Cancers

14 pages, 329 KiB

Open AccessReview

Endoscopic Immuno-Oncology: A New Frontier in Treatment of Pancreatic Cancer

by Varun Vemulapalli, Cristina Natha and Nirav Thosani

Cancers 2025, 17(13), 2091; https://doi.org/10.3390/cancers17132091 (registering DOI) - 23 Jun 2025

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging malignancies to treat, largely due to late diagnosis, limited surgical options, and profound resistance to systemic therapies, all of which contribute to a five-year survival rate of approximately 9%. The dense, hypoxic, and [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging malignancies to treat, largely due to late diagnosis, limited surgical options, and profound resistance to systemic therapies, all of which contribute to a five-year survival rate of approximately 9%. The dense, hypoxic, and immunosuppressive tumor microenvironment (TME) of PDAC plays a critical role in immune evasion and therapeutic failure. As conventional immunotherapies have shown limited efficacy in PDAC, attention has shifted toward local interventions capable of remodeling the TME to enhance immune responsiveness. Endoscopic ultrasound (EUS)-guided ablative therapies have emerged as promising strategies to overcome these barriers. A range of modalities—including irreversible electroporation, microwave ablation, photodynamic therapy, and cryoablation—are under investigation. Among these, radiofrequency ablation (RFA) stands out as the most promising therapy as it not only induces direct tumor cytoreduction but also promotes antigen release, triggers immunogenic cell death, and may work synergistically with systemic therapies such as immune checkpoint inhibitors and adenosine pathway blockade. This review aims to explore the evolving role of endoscopic ablative therapies with a focus on RFA as a potential platform for immune activation in pancreatic cancer. Full article

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

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16 pages, 336 KiB

Open AccessArticle

Immunotherapy-Associated Renal Dysfunction in Metastatic Cancer: An Emerging Challenge in Onco-Nephrology

by Francesco Trevisani, Andrea Angioi, Michele Ghidini, Matteo Floris, Davide Izzo, Renato Maria Marsicano, Nerina Denaro, Gianluca Tomasello and Ornella Garrone

Cancers 2025, 17(13), 2090; https://doi.org/10.3390/cancers17132090 - 23 Jun 2025

Abstract

Background: Immune checkpoint inhibitors (ICIs) have significantly modified the management of metastatic cancers; however, their nephrotoxic potential remains underappreciated. While acute kidney injury (AKI) is a known immune-related adverse event, the subacute spectrum of kidney injury—termed acute kidney disease (AKD)—has not been adequately [...] Read more.

Background: Immune checkpoint inhibitors (ICIs) have significantly modified the management of metastatic cancers; however, their nephrotoxic potential remains underappreciated. While acute kidney injury (AKI) is a known immune-related adverse event, the subacute spectrum of kidney injury—termed acute kidney disease (AKD)—has not been adequately explored in this setting. Methods: We conducted a retrospective cohort study in 226 adult patients with metastatic solid tumors who received ICIs between 2017 and 2023 at a single tertiary care center. AKD was defined according to the 2024 “Kidney Disease: Improving Global Outcomes” (KDIGO) criteria. Multivariable logistic regression was used to identify predictors of AKD. Results: AKD occurred in 46 patients (20.4%) within 90 days of ICI initiation, with 16 (7.1%) experiencing persistent dysfunction beyond 30 days. Independent predictors of AKD included higher body surface area (OR 8.17, p = 0.03) and baseline use of nonsteroidal anti-inflammatory drugs (OR 29.74, p = 0.014). Baseline antibiotics showed a trend toward association (p = 0.054). Concurrent chemotherapy was associated with a trend toward protection. The predictive model showed good discrimination (AUC 0.778). No significant differences in other grade ≥2 immune-related adverse events were observed between the AKD and non-AKD groups. Conclusions: AKD is a frequent and underrecognized renal complication in patients receiving ICIs, with implications for both renal and oncological outcomes. Identifying high-risk patients and integrating longitudinal renal monitoring into immunotherapy care pathways may improve safety and treatment continuity. Full article

(This article belongs to the Section Cancer Therapy)

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14 pages, 1101 KiB

Open AccessSystematic Review

TRK Inhibitors in Adult and Pediatric High-Grade Gliomas: A Systematic Review and Individual Participant Data Meta-Analysis

by Massimiliano Domenico Rizzaro, Claudia Fanizzi, Giorgio Fiore, Luigi Gianmaria Remore, Antonella Maria Ampollini, Mauro Pluderi, Manuela Caroli and Marco Locatelli

Cancers 2025, 17(13), 2089; https://doi.org/10.3390/cancers17132089 - 23 Jun 2025

Abstract

Background: High-grade glioma (HGG) is the most common primary malignant brain tumor, with peak incidence in the fifth and sixth decades of life. Although HGG is rare in children, the prognosis remains poor, with a median overall survival (OS) of less than two [...] Read more.

Background: High-grade glioma (HGG) is the most common primary malignant brain tumor, with peak incidence in the fifth and sixth decades of life. Although HGG is rare in children, the prognosis remains poor, with a median overall survival (OS) of less than two years. Recently, TRK inhibitors have been approved for the treatment of tumors harboring NTRK gene fusions. In this review, we analyzed data from early clinical trials investigating the use of these agents in patients with HGG. Methods: A systematic literature search was performed in the PubMed database. Studies involving patients with HGG treated with TRK inhibitors were included. We analyzed progression-free survival (PFS), 24-week disease control rate, and complete or partial radiological responses according to the Response Assessment in Neuro-Oncology (RANO) criteria. Results: Sixteen studies comprising 55 patients with HGG harboring NTRK gene fusions (19 adults and 36 children) were included. A statistically significant difference in PFS was observed between pediatric and adult patients treated with TRK inhibitors (17 vs. 8.5 months; p < 0.001). Pediatric patients also exhibited a higher rate of complete or partial radiological response compared to adults (94% vs. 57%). Discussion: Although the available evidence on TRK inhibitors in HGG is limited, the findings of this review highlight a potentially promising role for these agents, particularly in the treatment of pediatric HGGs. Full article

(This article belongs to the Special Issue Neurosurgery Research on Brain Tumors: A Focus on Gliomas and Other Intra-axial Brain Tumors)

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33 pages, 1469 KiB

Open AccessReview

Lymphoproliferations in People Living with HIV: Oncogenic Pathways, Diagnostic Challenges, and New Therapeutic Opportunities

by Riccardo Dolcetti, Emanuela Vaccher and Antonino Carbone

Cancers 2025, 17(13), 2088; https://doi.org/10.3390/cancers17132088 - 22 Jun 2025

Abstract

Although efficiently managed by cART, chronic HIV infection remains associated with a high incidence of malignant lymphomas. This diverse group of tumors presents considerable challenges in research, diagnosis, and treatment due to their complex pathogenesis, heterogeneous tumor microenvironment, and frequently aggressive clinical behavior. [...] Read more.

Although efficiently managed by cART, chronic HIV infection remains associated with a high incidence of malignant lymphomas. This diverse group of tumors presents considerable challenges in research, diagnosis, and treatment due to their complex pathogenesis, heterogeneous tumor microenvironment, and frequently aggressive clinical behavior. In this review, we examine the multifactorial pathogenesis of lymphomas arising in people living with HIV (PLWH), encompassing both direct and indirect oncogenic mechanisms. We summarize the key histopathological features and microenvironmental characteristics that may influence therapeutic responses. Current treatment strategies approved for the treatment of lymphomas in PLWH are showing outcomes comparable with those observed in patients without HIV. Notably, the immune reconstitution achieved through cART has renewed interest in immunotherapeutic approaches for HIV-associated lymphomas, with several strategies under clinical investigation. However, progress in the diagnosis and management of these malignancies is hindered by fragmented research efforts and the frequent exclusion of PLWH from pivotal clinical trials. Coordinated efforts are essential to overcome these barriers, reduce lymphoma incidence, and improve survival outcomes in this vulnerable population. Full article

(This article belongs to the Special Issue Oncogenesis of Lymphoma)

13 pages, 1948 KiB

Open AccessArticle

Tropisetron Suppresses Chronic Pancreatitis and Pancreatic Cancer by Blocking Interleukin 33 Expression

by An-Na Bae, Mahsa Mortaja, YeePui Yeung, Jiao Huang, Jong Ho Park and Shadmehr Demehri

Cancers 2025, 17(13), 2087; https://doi.org/10.3390/cancers17132087 - 22 Jun 2025

Abstract

Background/Objectives: Chronic inflammation is a key driver of cancer. Interleukin 33 (IL-33) has emerged as a crucial factor involved in the pathogenesis of cancer-prone chronic inflammation. IL-33 functions as a cytokine and a nuclear protein to initiate chronic inflammation and cancer. However, small [...] Read more.

Background/Objectives: Chronic inflammation is a key driver of cancer. Interleukin 33 (IL-33) has emerged as a crucial factor involved in the pathogenesis of cancer-prone chronic inflammation. IL-33 functions as a cytokine and a nuclear protein to initiate chronic inflammation and cancer. However, small molecules capable of suppressing IL-33 expression to block its cytokine and nuclear functions are underexplored. Methods: The impact of tropisetron on IL-33 expression and its role in suppressing pancreatitis and pancreatitis-mediated pancreatic cancer were examined. Results: We demonstrate that tropisetron suppresses IL-33 expression, with high potential to serve as a novel therapeutic strategy for preventing chronic inflammation and its cancer sequela. Through screening 1018 Food and Drug Administration (FDA)-approved drugs, we discovered that tropisetron, a 5-hydroxytryptamine type 3 (5-HT3) antagonist commonly used to prevent and treat nausea and vomiting, effectively blocked IL-33 expression by suppressing IRF3 activation. Tropisetron inhibited pancreatitis and its progression to pancreatic cancer in mice. Conclusions: Tropisetron is an IL-33 inhibitor and can provide a novel therapeutic strategy to prevent and treat chronic pancreatitis and its associated cancer. Full article

(This article belongs to the Special Issue Advances in Drug Delivery for Cancer Therapy)

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17 pages, 1478 KiB

Open AccessArticle

Impact of Bowel Resection on Operative Mortality and Overall Survival in Advanced Epithelial Ovarian Cancer

by Özgür Ozan Ceylan, İlyas Turan, Evrim Erdemoglu, Marina Santos González and Javier Magrina

Cancers 2025, 17(13), 2086; https://doi.org/10.3390/cancers17132086 - 22 Jun 2025

Abstract

Background/Objectives: Bowel resection may be necessary during cytoreductive surgery (CS) in advanced epithelial ovarian cancer to achieve complete tumor removal. However, concerns about increased perioperative risks and unclear survival benefits have led to ongoing debate. This study aimed to evaluate the impact [...] Read more.

Background/Objectives: Bowel resection may be necessary during cytoreductive surgery (CS) in advanced epithelial ovarian cancer to achieve complete tumor removal. However, concerns about increased perioperative risks and unclear survival benefits have led to ongoing debate. This study aimed to evaluate the impact of bowel resection on perioperative mortality and overall survival (OS) in patients undergoing CS. Methods: We retrospectively reviewed 127 patients with FIGO stage IIB–IV epithelial ovarian cancer who underwent primary or interval CS between 2007 and 2021. Patients were stratified based on the performance of bowel resection. Clinical, surgical, and survival data were analyzed using Kaplan–Meier survival analysis and Cox proportional hazards modeling. Primary outcomes were 90-day mortality and OS. Results: Bowel resection was performed in 58 patients (46%) with more extensive disease and poorer ECOG performance scores. Although the resection group had increased perioperative risks (e.g., higher transfusion rates and ICU use), OS was similar between groups (log-rank p = 0.122). Multivariate analysis identified that increasing age (HR = 1.042, p = 0.005) was independently associated with poorer OS, whereas lymph node dissection (HR = 0.450, p = 0.003) and undergoing primary CS (HR = 0.540, p = 0.047) were associated with improved survival. Bowel resection was not independently associated with OS. Conclusions: Bowel resection does not adversely affect OS when optimal cytoreduction is achieved. Although it increases perioperative complexity, it can be safely incorporated into CS in selected patients. These findings support its use as part of an individualized surgical strategy for advanced ovarian cancer. Full article

(This article belongs to the Special Issue Surgical Advances in Cancer Treatments: Exploring Innovative Approaches and Emerging Perspectives by the Italian College of Associate Professors of Surgery)

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13 pages, 2547 KiB

Open AccessArticle

Improving Diagnostic Robustness of Perfusion MRI in Brain Metastases: A Focus on 3D ROI Techniques and Automatic Thresholding

by Stéphanie Rudzinska-Mistarz, Brieg Dissaux, Laurie Marchi, Anne-Charlotte Roux, Alexis Perrot, François Lucia, Romuald Seizeur, Olivier Pradier, Gurvan Dissaux, Moncef Morjani and Vincent Bourbonne

Cancers 2025, 17(13), 2085; https://doi.org/10.3390/cancers17132085 - 22 Jun 2025

Abstract

Background: Distinguishing tumor recurrence from radiation necrosis after radiotherapy for brain metastases remains a major diagnostic challenge. Perfusion MRI, particularly the measurement of relative cerebral blood volume (rCBV), is a commonly used technique to differentiate between these two entities. However, variations in [...] Read more.

Background: Distinguishing tumor recurrence from radiation necrosis after radiotherapy for brain metastases remains a major diagnostic challenge. Perfusion MRI, particularly the measurement of relative cerebral blood volume (rCBV), is a commonly used technique to differentiate between these two entities. However, variations in the placement of regions of interest (ROIs) affect diagnostic accuracy. This study compares the diagnostic performance of different cerebral perfusion methods, including a novel volumetric 3D ROI method and automatic thresholding, to differentiate tumor recurrence from radiation necrosis. Methods: We retrospectively analyzed data from 23 patients, including 25 brain metastases treated with stereotactic radiotherapy, who were suspected of local recurrence and had histological confirmation via biopsy or surgical resection. Each patient underwent perfusion MRI before surgery. The diagnostic performance of the different ROI methods (manual and 3D) was evaluated using the area under the ROC curve (AUC), as well as sensitivity and specificity measures. An automatic thresholding method was also applied, generating tumor sub-volumes with predefined cut-off values to determine the rCBV threshold most specific for differentiating relapse from necrosis. Results: The 3D ROI method, considering the whole lesion and a healthy ROI in the head of the caudate nucleus, demonstrated superior diagnostic performance (AUC = 0.65), outperforming manual methods (AUC = 0.53). Robustness was moderate, with an intraclass correlation coefficient of 0.60 between Syngo.via and IntelliSpace. Conclusions: The 3D ROI method shows promise in improving diagnostic accuracy in distinguishing tumor recurrence from radiation necrosis. Further studies with standardized protocols and larger populations are needed to validate these results. Full article

(This article belongs to the Special Issue Radiation Therapy for Brain Tumors)

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10 pages, 293 KiB

Open AccessArticle

Oncological and Functional Outcomes of Hemi-Ablation Versus Focal Ablation for Localized Prostate Cancer Using Irreversible Electroporation

by Michel Suberville, Kai Zhang, Jean Baptiste Woillard, Isabelle Herafa, Dorothée Ducoux, Rachid Nachef, Jeremy Teoh, Gang Zhu, Chi-Fai Ng, Pilar Laguna and Jean de la Rosette

Cancers 2025, 17(13), 2084; https://doi.org/10.3390/cancers17132084 - 22 Jun 2025

Abstract

Background: Irreversible electroporation (IRE) is a novel ablative treatment modality for localized prostate cancer and aims at achieving oncological control while minimizing the related side effects. We present the functional and oncological outcomes of focal IRE ablation versus hemi-ablation from a single-center [...] Read more.

Background: Irreversible electroporation (IRE) is a novel ablative treatment modality for localized prostate cancer and aims at achieving oncological control while minimizing the related side effects. We present the functional and oncological outcomes of focal IRE ablation versus hemi-ablation from a single-center patient series. Methods: Men with histologically confirmed low–intermediate risk prostate cancer received focal IRE ablation or hemi-ablation. All the patients were recommended an MRI-targeted fusion biopsy plus systematic biopsy at 1 year post-IRE ablation. The functional outcomes were measured by the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF) questionnaires. Results: In total, 106 patients were recruited in this study. The median follow-up time was 24 months (IQR 15–36). Overall, 94 patients underwent repeat prostate biopsy at 12 months after IRE. Persistent tumor was detected in 72.2% in the focal ablation group and in 31% in the hemi-ablation group (p < 0.001). Clinically significant prostate cancer (Gleason ≥ 3 + 4) was detected in 25% in the focal ablation group and in 8.6% in the hemi-ablation group (p = 0.003). There was no significant difference between the two groups in terms of IPSS and IIEF at each follow-up time point. Conclusion: For men with localized low–intermediate risk prostate cancer, hemi-IRE ablation treatment displayed better oncological control than focal ablation without compromising on functional or sexual outcomes. Full article

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

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15 pages, 242 KiB

Open AccessArticle

Efficacy of Dual Hormonal Therapy with Fulvestrant and Aromatase Inhibitors as Neoadjuvant Endocrine Treatment for Locally Advanced Breast Cancer

by Ana Majić, Žarko Bajić, Marija Ban, Ivana Tica Sedlar, Dora Čerina Pavlinović, Branka Petrić Miše, Ante Strikić, Snježana Tomić and Eduard Vrdoljak

Cancers 2025, 17(13), 2083; https://doi.org/10.3390/cancers17132083 - 21 Jun 2025

Abstract

Background: The role of neoadjuvant endocrine therapy (NET) in patients with luminal tumors is still not well defined in everyday clinical practice. To assess the efficacy of combination NET, we analyzed the outcomes of fulvestrant and aromatase inhibitors (AI) in combination in [...] Read more.

Background: The role of neoadjuvant endocrine therapy (NET) in patients with luminal tumors is still not well defined in everyday clinical practice. To assess the efficacy of combination NET, we analyzed the outcomes of fulvestrant and aromatase inhibitors (AI) in combination in a real-world population. Methods: This was a single-arm, retrospective longitudinal study of the total population of patients diagnosed with locoregionally advanced, clinical stage II-III, HR+ HER2-, luminal-type eBC, who were treated with the neoadjuvant combination of fulvestrant and AI between 2019 and 2024 at the Clinical University Hospital of Split, Croatia. Results: We enrolled 44 patients in the intention-to-treat (ITT) population, while 34 completed NET and surgery (per-protocol population; PPP). The median duration of NET was 11 months (interquartile range [IQR] of 9–16 months). The best radiological objective response rate (partial or complete response) was achieved by 30 (68.2%) in ITT, and 26 (76.5%) in PPP, defined by radiological examination, breast ultrasound, or MR. In the PPP, the minimal or moderate pathological response according to residual cancer burden (I or II) was observed in 29 (85.3%) patients. The median of absolute changes in Ki-67 was −5 (95% CI: −9 to 0), and the median of relative Ki67 changes was −40% (95% CI: −72% to 0%). Post-surgical Ki-67 was significantly predicted by initial Ki-67, positive lymph nodes, and time from diagnosis to the initiation of NET. Treatment was well tolerated, with no therapy discontinuation or dose reductions needed due to toxicity. The most commonly reported side effects included musculoskeletal pain (45.5%), asthenia (34.1%), and hot flashes (29.5%). Conclusions: Dual hormonal therapy with fulvestrant and AI is an active, easily given, non-toxic, promising neoadjuvant treatment in real-world patients with locally advanced luminal-type eBC who are not candidates for chemotherapy. Full article

(This article belongs to the Section Cancer Therapy)

13 pages, 1922 KiB

Open AccessArticle

Subclassification-Specific Tumor Immune Microenvironment in Intrahepatic Cholangiocarcinoma: Implications for Appropriate Pharmacotherapy

by Masahiko Kinoshita, Yasunori Sato, Shoji Kubo, Hiroji Shinkawa, Kenjiro Kimura, Kohei Nishio, Ryota Tanaka, Shigeaki Kurihara and Takeaki Ishizawa

Cancers 2025, 17(13), 2082; https://doi.org/10.3390/cancers17132082 - 21 Jun 2025

Abstract

Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is subclassified into small- and large-duct types. Small-duct-type iCCAs are associated with a better prognosis, and each subclassification requires different surgical strategies. The efficacy of chemotherapy, including immune checkpoint inhibitors, may vary between subclassifications. However, there are no [...] Read more.

Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is subclassified into small- and large-duct types. Small-duct-type iCCAs are associated with a better prognosis, and each subclassification requires different surgical strategies. The efficacy of chemotherapy, including immune checkpoint inhibitors, may vary between subclassifications. However, there are no reports on tumor immune microenvironment (TIME) analyses based on iCCA subclassifications. This study investigated subclassification-specific TIMEs in iCCAs for the purpose of establishing appropriate pharmacotherapy. Methods: A total of 131 resected iCCA cases were analyzed, comprising 73 tumors classified as small-duct-type and 58 as large-duct-type based on pathological evaluation. Immunohistochemical analyses targeting CD8, PD-1, PD-L1, CTLA-4, and S100 protein (a dendritic cell [DC] marker) were performed to investigate the immune-cell status in each subclassification. Results: Large-duct-type iCCA had a significantly higher CD8 expression in tumor-infiltrating cells than small-duct-type ICC. However, the expression of other molecules did not significantly differ between the two tumor types. The proportion of tumors with a high level of S100 protein expression (DC-high group) in tumor-infiltrating cells was significantly higher in small-duct-type ICCs than in large-duct-type iCCAs (30% vs. 1.7%). In small-duct-type iCCAs, the expression levels of CD8, PD-1, PD-L1, and CTLA-4 were significantly higher in the DC-high group than in the DC-low group. Conclusions: We revealed subclassification-specific TIMEs in iCCAs. A subset of small-duct-type iCCAs exhibited strong DC infiltration. In these patients, the tumors may establish an immunosuppressive TIME to evade antitumor immunity triggered by DC-mediated antigen presentation. These findings may contribute to the development of tailored pharmacotherapy for each iCCA subclassification. Full article

(This article belongs to the Special Issue The Pathology of Biliary Tract Carcinoma (BTC))

16 pages, 1075 KiB

Open AccessSystematic Review

Supraclavicular Lymph Node Dissection in Breast Cancer with Synchronous Supraclavicular Metastases: A Systematic Review and Network Meta-Analysis

by George Shiyao He, Jolene Li Ling Chia, Emmeline Elaine Cua-De Los Santos, Wong Hung Chew, Wee Yao Koh, Qin Xiang Ng, Samuel Ow and Serene Si Ning Goh

Cancers 2025, 17(13), 2081; https://doi.org/10.3390/cancers17132081 - 21 Jun 2025

Abstract

Background/Objectives: Synchronous ipsilateral supraclavicular lymph node metastases (sISLMs) in breast cancer are rare and associated with poor prognosis. The optimal locoregional treatment strategy remains unclear, particularly regarding the role of supraclavicular lymph node dissection (SLND). Methods: We conducted a systematic review and network [...] Read more.

Background/Objectives: Synchronous ipsilateral supraclavicular lymph node metastases (sISLMs) in breast cancer are rare and associated with poor prognosis. The optimal locoregional treatment strategy remains unclear, particularly regarding the role of supraclavicular lymph node dissection (SLND). Methods: We conducted a systematic review and network meta-analysis, including studies published up to end December 2023, to compare the outcomes of SLND combined with radiotherapy (RT) and systemic therapy (ST), SLND with ST alone, and ST alone, using RT + ST as the reference. Results: Ten studies involving 3346 patients were included for overall survival (OS) analysis, and six studies were included for disease-free survival (DFS). SLND + RT + ST showed similar OS and DFS compared to RT + ST. Sensitivity analyses revealed that SLND limited to level V improved OS (HR: 0.47, 95% CI: 0.29–0.77), while more extensive dissections (level V+) worsened outcomes (HR: 1.41, 95% CI: 1.10–1.80). Conclusions: These findings suggest that selective SLND may benefit certain patients, but broader application should be approached with caution pending results from future randomized trials. Full article

(This article belongs to the Special Issue Recent Advances and Challenges in Breast Cancer Surgery: 2nd Edition)

21 pages, 1343 KiB

Open AccessReview

The Evolving Landscape of GEP-NENs in the Era of Precision Oncology: Molecular Insights into Tumor Heterogeneity

by Sunanda Biswas Mukherjee, Rachyl M. Shanker, James P. Madigan and Samira M. Sadowski

Cancers 2025, 17(13), 2080; https://doi.org/10.3390/cancers17132080 - 21 Jun 2025

Abstract

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a varied group of tumors that originate from neuroendocrine cells found throughout the gastrointestinal tract. These tumors encompass a broad spectrum of biological behaviors, ranging from slow-growing, well-differentiated neuroendocrine tumors (GEP-NETs) to aggressive and poorly differentiated neuroendocrine carcinomas [...] Read more.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a varied group of tumors that originate from neuroendocrine cells found throughout the gastrointestinal tract. These tumors encompass a broad spectrum of biological behaviors, ranging from slow-growing, well-differentiated neuroendocrine tumors (GEP-NETs) to aggressive and poorly differentiated neuroendocrine carcinomas (GEP-NECs), complicating their accurate classification and effective treatment. While advances in molecular research have refined our understanding of these tumors, their complexity, unpredictable progression, and differential response to therapies remain major clinical hurdles. A significant clinical challenge is the accurate grading and diagnosis of GEP-NENs, which is traditionally reliant on subjective methods. However, innovative technologies, such as artificial intelligence-based diagnostics, multi-omics approaches, and precision oncology, are now offering solutions for more precise and reliable classification. Meanwhile, emerging therapies aiming to activate the immune response or modify the tumor environment present promising avenues for improved outcomes. Realizing the full potential of these advances will require a thoughtful integration of molecular insights with standardized diagnostic practices and evolving therapeutic strategies, ensuring that progress in research meaningfully informs and enhances patient care across diverse clinical settings. This review discusses new advancements and explores future directions toward personalized and effective treatments for GEP-NENs. Full article

(This article belongs to the Special Issue Advances in Molecular Mechanisms of Gastrointestinal Tumors (2nd Edition))

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20 pages, 3082 KiB

Open AccessArticle

Diagnosis and Evaluation of Aggressiveness Using Circulating Plasma miRNAs in Papillary Thyroid Microcarcinoma

by Jiwon Jang, Ji Min Kim, Sung-Chan Shin, Yong-il Cheon, Bo Hyun Kim, Mijin Kim, Sang Soo Kim and Byung-Joo Lee

Cancers 2025, 17(13), 2079; https://doi.org/10.3390/cancers17132079 - 21 Jun 2025

Abstract

Background/Objectives: MicroRNAs are emerging as valuable diagnostic markers for various diseases, including papillary thyroid carcinoma (PTC). However, there is limited research on circulating miRNA expression in papillary thyroid microcarcinoma (PTMC). Therefore, we conducted a study to explore whether plasma-derived miRNAs can distinguish PTMC [...] Read more.

Background/Objectives: MicroRNAs are emerging as valuable diagnostic markers for various diseases, including papillary thyroid carcinoma (PTC). However, there is limited research on circulating miRNA expression in papillary thyroid microcarcinoma (PTMC). Therefore, we conducted a study to explore whether plasma-derived miRNAs can distinguish PTMC from benign nodules or predict aggressiveness. Methods: A total of 150 patients who underwent thyroidectomy from January 2013 to July 2021 were enrolled in this study. Patients were divided into three groups: benign, low-risk PTMC, and advanced PTMC. Nine patients from each group were selected for microarray analysis for plasma miRNAs. Six miRNAs were selected for comparison of expression levels using TaqMan assay. The ROC curve was utilized to evaluate the diagnostic and aggressiveness value of the miRNAs. Results: From the microarray analysis, miR-455-3p and miR-548ac were identified as miRNAs that can significantly differentiate between benign nodules and PTMC. A combination of six miRNAs (miR-455-3p, miR-548ac., miR-221, miR-222, miR-146a. miR-146b) rather than individual miRNAs had the highest AUC (0.857), sensitivity (0.867), and specificity (0.800) in differentiating benign and PTMC. In microarray analysis, no significant miRNAs were observed to distinguish between low-risk group and aggressive PTMC. However, in the six-miRNA combination, it was possible to distinguish low-risk PTMC from aggressive PTMC with an AUC of 0.763, sensitivity of 0.739, and the specificity of 0.727. Conclusions: A combination of six miRNAs presents the possibility of distinguishing between benign and PTMC and low-risk and aggressive PTMC with an acceptable AUC, sensitivity, and specificity. Full article

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

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16 pages, 4101 KiB

Open AccessArticle

Bimodal Genomic Approach Predicting Semaphorin 7A (SEMA7A) as Prognostic Biomarker in Adrenocortical Carcinoma

by Anjali Dhall, Daiki Taniyama, Fathi Elloumi, Augustin Luna, Sudhir Varma, Suresh Kumar, Lauren Escobedo, Yilun Sun, Mirit I. Aladjem, Christophe E. Redon, Nitin Roper, William C. Reinhold, Jaydira Del Rivero and Yves Pommier

Cancers 2025, 17(13), 2078; https://doi.org/10.3390/cancers17132078 - 21 Jun 2025

Abstract

Background: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with a high mortality and poor prognosis. To elucidate the genetic underpinnings of ACCs, we have analyzed the transcriptome profiles of ACC tumor samples from patients enrolled in the TCGA and NCI [...] Read more.

Background: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with a high mortality and poor prognosis. To elucidate the genetic underpinnings of ACCs, we have analyzed the transcriptome profiles of ACC tumor samples from patients enrolled in the TCGA and NCI cohorts. Methods: We developed a bimodal approach using Gaussian Mixture Models to identify genes with bimodal distribution in ACC samples. Among the 72 bimodally expressed genes that are used to stratify patients into prognostic groups, we focused on SEMA7A, as it encodes a glycosylphosphatidylinositol-anchored membrane glycoprotein (Semaphorin 7a) regulating integrin-mediated signaling, cell migration and immune responses. Results: Our findings reveal that high expression levels of SEMA7A gene are associated with poor prognosis (hazard ratio = 4.27; p-value < 0.001). In hormone-producing ACCs, SEMA7A expression is elevated and positively correlated with genes driving steroidogenesis, aldosterone and cortisol synthesis, including CYP17A1, CYP11A1, INHA, DLK1, NR5A1 and MC2R. Correlation analyses show that SEMA7A is co-expressed with the integrin-β1, FAK (focal adhesion kinase) and MAPK/ERK (mitogen-activated protein kinase/extracellular signal regulated kinases) signaling pathways. Immunohistochemistry (IHC) staining demonstrates the feasibility of evaluating SEMA7A in ACC tissues and shows a significant correlation between gene expression (RNA-Seq) and protein expression (IHC). Conclusions: These findings suggest SEMA7A as a candidate for further research in ACC biology and a candidate for cancer therapy, as well as a potential prognosis biomarker for ACC patients. Full article

(This article belongs to the Section Cancer Biomarkers)

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18 pages, 281 KiB

Open AccessReview

Neoadjuvant, Perioperative, and Adjuvant Immunotherapy in Early-Stage Surgically Resectable Non-Small Cell Lung Cancer: Updates and Future Perspectives

by Diamone Gathers, Cameron Oswalt, Laura Alder, Kevin Chen, Jordyn P. Higgins, Jeffrey M. Clarke and Eziafa I. Oduah

Cancers 2025, 17(13), 2077; https://doi.org/10.3390/cancers17132077 - 21 Jun 2025

Abstract

Historically, systemic therapy for resectable non-small cell lung cancer (NSCLC) has been associated with a modest impact on overall survival. The current treatment options for early-stage resectable NSCLC include neoadjuvant, adjuvant, and perioperative immunotherapy in combination with chemotherapy. In this review, we explore [...] Read more.

Historically, systemic therapy for resectable non-small cell lung cancer (NSCLC) has been associated with a modest impact on overall survival. The current treatment options for early-stage resectable NSCLC include neoadjuvant, adjuvant, and perioperative immunotherapy in combination with chemotherapy. In this review, we explore the current treatment paradigms and emerging opportunities for improved survival outcomes from using immunotherapeutic approaches in the treatment of early-stage resectable NSCLC. The incorporation of immunotherapy into neoadjuvant, adjuvant, and perioperative treatment of surgically resectable NSCLC has yielded improved outcomes beyond chemotherapy-alone approaches. Despite this, there remains a margin for improving survival outcomes for patients. Clinical trials utilizing novel agents and approaches that modulate the anti-tumor immune response are currently ongoing and will likely inform the future treatment landscape for early-stage surgically resectable NSCLC. Full article

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

26 pages, 1531 KiB

Open AccessSystematic Review

The Impact of Treatment Delay on Endometrial and Ovarian Cancer Patients: A Systematic Review

by Dimitrios Zouzoulas, Tilemachos Karalis, Iliana Sofianou, Christos Anthoulakis, Katerina Tzika, Menelaos Zafrakas, Eleni Timotheadou, Grigoris Grimbizis and Dimitrios Tsolakidis

Cancers 2025, 17(13), 2076; https://doi.org/10.3390/cancers17132076 - 21 Jun 2025

Abstract

Background/Objectives: Ovarian and endometrial cancers present significant health burdens due to their substantial morbidity and mortality. Surgery delay is hypothesized to negatively impact patient outcomes, yet evidence remains inconsistent. This systematic review aims to comprehensively evaluate current evidence regarding the effects of treatment [...] Read more.

Background/Objectives: Ovarian and endometrial cancers present significant health burdens due to their substantial morbidity and mortality. Surgery delay is hypothesized to negatively impact patient outcomes, yet evidence remains inconsistent. This systematic review aims to comprehensively evaluate current evidence regarding the effects of treatment delay on survival and quality of life in these patients. Methods: A systematic literature search was conducted in MEDLINE (PubMed), Cochrane Library, Scopus, and ClinicalTrials.gov databases, complemented by a manual screening of reference lists, with studies included up to March 2025. Two independent reviewers screened and assessed the methodological quality using the ROBINS-E tool and extracted the data from the studies. Due to substantial methodological and clinical heterogeneity, results were synthesized qualitatively through narrative synthesis. Results: Twenty-one studies met the inclusion criteria, comprising predominantly retrospective cohort analyses. Treatment delays consistently correlated with decreased survival and advanced disease stages. Among studies, optimal intervals from diagnosis to treatment were varied from 2 to 8 weeks. Patient-reported outcomes indicated heightened anxiety, increased distress, and poor satisfaction with prolonged delays. Healthcare system factors such as resource allocation, geographic disparities, and socioeconomic inequalities significantly contributed to delays. Quantitative survival metrics supported a clear negative association between treatment delays and survival, although paradoxical outcomes in select subgroups highlighted underlying complexities. Conclusions: This systematic review underscores the critical importance of minimizing delays in the treatment of ovarian and endometrial cancers to improve patient survival and psychological outcomes. Identified healthcare system barriers demand targeted policy interventions to ensure timely and equitable access to tertiary healthcare infrastructures. Future research should prioritize standardizing delay definitions to strengthen and homogenize evidence. Full article

(This article belongs to the Special Issue Novel Approaches to Gynecologic Cancers Biology and Treatment: 2nd Edition)

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11 pages, 946 KiB

Open AccessArticle

Socioeconomic and Healthcare Indicators and Colorectal Cancer Burden: Analysis of Eurostat and Global Burden of Disease Study 2021 Data

by Nóra Kovács and Orsolya Varga

Cancers 2025, 17(13), 2075; https://doi.org/10.3390/cancers17132075 - 21 Jun 2025

Abstract

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide, posing a substantial health and economic burden. Despite advances in screening and treatment, significant socioeconomic and healthcare-related disparities persist across European Union (EU) member states. This study aims to [...] Read more.

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide, posing a substantial health and economic burden. Despite advances in screening and treatment, significant socioeconomic and healthcare-related disparities persist across European Union (EU) member states. This study aims to identify trends and inequality in CRC burden over time and to explore the relationship between country-level socioeconomic and healthcare indicators and CRC burden across EU member states. Methods: Age-standardized mortality, years lived with disability (YLD), years of life lost (YLL), and disability-adjusted life years (DALY) rates were extracted from Global Burden of Diseases Study 2021 for 24 EU countries. Socioeconomic and healthcare indicators were extracted from Eurostat between 2005 and 2021. The Gini index was calculated to evaluate CRC-related health inequality, and generalized linear mixed models were used to assess the link between indicators and disease burden. Results: The Gini index for age-standardized YLDs declined from 0.19 to 0.12 between 1990 and 2021, while inequality in YLL (from 0.11 to 0.16), DALY (from 0.11 to 0.15), and mortality rates (from 0.12 to 0.14) increased. The number of practicing physicians (p < 0.05) and higher levels of education (p < 0.001) were related to lower death, DALY, YLD, and YLL rates. Conversely, greater income inequality was linked to higher mortality, DALY, and YLL rates (p < 0.05). Conclusions: Our findings underscore that, in addition to expanding organized screening programs, enhancing physician availability and addressing socioeconomic inequalities are essential for reducing the burden of CRC. Full article

(This article belongs to the Special Issue Socio-Demographic Factors and Cancer Research)

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18 pages, 3694 KiB

Open AccessReview

Beyond the Signal: Imaging Insights and Diagnostic Relevance of Bone Oedema in Bone Tumours and Tumour-like Lesions

by Neel R. Raja, Hasaam Uldin, Ali Shah, Shashank Chapala and Rajesh Botchu

Cancers 2025, 17(13), 2074; https://doi.org/10.3390/cancers17132074 (registering DOI) - 20 Jun 2025

Abstract

Bone oedema is a non-specific imaging finding associated with a wide range of pathologies, including trauma, infection, inflammation, and neoplasms [...] Full article

(This article belongs to the Special Issue Sarcoma Management in Orthopaedic Oncology)

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14 pages, 1423 KiB

Open AccessArticle

Evaluating the Accuracy of Privacy-Preserving Large Language Models in Calculating the Spinal Instability Neoplastic Score (SINS)

by Li Yi Tammy Chan, Ding Zhou Matthew Chan, Yi Liang Tan, Qai Ven Yap, Wilson Ong, Aric Lee, Shuliang Ge, Wenxin Naomi Leow, Andrew Makmur, Yonghan Ting, Ee Chin Teo, Tan Jiong Hao, Naresh Kumar and James Thomas Patrick Decourcy Hallinan

Cancers 2025, 17(13), 2073; https://doi.org/10.3390/cancers17132073 (registering DOI) - 20 Jun 2025

Abstract

Background: Large language models (LLMs) have emerged as powerful tools in healthcare. In diagnostic radiology, LLMs can assist in the computation of the Spine Instability Neoplastic Score (SINS), which is a critical tool for assessing spinal metastases. However, the accuracy of LLMs in [...] Read more.

Background: Large language models (LLMs) have emerged as powerful tools in healthcare. In diagnostic radiology, LLMs can assist in the computation of the Spine Instability Neoplastic Score (SINS), which is a critical tool for assessing spinal metastases. However, the accuracy of LLMs in calculating the SINS based on radiological reports remains underexplored. Objective: This study evaluates the accuracy of two institutional privacy-preserving LLMs—Claude 3.5 and Llama 3.1—in computing the SINS from radiology reports and electronic medical records, comparing their performance against clinician readers. Methods: A retrospective analysis was conducted on 124 radiology reports from patients with spinal metastases. Three expert readers established a reference standard for the SINS calculation. Two orthopaedic surgery residents and two LLMs (Claude 3.5 and Llama 3.1) independently calculated the SINS. The intraclass correlation coefficient (ICC) was used to measure the inter-rater agreement for the total SINS, while Gwet’s Kappa was used to measure the inter-rater agreement for the individual SINS components. Results: Both LLMs and clinicians demonstrated almost perfect agreement with the reference standard for the total SINS. Between the two LLMs, Claude 3.5 (ICC = 0.984) outperformed Llama 3.1 (ICC = 0.829). Claude 3.5 was also comparable to the clinician readers with ICCs of 0.926 and 0.986, exhibiting a near-perfect agreement across all individual SINS components [0.919–0.990]. Conclusions: Claude 3.5 demonstrated high accuracy in calculating the SINS and may serve as a valuable adjunct in clinical workflows, potentially reducing clinician workload while maintaining diagnostic reliability. However, variations in LLM performance highlight the need for further validation and optimisation before clinical integration. Full article

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

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