Cancers

18 pages, 2990 KiB

Open AccessArticle

Prognostic Value of Post-Transplant MRD Negativity in Standard Versus High- and Ultra-High-Risk Multiple Myeloma Patients

by Lea Jasmin Kündgen, Dilara Akhoundova, Michele Hoffmann, Myriam Legros, Inna Shaforostova, Katja Seipel, Ulrike Bacher and Thomas Pabst

Cancers 2025, 17(9), 1565; https://doi.org/10.3390/cancers17091565 (registering DOI) - 4 May 2025

Abstract

Background: Cytogenetic abnormalities and the persistence of minimal residual disease (MRD) following autologous stem cell transplantation (ASCT) are two established prognostically unfavorable biomarkers in multiple myeloma (MM). Previous studies have shown that post-transplant MRD status is a powerful predictor of progression-free survival (PFS) [...] Read more.

Background: Cytogenetic abnormalities and the persistence of minimal residual disease (MRD) following autologous stem cell transplantation (ASCT) are two established prognostically unfavorable biomarkers in multiple myeloma (MM). Previous studies have shown that post-transplant MRD status is a powerful predictor of progression-free survival (PFS) and overall survival (OS). However, the impact of MRD remains poorly characterized in MM patients with high- or ultra-high-risk cytogenetics. Objectives: This study investigated the prognostic value of post-transplant MRD in standard- versus high- and ultra-high-risk MM. To this aim, we performed a retrospective analysis of 137 MM patients who underwent high-dose chemotherapy (HDCT) and ASCT at our institution between January 2019 and December 2021. Cytogenetics were assessed by fluorescence in situ hybridization. High-risk genomic alterations included del(17p), t(4;14), t(14;16), t(14;20), gain(1q), and TP53 mutations, with two or more alterations defining the ultra-high-risk category. MRD was assessed in bone marrow aspirates post-ASCT using flow cytometry. Results: Eighty-two (60%) patients were categorized as being at standard risk, forty (29%) as high risk, and fifteen (11%) as ultra-high risk. Median follow-up was 47 months. MRD negativity was achieved in 76 (55%) patients. At 48 months, the overall PFS rate was 61% (72%, 50%, and 32% for the standard-, high-, and ultra-high-risk subgroups, respectively; p = 0.0004), while the OS rate was 85% (89%, 79%, and 80% in standard-, high-, and ultra-high-risk MM patients, respectively; p = 0.1494). Within the standard-risk subgroup, longer PFS was observed for patients achieving MRD negativity (p = 0.0172). High- and ultra-high-risk patients showed no significant differences in PFS when stratified by MRD status, possibly due to prompt progression to MRD positivity. Conclusions: Our results suggest that high- and ultra-high-risk MM patients might benefit from closer response monitoring, including dynamic MRD assessment. Further, high- and ultra-high-risk patients might require a more intensive peri-transplant treatment. Full article

(This article belongs to the Topic Advances in Molecular Pathogenesis and Targeted Therapies for Multiple Myeloma)

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17 pages, 2471 KiB

Open AccessArticle

The Role of Gamma Knife Surgery in the Treatment of Rare Sellar Neoplasms: A Report of Nine Cases

by Michele Longhi, Riccardo Lavezzo, Valeria Barresi, Giorgia Bulgarelli, Anna D’Amico, Antonella Lombardo, Emanuele Zivelonghi, Paolo Maria Polloniato, Giuseppe Kenneth Ricciardi, Francesco Sala, Angelo Musumeci, Giampietro Pinna and Antonio Nicolato

Cancers 2025, 17(9), 1564; https://doi.org/10.3390/cancers17091564 (registering DOI) - 3 May 2025

Abstract

Introduction: The group of so-called “sellar-region masses” consists of a heterogeneous group of neoplasms and tumor-mimicking lesions, whose differential diagnosis may be challenging due to the overlapping of clinical and radiological features, which can be found both in “common” and “uncommon” lesions. The [...] Read more.

Introduction: The group of so-called “sellar-region masses” consists of a heterogeneous group of neoplasms and tumor-mimicking lesions, whose differential diagnosis may be challenging due to the overlapping of clinical and radiological features, which can be found both in “common” and “uncommon” lesions. The choice of a correct treatment strategy is still arduous and requires histological analysis. Gamma Knife Radiosurgery (GKRS) has already been reported as a safe and effective treatment in these cases. The objective of this study is to evaluate single-center pre-operative data, post-operative outcomes, and long-term follow-up in patients treated with GKRS for unusual sellar tumors. Methods: We retrospectively identified and analyzed nine patients treated with GKRS from 2004 to 2015, according to a standard protocol. Lesions consist of hypothalamic hamartoma (HH), Rathke’s cleft cist (RCC), Langerhans cell histiocytosis (LCH), spindle cell oncocytoma (SCO), choroid plexus papilloma (CPP), and ossifying fibroma (OF). The diagnosis was histologically confirmed in six patients that underwent surgery, while in three patients, diagnosis was based on characteristic clinical and radiological findings (two HH and one RCC). Pre-operative and post-operative data were retrieved from medical archives, and long-term follow-up was obtained through clinical and neuroradiological periodic examination. Results: In our series, all the “rare” sellar lesions treated, had a successful radiographic and clinical response in a medium-long follow-up period. Conclusions: The long-term follow-up results suggest that GKRS is a safe and effective treatment in rare sellar lesions, with very low toxicity. To the best of our knowledge, this report represents the largest series of unusual sellar lesions treated with GKRS in a single high-volume center, suggesting that GKRS might be an effective non-invasive adjuvant treatment option. Further studies and a larger number of patients are needed to confirm if residuals of these rare sellar lesions might regress on their own without treatment or if other non-invasive treatments could be as effective as GKRS. Full article

(This article belongs to the Special Issue Personalized Radiotherapy in Cancer Care (2nd Edition))

18 pages, 2650 KiB

Open AccessArticle

Computer-Aided Detection (CADe) of Small Metastatic Prostate Cancer Lesions on 3D PSMA PET Volumes Using Multi-Angle Maximum Intensity Projections

by Amirhosein Toosi, Sara Harsini, Ghasemali Divband, François Bénard, Carlos F. Uribe, Felipe Oviedo, Rahul Dodhia, William B. Weeks, Juan M. Lavista Ferres and Arman Rahmim

Cancers 2025, 17(9), 1563; https://doi.org/10.3390/cancers17091563 (registering DOI) - 3 May 2025

Abstract

Objectives: We aimed to develop and evaluate a novel computer-aided detection (CADe) approach for identifying small metastatic biochemically recurrent (BCR) prostate cancer (PCa) lesions on PSMA-PET images, utilizing multi-angle Maximum Intensity Projections (MA-MIPs) and state-of-the-art (SOTA) object detection algorithms. Methods: We fine-tuned and [...] Read more.

Objectives: We aimed to develop and evaluate a novel computer-aided detection (CADe) approach for identifying small metastatic biochemically recurrent (BCR) prostate cancer (PCa) lesions on PSMA-PET images, utilizing multi-angle Maximum Intensity Projections (MA-MIPs) and state-of-the-art (SOTA) object detection algorithms. Methods: We fine-tuned and evaluated 16 SOTA object detection algorithms (selected across four main categories of model types) applied to MA-MIPs as extracted from rotated 3D PSMA-PET volumes. Predicted 2D bounding boxes were back-projected to the original 3D space using the Ordered Subset Expectation Maximization (OSEM) algorithm. A fine-tuned Medical Segment-Anything Model (MedSAM) was then also used to segment the identified lesions within the bounding boxes. Results: The proposed method achieved a high detection performance for this difficult task, with the FreeAnchor model reaching an F1-score of 0.69 and a recall of 0.74. It outperformed several 3D methods in efficiency while maintaining comparable accuracy. Strong recall rates were observed for clinically relevant areas, such as local relapses (0.82) and bone metastases (0.80). Conclusion: Our fully automated CADe tool shows promise in assisting physicians as a “second reader” for detecting small metastatic BCR PCa lesions on PSMA-PET images. By leveraging the strength and computational efficiency of 2D models while preserving 3D spatial information of the PSMA-PET volume, the proposed approach has the potential to improve detectability and reduce workload in cancer diagnosis and management. Full article

(This article belongs to the Special Issue Radioligand Therapy in Cancer)

16 pages, 1416 KiB

Open AccessArticle

Heart and Left Anterior Descending Coronary Artery (LAD) Exposure from Hypo-Fractionated Whole Breast Radiotherapy with a Prone Setup

by Fabiana Gregucci, Elisabetta Bonzano, John Ng, Fereshteh Talebi, Maahi Patel, Dakota Trick, Sharanya Chandrasekhar, Xi Kathy Zhou, Maria Fenton-Kerimian, Ryan Pennell and Silvia C. Formenti

Cancers 2025, 17(9), 1562; https://doi.org/10.3390/cancers17091562 (registering DOI) - 3 May 2025

Abstract

Background: Prone breast radiotherapy has been shown to optimally spare the dose to the heart and lungs; we report on the heart and left anterior descending coronary artery (LAD) dosimetry and their implications for current care. Aims: (I) To measure the mean [...] Read more.

Background: Prone breast radiotherapy has been shown to optimally spare the dose to the heart and lungs; we report on the heart and left anterior descending coronary artery (LAD) dosimetry and their implications for current care. Aims: (I) To measure the mean heart dose (MHD) and LAD mean and maximum doses (Dmean and Dmax) in patients with left-side breast cancer who have undergone hypo-fractionated whole breast radiotherapy (WBRT) with a concomitant boost to the post-operative cavity (40.50 Gy to the breast and 48 Gy to the cavity in 15 fractions) in the prone position; (II) to compare the dosimetry results to those reported in the literature for other techniques. Materials and Methods: In a consecutive series of 524 irradiated left-side breast cancer patients, heart and LAD dosimetry data were collected and correlated to breast volume and the volume of the radiation boost to the tumor cavity. A descriptive statistical analysis was performed to compare the same dosimetry data with those reported in the literature from supine techniques. To account for dosimetry differences in hypo-fractionation and conventional fractionated regimens (50–60 Gy in 25–30 fractions) reported in the literature, the cardiac doses were converted to the equivalent dose in 2 Gy fractions (EQD2). As previously reported, the prone setup protocol placed the medial edges of the tangential radiation fields at least 2.5 mm from the contoured LAD. Results: In all patients’ plans, the target coverage was successfully achieved. The mean values (±SD) were as follows: MHD = 0.69 Gy (±0.19) (EQD2 0.35 Gy ± 0.1); LAD Dmean = 2.20 Gy (±0.68) (EQD2 1.18 Gy ± 0.35); LAD Dmax = 4.44 Gy (±1.82) (EQD2 2.55 Gy ± 0.97). The values were consistently lower compared with those achieved by the multiple supine techniques reported in the literature. Spearman’s correlation analysis revealed a strong positive correlation between LAD and heart dosimetry variables. In contrast, no strong correlation was observed between the cardiac dose metrics and breast volume, boost volume, or their ratio index. A linear correlation was detected between LAD Dmean and LAD D2% (R2 0.64); LAD D2% and heart D2% (R2 0.60); LAD Dmax and heart D2% (R2 0.41). Conclusions: The prone position protocol minimizes heart and LAD exposure. This approach results in a dosimetry advantage when compared with more complex and expensive WBRT techniques in the supine position. Full article

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

11 pages, 2428 KiB

Open AccessArticle

Upfront Oxaliplatin–Fluoropyrimidine Chemotherapy and Somatostatin Analogues in Advanced Well-Differentiated Gastro-Entero-Pancreatic Neuroendocrine Tumors

by Maria Grazia Maratta, Ileana Sparagna, Denis Occhipinti, Luigi Roca, Margherita Sgambato, Salvatore Raia, Antonio Bianchi, Sabrina Chiloiro, Ernesto Rossi, Guido Rindi, Giampaolo Tortora and Giovanni Schinzari

Cancers 2025, 17(9), 1561; https://doi.org/10.3390/cancers17091561 (registering DOI) - 3 May 2025

Abstract

(1) Background: GEP-NETs are frequently diagnosed at advanced stage. For well-differentiated somatostatin receptor-positive (SSTR+) NETs, SSA are the preferred first-line therapy. However, in newly diagnosed patients with G2/G3 and a high tumor burden, SSA alone might not be enough; (2) Methods: We conducted [...] Read more.

(1) Background: GEP-NETs are frequently diagnosed at advanced stage. For well-differentiated somatostatin receptor-positive (SSTR+) NETs, SSA are the preferred first-line therapy. However, in newly diagnosed patients with G2/G3 and a high tumor burden, SSA alone might not be enough; (2) Methods: We conducted a retrospective analysis to assess the effectiveness of combining oxaliplatin–fluoropyrimidine chemotherapy with SSA as an upfront strategy in newly diagnosed metastatic G2/G3 GEP-NET patients treated with oxaliplatin–fluoropyrimidine-based chemotherapy; (3) Results: Between March 2017 and October 2023, 32 pts (19 males, 13 females; M:F = 1.5:1; median age 54 years, range 31–82) were deemed eligible to receive oxaliplatin–fluoropyrimidine chemotherapy in addition to SSA; 14 received XELOX and 18 FOLFOX. After a median follow-up of 26 mo., each patient had completed at least two cycles of chemotherapy. The ORR was 25%, with a median DoR of 21.3 mo. The DCR was 87.5%. Notably, 28.1% of patients experienced tumor shrinkage sufficient for radical surgery on residual tumor lesions, encompassing both primary tumors and metastases; (4) Conclusions: Upfront treatment with the combination of oxaliplatin–fluoropyrimidine and SSA demonstrated effectiveness and safety. This approach may be considered to facilitate conversion surgery in eligible patients. Full article

(This article belongs to the Section Molecular Cancer Biology)

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13 pages, 2057 KiB

Open AccessArticle

Patient-Reported Functional Outcomes and Quality of Life After Contact X-Ray Brachytherapy (CXB) in Organ-Preserving Management of Rectal Cancer

by Ngu Wah Than, D. Mark Pritchard, David M. Hughes, Carrie A. Duckworth, Muneeb Ul Haq, Thomas Cummings, Charlotte Jardine, Sarah Stead, Rajaram Sripadam and Arthur Sun Myint

Cancers 2025, 17(9), 1560; https://doi.org/10.3390/cancers17091560 (registering DOI) - 3 May 2025

Abstract

Background/Objectives: With recent advancements in rectal cancer management leading to longer patient survival, the impact of various treatment approaches on patients’ quality of life (QOL) becomes an important focus of attention. While QOL studies exist for watch-and-wait after (chemo)radiation with/without local excision, data [...] Read more.

Background/Objectives: With recent advancements in rectal cancer management leading to longer patient survival, the impact of various treatment approaches on patients’ quality of life (QOL) becomes an important focus of attention. While QOL studies exist for watch-and-wait after (chemo)radiation with/without local excision, data on health-related QOL (HRQOL) outcomes after contact X-ray brachytherapy (CXB) remain limited. This study evaluated functional and HRQOL outcomes in rectal cancer patients undergoing CXB and (chemo)radiation over one year. Methods: This prospective observational study (enrolment January–October 2023) with one-year follow-up assessed functional and HRQOL outcomes after CXB and (chemo)radiation using EORTC-QLQ-CR29, HADS, and EQ-5D-3L questionnaires. Longitudinal analyses were conducted using linear mixed-effects models, incorporating both fixed and random effects, following data processing based on relevant scoring manuals. Results: QOL was assessed in 53 patients who attended our centre for CXB for various clinical indications, with 51, 47, and 42 remaining at the end of treatment, 6-month, and 12-month follow-ups, respectively. Overall, symptom and functional scores from EORTC-QLQ-CR29 remained stable throughout the follow-up period. Significant improvements were observed in abdominal pain, flatulence, urinary frequency, and body weight at 12 months. HADS and EQ-5D-3L scores remained stable, while EQ-VAS scores showed improvement, indicating a good overall quality of life following CXB treatment. Conclusions: CXB treatment combined with (chemo)radiation maintained stable HRQOL, with some improvements in symptoms and QOL noted during the subsequent year. These findings will help rectal cancer patients understand the benefits and limitations of CXB as a treatment option. Full article

(This article belongs to the Special Issue Advances in Brachytherapy in the Treatment of Tumors)

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18 pages, 4987 KiB

Open AccessArticle

Impacts of Dental Follicle Cells and Periodontal Ligament Cells on the Bone Invasion of Well-Differentiated Oral Squamous Cell Carcinoma

by Anqi Chang, Kiyofumi Takabatake, Tianyan Piao, Takuma Arashima, Hotaka Kawai, Htoo Shwe Eain, Yamin Soe, Zin Zin Min, Keisuke Nakano and Hitoshi Nagatsuka

Cancers 2025, 17(9), 1559; https://doi.org/10.3390/cancers17091559 (registering DOI) - 3 May 2025

Abstract

Background: Oral squamous cell carcinoma (OSCC) frequently invades the jawbone, leading to diagnostic and therapeutic challenges. While tumor–bone interactions have been studied, the specific roles of dental follicle cells (DFCs) and periodontal ligament cells (PDLCs) in OSCC-associated bone resorption remain unclear. This study [...] Read more.

Background: Oral squamous cell carcinoma (OSCC) frequently invades the jawbone, leading to diagnostic and therapeutic challenges. While tumor–bone interactions have been studied, the specific roles of dental follicle cells (DFCs) and periodontal ligament cells (PDLCs) in OSCC-associated bone resorption remain unclear. This study aimed to compare the effects of DFCs and PDLCs on OSCC-induced bone invasion and elucidate the underlying mechanisms. Methods: Primary human DFCs and PDLCs were isolated from extracted third molars and characterized by Giemsa and immunofluorescence staining. An in vitro co-culture system and an in vivo xenograft mouse model were established using the HSC-2 OSCC cell line. Tumor invasion and osteoclast activation were assessed by hematoxylin and eosin (HE) and tartrate-resistant acid phosphatase (TRAP) staining. Immunohistochemical analysis was performed to evaluate the expression of receptor activator of NF-κB ligand (RANKL) and parathyroid hormone-related peptide (PTHrP). Results: DFCs significantly enhanced OSCC-induced bone resorption by promoting osteoclastogenesis and upregulating RANKL and PTHrP expression. In contrast, PDLCs suppressed RANKL expression and partially modulated PTHrP levels, thereby reducing osteoclast activity. Conclusions: DFCs and PDLCs exert opposite regulatory effects on OSCC-associated bone destruction. These findings underscore the importance of stromal heterogeneity and highlight the therapeutic potential of targeting specific stromal–tumor interactions to mitigate bone-invasive OSCC. Full article

(This article belongs to the Special Issue Oral Potentially Malignant Disorders and Oral Cavity Cancer)

14 pages, 1653 KiB

Open AccessArticle

Five Cellular Genes as Candidates for Cervical Adenocarcinoma Molecular Markers

by Isui Abril García-Montoya, Karla Berenice López-Córdova, Daniel Marrero-Rodríguez, Mauricio Salcedo-Vargas, Claudia Lucía Vargas-Requena, Angélica Maria Escárcega-Avila, Santos Adriana Martel-Estrada and Florinda Jiménez-Vega

Cancers 2025, 17(9), 1558; https://doi.org/10.3390/cancers17091558 (registering DOI) - 3 May 2025

Abstract

Background/Aim: Cervical adenocarcinoma associated with Human Papillomavirus (HPV) infection represents 85–90% of all adenocarcinomas that have poor prognostic factors and is an important health public concern. Currently, cervical adenocarcinoma molecular markers are scarce. This study searched databases and the literature regarding candidate genes [...] Read more.

Background/Aim: Cervical adenocarcinoma associated with Human Papillomavirus (HPV) infection represents 85–90% of all adenocarcinomas that have poor prognostic factors and is an important health public concern. Currently, cervical adenocarcinoma molecular markers are scarce. This study searched databases and the literature regarding candidate genes to find these molecular markers, which were experimentally evaluated in fresh cervical samples. Materials and Methods: Bioinformatic analysis of 161 transcriptomic libraries of cervical tissues with or without lesions from the NCBI database was performed using the Partek Genomics Suite 6.6v software. The selected genes with a p value of >0.05, and 1.5-fold change were considered. A search of molecular marker candidates of cervical lesions that were already published in the literature was performed. To validate the selected genes, total RNA from fresh cervical adenocarcinoma and cervical normal tissues were subjected to RT-PCR experiments; HPV detection was also performed. Results: Initially, twenty-five genes were identified using bioinformatic analysis, and their expression was evaluated. The results showed that the HOXC6, HOXC8, RARβ, ELAVL2, URG4, CISD2, CA9, BCL2, Survivin, MACC1, CDKN2A, and HPV E6/E7 genes were found to be differentially expressed in CC. Among these, RARβ, MACC1, BCL2, HOXC8, and E6/E7/HPV exhibited higher statistical significance for CC samples. Conclusions: This five-gene panel could serve as a novel molecular tool for HPV-associated cervical adenocarcinoma detection. Full article

(This article belongs to the Special Issue Cervical Cancer: Study on Molecular Landscape and Protein Biomarkers. Current Diagnostic and Therapeutic Capabilities)

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15 pages, 333 KiB

Open AccessArticle

Patterns of Recurrence After Postoperative Stereotactic Radiotherapy for Brain Metastases

by Jeroen A. Crouzen, Anna L. Petoukhova, Martijn Hakstege, Elise E. M. W. van Schaik, Rishi D. S. Nandoe Tewarie, Rob J. A. Nabuurs, Maaike J. Vos, Melissa Kerkhof, Thijs van der Vaart, Johan A. F. Koekkoek, Rogier E. Hagenbeek, Fatih M. Yildirim, Lisette M. Wiltink, Noëlle C. M. G. van der Voort van Zyp, Mandy Kiderlen, Marike L. D. Broekman, Mirjam E. Mast and Jaap D. Zindler

Cancers 2025, 17(9), 1557; https://doi.org/10.3390/cancers17091557 (registering DOI) - 3 May 2025

Abstract

Background/Objectives: Neurosurgical resection is the standard treatment for large brain metastases (BMs). Postoperative stereotactic radiotherapy (SRT) is used to reduce local recurrence (LR) but does not always prevent leptomeningeal disease (LMD). This study aims to analyze patterns of tumor recurrence and to identify [...] Read more.

Background/Objectives: Neurosurgical resection is the standard treatment for large brain metastases (BMs). Postoperative stereotactic radiotherapy (SRT) is used to reduce local recurrence (LR) but does not always prevent leptomeningeal disease (LMD). This study aims to analyze patterns of tumor recurrence and to identify opportunities for the further improvement of treatment efficacy. Methods: We included 147 patients who underwent resection and SRT for BMs. The distance between the resection cavity target volume and the new tumor growth was calculated. Cox regression analyses were used to assess associations of LMD with various patient characteristics. Results: Median survival after postoperative SRT was 14 months (IQR 6–30) with a 3-year actuarial survival rate of 21%. LR occurred in 20/147 patients (14%). After total resection, LR occurred in 21% of patients after 3 years of follow-up compared to 36% after subtotal resection. Marginal LR occurred in 5/147 patients (3%). LMD was found in 21/147 patients (14%; 3-year actuarial rate, 26%), and it was found more commonly in patients with resected cerebellar metastases (23%; 3-year actuarial rate, 46%) compared to those with cerebral metastases (11%; 3-year actuarial rate 17%) (HR 2.54, 95% CI 1.07–6.04, p = 0.034). Conclusions: This study examined patterns of recurrence after postoperative radiotherapy and its implications for radiation dose, radiation field size, and treatment sequence. Local control was high after total resection. Radiation field size appeared adequate given the low incidence of marginal recurrences. Patients with cerebellar metastases showed an increased risk of LMD, underscoring the need for preventive measures, particularly preoperative SRT. Full article

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

17 pages, 2678 KiB

Open AccessArticle

A Multiparametric MRI and Baseline-Clinical-Feature-Based Dense Multimodal Fusion Artificial Intelligence (MFAI) Model to Predict Castration-Resistant Prostate Cancer Progression

by Dianning He, Haoming Zhuang, Ying Ma, Bixuan Xia, Aritrick Chatterjee, Xiaobing Fan, Shouliang Qi, Wei Qian, Zhe Zhang and Jing Liu

Cancers 2025, 17(9), 1556; https://doi.org/10.3390/cancers17091556 (registering DOI) - 3 May 2025

Abstract

Objectives: The primary objective of this study was to identify whether patients with prostate cancer (PCa) could progress to denervation-resistant prostate cancer (CRPC) after 12 months of hormone therapy. Methods: A total of 96 PCa patients with baseline clinical data who underwent multiparametric [...] Read more.

Objectives: The primary objective of this study was to identify whether patients with prostate cancer (PCa) could progress to denervation-resistant prostate cancer (CRPC) after 12 months of hormone therapy. Methods: A total of 96 PCa patients with baseline clinical data who underwent multiparametric magnetic resonance imaging (MRI) between September 2018 and September 2022 were included in this retrospective study. Patients were classified as progressing or not progressing to CRPC on the basis of their outcome after 12 months of hormone therapy. A dense multimodal fusion artificial intelligence (Dense-MFAI) model was constructed by incorporating a squeeze-and-excitation block and a spatial pyramid pooling layer into a dense convolutional network (DenseNet), as well as integrating the eXtreme Gradient Boosting machine learning algorithm. The accuracy, sensitivity, specificity, positive predictive value, negative predictive value, receiver operating characteristic curves, area under the curve (AUC) and confusion matrices were used as classification performance metrics. Results: The Dense-MFAI model demonstrated an accuracy of 94.2%, with an AUC of 0.945, when predicting the progression of patients with PCa to CRPC after 12 months of hormone therapy. The experimental validation demonstrated that combining radiomics feature mapping with baseline clinical characteristics significantly improved the model’s classification performance, confirming the importance of multimodal data. Conclusions: The Dense-MFAI model proposed in this study has the ability to more accurately predict whether a PCa patient could progress to CRPC. This model can assist urologists in developing the most appropriate treatment plan and prognostic measures. Full article

(This article belongs to the Special Issue MRI in Prostate Cancer)

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36 pages, 4226 KiB

Open AccessReview

Beyond the Transcript: Translating Non-Coding RNAs and Their Impact on Cellular Regulation

by Ananya Deshpande, Sagar Mahale and Chandrasekhar Kanduri

Cancers 2025, 17(9), 1555; https://doi.org/10.3390/cancers17091555 (registering DOI) - 3 May 2025

Abstract

Non-coding RNAs (ncRNAs) constitute the majority of the human transcriptome and play diverse structural, catalytic, and regulatory roles. The ability of ncRNAs to be translated into functional peptides and microproteins expands our understanding of their regulatory potential beyond their established non-coding functions. Our [...] Read more.

Non-coding RNAs (ncRNAs) constitute the majority of the human transcriptome and play diverse structural, catalytic, and regulatory roles. The ability of ncRNAs to be translated into functional peptides and microproteins expands our understanding of their regulatory potential beyond their established non-coding functions. Our comprehensive search identified 86 translating “non-coding” RNAs. While translating ncRNAs have traditionally been categorized as “peptide-encoding”, in this study, we introduce a novel classification based on amino acid length, distinguishing their products as ncRNA encoded peptides (ncRNA-PEPs), which are less than 60 amino acids, or ncRNA encoded microproteins (ncRNA-MPs) ranging from 61 to 200 amino acids. These peptides and microproteins act as co-regulators in cell signaling, transcriptional regulation, and protein complex assembly, playing a role in both health and disease. We outline the molecular pathways by which ncRNA-PEPs and ncRNA-MPs could govern cell cycle progression, highlighting their influence on cell cycle transitions, oncogenic and tumor suppressor pathways, metabolic homeostasis, autophagy, and on key cell cycle regulators like PCNA, Rad18, and CDK–cyclin complexes. Furthermore, we highlight recent advancements in their detection and characterization, exploring their evolutionary origins, species-specific conservation, and potential therapeutic applications. Our findings underscore the emerging significance of ncRNA-PEPs and ncRNA-MPs as integral regulators of cellular processes, highlighting their functional versatility and opening promising avenues for further research and potential therapeutic applications. Full article

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

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25 pages, 2097 KiB

Open AccessReview

Mechanistic Roles of Transcriptional Cyclin-Dependent Kinases in Oncogenesis: Implications for Cancer Therapy

by Mohammed Alrouji, Mohammed S. Alshammari, Saleha Anwar, Kumar Venkatesan and Anas Shamsi

Cancers 2025, 17(9), 1554; https://doi.org/10.3390/cancers17091554 (registering DOI) - 3 May 2025

Abstract

Cyclin-dependent kinases (CDKs) are pivotal in regulating cell cycle progression and transcription, making them crucial targets in cancer research. The two types of CDKs that regulate different biological activities are transcription-associated CDKs (e.g., CDK7, 8, 9, 12, and 13) and cell cycle-associated CDKs [...] Read more.

Cyclin-dependent kinases (CDKs) are pivotal in regulating cell cycle progression and transcription, making them crucial targets in cancer research. The two types of CDKs that regulate different biological activities are transcription-associated CDKs (e.g., CDK7, 8, 9, 12, and 13) and cell cycle-associated CDKs (e.g., CDK1, 2, 4, and 6). One characteristic of cancer is the dysregulation of CDK activity, which results in unchecked cell division and tumor expansion. Targeting transcriptional CDKs, which control RNA polymerase II activity and gene expression essential for cancer cell survival, has shown promise as a therapeutic approach in recent research. While research into selective inhibitors for transcriptional CDKs is ongoing, inhibitors that target CDK4/6, such as palbociclib and ribociclib, have demonstrated encouraging outcomes in treating breast cancer. CDK7, CDK8, and CDK9 are desirable targets for therapy since they have shown oncogenic roles in a variety of cancer types, such as colorectal, ovarian, and breast malignancies. Even with significant advancements, creating selective inhibitors with negligible off-target effects is still difficult. This review highlights the need for more research to optimize therapeutic strategies and improve patient outcomes by giving a thorough overview of the non-transcriptional roles of CDKs in cancer biology, their therapeutic potential, and the difficulties in targeting these kinases for cancer treatment. Full article

(This article belongs to the Special Issue Protein Kinases and Their Impact on Tumor Growth: Mechanisms and Therapeutic Targets)

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14 pages, 3816 KiB

Open AccessArticle

Deep Learning-Based Synthetic CT for Personalized Treatment Modality Selection Between Proton and Photon Therapy in Thoracic Cancer

by Libing Zhu, Nathan Y. Yu, Riley C. Tegtmeier, Jonathan B. Ashman, Aman Anand, Jingwei Duan, Quan Chen and Yi Rong

Cancers 2025, 17(9), 1553; https://doi.org/10.3390/cancers17091553 (registering DOI) - 3 May 2025

Abstract

Objectives: Identifying patients’ advantageous radiotherapy modalities prior to CT simulation is challenging. This study aimed to develop a workflow using deep learning (DL)-predicted synthetic CT (sCT) for treatment modality comparison based solely on a diagnostic CT (dCT). Methods: A DL network, [...] Read more.

Objectives: Identifying patients’ advantageous radiotherapy modalities prior to CT simulation is challenging. This study aimed to develop a workflow using deep learning (DL)-predicted synthetic CT (sCT) for treatment modality comparison based solely on a diagnostic CT (dCT). Methods: A DL network, U-Net, was trained utilizing 46 thoracic cases from a public database to generate sCT images predicting planning CT (pCT) scans based on the latest dCT, and tested on 15 institutional patients. The sCT accuracy was evaluated against the corresponding pCT and a commercial algorithm deformed CT (MdCT) based on Mean Absolute Error (MAE) and Universal Quality Index (UQI). To determine advantageous treatment modality, clinical dose-volume histogram (DVH) metrics and Normal Tissue Complication Probability (NTCP) differences between proton and photon treatment plans were analyzed on the sCTs via concordance correlation coefficient (CCC). Results: The AI-generated sCTs closely resembled those of the commercial deformation algorithm in the tested cases. The differences in MAE and UQI values between the sCT-vs-pCT and MdCT-vs-pCT were 19.38 HU and 0.06, respectively. The mean absolute NTCP deviation between sCT and pCT was 1.54%, 0.21%, and 2.36% for esophagus perforation, lung pneumonitis, and heart pericarditis, respectively. The CCC between sCT and pCT was 0.90 for DVH metrics and 0.97 for NTCP, indicating moderate agreement for DVH metrics and substantial agreement. Conclusions: Radiation oncologists can potentially utilize this personalized sCT based approach as a clinical support tool to rapidly compare the treatment modality benefit during patient consultation and facilitate in-depth discussion on potential toxicities at a patient-specific level. Full article

(This article belongs to the Special Issue New Approaches in Radiotherapy for Cancer)

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20 pages, 617 KiB

Open AccessReview

Advancements in Electronic Medical Records for Clinical Trials: Enhancing Data Management and Research Efficiency

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

Cancers 2025, 17(9), 1552; https://doi.org/10.3390/cancers17091552 - 2 May 2025

Abstract

Recent advancements in electronic medical records (EMRs) have transformed clinical trials and healthcare systems by improving data accuracy, regulatory compliance, and integration with decision support tools. These innovations enhance trial efficiency, streamline patient recruitment, and enable large-scale data analysis while bridging clinical practice [...] Read more.

Recent advancements in electronic medical records (EMRs) have transformed clinical trials and healthcare systems by improving data accuracy, regulatory compliance, and integration with decision support tools. These innovations enhance trial efficiency, streamline patient recruitment, and enable large-scale data analysis while bridging clinical practice with research. Despite these benefits, challenges such as data standardization, privacy concerns, and usability issues persist. Overcoming these barriers through policy reforms, technological innovations, and robust methodologies is essential to maximizing the potential of EMRs. We examine current developments, challenges, and future directions for optimizing EMRs in clinical trials and healthcare delivery. Full article

(This article belongs to the Special Issue Advances in Clinical Trials: Outcome, Innovations, Challenges, and Ethical Practice in Cancer Research 2024–2025)

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13 pages, 1872 KiB

Open AccessArticle

Prospective Multi-Institutional Observational Study of Retreatment with Anti-PD-1/PD-L1 Antibodies in Patients with Non-Small Cell Lung Cancer Previously Treated with Anti-PD-1/PD-L1 Plus Chemotherapy: NJLCG (North Japan Lung Cancer Group) Trial 1901

by Shin Saito, Yosuke Kawashima, Hisashi Tanaka, Naruo Yoshimura, Yoko Tsukita, Ryota Saito, Taku Nakagawa, Minehiko Inomata, Hiromi Nagashima and Shunichi Sugawara

Cancers 2025, 17(9), 1551; https://doi.org/10.3390/cancers17091551 - 2 May 2025

Abstract

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized standard therapies for non-small cell lung cancer (NSCLC) [...] Full article

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

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13 pages, 1387 KiB

Open AccessArticle

Development of an Evaluation Tool for Monitoring the Delivery of Psychosocial Care in Pediatric Oncology Settings

by Kristin Foster, Bethany Sadler, Amy L. Conrad and Amanda Grafft

Cancers 2025, 17(9), 1550; https://doi.org/10.3390/cancers17091550 - 2 May 2025

Abstract

In January of 2019, the University of Iowa Stead Family Children’s Hospital (UI SFCH) formalized their Pediatric Psychosocial Oncology Program by utilizing 15 evidence-based Standards for Psychosocial Care for Children with Cancer and Families as a foundation for program development. The psychosocial oncology [...] Read more.

In January of 2019, the University of Iowa Stead Family Children’s Hospital (UI SFCH) formalized their Pediatric Psychosocial Oncology Program by utilizing 15 evidence-based Standards for Psychosocial Care for Children with Cancer and Families as a foundation for program development. The psychosocial oncology clinical team members identified ongoing gaps in care and a need to improve progress toward achieving these standards. Reviewing and analyzing the Pediatric Psychosocial Standard of Care Institutional Assessment Tool further highlighted the need for program development but also demonstrated the need to design institutionally specific objective measures to monitor program improvements over time. The current project focused on the creation of a program evaluation system with objective measures specific to the UI SFCH practice setting. Barriers such as staffing and cost were identified and addressed. Additionally, a REDCap^® database using a structured chart review as its foundation was initiated, which permitted the comprehensive evaluation of the standards of care at UI SFCH. The Matrix and Guidelines included in the Pediatric Psychosocial Standard of Care Institutional Assessment Tool comprised the framework to develop institution specific objective measurements for each standard of care. The objective measures of interest were social work assessments and provider biopsychosocial assessments. Data were exported and uploaded to a statistical program for data analysis. The statistical significance of percentage changes was evaluated with a one-tailed t-test; p values < 0.05 were considered significant. The development of this REDCap^® database project allowed for the evaluation of the program’s current efficiency in implementing the PSCPCC standards of care. Using the database in the future will allow psychosocial oncology team members to easily identify other areas for improvement and to ensure that all 15 standards of psychosocial care are being comprehensively addressed in the care of pediatric oncology patients and interactions with their families. Full article

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

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21 pages, 714 KiB

Open AccessReview

Paediatric Thyroid Carcinoma: The Genetic Revolution and Its Implications for Therapy and Outcomes

by Joel A. Vanderniet, Noemi A. Fuentes-Bolanos, Yoon Hi Cho, Katherine M. Tucker, Antoinette Anazodo, Andrew J. Bauer and Paul Z. Benitez-Aguirre

Cancers 2025, 17(9), 1549; https://doi.org/10.3390/cancers17091549 - 2 May 2025

Abstract

Background: The understanding of the molecular basis of paediatric thyroid carcinoma has expanded rapidly in the last decade. Most carcinomas are associated with de novo somatic gene alterations that confer distinct clinicopathological characteristics. In comparison to adults, paediatric carcinomas are less commonly [...] Read more.

Background: The understanding of the molecular basis of paediatric thyroid carcinoma has expanded rapidly in the last decade. Most carcinomas are associated with de novo somatic gene alterations that confer distinct clinicopathological characteristics. In comparison to adults, paediatric carcinomas are less commonly associated with point mutations and more commonly with gene fusions, which are characterised by more-invasive disease. Cancer predisposition genes play an important role in a small percentage of tumours, and the family history and the recognition of other syndromic features are key to identifying these patients. Molecular testing platforms for clinical use have been developed and validated in adults, and their use is becoming established in the management of indeterminate thyroid nodules, where they significantly reduce the rates of diagnostic lobectomy. Paediatric data are more limited than adult data, and the role of molecular testing in paediatric thyroid carcinoma management is evolving. Methods: This review describes the current knowledge of molecular alterations in paediatric thyroid carcinomas, evidence supporting molecular testing in clinical practice, and future directions for research. Results and Conclusions: A molecular diagnosis enables the use of molecularly targeted therapies for children and adolescents with advanced or radioiodine-refractory disease. There is also great potential for molecular testing to improve the accuracy of the risk-stratification of paediatric thyroid nodules, reducing surgical intervention and complications without negatively impacting outcomes, and data to support such an approach are emerging. Full article

(This article belongs to the Special Issue 2nd Edition: Molecular Testing for Thyroid Nodules and Cancer)

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15 pages, 2700 KiB

Open AccessArticle

Differential Infiltration of T-Cell Populations in Tumor and Liver Tissues Predicts Recurrence-Free Survival in Surgically Resected Hepatocellular Carcinoma

by Eun Ji Jang, Ho Joong Choi, Young Kyoung You, Deok Hwa Seo, Mi Hyun Kwon, Keungmo Yang, Jaejun Lee, Jeong Won Jang, Seung Kew Yoon, Ji Won Han and Pil Soo Sung

Cancers 2025, 17(9), 1548; https://doi.org/10.3390/cancers17091548 - 2 May 2025

Abstract

Background/Objectives: Liver and tumor-infiltrating T cells in hepatocellular carcinoma (HCC) are heterogeneous, comprising the CD69⁺ tissue-resident T-cell and the CD69⁻ circulating T-cell populations. However, the impact of these distinct T-cell populations on patient prognosis is unclear; hence, further studies are [...] Read more.

Background/Objectives: Liver and tumor-infiltrating T cells in hepatocellular carcinoma (HCC) are heterogeneous, comprising the CD69⁺ tissue-resident T-cell and the CD69⁻ circulating T-cell populations. However, the impact of these distinct T-cell populations on patient prognosis is unclear; hence, further studies are needed. Methods: Tumor and distant liver tissues from 57 HCC patients with various chronic liver disease etiologies were analyzed. Single-cell dissociation and flow cytometry were used to assess CD69⁺ and CD69⁻ T-cell populations and their correlation with recurrence-free survival (RFS). Results: CD69⁺/CD69⁻ subpopulations within CD4⁺ and CD8⁺ T cells varied by patient and alcohol etiology. CD69⁻ populations among CD4⁺ T cells were less frequent in both tumor and non-tumor tissues of alcohol-related HCC patients (p < 0.05). Higher frequencies of CD69⁻CD4⁺ and CD8⁺ T cells in tumors and CD69⁺CD103⁺CD8⁺ T cells in liver tissues were associated with better RFS. CD69- T cells expressed lower PD-1 levels, indicating less exhaustion, with PD-1 expression inversely correlated with CD69⁻ frequency. PD-1 expression was higher in CD69⁻CD4⁺ T cells in alcohol-related HCC. Conclusions: We provided a detailed analysis of the heterogeneous characteristics of tumor- and liver-infiltrating T cells in HCC, emphasizing the distinct roles of CD69⁺ and CD69⁻ cell populations and their impact on RFS. CD69⁺ T cells were associated with immune exhaustion and tumor aggressiveness, whereas CD69⁻ T cells appeared to significantly contribute to the influence of alcohol intake on the immune landscape of HCC in the tumor microenvironment. However, further research should validate these findings in larger cohorts to enhance our understanding. Full article

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

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45 pages, 4168 KiB

Open AccessReview

Reciprocal Modulation of Tumour and Immune Cell Motility: Uncovering Dynamic Interplays and Therapeutic Approaches

by Angelo Aquino and Ornella Franzese

Cancers 2025, 17(9), 1547; https://doi.org/10.3390/cancers17091547 - 1 May 2025

Abstract

Dysregulated cell movement is a hallmark of cancer progression and metastasis, the leading cause of cancer-related mortality. The metastatic cascade involves tumour cell migration, invasion, intravasation, dissemination, and colonisation of distant organs. These processes are influenced by reciprocal interactions between cancer cells and [...] Read more.

Dysregulated cell movement is a hallmark of cancer progression and metastasis, the leading cause of cancer-related mortality. The metastatic cascade involves tumour cell migration, invasion, intravasation, dissemination, and colonisation of distant organs. These processes are influenced by reciprocal interactions between cancer cells and the tumour microenvironment (TME), including immune cells, stromal components, and extracellular matrix proteins. The epithelial–mesenchymal transition (EMT) plays a crucial role in providing cancer cells with invasive and stem-like properties, promoting dissemination and resistance to apoptosis. Conversely, the mesenchymal–epithelial transition (MET) facilitates metastatic colonisation and tumour re-initiation. Immune cells within the TME contribute to either anti-tumour response or immune evasion. These cells secrete cytokines, chemokines, and growth factors that shape the immune landscape and influence responses to immunotherapy. Notably, immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often dictated by the immune composition of the tumour site. Elucidating the molecular cross-talk between immune and cancer cells, identifying predictive biomarkers for ICB response, and developing strategies to convert cold tumours into immune-active environments is critical to overcoming resistance to immunotherapy and improving patient survival. Full article

(This article belongs to the Special Issue Cancer Cell Motility)

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