Cancers

26 pages, 4295 KiB

Open AccessCommunication

Association of Proteasome Activity and Pool Heterogeneity with Markers Determining the Molecular Subtypes of Breast Cancer

by Irina Kondakova, Elena Sereda, Evgeniya Sidenko, Sergey Vtorushin, Valeria Vedernikova, Alexander Burov, Pavel Spirin, Vladimir Prassolov, Timofey Lebedev, Alexey Morozov and Vadim Karpov

Cancers 2025, 17(1), 159; https://doi.org/10.3390/cancers17010159 - 6 Jan 2025

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Abstract

Background: Proteasomes degrade intracellular proteins. Different proteasome forms were identified. Proteasome inhibitors are used in cancer therapy, and novel drugs directed to specific proteasome forms are developed. Breast cancer (BC) therapy depends on the subtype of the tumor, determined by the expression level [...] Read more.

Background: Proteasomes degrade intracellular proteins. Different proteasome forms were identified. Proteasome inhibitors are used in cancer therapy, and novel drugs directed to specific proteasome forms are developed. Breast cancer (BC) therapy depends on the subtype of the tumor, determined by the expression level of Ki67, HER-2, estrogen and progesterone receptors. Relationships between the presence of specific proteasome forms and proteins that determine the BC subtype remain unclear. Here, using gene expression data in 19,145 tumor samples from 144 datasets and tissues from 159 patients with different subtypes of BC, we investigated the association between the activity and expression of proteasomes and levels of BC subtype markers. Methods: Bioinformatic analysis of proteasome subunit (PSMB1-10) gene expression in BC was performed. Proteasome heterogeneity in BC cell lines was investigated by qPCR. By Western blotting, proteasome composition was assessed in cells and patient tissue lysates. Proteasome activities were studied using fluorogenic substrates. BC molecular subtypes were determined by immunohistochemistry. Results: BC subtypes demonstrate differing proteasome subunit expression pattern and strong PSMB8-10 co-correlation in tumors. A significant increase in chymotrypsin- and caspase-like proteasome activities in BC compared to adjacent tissues was revealed. The subunit composition of proteasomes in tumor tissues of BC subtypes varied. Regression analysis demonstrated a positive correlation between proteasome activities and the expression of Ki67, estrogen receptors and progesterone receptors. Conclusion: BC subtypes demonstrate differences within the proteasome pool. Correlations between the proteasome activity, hormone receptors and Ki67 indicate possible mutual influence. Obtained results facilitate development of novel drug combinations for BC therapy. Full article

(This article belongs to the Section Molecular Cancer Biology)

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Figure 1
The PSMB1-10 gene expression in breast carcinomas. (a) Comparison of PSMB1-10 gene expression and gene fitness data for breast cancer cell lines. Gene expression z-scores based on analysis of 20 cancer types from 144 datasets (R2: Genomics Analysis and Visualization Platform) represent how the PSMB1-10 gene expression in BC differs from other tumor types. Positive scores mean increased expression and negative scores - lower expression. Z-scores for gene dependency were obtained from DepMap data, and negative z-scores mean that proliferation and survival of breast cancer cells are more dependent on this gene expression than in other cell types. (b) The PSMB8 dependency score across 33 cancer cell types comparing cancers from DepMap database. Negative scores mean that there are fewer cells in screens after gene knockdown/knockout. Cells with potentially reduced proliferation due to PSMB8 downregulation are highlighted in red. (c) Gene expression in cell types identified in single cell data from CZ CELLxGENE Discover dataset. Color is proportional to gene expression and circle area proportional to percentage of cells expressing a gene. Data was clustered using weighted gene expression with Ward D2 algorithm. (d) Gene expression between malignant and histologically normal breast tissues. (e) Spearman correlation between PSMB genes in 143 normal breast tissues (lower-left half) and in 3207 breast cancer tumors (upper-right half). (f) Correlation between PSMB8 and PSMB9 (left), as well as PSMB5 and PSMB9 (right) gene expression in tumors. Spearman correlation was calculated, and linear regression line is shown. Color marks samples according to Nottingham histologic grading. *—p < 0.001 as calculated by two-sided Student’s t-test for each gene expression between normal and tumor tissues with Benjamini–Hochberg correction for comparing multiple genes. Full article ">Figure 2
Association of PSMB1-10 gene expression with clinical features of breast carcinomas. (a) The PSMB1-10 gene expression in breast carcinomas with various grades according to Nottingham histologic grading. The PSMB1-10 gene expression in (b) ER-negative vs. ER-positive, (c) PR-negative vs. PR-positive, (d) HER2-negative vs. HER2-positive, (e) Ki67-low vs. Ki-67 high breast carcinomas. (f) The PSMB1-10 gene expression in tumors with metastasis to different amount of lymph nodes. Gene expression data was extracted from GSE202203 dataset (n = 3207). *—p < 0.001 as calculated by two-sided Student’s t-test for each gene expression between two patient groups (b–e), and one-way ANOVA was used for comparison of multiple groups (a,f) with Benjamini-Hochberg correction for comparing multiple genes. Full article ">Figure 3
Immunoproteasome subunit expression affects sensitivity of BC cell lines of different origin to immunoproteasome inhibition. (a) Relative mRNA levels of PSMB8, PSMB9 and PSMB10 in MCF-7, SKBR3, ZR-75-1 and BT-474 cell lines normalized to the mean among all studied cell lines. p-values were calculated using Ordinary one-way ANOVA test, with significance levels denoted as follows: ns—p > 0.05; **—p < 0.01; ***—p < 0.001. (b) Western blotting of BC cell lysates with antibodies to LMP-2, MECL-1 and LMP-7. (c) Quantification of blots (b) using the ImageJ software ver.1.54i. (d) Viability of cells treated with ONX-0914 (Onx) for 72 h (% to DMSO-treated control) was measured using Resazurin cytotoxicity assay kit, and the half-maximal inhibitory concentrations (IC50s) were determined using nonlinear regression analysis with variable slope fitting (IC50 values represented in parentheses right side from the graph). The dotted line represents the level with 50% viability (IC50). All experiments were conducted in triplicates, and standard error of the mean (SEM) is indicated for each bar. Full article ">Figure 4
Proteasome activities and content in BC and adjacent tissues. Representative immunohistochemical staining of tumor tissues (a). First row (A1–A4) Invasive carcinoma of nonspecific type (Luminal A subtype): A1—Strong expression of ER; A2—Strong expression of PR; A3—negative expression of HER-2; A4—low level of Ki-67. Second row (B1–B4) Invasive carcinoma of nonspecific type (Luminal B subtype): B1—Strong expression of ER; B2—Strong expression of PR; B3—weak (1+) expression of HER-2; A4—high level of Ki-67 (>20%). Third row (C1–C4) Invasive carcinoma of nonspecific type (Triple negative subtype): C1—negative expression of ER; C2, negative expression of PR; C3, negative expression of HER-2; A4, high level of Ki-67 (>50%). Immunohistochemistry, ×200. Scale bar—100 μm. (b) ChTL and CL proteasome activities in BC and adjacent tissues (c). Proteasome activities in tissues of various molecular subtypes of BC. (d) The content of 20S proteasome or proteasome regulator subunits ((α1, α2, α3, α5, α6, α7), Rpt6, PA28β LMP-2, LMP-7) determined by Western blotting in BC (1) and adjacent tissues (2). Representative Western blots are shown. (e) Content of proteasome subunits in tumour and adjacent tissue; and in different molecular subtypes of the BC (f) determined via quantification of blots using the ImageJ software ver. 1.54i. Red box indicates the relative content of proteasome subunits in the adjacent tissue, which was considered as 100%; * p < 0.05, ** p < 0.01, Mann-Whitney test. Full article ">Figure 5
Interrelation and mutual influence of proteasome activities and indicators on the basis of which the molecular subtype of breast cancer is determined. Note: → The positive influence of one characteristic on another. Full article ">

14 pages, 737 KiB

Open AccessReview

Congenital Dermatofibrosarcoma Protuberans—An Update on the Ongoing Diagnostic Challenges

by Fortunato Cassalia, Andrea Danese, Enrico Cocchi, Silvia Vaienti, Anna Bolzon, Ludovica Franceschin, Roberto Mazzetto, Francesca Caroppo, Davide Melandri and Anna Belloni Fortina

Cancers 2025, 17(1), 158; https://doi.org/10.3390/cancers17010158 - 6 Jan 2025

Viewed by 362

Abstract

Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade sarcoma that presents diagnostic challenges due to its resemblance to benign lesions [...] Full article

(This article belongs to the Special Issue Rare Tumors in Children: Trends in Diagnosis, Treatment and Prevention (2nd Edition))

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24 pages, 1064 KiB

Open AccessArticle

Impact of Early Nutritional Intervention During Cancer Treatment on Dietary Intakes and Cardiometabolic Health in Children and Adolescents

by Josianne Delorme, Andra Dima, Véronique Bélanger, Mélanie Napartuk, Isabelle Bouchard, Caroline Meloche, Daniel Curnier, Serge Sultan, Caroline Laverdière, Daniel Sinnett and Valérie Marcil

Cancers 2025, 17(1), 157; https://doi.org/10.3390/cancers17010157 - 6 Jan 2025

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Abstract

Background/Objectives: Pediatric cancer survivors are at greater risk of cardiometabolic complications than their peers. This study evaluates the preliminary impact of the VIE (Valorization, Implication, Education) intervention, which integrates nutrition, physical activity, and psychological support, on dietary intake and cardiometabolic health among children [...] Read more.

Background/Objectives: Pediatric cancer survivors are at greater risk of cardiometabolic complications than their peers. This study evaluates the preliminary impact of the VIE (Valorization, Implication, Education) intervention, which integrates nutrition, physical activity, and psychological support, on dietary intake and cardiometabolic health among children and adolescents during cancer treatment. Methods: This comparative study includes pediatric cancer patients recruited to either the VIE intervention group or a control group receiving standard care. Post-treatment data on dietary intake, anthropometric measures, blood pressure, and biochemical parameters were compared between groups and stratified by level of involvement in the nutritional intervention and age at diagnosis (children and adolescents). Results: In the intervention group, 45 participants were included (51.1% male, mean age at evaluation 10.2 ± 4.5 years, mean time since end of treatment of 1.3 ± 0.8 years), and the control group comprised 77 participants (44.2% male, mean age at evaluation 12.0 ± 5.6 years, mean time since end of treatment of 1.4 ± 0.8 years). The intervention group had lower total caloric intake (mean: 1759 ± 513 vs. 1997 ± 669 kcal, p = 0.042) and higher calcium intake (mean: 567 ± 240 vs. 432 ± 197 mg/1000 kcal, p = 0.001). The participants who were highly involved in the nutritional intervention had greater protein-derived energy intake than the controls (mean: 17 ± 5 vs. 15 ± 4%, p = 0.029). While there was a tendency for a lesser proportion of cardiometabolic risk factors in the adolescents from the intervention group, the differences did not reach statistical significance. Conclusions: The VIE intervention improved some specific dietary intakes in the medium term after treatment completion but did not significantly impact cardiometabolic health outcomes. Additional strategies are needed to improve the diet of pediatric cancer patients, and further research is warranted to assess the long-term impact of such interventions. Full article

(This article belongs to the Topic Nutrition and Health During and After Childhood Cancer)

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7 pages, 214 KiB

Open AccessEditorial

Learning from Other Tumors: Pathways for Progress and Overcoming Challenges in Cholangiocarcinoma

by Giulia Tesini, Chiara Braconi, Lorenza Rimassa and Rocio I. R. Macias

Cancers 2025, 17(1), 156; https://doi.org/10.3390/cancers17010156 - 6 Jan 2025

Viewed by 468

Abstract

Cholangiocarcinoma (CCA) is a group of complex and heterogeneous tumors originating from the epithelial cells of bile ducts that can occur in intrahepatic, perihilar, or distal localizations [...] Full article

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

45 pages, 956 KiB

Open AccessReview

Metabolic Signaling in the Tumor Microenvironment

by Ryan Clay, Kunyang Li and Lingtao Jin

Cancers 2025, 17(1), 155; https://doi.org/10.3390/cancers17010155 - 6 Jan 2025

Viewed by 434

Abstract

Cancer cells must reprogram their metabolism to sustain rapid growth. This is accomplished in part by switching to aerobic glycolysis, uncoupling glucose from mitochondrial metabolism, and performing anaplerosis via alternative carbon sources to replenish intermediates of the tricarboxylic acid (TCA) cycle and sustain [...] Read more.

Cancer cells must reprogram their metabolism to sustain rapid growth. This is accomplished in part by switching to aerobic glycolysis, uncoupling glucose from mitochondrial metabolism, and performing anaplerosis via alternative carbon sources to replenish intermediates of the tricarboxylic acid (TCA) cycle and sustain oxidative phosphorylation (OXPHOS). While this metabolic program produces adequate biosynthetic intermediates, reducing agents, ATP, and epigenetic remodeling cofactors necessary to sustain growth, it also produces large amounts of byproducts that can generate a hostile tumor microenvironment (TME) characterized by low pH, redox stress, and poor oxygenation. In recent years, the focus of cancer metabolic research has shifted from the regulation and utilization of cancer cell-intrinsic pathways to studying how the metabolic landscape of the tumor affects the anti-tumor immune response. Recent discoveries point to the role that secreted metabolites within the TME play in crosstalk between tumor cell types to promote tumorigenesis and hinder the anti-tumor immune response. In this review, we will explore how crosstalk between metabolites of cancer cells, immune cells, and stromal cells drives tumorigenesis and what effects the competition for resources and metabolic crosstalk has on immune cell function. Full article

(This article belongs to the Special Issue Recent Updates on Cancer Stem Cells and Tumor Microenvironment)

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30 pages, 2082 KiB

Open AccessReview

The Role of Chronic Inflammation in Pediatric Cancer

by Christine Mella, Panogiotis Tsarouhas, Maximillian Brockwell and Hope C. Ball

Cancers 2025, 17(1), 154; https://doi.org/10.3390/cancers17010154 - 6 Jan 2025

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Abstract

Inflammation plays a crucial role in wound healing and the host immune response following pathogenic invasion. However, unresolved chronic inflammation can result in tissue fibrosis and genetic alterations that contribute to the pathogenesis of human diseases such as cancer. Recent scientific advancements exploring [...] Read more.

Inflammation plays a crucial role in wound healing and the host immune response following pathogenic invasion. However, unresolved chronic inflammation can result in tissue fibrosis and genetic alterations that contribute to the pathogenesis of human diseases such as cancer. Recent scientific advancements exploring the underlying mechanisms of malignant cellular transformations and cancer progression have exposed significant disparities between pediatric and adult-onset cancers. For instance, pediatric cancers tend to have lower mutational burdens and arise in actively developing tissues, where cell-cycle dysregulation leads to gene, chromosomal, and fusion gene development not seen in adult-onset counterparts. As such, scientific findings in adult cancers cannot be directly applied to pediatric cancers, where unique mutations and inherent etiologies remain poorly understood. Here, we review the role of chronic inflammation in processes of genetic and chromosomal instability, the tumor microenvironment, and immune response that result in pediatric tumorigenesis transformation and explore current and developing therapeutic interventions to maintain and/or restore inflammatory homeostasis. Full article

(This article belongs to the Section Pediatric Oncology)

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Chronic inflammation in pediatric cancer. Chronic inflammation plays a unique role in pediatric cancer, targeting differentiating cells and tissues. Alterations in the normal regulation of DNA repair, and abnormal epigenetic and chromosomal regulation alter the tumor microenvironment, promoting malignant transformation and tumor progression. The undeveloped and weakened pediatric immune system is limited in its ability to recognize and counter malignant cells contributing to cancer onset. Full article ">Figure 2
Chronic inflammation contributes to DNA and chromosomal instability. Chronic inflammation impairs the DNA damage response machinery resulting in the maintenance of oncogenic DNA breaks, splicing errors, and gene fusions. Exposure to chronic inflammation also contributes to the chromosomal abnormalities associated with pediatric cancer. Full article ">Figure 3
Chronic inflammation contributes to oncogenic genetic and epigenetic alterations. Exposure to chronic inflammation results in abnormal DNA and promoter methylation patterns that promote tumor growth and progression. Abnormal histone methylation and acetylation in malignant cells contribute to altered gene expression patterns affecting prognosis and drug response. Non-coding RNA alterations inhibit normal cell-cycle regulation and promote cancer cell migration. Full article ">Figure 4
Chronic inflammation alters the tissue microenvironment and immune recruitment to promote tumor onset, progression, and metastasis. Chronic inflammation promotes de-differentiation and/or malignant transformation of cells within the microenvironment, increased angiogenesis, and proinflammatory cytokine release. Conditions within the tumor microenvironment (TME) promote metastasis and inhibit immune cell recognition and targeting of malignantly transformed cancer cells. Arrows indicate an increase. Full article ">

10 pages, 233 KiB

Open AccessArticle

Quality of Nursing Care as Perceived by Patients Treated for Multiple Myeloma in Polish Oncology Units: A Cross-Sectional Study

by Magdalena Kurek, Tomasz Tatara, Jakub Świtalski, Adam Fronczak, Magdalena Tatara and Anna Augustynowicz

Cancers 2025, 17(1), 153; https://doi.org/10.3390/cancers17010153 - 6 Jan 2025

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Abstract

Background/Objectives: Patient satisfaction is one of the indicators of the quality of nursing care. The purpose of this study is to find out the level of satisfaction of patients with multiple myeloma with the quality of nursing care in oncology units. Methods: Data [...] Read more.

Background/Objectives: Patient satisfaction is one of the indicators of the quality of nursing care. The purpose of this study is to find out the level of satisfaction of patients with multiple myeloma with the quality of nursing care in oncology units. Methods: Data were obtained by a diagnostic survey method, using the Newcastle Nursing Satisfaction Scale. The survey was conducted among patients from four oncology departments in Poland on the day the patient was discharged or transferred to another unit. Participation in the study was voluntary and required patient consent. Patients were assured of the anonymity of their responses. Results: The study included 65 men and 75 women treated with chemotherapy and autologous hematopoietic stem cell transplant. Experiences and satisfaction with nursing care presented a level of 71.80 points and 74.46 points, respectively. The analysis showed no statistically significant differences between the groups in terms of treatment and gender. A statistically significant negative association was shown between age and nursing care experience score (r = −0.19; p = 0.024). Positive associations were shown between length of stay on the unit and rating of experience of nursing care (r = 0.23; p = 0.006) and satisfaction with nursing care (r = 0.26; p = 0.002). Conclusions: The experience and satisfaction with nursing care among patients treated for multiple myeloma in Polish oncology units is moderate. Efforts should be made to improve the quality of nursing care, especially taking into account the needs of the elderly. Full article

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

2 pages, 450 KiB

Open AccessCorrection

Correction: Häyrinen et al. The Transcription Factor Twist1 Has a Significant Role in Mycosis Fungoides (MF) Cell Biology: An RNA Sequencing Study of 40 MF Cases. Cancers 2023, 15, 1527

by Marjaana J. Häyrinen, Jenni Kiiskilä, Annamari Ranki, Liisa Väkevä, Henry J. Barton, Milla E. L. Kuusisto, Katja Porvari, Hanne Kuitunen, Kirsi-Maria Haapasaari, Hanna-Riikka Teppo and Outi Kuittinen

Cancers 2025, 17(1), 152; https://doi.org/10.3390/cancers17010152 - 6 Jan 2025

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Abstract

In the original publication [...] Full article

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10 pages, 2408 KiB

Open AccessArticle

Benign or Malignant? Ex Vivo Confocal Laser Scanning Microscopy for Bedside Histological Assessment of Melanocytic Lesions

by Maximilian Deußing, Lisa Buttgereit, Michaela Maurer, Alisa Swarlik, Lara Stärr, Andreas Ohlmann, Katrin Kerl-French, Michael Flaig, Elke C. Sattler, Lars E. French and Daniela Hartmann

Cancers 2025, 17(1), 151; https://doi.org/10.3390/cancers17010151 - 6 Jan 2025

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Abstract

Objective: Ex vivo confocal laser scanning microscopy (EVCM) is an emerging imaging technique, which offers rapid tissue examination. While the current literature shows promising results in the evaluation of non-melanoma skin cancer, only limited research exists on the application of EVCM in melanocytic [...] Read more.

Objective: Ex vivo confocal laser scanning microscopy (EVCM) is an emerging imaging technique, which offers rapid tissue examination. While the current literature shows promising results in the evaluation of non-melanoma skin cancer, only limited research exists on the application of EVCM in melanocytic lesions. This study aimed to assess the utility of EVCM in the characterization of melanocytic lesions and compare its findings with gold-standard histopathology. Methods: A total of 130 skin lesions, including 76 benign and 54 malignant melanocytic lesions, were prospectively collected and imaged using EVCM. Three blinded investigators were asked to identify characteristic morphologic features observed in the lesions and classify them into benign vs. malignant. The results were then compared with the corresponding histopathology. Sensitivity and specificity were calculated using contingency tables to assess the diagnostic performance. Results: The application of EVCM allowed for the visualization of cellular and tissue-level details, including cellular pleomorphism and atypical melanocytes. A comprehensive list of benign and malignant features identified by EVCM was compiled. Using these diagnostic criteria, the imaging of the inexperienced and dermatohistopathology-experienced investigator reached 67.7% concordance, and the imaging trained dermatologist obtained 69.2% agreement with dermatohistopathology in differentiating benign vs. malignant lesions. The imaging-trained dermatohistopathologist performed best with concordance up to 79.2%. Conclusions: In conclusion, EVCM is a promising technique for the rapid assessment of melanocytic lesions. Our study provides a comprehensive overview of morphologic EVCM features, which will contribute to the development of diagnostic algorithms for accurate diagnosis and appropriate treatment planning. Further studies are needed to evaluate its clinical utility and validate our diagnostic criteria. Full article

(This article belongs to the Special Issue Advanced Diagnostics and Optical Imaging Technologies in Cancer Research)

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17 pages, 3052 KiB

Open AccessSystematic Review

Robotic Versus Laparoscopic Adrenalectomy for Adrenal Tumors: An Up-to-Date Meta-Analysis on Perioperative Outcomes

by Giuseppe Esposito, Barbara Mullineris, Giovanni Colli, Serena Curia and Micaela Piccoli

Cancers 2025, 17(1), 150; https://doi.org/10.3390/cancers17010150 - 5 Jan 2025

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Abstract

Background: Minimally invasive surgery (MIS) for adrenal glands is becoming increasingly developed worldwide and robotic surgery has advanced significantly. Although there are still concerns about the generalization of outcomes and the cost burden, the robotic platform shows several advantages in overcoming some laparoscopic [...] Read more.

Background: Minimally invasive surgery (MIS) for adrenal glands is becoming increasingly developed worldwide and robotic surgery has advanced significantly. Although there are still concerns about the generalization of outcomes and the cost burden, the robotic platform shows several advantages in overcoming some laparoscopic shortcomings. Materials and Methods: A systematic review and meta-analysis were conducted using the PubMed, MEDLINE and Cochrane library databases of published articles comparing RA and LA up to January 2024. The evaluated endpoints were technical and post-operative outcomes. Dichotomous data were calculated using the odds ratio (OR), while continuous data were analyzed usingmean difference (MD) with a 95% confidence interval (95% CI). A random-effects model (REM) was applied. Results: By the inclusion of 28 studies, the meta-analysis revealed no statistically significant difference in the rates of intraoperative RBC transfusion, 30-day mortality, intraoperative and overall postoperative complications, re-admission, R1 resection margin and operating time in the RA group compared with the LA. However, the overall cost of hospitalization was significantly higher in the RA group than in the LA group, [MD USD 4101.32, (95% CI 3894.85, 4307.79) p < 0.00001]. With respect to the mean intraoperative blood loss, conversion to open surgery rate, time to first flatus and length of hospital stay, the RA group showed slightly statistically significant lower rates than the laparoscopic approach. Conclusions: To our knowledge, this is the largest and most recent meta-analysis that makes these comparisons. RA can be considered safe, feasible and comparable to LA in terms of the intraoperative and post-operative outcomes. In the near future, RA could represent a promising complementary approachto LA for benign and small malignant adrenal masses, particularly in high-volume referral centers specializing in robotic surgery. However, further studies are needed to confirm these findings. Full article

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

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14 pages, 570 KiB

Open AccessArticle

Long-Term Outcomes and Quality of Life of High-Risk Neuroblastoma Patients Treated with a Multimodal Treatment Including Anti-GD2 Immunotherapy: A Retrospective Cohort Study

by Tim Flaadt, Jonas Rehm, Thorsten Simon, Barbara Hero, Ruth L. Ladenstein, Holger N. Lode, Desiree Grabow, Sandra Nolte, Roman Crazzolara, Johann Greil, Martin Ebinger, Michael Abele, Ursula Holzer, Michaela Döring, Johannes H. Schulte, Peter Bader, Paul-Gerhardt Schlegel, Matthias Eyrich, Peter Lang, Thomas Klingebiel and Rupert Handgretinger Show full author list Hide full author list

Cancers 2025, 17(1), 149; https://doi.org/10.3390/cancers17010149 - 5 Jan 2025

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Abstract

Background: The incorporation of anti-GD2 antibodies such as ch14.18/SP2/0 into the multimodal treatment of high-risk neuroblastoma (HR-NB) patients has improved their outcomes. As studies assessing the long-term outcomes, long-term sequelae, and health-related quality of life (HRQoL) of this treatment are limited, this retrospective [...] Read more.

Background: The incorporation of anti-GD2 antibodies such as ch14.18/SP2/0 into the multimodal treatment of high-risk neuroblastoma (HR-NB) patients has improved their outcomes. As studies assessing the long-term outcomes, long-term sequelae, and health-related quality of life (HRQoL) of this treatment are limited, this retrospective analysis aimed to explore these. Patients and Methods: Between 1991 and 2002, 65 children received a multimodal treatment, including ch14.18/SP2/0, for primary HR-NB. All received chemotherapy according to the NB90/NB97 trial, 51 received high-dose chemotherapy, and all received ch14.18/SP2/0 treatment. We analyzed the long-term sequelae and HRQoL (EORTC QLQ-C30), and evaluated overall and event-free survival (OS/EFS). Results: Twenty-five survivors were evaluated for HRQoL and long-term effects. All reported long-term sequelae, including ototoxicity in 16/25 (64%), cardiac toxicity in 6/25 (24%), and endocrine toxicity in 19/25 (76%) patients. Chronic diarrhea was reported in 20% of female patients. Seven patients developed autoimmune diseases. HRQoL scores were better across multiple scales than those of the matched German general population. Twenty-five-year OS and EFS were 50.8% (95% confidence interval: 31–55) and 43% (30.1–55.3), with 33 (50.8%) long-term survivors. Thirty-two patients died: 28 (43.1%) because of progression/relapse and 4 (6.2%) because of secondary neoplasms. Conclusions: Multimodal treatment, including ch14.18/SP2/0, can achieve long-term survival in HR-NB patients, with a substantial proportion of survivors reporting better HRQoL compared to the general population. All patients reported long-term side effects mostly attributable to chemotherapy and radiotherapy. The relatively high prevalence of autoimmune diseases and persistent diarrhea warrants additional longitudinal research on individuals treated with anti-GD2 antibodies. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Novel Therapeutic Strategies in Pediatric Oncology)

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19 pages, 10343 KiB

Open AccessArticle

Integrated Analysis of Single-Cell and Bulk RNA Data Reveals Complexity and Significance of the Melanoma Interactome

by Michael J. Diaz, Jasmine T. Tran, Arthur M. Samia, Mahtab Forouzandeh, Jane M. Grant-Kels and Marjorie E. Montanez-Wiscovich

Cancers 2025, 17(1), 148; https://doi.org/10.3390/cancers17010148 - 5 Jan 2025

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Abstract

Background: Despite significant strides in anti-melanoma therapies, resistance and recurrence remain major challenges. A deeper understanding of the underlying biology of these challenges is necessary for developing more effective treatment paradigms. Methods: Melanoma single-cell data were retrieved from the Broad Single Cell Portal [...] Read more.

Background: Despite significant strides in anti-melanoma therapies, resistance and recurrence remain major challenges. A deeper understanding of the underlying biology of these challenges is necessary for developing more effective treatment paradigms. Methods: Melanoma single-cell data were retrieved from the Broad Single Cell Portal (SCP11). High-dimensional weighted gene co-expression network analysis (hdWGCNA), CellChat, and ligand-receptor relative crosstalk (RC) scoring were employed to evaluate intercellular and intracellular signaling. The prognostic value of key regulatory genes was assessed via Kaplan-Meier (KM) survival analysis using the ‘SKCM-TCGA’ dataset. Results: Twenty-seven (27) gene co-expression modules were identified via hdWGCNA. Notable findings include NRAS Q61L melanomas being enriched for modules involving C19orf10 and ARF4, while BRAF V600E melanomas were enriched for modules involving ALAS1 and MYO1B. Additionally, CellChat analysis highlighted several dominant signaling pathways, namely MHC-II, CD99, and Collagen-receptor signaling, with numerous significant ligand-receptor interactions from melanocytes, including CD99-CD99 communications with cancer-associated fibroblasts, endothelial cells, NK cells, and T-cells. KM analysis revealed that higher expression of SELL, BTLA, IL2RG, PDGFA, CLDN11, ITGB3, and SPN improved overall survival, while higher FGF5 expression correlated with worse survival. Protein-protein interaction network analysis further indicated significant interconnectivity among the identified prognostic genes. Conclusions: Overall, these insights underscore critical immune interactions and potential therapeutic targets to combat melanoma resistance, paving the way for more personalized and effective treatment strategies. Full article

(This article belongs to the Collection Emerging Therapeutics in Advanced Melanoma)

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21 pages, 966 KiB

Open AccessReview

A Personalized Approach for Oligometastatic Prostate Cancer: Current Understanding and Future Directions

by Parissa Alerasool, Susu Zhou, Eric Miller, Jonathan Anker, Brandon Tsao, Natasha Kyprianou and Che-Kai Tsao

Cancers 2025, 17(1), 147; https://doi.org/10.3390/cancers17010147 - 5 Jan 2025

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Abstract

Oligometastatic prostate cancer (OMPC) represents an intermediate state in the progression from localized disease to widespread metastasis when the radiographically significant sites are limited in number and location. With no clear consensus on a definition, its diagnostic significance and associated optimal therapeutic approach [...] Read more.

Oligometastatic prostate cancer (OMPC) represents an intermediate state in the progression from localized disease to widespread metastasis when the radiographically significant sites are limited in number and location. With no clear consensus on a definition, its diagnostic significance and associated optimal therapeutic approach remain controversial, posing a significant challenge for clinicians. The current standard of care for metastatic disease is to start systemic therapy; however, active surveillance and targeted radiotherapy have become attractive options to mitigate the long-term effects of androgen deprivation therapy (ADT). Furthermore, evolving biomarker methodologies may further define optimal treatment selection. In this review, we summarize the current understanding that guides the treatment of OMPC, with a focus on how host response can be an important contributing factor. Evolving scientific understanding and clinical development will continue to shape the landscape of treatment strategies for this distinct disease state. Full article

(This article belongs to the Special Issue Updates on Urologic Oncology: From Diagnosis to Localized and Systemic Therapy Options (2nd Edition))

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17 pages, 303 KiB

Open AccessReview

Glioblastoma: Clinical Presentation, Multidisciplinary Management, and Long-Term Outcomes

by David Sipos, Bence L. Raposa, Omar Freihat, Mihály Simon, Nejc Mekis, Patrizia Cornacchione and Árpád Kovács

Cancers 2025, 17(1), 146; https://doi.org/10.3390/cancers17010146 - 5 Jan 2025

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Abstract

Glioblastoma, the most common and aggressive primary brain tumor in adults, presents a formidable challenge due to its rapid progression, treatment resistance, and poor survival outcomes. Standard care typically involves maximal safe surgical resection, followed by fractionated external beam radiation therapy and concurrent [...] Read more.

Glioblastoma, the most common and aggressive primary brain tumor in adults, presents a formidable challenge due to its rapid progression, treatment resistance, and poor survival outcomes. Standard care typically involves maximal safe surgical resection, followed by fractionated external beam radiation therapy and concurrent temozolomide chemotherapy. Despite these interventions, median survival remains approximately 12–15 months, with a five-year survival rate below 10%. Prognosis is influenced by factors such as patient age, molecular characteristics, and the extent of resection. Patients with IDH-mutant tumors or methylated MGMT promoters generally have improved survival, while recurrent glioblastoma is associated with a median survival of only six months, as therapies in these cases are often palliative. Innovative treatments, including TTFields, add incremental survival benefits, extending median survival to around 20.9 months for eligible patients. Symptom management—addressing seizures, headaches, and neurological deficits—alongside psychological support for patients and caregivers is essential to enhance quality of life. Emerging targeted therapies and immunotherapies, though still limited in efficacy, show promise as part of an evolving treatment landscape. Continued research and clinical trials remain crucial to developing more effective treatments. This multidisciplinary approach, incorporating diagnostics, personalized therapy, and supportive care, aims to improve outcomes and provides a hopeful foundation for advancing glioblastoma management. Full article

(This article belongs to the Special Issue Outcomes in Glioblastoma Patients: From Diagnosis to Palliation)

13 pages, 1558 KiB

Open AccessArticle

Oral Maintenance Therapy in Early Breast Cancer—How Many Patients Are Potential Candidates?

by Nikolas Tauber, Lisbeth Hilmer, Dominik Dannehl, Franziska Fick, Franziska Hemptenmacher, Natalia Krawczyk, Thomas Meyer-Lehnert, Kay Milewski, Henriette Princk, Andreas Hartkopf, Achim Rody and Maggie Banys-Paluchowski

Cancers 2025, 17(1), 145; https://doi.org/10.3390/cancers17010145 - 5 Jan 2025

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Abstract

Background/Objectives: This single-center analysis evaluated the number of potential candidates for endocrine-based oral maintenance therapy in a real-world setting, focusing on three therapeutic agents, namely, olaparib, abemaciclib, and ribociclib, for patients with hormone receptor-positive HER2-negative early breast cancer. Methods: All breast cancer cases [...] Read more.

Background/Objectives: This single-center analysis evaluated the number of potential candidates for endocrine-based oral maintenance therapy in a real-world setting, focusing on three therapeutic agents, namely, olaparib, abemaciclib, and ribociclib, for patients with hormone receptor-positive HER2-negative early breast cancer. Methods: All breast cancer cases from the past 10 years (n = 3230) that underwent treatment at the certified Breast Cancer Center of the Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Lübeck Campus, were analyzed. Results: Of a total of 2038 patients with HR+ HER2− eBC, 685 patients (33.6%) qualified for one or more of the three agents—olaparib, abemaciclib, and ribociclib. Of these 685 patients, 523 patients (76.4%) had node-positive and 162 (23.6%) node-negative disease. Moreover, 368 patients (18.1% of a total of 2038 patients with HR+ HER2− eBC) were eligible exclusively for ribociclib, including all node-negative patients. A total of 141 patients (6.9%) met the criteria for all three agents. In contrast, 1353 patients (66.4%) had no indication for combined endocrine therapy. Conclusions: To our knowledge, this is the largest analysis addressing all three therapeutic strategies for combined endocrine therapy. The broad indication criteria of the NATALEE study may increase clinic workloads due to more frequent physician/patient interactions. It also remains unclear how therapy recommendations will influence actual treatment, as increased visits and potential side effects could affect patient compliance and adherence. Full article

(This article belongs to the Special Issue Advances in Invasive Breast Cancer: Treatment and Prognosis)

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The most important characteristics of three available strategies for early HR+ HER2− eBC. Abbreviations: AI: aromatase inhibitor; gBRCA1/2mt: germline breast cancer 1/2 mutation; CTX: chemotherapy; GnRHa: gonadotropin-releasing hormone agonist; RS: recurrence score; TAM: tamoxifen. Full article ">Figure 2
Flowchart of all patients with newly diagnosed breast cancer at the University Hospital Schleswig-Holstein, Campus Lübeck. Full article ">Figure 3
Potential candidates for ribociclib categorized according to the eligibility criteria of the NATALEE study. Full article ">Figure 4
Potential candidates for oral endocrine-based maintenance therapy in early breast cancer. Full article ">Figure 5
Venn diagram showing all patients with multiple and single indications for combined endocrine-based therapy in HR+ HER2− eBC. The pink circle represents all the patients in our analysis with HR+ HER2− early breast cancer (n = 2038). The yellow circle includes all patients indicated for ribociclib (n = 685) and the light-green circle represents all patients indicated for abemaciclib (n = 312). The small turquoise circle denotes all patients indicated for olaparib (n = 146). Full article ">

19 pages, 792 KiB

Open AccessReview

Recurrent and Metastatic Head and Neck Cancer: Mechanisms of Treatment Failure, Treatment Paradigms, and New Horizons

by William T. Barham, Marshall Patrick Stagg, Rula Mualla, Michael DiLeo and Sagar Kansara

Cancers 2025, 17(1), 144; https://doi.org/10.3390/cancers17010144 - 5 Jan 2025

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Abstract

Background: Head and neck cancer is a deadly disease with over 500,000 cases annually worldwide. Metastatic head and neck cancer accounts for a large proportion of the mortality associated with this disease. Many advances have been made in our understanding of the mechanisms [...] Read more.

Background: Head and neck cancer is a deadly disease with over 500,000 cases annually worldwide. Metastatic head and neck cancer accounts for a large proportion of the mortality associated with this disease. Many advances have been made in our understanding of the mechanisms of metastasis. The application of immunotherapy to locally recurrent or metastatic head and neck cancer has not only improved oncologic outcomes but has also provided valuable insights into the mechanisms of immune evasion and ultimately treatment failure. Objectives: This review paper will review our current understanding of biological mechanisms of treatment failure and metastasis. Published and ongoing clinical trials in the management of metastatic head and neck cancer will also be summarized. Methods: A narrative review was conducted to address the current understanding of the mechanisms of treatment failure and current treatment paradigms in recurrent and metastatic head and neck carcinoma. Conclusions: Our understanding of treatment failure in this disease is rapidly evolving. Immunotherapy represents a valuable new tool in the fight against recurrent and metastatic head and neck squamous cell carcinoma. Integrating patient and tumor specific data via artificial intelligence and deep learning will allow for a precision oncology approach, thereby achieving better prognostication and management of patients with this deadly disease. Full article

(This article belongs to the Collection Advances in Diagnostics and Treatment of Head and Neck Cancer)

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14 pages, 1438 KiB

Open AccessArticle

Adjuvant Immunotherapy After Resected Melanoma: Survival Outcomes, Prognostic Factors and Patterns of Relapse

by Sergio Martinez-Recio, Maria Alejandra Molina-Pérez, Eva Muñoz-Couselo, Alberto R. Sevillano-Tripero, Francisco Aya, Ana Arance, Mayra Orrillo, Juan Martin-Liberal, Luis Fernandez-Morales, Rocio Lesta, María Quindós-Varela, Maria Nieva, Joana Vidal, Daniel Martinez-Perez, Andrés Barba and Margarita Majem

Cancers 2025, 17(1), 143; https://doi.org/10.3390/cancers17010143 - 5 Jan 2025

Viewed by 380

Abstract

Background: Anti-PD-1-based immunotherapy has improved outcomes in stage IIB to IV resected melanoma patients in clinical trials. However, little is known about real-world outcomes, prognostic factors and patterns of relapse. Methods: This is a retrospective multicenter observational study including patients with resected melanoma [...] Read more.

Background: Anti-PD-1-based immunotherapy has improved outcomes in stage IIB to IV resected melanoma patients in clinical trials. However, little is known about real-world outcomes, prognostic factors and patterns of relapse. Methods: This is a retrospective multicenter observational study including patients with resected melanoma treated with subsequent anti-PD-1-based adjuvant immunotherapy. Data on clinical and demographic characteristics, delivered treatment, prognostic factors, time and pattern of relapse were collected. Results: We included 245 patients from eight centers; 4% of patients were at stage IIB-C, 80% at stage IIIA-D and 16% at stage IV. Recurrence-free survival (RFS) rates at 18 and 36 months were 60% and 48%, respectively, with a median RFS of 33.7 months. Prognostic factors associated with recurrence were melanoma primary site (HR 2.64, 95% CI 1.15–6.01) and starting adjuvant therapy more than 12 weeks after the last resection (HR 1.68, 95% CI 1.13–2.5); presence of serious immune-related adverse events was associated with better RFS (HR 0.4, 95% CI 0.19–0.87). Early relapses accounted for 63% of the total recurrences, with a higher number of metastatic sites (18%); in contrast, late relapses presented more frequently with brain metastases (20%). Conclusions: In our patients with resected melanoma who underwent anti-PD-1-based adjuvant immunotherapy, survival outcomes were worse than those reported in clinical trials. Primary melanoma site and time interval between the last resection and the start of adjuvant therapy were associated with survival. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Cutaneous Melanoma)

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19 pages, 980 KiB

Open AccessReview

Menin Inhibitors: New Targeted Therapies for Specific Genetic Subtypes of Difficult-to-Treat Acute Leukemias

by Pasquale Niscola, Valentina Gianfelici, Marco Giovannini, Daniela Piccioni, Carla Mazzone and Paolo de Fabritiis

Cancers 2025, 17(1), 142; https://doi.org/10.3390/cancers17010142 - 4 Jan 2025

Viewed by 666

Abstract

Menin (MEN1) is a well-recognized powerful tumor promoter in acute leukemias (AL) with KMT2A rearrangements (KMT2Ar, also known as MLL) and mutant nucleophosmin 1 (NPM1m) acute myeloid leukemia (AML). MEN1 is essential for sustaining leukemic transformation due to its interaction with wild-type KMT2A [...] Read more.

Menin (MEN1) is a well-recognized powerful tumor promoter in acute leukemias (AL) with KMT2A rearrangements (KMT2Ar, also known as MLL) and mutant nucleophosmin 1 (NPM1m) acute myeloid leukemia (AML). MEN1 is essential for sustaining leukemic transformation due to its interaction with wild-type KMT2A and KMT2A fusion proteins, leading to the dysregulation of KMT2A target genes. MEN1 inhibitors (MIs), such as revumenib, ziftomenib, and other active small molecules, represent a promising new class of therapies currently under clinical development. By disrupting the MEN1-KMT2Ar complex, a group of proteins involved in chromatin remodeling, MIs induce apoptosis and differentiation AL expressing KMT2Ar or NPM1m AML. Phase I and II clinical trials have evaluated MIs as standalone treatments and combined them with other synergistic drugs, yielding promising results. These trials have demonstrated notable response rates with manageable toxicities. Among MIs, ziftomenib received orphan drug and breakthrough therapy designations from the European Medicines Agency in January 2024 and the Food and Drug Administration (FDA) in April 2024, respectively, for treating R/R patients with NPM1m AML. Additionally, in November 2024, the FDA approved revumenib for treating R/R patients with KMT2Ar-AL. This review focuses on the pathophysiology of MI-sensitive AL, primarily AML. It illustrates data from clinical trials and discusses the emergence of resistance mechanisms. In addition, we outline future directions for the use of MIs and emphasize the need for further research to fully realize the potential of these novel compounds, especially in the context of specific genetic subtypes of challenging AL. Full article

(This article belongs to the Section Cancer Therapy)

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19 pages, 6330 KiB

Open AccessArticle

Characterisation of Castration-Resistant Cell-Derived Exosomes and Their Effect on the Metastatic Phenotype

by Jorge Recio-Aldavero, Lorena Parra-Gutiérrez, Laura Muñoz-Moreno, Irene D. Román, María Isabel Arenas and Ana M. Bajo

Cancers 2025, 17(1), 141; https://doi.org/10.3390/cancers17010141 - 4 Jan 2025

Viewed by 407

Abstract

Background/Objectives: Prostate cancer (PCa) is characterised by its progression to a metastatic and castration-resistant phase. Prostate tumour cells release small extracellular vesicles or exosomes which are taken up by target cells and can potentially facilitate tumour growth and metastasis. The present work studies [...] Read more.

Background/Objectives: Prostate cancer (PCa) is characterised by its progression to a metastatic and castration-resistant phase. Prostate tumour cells release small extracellular vesicles or exosomes which are taken up by target cells and can potentially facilitate tumour growth and metastasis. The present work studies the effect of exosomes from cell lines that are representative of the different stages of the disease on the tumoral phenotype of PC3 cells. Methods: Exosomes were isolated by ultracentrifugation from human prostate epithelial cells (RWPE-1) and androgen-dependent PCa cells (LNCaP) and castration-resistant PCa cells (CRPC) with moderate (DU145) or high (PC3) metastatic capacity. The biophysical and biochemical properties of the exosomes were characterised as well as their effects on PC3 cell viability and migration. Results: The study of the exosomes of prostate cell lines shows heterogeneity in their size, presenting in some of them two types of populations; in both populations, a larger size in those derived from PC3 cells and a smaller size in those derived from non-tumourigenic prostate cells were detected. Differences were found in the physical properties of those derived from healthy and PCa cells, as well as between cells representative of the most aggressive stages of the disease. The highest gamma-glutamyl transferase (GGT) activity was observed in androgen-dependent cells and differences in the pro-metalloproteinases (MMP) activity were detected in healthy cells and in castration-resistant cells with moderate metastatic capacity with respect to PC3 cells. The treatment of PC3 cells with their own exosomes increased PC3 cell viability and migration. Conclusion: Exosomes represent a promising field of research in the diagnosis, prognosis, and treatment of prostate cancer. Full article

(This article belongs to the Special Issue Exosomes in Cancer Metastasis)

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13 pages, 3107 KiB

Open AccessArticle

Maxillectomy Guided by 3D Printing Versus Conventional Surgery for Patients with Head and Neck Cancer

by Sung Yool Park, Sung Ha Jung, Anna Seo, Hakjong Noh, Hwansun Lee, Hyo Jun Kim, Younghac Kim, Man Ki Chung, Han-Sin Jeong, Chung-Hwan Baek, Young-Ik Son and Nayeon Choi

Cancers 2025, 17(1), 140; https://doi.org/10.3390/cancers17010140 - 4 Jan 2025

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Abstract

Background: This study evaluates the impact of three-dimensional (3D) printing-guided maxillectomy compared with conventional maxillectomy on surgical precision and oncological outcomes in patients with head and neck cancer. Materials and Methods: A retrospective analysis was conducted on 42 patients undergoing maxillectomy (16 in [...] Read more.

Background: This study evaluates the impact of three-dimensional (3D) printing-guided maxillectomy compared with conventional maxillectomy on surgical precision and oncological outcomes in patients with head and neck cancer. Materials and Methods: A retrospective analysis was conducted on 42 patients undergoing maxillectomy (16 in a 3D printing-guided group and 26 in a conventional group). Patient demographics, tumor characteristics, and outcomes were compared. Survival outcomes were analyzed using the Kaplan–Meier method. Results: The 3D printing group showed higher rates of negative resection margins (81.3% vs. 76.9%) compared with the conventional group and a trend toward improved 5-year local recurrence-free survival (87.5% vs. 58.7%, respectively) and overall survival (84.4% vs. 70.1%, respectively). However, the differences were not statistically significant. Conclusions: Maxillectomy guided by 3D printing may offer enhanced surgical precision and improved local control in patients undergoing head and neck cancer surgeries. Further research with larger cohorts is necessary to confirm these findings. Full article

(This article belongs to the Special Issue Advancements in Head and Neck Cancer Surgery)

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Example of 3D printing guidance design using Reconeasy-3D Software. (A) Preoperative virtual simulation created using DICOM data extracted from computed tomography (CT) and magnetic resonance imaging (MRI), virtually marking the areas for osteotomy guidance (B) The rapid prototype 3D model of the maxilla, displaying osteotomy lines to guide tumor resection and a prefabricated orbital mesh plate customized for the orbital floor defect, prepared for precise anatomical restoration during surgery. (C) Intraoperative view showing maxillectomy performed according to the preoperative plan created with 3D printing. Full article ">Figure 2
Clinical images of 79 years old male who had 3D printing-guided salvage maxillectomy after the failure of definitive chemoradiation. (A) PET-CT revealed maxillary sinus cancer in anterolateral wall of sinus. (B) Preoperative CT coronal image showed maxillary sinus cancer involving orbital inferior wall, inferolateral wall of maxillary sinus. (C) Postoperative CT image revealed well-reconstructed orbital plated and anterolateral thigh free flap at 3 months after the surgery. (D) Intraoperative image of maxillectomy defect and reconstruction with anterolateral thigh free flap and prefabricated orbital mesh plate. (E,F) Endoscopic image of hard palate and nasal cavity reconstructed by anterolateral free flap at 3 months post operation. Full article ">Figure 3
Kaplan–Meier survival plot with log-rank test between the 3D printing-guided maxillectomy group and conventional maxillectomy group. (A) Local recurrence free survival (p = 0.236); (B) overall recurrence free survival (p = 0.233); (C) overall survival (p = 0.435). Full article ">

13 pages, 2767 KiB

Open AccessArticle

A Digital Phenotypic Assessment in Neuro-Oncology (DANO): A Pilot Study on Sociability Changes in Patients Undergoing Treatment for Brain Malignancies

by Francesca Siddi, Patrick Emedom-Nnamdi, Michael P. Catalino, Aakanksha Rana, Alessandro Boaro, Hassan Y. Dawood, Francesco Sala, Jukka-Pekka Onnela and Timothy R. Smith

Cancers 2025, 17(1), 139; https://doi.org/10.3390/cancers17010139 - 4 Jan 2025

Viewed by 408

Abstract

Background: The digital phenotyping tool has great potential for the deep characterization of neurological and quality-of-life assessments in brain tumor patients. Phone communication activities (details on call and text use) can provide insight into the patients’ sociability. Methods: We prospectively collected digital-phenotyping data [...] Read more.

Background: The digital phenotyping tool has great potential for the deep characterization of neurological and quality-of-life assessments in brain tumor patients. Phone communication activities (details on call and text use) can provide insight into the patients’ sociability. Methods: We prospectively collected digital-phenotyping data from six brain tumor patients. The data were collected using the Beiwe application installed on their personal smartphones. We constructed several daily sociability features from phone communication logs, including the number of incoming and outgoing text messages and calls, the length of messages and duration of calls, message reciprocity, the number of communication partners, and number of missed calls. We compared variability in these sociability features against those obtained from a control group, matched for age and sex, selected among patients with a herniated disc. Results: In brain tumor patients, phone-based communication appears to deteriorate with time, as evident in the trend for total outgoing minutes, total outgoing calls, and call out-degree. Conclusions: These measures indicate a possible decrease in sociability over time in brain tumor patients that may correlate with survival. This exploratory analysis suggests that a quantifiable digital sociability phenotype exists and is comparable for patients with different survival outcomes. Overall, assessing neurocognitive function using digital phenotyping appears promising. Full article

(This article belongs to the Special Issue Novel Diagnostic and Therapeutic Approaches in Diffuse Gliomas)

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The daily number of outgoing calls made by each subject. The vertical solid line (in red) represents the day of surgery. The smooth solid line (in blue) is a LOESS (or local polynomial regression) line that averages outgoing calls made within a spanning window of 0.75 (i.e., the proportion of points used for each local regression). Full article ">Figure 2
The daily total number of minutes spent on calls (both incoming and outgoing). The vertical solid line (in red) represents the day of surgery. The smooth solid line (in blue) is a LOESS (or local polynomial regression) line that averages the total minutes spent on calls within a spanning window of 0.75 (i.e., the proportion of points used for each local regression). Full article ">Figure 3
The daily number of texts sent. The vertical solid line (in red) represents the day of surgery. The smooth solid line (in blue) is a LOESS (or local polynomial regression) line that averages the total number of sent texts within a spanning window of 0.75 (i.e., the proportion of points used for each local regression). Full article ">Figure 4
Temporal patterns of text-based communication metrics comparing brain tumor and spine disease patients over 150 days post-surgery. Points represent individual daily observations; solid lines show model-predicted trajectories; and shaded regions indicate 95% confidence intervals from linear mixed effects models. Brain tumor patients (blue) and spine disease controls (red) show distinct patterns of text-based social engagement during recovery. Full article ">Figure 5
Temporal patterns of call-based communication metrics comparing brain tumor and spine disease patients over 150 days post-surgery. Points represent individual daily observations; solid lines show model-predicted trajectories; and shaded regions indicate 95% confidence intervals from linear mixed effects models. Brain tumor patients (blue) and spine disease controls (red) demonstrate divergent trajectories in call-based social interactions during recovery. Full article ">

10 pages, 233 KiB

Open AccessArticle

Exploring the Role of Symptom Diversity in Facial Basal Cell Carcinoma: Key Insights into Preoperative Quality of Life and Disease Progression

by Domantas Stundys, Alvija Kučinskaitė, Simona Gervickaitė, Jūratė Grigaitienė, Janina Tutkuvienė and Ligita Jančorienė

Cancers 2025, 17(1), 138; https://doi.org/10.3390/cancers17010138 - 4 Jan 2025

Viewed by 332

Abstract

Facial basal cell carcinoma (BCC) is the most common skin cancer, yet delays in diagnosis and treatment persist. These delays affect quality of life (QoL), advance disease progression, and increase healthcare burden. This study explores the relationship between symptom diversity, QoL, and care-seeking [...] Read more.

Facial basal cell carcinoma (BCC) is the most common skin cancer, yet delays in diagnosis and treatment persist. These delays affect quality of life (QoL), advance disease progression, and increase healthcare burden. This study explores the relationship between symptom diversity, QoL, and care-seeking behaviors, focusing on the impact of symptoms on clinical outcomes and consultation timing. A total of 278 adults with histologically confirmed facial BCC underwent surgical treatment at Vilnius University Hospital from November 2022 to April 2024. The data collected included demographics, tumor characteristics, and self-reported symptoms (pain, bleeding, itching, tumor presence, discomfort, and erosion). Disease-specific QoL was assessed using the Skin Cancer Index. ANCOVA compared QoL across symptom groups, multiple regression analyzed symptom effects on QoL, and logistic regression evaluated care-seeking behavior over time. Cox regression assessed symptom associations with time to medical consultation. The mean time from symptom onset to consultation was 21 months. Tumor presence (27%), erosion (18%), and discomfort (17%) were the most reported symptoms. Discomfort significantly reduced QoL in emotional, social, and appearance domains (p < 0.05). Logistic regression showed tumor presence and pain were associated with earlier care-seeking within 12 months (p < 0.05). Other symptoms, such as bleeding, itching, and erosion, did not significantly influence consultation timing. The findings highlight the need for public education and proactive patient counseling to promote timely intervention and reduce the disease progression. Full article

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

15 pages, 4485 KiB

Open AccessArticle

AI-Driven Enhancement of Skin Cancer Diagnosis: A Two-Stage Voting Ensemble Approach Using Dermoscopic Data

by Tsu-Man Chiu, Yun-Chang Li, I-Chun Chi and Ming-Hseng Tseng

Cancers 2025, 17(1), 137; https://doi.org/10.3390/cancers17010137 - 3 Jan 2025

Viewed by 545

Abstract

Background: Skin cancer is the most common cancer worldwide, with melanoma being the deadliest type, though it accounts for less than 5% of cases. Traditional skin cancer detection methods are effective but are often costly and time-consuming. Recent advances in artificial intelligence have [...] Read more.

Background: Skin cancer is the most common cancer worldwide, with melanoma being the deadliest type, though it accounts for less than 5% of cases. Traditional skin cancer detection methods are effective but are often costly and time-consuming. Recent advances in artificial intelligence have improved skin cancer diagnosis by helping dermatologists identify suspicious lesions. Methods: The study used datasets from two ethnic groups, sourced from the ISIC platform and CSMU Hospital, to develop an AI diagnostic model. Eight pre-trained models, including convolutional neural networks and vision transformers, were fine-tuned. The three best-performing models were combined into an ensemble model, which underwent multiple random experiments to ensure stability. To improve diagnostic accuracy and reduce false negatives, a two-stage classification strategy was employed: a three-class model for initial classification, followed by a binary model for secondary prediction of benign cases. Results: In the ISIC dataset, the false negative rate for malignant lesions was significantly reduced, and the number of malignant cases misclassified as benign dropped from 124 to 45. In the CSMUH dataset, false negatives for malignant cases were completely eliminated, reducing the number of misclassified malignant cases to zero, resulting in a notable improvement in diagnostic precision and a reduction in the false negative rate. Conclusions: Through the proposed method, the study demonstrated clear success in both datasets. First, a three-class AI model can assist doctors in distinguishing between melanoma patients who require urgent treatment, non-melanoma skin cancer patients who can be treated later, and benign cases that do not require intervention. Subsequently, a two-stage classification strategy effectively reduces false negatives in malignant lesions. These findings highlight the potential of AI technology in skin cancer diagnosis, particularly in resource-limited medical settings, where it could become a valuable clinical tool to improve diagnostic accuracy, reduce skin cancer mortality, and reduce healthcare costs. Full article

(This article belongs to the Special Issue Recent Advances in Skin Cancers)

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19 pages, 2749 KiB

Open AccessReview

Prioritizing Context-Dependent Cancer Gene Signatures in Networks

by Enrico Capobianco, Thomas S. Lisse and Sandra Rieger

Cancers 2025, 17(1), 136; https://doi.org/10.3390/cancers17010136 - 3 Jan 2025

Viewed by 363

Abstract

There are numerous ways of portraying cancer complexity based on combining multiple types of data. A common approach involves developing signatures from gene expression profiles to highlight a few key reproducible features that provide insight into cancer risk, progression, or recurrence. Normally, a [...] Read more.

There are numerous ways of portraying cancer complexity based on combining multiple types of data. A common approach involves developing signatures from gene expression profiles to highlight a few key reproducible features that provide insight into cancer risk, progression, or recurrence. Normally, a selection of such features is made through relevance or significance, given a reference context. In the case of highly metastatic cancers, numerous gene signatures have been published with varying levels of validation. Then, integrating the signatures could potentially lead to a more comprehensive view of the connection between cancer and its phenotypes by covering annotations not fully explored in individual studies. This broader understanding of disease phenotypes would improve the predictive accuracy of statistical models used to identify meaningful associations. We present an example of this approach by reconciling a great number of published signatures into meta-signatures relevant to Osteosarcoma (OS) metastasis. We generate a well-annotated and interpretable interactome network from integrated OS gene expression signatures and identify key nodes that regulate essential aspects of metastasis. While the connected signatures link diverse prognostic measurements for OS, the proposed approach is applicable to any type of cancer. Full article

(This article belongs to the Special Issue Technological Development for Advances in Cancer Research and Precision Oncology)

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Approach. Steps include literature-based coverage of target metastasis-related signatures, assessment of topological relevance within interactome networks, and integration of signatures. Graphical sketch from PowerPoint artwork. Full article ">Figure 2
Meta-interactome signature networks. Innate.DB and STRING.DB as examples of network sources. The blue-circled nodes are network backbone components of the meta-signature; the red nodes are associated interactors. The plots show protein interactions putting signature components in relationships with biologically associated nodes. Full article ">Figure 3
Physical associations then expanded in functional–physical view. The map has been significantly reduced according to the most stringent confidence level of the interactions (level = 0.9). Full article ">Figure 4
STRING.DB clustering of the functional–physical meta-interactome network. Two standard methods were employed: (a) K-Means: 3 clusters are separated by color and serve as a coarse reference for associations (see, for instance, the EGFR and TP53 central nodes). (b) Markov Cluster Algorithm (MCL): more groups appear as a result of a finer resolution. As a note, these two clustering methods are complementary, being K-Means based on an arbitrary definition of the number of groups, while MCL is implicitly controlled by an inflation parameter. Full article ">Figure 5
Perturbed meta-interactome network. From STRIG.DB, the SNAI2 perturbation is shown with the node mapped onto the network (left), and the specific SNAIL2 interactome is visualized (right). The induced SNAI2 interactome associations suggest potential network influence. Full article ">Figure 6
GATA3 direct interactome (source: STRING.DB). Interactome of anticancer activity genes related to GATA3, which is downregulated in OS cells and tissues and whose expression levels depend on factors such as tumor size, metastasis, and suppression of proliferation, migration and invasion. Full article ">

18 pages, 5480 KiB

Open AccessArticle

A Novel In Vitro Model of the Bone Marrow Microenvironment in Acute Myeloid Leukemia Identifies CD44 and Focal Adhesion Kinase as Therapeutic Targets to Reverse Cell Adhesion-Mediated Drug Resistance

by Eleni E. Ladikou, Kim Sharp, Fabio A. Simoes, John R. Jones, Thomas Burley, Lauren Stott, Aimilia Vareli, Emma Kennedy, Sophie Vause, Timothy Chevassut, Amarpreet Devi, Iona Ashworth, David M. Ross, Tanja Nicole Hartmann, Simon A. Mitchell, Chris J. Pepper, Giles Best and Andrea G. S. Pepper

Cancers 2025, 17(1), 135; https://doi.org/10.3390/cancers17010135 - 3 Jan 2025

Viewed by 482

Abstract

Background/Objectives: Acute myeloid leukemia (AML) is an aggressive neoplasm. Although most patients respond to induction therapy, they commonly relapse due to recurrent disease in the bone marrow microenvironment (BMME). So, the disruption of the BMME, releasing tumor cells into the peripheral circulation, has [...] Read more.

Background/Objectives: Acute myeloid leukemia (AML) is an aggressive neoplasm. Although most patients respond to induction therapy, they commonly relapse due to recurrent disease in the bone marrow microenvironment (BMME). So, the disruption of the BMME, releasing tumor cells into the peripheral circulation, has therapeutic potential. Methods: Using both primary donor AML cells and cell lines, we developed an in vitro co-culture model of the AML BMME. We used this model to identify the most effective agent(s) to block AML cell adherence and reverse adhesion-mediated treatment resistance. Results: We identified that anti-CD44 treatment significantly increased the efficacy of cytarabine. However, some AML cells remained adhered, and transcriptional analysis identified focal adhesion kinase (FAK) signaling as a contributing factor; the adhered cells showed elevated FAK phosphorylation that was reduced by the FAK inhibitor, defactinib. Importantly, we demonstrated that anti-CD44 and defactinib were highly synergistic at diminishing the adhesion of the most primitive CD34^high AML cells in primary autologous co-cultures. Conclusions: Taken together, we identified anti-CD44 and defactinib as a promising therapeutic combination to release AML cells from the chemoprotective AML BMME. As anti-CD44 is already available as a recombinant humanized monoclonal antibody, the combination of this agent with defactinib could be rapidly tested in AML clinical trials. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))

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Figure 1
The optimized BMAS. (a) The 10× magnification light microscopy images of co-culture. KG1a cells (bright round) attached to BMAS cells (darker and elongated). Images were captured using an Olympus CKX41 microscope, with a micropix camera and Tsview 7 version 7.1 software. (b) The number of non-adhered AML cells (mean ± SD) when co-cultured with ratio of 1:1:1 hFOB1.19/HS-5/HUVEC, KG1a cells (n = 3) and OCI-AML3 cells (n = 3) as a percentage of the number in monoculture. Significance determined using a one-way ANOVA, following the Shapiro–Wilk test for normality. (c) Percentage Annexin V-positive (apoptotic) adhered versus non-adhered OCI-AML3 (n = 3) and KG1a (n = 3) cells. Significance determined using paired t-test, following the Shapiro-Wilk test for normality. Significance determined using one-sample t-test, following the Shapiro-Wilk test for normality. **** p ≤ 0.0001, *** p ≤ 0.001 and ** p ≤ 0.01. Full article ">Figure 2
BMAS-modeled CAM-DR and SFM-DR following 72-h of co-culture. Cytarabine dose response curves (72 h). (a) OCI-AML3 cells (n = 3) and (b) KG1a cells (n = 3) were treated with increasing doses of cytarabine for 72 h and viability measured using Annexin V staining and flow cytometry. Sigmoidal dose response curves were plotted (mean ± SD). Full article ">Figure 3
Anti-CD44 treatment was the most effective in blocking AML cell adhesion in cell lines and primary cells. Incubation of AML cells with anti-CD44 antibody. (a) Compared to the untreated sample, the fold change (FC) in non-adhered AML cells (mean ± SD) when treated with increasing doses of anti-CD44 and co-cultured for 3 h on the BMAS in (a) OCI-AML3 and (b) KG1a. Significance determined using one-way ANOVA and Dunnett’s multiple-comparisons test for comparing every mean to a no-treatment control equal to 1. (c) A comparison between the best dose for each drug tested, showing anti-CD44 was the most effective (OCI-AML3 blue dots and KG1a red dots). Significance determined using Welch’s ANOVA with Dunnett’s multiple comparisons. (d) Compared to the untreated sample, the fold change (FC) in non-adhered primary AML cells (mean ± SD) when treated with 5 µg/mL of anti-CD44 in BM (n = 10) and PB (n = 15) samples. Primary AML cells were identified using a full AML panel and patient-specific phenotyping data provided by the diagnostic laboratory. A representative panel and gating strategy for primary AML cells can be found in <a href="#app1-cancers-17-00135" class="html-app">Supplementary Figure S3</a>. Significance determined using one-sample Wilcoxon, following the Shapiro–Wilk test for normality. Results are compared to a no-treatment control equal to 1. (e) Correlation of CD44 expression (median fluorescent intensity [MFI]) in BM-derived samples (n = 8) with PB WBC count on samples taken at the same time. Correlation was determined using Pearson’s correlation, with the 95% confidence interval shown as dotted lines. (f) Correlation of BM AML cell CD44 mRNA with the percentage of AML blast cells in the BM from BEATAML2 [<a href="#B32-cancers-17-00135" class="html-bibr">32</a>]. Correlation was determined using Pearson’s correlation with 95% confidence intervals. **** p ≤ 0.0001, *** p ≤ 0.001, ** p ≤ 0.01 and * p ≤ 0.05. Full article ">Figure 4
The combination of anti-CD44 with cytarabine can overcome CAM-DR. AML cells were incubated with three different concentrations of cytarabine ± pre-treatment with 5 µg/mL anti-CD44 (a) For each cytarabine concentration (10 µM, 5 µM and 1 µM), the fold change (FC) in the number of Annexin V-positive AML cells (mean ± SD) in the presence of anti-CD44 is compared to its absence (the absence of anti-CD44 is normalized to 1): OCI-AML3 (n = 3) and KG1a cells (n = 3). Significance determined using one-way ANOVA and Dunnett’s multiple-comparisons test comparing every mean to a no-treatment control equal to 1 following the Shapiro–Wilk test for normality (b) Representative dot plot of Annexin V staining of non-adhered KG1a cells following treatment with 1 µM cytarabine alone (left) or 1 µM cytarabine with 5 µg/mL anti-CD44 (right). Although the proportion of apoptotic cells is similar in both, there are far more non-adhered KG1a cells in the presence of anti-CD44 (right) and, therefore, far more apoptotic KG1a cells. (c) Representative 10× magnification light microscopy images (scale bar represents 100 µm) of the co-culture following treatment with 5 µM cytarabine alone (left), 5 µg/mL anti-CD44 alone (middle) or both (right). Elongated darker cells are the BMAS, which adhered to the base of the well and were unaffected by chemotherapy and anti-CD44 treatment. Some persistently adhered AML cells (round with dark center) were observed following cytarabine treatment alone (left image). More bright, shiny AML cells are seen in the presence of anti-CD44 alone (middle image), but when cytarabine is added to anti-CD44, a marked reduction in the number of adhered AML cells was observed (right image). Images were captured using an Olympus CKX41 microscope, a micropix camera and Tsview 7 version 7.1 software. (d,e) For each cytarabine concentration (10 µM, 5 µM and 1 µM), the fold change (FC) in the number of Annexin V-positive AML cells (mean ± SD) in the presence of anti-CD44 is compared to its absence (the absence of anti-CD44 is normalized to 1) using (d) PB-derived samples (n = 10) and (e) BM-derived samples (n = 5). Significance was determined using the Kruskal–Wallis test and Dunnett’s multiple-comparisons test (d) and one-way ANOVA test and Dunnett’s multiple-comparisons test (e), following the Shapiro–Wilk test for normality. (f) Number of Annexin V-positive AML cells (in 50 µL) following treatment with 5 µM of cytarabine alone added to that in 5 µg/mL anti-CD44 alone in primary AML cells. The sum of their individual effects (red/blue column on left) is compared to their combined effect when cells were treated with both agents simultaneously (green column on right). Results for each individual patient are shown in <a href="#app1-cancers-17-00135" class="html-app">Supplementary Figure S4a</a>). Each sample represents a biological repeat (n = 15). Significance was determined using a paired t-test, following the Shapiro–Wilk test for normality. **** p ≤ 0.0001, *** p ≤ 0.001, ** p ≤ 0.01 and * p ≤ 0.05. Full article ">Figure 5
Transcriptomic analysis identified the FAK signaling pathways as the top determinant of persistent adhesion following treatment with anti-CD44. (a) Unsupervised hierarchical clustered heatmap for each sample in the RNA sequencing dataset. Every row of the heatmap represents a single gene, every column represents a sample, and every cell displays normalized gene expression values. (b) Venn diagram summarizing the overlap between differentially expressed genes between adhered versus non-adhered AML cells after each cell line was analyzed separately. The left circle (blue) represents the genes differentially expressed in OCI-AML3-adhered cells compared non-adhered cells. The right circle (red) represents the genes differentially expressed in KG1a-adhered cells compared to non-adhered cells. (c) Volcano Plot displaying the log2-fold changes of each gene, calculated by performing a differential gene expression analysis. Every point in the plot represents a gene. Red points indicate significantly upregulated genes, and blue points indicate downregulated genes for OCI-AML3 (right; 486 upregulated and 18 downregulated) and KG1a (left; 364 upregulated and 7 downregulated) cells. The thresholds used for this analysis were log2FC ≥1.5 and an adjusted p ≤ 0.05. (d) Pathway enrichment analysis (KEGG pathways) for OCI-AML3 (right) and KG1a (left) cells. The x-axis indicates the −log10 (p-value) for each term. Significant terms are highlighted in bold. (e) MFI of pFAK in monoculture, adhered and non-adhered KG1a cells in the presence (triangle points) and absence (circle points) of 5 µg/mL anti-CD44. (f) pFAK MFI in adhered (orange triangles and circles) and non-adhered (purple triangles and circles) KG1a cells in the presence and absence of 5 µM of defactinib. Full article ">Figure 6
Defactinib in combination with anti-CD44 is additive/synergistic in preventing AML cell adhesion. (a) FC in non-adhered KG1a AML cells (mean ± SD) when treated with increasing doses of anti-CD44 alone, increasing doses of defactinib alone or in combination. Synergy plot (right) was generated using SynergyFinder software (version 3.0, <a href="https://synergyfinder.fimm.fi" target="_blank">https://synergyfinder.fimm.fi</a> (accessed on 15 February 2023)), showing an additive mean Bliss score of 1.627 (>1 = additive) and maximum of 4.39 (5 µg/mL + 5 µM). Results are compared to the no-treatment control, which is equal to 1. (b) Representative scatter plots of no drug, anti-CD44, defactinib and the combination of both, showing the proportions of total and CD34+ non-adhered primary AML cells after 2 min of acquisition on a Cytoflex S flow cytometer. This shows substantially more viable non-adhered CD34+ and CD34− AML cells in the presence of both anti-CD44 and defactinib than no drug or either alone. (c) Individual FC (compared to no drug) in viable non-adhered primary AML cell numbers (mean ± SD) when treated with increasing doses of anti-CD44, defactinib or both and co-cultured for 3 h with a confluent layer of autologous stromal cells. Different concentrations of anti-CD44 alone and defactinib alone versus the combination of both were determined using a one-way ANOVA, and the results are tabulated in <a href="#app1-cancers-17-00135" class="html-app">Supplementary Table S5</a>; all comparisons were significant. (d) Combined FC in non-adhered primary AML cells (n = 3, mean ± SD) when treated with increasing doses of anti-CD44 alone, increasing doses of defactinib alone or in combination. A representative synergy contour plot for patient AML13 (right) was generated using SynergyFinder and shows a mean Bliss score of 8.12 (>1 = additive) and a synergistic maximum of 18.74 (2.5 µg/mL + 2.5 µM; >10 = synergistic). Full article ">

14 pages, 1383 KiB

Open AccessArticle

Impact of the COVID-19 Pandemic on Histopathological Cancer Diagnostics in Lower Silesia: A Comparative Analysis of Prostate, Breast, and Colorectal Cancer from 2018 to 2022

by Danuta Szkudlarek, Katarzyna Kalinowska and Benita Wiatrak

Cancers 2025, 17(1), 134; https://doi.org/10.3390/cancers17010134 - 3 Jan 2025

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Abstract

Background/Objective: The COVID-19 pandemic significantly disrupted healthcare systems worldwide including cancer diagnostics. This study aimed to assess the impact of the pandemic on histopathological cancer diagnostics in Lower Silesia, Poland, specifically focusing on prostate, breast, and colorectal cancer cases from 2018 to 2022. [...] Read more.

Background/Objective: The COVID-19 pandemic significantly disrupted healthcare systems worldwide including cancer diagnostics. This study aimed to assess the impact of the pandemic on histopathological cancer diagnostics in Lower Silesia, Poland, specifically focusing on prostate, breast, and colorectal cancer cases from 2018 to 2022. The objective was to evaluate diagnostic volumes and trends before, during, and after the pandemic and to understand the effect of healthcare disruptions on cancer detection. Methods: Histopathological and cytological data were collected from multiple laboratories across Lower Silesia. Samples were categorized into three periods: pre-pandemic (January 2018–February 2020), pandemic (March 2020–May 2022), and post-pandemic (June–December 2022). Statistical analyses included comparisons of diagnostic volumes and positive diagnoses across these periods. Results: A significant reduction in the number of histopathological examinations occurred during the pandemic, particularly during its early phase. This decline was accompanied by a higher frequency of positive cancer diagnoses, suggesting the prioritization of high-risk cases. Post-pandemic, diagnostic activity showed partial recovery, though it remained below the pre-pandemic levels, with notable differences across cancer types. Conclusions: The COVID-19 pandemic significantly disrupted cancer diagnostics in Lower Silesia, delaying detection and highlighting healthcare system vulnerabilities. These findings underscore the importance of resilient healthcare systems that can ensure the continuity of essential diagnostic services and address inequalities in access to care during crises. Full article

(This article belongs to the Special Issue How COVID-19 Affects Cancer Patients)

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Distribution of monthly histopathological tests for prostate cancer (2018–2022) represented as a box plot: (A) total number of tests performed; (B) frequency of positive prostate cancer diagnosis. Full article ">Figure 2
Monthly trends in histopathological tests for prostate cancer performed between 2018 and 2022: (A) total number of tests performed; (B) frequency of positive prostate cancer diagnosis. Full article ">Figure 3
Distribution of monthly histopathological tests for breast cancer (2018–2022) represented as a box plot: (A) total number of tests performed; (B) frequency of positive breast cancer diagnosis. Full article ">Figure 4
Monthly trends in histopathological tests for breast cancer performed between 2018 and 2022: (A) total number of tests performed; (B) frequency of positive breast cancer diagnosis. Full article ">Figure 5
Distribution of monthly histopathological tests for colorectal cancer (2018–2022) represented as a box plot: (A) total number of tests performed; (B) frequency of diagnosis of colorectal cancer of adenoma. Full article ">Figure 6
Monthly trends in histopathological tests for colorectal cancer performed between 2018 and 2022: (A) total number of tests performed; (B) frequency of diagnosis of colorectal cancer or adenoma. Full article ">

32 pages, 3337 KiB

Open AccessReview

Exploring the Metabolic Impact of FLASH Radiotherapy

by Febe Geirnaert, Lisa Kerkhove, Pierre Montay-Gruel, Thierry Gevaert, Inès Dufait and Mark De Ridder

Cancers 2025, 17(1), 133; https://doi.org/10.3390/cancers17010133 - 3 Jan 2025

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Abstract

FLASH radiotherapy (FLASH RT) is an innovative modality in cancer treatment that delivers ultrahigh dose rates (UHDRs), distinguishing it from conventional radiotherapy (CRT). FLASH RT has demonstrated the potential to enhance the therapeutic window by reducing radiation-induced damage to normal tissues while maintaining [...] Read more.

FLASH radiotherapy (FLASH RT) is an innovative modality in cancer treatment that delivers ultrahigh dose rates (UHDRs), distinguishing it from conventional radiotherapy (CRT). FLASH RT has demonstrated the potential to enhance the therapeutic window by reducing radiation-induced damage to normal tissues while maintaining tumor control, a phenomenon termed the FLASH effect. Despite promising outcomes, the precise mechanisms underlying the FLASH effect remain elusive and are a focal point of current research. This review explores the metabolic and cellular responses to FLASH RT compared to CRT, with particular focus on the differential impacts on normal and tumor tissues. Key findings suggest that FLASH RT may mitigate damage in healthy tissues via altered reactive oxygen species (ROS) dynamics, which attenuate downstream oxidative damage. Studies indicate the FLASH RT influences iron metabolism and lipid peroxidation pathways differently than CRT. Additionally, various studies indicate that FLASH RT promotes the preservation of mitochondrial integrity and function, which helps maintain apoptotic pathways in normal tissues, attenuating damage. Current knowledge of the metabolic influences following FLASH RT highlights its potential to minimize toxicity in normal tissues, while also emphasizing the need for further studies in biologically relevant, complex systems to better understand its clinical potential. By targeting distinct metabolic pathways, FLASH RT could represent a transformative advance in RT, ultimately improving the therapeutic window for cancer treatment. Full article

(This article belongs to the Special Issue Feature Paper in Section “Cancer Therapy” in 2024)

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Figure 1
Schematic overview of cellular metabolic impact of FLASH radiotherapy (FLASH RT) (orange) compared to conventional radiotherapy (CRT) (blue). FLASH RT is delivered at an ultrahigh dose rate (UHDR), resulting in reduced reactive oxygen species (ROS) generation compared to CRT. This reduction minimized damage to normal tissues by preserving the integrity of mitochondria, lipid membranes, and nuclear DNA. Ionizing radiation (IR) generates ROS through water radiolysis, including hydroxyl radicals (∙OH). (Top right frame): IR damages DNA directly and indirectly via ROS-mediated damage. (Lower right frame): IR-induced mitochondrial ROS (mtROS) triggers apoptotic and inflammatory responses. (Lower left frame): IR induces oxidative stress in the lipid membrane, where labile iron (Fe2+) catalyzes ROS production, resulting in lipid peroxidation. This schematic highlights the distinct biological impacts of FLASH RT compared to CRT, which may play a role in the FLASH effect. Full article ">Figure 2
(A) Differential response of ROS dynamics in FLASH radiotherapy (FLASH RT) (orange) compared to conventional radiotherapy (CRT) (blue). Dose rate (DR) and ionizing radiation (IR): the left panel shows the interaction between IR and water molecules, highlighting the higher DR difference in FLASH RT, which results in more ionization events within a shorter time frame compared to CRT. Radiolysis of water: IR induces water radiolysis, producing reactive oxygen species (ROS), including hydroxyl radicals (∙OH), which form organic peroxides (ROO∙s to ROOHs). The right panel demonstrates that FLASH RT results in lower ROS levels, reducing oxidative damage to biological processes. Radical–radical recombination hypothesis: the bottom panel suggests that rapid radical formation increases recombination, creating hydrogen-bonded clusters that localize ROS and reduce DNA damage. Grey panel from top to bottom: hydroxyl radical (∙OH), hydrogen radical (H∙), hydrogen proton (H+), hydrogen peroxide (H2O2), aqueous electron (e−aq), hydroxide ion (OH−), superoxide anion (O2−), superoxide radical (O2∙−), hydroxonium (H3O+), and peroxyl radical (ROO∙). (B) Side-by-side comparison of ROS dynamics following FLASH RT versus CRT in normal and tumor tissue. (Top left): CRT increases ROS levels in normal tissue, overwhelming its antioxidant (AO) reserve, with the oxygen-rich environment rendering it particularly sensitive to CRT. (Top right): FLASH RT leads to lower ROS levels in normal tissue, attributable to the higher AO reserve and radical–radical recombination. FLASH RT-induced ROS also contributes to oxygen consumption, potentially affecting local oxygen levels. (Bottom left): CRT elevates ROS levels in tumor tissue, overwhelming its limited AO capacity. Tumor hypoxia further contributes to radioresistance. (Bottom right): FLASH RT generates higher ROS levels in tumor tissue, which lacks a sufficient AO pool for neutralization, while the radical–radical recombination remains relevant in this context. While ROS dynamics may influence oxygen consumption, the impact is hypothesized to be minimal in hypoxic tumor tissues. Full article ">Figure 3
(A) Differential impact on iron and lipid metabolism following FLASH radiotherapy (FLASH RT) (orange) compared to conventional radiotherapy (CRT) (blue). Reactive oxygen species (ROS) generated from water radiolysis interact with iron-containing proteins leading to Fe2+ release. Iron transport relies on circulating transferrin, ferritin which stores iron, and ferroportin acting as an iron exporter. Labile Fe2+ can participate in Fenton reactions with hydrogen peroxide (H2O2) and organic or lipid hydroperoxides (ROOHs) generating hydroxyl radicals (∙OH) that further fuel ROS production, increasing oxidative stress. ROS can oxidize biomolecules, including polyunsaturated fatty acids (PUFAs) in phospholipids, initiating lipid peroxidation. Lipid peroxidation is a chain reaction that can be initiated via non-enzymatic Fenton reactions and enzymatic pathways with cytochrome P450 and lipoxygenases. Lipid hydroperoxide (ROOH) accumulation result in a self-propagating reaction that can trigger ferroptosis, a form of iron-dependent cell death. Additionally, lipid hydroperoxides (ROOHs) give rise to malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Antioxidants (AOs), including glutathione (GSH) and glutathione peroxidase 4 (GPX4) inhibit this cascade. (B) Side-by-side comparison of iron and lipid metabolism after FLASH RT versus CRT in normal and tumor tissue. (Top left): CRT elevates ROS levels in normal tissue, increasing Fenton reactions despite high iron sequestration capacity. Oxidative stress is further enhanced by increased lipid peroxidation, overwhelming antioxidant (AO) reserves. This results in the accumulation of lipid hydroperoxides (ROOHs), which can trigger ferroptosis, contributing to normal tissue toxicity. (Top right): reduced ROS levels after FLASH RT decrease the activation of Fenton reactions in normal tissue. This effect is further supported by the intrinsically low levels of labile Fe2+ and the tissue’s efficient iron sequestration capacity. As a result, there is less lipid peroxidation due to reduced Fenton reactions and the effective elimination of ROOH by the AO reserve. Thus, the likelihood of ferroptosis occurring is hypothesized to be reduced. (Bottom left): CRT elevates ROS levels in tumor tissue, leading to more Fenton reactions. This effect is amplified by the higher levels of labile Fe2+ iron and reduced capacity for iron uptake in tumors. In turn, lipid peroxidation rises, driven by the upregulated lipid metabolism in tumors that enables them to cope with cellular stresses. The resulting accumulation of ROOH cannot be effectively eliminated by the limited AO reserve, leading to increased ferroptosis. This form of programmed cell death can be inhibited by hypoxia, which may contribute to the radioresistance of the tumor. (Bottom right): while FLASH RT results in less ROS formation, it is the heightened levels of labile Fe2+ in tumor tissue and its reduced iron sequestration capacity that fuel the Fenton reactions. In turn, lipid peroxidation is elevated, also driven by the active lipid metabolism is tumor tissue. The accumulation of ROOH overwhelms the already-limited AO reserve, potentially increasing ferroptosis. This suggests a localized effect of FLASH RT on cancer cells. Full article ">Figure 4
(A) Differential impact on mitochondrial metabolism following FLASH radiotherapy (FLASH RT) (orange) compared to conventional radiotherapy (CRT) (blue). Ionizing radiation (IR) generates reactive oxygen species (ROS) through water radiolysis and as byproducts of mitochondrial oxidative phosphorylation (OXPHOS). Mitochondrial ROS (mtROS) are predominantly formed at complex I, II, and III of the mitochondrial electron transport chain (ETC), converting superoxide (O2∙−) to hydrogen peroxide (H2O2) via superoxide dismutase (SOD). Cytochrome c is involved in mitochondrial respiration and ATP synthesis. Following glycolysis, the tricarboxylic acid (TCA) cycle generates NADH and FADH2, which fuel the ETC in the inner mitochondrial membrane (IMM). Excessive mtROS can damage mitochondrial DNA (mtDNA), disrupting the expression of mitochondrial respiration proteins. When oxidative damage surpasses repair mechanisms, mitochondria may be degraded through mitophagy. IR can activate pro-apoptotic proteins BAX and BAK, permeabilizing the outer membrane and causing cytochrome c leakage, leading to caspase activation and apoptosis. Mitochondrial disruption can release mtROS and mtDNA, potentially causing necrosis and inflammatory responses. (B) Side-by-side comparison of mitochondrial metabolism after FLASH RT versus CRT in normal and tumor tissue. (Top left): CRT elevates ROS levels in normal tissue, impairing OXPHOS and ATP production while elevating mtROS, damaging mitochondria. This results in cytochrome c release, apoptosis, and necrosis. CRT enhances mitochondrial fission via Drp1. Despite the CRT-induced changes, the metabolic profile remains OXPHOS-dependent. (Top right): FLASH RT results in less ROS formation in normal tissue, preserving OXPHOS and ATP production, maintaining mtROS levels, and sparing mitochondria. Cytochrome c leakage is reduced, favoring apoptosis over necrosis. FLASH RT preserves phosphorylation of Drp1 (pDrp1), preventing excessive fission and necrosis. The metabolic profile remains OXPHOS-dependent. (Bottom left): CRT elevates ROS levels in tumor tissue, impairing OXPHOS and ATP production while elevating mtROS, damaging mitochondria. This triggers cytochrome c release, apoptosis, and necrosis. CRT enhances mitochondrial fission via Drp1. The metabolic profile shifts from OXPHOS to glycolysis to adapt to hypoxia and IR. (Bottom right): FLASH RT elevates ROS levels in tumor tissue, impairing OXPHOS and ATP production, while elevating mtROS, damaging mitochondria. This results in cytochrome c release, favoring apoptosis over necrosis. CRT enhances mitochondrial fission via Drp1. The metabolic profile shifts from OXPHOS to glycolysis to adapt to hypoxia and IR. Full article ">

11 pages, 2882 KiB

Open AccessArticle

Doxycycline Restores Gemcitabine Sensitivity in Preclinical Models of Multidrug-Resistant Intrahepatic Cholangiocarcinoma

by Annamaria Massa, Francesca Vita, Caterina Peraldo-Neia, Chiara Varamo, Marco Basiricò, Chiara Raggi, Paola Bernabei, Jessica Erriquez, Francesco Leone, Massimo Aglietta, Giuliana Cavalloni and Serena Marchiò

Cancers 2025, 17(1), 132; https://doi.org/10.3390/cancers17010132 - 3 Jan 2025

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Abstract

Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with a rising global incidence and poor prognosis, largely due to late-stage diagnosis and limited effective treatment options. Standard chemotherapy regimens, including cisplatin and gemcitabine, often fail because of the development of multidrug resistance [...] Read more.

Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with a rising global incidence and poor prognosis, largely due to late-stage diagnosis and limited effective treatment options. Standard chemotherapy regimens, including cisplatin and gemcitabine, often fail because of the development of multidrug resistance (MDR), leaving patients with few alternative therapies. Doxycycline, a tetracycline antibiotic, has demonstrated antitumor effects across various cancers, influencing cancer cell viability, apoptosis, and stemness. Based on these properties, we investigated the potential of doxycycline to overcome gemcitabine resistance in iCCA. Methods: We evaluated the efficacy of doxycycline in two MDR iCCA cell lines, MT-CHC01R1.5 and 82.3, assessing cell cycle perturbation, apoptosis induction, and stem cell compartment impairment. We assessed the in vivo efficacy of combining doxycycline and gemcitabine in mouse xenograft models. Results: Treatment with doxycycline in both cell lines resulted in a significant reduction in cell viability (IC₅₀ ~15 µg/mL) and induction of apoptosis. Doxycycline also diminished the cancer stem cell population, as indicated by reduced cholangiosphere formation. In vivo studies showed that while neither doxycycline nor gemcitabine alone significantly reduced tumor growth, their combination led to marked decreases in tumor volume and weight at the study endpoint. Additionally, metabolic analysis revealed that doxycycline reduced glucose uptake in tumors, both as a monotherapy and more effectively in combination with gemcitabine. Conclusions: These findings suggest that doxycycline, especially in combination with gemcitabine, can restore chemotherapy sensitivity in MDR iCCA, providing a promising new strategy for improving outcomes in this challenging disease. Full article

(This article belongs to the Collection Primary Liver Cancer)

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Cell cycle analysis. MT-CHC01R1.5 and 82.3 cells were treated with doxycycline (15 µg/mL) or gemcitabine (1.5 µM) for 48 h, and cell cycle distribution was analyzed using PI staining and flow cytometry. The bars show the mean ± SEM percentage of cells in each phase of the cell cycle from three independent experiments. Control: no treatment; DOXY: doxycycline; GEM: gemcitabine. * p < 0.05 for GEM vs. Control (two-way ANOVA). Full article ">Figure 2
Apoptosis assay. (A) The percentages of cells in early apoptosis (Annexin V-positive only) and late apoptosis (Annexin V- and PI-double-positive) are shown. These data are representative of three independent flow cytometry experiments with consistent results. (B) The average percentage of Annexin V-positive cells was used to calculate the treatment-to-control ratio. Histograms display the mean ± SD from three independent experiments. Control: no treatment; DOXY: doxycycline; GEM: gemcitabine. * p < 0.05 and ** p < 0.01 for DOXY vs. Control (one-way ANOVA). Full article ">Figure 3
Tumor sphere formation assay. (A) Representative images of spheres formed by MT-CHC01R1.5 and 82.3 cells after 7 days of treatment with the indicated drugs. Scale bar, 200 μm. (B) Cholangiospheres with a diameter greater than 50 µm were counted across three separate optical fields. Results are presented as the mean ± S from three independent experiments. Control: no treatment; DOXY: doxycycline; GEM: gemcitabine. * p < 0.05 for DOXY vs. Control; § p < 0.05 for DOXY vs. GEM (one-way ANOVA). Full article ">Figure 4
In vivo growth of MT-CHC01R.1.5 xenografted tumor models. Mice were divided into four groups, with treatments administered twice weekly for a total of 26 days. (A) Tumor volumes measured with a caliper at the indicated time points. (B) Tumor weights measured at the endpoint (day 26). Results are presented as the mean ± SEM for each treatment group. Control: no treatment; DOXY: doxycycline; GEM: gemcitabine; COMBO: doxycycline +gemcitabine. * p < 0.05 and *** p < 0.001 for COMBO vs. Control (one-way ANOVA). Full article ">Figure 5
In vivo and ex vivo metabolic activity in xenografted tumor models. (A) Representative images showing tumor uptake of 2-DG 750, acquired using an IVIS instrument in live animals (in vivo) and in explanted tumors (ex vivo). (B) Cumulative analysis of the total fluorescence flux in tumor masses (in vivo) and the average radiance values (ex vivo). Results are expressed as the mean ± SEM for each treatment group, based on three independent experiments. Control: no treatment; DOXY: doxycycline; GEM: gemcitabine; COMBO: doxycycline + gemcitabine. § p < 0.05 for DOXY vs. Control, * p < 0.05, ** p < 0.01 for COMBO vs. Control (one-way ANOVA). Full article ">

15 pages, 1134 KiB

Open AccessArticle

Does Personality Influence the Quality of Life of Patients with Brain Tumors Treated with Radiotherapy?

by Agnieszka Pilarska, Anna Pieczyńska, Krystyna Adamska and Katarzyna Hojan

Cancers 2025, 17(1), 131; https://doi.org/10.3390/cancers17010131 - 3 Jan 2025

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Abstract

Background: Understanding the role of personality traits in shaping treatment outcomes is crucial given the multifaceted challenges posed by brain tumors and the significant adverse impact of radiotherapy (RT) on patients’ well-being. Purpose: This study aimed to provide insights into how personality traits [...] Read more.

Background: Understanding the role of personality traits in shaping treatment outcomes is crucial given the multifaceted challenges posed by brain tumors and the significant adverse impact of radiotherapy (RT) on patients’ well-being. Purpose: This study aimed to provide insights into how personality traits affect psychosocial well-being and quality of life during RT in patients with high-grade malignant brain tumors. Methods: Personality traits in patients with high-grade glioma were assessed using the Eysenck Personality Questionnaire-Revised (EPQ-R). Quality of life was analyzed using EORTC questionnaires: the Questionnaire-Core 30 (QLQ-C30) and the Brain Cancer Module (QLQ-BN20). Patients were evaluated before RT, immediately after 6 weeks of RT, and 3 months post-RT. Results: Neuroticism predicted emotional function only three months post-RT. Extraversion decreased quality of life in global health status (third assessment), role function (second assessment), and emotional function (second and third assessments) but improved cognitive (first assessment) and social function (second assessment). The trait associated with lying was linked to a better quality of life in all domains except physical and cognitive function. Anxiety predicted a lower quality of life in brain tumor patients across all domains at various stages of RT treatment. Conclusions: This study advances our understanding of the psychosocial aspects of brain tumor care by highlighting the influence of personality traits on quality-of-life outcomes during RT. Identifying high-grade glioma patients at greater risk of a diminished quality of life based on personality profiles allows healthcare professionals to tailor interventions to address specific psychosocial needs, ultimately enhancing patient outcomes and holistic care during oncological treatment. Full article

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

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18 pages, 4377 KiB

Open AccessArticle

Deep Convolutional Framelets for Dose Reconstruction in Boron Neutron Capture Therapy with Compton Camera Detector

by Angelo Didonna, Dayron Ramos Lopez, Giuseppe Iaselli, Nicola Amoroso, Nicola Ferrara and Gabriella Maria Incoronata Pugliese

Cancers 2025, 17(1), 130; https://doi.org/10.3390/cancers17010130 - 3 Jan 2025

Viewed by 357

Abstract

Background: Boron neutron capture therapy (BNCT) is an innovative binary form of radiation therapy with high selectivity towards cancer tissue based on the neutron capture reaction ¹⁰B(n,

α

)⁷Li, consisting in the exposition of patients to neutron beams after administration [...] Read more.

Background: Boron neutron capture therapy (BNCT) is an innovative binary form of radiation therapy with high selectivity towards cancer tissue based on the neutron capture reaction ¹⁰B(n,

α

)⁷Li, consisting in the exposition of patients to neutron beams after administration of a boron compound with preferential accumulation in cancer cells. The high linear energy transfer products of the ensuing reaction deposit their energy at the cell level, sparing normal tissue. Although progress in accelerator-based BNCT has led to renewed interest in this cancer treatment modality, in vivo dose monitoring during treatment still remains not feasible and several approaches are under investigation. While Compton imaging presents various advantages over other imaging methods, it typically requires long reconstruction times, comparable with BNCT treatment duration. Methods: This study aims to develop deep neural network models to estimate the dose distribution by using a simulated dataset of BNCT Compton camera images. The models pursue the avoidance of the iteration time associated with the maximum-likelihood expectation-maximization algorithm (MLEM), enabling a prompt dose reconstruction during the treatment. The U-Net architecture and two variants based on the deep convolutional framelets framework have been used for noise and artifact reduction in few-iteration reconstructed images. Results: This approach has led to promising results in terms of reconstruction accuracy and processing time, with a reduction by a factor of about 6 with respect to classical iterative algorithms. Conclusions: This can be considered a good reconstruction time performance, considering typical BNCT treatment times. Further enhancements may be achieved by optimizing the reconstruction of input images with different deep learning techniques. Full article

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

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Cancers, Volume 17, Issue 1 (January-1 2025) – 159 articles

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