocols is the most critical next step for this field. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: Genetics, Surgical Management, and Systemic Therapy)

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Cancers, Volume 18, Issue 11 (June-1 2026) – 183 articles

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