Cancers

18 pages, 1458 KiB

Open AccessArticle

Effectiveness of First-Line Treatment with Anaplastic Lymphoma Kinase and ROS1 Protoncogene Inhibitors in Non-Small Cell Lung Cancer Patients—Real-World Evidence of Two Polish Cancer Centers

by Michał Gil, Kinga Winiarczyk, Paweł Krawczyk, Kamila Wojas-Krawczyk, Aleksandra Łomża-Łaba, Adrian Obara, Łukasz Gajek, Katarzyna Reszka, Andrzej Tysarowski, Jarosław Buczkowski, Izabela Chmielewska, Tomasz Jankowski, Magdalena Szuba-Gil, Maciej Strzemski, Dariusz M. Kowalski, Janusz Milanowski and Maciej Krzakowski

Cancers 2025, 17(7), 1253; https://doi.org/10.3390/cancers17071253 - 7 Apr 2025

Viewed by 307

Abstract

Introduction: The use of ALK (anaplastic lymphoma kinase) and ROS1 (ROS1 protoncogene) inhibitors are the standard of care in advanced non-small-cell lung cancer (NSCLC) patients with ALK or ROS1 gene rearrangements (approximately 5.5% of patients). Three generations of inhibitors are available, but [...] Read more.

Introduction: The use of ALK (anaplastic lymphoma kinase) and ROS1 (ROS1 protoncogene) inhibitors are the standard of care in advanced non-small-cell lung cancer (NSCLC) patients with ALK or ROS1 gene rearrangements (approximately 5.5% of patients). Three generations of inhibitors are available, but there is no direct comparison of their efficacy in homogeneous Caucasian populations in real-world practice. In this retrospective study, we compare the efficacy of crizotinib, brigatinib, and alectinib in NSCLC patients with different clinical courses of the disease. Materials and Methods: One hundred four NSCLC patients with ALK or ROS1 gene rearrangement were enrolled for first-line therapy with ALK inhibitors (crizotinib in 25 patients, brigatinib in 22 patients, and alectinib in 41 patients) or the ROS1 inhibitor (crizotinib in 16 patients) as part of daily clinical practice in two Polish cancer centers. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared according to treatment methods and clinical data. Results: In ALK-rearranged patients, ORR was insignificantly higher in patients treated with second-generation ALK inhibitors than in patients receiving crizotinib (68.25% vs. 48% of patients, p = 0.0547). Median PFS in the crizotinib group was 8 months, and in the group that received second-generation ALK inhibitors this was not reached (HR = 5.2182, 95% CI: 2.6163–10.4079, p < 0.0001). Similarly, median OS was significantly lower in patients treated with crizotinib than in patients receiving second-generation ALK inhibitors (26 vs. not reached, HR = 3.529, 95% CI: 1.5559–7.2258, p = 0.002). The efficacy of crizotinib in patients with ROS1 and ALK gene rearrangement did not differ significantly (ORR—37.5 vs. 48%, median PFS—6 vs. 7 months, median OS—8 vs. 26 months, respectively). In ALK-rearranged patients, multivariate analysis showed that the only factor significantly increasing the risk of progression was liver metastases (HR = 2.1917, p = 0.0418). The risk of death was significantly higher in patients treated with crizotinib (HR = 2.4823, p = 0.0359) and in patients with liver metastases (HR = 3.1266, p = 0.0104). Conclusions: Second-generation ALK inhibitors are more effective than crizotinib in ALK-rearranged patients. Liver metastases, but not brain metastases, are the main clinical factors shortening PFS and OS in NSCLC patients treated with ALK inhibitors. Full article

(This article belongs to the Special Issue Pathology, Diagnosis and Treatment in Non-small Cell Lung Cancer)

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25 pages, 1167 KiB

Open AccessReview

Optimizing Cancer Treatment Through Gut Microbiome Modulation

by Kyuri Kim, Mingyu Lee, Yoojin Shin, Yoonji Lee and Tae-Jung Kim

Cancers 2025, 17(7), 1252; https://doi.org/10.3390/cancers17071252 - 7 Apr 2025

Viewed by 502

Abstract

The gut microbiome plays a pivotal role in modulating cancer therapies, including immunotherapy and chemotherapy. Emerging evidence demonstrates its influence on treatment efficacy, immune response, and resistance mechanisms. Specific microbial taxa enhance immune checkpoint inhibitor efficacy, while dysbiosis can contribute to adverse outcomes. [...] Read more.

The gut microbiome plays a pivotal role in modulating cancer therapies, including immunotherapy and chemotherapy. Emerging evidence demonstrates its influence on treatment efficacy, immune response, and resistance mechanisms. Specific microbial taxa enhance immune checkpoint inhibitor efficacy, while dysbiosis can contribute to adverse outcomes. Chemotherapy effectiveness is also influenced by microbiome composition, with engineered probiotics and prebiotics offering promising strategies to enhance drug delivery and reduce toxicity. Moreover, microbial metabolites, such as short-chain fatty acids, and engineered microbial systems have shown potential to improve therapeutic responses. These findings underscore the importance of personalized microbiome-based approaches in optimizing cancer treatments. Full article

(This article belongs to the Special Issue Human Microbiome, Diet and Cancerogenesis)

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14 pages, 2404 KiB

Open AccessArticle

Innovative qPCR Algorithm Using Platelet-Derived RNA for High-Specificity and Cost-Effective Ovarian Cancer Detection

by Eunyong Ahn, Se Ik Kim, Sungmin Park, Sarah Kim, Hyunjung Kim, Hyejin Lee, Heeyeon Kim, Eun Ji Song, TaeJin Ahn and Yong-Sang Song

Cancers 2025, 17(7), 1251; https://doi.org/10.3390/cancers17071251 - 7 Apr 2025

Viewed by 607

Abstract

Background/Objectives: Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies, largely due to the challenges of early detection. While next-generation sequencing (NGS) has been explored for screening, its high cost limits large-scale implementation. To develop a more accessible diagnostic solution, [...] Read more.

Background/Objectives: Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies, largely due to the challenges of early detection. While next-generation sequencing (NGS) has been explored for screening, its high cost limits large-scale implementation. To develop a more accessible diagnostic solution, we designed a qPCR-based algorithm optimized for early OC detection, with a focus on high-grade serous ovarian cancer (HGSOC), the most aggressive subtype. Methods: Peripheral blood samples from 19 ovarian cancer patients, 37 benign tumor patients, and 34 asymptomatic controls were analyzed using RNA sequencing to identify splice junction-based biomarkers with minimal expression in benign samples but elevated in OC. Results: A final panel of 10 markers was validated via qPCR, demonstrating strong agreement with sequencing data (R² = 0.44–0.98). The classification algorithm achieved 94.1% sensitivity and 94.4% specificity (AUC = 0.933). Conclusions: By leveraging platelet RNA profiling, this approach offers high specificity, accessibility, and potential for early OC detection. Future studies will focus on expanding histologic diversity and refining biomarker panels to further enhance diagnostic performance. Full article

(This article belongs to the Section Cancer Biomarkers)

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21 pages, 762 KiB

Open AccessReview

Beyond Adaptive Immunity: Trained Innate Immune Responses as a Novel Frontier in Hepatocellular Carcinoma Therapy

by Ching-Hua Hsieh, Pei-Chin Chuang and Yueh-Wei Liu

Cancers 2025, 17(7), 1250; https://doi.org/10.3390/cancers17071250 (registering DOI) - 7 Apr 2025

Viewed by 404

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally, with the majority of cases detected at advanced stages when curative options are limited. Current systemic therapies, including immune checkpoint inhibitors, demonstrate limited efficacy with durable responses in only 15–20% of patients. [...] Read more.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally, with the majority of cases detected at advanced stages when curative options are limited. Current systemic therapies, including immune checkpoint inhibitors, demonstrate limited efficacy with durable responses in only 15–20% of patients. This poor response is largely attributed to HCC’s immunosuppressive microenvironment, which blunts effective T-cell responses. By illustrating that innate immune cells can acquire memory-like characteristics through a process known as trained immunity, recent evidence has challenged the conventional belief that innate immunity is devoid of memory. This review investigates the potential of trained immunity, which is defined by the long-term functional reprogramming of innate immune cells through epigenetic, transcriptomic, and metabolic changes, to provide new therapeutic opportunities for HCC. We discuss mechanisms by which trained immunity can transform the HCC microenvironment, including enhanced inflammatory cytokine production, repolarization of tumor-associated macrophages toward anti-tumor phenotypes, increased immune cell infiltration, and improved bridging to adaptive immunity. We further evaluate emerging therapeutic strategies leveraging trained immunity principles, including BCG vaccination, β-glucan administration, cytokine-trained NK cell therapy, and innovative combination approaches. Finally, we address potential resistance mechanisms and future directions for clinical application. By integrating trained immunity into conventional immunotherapeutic regimens, we may significantly improve outcomes for HCC patients, potentially transforming advanced disease into a more manageable condition. Full article

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

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15 pages, 1458 KiB

Open AccessArticle

FDG-PET/CT and Multimodal Machine Learning Model Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

by David Groheux, Loïc Ferrer, Jennifer Vargas, Antoine Martineau, Adrien Borgel, Luis Teixeira, Philippe Menu, Philippe Bertheau, Olivier Gallinato, Thierry Colin and Jacqueline Lehmann-Che

Cancers 2025, 17(7), 1249; https://doi.org/10.3390/cancers17071249 (registering DOI) - 7 Apr 2025

Viewed by 285

Abstract

Purpose: Triple-negative breast cancer (TNBC) is a biologically and clinically heterogeneous disease, associated with poorer outcomes when compared with other subtypes of breast cancer. Neoadjuvant chemotherapy (NAC) is often given before surgery, and achieving a pathological complete response (pCR) has been associated with [...] Read more.

Purpose: Triple-negative breast cancer (TNBC) is a biologically and clinically heterogeneous disease, associated with poorer outcomes when compared with other subtypes of breast cancer. Neoadjuvant chemotherapy (NAC) is often given before surgery, and achieving a pathological complete response (pCR) has been associated with patient outcomes. There is thus strong clinical interest in the ability to accurately predict pCR status using baseline data. Materials and Methods: A cohort of 57 TNBC patients who underwent FDG-PET/CT before NAC was analyzed to develop a machine learning (ML) algorithm predictive of pCR. A total of 241 predictors were collected for each patient: 11 clinical features, 11 histopathological features, 13 genomic features, and 206 PET features, including 195 radiomic features. The optimization criterion was the area under the ROC curve (AUC). Event-free survival (EFS) was estimated using the Kaplan–Meier method. Results: The best ML algorithm reached an AUC of 0.82. The features with the highest weight in the algorithm were a mix of PET (including radiomics), histopathological, genomic, and clinical features, highlighting the importance of truly multimodal analysis. Patients with predicted pCR tended to have a longer EFS than patients with predicted non-pCR, even though this difference was not significant, probably due to the small sample size and few events observed (p = 0.09). Conclusions: This study suggests that ML applied to baseline multimodal data can help predict pCR status after NAC for TNBC patients and may identify correlations with long-term outcomes. Patients predicted as non-pCR may benefit from concomitant treatment with immunotherapy or dose intensification. Full article

(This article belongs to the Special Issue Medical Imaging and Artificial Intelligence in Cancer)

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19 pages, 786 KiB

Open AccessReview

Infectious Agents and Esophageal Cancer: A Comprehensive Review

by Ahan Bhatt, Hasan Musanna Zaidi, Radhashree Maitra and Sanjay Goel

Cancers 2025, 17(7), 1248; https://doi.org/10.3390/cancers17071248 - 7 Apr 2025

Viewed by 405

Abstract

Esophageal cancer, primarily comprising the squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) subtypes, is the sixth leading cause of cancer deaths globally. In addition to many well-established endogenous and exogenous risk factors, there is emerging evidence for the etiologic role of infectious agents [...] Read more.

Esophageal cancer, primarily comprising the squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) subtypes, is the sixth leading cause of cancer deaths globally. In addition to many well-established endogenous and exogenous risk factors, there is emerging evidence for the etiologic role of infectious agents in esophageal cancer, although these associations are incompletely understood. Here, we review the currently available literature on the relationship between infectious agents and esophageal cancer. By far, human papilloma virus (HPV), particularly HPV 16 and 18, have the strongest etiologic association with ESCC. Less robust is the association of high-risk HPV (hr-HPV) with EAC. Although H. pylori has been implicated in the development of EAC via increased acid reflux, decreased lower esophageal sphincter tone, and the resultant Barrett’s metaplasia–dysplasia–adenocarcinoma pathway, some hypothesize based on epidemiological trends that H. pylori may in fact be a protective factor. In rare cases, EBV can cause esophageal lymphoepithelial carcinoma. Several other agents including HSV, polyomaviruses, and Candida are associated with esophageal cancer to varying degrees. In summary, while several studies, including those conflicting with each other, implicate several infectious agents, the evidence is weak, at best. Clearly, further work is needed to help solidify clear etiologies that will help facilitate prevention and treatment. Full article

(This article belongs to the Special Issue Infectious Agents and Oesophageal Cancer)

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24 pages, 1200 KiB

Open AccessReview

Theranostics in Hematological Malignancies: Cutting-Edge Advances in Diagnosis and Targeted Therapy

by Bojana Bogdanovic, Florent Hugonnet and Christopher Montemagno

Cancers 2025, 17(7), 1247; https://doi.org/10.3390/cancers17071247 - 7 Apr 2025

Viewed by 461

Abstract

Hematologic malignancies, including leukemia, lymphoma, and multiple myeloma, continue to challenge clinicians with complex treatment regimens that often involve significant side effects and limited success, especially in advanced stages. Recent advancements in nuclear medicine have introduced theranostic strategies that merge diagnostic imaging with [...] Read more.

Hematologic malignancies, including leukemia, lymphoma, and multiple myeloma, continue to challenge clinicians with complex treatment regimens that often involve significant side effects and limited success, especially in advanced stages. Recent advancements in nuclear medicine have introduced theranostic strategies that merge diagnostic imaging with targeted therapeutic approaches, offering the potential for more precise and personalized treatment. A key area of progress lies in the development of alpha-emitting radiopharmaceuticals, such as ²²⁵Ac, ²¹¹At, or ²¹²Pb, which can deliver potent radiation directly to tumor cells, sparing healthy tissue and minimizing collateral damage. In parallel with these therapeutic advancements, molecular imaging using radiolabeled agents enables better disease monitoring, assessment of treatment efficacy, and personalized management of patients with hematologic malignancies. The integration of diagnostic imaging with radiotherapy allows for a more tailored approach, where treatment can be adjusted based on real-time information about tumor progression and response. This review examines the recent strides made in both the development of radiopharmaceuticals and their applications in molecular imaging, with a focus on the potential to improve precision, reduce toxicity, and optimize patient outcomes. The synergy between targeted therapy and molecular imaging represents a transformative shift in the management of hematologic malignancies. As these technologies evolve, they are poised to redefine treatment paradigms, offering new hope for patients and potentially improving survival rates with more effective and less toxic treatment options. Full article

(This article belongs to the Special Issue Cancer Treatment: Present and Future of Radioligand Therapy)

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28 pages, 1428 KiB

Open AccessReview

Immune-Based Strategies for Pancreatic Cancer in the Adjuvant Setting

by Kai-Li Liang and Nilofer S. Azad

Cancers 2025, 17(7), 1246; https://doi.org/10.3390/cancers17071246 - 7 Apr 2025

Viewed by 572

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality in the United States, with poor overall survival across all stages. Less than 20% of patients are eligible for curative surgical resection at diagnosis, and despite adjuvant chemotherapy, most will experience [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality in the United States, with poor overall survival across all stages. Less than 20% of patients are eligible for curative surgical resection at diagnosis, and despite adjuvant chemotherapy, most will experience disease recurrence within two years. The incorporation of immune-based strategies in the adjuvant setting remains an area of intense investigation with unrealized promise. It offers the potential of providing durable disease control for micro-metastatic disease following curative intent surgery and enabling personalized treatments based on mutational neoantigen profiles derived from resected specimens. However, most of these attempts have failed to demonstrate significant clinical success, likely due to the immunosuppressive tumor microenvironment (TME) and individual genetic heterogeneity. Despite these challenges, immune-based strategies, such as therapeutic vaccines targeted towards neoantigens, have demonstrated promise via immune activation and induction of T-cell tumor infiltration. In this review, we will highlight the foundational lessons learned from previous clinical trials of adjuvant immunotherapy, discussing the knowledge gained from analyses of trials with disappointing results. In addition, we will discuss how these data have been incorporated to design new agents and study concepts that are proving to be exciting in more recent trials, such as shared antigen vaccines and combination therapy with immune-checkpoint inhibitors and chemotherapy. This review will evaluate novel approaches in ongoing and future clinical studies and provide insight into how these immune-based strategies might evolve to address the unique challenges for treatment of PDAC in the adjuvant setting. Full article

(This article belongs to the Special Issue Adjuvant Therapy for Pancreatic Cancer)

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17 pages, 9539 KiB

Open AccessArticle

Tumor Bud Classification in Colorectal Cancer Using Attention-Based Deep Multiple Instance Learning and Domain-Specific Foundation Models

by Mesut Şeker, M. Khalid Khan Niazi, Wei Chen, Wendy L. Frankel and Metin N. Gurcan

Cancers 2025, 17(7), 1245; https://doi.org/10.3390/cancers17071245 - 7 Apr 2025

Viewed by 329

Abstract

Background/Objectives: Identifying tumor budding (TB) in colorectal cancer (CRC) is vital for better prognostic assessment as it may signify the initial stage of metastasis. Despite its importance, TB detection remains challenging due to subjectivity in manual evaluations. Identifying TBs remains difficult, especially at [...] Read more.

Background/Objectives: Identifying tumor budding (TB) in colorectal cancer (CRC) is vital for better prognostic assessment as it may signify the initial stage of metastasis. Despite its importance, TB detection remains challenging due to subjectivity in manual evaluations. Identifying TBs remains difficult, especially at high magnification levels, leading to inconsistencies in prognosis. To address these issues, we propose an automated system for TB classification using deep learning. Methods: We trained a deep learning model to identify TBs through weakly supervised learning by aggregating positive and negative bags from the tumor invasive front. We assessed various foundation models for feature extraction and compared their performance. Attention heatmaps generated by attention-based multi-instance learning (ABMIL) were analyzed to verify alignment with TBs, providing insights into the interpretability of the features. The dataset includes 29 WSIs for training and 70 whole slide images (WSIs) for the hold-out test set. Results: In six-fold cross-validation, Phikon-v2 achieved the highest average AUC (0.984 ± 0.003), precision (0.876 ± 0.004), and recall (0.947 ± 0.009). Phikon-v2 again achieved the highest AUC (0.979) and precision (0.980) on the external hold-out test set. Moreover, its recall rate (0.910) was still higher than that of UNI’s (0.879). UNI exhibited a balanced performance on the hold-out test set, with an AUC of 0.960 and a precision of 0.968. CtransPath showed strong precision on the external hold-out test set (0.947) but had a slightly lower recall (0.911). Conclusions: The proposed technique enhances the accuracy of TB assessment, offering potential applications for CRC and other cancer types. Full article

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

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23 pages, 1287 KiB

Open AccessReview

Can the Tumor Microenvironment Alter Ion Channels? Unraveling Their Role in Cancer

by Rosaria Gentile, Davide Feudi, Luana Sallicandro and Andrea Biagini

Cancers 2025, 17(7), 1244; https://doi.org/10.3390/cancers17071244 - 6 Apr 2025

Viewed by 450

Abstract

Neoplastic cells are characterized by metabolic reprogramming, known as the Warburg effect, in which glucose metabolism is predominantly directed toward aerobic glycolysis, with reduced mitochondrial oxidative phosphorylation and increased lactate production even in the presence of oxygen. This phenomenon provides cancer cells with [...] Read more.

Neoplastic cells are characterized by metabolic reprogramming, known as the Warburg effect, in which glucose metabolism is predominantly directed toward aerobic glycolysis, with reduced mitochondrial oxidative phosphorylation and increased lactate production even in the presence of oxygen. This phenomenon provides cancer cells with a proliferative advantage, allowing them to rapidly produce energy (in the form of ATP) and generate metabolic intermediates necessary for the biosynthesis of macromolecules essential for cell growth. It is important to understand the role of ion channels in the tumor context since they participate in various physiological processes and in the regulation of the tumor microenvironment. These changes may contribute to the development and transformation of cancer cells, as well as affect the communication between cells and the surrounding microenvironment, including impaired or altered expression and functionality of ion channels. Therefore, the aim of this review is to elucidate the impact of the tumor microenvironment on the electrical properties of the cellular membranes in several cancers as a possible therapeutic target. Full article

(This article belongs to the Special Issue Epigenetic and Metabolic Alterations in the Tumor Microenvironment: 2nd Edition)

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24 pages, 2274 KiB

Open AccessReview

Biomarkers and Management of Cholangiocarcinoma: Unveiling New Horizons for Precision Therapy

by Naoshi Nishida

Cancers 2025, 17(7), 1243; https://doi.org/10.3390/cancers17071243 - 6 Apr 2025

Viewed by 391

Abstract

Cholangiocarcinoma (CCA) is an aggressive malignancy with limited methods for early detection, necessitating the development of reliable biomarkers for diagnosis and management. However, conventional tumor markers, such as CA19-9 and CEA, exhibit insufficient diagnostic accuracy. Recent advancements in molecular genetics have identified several [...] Read more.

Cholangiocarcinoma (CCA) is an aggressive malignancy with limited methods for early detection, necessitating the development of reliable biomarkers for diagnosis and management. However, conventional tumor markers, such as CA19-9 and CEA, exhibit insufficient diagnostic accuracy. Recent advancements in molecular genetics have identified several actionable mutations in CCA, enabling molecularly targeted therapies that improve survival in patients harboring these genetic alterations. Cancer panels, which facilitate multiplex genetic profiling, are critical for identifying these mutations. Studies indicate that several actionable mutations are detected in CCA cases, with patients receiving mutation-guided therapies achieving markedly better outcomes. Liquid biopsies, including cell-free DNA and circulating tumor DNA, offer real-time, non-invasive approaches to monitoring tumor dynamics, heterogeneity, and treatment responses. Furthermore, numerous studies have identified non-coding RNAs in serum and bile as promising biomarkers for the diagnosis and management of CCA. On the other hand, immunotherapy, particularly immune checkpoint inhibitors, has shown efficacy in subsets of CCA patients. However, the success of these therapies is often affected by the status of the tumor immune microenvironment (TME), underscoring the need for comprehensive TME analysis to predict responses to immune checkpoint inhibitors. Despite these advances, no single biomarker currently demonstrates sufficient sensitivity or specificity for clinical application. The integration of multi-omics approaches with cutting-edge technologies holds promise for enhancing diagnostic accuracy, optimizing treatment stratification, and advancing precision medicine in CCA. These developments highlight the transformative potential of biomarkers to improve early detection, prognostic assessment, and personalized therapeutic interventions for CCA. Full article

(This article belongs to the Special Issue Novel Biomarkers of Hepatobiliary Tumors)

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18 pages, 9665 KiB

Open AccessArticle

Endoscopic Submucosal Dissection (ESD) for the Management of Fibrotic Non-Lifting Colorectal Lesions (NLCLs): Results from a Large Multicenter Retrospective Study

by Giuseppe Dell’Anna, Ernesto Fasulo, Paolo Cecinato, Giovanni Barbara, Alberto Barchi, Edi Viale, Dario Esposito, Simone Grillo, Romano Sassatelli, Alberto Malesci, Sara Massironi, Vito Annese, Lorenzo Fuccio, Antonio Facciorusso, Gianfranco Donatelli, Silvio Danese and Francesco Azzolini

Cancers 2025, 17(7), 1242; https://doi.org/10.3390/cancers17071242 - 6 Apr 2025

Viewed by 330

Abstract

Background/Objectives: The management of non-lifting colorectal lesions (NLCLs), often resulting from previous unsuccessful treatments or biopsies, remains challenging due to submucosal fibrosis that prevents adequate lifting. Endoscopic submucosal dissection (ESD) is a viable option for achieving complete resection in such cases. However, [...] Read more.

Background/Objectives: The management of non-lifting colorectal lesions (NLCLs), often resulting from previous unsuccessful treatments or biopsies, remains challenging due to submucosal fibrosis that prevents adequate lifting. Endoscopic submucosal dissection (ESD) is a viable option for achieving complete resection in such cases. However, when standard ESD is not feasible, conversion to hybrid ESD (H-ESD) has been proposed as a rescue strategy. This study aimed to assess ESD’s feasibility, effectiveness, and safety for NLCLs, including cases requiring conversion to H-ESD, when performed by experienced endoscopists in tertiary referral centers. Methods: In this multicenter retrospective study, data from patients with NLCLs treated by ESD/H-ESD between January 2009 and September 2022 were analyzed. The primary endpoint was the recurrence rate (RR). Secondary endpoints included the adverse event (AE) rate, technical success (TS) rate (en bloc resection regardless of technique), complete resection (CR), curative resection (cR) rates, and surgical intervention rate. Predictors of ESD technical success were identified. Results: In total, 178 patients with NLCLs were included (52 previously biopsied, 126 recurrent after previous resection). ESD was used in 111 (62.4%) and H-ESD in 67 (37.6%) cases. During a median follow-up of 373 days (IQR 540), the overall RR was 3.6%. The overall AE rate was 13.4%, and perforation was the most frequent (8.4%). All AEs were successfully managed endoscopically. The TS rate was 71.9%, significantly higher in previously biopsied lesions compared to recurrent ones (78.8% vs. 55.6%, p = 0.04). On multivariate analysis, rectal location (p < 0.001), F1 fibrosis (p = 0.026), and previously biopsied lesions (p = 0.006) predicted ESD TS without the need for conversion to H-ESD. Conclusions: ESD/H-ESD is feasible and safe for NLCLs when performed by experienced operators, with low RR amenable to endoscopic treatment. Previously biopsied lesions, rectal location, and low fibrosis predict ESD TS. Full article

(This article belongs to the Special Issue The Application of Laparo-Endoscopic and Robotic Surgery in Cancer Treatments and Research)

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17 pages, 3634 KiB

Open AccessArticle

CO₂ Laser Therapy for Genitourinary Syndrome of Menopause in Women with Breast Cancer: A Randomized, Sham-Controlled Trial

by Sireen Jaber, Gabriel Levin, Maya Ram-Weiner and Ahinoam Lev-Sagie

Cancers 2025, 17(7), 1241; https://doi.org/10.3390/cancers17071241 - 6 Apr 2025

Viewed by 323

Abstract

Objectives: We aimed to study the efficacy of fractional CO₂ laser for genitourinary syndrome of menopause (GSM) symptoms in breast cancer (BC) survivors through a randomized, sham-controlled study, followed by an open-phase study assessing the impact of additional treatments. Methods: BC survivors [...] Read more.

Objectives: We aimed to study the efficacy of fractional CO₂ laser for genitourinary syndrome of menopause (GSM) symptoms in breast cancer (BC) survivors through a randomized, sham-controlled study, followed by an open-phase study assessing the impact of additional treatments. Methods: BC survivors with GSM were randomized to receive either three sessions of intravaginal CO₂ laser or sham treatment every 3–4 weeks. The laser’s energy was 45–60 mJ/pixel. Outcomes were compared one month following the last session. Participants initially receiving laser treatment were offered three more sessions, while those receiving sham had six laser sessions in an open-label study. Results: Thirty-four BC survivors were randomized to laser (n = 19) or sham (n = 15) treatments. Dyspareunia and intercourse dryness scores improved in both groups one month post-treatment, without a significant advantage of laser over sham. The laser treatment resulted in a reduction in daily dryness (−1.30 ± 0.55, p = 0.017), an increase in vaginal hydration (3.24 ± 1.13, p = 0.004), and an increase in Vaginal Health Index (VHI) (2.26 ± 0.50, p < 0.001). Most participants (18/19 and 9/15, respectively) opted to continue laser treatments after unblinding, resulting in 27 patients receiving six laser treatments. Increasing the number of laser treatments was associated with a constant improvement in Visual Analogue Score (VAS) scores for dyspareunia, intercourse dryness, daily dryness, burning, discomfort, itch, and average VAS, as well as pH, VHI, and hydration. Conclusions Three fractional CO₂ laser treatments for BC survivors reduced daily dryness but did not improve dyspareunia and sexual dryness when compared to sham in this randomized trial. Increasing the number of treatment sessions seemed to improve outcomes; however, it remained clinically insufficient, even after six treatments. Full article

(This article belongs to the Special Issue Cancer Survivorship: During and After Treatment)

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16 pages, 2014 KiB

Open AccessArticle

Intraoperative Radiation Therapy for Gynecologic Malignancies: When Is It Indicated?

by Flavia Pagano, Flurina Annacarina Maria Saner, Codruta Ionescu, Elena Riggenbach, Kristina Lössl, Franziska Siegenthaler, Michael David Mueller and Sara Imboden

Cancers 2025, 17(7), 1240; https://doi.org/10.3390/cancers17071240 - 6 Apr 2025

Viewed by 228

Abstract

Background: Intraoperative radiation therapy (IORT) is the delivery of a single large dose of radiation to a limited volume of tissue at the time of surgery. The aim of this study is to assess outcomes in patients who underwent IORT for gynecologic [...] Read more.

Background: Intraoperative radiation therapy (IORT) is the delivery of a single large dose of radiation to a limited volume of tissue at the time of surgery. The aim of this study is to assess outcomes in patients who underwent IORT for gynecologic malignancies and to identify parameters that can predict a good outcome. Methods: This is a retrospective single-center cohort study including all women treated with surgery and IORT for a primary or recurrent gynecologic cancer between 2014 and 2022 at the Bern University Hospital, Switzerland. Results: A total of 30 patients with gynecologic malignancies were treated with surgery and IORT. Of these patients, 63.3% presented with cervical cancer, 23.3% with sarcoma, 10% with endometrial cancer, and 3.3% with carcinosarcoma of the ovary. Seventy percent (21/30) of women had an ECOG performance status of 0 at time of IORT. There was no difference in survival among women with incomplete surgical resection (R1/2 vs. R0) at time of IORT. Fifty percent of patients suffered postoperative complication of Clavien-Dindo grade >III, but there was no significant correlation of these complications to overall survival (p = 0.58). Three-year disease-free survival was 53.3%, and five-year overall survival was 53.3%. ECOG status was a significant parameter in DSS (p = 0.002) and OS (p = 0.02). Conclusion: Surgery with IORT is potentially a good treatment option in selected patients with recurrent or locally advanced cervical or endometrial cancer. An ECOG status of 0 is a significant parameter for good outcomes and should be taken into consideration for treatment decisions. Full article

(This article belongs to the Special Issue Radiotherapy in Gynecological Cancer: State of the Art)

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14 pages, 2481 KiB

Open AccessArticle

Evaluating the Potential of PSMA Targeting in CNS Tumors: Insights from Large-Scale Transcriptome Profiling

by Adam Kraya, Komal Rathi, Run Jin, Varun Kesherwani, Adam C. Resnick, Phillip B. Storm and Ali Nabavizadeh

Cancers 2025, 17(7), 1239; https://doi.org/10.3390/cancers17071239 - 6 Apr 2025

Viewed by 355

Abstract

Background/Objectives: Prostate-specific membrane antigen (PSMA) is a well-established target in prostate cancer therapy that has shown potential as a theranostic target across non-central nervous system (CNS) and CNS tumor types. We aimed to investigate the pan-tissue expression pattern of the PSMA-encoding gene FOLH1 [...] Read more.

Background/Objectives: Prostate-specific membrane antigen (PSMA) is a well-established target in prostate cancer therapy that has shown potential as a theranostic target across non-central nervous system (CNS) and CNS tumor types. We aimed to investigate the pan-tissue expression pattern of the PSMA-encoding gene FOLH1 to assess whether transcriptome profiling can inform tumor diagnostic and theranostic probes. Methods: We assessed FOLH1 expression from the Open Pediatric Cancer Project (OpenPedCan, n = 2132 specimens), the Cancer Genome Atlas (TCGA, n = 10,411 specimens), and the Genotype Tissue Expression Project (GTEx, n = 17,382 specimens) in relation to published reports of PSMA radionuclide uptake in various tumors. Results: When comparing FOLH1 expression across tumor versus normal tissues, we found that non-CNS tumors exhibiting elevated expression of at least two-fold (FDR < 0.05) were reported to have significant PSMA radionuclide uptake in contrast to tumors with less than a two-fold elevation or with lower expression of FOLH1 relative to normal tissues. Notably, CNS tumors universally exhibited lower expression of FOLH1 relative to normal brain tissue, but we observed considerable variation in the expression of blood–tumor barrier (BTB) components associated with reports of BTB integrity and uptake of PSMA radiotracers. Conclusions: Large-scale transcriptomics data may help guide the application of PSMA-based radionuclide therapies in non-CNS tumors, but care should be taken to account for BTB effects in CNS tumors when assessing the potential for radionuclide success. This study demonstrates that FOLH1 showed a lack of tumor-specific expression for both adult and pediatric CNS tumors when compared to normal brain tissue, suggesting that PSMA is not a desirable target in brain tumors. Full article

(This article belongs to the Special Issue Molecular Pathology of Brain Tumors)

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20 pages, 1738 KiB

Open AccessArticle

Psychosocial Outcomes in Parents of Children with Acute Lymphoblastic Leukaemia in Australia and New Zealand Through and Beyond Treatment

by Clare Parker, Clarissa E. Schilstra, Karen McCleary, Michelle Martin, Toby N. Trahair, Rishi S. Kotecha, Shanti Ramachandran, Ruellyn Cockcroft, Rachel Conyers, Siobhan Cross, Luciano Dalla-Pozza, Peter Downie, Tamas Revesz, Michael Osborn, Glenn M. Marshall, Claire E. Wakefield, Marion K. Mateos and Joanna E. Fardell

Cancers 2025, 17(7), 1238; https://doi.org/10.3390/cancers17071238 - 6 Apr 2025

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Abstract

Background/Objectives: Parents of children with acute lymphoblastic leukaemia (ALL) experience emotional distress throughout their child’s treatment course. This study describes the psychological experience of Australian and New Zealand parents of children diagnosed with ALL. Methods: This prospective, longitudinal study assessed distress, anxiety, depression, [...] Read more.

Background/Objectives: Parents of children with acute lymphoblastic leukaemia (ALL) experience emotional distress throughout their child’s treatment course. This study describes the psychological experience of Australian and New Zealand parents of children diagnosed with ALL. Methods: This prospective, longitudinal study assessed distress, anxiety, depression, anger and the need for help in parents of children with newly diagnosed ALL across eight sites between October 2018 and November 2022. Psychological symptoms were quantified using the Emotion Thermometer (ET) tool and Patient-Reported Outcome Measurement Information System (PROMIS) questionnaires. Participants were recruited within ninety days of chemotherapy commencement, with surveys distributed bimonthly thereafter. Results: One hundred and seventeen participants completed 327 survey responses spanning 0 to 62 months post-diagnosis. Parental distress peaked within the first 6 months and 40% of parents reported clinically significant symptoms across four or more domains as measured by our questionnaires. Anxiety was the most consistently elevated symptom, with over 50% of responses above the clinical cut-off. Depression and the need for help also peaked closer to diagnosis and declined over time. In contrast, anger remained stable, with 27% reporting clinically significant scores across all time points. Increased time since diagnosis was significantly associated with reductions in distress, anxiety and depression scores. Conclusions: Australian and New Zealand parents experience high levels of psychological distress within the first six months following their child’s diagnosis of ALL. A notable minority continue to report elevated distress levels over time, identifying a need for improved psychological support for family wellbeing throughout the ALL treatment trajectory. Full article

(This article belongs to the Special Issue Advances in Pediatric and Adolescent Psycho-Oncology)

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17 pages, 2119 KiB

Open AccessArticle

Trends in Overall Survival in Lung Adenocarcinoma with EFGR Mutation, KRAS Mutation, or No Mutation

by Martin Faehling, Sabine Fallscheer, Birgit Schwenk, Harald Seifarth, Jörn Sträter, Claudia Lengerke and Petros Christopoulos

Cancers 2025, 17(7), 1237; https://doi.org/10.3390/cancers17071237 - 5 Apr 2025

Viewed by 331

Abstract

Background: Treatment of lung adenocarcinoma has changed and now includes checkpoint inhibitors (CPIs) or, in the case of an EGFR mutation, third-generation EGFR TKI osimertinib. Few data compare the long-term overall survival (OS) of current and historic subgroups. Methods: This real-world analysis (KOMPASS [...] Read more.

Background: Treatment of lung adenocarcinoma has changed and now includes checkpoint inhibitors (CPIs) or, in the case of an EGFR mutation, third-generation EGFR TKI osimertinib. Few data compare the long-term overall survival (OS) of current and historic subgroups. Methods: This real-world analysis (KOMPASS study) included stage IV lung-adenocarcinoma patients with either EGFR, KRAS, or no mutation. Patients were assigned to the “current” EGFR, KRAS, or no-mutation cohort if they had mutation testing using NGS (n = 199; median date of diagnosis 2021). If they had an EGFR PCR test only, they were assigned to the “historic” EGFR or no-mutation cohort (n = 127; median date of diagnosis 2014). Results: Both the current and the historic EGFR cohorts had significantly longer OS than the respective no-mutation cohorts (HR 0.58 and 0.60, respectively). The current no-mutation and EGFR cohorts had a strong trend to longer OS than the respective historic cohorts. In the no-mutation cohorts, the improvement was due to an increase in long-term survivors (HR 0.71), whereas in the EGFR mutation cohorts, the median OS was improved without long-term survivors (HR 0.70). The KRAS cohort showed OS like the no-mutation cohort, with a plateau of long-term survivors around 20%. Conclusions: A comparison of our data with that of the phase III trials KEYNOTE-189 and FLAURA suggests that the improved outcomes are due to the use of CPIs or osimertinib. The clinical trial results are well translated into real-world clinical practice with comparable OS. KRAS patients benefit from CPI treatment like no-mutation patients. Full article

(This article belongs to the Special Issue The EGFR-Tyrosine Kinase Inhibitors (EGFR-TKIs) and Immune Checkpoint Inhibitors (ICIs) for Non-Small Cell Lung Cancer)

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16 pages, 1829 KiB

Open AccessArticle

Perioperative and Mid-Term Oncological and Functional Outcomes After Partial Nephrectomy for Entirely Endophytic Renal Tumors: A Prospective Multicenter Observational Study (The RECORD2 Project)

by Fabrizio Di Maida, Andrea Mari, Daniele Amparore, Alessandro Antonelli, Riccardo Schiavina, Riccardo Giuseppe Bertolo, Alessandro Veccia, Eugenio Brunocilla, Riccardo Campi, Luigi Da Pozzo, Cristian Fiori, Paolo Gontero, Antonio Andrea Grosso, Luca Lambertini, Nicola Longo, Ciro Imbimbo, Alberto Briganti, Francesco Montorsi, Francesco Porpiglia, Luigi Schips, Nazareno Suardi, Sergio Serni, Bernardo Rocco and Andrea Minervini Show full author list Hide full author list

Cancers 2025, 17(7), 1236; https://doi.org/10.3390/cancers17071236 - 5 Apr 2025

Viewed by 288

Abstract

Background and Objectives: Totally endophytic renal tumors are a unique subset that pose significant technical challenges during partial nephrectomy (PN). The aim of this study was to evaluate the perioperative, oncologic, and functional outcomes of PN in this particular setting. Materials and Methods: [...] Read more.

Background and Objectives: Totally endophytic renal tumors are a unique subset that pose significant technical challenges during partial nephrectomy (PN). The aim of this study was to evaluate the perioperative, oncologic, and functional outcomes of PN in this particular setting. Materials and Methods: We retrospectively evaluated 4151 patients who had surgical treatment for renal tumors between January 2013 and December 2016 at 26 urological Italian Centers (RECORD 2 project). Only patients treated with PN for entirely endophytic renal tumor were considered for final analyses. Results: A total of 211 patients were included, with a median PADUA score of 10 (IQR 9-11). Open, laparoscopic, and robotic approaches were used in 94 (44.5%), 52 (24.6%), and 65 (30.8%) cases, respectively. While surgical approach did not impact complication rates, robotic PN had significantly lower median blood loss (100 vs. 185 vs. 175 cc, p = 0.04) and shorter operative time (126 vs. 140 vs. 160 min, p = 0.01) compared to open and laparoscopic PN. At a median follow-up of 36.3 months (IQR 21.9–49.2), recurrence-free survival was 93.8%. Median %eGFR drop at 24 months was 12.1 (IQR 5.1–21.9), with significant eGFR loss (≥25%) in 36 (17.1%) patients. The robotic approach was associated with a lower %eGFR drop at 1-month and 1-year evaluations, but the benefit diminished at 24 months. Multivariate analysis showed age and open surgery as independent predictors of renal function loss at 1 month and Trifecta failure. Conclusions: The conservative management of entirely endophytic renal tumors is associated with favorable functional and oncologic outcomes. Whenever technically feasible, conservative surgery should be prioritized to optimize early renal function recovery. Full article

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

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37 pages, 972 KiB

Open AccessSystematic Review

Real-World Evidence Evaluating Teclistamab in Patients with Relapsed/Refractory Multiple Myeloma: A Systematic Literature Review

by Benjamin Derman, Carlyn Tan, Ian Steinfield, Florence R. Wilson, Dee Lin, Bingcao Wu, Mariana Fernandez, Jessica Fowler, Agne Paner-Straseviciute, Nina Kim, Margaret Doyle, Alexander Marshall, Jessica Cheadle, Sam Keeping and Jane Jijun Liu

Cancers 2025, 17(7), 1235; https://doi.org/10.3390/cancers17071235 - 5 Apr 2025

Viewed by 365

Abstract

Background: Teclistamab (TEC) is the first B-cell maturation antigen-directed bispecific antibody approved in 2022 by the European Medicines Agency and Food and Drug Administration for triple-class exposed relapsed/refractory multiple myeloma (RRMM). Objectives: As TEC is increasingly used in real-world (RW) settings, [...] Read more.

Background: Teclistamab (TEC) is the first B-cell maturation antigen-directed bispecific antibody approved in 2022 by the European Medicines Agency and Food and Drug Administration for triple-class exposed relapsed/refractory multiple myeloma (RRMM). Objectives: As TEC is increasingly used in real-world (RW) settings, this study seeks to gather existing RW evidence on effectiveness, safety, healthcare resource utilization, and clinical practices associated with TEC. Methods: A systematic literature review was performed to identify RW observational studies of TEC-treated adults with RRMM from 2023 to June 2024. Results: Sixty-one records representing 41 unique studies were included; sample sizes ranged from 8 to 572 patients. Where reported, median follow-up ranged from 2.3 to 33.6 months, and >65% of the patients would have been ineligible for the pivotal trial of TEC (MajesTEC-1) in all but one study. In eight studies with ≥50 patients and ≥3 months follow-up, overall response rates were 59–66% and cytokine release syndrome (CRS) rates were 18–64%. Tocilizumab use for CRS management was reported in 14 studies, with two indicating CRS rates of 13% and 26% when used prophylactically. Survival and infection outcomes showed wide variability due to short follow-up in most studies. Conclusions: Overall, early RW effectiveness and safety outcomes of TEC were comparable to findings from MajesTEC-1. Full article

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

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27 pages, 15911 KiB

Open AccessArticle

Pro-Inflammatory Cytokines Transactivate Glycosylated Cytokine Receptors on Cancer Cells to Induce Epithelial–Mesenchymal Transition to the Metastatic Phenotype

by Leili Baghaie, David A. Bunsick, Emilyn B. Aucoin, Elizabeth Skapinker, Abdulrahman M. Yaish, Yunfan Li, William W. Harless and Myron R. Szewczuk

Cancers 2025, 17(7), 1234; https://doi.org/10.3390/cancers17071234 - 5 Apr 2025

Viewed by 362

Abstract

Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of [...] Read more.

Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of primary breast, colorectal, and prostate cancer. We also investigated the regulation of their cognate receptors. Methods: All experiments were conducted using the PANC-1, SW620, and MCF-7 cell lines, treated with three different cytokines (TGF-β1, HGF, and IL-6). The effect of these cytokines on the expression of epithelial–mesenchymal transition (EMT) cell surface markers and neuraminidase-1 activity was measured via fluorescent microscopy and image analysis software. Results: The findings show that these cytokines increase the expression of mesenchymal markers while reducing epithelial markers, corresponding to the EMT process. A strong link between cytokine receptor signaling and the Neu-1-MMP-9-GPCR crosstalk was identified, suggesting that cytokine receptor binding leads to increased Neu-1 activity and subsequent signaling pathway activation. Oseltamivir phosphate (OP) prevented sialic acid hydrolysis by neuraminidase-1 (Neu-1), leading to the downregulation of these signaling cascades. Conclusions: In concert with the previous work revealing the role of Neu-1 in regulating other glycosylated receptors implicated in cancer cell proliferation and EMT, targeting Neu-1 may provide effective treatment against a variety of malignancies. Most significantly, the treatment of patients with specific inhibitors of Neu-1 soon after primary cancer surgery may improve our ability to cure early-stage cancer by inhibiting the EMT process and disrupting the ability of any residual cancer cell population to metastasize. Full article

(This article belongs to the Special Issue Role of Cytokines in Cancer)

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13 pages, 217 KiB

Open AccessReview

Treatment Approaches for Oligoprogressive Non-Small Cell Lung Cancer: A Review of Ablative Radiotherapy

by William Gombrich, Nicholas Eustace, Yufei Liu, Ramya Muddasani, Adam Rock, Ravi Salgia, Terence Williams, Jyoti Malhotra, Percy Lee and Arya Amini

Cancers 2025, 17(7), 1233; https://doi.org/10.3390/cancers17071233 - 5 Apr 2025

Viewed by 443

Abstract

Oligoprogressive disease refers to the setting of a prior or ongoing receipt of systemic therapy, with typically up to three metastatic areas having increased in size and/or avidity compared to the start of the systemic therapy. The role of local ablative therapy (LAT) [...] Read more.

Oligoprogressive disease refers to the setting of a prior or ongoing receipt of systemic therapy, with typically up to three metastatic areas having increased in size and/or avidity compared to the start of the systemic therapy. The role of local ablative therapy (LAT) including radiation has mostly been evaluated in the oligometastatic setting with limited data in oligoprogression. A similar principle of using ablative radiation in the oligometastatic setting may be applied to consolidative therapy for oligoprogressive disease. If systemic therapy can control the majority of the disease, and a few areas of therapy-resistant clones continue to proliferate, then potentially controlling those few resistant clones while maintaining systemic control may be beneficial. Doing so may also extend the duration of benefit of the systemic therapy and reserve next systemic line options at a later point, and potentially improve progression free survival (PFS). Here, we review the current data evaluating the role of radiation in oligoprogressive non-small cell lung cancer (NSCLC) and ongoing trials. Full article

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

33 pages, 10838 KiB

Open AccessReview

Neutrophils and Neutrophil-Based Drug Delivery Systems in Anti-Cancer Therapy

by Hicham Wahnou, Riad El Kebbaj, Soufyane Hba, Zaynab Ouadghiri, Othman El Faqer, Aline Pinon, Bertrand Liagre, Youness Limami and Raphaël Emmanuel Duval

Cancers 2025, 17(7), 1232; https://doi.org/10.3390/cancers17071232 - 5 Apr 2025

Viewed by 450

Abstract

Neutrophils, the most abundant white blood cells, play a dual role in cancer progression. While they can promote tumor growth, metastasis, and immune suppression, they also exhibit anti-tumorigenic properties by attacking cancer cells and enhancing immune responses. This review explores the complex interplay [...] Read more.

Neutrophils, the most abundant white blood cells, play a dual role in cancer progression. While they can promote tumor growth, metastasis, and immune suppression, they also exhibit anti-tumorigenic properties by attacking cancer cells and enhancing immune responses. This review explores the complex interplay between neutrophils and the tumor microenvironment (TME), highlighting their ability to switch between pro- and anti-tumor phenotypes based on external stimuli. Pro-tumorigenic neutrophils facilitate tumor growth through mechanisms such as neutrophil extracellular traps (NETs), secretion of pro-inflammatory cytokines, and immune evasion strategies. They contribute to angiogenesis, tumor invasion, and metastasis by releasing vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Conversely, anti-tumor neutrophils enhance cytotoxicity by generating reactive oxygen species (ROS), promoting antibody-dependent cell-mediated cytotoxicity (ADCC), and activating other immune cells such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Recent advances in neutrophil-based drug delivery systems have harnessed their tumor-homing capabilities to improve targeted therapy. Neutrophil-mimicking nanoparticles and membrane-coated drug carriers offer enhanced drug accumulation in tumors, reduced systemic toxicity, and improved therapeutic outcomes. Additionally, strategies to modulate neutrophil activity, such as inhibiting their immunosuppressive functions or reprogramming them towards an anti-tumor phenotype, are emerging as promising approaches in cancer immunotherapy. Understanding neutrophil plasticity and their interactions with the TME provides new avenues for therapeutic interventions. Targeting neutrophil-mediated mechanisms could enhance existing cancer treatments and lead to the development of novel immunotherapies, ultimately improving patient survival and clinical outcomes. Full article

(This article belongs to the Special Issue The Role of Neutrophils in Tumor Progression and Metastasis)

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14 pages, 613 KiB

Open AccessArticle

Exploratory Algorithms to Aid in Risk of Malignancy Prediction for Indeterminate Pulmonary Nodules

by Laurel Jackson, Claire Auger, Nicolette Jeanblanc, Christopher Jacobson, Kinnari Pandya, Susan Gawel, Hita Moudgalya, Akanksha Sharma, Christopher W. Seder, Michael J. Liptay, Ramya Gaddikeri, Nicole M. Geissen, Palmi Shah, Jeffrey A. Borgia and Gerard J. Davis

Cancers 2025, 17(7), 1231; https://doi.org/10.3390/cancers17071231 - 5 Apr 2025

Viewed by 315

Abstract

Background/Objectives: Lung cancer screening can reduce patient mortality. Multiple issues persist including timely management of patients with a radiologically defined indeterminate pulmonary nodule (IPN), which carries unknown pathological significance. This pilot study focused on combining demographic, clinical, radiographic, and common circulating biomarkers for [...] Read more.

Background/Objectives: Lung cancer screening can reduce patient mortality. Multiple issues persist including timely management of patients with a radiologically defined indeterminate pulmonary nodule (IPN), which carries unknown pathological significance. This pilot study focused on combining demographic, clinical, radiographic, and common circulating biomarkers for their ability to aid in IPN risk of malignancy prediction. Methods: A case-control cohort consisting of 379 patients with IPNs (251 stage I lung tumors and 128 nonmalignant nodules) was used for this effort, divided into training (70%) and testing (30%) sets. Demographic variables (age, sex, race, ethnicity), radiographic information (nodule size and location), smoking pack-years, and plasma biomarker levels of CA-125, SCC, CEA, HE4, ProGRP, NSE, Cyfra 21-1, IL-6, PlGF, sFlt-1, hs-CRP, Ferritin, IgG, IgE, IgM, IgA, and Kappa and Lambda Free Light Chains were assessed for this purpose. Results: Multivariable analyses of biomarker, demographic, and radiographic variables yielded a model consisting of age, lesion size, pack-years, history of extrathoracic cancer, upper lobe location, spiculation, hs-CRP, NSE, Ferritin, and CA-125 (AUC = 0.872 in training, 0.842 in testing) with superior performance over the Mayo Score model, which consists of age, lesion size, history of smoking, history of extrathoracic cancer, upper lobe location, and spiculation (AUC = 0.816 in training, 0.787 in testing). Conclusions: In conclusion, a simple reduced algorithm consisting of biomarkers, clinical information, and demographic variables may have value for malignancy prediction of screen-detected IPNs. Upon further validation, this method stands to reduce the need for serial radiographic studies and the risks of diagnostic delay. Full article

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

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14 pages, 579 KiB

Open AccessArticle

Cancer and Pregnancy: Update of Estimates in Italy by Linking Data from Cancer Registries and Hospital Discharge Records

by Daniela Pierannunzio, Alice Maraschini, Tania Lopez, Serena Donati, Edoardo Corsi Decenti, Paola Ballotari, Francesca Bella, Fortunato Bianconi, Ettore Bidoli, Rossella Bruni, Claudia Cirilli, Rosa Pasqualina De Vincenzo, Giovanna Fantaci, Giuseppe Furgiuele, Silvia Iacovacci, Antonella Ippolito, Lucia Mangone, William Mantovani, Elisabetta Merlo, Michael Mian, Walter Mazzucco, Maria Teresa Pesce, Giuseppe Sampietro, Giovanni Scambia, Fabrizio Stracci, Antonina Torrisi, Maria Francesca Vitale, Manuel Zorzi and Silvia Francisci Show full author list Hide full author list

Cancers 2025, 17(7), 1230; https://doi.org/10.3390/cancers17071230 - 5 Apr 2025

Viewed by 278

Abstract

Background/Objectives: The increasing incidence of cancer during pregnancy is a growing public health concern, driven by delayed parenthood and rising maternal age. Pregnancy-associated cancer (PAC) presents complex clinical challenges, necessitating a balance between maternal cancer treatment and fetal safety. Historically considered incompatible [...] Read more.

Background/Objectives: The increasing incidence of cancer during pregnancy is a growing public health concern, driven by delayed parenthood and rising maternal age. Pregnancy-associated cancer (PAC) presents complex clinical challenges, necessitating a balance between maternal cancer treatment and fetal safety. Historically considered incompatible with favorable pregnancy outcomes, evidence now suggests that pregnancy can often proceed without affecting cancer prognosis. A 2022 study in Italy provided the first population-based PAC estimates by linking cancer registries (CRs) and hospital discharge records (HDRs). This study aimed to update PAC estimates to 2019, covering 30% of the Italian population and addressing prior data limitations. Methods: A retrospective longitudinal analysis was conducted on women aged 15–49 diagnosed with malignant cancers between 2003 and 2019. Data from 21 Italian CRs were linked with HDRs to identify PAC cases, defined as obstetric hospitalizations occurring for women diagnosed with cancer in our study cohort in the period spanning from one year before to two years after a cancer diagnosis. All malignant cancers, excluding non-melanoma skin cancers, were analyzed. PAC rates were calculated per 1000 pregnancies, and trends were assessed using log-linear and JoinPoint regression models. Results: Among 131,774 women diagnosed with cancer, 6329 PAC cases were identified, with a PAC rate of 1.43 per 1000 pregnancies, consistent with global estimates. Thyroid (24.4%) and breast cancer (23.2%) were the most common. Analyzing the PAC rate by pregnancy outcome, in the period 2015–2019, this increased for both childbirths and miscarriages but decreased for voluntary terminations. Most hospitalizations (54%) occurred pre-diagnosis, peaking at diagnosis, especially for breast cancer (69%). Conclusions: PAC incidence is rising, particularly for live births and miscarriages, underscoring the need for multidisciplinary care and robust epidemiological insights to guide clinical management. Full article

(This article belongs to the Special Issue Epidemiology of Cancer and Risk Factors: Pushing Boundaries in Public Health Research and Policy)

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15 pages, 2154 KiB

Open AccessArticle

Usefulness of Flow Cytometry Monocyte Partitioning in the Diagnosis of Chronic Myelomonocytic Leukemia in a Real-World Setting

by Yijie Liu, Hamza Tariq, Lucy Fu, Juehua Gao, Taruna Jagtiani, Kristy Wolniak, Barina Aqil, Peng Ji, Yi-Hua Chen and Qing Ching Chen

Cancers 2025, 17(7), 1229; https://doi.org/10.3390/cancers17071229 - 5 Apr 2025

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Abstract

Background: Based on CD14/CD16 expression, monocytes can be divided into the following three functionally distinct subsets: classical (MO1, CD14++/CD16-), intermediate (MO2, CD14+/CD16+) and non-classical (MO3, CD14^dim/CD16-). An expanded MO1 subset (cutoff, ≥94%) was found to be predictive of CMML. However, the [...] Read more.

Background: Based on CD14/CD16 expression, monocytes can be divided into the following three functionally distinct subsets: classical (MO1, CD14++/CD16-), intermediate (MO2, CD14+/CD16+) and non-classical (MO3, CD14^dim/CD16-). An expanded MO1 subset (cutoff, ≥94%) was found to be predictive of CMML. However, the utility of this test in routine practice has important limitations, with some reporting low sensitivity or a lack of correlation. Here, we sought to evaluate the practical usefulness of this test by using our routine antibody panel and a new gating strategy. Methods: Our study included 56 peripheral blood (PB) and 69 bone marrow (BM) samples. The PB cohort included 20 patients with CMML, 21 with no myeloid neoplasms (non-MN) and 15 with other myeloid neoplasms (non-CMML-MN). The BM cohort included 25 CMML, 16 non-MN and 28 non-CMML-MN cases. Taking advantage of an existing 8-color myelomonocytic tube routinely used in our lab, we conducted a retrospective monocyte subset analysis using a new sequential gating strategy. Results: The assay was able to distinguish CMML from non-CMML cases with high sensitivity (90.0%) and specificity (88.9%) in blood samples using a cutoff value of MO1 > 94%. For BM samples, a reduced MO3 < 1.24% was more closely associated with CMML with a sensitivity of 96.0% and a specificity of 79.5%. A side-by-side comparison of our assay with the original “monocyte assay” showed strong agreement. Conclusions: Our study demonstrates the utility of a practical and robust approach for monocyte subset analysis in the diagnosis of CMML. Full article

(This article belongs to the Special Issue Flow Cytometry of Hematological Malignancies)

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29 pages, 494 KiB

Open AccessReview

Exploring the Microbiome’s Impact on Glioma and Brain Metastases: Insights into Development, Progression, and Treatment Response—A Scoping Review

by Jennifer Leigh, Becky Skidmore, Adrian Wong, Saman Maleki Vareki and Terry L. Ng

Cancers 2025, 17(7), 1228; https://doi.org/10.3390/cancers17071228 - 4 Apr 2025

Viewed by 480

Abstract

Background: The human microbiome plays a crucial role in health and disease. Dysbiosis, an imbalance of microorganisms, has been implicated in cancer development and treatment response, including in primary brain tumors and brain metastases, through interactions mediated by the gut–brain axis. This [...] Read more.

Background: The human microbiome plays a crucial role in health and disease. Dysbiosis, an imbalance of microorganisms, has been implicated in cancer development and treatment response, including in primary brain tumors and brain metastases, through interactions mediated by the gut–brain axis. This scoping review synthesizes current evidence on the relationship between the human microbiome and brain tumors. Methods: A systematic search of five electronic databases was conducted by an expert librarian, using controlled vocabulary and keywords. A targeted grey literature search in Google Scholar and clinical trial registries was also undertaken. Eligible studies included primary research involving human patients, or in vivo, or in vitro models of glioma or brain metastasis, with a focus on the microbiome’s role in tumor development, treatment response, and outcomes. Results: Out of 584 citations screened, 40 studies met inclusion criteria, comprising 24 articles and 16 conference abstracts. These included 12 human studies, 16 using mouse models, 7 combining both, and 5 employing large datasets or next-generation sequencing of tumor samples. Thirty-one studies focused on primary brain tumors, six on brain metastases, and three on both. Of the 20 studies examining dysbiosis in tumor development, 95% (n = 19) found an association with tumor growth. Additionally, 71.4% (n = 5/7) of studies reported that microbiome alterations influenced treatment efficacy. Conclusions: Although the role of the gut–brain axis in brain tumors is still emerging and is characterized by heterogeneity across studies, existing evidence consistently supports a relationship between the gut microbiome and both brain tumor development and treatment outcomes. Full article

(This article belongs to the Special Issue Novel Experimental Therapeutic Targets and Strategies for Brain Tumors)

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17 pages, 3365 KiB

Open AccessArticle

A Retrospective Analysis of Ambiguous Spitz Tumors Using Next-Generation Sequencing

by Mario Teufer, Martin Theiler, Joana Lanz, Lisa Weibel, Ulrich Wagner, Mitchell P. Levesque, Jivko Kamarachev, Reinhard Dummer and Egle Ramelyte

Cancers 2025, 17(7), 1227; https://doi.org/10.3390/cancers17071227 - 4 Apr 2025

Viewed by 354

Abstract

Background: Spitz tumors (STs) are a diverse group of melanocytic lesions that range from benign to malignant. STs pose significant classification challenges due to overlapping histological and immunohistochemical (IHC) features among the STs with different malignant potential. This study aimed to assess the [...] Read more.

Background: Spitz tumors (STs) are a diverse group of melanocytic lesions that range from benign to malignant. STs pose significant classification challenges due to overlapping histological and immunohistochemical (IHC) features among the STs with different malignant potential. This study aimed to assess the diagnostic value of a melanoma-specific next-generation sequencing (NGS) panel (MelArray) combined with IHC analysis to improve the assessment of diagnostically challenging ST cases. Methods: Patients with STs and available MelArray results were included in this retrospective analysis. Molecular analysis (genetic alterations, tumor mutational burden (TMB), and copy number variations (CNV)), clinical data (demographics and clinical course), and IHC data (scores for markers such as p16, Ki-67, HMB45, PRAME, and Melan A) were evaluated in conjunction and correlated with patient outcomes. Results: Atypical Spitz tumors (ASTs, n = 20) predominantly exhibited heterozygous deletions in melanoma-relevant genes, but these were not accompanied by the multiple damaging mutations commonly associated with melanoma. IHC scores were higher in ASTs compared to Spitz nevi (SN, n = 3), suggesting an intermediate biologic potential. SN exhibited minimal genetic alterations and low IHC scores, reflecting a benign profile. Genetic analysis of the Spitz melanoma (SM, n = 1) revealed a distinct molecular profile with damaging mutations affecting the key regulatory pathways involved in tumor progression, along with a high TMB, and an IHC score comparable to ASTs. During a median follow-up of 36 months (range: 6–48 months, n = 23), no recurrences, distant metastases, or tumor-related deaths were observed. Conclusions: The integration of NGS analysis with the MelArray panel, histology, and immunohistochemistry, enhances the diagnostic accuracy of challenging STs by identifying the genetic alterations linked to malignancy risk. This aids in the detection of high-risk lesions that need a more detailed work-up and more stringent follow-up, and those that will follow a benign course. Larger studies are needed to validate the clinical utility and broader applicability. Full article

(This article belongs to the Special Issue Immunotherapy for Skin Cancers)

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16 pages, 2354 KiB

Open AccessReview

Unlocking the Genetic Secrets of Pancreatic Cancer: KRAS Allelic Imbalances in Tumor Evolution

by Vasiliki Liaki, Blanca Rosas-Perez and Carmen Guerra

Cancers 2025, 17(7), 1226; https://doi.org/10.3390/cancers17071226 - 4 Apr 2025

Viewed by 422

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) belongs to the types of cancer with the highest lethality. It is also remarkably chemoresistant to the few available cytotoxic therapeutic options. PDAC is characterized by limited mutational heterogeneity of the known driver genes, KRAS, CDKN2A, TP53, and SMAD4, observed in both early-stage [...] Read more.

Pancreatic Ductal Adenocarcinoma (PDAC) belongs to the types of cancer with the highest lethality. It is also remarkably chemoresistant to the few available cytotoxic therapeutic options. PDAC is characterized by limited mutational heterogeneity of the known driver genes, KRAS, CDKN2A, TP53, and SMAD4, observed in both early-stage and advanced tumors. In this review, we summarize the two proposed models of genetic evolution of pancreatic cancer. The gradual or stepwise accumulated mutations model has been widely studied. On the contrary, less evidence exists on the more recent simultaneous model, according to which rapid tumor evolution is driven by the concurrent accumulation of genetic alterations. In both models, oncogenic KRAS mutations are the main initiating event. Here, we analyze the emerging topic of KRAS allelic imbalances and how it arises during tumor evolution, as it is often detected in advanced and metastatic PDAC. We also summarize recent evidence on how it affects tumor biology, metastasis, and response to therapy. To this extent, we highlight the necessity to include studies of KRAS allelic frequencies in the design of future therapeutic strategies against pancreatic cancer. Full article

(This article belongs to the Special Issue RAS Signaling Pathway in Cancer Therapy)

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11 pages, 983 KiB

Open AccessArticle

Machine Learning Insight: Unveiling Overlooked Risk Factors for Postoperative Complications in Gastric Cancer

by Sejin Lee, Hyo-Jung Oh, Hosuon Yoo and Chan-Young Kim

Cancers 2025, 17(7), 1225; https://doi.org/10.3390/cancers17071225 - 4 Apr 2025

Viewed by 267

Abstract

Background: Since postoperative complications after gastrectomy for gastric cancer are associated with poor clinical outcomes, it is important to predict and prepare for the occurrence of complications preoperatively. Conventional models for predicting complications have limitations, prompting interest in machine learning algorithms. Machine learning [...] Read more.

Background: Since postoperative complications after gastrectomy for gastric cancer are associated with poor clinical outcomes, it is important to predict and prepare for the occurrence of complications preoperatively. Conventional models for predicting complications have limitations, prompting interest in machine learning algorithms. Machine learning models have a superior ability to identify complex interactions among variables and nonlinear relationships, potentially revealing new risk factors. This study aimed to explore previously overlooked risk factors for postoperative complications and compare machine learning models with linear regression. Materials and Methods: We retrospectively reviewed data from 865 patients who underwent gastrectomy for gastric cancer from 2018 to 2022. A total of 85 variables, including demographics, clinical features, laboratory values, intraoperative parameters, and pathologic results, were used to conduct the machine learning model. The dataset was partitioned into 80% for training and 20% for validation. To identify the most accurate prediction model, missing data handling, variable selection, and hyperparameter tuning were performed. Results: Machine learning models performed notably well when using the backward elimination method and a moderate missing data strategy, achieving the highest area under the curve values (0.744). A total of 15 variables associated with postoperative complications were identified using a machine learning algorithm. Operation time was the most impactful variable, followed closely by pre-operative levels of albumin and mean corpuscular hemoglobin. Machine learning models, especially Random Forest and XGBoost, outperformed linear regression. Conclusions: Machine learning, coupled with advanced variable selection techniques, showed promise in enhancing risk prediction of postoperative complications for gastric cancer surgery. Full article

(This article belongs to the Special Issue Clinical Studies in Gastrointestinal Malignancies)

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22 pages, 2653 KiB

Open AccessArticle

Targeting Hsp70 Immunosuppressive Signaling Axis with Lipid Nanovesicles: A Novel Approach to Treat Pancreatic Cancer

by Ahmet Kaynak, Subrahmanya D. Vallabhapurapu, Eric P. Smith, Harold W. Davis, Clayton S. Lewis, Joseph Ahn, Petr Muller, Borek Vojtesek, Keith F. Stringer, Robert S. Franco, Vladimir Y. Bogdanov, Wen-Hai Shao and Xiaoyang Qi

Cancers 2025, 17(7), 1224; https://doi.org/10.3390/cancers17071224 - 4 Apr 2025

Viewed by 366

Abstract

Background: Despite many efforts to effectively treat PDAC, PDAC carries one of the highest mortality rates of all major cancers. Thus, there is a critical unmet need to develop novel approaches to improve the clinical outcome of PDAC. It is well known that [...] Read more.

Background: Despite many efforts to effectively treat PDAC, PDAC carries one of the highest mortality rates of all major cancers. Thus, there is a critical unmet need to develop novel approaches to improve the clinical outcome of PDAC. It is well known that many cancers, including PDAC, generate a local TME that allows cancer to escape normal immune surveillance. Phosphatidylserine (PS), a negatively charged phospholipid that is abundant on the cancer cell membrane and with known actions to promote the secretion of immunomodulatory proteins, may provide a mechanism to regulate the TME. This study explored that possibility. Methods: MΦ differentiation and polarization were assessed by Western blotting and flow cytometric approaches. PS exposure and surface markers were analyzed by flow cytometry. Protein–protein and protein–lipid interactions were analyzed by immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Phospholipid and SapC-DOPG treatment were employed to assess target protein functions in MΦ polarization, tumor growth, and survival in subcutaneous and orthotopic tumor models. The PK-PD and safety of SapC-DOPG were tested on orthotopic mouse models. Results: Our studies show that PDAC secretes Hsp70 that stimulates the MΦ polarization to the immunosuppressive M2 phenotype. We found that high surface PS on cancer cells correlates with increased secretion of Hsp70 and is associated with higher MΦ differentiation activity in vitro and in vivo. Furthermore, blocking cancer cell-secreted Hsp70 with SapC-DOPG reverses the immune suppression and reduces tumor growth. Conclusions: These preclinical results reveal a novel immunotherapeutic approach to potentially improve the outcome of PDAC treatment in humans. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches for Cancer Treatment)

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Cancers, Volume 17, Issue 7 (April-1 2025) – 202 articles

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