Cancers

13 pages, 8280 KB

Open AccessReview

Contemporary Lung Cancer Nodal Staging and Therapeutic Decision-Making in the 9th TNM Era

by Takahiro Nakajima and George A. Eapen

Cancers 2026, 18(13), 2071; https://doi.org/10.3390/cancers18132071 (registering DOI) - 25 Jun 2026

In the era of precision medicine, managing non-small cell lung cancer (NSCLC) requires pathological confirmation, accurate nodal staging, and comprehensive biomarker profiling performed rapidly and concurrently. In the 9th edition of the TNM classification, the N2 category is subdivided into single-station (N2a) and [...] Read more.

In the era of precision medicine, managing non-small cell lung cancer (NSCLC) requires pathological confirmation, accurate nodal staging, and comprehensive biomarker profiling performed rapidly and concurrently. In the 9th edition of the TNM classification, the N2 category is subdivided into single-station (N2a) and multistation (N2b) subcategories, highlighting the clinical importance of precise mediastinal staging. This refinement necessitates systematic nodal evaluation using minimally invasive modalities such as endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) to appropriately stratify patients for surgery, neoadjuvant therapy, and definitive chemoradiotherapy. Concurrently, although N1 has not been formally subclassified because of the lack of standardized clinical diagnostic criteria, the increasing use of sublobar resection for early-stage NSCLC requires more precise hilar and intrapulmonary nodal assessments, which can potentially be facilitated by emerging technologies such as thin convex-probe EBUS. Concurrently, adequate tissue acquisition is essential for timely biomarker testing. Before administering neoadjuvant immune checkpoint inhibitors, actionable driver alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, must be identified to select appropriate treatment and prevent severe sequential toxicities associated with subsequent targeted therapies. This review highlights the indispensable role of endoscopic nodal staging and multidisciplinary collaboration in adapting to the updated TNM classification and optimizing personalized treatment strategies for patients with NSCLC. Full article

(This article belongs to the Special Issue Contemporary Lung Cancer Nodal Staging and Evolving Therapeutic Paradigms)

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16 pages, 638 KB

Open AccessReview

Patient and Technology Selection for Focal Therapy in Prostate Cancer

by Mustafa Dinckal, Rodrigo Rodrigues Pessoa, Julio Pow-Sang and Alice Yu

Cancers 2026, 18(13), 2070; https://doi.org/10.3390/cancers18132070 (registering DOI) - 25 Jun 2026

Abstract

Focal therapy is emerging as an organ-preserving strategy for selected patients with localized prostate cancer, aiming to preserve urinary and sexual function while maintaining acceptable cancer control. However, patient and technology selection remain complex because prostate cancer is often multifocal, clinically significant lesions [...] Read more.

Focal therapy is emerging as an organ-preserving strategy for selected patients with localized prostate cancer, aiming to preserve urinary and sexual function while maintaining acceptable cancer control. However, patient and technology selection remain complex because prostate cancer is often multifocal, clinically significant lesions may be missed by imaging or biopsy, and long-term comparative oncological data are limited. This narrative review summarizes current evidence and consensus recommendations on oncological suitability, histopathological risk features, tumor burden, imaging assessment, anatomical considerations, functional priorities, and follow-up. We also discuss the complementary roles of multiparametric magnetic resonance imaging, prostate-specific membrane antigen positron emission tomography, micro-ultrasound, and artificial intelligence-assisted planning. Finally, we review how tumor location and proximity to critical structures guide selection among high-intensity focused ultrasound, cryotherapy, irreversible electroporation, transurethral ultrasound ablation, laser ablation, and photodynamic therapy. Focal therapy remains promising but requires careful selection, shared decision-making, and structured follow-up. Full article

(This article belongs to the Special Issue Focus on Focal Therapy for Prostate Cancer)

30 pages, 7506 KB

Open AccessReview

Tumor Treating Fields and the Glioblastoma Microenvironment: Mechanistic Convergences with Radiotherapy

by Flavio Donnini, Giuseppe Battaglia, Salvatore Chibbaro, Francesco Marampon, Giuseppe Minniti and Paolo Tini

Cancers 2026, 18(13), 2069; https://doi.org/10.3390/cancers18132069 (registering DOI) - 25 Jun 2026

Abstract

Glioblastoma (GBM) remains the most lethal primary brain tumor in adults, with a median overall survival of approximately 15–20 months despite multimodal treatment including surgery, chemoradiation, and Tumor Treating Fields (TTFields). While the survival benefit of TTFields was established by the EF-14 phase [...] Read more.

Glioblastoma (GBM) remains the most lethal primary brain tumor in adults, with a median overall survival of approximately 15–20 months despite multimodal treatment including surgery, chemoradiation, and Tumor Treating Fields (TTFields). While the survival benefit of TTFields was established by the EF-14 phase III trial, their biological effects extend well beyond the canonical anti-mitotic mechanism and encompass extensive interactions with the GBM tumor microenvironment (TME). This review provides an integrated mechanistic analysis of TTFields–TME interactions in GBM, with a distinctive focus on their convergence with radiotherapy. We examine how TTFields activate innate immune sensing through cGAS/STING and AIM2 inflammasome pathways, drive immunogenic cell death, reprogram tumor-associated macrophages, and prime adaptive T cell responses. We further address TTFields effects on glioma stem cells, blood–brain barrier permeability, and intracellular signaling governing invasion, angiogenesis, and autophagy. Critically, we develop the mechanistic and clinical case for TTFields-radiotherapy combinations, highlighting convergent mechanisms of DNA repair impairment, mitotic catastrophe, and innate immune activation. Practical considerations for concurrent clinical implementation are discussed alongside a research agenda centered on optimal timing, hypofractionation, and predictive biomarkers. Available evidence—largely preclinical—suggests that TTFields may act as a TME-remodeling platform whose potential is most likely to be realized through mechanistically informed combinations. Full article

(This article belongs to the Special Issue Radiosensitivity and Radiotoxicity in Cancer)

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14 pages, 1036 KB

Open AccessArticle

Diagnostic Considerations for Neurolymphomatosis: A Natural History Analysis

by Francesca Rothell, Mary Ann Nguyen, Elizabeth Xu, Quan Ho, Sibo Zhou, Shiva Gautam and Eric T. Wong

Cancers 2026, 18(13), 2068; https://doi.org/10.3390/cancers18132068 (registering DOI) - 25 Jun 2026

Abstract

Neurolymphomatosis (NL), a rare manifestation of non-Hodgkin’s lymphoma affecting the peripheral nervous system, remains a diagnostic challenge. This study aimed to define an optimal diagnostic approach for timely and effective identification of NL. We analyzed 559 NL cases from 231 articles published from [...] Read more.

Neurolymphomatosis (NL), a rare manifestation of non-Hodgkin’s lymphoma affecting the peripheral nervous system, remains a diagnostic challenge. This study aimed to define an optimal diagnostic approach for timely and effective identification of NL. We analyzed 559 NL cases from 231 articles published from 1951 to 2022, examining how patient outcomes correlated with various diagnostic modalities, including magnetic resonance imaging (MRI), computed tomography (CT), [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET), electromyography-nerve conduction studies (EMG-NCS), ultrasound, and tissue biopsy when used individually or in combination. Separate analyses were performed in a mutually exclusive fashion to minimize confounding effects from multiple modalities. The results of this investigation revealed that patients with biopsies had a longer time interval from first treatment to progression (Kruskal–Wallis p < 0.0001), survival from diagnosis (overall survival) (p < 0.0001), and survival from symptom onset (p < 0.0001), but not symptom onset to diagnosis (p = 0.2134). Pairwise comparisons of biopsy plus 2, 3, or 4 diagnostic modalities revealed a positive trend for the combination of biopsy + PET + MRI + EMG-NCS. A majority of patients without biopsy had secondary NL. In this non-biopsied population, no diagnostic modality had a significant correlation with outcome. The data collectively indicate that histological confirmation of NL from biopsy was associated with a positive patient outcome. Management of NL patients requires timely testing using PET, MRI, and EMG-NCS to quickly identify a site for image-guided nerve biopsy. Full article

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

14 pages, 484 KB

Open AccessArticle

Evaluation of Human and Viral Methylation, in Addition to Partial Genotyping, for a Molecular Triage Strategy in Women Under Active Surveillance for CIN2

by Silvia Gori, Helena Frayle, Alessio Pagan, Marika Soldà, Cesare Romagnolo, Egle Insacco, Licia Laurino, Mario Matteucci, Giuseppe Sordi, Enrico Busato, Manuel Zorzi, Tiziano Maggino and Annarosa Del Mistro

Cancers 2026, 18(13), 2067; https://doi.org/10.3390/cancers18132067 (registering DOI) - 25 Jun 2026

Abstract

Background/Objective: Cervical intraepithelial neoplasia grade 2 (CIN2) shows heterogeneous clinical behavior, with substantial rates of spontaneous regression under active surveillance. Reliable molecular biomarkers are needed to distinguish regressive from transforming lesions and reduce overtreatment. We evaluated the prognostic role of host and [...] Read more.

Background/Objective: Cervical intraepithelial neoplasia grade 2 (CIN2) shows heterogeneous clinical behavior, with substantial rates of spontaneous regression under active surveillance. Reliable molecular biomarkers are needed to distinguish regressive from transforming lesions and reduce overtreatment. We evaluated the prognostic role of host and viral DNA methylation, alone and combined with HPV genotyping, in predicting CIN2 regression. Methods: This subanalysis derives from a prospective, multicenter Italian cohort of women with histologically confirmed CIN2 managed conservatively. Among 319 enrolled women, 134 with single HPV infections and valid host (FAM19A4/miR124-2) and viral (HPV L1 region) methylation results were included. HPV genotyping was performed with partial stratification (HPV16/18 vs. non-16/18). Clinical outcomes at 24 months were classified as regression versus persistence/progression. Logistic regression models assessed associations between biomarkers and regression. Results: At 24 months, 50% of women showed regression. Host and viral methylation positivity rates were more frequent in non-regressive lesions (40.3% vs. 19.4%, p = 0.01, and 52.2% vs. 32.8%, p = 0.02, respectively). Negative host methylation was significantly associated with regression (Odds Ratio OR = 0.37, 95% CI 0.17–0.81, p = 0.02), as was negative viral methylation (OR = 0.47, 95% CI 0.23–0.96, p = 0.04). Conclusions: Both host and viral methylation are inversely associated with CIN2 regression. Combining methylation markers did not substantially improve predictive accuracy; however, methylation negativity emerged as a potential molecular reassurance marker. When integrated with HPV genotyping, the highest probability of regression was observed among women with non-HPV16/18 infections and negative methylation results. These results endorse DNA methylation testing as a molecular tool for the conservative management of CIN2. Full article

(This article belongs to the Special Issue Molecular Markers and Targets in Modern Gynecologic Oncology)

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1 pages, 137 KB

Open AccessCorrection

Correction: Mesolella et al. Obstructive Sleep Apnea After Supracricoid Laryngeal Surgery (OPHL II): A Monocentric Prospective Pilot Study. Cancers 2026, 18, 1212

by Massimo Mesolella, Salvatore Allosso, Fabio Perrotta, Carlo Iadevaia, Carmela Cirillo, Nicola Serra, Pasquale Capriglione, Martina Ricciardiello, Anna Leoni and Anna Rita Fetoni

Cancers 2026, 18(13), 2066; https://doi.org/10.3390/cancers18132066 (registering DOI) - 25 Jun 2026

Abstract

Addition of a Corresponding Author [...] Full article

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

23 pages, 1979 KB

Open AccessArticle

Tumor-Infiltrating Lymphocytes as Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: Added Value of Morphological Characterization Beyond Quantification

by Juan Azcárate, Anna Petit, Teresa Soler-Monsó, Eugenia Quirós, Andrea Vethencourt, Agostina Stradella, Amparo García-Tejedor, Maria Jesús Pla-Farnos, Héctor Pérez-Montero, Anna Gumà, Raúl Ortega, Diana Pérez, Cristina Capó, Mar Varela, Luis M. Molinos-Albert, María del Rosario Taco-Sánchez, Esther Guerra, Jan Bosch-Schips, August Vidal, Evelyn Martínez-Pérez, Sonia Pernas, Miguel Gil-Gil and Catalina Falo Show full author list Hide full author list

Cancers 2026, 18(13), 2065; https://doi.org/10.3390/cancers18132065 (registering DOI) - 25 Jun 2026

Abstract

Background/Objectives: Tumor-infiltrating lymphocytes (TILs) are recognized predictors of response to neoadjuvant chemotherapy (NACT) and prognosis in breast cancer, particularly in triple-negative (TN) and HER2-positive subtypes. However, the additional predictive value of morphological features of the inflammatory infiltrate beyond TIL quantification is not [...] Read more.

Background/Objectives: Tumor-infiltrating lymphocytes (TILs) are recognized predictors of response to neoadjuvant chemotherapy (NACT) and prognosis in breast cancer, particularly in triple-negative (TN) and HER2-positive subtypes. However, the additional predictive value of morphological features of the inflammatory infiltrate beyond TIL quantification is not fully established. We aimed to assess the predictive value of TILs for response to NACT in breast cancer and to determine whether morphological characteristics of the inflammatory infiltrate enhance predictive accuracy. Methods: We analyzed 477 patients with stage II–III breast cancer treated with NACT between 2009 and 2016. Diagnostic core needle biopsies were prospectively re-evaluated. TILs were quantified according to International TILs Working Group recommendations. Morphological features of the infiltrate, including cell composition (lymphocytic vs. plasma cell-rich), heterogeneity, and localization, were evaluated using standardized criteria. Pathologic complete response (pCR) was defined as absence of invasive tumor in the breast and in the axillary lymph nodes (ypT0/Tis ypN0). Univariate and multivariate logistic regression analyses were performed to assess the predictive value of TILs (quantitative and morphological assessment) to achieve pCR for the entire cohort and by surrogate molecular subtype. Results: A TIL cutoff of >20% was identified as optimal for predicting pCR. High TILs were significantly associated with high-grade tumors, elevatedKi67, HER2-positive and TN subtypes, presence of plasma cells, and intraepithelial and heterogeneous infiltrates. In the overall cohort, TILs > 20% significantly increased the likelihood of pCR (OR 3.9, 95%IC 2.5–6.0, p < 0.001) and was an independent predictor of pCR. A combined variable incorporating TIL level and homogeneity improved predictive performance, with homogeneously high TILs emerging as a strong predictor of pCR (OR 5.521, 95%CI 3.174–9.603, p < 0.01). Plasma cell-rich and intraepithelial infiltrates were also associated with higher pCR rates (respectively, OR 2.7, 95%CI 1.5–5.0, p = 0.001 and OR 2.8, 95%CI 1.6–5.0, p < 0.001). Subtype-specific analyses confirmed the predictive value of TILs in TN tumors, but not in HER2-positive ones. Notably, in luminal B-like tumors, high TILs were the only independent predictor of response (OR 17.982, 95%CI 3.115–103.815, p = 0.001). Conclusions: TIL assessment on routine H&E-stained biopsies is a robust predictor of response to NACT in breast cancer that is readily available, cost-neutral and does not require additional techniques. Integration of simple morphological features significantly enhances predictive accuracy and may refine treatment stratification, particularly in luminal B-like tumors. Full article

(This article belongs to the Section Cancer Biomarkers)

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28 pages, 2611 KB

Open AccessArticle

Role of Surgery in the Multimodal Treatment of Pituitary Carcinoma: A Retrospective Single-Institution Case Series

by Christina Abi Faraj, Maxwell Tran, Sherise D. Ferguson, Maria A. Gubbiotti, Heather Y. Lin, Dima Suki, Nazanin Majd, Steven G. Waguespack and Ian E. McCutcheon

Cancers 2026, 18(13), 2064; https://doi.org/10.3390/cancers18132064 (registering DOI) - 25 Jun 2026

Abstract

Introduction: Pituitary carcinoma (PC) is a rare, aggressive endocrine neoplasm characterized by metastasis and challenging clinical management. The transformation from pituitary adenoma (PA) to PC is poorly understood, and predictors of metastasis remain elusive. This study evaluates the clinical course, surgical outcomes, and [...] Read more.

Introduction: Pituitary carcinoma (PC) is a rare, aggressive endocrine neoplasm characterized by metastasis and challenging clinical management. The transformation from pituitary adenoma (PA) to PC is poorly understood, and predictors of metastasis remain elusive. This study evaluates the clinical course, surgical outcomes, and molecular characteristics of PC. Methods: We retrospectively reviewed patients with PC treated at the M. D. Anderson Cancer Center between 1993 and 2023. Primary outcomes included metastasis-free survival and overall survival (OS). Clinical features, radiographic findings, surgical strategies and outcomes, immunohistochemical profiles, and MIB-1 were analyzed. Results: The cohort (n = 20) had a median age at PA and PC diagnosis of 33.9 and 43.3 years, respectively. The median metastasis-free interval was 7.4 years. GH- and ACTH-secreting tumors showed shorter times to PC diagnosis, while nonfunctioning PAs had longer metastasis-free survival. PAs with MIB-1 > 10% had shorter survival. Dura was the most common site of metastasis within the CNS, and bone was the most common outside the CNS. Leptomeningeal disease was seen in six patients. PAs became aggressive > five years after initial surgical resection (n = 13) or metastasized early within the first five years (n = 7). Median OS from PA diagnosis was 13.7 years, and 8.6 years from PC diagnosis. A total of 102 neurosurgical procedures were performed, with a median of five per patient; the median was similar in patients surviving longer than five years vs. those whose survival was shorter (5.0 vs. 4.5 procedures, p = 0.661). Most surgical interventions post-PC diagnosis were for optic decompression or metastasectomy. All long-term survivors (at least five years after PC diagnosis) received temozolomide-based therapy, with most also receiving radiotherapy. Conclusions: PC shows a variable clinical course, with some PAs progressing to PC after years, while others transform rapidly. All long-term survivors received temozolomide-based therapy, most in combination with radiotherapy and repeated surgical intervention, suggesting that aggressive multimodal management may be associated with prolonged survival. Future research will focus on identifying reliable predictors of metastasis at different time points in the complex clinical evolution of these tumors. Full article

(This article belongs to the Section Cancer Metastasis)

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18 pages, 3528 KB

Open AccessArticle

Prognostic Model Based on Sex, ALBI Grade, and ALR in Intermediate-to-Advanced HCC Patients Receiving Targeted Therapy Combined with ICIs and Interventional Treatment

by Xiaomeng Hu, Huiying Yan, Siyi Li, Zhiqiang Han, Hua Li, Xi Wei, Wei Zhang and Huikai Li

Cancers 2026, 18(13), 2063; https://doi.org/10.3390/cancers18132063 (registering DOI) - 25 Jun 2026

Abstract

Background/Objectives: Triple therapy combining targeted therapy (lenvatinib/bevacizumab), immune checkpoint inhibitors (ICIs), and interventional therapy (TACE/HAIC) has shown promising efficacy, but clinical outcomes differ among patients. We developed and tested a prognostic model based on sex, ALBI grade, and ALR to estimate survival [...] Read more.

Background/Objectives: Triple therapy combining targeted therapy (lenvatinib/bevacizumab), immune checkpoint inhibitors (ICIs), and interventional therapy (TACE/HAIC) has shown promising efficacy, but clinical outcomes differ among patients. We developed and tested a prognostic model based on sex, ALBI grade, and ALR to estimate survival in patients with intermediate-to-advanced HCC receiving triple therapy. Methods: This single center retrospective study included 184 intermediate-to-advanced HCC patients between November 2017 and December 2024. The patients enrolled received lenvatinib (n = 88) or bevacizumab (n = 96) plus PD-1/PD-L1 inhibitors and interventional therapy. The risk scoring model was derived from univariate Cox regression, LASSO Cox regression, and multivariate Cox regression analyses that were screened for independent prognostic factors. The median risk score defined the cutoff for separating patients into two risk subgroups (high- and low-risk). Overall survival (OS) across subgroups was evaluated and compared by Kaplan–Meier analysis and log-rank test. Model performance was evaluated using the C-index, time-dependent AUC at 6, 12, and 24 months, calibration curves, the Brier score, and decision curve analysis, with internal validation performed via Bootstrap resampling. Results: Multivariate analysis identified male sex, ALBI grade 3, and a high ALR level as independent risk factors of poorer OS. The resulting risk model showed a C-index of 0.62. Moreover, the median OS differed significantly between the two risk groups (p < 0.001). The model displayed moderate discrimination, with AUCs of 0.66, 0.66, and 0.74 at 6, 12, and 24 months. Calibration and the Brier score showed reasonable agreement and acceptable prediction errors. No interaction between risk factors and treatment type was observed (p > 0.05), indicating model applicability to both lenvatinib and bevacizumab-based regimens. Conclusions: A prognostic model integrating sex, ALBI grade, and ALR can offer some capacity to stratify survival risk in intermediate-to-advanced HCC patients. However, its overall discriminative performance is limited, and further validation in larger and external cohorts is needed to confirm its clinical value. Full article

(This article belongs to the Special Issue Cancer Biomarkers—Detection and Evaluation of Response to Therapy)

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15 pages, 2939 KB

Open AccessArticle

Platinum Rechallenge in Platinum-Resistant Ovarian Cancer: Clinical Outcomes and the Impact of BRCA Status

by David García-Illescas, Víctor Navarro, Lorena Fariñas-Madrid, Carmen García-Durán, Juan Francisco Grau Béjar, Lucia Musacchio, Roberta Mazzeo, Irene Giannubilo, Guillermo Villacampa and Ana Oaknin

Cancers 2026, 18(13), 2062; https://doi.org/10.3390/cancers18132062 (registering DOI) - 25 Jun 2026

Abstract

Objective: To evaluate the clinical benefit of platinum rechallenge in patients with platinum-resistant ovarian cancer (PROC) and to explore the predictive role of BRCA mutation status. Methods: We retrospectively evaluated platinum rechallenge in PROC at Vall d’Hebron University Hospital between 2010 [...] Read more.

Objective: To evaluate the clinical benefit of platinum rechallenge in patients with platinum-resistant ovarian cancer (PROC) and to explore the predictive role of BRCA mutation status. Methods: We retrospectively evaluated platinum rechallenge in PROC at Vall d’Hebron University Hospital between 2010 and 2023. Eligibility required ≥1 prior non-platinum regimen and ≥12 months since the last platinum dose. Objective response rate (ORR) per RECIST 1.1 and survival outcomes were analyzed by BRCA status and prior treatment lines. Results: ORR was 57% (95%CI, 42.1–73.0%) in the overall cohort (n = 63), 77% in BRCA-mutated patients (n = 13), and 50% in BRCA wild-type patients (n = 46). Median progression-free survival (PFS) was 7.3 months overall, which was longer in BRCA-mutated versus BRCA wild-type patients (8.4 vs. 7.4 months; HR 0.47, 95%CI 0.23–0.94; p = 0.033). An exploratory subgroup analysis suggested longer PFS among BRCA-mutated patients with ≤4 prior lines; however, this small subgroup finding should be considered hypothesis-generating. A platinum-free interval >6 months after rechallenging was observed in 38.5% of BRCA-mutated versus 13% of BRCA wild-type patients. Conclusions: Platinum rechallenge showed clinically meaningful activity in selected patients with PROC after an extended interval of intervening non-platinum therapy. These findings support the concept that platinum sensitivity may be dynamic and suggest that BRCA status and clinical selection factors may help inform individualized treatment sequencing in the post-PARP inhibitor era. Prospective validation with broader molecular characterization is warranted. Full article

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

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17 pages, 887 KB

Open AccessReview

Extended and Repeated Cytoreductive Surgery in Recurrent Uterine Leiomyosarcoma: A Narrative Review

by Antonio Maccio, Manuela Neri, Valerio Vallerino, Sonia Nemolato, Elisabetta Pusceddu, Gabriele Sole and Paolo Albino Ferrari

Cancers 2026, 18(13), 2061; https://doi.org/10.3390/cancers18132061 (registering DOI) - 25 Jun 2026

Abstract

Background/Objectives: Recurrent uterine leiomyosarcoma (ULMS) frequently poses a surgical question because systemic options remain limited and recurrence patterns are heterogeneous. We reviewed the published evidence on repeated and extended cytoreductive surgery for recurrent ULMS, focusing on selection criteria, operative boundaries, and the role [...] Read more.

Background/Objectives: Recurrent uterine leiomyosarcoma (ULMS) frequently poses a surgical question because systemic options remain limited and recurrence patterns are heterogeneous. We reviewed the published evidence on repeated and extended cytoreductive surgery for recurrent ULMS, focusing on selection criteria, operative boundaries, and the role of multivisceral, thoracic, and peritoneal-directed procedures. Methods: This narrative review synthesizes peer-reviewed literature on surgically managed recurrent or metastatic ULMS, prioritizing contemporary guidelines, retrospective cohorts, pooled analyses, selected systematic reviews when directly relevant to the surgical question, and published illustrative reports. The search covered records available from database inception through 14 May 2026 and used PubMed/MEDLINE, Web of Science Core Collection, Scopus, Google Scholar, selected publisher databases, and citation-linked records. No new patient-level or institution-specific clinical data are presented. Results: The available evidence is entirely retrospective and strongly affected by selection bias, yet it consistently suggests that the best outcomes are observed when complete gross resection is feasible. Across published series, favorable features include isolated or limited recurrence, longer time to relapse, compartmentalized disease, lung-only metastases, and preserved performance status. Contemporary reports also show that repeat surgery may evolve into extensive multivisceral procedures involving bowel resection, upper-abdominal dissection, urinary tract reconstruction, diaphragmatic resection, and thoracic surgery. Peritoneal-directed CRS/HIPEC-type strategies remain supported mainly by small heterogeneous studies and a ULMS-specific systematic review, reinforcing feasibility but not routine use. Published illustrative reports confirm that serial metastasectomies can occasionally support prolonged survival in exceptional patients, but they cannot establish effectiveness. Conclusions: In highly selected patients, repeated and even extensive cytoreductive surgery may remain a rational disease-control strategy for recurrent ULMS. The central unmet need is not proof that surgery can work in exceptional cases, but better criteria to identify who benefits from iterative resection and when escalation to multivisceral or thoracoabdominal surgery is justified. Full article

(This article belongs to the Special Issue Gynecological Cancers: From Bench to Bedside)

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24 pages, 6362 KB

Open AccessReview

Pharmacological Strategies for Mitigating Cytarabine-Induced Multi-Organ Toxicity: A Scoping Review on Mechanisms, Efficacy and Clinical Implications

by Ioannis Konstantinidis, Sophia Tsokkou, Kali Makedou, Eleni Gavriilaki, Georgios Delis and Theodora Papamitsou

Cancers 2026, 18(13), 2060; https://doi.org/10.3390/cancers18132060 (registering DOI) - 25 Jun 2026

Abstract

Background: Cytarabine (Ara-C) remains the cornerstone of remission-induction and consolidation chemotherapy for acute myeloid leukemia (AML) and related hematological malignancies. Despite more than six decades of clinical use, its multi-organ toxicity continues to be managed almost exclusively through dose attenuation and supportive care, [...] Read more.

Background: Cytarabine (Ara-C) remains the cornerstone of remission-induction and consolidation chemotherapy for acute myeloid leukemia (AML) and related hematological malignancies. Despite more than six decades of clinical use, its multi-organ toxicity continues to be managed almost exclusively through dose attenuation and supportive care, with no approved upstream pharmacological prevention strategy available. Objectives: This scoping review aimed to systematically map the breadth and nature of pharmacological agents tested in vivo for their capacity to mitigate cytarabine-induced multi-organ toxicity, to characterize their mechanisms of action and organ targets, and to identify evidence gaps and agents with translational potential. Methods: The review was designed and reported in accordance with the PRISMA-ScR checklist. A structured electronic search was conducted across PubMed/MEDLINE, Scopus, Cochrane Library and Embase, and Web of Science from database inception to 15 July 2025. Eligible studies were restricted to full-text, peer-reviewed, English-language research involving in vivo mammalian models administered cytarabine as the principal toxin, with at least one pharmacological co-intervention and at least one quantitative or histopathological organ-injury outcome. Results: From 5701 retrieved records, 36 eligible in vivo mammalian studies (spanning 1964–2024) were identified. Included studies addressed neurotoxicity (n = 6), gastrointestinal mucositis (n = 9), ocular toxicity (n = 3), hepatotoxicity (n = 3), bone marrow suppression (n = 4), chemotherapy-induced alopecia (n = 5), and reproductive and developmental toxicity (n = 4). Five recurring mechanistic strategies were identified across the heterogeneous agents tested: redox buffering (N-acetylcysteine, α-lipoic acid, rutin, swertiamarin, α-tocopherol), mitochondrial preservation (betanin, thymoquinone, vitamin D, sodium zinc dihydrolipoylhistidinate [DHLHZn]), tissue-microenvironment reprogramming (apraglutide, BADGE, plerixafor, short-chain fatty acids, β-glucan), molecular antagonism (deoxycytidine, dCMP), and immunomodulation (lienal peptide, IL-1β, AHCC). Conclusions: This scoping review provides the first systematic cartography of pharmacological mitigation strategies for cytarabine-induced multi-organ toxicity. Five mechanistic pathways converge across eight organ systems, with apraglutide and N-acetylcysteine representing the most clinically translatable candidates. Plerixafor and PPARγ blockade by BADGE constitute high-priority candidates for bone marrow niche protection, while the deoxycytidine antagonism principle warrants formal pharmacokinetic evaluation. The complete absence of cardiotoxicity mitigation data defines the most critical gap for future research. Full article

(This article belongs to the Section Cancer Drug Development)

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18 pages, 5929 KB

Open AccessReview

The Relationship Between Neutrophil Extracellular Traps and CD8⁺ T Lymphocytes in Cancer: A Comprehensive Review of Current Data

by Kellyn E. McKee, Hongji Zhang, Allan Tsung and Samantha M. Ruff

Cancers 2026, 18(13), 2059; https://doi.org/10.3390/cancers18132059 (registering DOI) - 25 Jun 2026

Abstract

Neutrophil extracellular traps (NETs) are web-like structures composed of decondensed DNA, histones, and proteins released by activated neutrophils. Originally identified as an innate defense mechanism against pathogens, NETs have since been implicated in cancer progression and immune evasion. Within the tumor microenvironment (TME), [...] Read more.

Neutrophil extracellular traps (NETs) are web-like structures composed of decondensed DNA, histones, and proteins released by activated neutrophils. Originally identified as an innate defense mechanism against pathogens, NETs have since been implicated in cancer progression and immune evasion. Within the tumor microenvironment (TME), NETs suppress anti-tumor immunity through multiple mechanisms, including the physical exclusion of CD8⁺ cytotoxic T lymphocytes from the tumor interior and upregulation of exhaustion markers via checkpoint ligands. This review synthesizes current preclinical and clinical evidence on the interplay between NETs and CD8⁺ T cells across multiple malignancies, including non-small cell lung cancer, pancreatic ductal adenocarcinoma, cholangiocarcinoma, colorectal cancer, bladder cancer, hepatocellular carcinoma, skin cancer, and penile cancer. Cancer-specific mechanisms of NET-mediated immune suppression are discussed, including IL-8, IL-17, CXCL6, and TGF-β-driven NETosis pathways. Clinical data consistently demonstrate that elevated NET levels correlate with reduced CD8⁺ T cell infiltration, T cell dysfunction, and worse patient outcomes. Emerging therapeutic strategies targeting this axis are reviewed, including DNase I-mediated NET degradation, Peptidyl arginine deiminase 4 (PAD4) inhibition, CXCR2 blockade, and combination approaches with immune checkpoint inhibitors. These interventions have shown promise in restoring CD8⁺ T cell cytotoxicity and overcoming immunotherapy resistance in preclinical models. Collectively, the evidence supports the NET-CD8⁺ T cell axis as a promising prognostic and therapeutic target warranting further clinical investigation. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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20 pages, 335 KB

Open AccessReview

Para-Aortic Lymph Node Staging and Oncologic Outcomes in Locally Advanced Cervical Cancer: A Narrative Review

by Juan Sebastián Obando-Rodríguez, Santiago Vieira-Serna, Jonathan Peralta, Juliana Rodríguez, Erick Estrada, Luisa López-Saldarriaga, Gabriel Levin and Rene Pareja

Cancers 2026, 18(13), 2058; https://doi.org/10.3390/cancers18132058 (registering DOI) - 25 Jun 2026

Abstract

Background: Para-aortic lymph node involvement is present in approximately 17–24% of women with locally advanced cervical cancer (LACC) and is one of the strongest adverse prognostic factors in this population. Current international guidelines recommend two alternative staging techniques: the International Federation of [...] Read more.

Background: Para-aortic lymph node involvement is present in approximately 17–24% of women with locally advanced cervical cancer (LACC) and is one of the strongest adverse prognostic factors in this population. Current international guidelines recommend two alternative staging techniques: the International Federation of Gynecology and Obstetrics (FIGO) and European Society of Gynecologic Oncology (ESGO) endorse imaging-based staging as the primary method to define radiation fields, whereas the National Comprehensive Cancer Network (NCCN) lists pre-treatment minimally invasive para-aortic lymphadenectomy as a Category 2B recommendation. Objective: We aimed to review and critically appraise the available evidence on the oncologic impact (progression-free and overall survival) of pre-treatment surgical para-aortic staging compared with clinical imaging-based staging in women with LACC. Methods: We searched MEDLINE (Ovid), Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Scopus from inception to January 2026, complemented by manually searching the reference lists for relevant articles and prior reviews. The review focused on comparative studies of women with LACC of squamous, adenocarcinoma, or adenosquamous histology—operationally defined as FIGO 2009 stages IB2–IVA with pelvic nodal involvement or FIGO 2018 stages IB3–IVA who received definitive-intent radiotherapy with or without concurrent chemotherapy and brachytherapy, and for whom comparative survival outcomes between a surgical-staging arm and an imaging-staging arm were reported. For this manuscript, a narrative review style was planned and reported in line with SANRA (Scale for the Assessment of Narrative Review Articles) quality criteria. Results: Twelve studies were included: two randomized controlled trials and ten observational studies (nine retrospective cohorts and one population-based analysis). Surgical staging consistently increased detection of occult para-aortic disease and led to more frequent use of extended-field radiotherapy (18–44%), but it did not yield a reproducible advantage in terms of progression-free or overall survival over imaging-guided chemoradiation. Conclusions: In LACC, pre-treatment surgical para-aortic staging improves anatomic and prognostic information but has not shown a consistent survival advantage over imaging-based staging combined with contemporary chemoradiation. Current comparative evidence does not support routine surgical staging, and its use still warrants further prospective evaluation in large clinical trials. Until results from ongoing phase III trials are available, surgical staging should be considered an individualized option in highly selected cases within multidisciplinary decision-making at experienced clinical centers. Full article

(This article belongs to the Special Issue Novel Approaches in the Management of Gynecological Cancers)

19 pages, 824 KB

Open AccessSystematic Review

Economic Evidence on Biliary Tract Cancer: A Systematic Review

by João Rocha-Gomes, Ana Sofia Teixeira, Marina Ruiz-Romeo, José Manuel Oliveira and Patrícia Ramos

Cancers 2026, 18(13), 2057; https://doi.org/10.3390/cancers18132057 (registering DOI) - 25 Jun 2026

Abstract

Background: Biliary tract cancers (BTCs), encompassing cholangiocarcinoma and gallbladder carcinoma, are aggressive malignancies with poor prognosis and increasing incidence in selected regions worldwide. Advances in imaging, biomarker profiling, immunotherapy, and targeted therapies have improved treatment options but have also increased the economic [...] Read more.

Background: Biliary tract cancers (BTCs), encompassing cholangiocarcinoma and gallbladder carcinoma, are aggressive malignancies with poor prognosis and increasing incidence in selected regions worldwide. Advances in imaging, biomarker profiling, immunotherapy, and targeted therapies have improved treatment options but have also increased the economic pressure on health systems. Understanding the economic evidence on BTC is therefore important for resource allocation and health technology assessment. Methods: We systematically searched PubMed/MEDLINE, Embase, Scopus, and Web of Science for peer-reviewed economic studies of BTC published from January 2010 to March 2025. Eligible studies included cost-effectiveness, cost–utility, cost–benefit, cost-of-illness, and resource-use analyses. The review followed PRISMA reporting principles. Reporting completeness was assessed using CHEERS 2022, and methodological credibility was appraised using the Drummond framework. Results: Twenty studies were included: 13 cost-effectiveness or cost–utility analyses and seven cost-of-illness or resource-use studies. Conventional chemotherapy strategies, including gemcitabine plus cisplatin in some settings and other cytotoxic combinations in selected jurisdictions, generally produced more favorable economic results than newer systemic therapies, although findings varied by country, threshold, comparator, and price assumptions. First-line immunotherapy combinations and biomarker-directed targeted therapies frequently produced ICERs above jurisdiction-specific willingness-to-pay thresholds at current prices, often requiring substantial price reductions to approach cost-effectiveness. Real-world studies showed high resource use and costs, particularly with hospitalizations and later treatment lines. Evidence on screening and prevention was limited, with one study suggesting that ultrasound surveillance may be cost-effective in a liver fluke-endemic region of Thailand. Discussion: The available economic evidence suggests that affordability and jurisdiction-specific value assessment are central to BTC policy decisions. Current prices for several immunotherapy and targeted agents limit cost-effectiveness in published models, while evidence on prevention, early detection, and care-pathway interventions remains sparse and context-specific. Full article

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

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14 pages, 4156 KB

Open AccessArticle

Time-Dependent Diffusion MRI-Based Microstructural Mapping for Characterization of Cribriform and Intraductal Carcinoma Morphologies in Prostate Cancer: A Preliminary Study

by Yanchun Wei, Shicong Yang, Tuo Ren, Zhihua Wen, Xiang Li, Jian Ling, Jinhua Lin, Yan Guo, Xueying Zhao, Huanjun Wang and Yanling Chen

Cancers 2026, 18(13), 2056; https://doi.org/10.3390/cancers18132056 (registering DOI) - 25 Jun 2026

Abstract

Background: Intraductal carcinoma (IDC) and invasive cribriform (Cr) histologic patterns are important adverse morphologies in prostate cancer (PCa) and may influence pretreatment risk stratification. This study evaluated the feasibility of time-dependent diffusion magnetic resonance imaging (t_d-dMRI)-based microstructural mapping for preoperative characterization [...] Read more.

Background: Intraductal carcinoma (IDC) and invasive cribriform (Cr) histologic patterns are important adverse morphologies in prostate cancer (PCa) and may influence pretreatment risk stratification. This study evaluated the feasibility of time-dependent diffusion magnetic resonance imaging (t_d-dMRI)-based microstructural mapping for preoperative characterization of these aggressive morphologies. Methods: This retrospective study included 95 men with pathologically confirmed PCa on radical prostatectomy specimens from March 2023 to March 2025. T_d-dMRI was performed using pulsed and oscillating gradient diffusion sequences. Microstructural parameters, including extracellular diffusivity (D_ex), cell diameter (d), intracellular volume fraction (f_in), cellularity, and diffusivities at 0, 17, and 33 Hz (ADC_0Hz, ADC_17Hz, and ADC_33Hz), were estimated using a two-compartment model. Conventional apparent diffusion coefficient (ADC_DWI) values were obtained from standard diffusion-weighted imaging. Parameters were compared between tumors with and without Cr/IDC patterns, and diagnostic performance was assessed using receiver operating characteristic analysis. Pairwise comparisons of AUCs were performed using the DeLong test. Results: Among 95 participants, 62 (65.3%) had Cr/IDC patterns. Compared with Cr/IDC-negative tumors, Cr/IDC-positive tumors showed higher f_in and cellularity (both p < 0.001) and lower ADC_DWI, ADC_0Hz, ADC_17Hz, and ADC_33Hz values (all p < 0.05). D_ex and d did not differ significantly between groups. Among t_d-dMRI-derived parameters, f_in showed the highest diagnostic performance (AUC = 0.757; 95% CI, 0.654–0.860). Conclusions: T_d-dMRI-based microstructural mapping demonstrates promise for characterizing the Cr/IDC morphologies in PCa. Full article

(This article belongs to the Special Issue Clinical and Translational Research of Prostate Cancer)

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2 pages, 153 KB

Open AccessCorrection

Correction: Benna-Doyle et al. Investigating the Prognostic Value of Pretreatment Body Composition in Women with Ovarian Cancer: Impact on Clinical Outcomes. Cancers 2026, 18, 1478

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

Cancers 2026, 18(13), 2055; https://doi.org/10.3390/cancers18132055 (registering DOI) - 25 Jun 2026

Abstract

In the original publication [...] Full article

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

16 pages, 831 KB

Open AccessArticle

Integrating the Neutrophil-to-Lymphocyte Ratio into a Clinicopathological Nomogram for Event-Free Survival Prediction in Cisplatin-Treated Muscle-Invasive Bladder Cancer

by Mariona Figols, Andrea González, Maria Fernandez-Saorín, Ana Bautista, Olatz Etxaniz, Ester Ruz, Jose Luis Gago, Daniela Gómez-Díaz, Juan Carlos Pardo, Marta Galí, Sergi Bernal, Cristina Camps, Lorena Rifa, Montserrat Domenech, Vicenç Ruiz de Porras, Anna Esteve and Albert Font

Cancers 2026, 18(13), 2054; https://doi.org/10.3390/cancers18132054 (registering DOI) - 24 Jun 2026

Abstract

Background/Objectives: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC) is a standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC), yet baseline tools to refine prognostic stratification remain limited. We aimed to develop and internally validate a clinicopathological nomogram integrating the [...] Read more.

Background/Objectives: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC) is a standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC), yet baseline tools to refine prognostic stratification remain limited. We aimed to develop and internally validate a clinicopathological nomogram integrating the neutrophil-to-lymphocyte ratio (NLR) to estimate event-free survival (EFS) in patients with MIBC treated with NAC. Methods: We retrospectively analyzed 210 patients with cT2–T4aN0–1M0 MIBC treated with cisplatin-based NAC at two Spanish institutions between 2010 and 2021. Candidate predictors included demographic, clinicopathological, and routine laboratory variables. A multivariable Cox model with backward selection based on the Akaike information criterion (AIC) was used to derive the final model, and internal validation was performed using 1000 bootstrap resamples. Results: Sex, age, prior non–muscle-invasive bladder cancer (NMIBC), and NLR were retained in the final nomogram. The model showed moderate discrimination, with a Harrell’s c-index of 0.60 and an optimism-corrected c-index of 0.58. The nomogram stratified patients into low-, intermediate-, and high-risk groups, with median EFS not reached, 47.5 months, and 18.0 months, respectively. High-risk patients also showed lower pathological complete response (pCR) rates. Conclusions: This exploratory nomogram integrates an accessible systemic inflammatory marker with baseline clinical variables to identify patients with poorer outcomes despite NAC. External validation in contemporary cohorts is warranted before clinical implementation. Full article

(This article belongs to the Special Issue Diagnosis and Therapy in Urothelial Cancer)

17 pages, 1364 KB

Open AccessArticle

Explainable Boosting Machine Predicting Length of Stay After Liver Surgery in Patients with Colorectal Liver Metastases

by Lucas Alexander Knøfler, Andreas Skov Millarch, Sanne Pagh Møller, Jeanett Klubien, Rasmus Virenfeldt Flak, Claus Wilki Fristrup, Jens Georg Hillingsø, Susanne Dam Nielsen, Martin Sillesen, Henry George Smith and Hans-Christian Pommergaard

Cancers 2026, 18(13), 2053; https://doi.org/10.3390/cancers18132053 (registering DOI) - 24 Jun 2026

Abstract

Background: Accurate preoperative prediction of length of hospital stay (LOS) after surgery for colorectal liver metastases (CRLMs) could improve patient counselling and resource planning, yet reliable risk tools are lacking. We aimed to develop an interpretable machine learning model predicting LOS following first-time [...] Read more.

Background: Accurate preoperative prediction of length of hospital stay (LOS) after surgery for colorectal liver metastases (CRLMs) could improve patient counselling and resource planning, yet reliable risk tools are lacking. We aimed to develop an interpretable machine learning model predicting LOS following first-time liver-directed surgery for CRLMs. Methods: In this multicenter cohort study, we included patients who underwent first-time liver resection, ablation, or a combination for CRLMs at three Danish hepatobiliary centers between 2016 and 2023. Preoperative features from two national registries were used to train Elastic Net, Random Forest, HistGradientBoosting, and Explainable Boosting Machine (EBM) algorithms. Hyperparameters were optimized using five-fold cross-validation. Performance was evaluated on a 20% hold-out test sample using mean absolute error (MAE) with bootstrapped 95% confidence intervals (CIs). Results: Among 915 patients, median LOS was 4.0 days (interquartile range (IQR) 3.0–6.0). All four algorithms achieved comparable prediction error (MAE 3.0–3.1 days). The EBM (MAE 3.1 days, 95% CI 2.6–4.3) algorithm was selected for its inherent interpretability. Surgical approach was the strongest predictor, where percutaneous and laparoscopic approaches were associated with reductions of 1.9 and 1.2 days, respectively. Tumor burden, including number of lesions and largest lesion diameter, showed progressive non-linear associations with longer stays. Nonetheless, overall explained variance was low (R² ≤ 0.10), and calibration showed systematic underestimation of stays beyond five days. Conclusions: An inherently interpretable machine learning model matched the predictive performance of opaque algorithms for LOS after CRLM surgery, although overall predictive accuracy was modest and longer stays were underestimated. Explainability analysis identified surgical approach and tumor burden as the most influential predictors. External validation in healthcare systems with different discharge practices is warranted. Full article

(This article belongs to the Special Issue Recent Advance in Colorectal Cancer Liver Metastases)

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