Cancers

16 pages, 3119 KiB

Open AccessArticle

Synergistic Effects of Cryotherapy and Radiotherapy in Glioblastoma Treatment: Evidence from a Murine Model

by Hélène Cebula, Chrystelle Po, Carole Mura, Benoit Lhermitte, Roberto Luigi Cazzato, Marion Rame, Clara Le Fèvre, Julien Todeschi, Charles-Henry Mallereau, Afshin Gangi, Georges Noël, Michel de Mathelin, François Proust and Hélène Burckel

Cancers 2025, 17(10), 1692; https://doi.org/10.3390/cancers17101692 (registering DOI) - 17 May 2025

Abstract

Background/Objectives: Cryotherapy involves the insertion of cryoprobes into tumors to induce cell destruction through exposure to extremely low temperatures over several minutes. This localized treatment modality may enhance the efficacy of established therapies, such as radiotherapy, particularly for glioblastomas. Our study aimed to [...] Read more.

Background/Objectives: Cryotherapy involves the insertion of cryoprobes into tumors to induce cell destruction through exposure to extremely low temperatures over several minutes. This localized treatment modality may enhance the efficacy of established therapies, such as radiotherapy, particularly for glioblastomas. Our study aimed to provide proof-of-concept for the efficacy of combining cryotherapy and radiotherapy in the treatment of subcutaneous murine brain tumors (GL-261) in immunocompetent C57BL/6 mice. Methods: Tumor growth, survival and response were evaluated using MRI and histological analysis. Results: Partial cryotherapy alone showed no therapeutic efficacy. However, combining cryotherapy with radiotherapy significantly potentiated treatment outcomes. A statistically significant survival benefit was observed in the combined therapy group compared to control, cryotherapy and radiotherapy groups. Notably, 40% of mice receiving the combined treatment exhibited complete responses, with no detectable tumor cells on MRI or histological analysis. Furthermore, MRI-based monitoring revealed that the Apparent Diffusion Coefficient (ADC) map could predict complete response 14 days post-treatment, unlike caliper-based measurements. Conclusions: These findings suggest that cryotherapy may enhance radiotherapy efficacy, resulting in complete tumor regression in 4 out of 10 cases. ADC distribution may serve as a predictive marker for therapeutic response. However, given the limitations of the model, further studies in orthotopic models are needed to validate these findings and assess their clinical relevance. Full article

(This article belongs to the Special Issue Combination Therapies for Brain Tumors)

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39 pages, 1722 KiB

Open AccessReview

Interleukin-6 Is a Crucial Factor in Shaping the Inflammatory Tumor Microenvironment in Ovarian Cancer and Determining Its Hot or Cold Nature with Diagnostic and Prognostic Utilities

by Hina Amer, Katie L. Flanagan, Nirmala C. Kampan, Catherine Itsiopoulos, Clare L. Scott, Apriliana E. R. Kartikasari and Magdalena Plebanski

Cancers 2025, 17(10), 1691; https://doi.org/10.3390/cancers17101691 (registering DOI) - 17 May 2025

Abstract

Ovarian cancer (OC) remains the leading cause of cancer-related deaths among women, often diagnosed at advanced stages due to the lack of effective early diagnostic procedures. To reduce the high mortality rates in OC, reliable biomarkers are urgently needed, especially to detect OC [...] Read more.

Ovarian cancer (OC) remains the leading cause of cancer-related deaths among women, often diagnosed at advanced stages due to the lack of effective early diagnostic procedures. To reduce the high mortality rates in OC, reliable biomarkers are urgently needed, especially to detect OC at its earliest stage, predict specific drug responses, and monitor patients. The cytokine interleukin-6 (IL6) is associated with low survival rates, treatment resistance, and recurrence. In this review, we summarize the role of IL6 in inflammation and how IL6 contributes to ovarian tumorigenesis within the tumor microenvironment, influencing whether the tumor is subsequently classified as “hot” or “cold”. We further dissect the molecular and cellular mechanisms through which IL6 production and downstream signaling are regulated, to enhance our understanding of its involvement in OC development, as well as OC resistance to treatment. We highlight the potential of IL6 to be used as a reliable diagnostic biomarker to help detect OC at its earliest stage, and as a part of predictive and prognostic signatures to improve OC management. We further discuss ways to leverage artificial intelligence and machine learning to integrate IL6 into diverse biomarker-based strategies. Full article

(This article belongs to the Special Issue Current and Emerging Utility of Liquid Biopsy in Cancers: More than Surrogate Biomarkers (2nd Edition))

11 pages, 1207 KiB

Open AccessArticle

A Preoperative Diagnostic Nomogram to Predict Tumor Subclassifications of Intrahepatic Cholangiocarcinoma

by Mizuki Yoshida, Masahiko Kinoshita, Yuta Nonomiya, Ryota Kawai, Ayumi Shintani, Yasunori Sato, Takahito Kawaguchi, Ryota Tanaka, Shigeaki Kurihara, Kohei Nishio, Hiroji Shinkawa, Kenjiro Kimura, Akira Yamamoto, Shoji Kubo and Takeaki Ishizawa

Cancers 2025, 17(10), 1690; https://doi.org/10.3390/cancers17101690 (registering DOI) - 17 May 2025

Abstract

Background/Objectives: Intrahepatic cholangiocarcinoma (ICC) is subclassified into small and large duct types. Although these subclassifications may help determine the appropriate treatment strategy, subclassification diagnosis currently depends on postoperative pathological examinations. This study aimed to establish a nomogram to predict ICC subclassifications. Methods: This [...] Read more.

Background/Objectives: Intrahepatic cholangiocarcinoma (ICC) is subclassified into small and large duct types. Although these subclassifications may help determine the appropriate treatment strategy, subclassification diagnosis currently depends on postoperative pathological examinations. This study aimed to establish a nomogram to predict ICC subclassifications. Methods: This study included 126 patients with ICC who underwent liver resection. The participants were divided into small and large duct-type ICC groups. A nomogram to predict large duct-type ICC was developed using four diagnostic imaging findings: rim-type enhancement in the early phase, an absence of tumor enhancement in the early phase, the presence of peripheral biliary dilatation due to tumor invasion, the presence of penetrating Glisson’s vessels in the tumor, and two laboratory test results: serum gamma-glutamyl transpeptidase and carbohydrate antigen 19-9 levels. Nomogram performance was also assessed. Moreover, the bootstrap method and calibration plots were used to assess nomogram validity. Results: Seventy and fifty-six patients were pathologically diagnosed with small and large duct-type ICCs, respectively. The area under the curve of the established nomogram was 0.93 and remained 0.91 after Harrell’s bias correction. The sensitivity and specificity of the nomogram developed using the Youden index were higher than those of any of the characteristic imaging findings. Calibration plots demonstrated a strong association between the nomogram and the actual data. Conclusions: We developed a novel preoperative nomogram to predict large duct-type ICC. This nomogram can be clinically useful for predicting the subclassifications of ICCs and may contribute to the establishment of a more appropriate treatment strategy for ICC. Full article

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

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35 pages, 5451 KiB

Open AccessReview

Innate Immunity and Platelets: Unveiling Their Role in Chronic Pancreatitis and Pancreatic Cancer

by Juliane Blümke, Moritz Schameitat, Atul Verma, Celina Limbecker, Elise Arlt, Sonja M. Kessler, Heike Kielstein, Sebastian Krug, Ivonne Bazwinsky-Wutschke and Monika Haemmerle

Cancers 2025, 17(10), 1689; https://doi.org/10.3390/cancers17101689 (registering DOI) - 17 May 2025

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, characterized by a highly desmoplastic tumor microenvironment. One main risk factor is chronic pancreatitis (CP). Progression of CP to PDAC is greatly influenced by persistent inflammation promoting genomic [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, characterized by a highly desmoplastic tumor microenvironment. One main risk factor is chronic pancreatitis (CP). Progression of CP to PDAC is greatly influenced by persistent inflammation promoting genomic instability, acinar–ductal metaplasia, and pancreatic intraepithelial neoplasia (PanIN) formation. Components of the extracellular matrix, including immune cells, can modulate this progression phase. This includes cells of the innate immune system, such as natural killer (NK) cells, macrophages, dendritic cells, mast cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), either promoting or inhibiting tumor growth. On one hand, innate immune cells can trigger inflammatory responses that support tumor progression by releasing cytokines and growth factors, fostering tumor cell proliferation, invasion, and metastasis. On the other hand, they can also activate immune surveillance mechanisms, which can limit tumor development. For example, NK cells are cytotoxic innate lymphoid cells that are able to kill tumor cells, and active dendritic cells are crucial for a functioning anti-tumor immune response. In contrast, mast cells and MDSCs rather support a pro-tumorigenic tumor microenvironment that is additionally sustained by platelets. Once thought to play a role in hemostasis only, platelets are now recognized as key players in inflammation and cancer progression. By releasing cytokines, growth factors, and pro-angiogenic mediators, platelets help shape an immunosuppressive microenvironment that promotes fibrotic remodeling, tumor initiation, progression, metastasis, and immune evasion. Neutrophils and macrophages exist in different functional subtypes that can both act pro- and anti-tumorigenic. Understanding the complex interactions between innate immune cells, platelets, and early precursor lesions, as well as PDAC cells, is crucial for developing new therapeutic approaches that can harness the immune and potentially also the coagulation system to target and eliminate tumors, offering hope for improved patient outcomes. Full article

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

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20 pages, 2736 KiB

Open AccessArticle

Clinical Validation and Post-Implementation Performance Monitoring of a Neural Network-Assisted Approach for Detecting Chronic Lymphocytic Leukemia Minimal Residual Disease by Flow Cytometry

by Jansen N. Seheult, Gregory E. Otteson, Matthew J. Weybright, Michael M. Timm, Wenchao Han, Dragan Jevremovic, Pedro Horna, Horatiu Olteanu and Min Shi

Cancers 2025, 17(10), 1688; https://doi.org/10.3390/cancers17101688 (registering DOI) - 17 May 2025

Abstract

Background: Flow cytometric detection of minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL) is complex, time-consuming, and subject to inter-operator variability. Deep neural networks (DNNs) offer potential for standardization and efficiency improvement, but require rigorous validation and monitoring for safe clinical [...] Read more.

Background: Flow cytometric detection of minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL) is complex, time-consuming, and subject to inter-operator variability. Deep neural networks (DNNs) offer potential for standardization and efficiency improvement, but require rigorous validation and monitoring for safe clinical implementation. Methods: We evaluated a DNN-assisted human-in-the-loop approach for CLL MRD detection. Initial validation included method comparison against manual analysis (n = 240), precision studies, and analytical sensitivity verification. Post-implementation monitoring comprised four components: daily electronic quality control, input data drift detection, error analysis, and attribute acceptance sampling. Laboratory efficiency was assessed through a timing study of 161 cases analyzed by five technologists. Results: Method comparison demonstrated 97.5% concordance with manual analysis for qualitative classification (sensitivity 100%, specificity 95%) and excellent correlation for quantitative assessment (r = 0.99, Deming slope = 0.99). Precision studies confirmed high repeatability and within-laboratory precision across multiple operators. Analytical sensitivity was verified at 0.002% MRD. Post-implementation monitoring identified 2.97% of cases (26/874) with input data drift, primarily high-burden CLL and non-CLL neoplasms. Error analysis showed the DNN alone achieved 97% sensitivity compared to human-in-the-loop-reviewed results, with 13 missed cases (1.5%) showing atypical immunophenotypes. Attribute acceptance sampling confirmed 98.8% of reported negative cases were true negatives. The DNN-assisted workflow reduced average analysis time by 60.3% compared to manual analysis (4.2 ± 2.3 vs. 10.5 ± 5.8 min). Conclusions: The implementation of a DNN-assisted approach for CLL MRD detection in a clinical laboratory provides diagnostic performance equivalent to expert manual analysis while substantially reducing analysis time. Comprehensive performance monitoring ensures ongoing safety and effectiveness in routine clinical practice. This approach provides a model for responsible AI integration in clinical laboratories, balancing automation benefits with expert oversight. Full article

(This article belongs to the Special Issue AI-Driven Oncology: Advancing Cancer Detection, Diagnosis, and Personalized Treatment)

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11 pages, 229 KiB

Open AccessArticle

Occurrence of Malignancies Other than Breast and Ovarian Cancer in Female Carriers of a BRCA1/2 Germline Pathogenic Variant

by Annechien Stuursma, Bert van der Vegt, Lieke P. V. Berger, Maaike B. C. ten Hoor, Jan C. Oosterwijk, Marian J. E. Mourits and Geertruida H. de Bock

Cancers 2025, 17(10), 1687; https://doi.org/10.3390/cancers17101687 (registering DOI) - 17 May 2025

Abstract

Introduction: Previous studies have suggested an additional increased risk for types of malignancies other than breast and ovarian cancer for female BRCA1/2 GPV carriers, but risk estimates vary widely. The aim of this study was to investigate if female BRCA1/2 GPV carriers have [...] Read more.

Introduction: Previous studies have suggested an additional increased risk for types of malignancies other than breast and ovarian cancer for female BRCA1/2 GPV carriers, but risk estimates vary widely. The aim of this study was to investigate if female BRCA1/2 GPV carriers have an increased risk of malignancies other than breast and tubal/ovarian cancer at an early age. Methods: Prospectively collected data from female BRCA1/2 GPV carriers in our hospital-based data/biobank were linked to the PALGA Dutch Pathology Database. Incidences of malignancies occurring before 60 years of age were compared to crude rates/100.000 person-years in the Netherlands, stratified by age and calendar time. Standardized incidence ratios (SIRs) were calculated with 95% confidence intervals (95%CIs). Results: In 1347 women, 82 malignancies other than breast and tubal/ovarian cancer were detected in patients under 60 years of age in 37,068 person-years. An increased risk of cancer in general (SIR:2.25, 95%CI:1.78–2.80, p < 0.001), head and neck cancer (SIR:3.17, 95%CI:1.03–7.39, p < 0.05), gastrointestinal cancer (SIR:1.96, 95%CI:1.14–3.13, p < 0.05), and female genital cancer (SIR:2.48, 95%CI:1.61–3.65, p < 0.001) was found. Conclusions: If confirmed in larger, prospective studies that include the role of bias and previous cancer treatment, awareness of the possible increased risks of head and neck, gastrointestinal, and female genital cancer may be used to tailor clinical guidelines for female BRCA1/2 GPV carriers. Full article

(This article belongs to the Special Issue Rare Cancers, Diagnostic Challenges and Personalized Therapeutic Approaches in the 21st Century (2nd Edition))

12 pages, 506 KiB

Open AccessArticle

Revealing New Patterns in Colorectal Cancer Screening with a Focus on a Younger Patient Population

by Lynette Sequeira, Dhananjay Vaidya, Jianqiao Ma, Aarav Bansal, Shanshan Huang, Ashish Nimgaonkar and Ekta Gupta

Cancers 2025, 17(10), 1686; https://doi.org/10.3390/cancers17101686 (registering DOI) - 16 May 2025

Abstract

Colorectal cancer (CRC) continues to impart a significant mortality burden in the United States, with a growing number of cases affecting younger individuals. In this study, we set out to characterize predictors of missed colorectal cancer screening in a general and age-stratified population. [...] Read more.

Colorectal cancer (CRC) continues to impart a significant mortality burden in the United States, with a growing number of cases affecting younger individuals. In this study, we set out to characterize predictors of missed colorectal cancer screening in a general and age-stratified population. Methods: We analyzed a patient population of over 85,000 patients who presented to a large outpatient network in the Baltimore, Maryland area and were due for CRC screening. We analyzed different characteristics, including race, occupation, relationship status, tobacco smoking status, and body mass index, of patients up to date and overdue on their CRC screening. The majority (over 99%) of our patient population was insured. We performed this analysis on the patient population as a whole and as an age-stratified patient population. Results: In our overall patient population, all of the aforementioned characteristics were significantly different between patients up to date and those overdue on CRC screening. Races with the highest up-to-date CRC screening proportion were Pacific Islanders, East Asian, and White patients, while Asian Indian patients had the lowest up-to-date percentage. Non-employed patients (including patients with disabilities and students), single patients, and current or past tobacco smokers were all found to have significantly lower percentages of up-to-date patients as compared to other groups within these categories. BMI was significantly lower in up-to-date patients. In our age-stratified analysis, younger patients had a significantly lower percentage of up-to-date patients. Notably, younger patients had a significantly higher proportion of patients electing for noninvasive screening modalities. Conclusions: These disparities in CRC screening warrant targeted interventions to minimize future risk of heightened mortality in certain patient populations. Full article

(This article belongs to the Special Issue Developments in the Management of Gastrointestinal Malignancies)

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15 pages, 1801 KiB

Open AccessArticle

Breath Insights: Advancing Lung Cancer Early-Stage Detection Through AI Algorithms in Non-Invasive VOC Profiling Trials

by Bernardo S. Raimundo, Pedro M. Leitão, Manuel Vinhas, Maria V. Pires, Laura B. Quintas, Catarina Carvalheiro, Rita Barata, Joana Ip, Ricardo Coelho, Sofia Granadeiro, Tânia S. Simões, João Gonçalves, Renato Baião, Carla Rocha, Sandra Alves, Paulo Fidalgo, Alípio Araújo, Cláudia Matos, Susana Simões, Paula Alves, Patrícia Garrido, Marcos Pantarotto, Luís Carreiro, Rogério Matos, Cristina Bárbara, Jorge Cruz, Nuno Gil, Fernando Luis-Ferreira and Pedro D. Vaz Show full author list Hide full author list

Cancers 2025, 17(10), 1685; https://doi.org/10.3390/cancers17101685 - 16 May 2025

Abstract

Background: Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Effective screening strategies for early diagnosis that could improve disease prognosis are lacking. Non-invasive breath analysis of volatile organic compounds (VOC) is a potential method for earlier LC detection. This study [...] Read more.

Background: Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Effective screening strategies for early diagnosis that could improve disease prognosis are lacking. Non-invasive breath analysis of volatile organic compounds (VOC) is a potential method for earlier LC detection. This study explores the association of VOC profiles with artificial intelligence (AI) to achieve a sensitive, specific, and fast method for LC detection. Patients and methods: Exhaled breath air samples were collected from 123 healthy individuals and 73 LC patients at two clinical sites. The enrolled patients had LC diagnosed with different stages. Breath samples were collected before undergoing any treatment, including surgery, and analyzed using gas chromatography coupled to ion-mobility spectrometry (GC-IMS). AI methods classified the overall chromatographic profiles. Results: GC-IMS is highly sensitive, yielding detailed chromatographic profiles. AI methods ranked the sets of exhaled breath profiles across both groups through training and validation steps, while qualitative information was deliberately not taking part nor influencing the results. The K-nearest neighbor (KNN) algorithm classified the groups with an accuracy of 90% (sensitivity = 87%, specificity = 92%). Narrowing the LC group to those only in early-stage IA, the accuracy was 90% (sensitivity = 90%, specificity = 93%). Conclusions: Evaluation of the global exhaled breath profiles using AI algorithms enabled LC detection and demonstrated that qualitative information may not be required, thus easing the frustration that many studies have experienced so far. The results show that this approach coupled with screening protocols may improve earlier detection of LC and hence its prognosis. Full article

(This article belongs to the Special Issue Screening, Diagnosis and Staging of Lung Cancer)

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16 pages, 7921 KiB

Open AccessArticle

An Activation Likelihood Estimation Meta-Analysis of Voxel-Based Morphometry Studies of Chemotherapy-Related Brain Volume Changes in Breast Cancer

by Sonya Utecht, Horacio Gomez-Acevedo, Jonathan Bona, Ellen van der Plas, Fred Prior and Linda J. Larson-Prior

Cancers 2025, 17(10), 1684; https://doi.org/10.3390/cancers17101684 - 16 May 2025

Abstract

Background/Objectives: Breast cancer chemotherapy patients and survivors face cognitive side effects that are not fully understood. Neuroimaging can provide a unique way to study these effects; however, it can be difficult to recruit large numbers of subjects. Our meta-analysis aims to synthesize volumetric [...] Read more.

Background/Objectives: Breast cancer chemotherapy patients and survivors face cognitive side effects that are not fully understood. Neuroimaging can provide a unique way to study these effects; however, it can be difficult to recruit large numbers of subjects. Our meta-analysis aims to synthesize volumetric neuroimaging data to highlight consistent findings in regional brain volume changes to further advance our understanding of the chemotherapy-related cognitive impairments faced by breast cancer patients and survivors. Methods: An Activation Likelihood Estimation analysis was conducted across the data from eight voxel-based morphometry experiments examining changes in the brains of breast cancer patients and survivors exposed to chemotherapy over time and three voxel-based morphometry experiments comparing chemotherapy-exposed subjects to controls with and without breast cancer. Results: There were consistent volume reductions across the whole brain in both experiment groups. The subjects’ over-time analysis showed peak consistency among the studies in the right inferior frontal gyrus and the left insula. Conclusions: Chemotherapy for non-central nervous system cancers such as breast cancer can cause physical changes throughout the brain that can be quantitatively measured by neuroimaging methodologies and may underlie persistent cognitive deficits in some individuals. Full article

(This article belongs to the Section Cancer Therapy)

11 pages, 398 KiB

Open AccessReview

Impact of Pain Education on Pain Relief in Oncological Patients: A Narrative Review of Systematic Reviews and Meta-Analyses

by Erika Galietta, Costanza M. Donati, Alberto Bazzocchi, Rebecca Sassi, Arina A. Zamfir, Renée Hovenier, Clemens Bos, Nikki Hendriks, Martijn F. Boomsma, Mira Huhtala, Roberto Blanco Sequeiros, Holger Grüll, Simone Ferdinandus, Helena M. Verkooijen and Alessio G. Morganti

Cancers 2025, 17(10), 1683; https://doi.org/10.3390/cancers17101683 - 16 May 2025

Abstract

Pain is a complex and burdensome symptom frequently experienced by oncological patients. Despite increased attention from healthcare providers and novel approaches, pain remains undertreated and prevalent in this patient population. Programs of patient education about pain (pain education, PE) have been proposed as [...] Read more.

Pain is a complex and burdensome symptom frequently experienced by oncological patients. Despite increased attention from healthcare providers and novel approaches, pain remains undertreated and prevalent in this patient population. Programs of patient education about pain (pain education, PE) have been proposed as a potential method to enhance pain management. However, the effectiveness of such programs and their impact on pain relief have shown variable results across studies. In this narrative review, we analyzed existing systematic reviews and meta-analyses on PE in oncological patients. A comprehensive literature search was conducted using PubMed, Scopus, and the Cochrane Library databases, following established guidelines. Studies meeting the selection criteria were selected and analyzed to evaluate the effectiveness of PE interventions. A total of nine publications, comprising six systematic reviews and three meta-analyses, were included. Across various clinical settings (inpatient and outpatient), the impact of pain education (PE) on pain intensity showed considerable variability: some reviews reported significant reductions, while others observed minimal or no effects. In contrast, PE consistently improved patients’ knowledge about pain and adherence to medication. However, the available evidence did not demonstrate significant improvements in quality of life. The observed heterogeneity in the results of pain relief outcomes could be attributed to the various types of pain analyzed and the diversity of clinical settings evaluated. Furthermore, differences in study designs, comprising the inclusion of non-randomized studies, contributed to the variability in findings. It remains unclear whether the effectiveness of PE is solely attributed to the educational content or if the attention provided to patients during the intervention partly explains the effect. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Member)

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11 pages, 221 KiB

Open AccessArticle

Current Indications for Seed-Marked Axillary Lymph Node Dissection in Breast Cancer

by Adolfo Loayza, Elisa Moreno-Palacios, Laura Frías, Ylenia Navarro, Marcos Meléndez, Covadonga Martí, Diego Garrido, Alberto Berjón, Alicia Hernández and José I. Sánchez-Méndez

Cancers 2025, 17(10), 1682; https://doi.org/10.3390/cancers17101682 - 16 May 2025

Abstract

Purpose: Marker placement in a pathological node improves extirpation rates in breast cancer cases with limited axillary involvement. Our goal was to assess the current indications for seed-marked axillary lymph node dissection (SMALND). Methods: We conducted a descriptive observational study, including 93 patients [...] Read more.

Purpose: Marker placement in a pathological node improves extirpation rates in breast cancer cases with limited axillary involvement. Our goal was to assess the current indications for seed-marked axillary lymph node dissection (SMALND). Methods: We conducted a descriptive observational study, including 93 patients with cN1 breast cancer treated between January 2019 and December 2023. Seed placement was performed under ultrasound guidance, days before the procedure. Intraoperative detection was achieved using a probe, and resection was confirmed radiologically. Results: The primary indication was post-neoadjuvant therapy (72 patients: 60 for chemotherapy and 12 for hormone therapy), followed by initial surgery (14) and a single axillary recurrence (8). The extirpation rate of the marked axillary lymph node was 100%. In targeted axillary dissection (TAD), the concordance rate between the sentinel node and the marked axillary node was 85%. In the 12 cases of initial surgery, axillary lymphadenectomy was avoided because the marked node matched the sentinel node and was the only one involved. Conclusions: The use of seeds was proven to be highly useful in axillary surgery, both in cases of negativization following neoadjuvant therapy and in those with low axillary involvement or a single axillary recurrence. Full article

(This article belongs to the Section Cancer Therapy)

25 pages, 3056 KiB

Open AccessArticle

High KYNU Expression Is Associated with Poor Prognosis, KEAP1/STK11 Mutations, and Immunosuppressive Metabolism in Patient-Derived but Not Murine Lung Adenocarcinomas

by Ling Cai, Thomas J. Rogers, Reza Mousavi Jafarabad, Hieu Vu, Chendong Yang, Nicole Novaresi, Ana Galán-Cobo, Luc Girard, Edwin J. Ostrin, Johannes F. Fahrmann, Jiyeon Kim, John V. Heymach, Kathryn A. O’Donnell, Guanghua Xiao, Yang Xie, Ralph J. DeBerardinis and John D. Minna

Cancers 2025, 17(10), 1681; https://doi.org/10.3390/cancers17101681 - 16 May 2025

Abstract

Background/Objectives: We aimed to discover genes with bimodal expression linked to patient outcomes, to reveal underlying oncogenotypes and identify new therapeutic insights in lung adenocarcinoma (LUAD). Methods: We performed meta-analysis to screen LUAD datasets for prognostic genes with bimodal expression patterns. Kynureninase (KYNU), [...] Read more.

Background/Objectives: We aimed to discover genes with bimodal expression linked to patient outcomes, to reveal underlying oncogenotypes and identify new therapeutic insights in lung adenocarcinoma (LUAD). Methods: We performed meta-analysis to screen LUAD datasets for prognostic genes with bimodal expression patterns. Kynureninase (KYNU), a key enzyme in tryptophan catabolism, emerged as a top candidate. We then examined its relationship with LUAD mutations, metabolic alterations, immune microenvironment states, and expression patterns in human and mouse models using bulk and single-cell transcriptomics, metabolomics, and preclinical model datasets. Pan-cancer prognostic associations were also assessed. Results: Model-based clustering of KYNU expression outperformed median-based dichotomization in prognostic accuracy. KYNU was elevated in tumors with KEAP1 and STK11 co-mutations but remained a strong independent prognostic marker. Metabolomic analysis showed that KYNU-high tumors had increased anthranilic acid, a catalytic product, while maintaining stable kynurenine levels, suggesting a compensatory mechanism sustaining immunosuppressive signaling. Single-cell and bulk data showed KYNU expression was cancer cell-intrinsic in immune-cold tumors and myeloid-derived in immune-infiltrated tumors. In murine LUAD models, Kynu expression was predominantly immune-derived and uncoupled from Nrf2/Lkb1 signaling, indicating poor model fidelity. KYNU’s prognostic associations extended across cancer types, with poor outcomes in pancreatic and kidney cancers but favorable outcomes in melanoma, underscoring the need for lineage-specific considerations in therapy development. Conclusions:KYNU is a robust prognostic biomarker and potential immunometabolic target in LUAD, especially in STK11 and KEAP1 co-mutated tumors. Its cancer cell-intrinsic expression and immunosuppressive metabolic phenotype offer translational potential, though species-specific expression patterns pose challenges for preclinical modeling. Full article

(This article belongs to the Special Issue New Advances in Lung Cancer: Diagnosis, Pathophysiology and Emerging Treatments. A Selection of Papers from the 4th Joint Meeting on Lung Cancer of the FHU OncoAge (Nice, France) and the MD Anderson Cancer Center (Houston, TX, USA))

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21 pages, 792 KiB

Open AccessArticle

Developing Cancer Quality of Care Indicators to Quantify the Impact of a Global Destabilization of the Care System (COLLAT-COVID)

by Nathalie Piazzon, Julie Haesebaert, Philippe Michel, Anne Sophie Belmont, Vahan Kepenekian, Gery Lamblin, Charlotte Costentin and Julien Péron

Cancers 2025, 17(10), 1680; https://doi.org/10.3390/cancers17101680 - 16 May 2025

Abstract

Background/Objectives: The COVID-19 pandemic led to significant disruptions in healthcare systems, particularly impacting cancer care through delays in diagnoses and treatments. Quality indicators (QIs) are essential tools for monitoring healthcare performance, yet existing QIs may not be suited for crises. This study aimed [...] Read more.

Background/Objectives: The COVID-19 pandemic led to significant disruptions in healthcare systems, particularly impacting cancer care through delays in diagnoses and treatments. Quality indicators (QIs) are essential tools for monitoring healthcare performance, yet existing QIs may not be suited for crises. This study aimed to develop a set of hospital-based QIs tailored to assess the impact of care reorganization during health crises across four cancer types: breast cancer, hepatocellular carcinoma, gynecological cancers (excluding ovarian cancer), and peritoneal carcinomatosis. Methods: A multidisciplinary steering committee (SC) conducted a five-stage process, including a literature review, indicator selection, content validation via the RAND/UCLA method, final validation by the SC, and a pilot feasibility study. QIs were assessed based on clinical relevance, reproducibility, sensitivity to change, and feasibility. Expert panels evaluated and validated the indicators in two rounds of voting. Results: Among 150 initially identified QIs, 49 were validated: 12 for breast cancer, 11 for hepatocellular carcinoma, 8 for gynecological cancers, and 18 for peritoneal carcinomatosis. Most (92%) were process indicators, covering diagnosis, treatment, and care delays. Two common indicators were identified across all four cancers: multidisciplinary team meeting discussions and psychological support consultations. Conclusions: This study demonstrates the feasibility of developing crisis-responsive QIs to monitor cancer care during health system disruptions. Future work will focus on their real-time implementation, validation in international settings, and integration into healthcare policies to enhance crisis preparedness. Full article

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

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18 pages, 1666 KiB

Open AccessArticle

Multi-Steroid Profiling and Machine Learning Reveal Androgens as Candidate Biomarkers for Endometrial Cancer Diagnosis: A Case-Control Study

by Marija Gjorgoska, Angela E. Taylor, Špela Smrkolj and Tea Lanišnik Rižner

Cancers 2025, 17(10), 1679; https://doi.org/10.3390/cancers17101679 - 16 May 2025

Abstract

Objective: To evaluate the diagnostic and prognostic potential of preoperative serum steroid levels in endometrial cancer (EC) alone and in combination with clinical parameters and biomarkers CA-125 and HE4. Methods: This single-center observational study included 62 patients with EC and 70 controls with [...] Read more.

Objective: To evaluate the diagnostic and prognostic potential of preoperative serum steroid levels in endometrial cancer (EC) alone and in combination with clinical parameters and biomarkers CA-125 and HE4. Methods: This single-center observational study included 62 patients with EC and 70 controls with benign uterine conditions who underwent surgery between June 2012 and February 2020. Preoperative serum levels of classic androgens, 11-oxyandrogens, glucocorticoids and mineralocorticoids were measured using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Machine learning was used to assess their diagnostic and prognostic value alone and combined with clinical parameters and tumor biomarkers. Results: Patients with EC had significantly higher serum levels of classic androgens (androstenedione, testosterone), 11-oxyandrogens (11β-hydroxy-androstenedione, 11β-hydroxy-testosterone) and glucocorticoids (17α-hydroxy-progesterone, 11-deoxycortisol) compared to controls. While individual steroids had limited diagnostic value, a multivariate model including classic androgens, CA-125, HE4, BMI and parity achieved an AUC 0.87, 79.1% sensitivity and 74.7% specificity in distinguishing EC from benign uterine condition. This model outperformed our previously published model based on CA-125, HE4 and BMI (AUC: 0.81, p < 0.0001). Prognostically, HE4 was the strongest marker for lymphovascular space invasion (LVSI) (AUC: 0.79) and deep myometrial invasion (MI) (AUC: 0.71). Among steroids, androstenedione was the most predictive of LVSI (AUC: 0.67), while 11β-hydroxy-testosterone was the strongest predictor of deep MI (AUC: 0.64). Conclusions: Patients with EC exhibit distinct steroid hormone profiles. While steroids alone offer modest diagnostic and prognostic value, integrating them into multivariate models improves diagnostic accuracy. Full article

(This article belongs to the Special Issue Endometrial Cancer Prevention, Early Diagnosis and Treatment: Advances and Challenges)

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21 pages, 3451 KiB

Open AccessReview

Scalp Involvement in Primary Cutaneous Lymphomas—An Update on Clinical Presentation, Diagnostics, and Management

by Karol Kołkowski, Martyna Sławińska, Beata Zagórska, Roman J. Nowicki, Jerzy Jankau and Małgorzata Sokołowska-Wojdyło

Cancers 2025, 17(10), 1678; https://doi.org/10.3390/cancers17101678 - 16 May 2025

Abstract

Primary cutaneous lymphomas (PCLs) constitute a heterogeneous group of rare diseases. Previously, few studies have focused on the aspect of scalp involvement by PCLs. The objective of this study was to analyze the clinical presentation, diagnostic pathways, and treatment methods in patients diagnosed [...] Read more.

Primary cutaneous lymphomas (PCLs) constitute a heterogeneous group of rare diseases. Previously, few studies have focused on the aspect of scalp involvement by PCLs. The objective of this study was to analyze the clinical presentation, diagnostic pathways, and treatment methods in patients diagnosed with scalp PCLs. A comprehensive literature review was conducted using the PubMed database, with the search terms “scalp” AND “cutaneous lymphoma”, “folliculotropic mycosis fungoides” AND “scalp”, “trichoscopy” AND “lymphoma”, and “dermoscopy” AND “scalp” AND “lymphoma.” The search was limited to articles published from database inception to May 2, 2024. Based on the title and abstract analysis, we included articles on PCLs involving the scalp. After a thorough review of the full manuscripts, several were excluded due to irrelevance, the absence of essential clinical data, discrepancies in patient age, gender, and diagnosis, and a lack of information pertinent to scalp PCLs. The literature search identified 1482 patients with scalp involvement in PCLs. Of the total number of cases, 1096 were diagnosed with B-cell PCLs, 384 with T-cell PCLs, and two cases lacked a precise PCL diagnosis. Primary cutaneous follicle center lymphoma was the most frequently reported B-cell PCL of the scalp, while mycosis fungoides was the most common T-cell PCL. Alopecia was observed in 69.0% of the patients analyzed, with the most prevalent form being non-scarring focal alopecia. It is imperative to consider the scalp in patients with PCLs, particularly in light of the knowledge that some lymphomas affecting the scalp exhibit a higher degree of aggressiveness. Full article

(This article belongs to the Section Cancer Metastasis)

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25 pages, 20466 KiB

Open AccessArticle

Exploratory Analysis of Molecular Subtypes in Early-Stage Osteosarcoma: Identifying Resistance and Optimizing Therapy

by Luka Bojic, Mina Peric, Jelena Karanovic, Emilija Milosevic, Natasa Kovacevic Grujicic and Milena Milivojevic

Cancers 2025, 17(10), 1677; https://doi.org/10.3390/cancers17101677 - 16 May 2025

Abstract

Background: Osteosarcoma (OS) is a highly aggressive bone malignancy with limited treatment options and poor prognosis. This exploratory study aimed to identify molecular subtypes of early-stage, treatment-naive OS to guide precise therapeutic strategies. Methods: We analyzed RNA-seq data obtained from tumor tissues from [...] Read more.

Background: Osteosarcoma (OS) is a highly aggressive bone malignancy with limited treatment options and poor prognosis. This exploratory study aimed to identify molecular subtypes of early-stage, treatment-naive OS to guide precise therapeutic strategies. Methods: We analyzed RNA-seq data obtained from tumor tissues from 102 OS patients using a non-negative matrix factorization algorithm (NMF) to classify the tumors into three subtypes: S1, S2, and S3. Differential gene expression was evaluated using DESeq2, followed by functional enrichment analysis with clusterProfiler and CancerHallmarks. The tumor microenvironment was assessed through ESTIMATE and CIBERSORT, and drug sensitivity was predicted using OncoPredict. SAOS-2 and MG63 cells, representing the S1 subtype, were used in the viability essays to determine the effect of hesperidin, a natural phenolic compound noted for its anti-cancer potential, alone and in combination with doxorubicin and 5-fluorouracil. Results: This study revealed three OS subtypes: S1 was enriched in cell cycle regulation, vesicular transport, and RNA metabolism while S2 and S3 were enriched in pathways related to extracellular matrix organization and protein translation, respectively. S1 displayed high tumor purity, significant chemoresistance, and overexpression of KIF20 A, correlating with poor prognosis. AURKB, a hesperidin target, was implicated in S1 pathogenesis. In vitro, hesperidin significantly reduced the viability of SAOS-2 and MG63 cells and enhanced doxorubicin efficacy. Conclusions: Our findings support the molecular subclassification of OS, emphasizing subtype-specific mechanisms of tumor progression and chemoresistance, with hesperidin offering potential as a therapeutic adjunct for high-risk OS patients. Full article

(This article belongs to the Special Issue Challenges and New Developments in the Diagnosis and Treatment of Sarcoma)

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25 pages, 1413 KiB

Open AccessReview

From Genes to Environment: Elucidating Pancreatic Carcinogenesis Through Genetically Engineered and Risk Factor-Integrated Mouse Models

by Bin Yan, Anne-Kristin Fritsche, Erik Haußner, Tanvi Vikrant Inamdar, Helmut Laumen, Michael Beottcher, Martin Gericke, Patrick Michl and Jonas Rosendahl

Cancers 2025, 17(10), 1676; https://doi.org/10.3390/cancers17101676 - 15 May 2025

Abstract

Pancreatic cancer is characterized by late diagnosis, therapy resistance, and poor prognosis, necessitating the exploration of early carcinogenesis and prevention methods. Preclinical mouse models have evolved from cell line-based to human tumor tissue- or organoid-derived xenografts, now to humanized mouse models and genetically [...] Read more.

Pancreatic cancer is characterized by late diagnosis, therapy resistance, and poor prognosis, necessitating the exploration of early carcinogenesis and prevention methods. Preclinical mouse models have evolved from cell line-based to human tumor tissue- or organoid-derived xenografts, now to humanized mouse models and genetically engineered mouse models (GEMMs). GEMMs, primarily driven by oncogenic Kras mutations and tumor suppressor gene alterations, offer a realistic platform for investigating pancreatic cancer initiation, progression, and metastasis. The incorporation of inducible somatic mutations and CRISPR-Cas9 screening methods has expanded their utility. To better recapitulate tumor initiation triggered by inflammatory cues, common pancreatic risk factors are being integrated into model designs. This approach aims to decipher the role of environmental factors as secondary or parallel triggers of tumor initiation alongside oncogenic burdens. Emerging models exploring pancreatitis, obesity, diabetes, and other risk factors offer significant translational potential. This review describes current mouse models for studying pancreatic carcinogenesis, their combination with inflammatory factors, and their utility in evaluating pathogenesis, providing guidance for selecting the most suitable models for pancreatic cancer research. Full article

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

31 pages, 2194 KiB

Open AccessReview

Modelling Cancer Pathophysiology: Mechanisms and Changes in the Extracellular Matrix During Cancer Initiation and Early Tumour Growth

by Luis Larrea Murillo, Megan Green, Niall Mahon, Alberto Saiani and Olga Tsigkou

Cancers 2025, 17(10), 1675; https://doi.org/10.3390/cancers17101675 - 15 May 2025

Abstract

Cancer initiation and early tumour growth are complex processes influenced by multiple cellular and microenvironmental factors. A critical aspect of tumour progression is the dynamic interplay between cancer cells and the extracellular matrix (ECM), which undergoes significant alterations to support malignancy. The loss [...] Read more.

Cancer initiation and early tumour growth are complex processes influenced by multiple cellular and microenvironmental factors. A critical aspect of tumour progression is the dynamic interplay between cancer cells and the extracellular matrix (ECM), which undergoes significant alterations to support malignancy. The loss of cell polarity is an early hallmark of tumour progression, disrupting normal tissue architecture and fostering cancerous transformation. Circumstantially, cancer-associated microRNAs (miRNAs) regulate key oncogenic processes, including ECM remodelling, epithelial-to-mesenchymal transition (EMT), and tumorigenic vascular development, further driving tumour growth. ECM alterations, particularly changes in stiffness and mechanotransduction signals, create a supportive niche for cancer cells, enhancing their survival, proliferation, and invasion. EMT and its subtype, epithelial-to-endothelial transition (EET), contribute to tumour plasticity, promote the generation of cancer stem cells (CSCs), and support tumour vascularisation. Furthermore, processes of vascular development like vasculogenesis and angiogenesis are critical for sustaining early tumour growth, supplying oxygen and nutrients to hypoxic malignant cells within the evolving cancerous microenvironments. This review explores key mechanisms underlying these changes in tumorigenic microenvironments, with an emphasis on their collective role for tumour initiation and early tumour growth. It will further delve into present in vitro modelling strategies developed to closely mimic early cancer pathophysiology. Understanding these processes is crucial for developing targeted therapies aimed at disrupting key cancer-promoting pathways and improving clinical outcomes. Full article

(This article belongs to the Section Cancer Pathophysiology)

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24 pages, 2444 KiB

Open AccessReview

The CXCL1-CXCR2 Axis as a Component of Therapy Resistance, a Source of Side Effects in Cancer Treatment, and a Therapeutic Target

by Jan Korbecki, Mateusz Bosiacki, Maciej Pilarczyk, Marcin Kot, Piotr Defort, Ireneusz Walaszek, Dariusz Chlubek and Irena Baranowska-Bosiacka

Cancers 2025, 17(10), 1674; https://doi.org/10.3390/cancers17101674 - 15 May 2025

Abstract

CXCL1 (Gro-α, MGSA) is a chemokine functionally similar to CXCL8/IL-8, as both activate the same receptor, CXCR2. CXCL1 levels are frequently elevated in tumors compared to healthy tissue, where they play a key role in promoting cancer cell migration, angiogenesis, and neutrophil recruitment. [...] Read more.

CXCL1 (Gro-α, MGSA) is a chemokine functionally similar to CXCL8/IL-8, as both activate the same receptor, CXCR2. CXCL1 levels are frequently elevated in tumors compared to healthy tissue, where they play a key role in promoting cancer cell migration, angiogenesis, and neutrophil recruitment. While the involvement of CXCL1 in tumor progression is well established, its relevance to cancer therapy remains underexplored. This review examines the therapeutic potential of targeting CXCL1 and its receptor, CXCR2, in cancer treatment. It discusses anti-CXCL1 antibodies and CXCR2 antagonists, including AZD5069, SB225002, SCH-479833, navarixin/SCH-527123, ladarixin/DF2156A, and reparixin, as well as strategies to enhance CXCR2 expression in lymphocytes during adoptive cell therapy to improve immunotherapy outcomes. Particular attention is given to the role of CXCL1 in treatment resistance, including resistance to chemotherapy, radiotherapy, and anti-angiogenic therapy. Cancer therapies often upregulate CXCL1 expression, which in turn drives treatment resistance. Additionally, this review explores the contribution of CXCL1 to therapy-induced side effects, such as chemotherapy-induced metastasis, neuropathy, nephrotoxicity, diarrhea, and cardiotoxicity. CXCR2 inhibitors are well tolerated by patients in clinical trials. However, the limited number of studies evaluating these agents in combination with standard chemotherapy precludes any definitive conclusions. Full article

(This article belongs to the Section Cancer Therapy)

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