Cancers

20 pages, 3832 KB

Open AccessArticle

BRG1 Loss Is Frequent in Lung Cancer and Transforms Lung Epithelial Cells via Transcriptional and Epigenetic Reprograming

by Mathewos Tessema, Christin M. Yingling, Loryn M. Phillips, Kieu Do, Maria A. Picchi, Randy Willink and Steven A. Belinsky

Cancers 2025, 17(18), 3092; https://doi.org/10.3390/cancers17183092 - 22 Sep 2025

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Abstract

Background/Objectives: The BRG1 loss-of-function (LOF) mutation is found in ~10% of non-small cell lung cancer (NSCLC) cases, but its role in lung tumorigenesis is unclear and so it is investigated in this study. Methods: BRG1-knockout (KO) lines were generated from various non-malignant, pre-malignant, [...] Read more.

Background/Objectives: The BRG1 loss-of-function (LOF) mutation is found in ~10% of non-small cell lung cancer (NSCLC) cases, but its role in lung tumorigenesis is unclear and so it is investigated in this study. Methods: BRG1-knockout (KO) lines were generated from various non-malignant, pre-malignant, and malignant human lung epithelium-derived cell lines using CRISPR. The effects of BRG1-KO on cell growth, the transcriptome, the methylome, and epigenetic therapy were compared with those of wild-type (BRG1-WT) isogenic controls using standard in vitro and in vivo assays. Results: The BRG1 protein was expressed in all non-/pre-malignant lung epithelial cells but lost in 47% (14/30) of NSCLC cell lines. BRG1-KO and cigarette smoke (CS) exposure individually transformed human bronchial epithelial cell lines (HBECs), as evidenced by anchorage-independent growth. BRG1-KO and CS produced additive to synergistic effects on sensitivity to transformation that differed across HBECs. RNA-seq analysis revealed that BRG1-KO significantly changed the expression of over 8500 genes on average, impacting lung development, function, damage repair, and cancer pathways, including axonal guidance, pulmonary wound healing, and epithelial-to-mesenchymal transition (EMT). BRG1-KO also led to the hypermethylation of >47,000 promoter CpGs within ~9500 genes on average in different HBECs, including silencing of epithelial genes involved in EMT and tumor suppressor genes. BRG1-KO also moderately increased the in vitro and in vivo sensitivity of NSCLC cells to some epigenetic drugs. Conclusions: BRG1-LOF is frequent in NSCLC; can drive the transformation of lung epithelial cells such that they acquire properties of pre-malignant cells, indicating a potential role in lung cancer initiation; and sensitizes lung tumors to epigenetic therapy. Full article

(This article belongs to the Section Molecular Cancer Biology)

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17 pages, 1371 KB

Open AccessReview

Surgical Strategies for Tumors of the Pancreas and Duodenum

by Rosyli F. Reveron-Thornton, Kelly X. Huang, Daniel Delitto, Michael T. Longaker and Jeffrey A. Norton

Cancers 2025, 17(18), 3091; https://doi.org/10.3390/cancers17183091 - 22 Sep 2025

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Abstract

The recommended surgery for pancreatic tumors is dependent on the diagnosis. For pancreatic adenocarcinoma, duodenal, and ampullary adenocarcinoma, a Whipple pancreaticoduodenectomy with lymph node dissection is recommended. For small < 2 cm or non-imageable gastrinomas, duodenal transillumination, duodenotomy, duodenal tumor excision and adjacent [...] Read more.

The recommended surgery for pancreatic tumors is dependent on the diagnosis. For pancreatic adenocarcinoma, duodenal, and ampullary adenocarcinoma, a Whipple pancreaticoduodenectomy with lymph node dissection is recommended. For small < 2 cm or non-imageable gastrinomas, duodenal transillumination, duodenotomy, duodenal tumor excision and adjacent lymphadenectomy is recommended. For large > 3 cm gastrinomas, a Whipple pancreaticoduodenectomy with adjacent lymph node dissection is recommended. For small 1–2 cm insulinomas, intraoperative ultrasound with enucleation is recommended. If the patient with gastrinoma, insulinoma, or multiple nonfunctional NETs occurs in the setting of MEN-1, a subtotal pancreatectomy with or without splenectomy with enucleation of pancreatic head tumors is recommended, with adjacent lymph node dissection. The detail of each procedure is described with illustrations. Full article

(This article belongs to the Special Issue The Progress of Pancreatectomy for Pancreatic Cancer Treatment)

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22 pages, 1524 KB

Open AccessReview

Strategies to Target the Tumor-Associated Macrophages in the Immunosuppressive Microenvironment of Pancreatic Ductal Adenocarcinoma

by Ryu Matsumoto, Kiyonori Tanoue, Chieri Nakayama, Masashi Okawa, Yuto Hozaka, Tetsuya Idichi, Yuko Mataki and Takao Ohtsuka

Cancers 2025, 17(18), 3090; https://doi.org/10.3390/cancers17183090 - 22 Sep 2025

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a critical disease requiring the development of novel effective therapeutic approaches due to its increasing global incidence and associated low survival rates. While immunotherapy, including immune checkpoint inhibitors, has shown efficacy against various tumors, developing an effective treatment [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a critical disease requiring the development of novel effective therapeutic approaches due to its increasing global incidence and associated low survival rates. While immunotherapy, including immune checkpoint inhibitors, has shown efficacy against various tumors, developing an effective treatment approach for PDAC poses a challenge. This is primarily attributed to the complex and distinctive immune evasion mechanisms of PDAC. Recent studies have revealed that tumor-associated macrophages (TAMs) play a crucial role in enhancing immune evasion in PDAC. This role is mediated through multiple pathways, including cytokine secretion and the activation or suppression of diverse immune cells. A clear understanding of how macrophages contribute to PDAC proliferation could lead to the development of novel immune therapy approaches targeting TAMs. In this review, we summarized the multifaceted activities and roles of TAMs in PDAC and explored the potential effect of immunotherapeutic approaches on PDAC, with a particular focus on chimeric antigen receptor (CAR) macrophages. This review was based on promising findings from recent studies on CAR macrophage-based immunotherapy for solid tumors. Full article

(This article belongs to the Special Issue Novel Diagnosis and Treatment Approaches in Pancreatic Cancer)

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16 pages, 399 KB

Open AccessArticle

Breast Immunology Network: Toward a Multidisciplinary and Integrated Model for Breast Cancer Care in Italy

by Andrea Botticelli, Ovidio Brignoli, Francesco Caruso, Giuseppe Curigliano, Vincenzo Di Lauro, Carla Masini, Mario Taffurelli and Giuseppe Viale

Cancers 2025, 17(18), 3089; https://doi.org/10.3390/cancers17183089 - 22 Sep 2025

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Abstract

Background: Breast cancer is the most common female cancer in Italy. Despite better survival rates, significant disparities in access to diagnosis, treatment, and follow-up persist across regions. We propose an integrated, multidisciplinary care model—the Breast Immunology Network (BIN)—to address these challenges. Methods: The [...] Read more.

Background: Breast cancer is the most common female cancer in Italy. Despite better survival rates, significant disparities in access to diagnosis, treatment, and follow-up persist across regions. We propose an integrated, multidisciplinary care model—the Breast Immunology Network (BIN)—to address these challenges. Methods: The model was developed through a two-phase expert consultation with key opinion leaders and stakeholders, aligned with national and European oncology guidelines. No new patient data were collected; this is a qualitative analysis based on expert consensus and existing literature. The proposed model integrates a Hub-and-Spoke cancer network structure with fully functioning multidisciplinary teams (MDTs), standardized care pathways (PDTA), and digital tools to ensure continuity of care. Results: Experts identified critical gaps in Italy’s breast cancer care: limited access to specialized centers, inconsistent adherence to screening programs, and delays in treatment initiation. The proposed BIN model aims to bridge these gaps by enhancing collaboration across all care levels, incorporating immunotherapy where appropriate, and defining key performance indicators (KPIs) for continuous quality evaluation. For example, quantitative targets include achieving ≥65% nationwide mammography screening adherence and ensuring ≥90% of patients are treated in certified Breast Units. Conclusions: The Breast Immunology Network offers a strategic framework to improve equity, quality, and timeliness of breast cancer care in Italy. Importantly, unlike existing Hub–Spoke or CCCN models, the BIN formalizes governance tools, harmonized eligibility criteria, and a national registry for immunotherapy. By uniting Breast Units and community services under shared governance, and by integrating innovations such as immunotherapy and telemedicine, the BIN model could significantly improve clinical outcomes and ensure more equitable care for all patients. Its implementation may serve as a reference model for other health systems seeking to optimize oncology pathways through multidisciplinary integration and advanced treatments. Full article

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

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12 pages, 830 KB

Open AccessArticle

Can PSMA-Targeting Radiopharmaceuticals Be Useful for Detecting Brain Metastasis of Various Tumors Using Positron Emission Tomography?

by Esra Arslan, Nurhan Ergül, Rahime Şahin, Ediz Beyhan, Özge Erol Fenercioğlu, Yeşim Karagöz, Arzu Algün Gedik, Yakup Bozkaya and Tevfik Fikret Çermik

Cancers 2025, 17(18), 3088; https://doi.org/10.3390/cancers17183088 - 22 Sep 2025

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Abstract

Objective: The high expression of prostate-specific membrane antigen (PSMA) associated with neovascularization in non-prostatic malignant tumors and metastatic lesions has been documented in many studies. By taking advantage of the absence of PSMA-related background activity in brain tissue, in recent years, PSMA has [...] Read more.

Objective: The high expression of prostate-specific membrane antigen (PSMA) associated with neovascularization in non-prostatic malignant tumors and metastatic lesions has been documented in many studies. By taking advantage of the absence of PSMA-related background activity in brain tissue, in recent years, PSMA has been used for the imaging of glial tumors, especially for postoperative follow-up. The aim of this prospective study was to investigate the diagnostic value of ⁶⁸Ga-PSMA-11 PET/CT by comparing ⁶⁸Ga-PSMA-11 PET/CT, ¹⁸F-FDG PET/CT, and MRI findings in patients with brain metastases (BM). Materials and Method: In this prospective study, 27 cases, 11 female and 16 male, with a mean age of 59.48 ± 12.21 years, were included. Patients diagnosed with BM on ¹⁸F-FDG PET/CT or CT/MRI at initial diagnosis or in the follow-up period were included in the study. PET findings of BM lesions obtained from ¹⁸F-FDG and ⁶⁸Ga-PSMA-11 PET/CT imaging, demographic characteristics, histopathological data of the primary foci, and other clinical features were evaluated together. Results: Twenty-four (89%) patients were included in the study for restaging, two (7%) patients for local recurrence assessment, and one (4%) patient for local recurrence and suspicion of additional lesions. The indications for ¹⁸F-FDG PET/CT were breast carcinoma for 37% (n:10), followed by lung carcinoma for 26% (n:7), colorectal adenocarcinoma for 14% (n:4), squamous cell larynx carcinoma for 7% (n:2), gastric signet ring cell carcinoma for 4% (n:1), pancreatic NET3 for 4% (n:1), thyroid papillary carcinoma for 4% (n:1), and malignant melanoma for 4% (n:1). In total, 26/27 included patients had PSMA-positive brain metastases but only one patient had PSMA-negative brain metastases with ⁶⁸Ga-PSMA-11 PET/CT imaging. This patient was followed with a diagnosis of primary larynx squamous carcinoma and had a mass suspected of brain metastases. Further tests and an MRI revealed that the lesion in this patient was a hemorrhagic metastasis. The smallest metastatic focus on ⁶⁸Ga-PSMA-11 PET/CT imaging was 0.22 cm, also confirmed by MRI (range: 0.22–2.81 cm). The mean ± SD SUVmax of the BM lesions was 17.9 ± 8.6 and 6.8 ± 5.2 on ¹⁸F-FDG PET/CT and ⁶⁸Ga-PSMA-11 PET/CT imaging, respectively. Metastatic foci that could not be detected by ¹⁸F-FDG PET/CT imaging were successfully detected with ⁶⁸Ga-PSMA-11 PET/CT imaging in 11 cases (42%). The distribution and number of metastatic lesions observed on cranial MRI and ⁶⁸Ga-PSMA-11 PET/CT were compatible with each other for all patients. Immunohistochemical staining was performed in the primary tumor of 10 (38%) cases, and positive IHC staining with PSMA was detected in 5 patients. In addition, positive IHC staining with PSMA was detected in all of the four surgically excised brain metastatic tumor foci. Conclusions: In this study,⁶⁸Ga-PSMA-11 PET/CT appears to be superior to ¹⁸F-FDG in detecting BM from various tumors, largely due to its high expression associated with neovascularization and the absence of PSMA expression in normal brain parenchyma. This lack of physiological uptake in healthy brain tissue provides excellent tumor-to-background contrast, further supporting the advantage of ⁶⁸Ga-PSMA-11 over ¹⁸F-FDG for BM imaging. However, larger studies are required to confirm these findings, particularly through comparisons across tumor types and histopathological subgroups, integrating PSMA immunohistochemistry (IHC) scores with ⁶⁸Ga-PSMA-11 uptake levels. Beyond its diagnostic potential, our results may also inform PSMA-targeted therapeutic strategies, offering new perspectives for the management of patients with brain metastases from diverse primary tumors. Full article

(This article belongs to the Special Issue Hybrid Molecular Imaging Approaches in Cancer: PET/CT, PET/MRI, and Beyond)

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11 pages, 625 KB

Open AccessArticle

Laser Indirect Ophthalmoscopy-Guided Transpupillary Thermotherapy Versus I-125 Plaque Brachytherapy for Choroidal Hemangioma

by Rima Torosyan, Imad Jaradat, Reem AlJabari, Mona Mohammad, Ibrahim AlNawaiseh and Yacoub A. Yousef

Cancers 2025, 17(18), 3087; https://doi.org/10.3390/cancers17183087 - 22 Sep 2025

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Abstract

Background: Choroidal hemangioma, a rare benign vascular tumor, can cause visual loss due to subretinal fluid. Photodynamic therapy (PDT) with verteporfin has been the standard treatment, with plaque brachytherapy reserved for PDT failure. Verteporfin is unavailable in many regions in the Middle East, [...] Read more.

Background: Choroidal hemangioma, a rare benign vascular tumor, can cause visual loss due to subretinal fluid. Photodynamic therapy (PDT) with verteporfin has been the standard treatment, with plaque brachytherapy reserved for PDT failure. Verteporfin is unavailable in many regions in the Middle East, including Jordan, leaving plaque as the main alternative; however, plaque often leads to poor visual outcomes despite tumor control. To improve visual outcomes, we introduced transpupillary thermotherapy (TTT) via laser indirect ophthalmoscopy (LIO) as a practical, widely available, vision-preserving treatment. Methods: We retrospectively reviewed 13 patients with choroidal hemangioma treated at King Hussein Cancer Center. Patients received either plaque brachytherapy or LIO-guided TTT. Clinical data included visual acuity at baseline, tumor thickness reduction, subretinal fluid status, and visual outcome. Results: All patients had unilateral circumscribed choroidal hemangioma, and 10 (77%) were males. At diagnosis, the visual acuity was ≤0.5 in all patients (100%) and <0.1 in six (46%) patients. Seven patients (54%) received LIO-guided TTT and six (46%) underwent I-125 plaque brachytherapy. Tumor thickness was 3.0–5.0 mm in 12 (92%) cases; the median thickness in the I-125 plaque brachytherapy group was 4.5 mm (range, 4.5–5.0 mm), whereas in the LIO-guided TTT group it was 3.8 mm (range, 2.9–5.0 mm). At a median follow-up of 20 months (mean 24, range 12–48 months), five out of seven patients (71%) treated with TTT showed significant visual improvement, while the remaining two (29%) had stable vision; none experienced deterioration. In contrast, none of the six plaque-treated patients (0%) demonstrated any improvement in visual acuity; four remained stable and two worsened. This difference was statistically significant (p = 0.021). Tumor thickness was reduced in both groups, with a median reduction of −56% in the plaque group and −36% in the TTT group. All patients achieved complete resolution of subretinal fluid. Conclusions: LIO-guided TTT is an effective vision-preserving treatment for choroidal hemangioma. While both modalities-controlled tumor growth, only TTT resulted in significant visual improvement. This study demonstrates that LIO-guided TTT can replace plaque brachytherapy in regions where verteporfin (PDT) is unavailable, offering an accessible, practical, and superior alternative for preserving vision in patients with choroidal hemangioma. Full article

(This article belongs to the Special Issue Novel Treatments for Ocular and Periocular Cancers)

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11 pages, 1164 KB

Open AccessArticle

Contrast-Enhanced Mammography-Guided Biopsy in Patients with Extensive Suspicious Microcalcifications

by Yun-Chung Cheung, Wai-Shan Chung, Ya-Chun Tang and Chia-Wei Li

Cancers 2025, 17(18), 3086; https://doi.org/10.3390/cancers17183086 - 22 Sep 2025

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Abstract

Objectives: To investigate the feasibility of contrast-enhanced mammography-guided biopsy (CEM-Bx) to diagnose cancer via targeting the associated enhancements in the patients with extensive suspicious microcalcifications. Methods: All the women with extensive suspicious microcalcifications were mammographically screened. Contrast-enhanced mammography was first examined, [...] Read more.

Objectives: To investigate the feasibility of contrast-enhanced mammography-guided biopsy (CEM-Bx) to diagnose cancer via targeting the associated enhancements in the patients with extensive suspicious microcalcifications. Methods: All the women with extensive suspicious microcalcifications were mammographically screened. Contrast-enhanced mammography was first examined, followed by CEM-Bx if there was any relevant enhancement; otherwise, patients without enhancement were submitted to conventional mammography-guided biopsy (MG-Bx). We recorded and analyzed the histological results, morphologies and distributions of the microcalcifications. The outcomes were also compared to those patients (control group) who did not assess with CEM and received MG-Bx only by the Wilcoxon rank-sum test. Results: Between November 2021 and November 2023, a total of 61 participants participated in the test. A total of 26 women underwent CEM-Bx, and 35 underwent MG-Bx. In total, 19 of the 26 CEM-Bx were diagnosed as cancer, and none by MG-Bx. The cancer diagnostic rates (CDRs) identified by CEM-Bx were 81.8% for regional microcalcifications and 66.7% for segmental or diffuse distributions. The CDR of the test group was higher than the control group, 31.4% to 20%, respectively. Otherwise, the CDR of CEM-Bx was significantly higher than MG-Bx in the control group (73.08% to 20%, p-valve < 0.01). Conclusions: CEM-Bx was a safe and feasible procedure. With identification of the enhanced target, CEM-Bx faithfully performed among the extensive distributed suspicious microcalcifications. Although CEM-Bx improves CDR, larger prospective trials with surgical validation of all lesions are needed before widespread adoption. Full article

(This article belongs to the Special Issue Advances in Oncological Imaging (2nd Edition))

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10 pages, 247 KB

Open AccessPerspective

Neoadjuvant Therapy in Pancreatic Ductal Adenocarcinoma: Aligning Guideline Recommendations with Real-World Evidence

by Roberto Cammarata, Alberto Catamerò, Vincenzo La Vaccara, Roberto Coppola and Damiano Caputo

Cancers 2025, 17(18), 3085; https://doi.org/10.3390/cancers17183085 - 22 Sep 2025

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a 5-year overall survival below 12% and high recurrence rates even after R0 resection. Traditionally managed with a “surgery-first” approach, two consistent observations—the near-universal presence of micrometastatic disease at diagnosis and [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a 5-year overall survival below 12% and high recurrence rates even after R0 resection. Traditionally managed with a “surgery-first” approach, two consistent observations—the near-universal presence of micrometastatic disease at diagnosis and the frequent inability to complete adjuvant therapy—have driven the integration of neoadjuvant therapy (NAT) into clinical practice. NAT offers several theoretical and practical advantages: early systemic control of occult disease, improved delivery and completion of multimodal treatment, biological selection of surgical candidates, and increased R0 resection rates. While in borderline resectable PDAC, randomized trials have consistently demonstrated improved margin-negative resection rates and early survival benefits compared with upfront surgery, in resectable PDAC, evidence is more heterogeneous. Real-world studies corroborate trial findings, reporting higher R0 rates and reduced lymph node positivity without increased perioperative risk, but also highlight substantial heterogeneity in regimens, duration, and radiotherapy use. Limitations to universal NAT adoption include reliance on anatomy-based resectability criteria, absence of validated predictive biomarkers, challenges in response assessment, and concerns over disease progression during preoperative treatment. Future developments will focus on integrating molecular profiling, circulating tumor DNA dynamics, and advanced imaging into patient selection and treatment adaptation, supported by biomarker-enriched and adaptive trial designs. NAT is thus evolving from a selective strategy for borderline disease to an innovative framework to optimize multimodal treatment delivery and refine patient selection in PDAC, with the potential to improve surgical outcomes and inform systemic therapy decisions in both resectable and borderline resectable settings Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

12 pages, 540 KB

Open AccessArticle

Real World Data on the Efficacy of Brigatinib in ALK-Positive Non-Small Cell Lung Cancer: A Single-Center Experience

by Vesna Ćeriman Krstić, Natalija Samardžić, Mihailo Stjepanović, Spasoje Popević, Tatjana Adžić-Vukičević, Sofija Glumac, Ruža Stević, Dragana Marić, Marta Velinović, Milena Jovanović, Branislav Ilić, Milija Gajić, Nikola Čolić, Katarina Lukić, Brankica Milošević Maračić, Slavko Stamenić, Ivana Sekulović Radovanović and Jelena Milin Lazović

Cancers 2025, 17(18), 3084; https://doi.org/10.3390/cancers17183084 - 21 Sep 2025

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Abstract

Introduction: Lung cancer remains the leading cause of cancer death among all cancers. The discovery of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations led to an increased survival rate in patients with locally advanced and metastatic non-small cell [...] Read more.

Introduction: Lung cancer remains the leading cause of cancer death among all cancers. The discovery of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations led to an increased survival rate in patients with locally advanced and metastatic non-small cell lung cancer (NSCLC). Results of the ALTA 1L study showed superior outcomes for patients treated with brigatinib compared to patients treated with crizotinib. Background: We conducted research including 23 patients with ALK-positive lung adenocarcinoma who were treated with brigatinib in first or further lines of therapy. The median follow-up was 22 months (4–66 months). Results: There were no significant differences in patient population between the first and further lines of treatment regarding sex distribution (p = 0.692), smoking status (p = 0.554), ECOG performance status (p = 1.000), and baseline presence of brain metastases (p = 0.862). The response rate was 47.8%, and disease control was 95.6%. The 12-month progression-free survival (PFS) and overall survival (OS) rates were 85.3% and 86.5%, respectively, while the 60-month PFS rate was not reached, and the 60-month OS rate was 27.1%. The mPFS and mOS were 32 months. Conclusions: The results of this analysis are promising, as our patients experienced better outcomes compared to those in the ALTA 1L study, which may be attributed to the small sample size. However, the effectiveness of brigatinib has been confirmed in our clinical practice. Full article

(This article belongs to the Special Issue Advances in Thoracic Oncology: A Multi-disciplinary Approach to Lung Cancer)

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10 pages, 610 KB

Open AccessArticle

Discrepancies Between the Tennessee Nomogram and Oncotype DX: Implications for the Korean Breast Cancer Population—The BRAIN Study

by Suk Jun Lee, Joo Heung Kim, Jee Hyun Ahn, So Hyeon Gwon, Ilkyun Lee, Seho Park and Nak-Hoon Son

Cancers 2025, 17(18), 3083; https://doi.org/10.3390/cancers17183083 - 21 Sep 2025

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Abstract

Background: Oncotype DX (ODX) is widely used to estimate recurrence risk and guide adjuvant therapy in hormone receptor-positive (HR+), HER2-negative early-stage breast cancer. However, limited accessibility and high costs have prompted the use of alternative clinical models, such as the Tennessee nomogram. This [...] Read more.

Background: Oncotype DX (ODX) is widely used to estimate recurrence risk and guide adjuvant therapy in hormone receptor-positive (HR+), HER2-negative early-stage breast cancer. However, limited accessibility and high costs have prompted the use of alternative clinical models, such as the Tennessee nomogram. This study aimed to validate the predictive performance of the Tennessee nomogram in a Korean breast cancer cohort and identify factors contributing to discrepancies between nomogram predictions and ODX results. Methods: We retrospectively analyzed data on1298 patients with HR+/HER2−, node-negative invasive breast cancer who underwent ODX testing between May 2013 and August 2023. Predictive probabilities were calculated using the Tennessee nomogram and compared with actual ODX recurrence scores. Sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) were determined. Discordant cases were examined for clinicopathologic characteristics contributing to prediction errors. Results: The nomogram demonstrated an overall accuracy of 86.1% (sensitivity 0.130, specificity 0.989, AUC 0.776). Discordant results were observed in 13.9% of cases, primarily in patients with a high histologic grade, PR negativity, and elevated Ki-67 index. Most false negatives clustered within the ODX score range of 25–30, suggesting underestimation of risk in borderline-high cases. Conclusions: The Tennessee nomogram may be a useful surrogate when ODX testing is unavailable, but caution is warranted in patients with aggressive tumor biology. In such cases, ODX testing should be prioritized to guide adjuvant therapy decisions. Full article

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

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19 pages, 1781 KB

Open AccessArticle

Physiopathological Features in a Three-Dimensional In Vitro Model of Hepatocellular Carcinoma: Hypoxia-Driven Oxidative Stress and ECM Remodeling

by Maria Giovanna Rizzo, Enza Fazio, Claudia De Pasquale, Emanuele Luigi Sciuto, Giorgia Cannatà, Cristiana Roberta Multisanti, Federica Impellitteri, Federica Gilda D’Agostino, Salvatore Pietro Paolo Guglielmino, Caterina Faggio and Sabrina Conoci

Cancers 2025, 17(18), 3082; https://doi.org/10.3390/cancers17183082 - 21 Sep 2025

Viewed by 459

Abstract

Background: Hypoxia is a hallmark of solid tumors, including hepatocellular carcinoma (HCC), where it drives oxidative stress and extracellular matrix (ECM) remodeling, promoting tumor invasion and metastasis. Investigating these mechanisms in patients remains challenging due to the complexity of the tumor microenvironment. [...] Read more.

Background: Hypoxia is a hallmark of solid tumors, including hepatocellular carcinoma (HCC), where it drives oxidative stress and extracellular matrix (ECM) remodeling, promoting tumor invasion and metastasis. Investigating these mechanisms in patients remains challenging due to the complexity of the tumor microenvironment. Methods: We developed a scaffold-free three-dimensional (3D) spheroid model of HCC using human hepatocellular carcinoma HepG2 cells (ATCC HB-8065). To characterize hypoxia-driven processes, a multiparametric approach combining MTT assays for metabolic activity, confocal microscopy for viability and ECM organization, flow cytometry for apoptosis and ROS detection, qRT-PCR for gene expression, and FTIR spectroscopy for biochemical profiling were performed. Results: The 3D model exhibited progressive ROS accumulation, stabilization of HIF-1α, and metabolic reprogramming toward aerobic glycolysis. In parallel, ECM remodeling was evident, with increased expression of SPARC and FN1 and collagen fiber alignment, reflecting an invasive tumor phenotype. Conclusions: This scaffold-free 3D HCC model recapitulates key physiopathological features of tumor progression, providing a robust and physiologically relevant platform to investigate the hypoxia–ROS–ECM relationship and to support preclinical evaluation of targeted therapeutic strategies. Full article

(This article belongs to the Special Issue Extracellular Matrix Proteins in Cancer)

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18 pages, 1266 KB

Open AccessReview

The Usefulness of Indocyanine Green in Modern Gynecological Oncology—Analysis, Literature Review, and Future Perspectives

by Michał Kostrzanowski, Grzegorz Ziółkowski, Agata Mandes, Grzegorz Panek, Michał Ciebiera and Filip Dąbrowski

Cancers 2025, 17(18), 3081; https://doi.org/10.3390/cancers17183081 - 21 Sep 2025

Viewed by 902

Abstract

Indocyanine green (ICG) is a fluorescent agent which is characterized by a wide range of applications in the proper visualization of the operating field, differentiation of vital structures, and localization of lesions to be excised. An investigation and overview of novel approaches of [...] Read more.

Indocyanine green (ICG) is a fluorescent agent which is characterized by a wide range of applications in the proper visualization of the operating field, differentiation of vital structures, and localization of lesions to be excised. An investigation and overview of novel approaches of indocyanine green in modern gynecological oncology was conducted, including ovarian cancer surgery with its compartmental approach and compartmental surgery in endometrial cancer. Ureteral visualization and perfusion, lymphography, lymph node transfers, or the localization of anastomotic leakage in bowel surgery are examples of applications aimed at reducing the risk of surgical complications and improving the patients’ quality of life. The general use of indocyanine green in lymph node detection, subcategorized and analyzed, is constantly improved and reviewed. A therapeutic approach with macromolecules is being tested in preclinical models. Early results could suggest the future application of indocyanine green not only in broad-sense imaging but also as a cytotoxic agent conjugated with macromolecules. Further studies on the application of indocyanine green in laparoscopy, open surgery, and finally as a curative cytotoxic agent are needed. Full article

(This article belongs to the Special Issue Advances in Surgical Treatment of Gynecological Cancers)

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21 pages, 6628 KB

Open AccessArticle

Development of Nomograms to Predict the Probability of Recurrence at Specific Sites in Patients with Cutaneous Melanoma

by Eszter Anna Janka, Imre Lőrinc Szabó, Tünde Toka-Farkas, Lilla Soltész, Zita Szentkereszty-Kovács, Beatrix Ványai, Tünde Várvölgyi, Anikó Kapitány, Andrea Szegedi and Gabriella Emri

Cancers 2025, 17(18), 3080; https://doi.org/10.3390/cancers17183080 - 21 Sep 2025

Viewed by 363

Abstract

Background: Risk assessment models are increasingly being used in oncology to improve therapeutic and follow-up decisions for individual patients. Methods: In our study, we used a university hospital registry database containing data on patients diagnosed with invasive cutaneous melanoma between 2000 and 2019 [...] Read more.

Background: Risk assessment models are increasingly being used in oncology to improve therapeutic and follow-up decisions for individual patients. Methods: In our study, we used a university hospital registry database containing data on patients diagnosed with invasive cutaneous melanoma between 2000 and 2019 (training cohort: N = 1402; validation cohort: N = 601). Using multivariate Cox regression models, we identified clinicopathological variables that are independent risk factors for melanoma recurrence at specific sites. We then constructed nomograms to predict the probability of recurrence at 3, 5, and 10 years. Results: Age, sex, primary tumor location, histological subtype, Clark invasion level and AJCC pT category were independent prognostic factors for melanoma recurrence in regional lymph nodes. Age, sex, primary tumor location, Clark level of invasion, AJCC pT stage and regional lymph node metastasis were risk factors for skin/soft tissue (including muscle)/non-regional lymph node metastases. We found that AJCC pT category and sex were also independent prognostic factors for melanoma recurrence in the lung, visceral sites, and brain. Furthermore, the nomogram predicting recurrence in the lung and visceral sites incorporated the presence of regional lymph node and skin/soft tissue/non-regional lymph node metastases. ROC curves showed good performance of the nomograms in both the training and validation cohorts. The calibration curve showed a good fit. Conclusion: Our results support the high prognostic value of AJCC pT stage and patient sex, which remained consistent across all melanoma stages, and demonstrate the feasibility of creating nomogram models to predict recurrence risk in melanoma patients. Full article

(This article belongs to the Special Issue Skin Cancer: Epidemiology, Management and New Therapies)

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10 pages, 372 KB

Open AccessArticle

Benign and Malignant Tumors of the Hand: Patterns, Pathology, and Surgical Outcomes in a Large Retrospective Cohort

by Fabiana Battaglia, Roberta Giuffrida, Marco Pagano, Luigi Troisi and Gabriele Delia

Cancers 2025, 17(18), 3079; https://doi.org/10.3390/cancers17183079 - 21 Sep 2025

Viewed by 422

Abstract

Background: Hand tumors encompass a heterogeneous spectrum of benign, malignant, and tumor-like lesions with diverse clinical behavior. While international studies have reported epidemiological and clinicopathological features, large-scale data in Italian populations are scarce. This retrospective analysis represents one of the largest Italian surgical [...] Read more.

Background: Hand tumors encompass a heterogeneous spectrum of benign, malignant, and tumor-like lesions with diverse clinical behavior. While international studies have reported epidemiological and clinicopathological features, large-scale data in Italian populations are scarce. This retrospective analysis represents one of the largest Italian surgical series of histologically confirmed hand tumors. The objective was to evaluate clinicopathological characteristics, anatomical distribution, and surgical outcomes of these lesions over a 5-year period. Methods: A total of 250 patients who underwent surgery for hand tumors at the Department of Plastic and Reconstructive Surgery, University Hospital “G. Martino,” Messina, Italy, from January 2020 to December 2024, were retrospectively reviewed. Data from clinical records, imaging, and histopathology were categorized as tumor-like lesions, benign neoplasms, or malignant tumors. Demographic and clinical variables were compared across diagnostic groups. Results: The cohort included 127 males and 123 females (mean age 49.3 ± 18.6 years). Lesions were most frequently located in the digits (62%), followed by palm (21%), dorsum (11%), and wrist (6%). Tumor-like lesions represented 37.6% of cases, predominantly mucous cysts and foreign body granulomas. Benign tumors accounted for 49.2%, with giant cell tumors of the tendon sheath as the most common (31.7%). Malignant tumors were rare (10.4%), mainly squamous cell carcinoma, basal cell carcinoma, and melanoma. Patients with malignant lesions were significantly older (67.4 years) compared with those with benign or tumor-like lesions (p < 0.01). Conclusions: Benign and tumor-like lesions predominate among hand tumors, whereas malignancies are infrequent but clinically important. Surgical excision remains the treatment of choice, guided by preoperative imaging and confirmed histopathologically. Expanding this cohort and integrating molecular diagnostics with patient-reported outcomes may enhance future management strategies. Full article

(This article belongs to the Special Issue Advances in Skin Cancer: Diagnosis, Treatment and Prognosis)

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23 pages, 3165 KB

Open AccessReview

Bladder Cancer: Uncovering the Predictive Role of NOTCH as an Emerging Candidate Biomarker for Therapeutic Strategies

by Chiara Cusumano, Federica Squillante, Marco Roma, Roberto Miano and Maria Pia Felli

Cancers 2025, 17(18), 3078; https://doi.org/10.3390/cancers17183078 - 20 Sep 2025

Viewed by 501

Abstract

Bladder cancer (BCa) is one of the most diagnosed cancers worldwide. It is classified as non-muscle-invasive (NMIB), confined to the mucosa, and muscle-invasive (MIB), extended to deeper layers or formed metastases. The poor outcomes associated with MIBC indicate the urgent need for candidate [...] Read more.

Bladder cancer (BCa) is one of the most diagnosed cancers worldwide. It is classified as non-muscle-invasive (NMIB), confined to the mucosa, and muscle-invasive (MIB), extended to deeper layers or formed metastases. The poor outcomes associated with MIBC indicate the urgent need for candidate biomarkers to improve treatment strategies. Molecular characterisation of both NMIBC and MIBC, and especially the classification of tumours into molecular subtypes, could provide the development of novel therapeutics in high-risk muscle-invasive bladder cancer. A few studies have focused on pathways implicated in MIBC, including growth factors, DNA–RNA modifying enzymes and the differential roles played by the NOTCH receptors. NOTCH1 has been revealed as a tumour suppressor; in contrast, NOTCH2 and NOTCH3 have demonstrated an oncogenic role in BCa. Recent reports have found that NOTCH2 and NOTCH3 are associated with poor prognosis. Moreover, inhibiting these NOTCH receptors effectively restrained BCa growth and metastasis, suggesting the potential value of targeting NOTCH as a promising therapeutic strategy for bladder cancer. Given the crucial role of the NOTCH pathway, we will discuss the different predictive value of the four NOTCH receptors and the potential of NOTCH-combined therapy in BCa. Full article

(This article belongs to the Section Cancer Biomarkers)

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16 pages, 1497 KB

Open AccessArticle

Clinical and Molecular Characteristics of 100 Atypical Teratoid Rhabdoid Tumor Patients from Low- and Middle-Income Countries

by Noha A. Ismail, Shaimaa Aboubakr, Amal Mosaab, Eslam Maher, Hanafy Hafez, Hala Taha, Dina Yassin, Amal Refaat, Mohamed S. Zaghloul, Mohamed El-Beltagy, Abdelrahman Enayat, Volker Hovestadt, Olfat Ahmed, Mark W. Kieran, Ahmed El-Hemaly, Shahenda EI-Naggar and Alaa El-Haddad

Cancers 2025, 17(18), 3077; https://doi.org/10.3390/cancers17183077 - 20 Sep 2025

Viewed by 490

Abstract

Background: Atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive, rare pediatric central nervous system malignancy. Prognostic factors for optimizing risk stratification and management in a large uniformly treated cohort are lacking. Methods: We conducted a single-center retrospective cohort study analyzing clinical and [...] Read more.

Background: Atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive, rare pediatric central nervous system malignancy. Prognostic factors for optimizing risk stratification and management in a large uniformly treated cohort are lacking. Methods: We conducted a single-center retrospective cohort study analyzing clinical and outcome data for 100 newly diagnosed ATRT patients aged <18 years treated at the Children’s Cancer Hospital, Egypt, from 2008 to 2022. They were treated uniformly as per the Dana-Farber Cancer Institute modified IRS-III protocol. Molecular subgroups (MYC, SHH, and TYR) were determined via a DNA methylation array for patients who had sufficient DNA material available for the methylation analysis. Treatment toxicities were graded per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: The median age at diagnosis was 1.88 years (IQR 0.99, 3.01); 28% were under 1 year of age, 45% were between 1 and 3 years old, and 26% were above 3 years of age. At diagnosis, 39% of patients had metastatic disease. A total of 60% of patients had gross residual disease following surgical excision. In multivariable analysis, age < 1 year and metastatic disease had a significant impact on event-free survival (EFS) (p = 0.047 and p = 0.002, respectively); however, only metastatic disease had a significantly negative effect on overall survival (OS) and cumulative incidence of relapse (CIR) (p = 0.002 for OS and p < 0.001 for CIR). DNA methylation was performed for 69 patients who were classified as having a TYR (n = 13), SHH (n = 34), MYC (n = 17), or non-ATRT diagnosis (n = 5). In the cohort of the 64 patients with ATRT defined by methylation, no significant survival differences were observed. Treatment-related deaths were reported in 28% of our studied group. Gram-negative septicemia was the most common cause of toxic death. The 5-year EFS and OS of the whole cohort were 12% and 13%, respectively. Conclusions: In this cohort, no significant survival differences were observed among the methylation subgroups. The higher treatment-related mortality in our cohort compared to the original protocol’s toxic-related deaths suggested that intensive and lengthy chemotherapy regimens may need modification for our population. The need for a short intensified approach, including a limited induction cycle followed by an intensified high-dose consolidation therapy, may be more appropriate for our patients with low socioeconomic status to avoid a repeated and prolonged course of protracted neutropenia. Full article

(This article belongs to the Special Issue Current Concept and Management of Pediatric ATRTs)

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19 pages, 3573 KB

Open AccessArticle

PARP3 Promotes AML Progression via Activation of PI3K/AKT/mTOR Signaling

by Tingyong Cao, Yurong Zhang, Huan Liu, Hongbin Zhang, Liangliang Li, Xiaoli Li and Li Zhao

Cancers 2025, 17(18), 3076; https://doi.org/10.3390/cancers17183076 - 20 Sep 2025

Viewed by 346

Abstract

Background: Acute myeloid leukemia (AML) remains a hematopoietic clonal malignancy that is characterized by a poor prognosis, largely attributable to chemotherapy resistance and a high incidence of post-chemotherapy relapse. Therefore, the identification of novel molecular markers is crucial for optimizing treatment regimens [...] Read more.

Background: Acute myeloid leukemia (AML) remains a hematopoietic clonal malignancy that is characterized by a poor prognosis, largely attributable to chemotherapy resistance and a high incidence of post-chemotherapy relapse. Therefore, the identification of novel molecular markers is crucial for optimizing treatment regimens and improving outcomes for this disease. Methods: We first investigated the expression levels of poly(ADP-ribose)polymerase 3(PARP3) mRNA in data from our center and the Gene Expression Omnibus (GEO), then explored the role of PARP3 in AML through cell experiments. Results: Our results demonstrated that the expression levels of PARP3 were significantly elevated in AML samples compared to controls (p < 0.05). Based on the median expression of PARP3, 151 cases of AML from TCGA data were divided into two groups. The results showed that PARP3-high group had markedly shorter overall survival (OS) than the PARP3-low group (OS: median: 1.18 vs. 3.88 years; p < 0.001). The overexpression of PARP3 was correlated with older age and high-risk stratification in the AML from TCGA data (p < 0.05). Finally, we confirmed that specifically down-regulating PARP3 expression impaired AML cell proliferation, disrupted cell cycle process, inhibited migration, accelerated apoptosis, and impaired the PI3K/AKT/mTOR signaling pathway in vitro. Conclusions: PARP3-mediated activation of the PI3K/AKT/mTOR signaling pathway enhances AML cell proliferation and migration, identifying it as a potential therapeutic target for poor-prognosis AML. Full article

(This article belongs to the Section Molecular Cancer Biology)

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21 pages, 3426 KB

Open AccessSystematic Review

IDH Mutations and Intraoperative 5-ALA Fluorescence in Gliomas: A Systematic Literature Review with Novel Exploratory Hypotheses on the Modulatory Effect of Vorasidenib

by Magdalena Rybaczek, Marek Jadeszko, Aleksander Lebejko, Magdalena Sawicka, Zenon Mariak, Tomasz Łysoń, Halina Car and Przemysław Wielgat

Cancers 2025, 17(18), 3075; https://doi.org/10.3390/cancers17183075 - 19 Sep 2025

Viewed by 509

Abstract

Background: Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) enables the intraoperative visualization of glioma. However, its effectiveness varies based on tumor subtype and molecular profile, posing challenges for achieving complete resection. Our systematic review aims to explore the relationship between IDH mutation status [...] Read more.

Background: Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) enables the intraoperative visualization of glioma. However, its effectiveness varies based on tumor subtype and molecular profile, posing challenges for achieving complete resection. Our systematic review aims to explore the relationship between IDH mutation status and intraoperative fluorescence visualization. Importantly, this is the first study to propose that vorasidenib, an emerging IDH-targeting agent, could enhance 5-ALA-guided surgery, marking a novel direction for translational research. Methods: A systematic literature search was conducted using the PubMed, Cochrane Library, Scopus and Web of Science databases up to May 2025, following PRISMA guidelines. The primary outcomes included fluorescence detection rates across different glioma subtypes and their correlation with IDH mutation status. Secondary outcomes comprised surgical efficacy measures such as gross total resection (GTR), overall survival (OS), and progression-free survival (PFS). Additionally, we analyzed the metabolic consequences of IDH mutations and evaluated the potential role of vorasidenib in enhancing 5-ALA-induced fluorescence. Results: Seven studies including 621 patients included in the final analysis. Fluorescence detection was nearly universal in WHO grade 4 gliomas (94–100%), but lower in grade 3 (43–85%) and rare in grade 2 (7–26%). Several cohorts reported reduced fluorescence in IDH-mutant gliomas, although this was not consistent across all studies. In high-grade gliomas, visible fluorescence correlated with higher GTR rates and, in some series, longer OS. Conversely, in lower-grade IDH-mutant gliomas, fluorescence did not increase GTR and was associated with worse PFS and OS. Conclusions: The effectiveness of 5-ALA-guided fluorescence in glioma surgery is significantly influenced by both tumor grade and IDH mutation status. Vorasidenib may represent a potential avenue for modulating tumor metabolism and enhancing intraoperative fluorescence in IDH-mutant gliomas, a hypothesis that warrants further experimental validation. Full article

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

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15 pages, 521 KB

Open AccessArticle

Non-Restorative Low Anterior Resection Is Associated with Poor Intermediate-Term Oncological Outcomes in MRI-Defined Rectal Cancer

by Ritch T. J. Geitenbeek, Mark Broekman, Thijs A. Burghgraef, Esther C. J. Consten and Roel Hompes

Cancers 2025, 17(18), 3074; https://doi.org/10.3390/cancers17183074 - 19 Sep 2025

Viewed by 281

Abstract

Background: Non-restorative low anterior resection (NRLAR) may result in inferior oncological outcomes compared to restorative low anterior resection (RLAR) and abdominoperineal resection (APR). While NRLAR is often performed when poor functional or technical challenges are anticipated, comprehensive data on its oncological outcomes remain [...] Read more.

Background: Non-restorative low anterior resection (NRLAR) may result in inferior oncological outcomes compared to restorative low anterior resection (RLAR) and abdominoperineal resection (APR). While NRLAR is often performed when poor functional or technical challenges are anticipated, comprehensive data on its oncological outcomes remain scarce. This study aimed to retrospectively evaluate the intermediate-term oncological outcomes of patients—who underwent RLAR, NRLAR, or APR for primary rectal cancer. Methods: This analysis included all elective NRLAR, RLAR, and APR procedures for primary rectal carcinoma performed across 11 Dutch centers from 2013 to 2020. The primary outcome was 3-year disease-free survival (DFS). Secondary outcomes included 3-year overall survival (OS) and 3-year local recurrence (LR). KaplanMeier survival analysis with log-rank testing and multivariate Cox regression analysis were employed. Results: A total of 253 (12.5%) patients underwent NRLAR, 1109 (55.0%) RLAR, and 656 (32.5%) APR. NRLAR was associated with a lower 3-year DFS (71.4%) versus RLAR (82.0%) and APR (77.4%) (p = 0.003). The 3-year OS was lower for NRLAR (82.9%) versus RLAR (93.5%) and APR (90.2%) (p < 0.001), with a higher 3-year LR rate for NRLAR (8.1%) versus RLAR (3.3%) and APR (4.5%) (p = 0.003). Multivariate Cox regression analyses confirmed NRLAR as an independent predictor for poorer DFS (HR 1.34; 95% CI: 1.01–1.80; p = 0.046), OS (HR 1.57; 95% CI: 1.04–2.36, p = 0.032), and higher LR risk (HR 2.66; 95% CI: 1.53–4.65; p <= 0.001). Conclusions: NRLAR is associated with poorer intermediate-term oncological outcomes. When technically feasible, restorative options should be considered, and prospective studies are required to further investigate causal relationships. Full article

(This article belongs to the Special Issue Surgery for Colorectal Cancer)

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18 pages, 2221 KB

Open AccessArticle

Older Age Does Not Predict Inadequate Pain Management in Cancer Patients: A Multicenter Prospective Analysis from Italian Radiotherapy Departments (ARISE-Study)

by Costanza M. Donati, Erika Galietta, Francesco Cellini, Arina A. Zamfir, Alessia Di Rito, Maurizio Portaluri, Anna Santacaterina, Filippo Mammini, Rossella Di Franco, Salvatore Parisi, Antonella Bianculli, Pierpaolo Ziccarelli, Luigi Ziccarelli, Domenico Genovesi, Luciana Caravatta, Francesco Deodato, Gabriella Macchia, Francesco Fiorica, Silvia Cammelli, Milly Buwenge, Lucia Angelini, Romina Rossi, Marco C. Maltoni, Nam P. Nguyen, Alessio G. Morganti and Savino Cilla Show full author list Hide full author list

Cancers 2025, 17(18), 3073; https://doi.org/10.3390/cancers17183073 - 19 Sep 2025

Viewed by 294

Abstract

Background: Previous studies have often reported a link between advanced age and inadequate cancer pain management. Given Italy’s demographic profile as the country with the oldest population in Europe, it offers an ideal setting to explore whether this association remains valid today. Aim: [...] Read more.

Background: Previous studies have often reported a link between advanced age and inadequate cancer pain management. Given Italy’s demographic profile as the country with the oldest population in Europe, it offers an ideal setting to explore whether this association remains valid today. Aim: This study aimed primarily to assess the influence of advanced age on the adequacy of pain management among patients receiving treatment in Italian radiotherapy (RT) departments, and secondarily, to identify age-specific determinants of analgesic undertreatment. Methods: In this prospective, multicenter study, we enrolled 2104 consecutive patients attending 13 RT centers between October and November 2019. Pain intensity was evaluated using the numeric rating scale (NRS), and patients reporting scores ≥ 1 (n = 1353) were included in the analysis. Pain management adequacy was assessed using the Pain Management Index (PMI), with negative values indicating undertreatment. A two-step statistical approach was employed: variable selection via Least Absolute Shrinkage and Selection Operator regression, followed by Classification and Regression Tree analysis to identify key predictors. Separate analyses were performed for the overall population, older adults (≥65 years), and younger adults (18–64 years). Results: Overall, 42% of patients were undertreated (PMI < 0), without significant differences between older (41.0%) and younger patients (43.1%). However, factors contributing to undertreatment varied according to age. For the entire cohort, non-cancer pain was associated with substantially higher rates of undertreatment (74.3%) compared to cancer-related pain (34.2%). Among cancer patients, those receiving curative RT had poorer pain control (49.4%) than those receiving palliative RT (28.8%). In older patients, geographic location strongly influenced pain management, with higher rates of undertreatment in central and southern Italy compared to the north (e.g., palliative RT: 64.0% vs. 15.4%, respectively). Conversely, younger patients showed no geographical differences; instead, timing of assessment (beginning vs. end of RT) influenced outcomes, with improved PMI values towards the end of treatment. Conclusions: Unlike previous studies, advanced age itself was not associated with inadequate analgesia. However, the determinants of inadequate pain management differed significantly by age: geographic disparities were predominant among older patients, while assessment timing influenced outcomes for younger patients. Further longitudinal research and targeted interventions are needed to address these age-dependent challenges. Full article

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

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18 pages, 551 KB

Open AccessReview

Histotripsy: Recent Advances, Clinical Applications, and Future Prospects

by Mustaqueem Pallumeera, Marcus Hong, Jonathan C Giang and Mina S Makary

Cancers 2025, 17(18), 3072; https://doi.org/10.3390/cancers17183072 - 19 Sep 2025

Viewed by 963

Abstract

Histotripsy is a novel, non-invasive ultrasound-based ablative therapy that destroys tissue through focused cavitation. As solid tumors continue to be a major global health burden, there is interest in image-guided ablation techniques that reduce collateral damage and promote immune activation. This narrative review [...] Read more.

Histotripsy is a novel, non-invasive ultrasound-based ablative therapy that destroys tissue through focused cavitation. As solid tumors continue to be a major global health burden, there is interest in image-guided ablation techniques that reduce collateral damage and promote immune activation. This narrative review aims to synthesize current advancements, clinical applications, limitations, and future directions of histotripsy in both oncologic and non-oncologic contexts. A comprehensive literature search was conducted from database inception to July 2025. Search terms included combinations of subject headings and keywords such as “histotripsy,” “mechanical ablation,” “ultrasound,” and “solid tumors.” Boolean operators and truncation were used to increase sensitivity. Peer-reviewed studies were included, encompassing preclinical, clinical, and review articles. Reference lists of relevant articles were examined to identify additional sources. Histotripsy has shown strong potential in the treatment of tumors involving the liver, pancreas, kidney, brain, and cardiovascular system. It offers real-time imaging guidance, sharp lesion boundaries, and minimal damage to surrounding structures. Early clinical trials have demonstrated encouraging safety and efficacy, particularly in liver and kidney tumors. Its ability to preserve critical anatomy and stimulate innate and adaptive immune responses through the release of cellular debris and cytokines offers advantages over thermal ablation. Limitations include acoustic aberration, motion-related targeting challenges, and the need for further long-term clinical data. Histotripsy represents a promising advancement in noninvasive tumor ablation. Continued clinical investigation and technological refinement are necessary to validate its therapeutic value and define its role within comprehensive cancer care. Full article

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

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11 pages, 230 KB

Open AccessArticle

Factors Associated with the Detection of Actionable Genomic Alterations Using Liquid Biopsy in Biliary Tract Cancer

by Hiroshi Shimizu, Rei Suzuki, Hiroyuki Asama, Kentaro Sato, Kento Osawa, Rei Ohira, Keisuke Kudo, Mitsuru Sugimoto and Hiromasa Ohira

Cancers 2025, 17(18), 3071; https://doi.org/10.3390/cancers17183071 - 19 Sep 2025

Viewed by 331

Abstract

Background: Blood-based comprehensive genomic profiling (CGP), a form of liquid biopsy, is often used for biliary tract cancer (BTC) when tissue-based CGP (tissue CGP) is unavailable, despite lower detection rates. This study explored factors linked to detecting actionable genomic alterations to optimize [...] Read more.

Background: Blood-based comprehensive genomic profiling (CGP), a form of liquid biopsy, is often used for biliary tract cancer (BTC) when tissue-based CGP (tissue CGP) is unavailable, despite lower detection rates. This study explored factors linked to detecting actionable genomic alterations to optimize its use. Methods: We retrospectively analyzed BTC cases in Japan’s C-CAT (June 2019–January 2025), restricting panel comparisons to FoundationOne^® CDx (F1; n = 5019) and FoundationOne^® Liquid CDx (F1L; n = 1550). Missing covariates were handled by multiple imputations (m = 20). Between-panel balance used 1:1 propensity-score matching (caliper 0.2). Outcomes were modeled with logistic regression. Targets included MSI-H, TMB-H, FGFR2/RET/NTRK fusions, BRAF V600E, KRAS G12C, IDH1 mutations, and ERBB2 amplification. An exploratory analysis stratified results by the number of prespecified enrichment factors (0–4). Liquid biopsy was performed using plasma-based comprehensive genomic profiling assays (FoundationOne^® Liquid). Results: Missingness was low; after matching (n = 1549 per group) covariates were well balanced (all|SMD|≤0.05). Detection of any actionable alteration was lower with F1L than F1 (16.8% vs. 24.8%; OR 0.61, 95% CI 0.49–0.75; p < 0.001). F1L also had lower TMB-H (OR 0.62, 0.43–0.90; p = 0.01) and ERBB2 amplification (OR 0.42, 0.31–0.57; p < 0.001), with no significant differences for MSI-H, IDH1, KRAS G12C, or BRAF V600E. Within F1L, non-perihilar location (OR 2.05), liver (1.90), lymph-node (1.41), and lung metastases (1.52) predicted detection of actionable genomic alterations. F1L detection increased from 5.8% (zero factors) to 32.8% (four factors), approximating tissue at three factors. Conclusions: The utility of liquid biopsy can be maximized by carefully selecting samples on the basis of conditions that increase the detection rate. Full article

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

16 pages, 2368 KB

Open AccessArticle

Peptide Receptor Radionuclide Therapy (PRRT) Using Actinium-225- and Ac-225/Lutetium-177-Labeled (TANDEM) Somatostatin Receptor Antagonist DOTA-LM3 in Patients with Neuroendocrine Neoplasm: A Retrospective Study Concerning Safety and Survival

by Elisabetta Perrone, Maria Lucia Calcagni, Lucia Leccisotti, Roberto Moretti, Kriti Ghai, Aleksandr Eismant, Tanay Parkar, Lukas Greifenstein and Richard Paul Baum

Cancers 2025, 17(18), 3070; https://doi.org/10.3390/cancers17183070 - 19 Sep 2025

Viewed by 784

Abstract

Peptide Receptor Radionuclide Therapy (PRRT) offers radiomolecular precision medicine for somatostatin receptor (SSTR)-positive advanced neuroendocrine neoplasms (NEN). In cases resistant to Lutetium-177-labeled DOTATATE or DOTATOC PRRT, alpha-therapy with Actinium-225 labeled with SSTR antagonists like DOTA-LM3 can be a notable therapeutic option. This retrospective [...] Read more.

Peptide Receptor Radionuclide Therapy (PRRT) offers radiomolecular precision medicine for somatostatin receptor (SSTR)-positive advanced neuroendocrine neoplasms (NEN). In cases resistant to Lutetium-177-labeled DOTATATE or DOTATOC PRRT, alpha-therapy with Actinium-225 labeled with SSTR antagonists like DOTA-LM3 can be a notable therapeutic option. This retrospective study aimed to assess [²²⁵Ac]Ac-DOTA-LM3 safety in advanced NEN patients (as monotherapy and with Lutetium-177 as TANDEM), survival, and follow-up duration. Thirty-five patients received a total of 57 [²²⁵Ac]Ac-DOTA-LM3 cycles (March 2022–September 2024): 24 monotherapies and 33 TANDEM therapies. The pancreas was the most common primary site (n = 19). PRRT-related toxicity was assessed, focusing on hematological, renal, and hepatic toxicity (Common Terminology Criteria for Adverse Events—CTCAE v5.0). Therapy was generally well tolerated, with mostly mild acute adverse events (primarily nausea, n = 8). Some new grade 3/4 long-term adverse events were reported after treatment: anemia grade 3 (n = 2), leukocytopenia grade 4 (n = 1), absolute neutrophil count reduction grade 3 (n = 1), thrombocytopenia grade 3 (n = 7), acute myeloid leukemia (n = 1), nephrotoxicity grade 3 (n = 2), and hepatotoxicity grade 3 (n = 2). During follow-up, 13 patients died (survival range 5–30 months); 22 patients were alive (follow-up range 1–18 months). Our retrospective analysis shows that [²²⁵Ac]Ac-DOTA-LM3 PRRT is relatively safe concerning acute and long-term toxicity and bears promising survival outcomes in patients progressing after [¹⁷⁷Lu]Lu-DOTATATE or [¹⁷⁷Lu]Lu-DOTATOC PRRT. Full article

(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments—2nd Edition)

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13 pages, 733 KB

Open AccessArticle

Cure of Recurrent Ovarian Cancer: A Multicenter Retrospective Study

by Masahiro Sumitomo, Yasushi Kotani, Kosuke Murakami, Kaoru Abiko, Kazuko Sakai, Tomoyuki Otani, Akihiko Ueda, Masayo Ukita, Atsuko Taga, Ikuko Emoto, Kentaro Sekiyama, Minami Okudate, Motonori Matsubara, Yukio Yamanishi, Kazuto Nishio, Masaki Mandai and Noriomi Matsumura

Cancers 2025, 17(18), 3069; https://doi.org/10.3390/cancers17183069 - 19 Sep 2025

Viewed by 729

Abstract

Background: The prognosis for recurrent ovarian cancer is poor, but a small percentage of patients can be cured. The aim of this study was to clarify the criteria for being cured and the characteristics of cured cases. Methods: Ovarian cancer cases at 2 [...] Read more.

Background: The prognosis for recurrent ovarian cancer is poor, but a small percentage of patients can be cured. The aim of this study was to clarify the criteria for being cured and the characteristics of cured cases. Methods: Ovarian cancer cases at 2 university hospitals and 8 community hospitals were analyzed to identify patients who were considered cured after complete remission (CR) following recurrence. Analyses of the tumors were performed and included BRCA1/2 mutation analysis. Results: Of the 157 cases of recurrence, 21 (13%) showed no evidence of disease (NED). NED cases had a lower rate of ascites at the initial diagnosis, longer disease-free survival, a higher rate of solitary lesions, and a higher rate of secondary debulking surgery. All CR cases except for one showed no further recurrence when DFS reached 4 years, which was considered a criterion for being cured. The case of relapse occurred after long-term treatment with bevacizumab. Furthermore, 19.4% of the CR cases achieved 4-year DFS, which represents 9.3% of the cases of recurrent ovarian cancer and 2.3% of all cases of ovarian cancer. BRCA mutation analysis of the tumor was possible in 17 of the 30 cases of recurrent ovarian cancer that achieved a 4-year DFS. Pathogenic variants of BRCA were found in 5 of the 11 cases of high-grade serous carcinoma. Conclusions: Approximately 10% of patients with recurrent ovarian cancer achieved a 4-year DFS and were mostly cured. The curing of cases not involving high-grade serous carcinoma (HGSC) was unrelated to the presence of pathogenic BRCA variants. Full article

(This article belongs to the Special Issue Primary and Recurrent Gynecological Cancer: Epidemiology, Management and New Therapies)

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20 pages, 1051 KB

Open AccessReview

Future Directions and Priorities for Cellular Therapy in Sarcoma: A Report from the Strategic Advances in Sarcoma Science Cell Therapy Breakout

by Jacqueline Oliva-Ramirez, David Milewski, Lauren Banks, Kelly M. Bailey, Everett J. Moding, Jessica Lake, Alice Chen, Jessica D. Daley, Erin E. Resch, Rosandra N. Kaplan, Brian H. Ladle, Lindy Zhang, Margaret M. Chou, Rosa Nguyen, Urania Dagalakis, Nourhane Al Akoum, Poul H Sorensen, Jonathan A. Fletcher, Ronald DeMatteo, Nicolas J. Llosa and Seth M. Pollack Show full author list Hide full author list

Cancers 2025, 17(18), 3068; https://doi.org/10.3390/cancers17183068 - 19 Sep 2025

Viewed by 588

Abstract

Background: In September of 2024, the 2nd annual meeting of the Strategic Advances in Sarcoma Science (SASS) convened at the National Institutes of Health. This gathering of national sarcoma experts focused on preclinical studies, clinical trials, opportunities, challenges, and future directions in sarcoma [...] Read more.

Background: In September of 2024, the 2nd annual meeting of the Strategic Advances in Sarcoma Science (SASS) convened at the National Institutes of Health. This gathering of national sarcoma experts focused on preclinical studies, clinical trials, opportunities, challenges, and future directions in sarcoma biology and clinical care with a focus on immunotherapy. The Immunology in Sarcoma breakout group conducted a dedicated discussion focused on the current and future implementation of adoptive cellular therapies (ACTs) in sarcomas. The current manuscript summarizes these discussions and provides a comprehensive resource for researchers and clinicians. Results: Adoptive cell therapy (ACT) has shown encouraging results in sarcomas with afami-cel achieving durable responses in synovial sarcoma and early TCR-T trials against NY-ESO-1 and MAGE-A4 demonstrating meaningful response rates. Building on these outcomes will require discovering new targets, selecting optimal cell types, refining conditioning regimens, combining with alternative treatment strategies such as TKIs, and leveraging predictive biomarkers informed by a deeper understanding of the tumor microenvironment. Conclusions: Sarcomas are promising targets for adoptive cell therapy (ACT), as shown by afami-cel’s success in synovial sarcoma, but broader impact requires new target discovery, optimal cell selection, improved conditioning, combination treatments, deeper tumor microenvironment understanding, and predictive biomarkers to achieve more durable responses for more patients. Full article

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

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13 pages, 959 KB

Open AccessArticle

Alteration of Prognostic Factors for Patients with Brain Metastases from Lung Cancer Before and After the Introduction of Immune Checkpoint Inhibitors: A Retrospective Single-Institution Study

by Yohei Yamamoto, Tomona Maetani, Hiroki Narita, Yurika Terasawa, Naoki Kato, Yasuharu Akasaki, Yuichi Murayama and Toshihide Tanaka

Cancers 2025, 17(18), 3067; https://doi.org/10.3390/cancers17183067 - 19 Sep 2025

Viewed by 338

Abstract

Background/Objectives: Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced lung cancer, but their real-world impact on patients with brain metastases remains insufficiently characterized. This study aimed to compare treatment outcomes before and after the introduction of ICIs and to identify prognostic factors [...] Read more.

Background/Objectives: Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced lung cancer, but their real-world impact on patients with brain metastases remains insufficiently characterized. This study aimed to compare treatment outcomes before and after the introduction of ICIs and to identify prognostic factors in patients with lung cancer brain metastases. Methods: We retrospectively analyzed 186 patients treated for brain metastases from lung cancer at our institution between 2014 and 2023. Patients were classified into a Pre-ICI group (N = 93, 2014–2018) and a Post-ICI group (N = 93, 2019–2023). Overall survival (OS) was analyzed by Kaplan–Meier method and Cox regression. Baseline factors included age, sex, histology, Charlson–Deyo score, extracranial metastases, radiotherapy, systemic therapy, and neutrophil-to-lymphocyte ratio (NLR, cutoff = 4). Results: Median OS improved significantly in the Post-ICI group compared with the Pre-ICI group (10.9 vs. 4.7 months, p < 0.01). When stratified by systemic therapy, median OS was 4.7 months with conventional chemotherapy, 14.7 months with molecular targeted therapy overall, further prolonged to 25.5 months in the Post-ICI era, and 23.4 months for all patients receiving ICIs. The most notable benefits were observed in patients with squamous cell carcinoma and small cell carcinoma. Patients with NLR ≥ 4 showed shorter OS, but NLR did not remain significant in multivariate analysis. In EGFR-mutant adenocarcinoma, the survival benefit from ICIs was limited. Conclusions: ICIs significantly improved survival in patients with lung cancer brain metastases, particularly those with squamous cell carcinoma or small cell carcinoma. NLR may provide supportive prognostic information, while molecular targeted therapy and ICIs represent major drivers of improved survival in this population. Full article

(This article belongs to the Section Cancer Therapy)

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25 pages, 2243 KB

Open AccessSystematic Review

Impact of Endocrine Therapy for Cancer on Periodontal Health: A Systematic Review

by Federica Romano, Francesco Franco, Barbara Mognetti and Giovanni Nicolao Berta

Cancers 2025, 17(18), 3066; https://doi.org/10.3390/cancers17183066 - 19 Sep 2025

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Abstract

Background/Objectives: With the growing number of cancer survivors receiving long-term endocrine therapy, understanding its potential effects on oral and periodontal health is of increasing clinical relevance. This systematic review aimed to synthesize current evidence on the impact of hormone therapies used in [...] Read more.

Background/Objectives: With the growing number of cancer survivors receiving long-term endocrine therapy, understanding its potential effects on oral and periodontal health is of increasing clinical relevance. This systematic review aimed to synthesize current evidence on the impact of hormone therapies used in cancer treatment on periodontal status. Methods: A comprehensive literature search was conducted across the Medline, Web of Science, and Scopus databases to identify observational studies published up to June 2025 that evaluated the effects of endocrine therapy on periodontal parameters and tooth loss in cancer patients. Results: Thirteen studies met the inclusion criteria, twelve involving breast cancer patients and one prostate cancer. Third-generation aromatase inhibitors (AIs) were the most frequently studied agents, either alone or in comparison with tamoxifen. Most studies reported that AI therapy was associated with a higher prevalence of severe periodontitis, increased bleeding on probing and more severe alveolar bone loss compared to healthy controls. In contrast, tamoxifen appeared to have a comparatively milder impact on periodontal health. The single study on prostate cancer patients undergoing androgen deprivation therapy similarly indicated a higher prevalence of periodontitis with respect to controls. Conclusions: These findings suggest a potential link between endocrine therapy and periodontal status deterioration, particularly with AIs. This review highlights an important yet often neglected aspect of survivorship care and emphasizes the need for routine periodontal assessment and interdisciplinary collaboration in the management of patients undergoing hormone therapy for cancer. Full article

(This article belongs to the Section Cancer Therapy)

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9 pages, 863 KB

Open AccessArticle

Brainstem Glioma Prognostication: Static FET PET/CT

by Dávid Gergő Nagy, Júlia Singer and Katalin Borbély

Cancers 2025, 17(18), 3065; https://doi.org/10.3390/cancers17183065 - 19 Sep 2025

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Abstract

Background/Objectives: The classification and staging of brainstem glioma have its own pitfalls. Surgical biopsy is only possible in a small number of cases. Diagnosis relies mainly on radiological features. Any treatment may have a significant impact on quality of life; therefore, the correct [...] Read more.

Background/Objectives: The classification and staging of brainstem glioma have its own pitfalls. Surgical biopsy is only possible in a small number of cases. Diagnosis relies mainly on radiological features. Any treatment may have a significant impact on quality of life; therefore, the correct and early identification of potentially malignant lesions is essential to initiate proper therapy. Amino acid PET/CT with accurate metabolic mapping can help in this decision-making. Methods: We performed a retrospective analysis of 20 patients who underwent static FET PET/CT with uncertain brainstem lesions between November 2019 and April 2023. We used multiple tumor-to-brain ratios (TBR) to assess patient subgroups showing long-term and short-term survival. Results: The maximum Youden index was reached at TBR = 2.9. With this ratio, the estimated sensitivity was at the desired level (91.7%), both positive and negative predictive values are in the good performance range (68.8 and 75.0%), while specificity was lower than expected (37.5%). Conclusions: The prognosis of brainstem glioma remains challenging. The use of static FET PET/CT results in more accurate detection of high-grade lesions. In our analysis, we found a TBR value of 2.9 to be the most appropriate for identifying patients with a poor prognosis. Full article

(This article belongs to the Special Issue PET/CT and Conventional Imaging in Cancers)

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12 pages, 789 KB

Open AccessArticle

Melanoma Clues Beyond Dermoscopic Patterns: Lesion Orientation to Langer’s Lines as a Predictor on the Trunk

by Umberto Santaniello, Francesco Cavallo, Sara Diana, Silvia Giordano, Orsola Crespi, François Rosset, Andrea Agostini, Giovenale Moirano, Paolo Fava, Pietro Quaglino, Simone Ribero and Paolo Broganelli

Cancers 2025, 17(18), 3064; https://doi.org/10.3390/cancers17183064 - 19 Sep 2025

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Abstract

Background/Objectives: The diagnosis of melanocytic lesions on the trunk is challenging due to a high frequency of atypical features in benign nevi, leading to a high rate of unnecessary excisions. This study aimed to identify robust dermoscopic predictors of cutaneous melanoma on the [...] Read more.

Background/Objectives: The diagnosis of melanocytic lesions on the trunk is challenging due to a high frequency of atypical features in benign nevi, leading to a high rate of unnecessary excisions. This study aimed to identify robust dermoscopic predictors of cutaneous melanoma on the trunk and to evaluate a novel diagnostic criterion: the orientation of lesions relative to Langer’s skin tension lines. Methods: We conducted a retrospective analysis of 321 melanocytic lesions (227 nevi and 94 melanomas) excised from the trunk. Dermoscopic features were systematically evaluated. A chi-square test and an age- and sex-adjusted multivariate logistic regression were performed to calculate odds ratios (OR) and identify independent predictors of malignancy. A subgroup analysis was also conducted on “critical” versus “non-critical” anatomical sites. Results: Non-adherence to Langer’s lines was the most powerful predictor of melanoma (OR 5.55, 95% CI 3.22–9.81; p < 0.001). Other significant predictors included blue-white veil (OR 5.09) and polymorphous vessels (OR 4.06). Notably, 70% of melanomas did not align with Langer’s lines, whereas 72% of nevi did. Classic features such as scar-like regression were not statistically significant predictors in this cohort. In the subgroup analysis, color asymmetry was a significant predictor of melanoma only in non-critical sites (p for interaction = 0.026). Conclusions: The orientation of a melanocytic lesion relative to Langer’s lines is a powerful and independent predictor of melanoma on the trunk. This simple morphological feature, which may reflect differences in growth patterns between malignant and benign lesions, could serve as an additional clinical cue to support decision-making and improve diagnostic accuracy in this challenging anatomical location. Full article

(This article belongs to the Special Issue Dermoscopy in Skin Cancer)

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11 pages, 674 KB

Open AccessArticle

Impact of Body Composition Changes on Treatment-Related Toxicities and Clinical Outcomes in HER2-Positive Metastatic Breast Cancer Patients Receiving Trastuzumab Deruxtecan

by Alessio Molfino, Giovanni Imbimbo, Simona Pisegna, Simone Scagnoli, Claudia Alabiso, Massimiliano Ardovino, Carmen Gallicchio, Veronica Rizzo and Andrea Botticelli

Cancers 2025, 17(18), 3063; https://doi.org/10.3390/cancers17183063 - 19 Sep 2025

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Abstract

Background/Objectives: Breast cancer remains a significant global health concern, with HER2-positive metastatic breast cancer continuing to present persistent challenges despite advancements in targeted therapies, including trastuzumab deruxtecan (T-DXd). This study aimed to verify the impact of body composition changes on treatment-related toxicities, dose [...] Read more.

Background/Objectives: Breast cancer remains a significant global health concern, with HER2-positive metastatic breast cancer continuing to present persistent challenges despite advancements in targeted therapies, including trastuzumab deruxtecan (T-DXd). This study aimed to verify the impact of body composition changes on treatment-related toxicities, dose modifications, and clinical outcomes in patients receiving T-DXd. Methods: A retrospective analysis on 35 patients with HER2-positive metastatic breast cancer was conducted, analyzing body composition parameters such as subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscle area (SMA), and skeletal muscle index (SMI)—assessed using CT scans at baseline (T0) and after a median follow-up of 4 months (T1)—and calculating ΔT0–T1% of each parameter. Results: Significant reductions over time were observed in SAT (mean ΔSAT% = −5.7%, p = 0.023) and SMA (mean ΔSMA% = −4.9%, p = 0.001). Treatment-related adverse events (AEs) were common, with 31% of patients experiencing severe (Grade 3–4) toxicities. Patients with higher ΔSAT% (above the median value) experienced Grade 3–4 toxicities more frequently compared to those with lower ΔSAT% (below the median) (p < 0.05). Among patients without toxicities, a significant decrease in SAT was observed between T0 and T1 (p = 0.003), while no significant change was detected in patients with Grade 3–4 toxicities (p = 0.929). Greater reductions in SMA were associated with increased rates of treatment discontinuation (75% vs. 29%, p = 0.009). Kaplan–Meier analysis confirmed that greater reductions in SMA significantly increased the risk of mortality (HR 5.1, 95% CI: 1.05–24.79; p = 0.025) and showed a trend toward higher risk of disease progression (HR 2.58, 95% CI: 0.89–7.49; p = 0.063). Conclusions: Changes in body composition, particularly reductions in SMA, were associated with increased treatment discontinuation and mortality in HER2-positive metastatic breast cancer receiving T-DXd. Increase in SAT was associated with higher rates of severe toxicities, highlighting its potential role in predicting treatment-related complications, and the clinical relevance of nutritional changes on outcomes in this setting. Full article

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

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Cancers, Volume 17, Issue 18 (September-2 2025) – 152 articles

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