Cancers

18 pages, 5297 KB

Open AccessReview

HCC in the Era of Emerging MASH: The Role of Ultrasound in Surveillance and New Sonographic Features in Diagnosis

by Antonio Giorgio, Massimo De Luca, Anna Lombardi, Emanuela Ciracì, Valeria Cosima Rollo, Antonella Di Sarno, Luca Montesarchio, Giuseppe Stella and Valentina Giorgio

Cancers 2025, 17(24), 4037; https://doi.org/10.3390/cancers17244037 - 18 Dec 2025

Cited by 1 | Viewed by 1123

Abstract

Conventional ultrasound (US) has long been central to hepatocellular carcinoma (HCC) surveillance in cirrhotic patients, due to its low cost, wide availability, non-invasiveness, and adequate sensitivity for detecting small nodules. However, its specificity in distinguishing HCC from other lesions is limited. Contrast-enhanced ultrasound [...] Read more.

Conventional ultrasound (US) has long been central to hepatocellular carcinoma (HCC) surveillance in cirrhotic patients, due to its low cost, wide availability, non-invasiveness, and adequate sensitivity for detecting small nodules. However, its specificity in distinguishing HCC from other lesions is limited. Contrast-enhanced ultrasound (CEUS) has significantly improved the characterization of nodules first identified on conventional US. Yet, when CEUS is performed using sulfur hexafluoride (SonoVue)—the only contrast agent available in Western countries—assessment remains restricted to a single nodule per examination, and enhanced CT or MRI is still required for full characterization and staging. In clinical settings, such as hepatology, internal medicine, infectious diseases, and surgery, CEUS offers the advantage of immediate availability, enabling rapid characterization of suspicious nodules in cirrhotic livers and facilitating timely therapeutic decisions. Although the introduction of direct-acting antivirals (DAAs) has substantially reduced HCV-related HCC, HCC incidence is increasingly driven by metabolic dysfunction-associated steatohepatitis (MASH). Evidence on surveillance strategies for MASH patients remains limited, and current EASL guidelines recommend monitoring only patients with >F2 fibrosis. Additionally, the effectiveness of US in obese or diabetic/obese populations is under ongoing investigation; abbreviated non-contrast MRI has been proposed as an alternative surveillance tool, but its adoption would entail significant economic implications for healthcare systems. HCC arising from MASH—sometimes even without cirrhosis—exhibits different sonographic and pathological features. Instead of small, hypoechoic nodules, typically seen in HCV-related cirrhosis, clinicians increasingly encounter larger or multiple lesions, often accompanied by macrovascular invasion, limiting access to curative treatments. Furthermore, typical CEUS LI-RADS patterns are less frequently observed. This review summarizes the evolving US findings in the era of MASH-related HCC and underscores the continued importance of US as the primary imaging tool in routine clinical practice. Full article

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

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17 pages, 549 KB

Open AccessArticle

MRI-Derived Body Composition and Breast Cancer Risk in Postmenopausal Women: UK Biobank Study

by Livingstone Aduse-Poku, Lusine Yaghjyan, Stephen E. Kimmel, Susmita Datta, Shama D. Karanth, Jae Jeong Yang, Caretia Washington and Dejana Braithwaite

Cancers 2025, 17(24), 4036; https://doi.org/10.3390/cancers17244036 - 18 Dec 2025

Viewed by 831

Abstract

Background: Obesity is a risk factor for breast cancer mortality in postmenopausal women. However, it remains unclear which specific components of adipose tissue and skeletal muscle are associated with risk. This study assessed the associations between MRI-assessed adiposity, skeletal mass, and breast cancer [...] Read more.

Background: Obesity is a risk factor for breast cancer mortality in postmenopausal women. However, it remains unclear which specific components of adipose tissue and skeletal muscle are associated with risk. This study assessed the associations between MRI-assessed adiposity, skeletal mass, and breast cancer risk in a population-based cohort. Methods: We analyzed data from 15,669 postmenopausal women in the UK Biobank who underwent MRI for body composition assessment. Age- and multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional-hazards regression to evaluate the associations between body composition and breast cancer risk, adjusting for relevant confounders. Sensitivity analyses were conducted by excluding breast cancer cases diagnosed within 2 years of the MRI scan. To explore nonlinear relationships, we applied restricted cubic splines with three knots to model associations between visceral adipose tissue (VAT), muscle-fat infiltration (MFI), and breast cancer risk. Results: The mean age of participants was 58.6 years (SD = 5.2; range = 40–69). Higher VAT was significantly associated with increased breast cancer risk (3rd vs. 1st tertile aHR = 1.24, 95% CI: 1.10–1.45). Elevated MFI was also linked with greater risk (3rd vs. 1st tertile aHR = 1.53, 95% CI: 1.25–1.87). These associations persisted after excluding early cancer cases. We observed a J-shaped relationship between VAT, MFI, and breast cancer risk. Conclusions: Higher levels of VAT and MFI are associated with elevated breast cancer risk in postmenopausal women, suggesting that imaging-derived body composition measures may enhance risk prediction and inform prevention strategies. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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23 pages, 1290 KB

Open AccessArticle

Exploration of Predictive Factors for Acute Radiotherapy-Induced Gastro-Intestinal Symptoms in Prostate Cancer Patients

by Pauline De Bruyn, Malgorzata Klass, Alain Van Muylem, Nicolas Jullian, François-Xavier Otte, Romain Diamand and Jean-Charles Preiser

Cancers 2025, 17(24), 4035; https://doi.org/10.3390/cancers17244035 - 18 Dec 2025

Viewed by 640

Abstract

Background: Acute gastrointestinal (GI) toxicity is a frequent adverse effect of pelvic radiotherapy (RT) in prostate cancer and predicts chronic complications. Identifying predictive factors, especially modifiable ones, is essential to guide supportive interventions. Methods: This prospective observational non-randomized cohort included 32 [...] Read more.

Background: Acute gastrointestinal (GI) toxicity is a frequent adverse effect of pelvic radiotherapy (RT) in prostate cancer and predicts chronic complications. Identifying predictive factors, especially modifiable ones, is essential to guide supportive interventions. Methods: This prospective observational non-randomized cohort included 32 patients with prostate cancer treated with pelvic RT. Patient-reported GI symptoms were measured using the EORTC QLQ-PRT20 module, and clinician-reported toxicity was graded with CTCAE v5.0. Associations between GI outcomes and clinical, demographic, and lifestyle variables—including the systemic immune-inflammation index (SII) and the Diet Quality Index (DQI)—were examined using uni- and multivariable models. Results: Ninety-one percent of patients reported worsening GI symptoms during RT (median QLQ-PRT20 score increased from 4.2 to 26.8, p < 0.0001). In our final model, higher SII values were independently associated with greater symptom worsening (p = 0.001), whereas obesity (p = 0.03) and higher diet quality (p = 0.015) were protective. No significant interactions were found between SII and BMI or DQI, although diet quality partially attenuated the association between SII and symptom progression. Clinician-reported grade ≥ 2 GI toxicity occurred in 41% of patients and was significantly less frequent in obese individuals (adjusted OR = 0.04, 95% CI 0.0009–0.57, p = 0.02), with higher SII tending to increase risk and higher DQI showing a protective trend. Conclusions: In this exploratory analysis, systemic inflammation was associated with increased GI symptom burden, whereas obesity appeared to mitigate both patient- and clinician-reported outcomes. Higher dietary quality was similarly protective for patient-reported symptoms and showed a non-significant protective trend for clinician-reported toxicity. These findings highlight the interplay between metabolic and inflammatory status in shaping RT-related GI outcomes and support integrating nutritional and inflammatory profiling to guide personalized preventive strategies. Full article

(This article belongs to the Special Issue Empowering Cancer Survivors: A Comprehensive Approach to Supportive Care Through Pharmacological and Non-Pharmacological Approaches Including Exercise, Physical Activity and Nutrition)

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11 pages, 637 KB

Open AccessArticle

Two Decades of Female Breast Cancer Mortality in Hungary: Epidemiological Trends Since EU Accession

by Tamás Lantos, Tibor András Nyári and Giuseppe Verlato

Cancers 2025, 17(24), 4034; https://doi.org/10.3390/cancers17244034 - 18 Dec 2025

Viewed by 1279

Abstract

Objective: This study aimed to investigate annual and seasonal trends, as well as regional differences, in female breast cancer mortality in Hungary between 2004 and 2023. Methods: Data on cancer mortality were obtained from the publicly available nationwide population register. Poisson and quasi-Poisson [...] Read more.

Objective: This study aimed to investigate annual and seasonal trends, as well as regional differences, in female breast cancer mortality in Hungary between 2004 and 2023. Methods: Data on cancer mortality were obtained from the publicly available nationwide population register. Poisson and quasi-Poisson regression models were applied to investigate the annual trend in breast cancer mortality rates. Cyclic trends in mortality were analysed using the Walter–Elwood method, and regional differences in age-standardised mortality rates (ASMRs) were evaluated across Hungarian regions. Results: Over the two decades studied, a total of 42,779 deaths from breast cancer were recorded. A significant declining trend in annual ASMRs for female breast cancer was observed during the study period (IRR = 0.996; 95% CI [0.993–0.998]; p = 0.002). Seasonal analysis revealed a significant cyclic pattern, with the highest number of deaths occurring during the winter months, peaking in December. The highest age-standardised breast cancer mortality rate (43.9 ± 0.2 per 100,000 female persons per year) was observed in the Capital region (Budapest), while the lowest ASMR (36.2 ± 0.25 per 100,000 female persons per year) was found in the Northern Great Plain region (p = 0.028). Conclusions: Although Hungary has implemented a free national breast cancer screening programme, this study demonstrates that breast cancer mortality remains high in the country. Additionally, breast cancer mortality exhibits significant regional and seasonal variation. These findings underscore the need for targeted public health interventions and optimised resource allocation to improve outcomes. Full article

(This article belongs to the Special Issue Emerging Trends in Global Cancer Epidemiology: 2nd Edition)

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32 pages, 1490 KB

Open AccessReview

Silent Players, Loud Impact: The Influence of lncRNAs on Melanoma Progression

by Kajetan Kiełbowski, Maciej Ćmil, Aleksandra Dach, Aleksandra Cole, Oliwia Jerzyńska, Estera Bakinowska, Paulina Plewa and Andrzej Pawlik

Cancers 2025, 17(24), 4033; https://doi.org/10.3390/cancers17244033 - 18 Dec 2025

Cited by 1 | Viewed by 729

Abstract

Non-coding RNA (ncRNA) encompasses a large family of molecules that are crucial regulators of gene expression. This family includes microRNA, piwi-interacting RNA, and long non-coding RNA (lncRNA); each class is associated with different mechanisms of action that influence gene expression. Based on the [...] Read more.

Non-coding RNA (ncRNA) encompasses a large family of molecules that are crucial regulators of gene expression. This family includes microRNA, piwi-interacting RNA, and long non-coding RNA (lncRNA); each class is associated with different mechanisms of action that influence gene expression. Based on the available evidence, these molecules have important roles in physiological and pathological processes. For example, ncRNAs are strongly implicated in oncogenesis by mediating the expression of tumour suppressors and oncogenes. This review comprehensively describes the latest findings regarding the roles of lncRNAs in the pathophysiology of melanoma. Key aspects of melanoma biology and various mechanisms regulated by lncRNAs are discussed. Furthermore, future areas exploring potential biomarkers and therapeutic targets are presented. Full article

(This article belongs to the Special Issue Novel Research on the Diagnosis and Treatment of Melanoma)

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11 pages, 271 KB

Open AccessReview

Would Biopsy Change the Management of Kidney Cancer in the Coming Decade? The Role of Biopsy in Small Renal Masses: A Narrative Review

by Łukasz Dariusz Lisak, Paweł Hełka, Aleksandra Kaźmierczak, Anna Kaletka, Sarah Sampers, Piotr Kania, Miłosz Jasiński and Maciej Salagierski

Cancers 2025, 17(24), 4032; https://doi.org/10.3390/cancers17244032 - 18 Dec 2025

Viewed by 846

Abstract

Renal cell carcinoma (RCC) is the 14th-most common cancer worldwide, with 434,419 new cases recorded in 2022 [...] Full article

(This article belongs to the Special Issue New Insights into General, Functional and Oncologic Urology)

13 pages, 647 KB

Open AccessArticle

Pregnancy vs. Postpartum Breast Cancer: Distinct Tumor Biology and Survival Trends in a Contemporary Cohort

by Elena Jane Mason, Alba Di Leone, Beatrice Carnassale, Antonio Franco, Cristina Accetta, Sabatino D’Archi, Flavia De Lauretis, Federica Gagliardi, Elisabetta Gambaro, Marzia Lo Russo, Stefano Magno, Francesca Moschella, Federica Murando, Maria Natale, Alejandro Martin Sanchez, Lorenzo Scardina, Marta Silenzi, Alessandra Fabi, Ida Paris, Antonella Palazzo, Armando Orlandi, Fabio Marazzi, Angela Santoro, Paolo Belli, Giacomo Corrado, Patrizia Frittelli and Gianluca Franceschini Show full author list Hide full author list

Cancers 2025, 17(24), 4031; https://doi.org/10.3390/cancers17244031 - 18 Dec 2025

Cited by 1 | Viewed by 684

Abstract

Background: Pregnancy-associated breast cancer (PABC), defined as breast cancer diagnosed during pregnancy or within one year postpartum, is a unique and clinically challenging entity. Evidence suggests that tumors diagnosed during pregnancy (PrBC) and postpartum (PPBC) may differ in biology and prognosis. This [...] Read more.

Background: Pregnancy-associated breast cancer (PABC), defined as breast cancer diagnosed during pregnancy or within one year postpartum, is a unique and clinically challenging entity. Evidence suggests that tumors diagnosed during pregnancy (PrBC) and postpartum (PPBC) may differ in biology and prognosis. This study compares clinical features, treatment patterns and outcomes between PrBC and PPBC. Methods: We performed a retrospective analysis of 76 women diagnosed with PABC from January 2000 to June 2023 across two tertiary centers. Patients were classified according to ESMO guidelines as PrBC (n = 41) or PPBC (n = 35). Clinical presentation, tumor characteristics, treatment approaches and survival outcomes were evaluated. Overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan–Meier analysis and compared with log-rank tests. Results: A total of 76 patients with PABC were included (41 PrBC, 35 PPBC; median age 37 years). Most tumors were high-grade invasive ductal carcinomas, with Luminal B predominant in PrBC and triple-negative breast cancer (TNBC) in PPBC. Locally advanced disease was common (axillary involvement 52%; de novo metastases 9%). Surgery was performed in most cases, with breast conservative surgery (BCS) more frequent in PrBC and mastectomy in PPBC; 46% received neoadjuvant chemotherapy. At median follow-up of 68 months, 7.9% of patients had died and 29% experienced recurrence. Oncologic outcomes were similar between subgroups, with a trend in favor of PrBC. Pregnancy continuation did not adversely affect outcomes. Conclusions: PrBC and PPBC display heterogeneous clinical presentations with a trend toward more favorable outcomes in PrBC. These findings support the need for tailored counseling, individualized management and research designs that differentiate between PrBC and PPBC. Full article

(This article belongs to the Special Issue Breast Cancer and Pregnancy: Clinical, Translational, and Psychosocial Perspectives)

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11 pages, 261 KB

Open AccessArticle

Impact of Frailty on the Outcomes of Patients with Pancreatic Cancer Undergoing Neoadjuvant Therapy

by Nicholas R. Williams, Thomas Leuschner, Amanda K. Walsh, Kayla Gault, Amber Ingram, Alex B. Blair, Susan Tsai, Timothy M. Pawlik, Mary E. Dillhoff and Jordan M. Cloyd

Cancers 2025, 17(24), 4030; https://doi.org/10.3390/cancers17244030 - 18 Dec 2025

Cited by 1 | Viewed by 835

Abstract

Background: Neoadjuvant therapy (NT) is increasingly utilized for patients with localized pancreatic ductal adenocarcinoma (PDAC). Toxicities during NT are common, often leading to the inability to undergo surgical resection, yet risk factors for attrition are poorly understood. Therefore, we sought to evaluate [...] Read more.

Background: Neoadjuvant therapy (NT) is increasingly utilized for patients with localized pancreatic ductal adenocarcinoma (PDAC). Toxicities during NT are common, often leading to the inability to undergo surgical resection, yet risk factors for attrition are poorly understood. Therefore, we sought to evaluate the impact of baseline frailty on outcomes of patients with PDAC undergoing NT. Methods: All patients with potentially resectable (PR) or borderline resectable (BR) PDAC who initiated neoadjuvant chemotherapy and/or chemoradiation between 2019 and 2025 at a single institution were assessed retrospectively in an intention-to-treat fashion. The association between frailty as defined by the modified 11-item frailty index (mFI-11) and receipt of surgical resection as well as other secondary endpoints was assessed. Comprehensive functional frailty assessments were prospectively obtained in a subset of patients. Results: Among 252 eligible patients, the median age was 67 years, 56.7% were male, 90.9% were White, 49.6% had PR disease, and 5.2% were frail according to mFI-11. After a median 3.6 months of NT, 62.7% underwent surgical resection. Frail individuals had worse performance status and increased comorbidities compared with non-frail patients. On multivariable analysis, male sex, BR anatomic staging, initial use of Gemcitabine + nab-paclitaxel, and frailty (OR 0.09; 95%CI 0.02–0.44) were associated with reduced odds of undergoing resection. Along with increased baseline CA 19-9 levels, frailty was independently associated with worse overall survival (HR 3.00; 95%CI 1.46–6.20). Among 39 patients who underwent formal functional frailty assessment, only abnormal posture was associated with lower odds of surgical resection following NT (OR, 0.22; 95% CI, 0.05–0.92), and no aspects of functional frailty were associated with overall survival. Conclusions: Among patients with localized PDAC initiating NT, frailty as assessed by mFI-11 was associated with reduced odds of undergoing surgical resection and worse overall survival. Future research should focus on efforts to improve functional status during NT. Full article

(This article belongs to the Special Issue Developments in the Management of Gastrointestinal Malignancies (2nd Edition))

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17 pages, 1726 KB

Open AccessArticle

Complications of Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide—A Prospective Study on Behalf of the EBMT Transplant Complications Working Party

by Agnieszka Tomaszewska, Grzegorz W. Basak, Christophe Peczynski, Emmanuelle Polge, Pascale Ambron, William Boreland, Simona Sica, Mutlu Arat, Jakob Passweg, Jose Luis Lopez Lorenzo, Urpu Salmenniemi, Pavel Jindra, Alexander Kulagin, Rodrigo Martino Bufarull, Matthias Eder, Mohamed-Amine Bekadja, Alberto Mussetti, Charlotte E. Graham, Hélène Schoemans, Olaf Penack, Ivan Moiseev and Zinaida Perić Show full author list Hide full author list

Cancers 2025, 17(24), 4029; https://doi.org/10.3390/cancers17244029 - 18 Dec 2025

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Abstract

Background: Haploidentical hematopoietic cell transplantations (haplo-HCTs) with post-transplant cyclophosphamide (PT-Cy) are standard practice, but complications causing morbidity and mortality are not well described. Methods: The aim of this prospective non-interventional multicenter study was to document frequency of potential non-infectious and infection-related complications and [...] Read more.

Background: Haploidentical hematopoietic cell transplantations (haplo-HCTs) with post-transplant cyclophosphamide (PT-Cy) are standard practice, but complications causing morbidity and mortality are not well described. Methods: The aim of this prospective non-interventional multicenter study was to document frequency of potential non-infectious and infection-related complications and main transplant outcomes after the first unmanipulated haplo-HCT with PT-Cy between 2017 and 2019 in 129 adult patients with hematological malignancies. The median follow-up was 37.3 months [95% CI: 34.3–39.7]. Results: The cumulative incidence (CI) of acute graft versus host disease (aGvHD) at day +100 was 22.4% grade II-IV [95% CI: 15.5–30.1] and 8.8% grade III-IV [95% CI: 4.6–14.6], respectively. The cumulative incidence of chronic GvHD (cGvHD) at 24 months was 25.8% [95% CI: 18.5–33.6]; extensive cGvHD was 10.9% [95% CI: 6.3–17.1], respectively. The most frequent non-infectious complications for the whole study population were mucositis—37.5% (n = 48); renal insufficiency—18% (n = 23); and cardiovascular complications—10.9% (n = 14). The following infection-related complications were diagnosed: bacterial in 84 (65.1%), viral in 66 (51.6%), and fungal in 24 (18.6%) recipients. Two-year OS was 58.1% [95% CI: 50.2–67.3]; NRM—27.1% [95% CI: 19.7–35]; PFS—50.4% [95% CI: 42.5–59.8]; and GRFS—38.8% [95% CI: 31.2–48.1]. About 50% of all deaths were directly caused by infection or infection-related conditions. Conclusions: Disease remission status at transplant significantly affected PFS, chronic GvHD, and GRFS. Although clinical applications of haplo-HCT with PTCy are widespread, the study confirms the need to reduce infection-related mortality after this type of GvHD prophylaxis. Full article

(This article belongs to the Section Transplant Oncology)

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17 pages, 2139 KB

Open AccessArticle

Examination of Appendiceal Neoplasms—A Retrospective, Single-Centre, Cohort Study

by Berkenye Csonka, Tamás Lantos and Anita Sejben

Cancers 2025, 17(24), 4028; https://doi.org/10.3390/cancers17244028 - 18 Dec 2025

Viewed by 852

Abstract

Background: Appendiceal neoplasms are rare, but recent data indicate a rising trend, particularly in patients under the age of 50. These tumours are often diagnosed incidentally during histopathological examination. This study has aimed to examine the incidence and histological subtypes of appendiceal neoplasms [...] Read more.

Background: Appendiceal neoplasms are rare, but recent data indicate a rising trend, particularly in patients under the age of 50. These tumours are often diagnosed incidentally during histopathological examination. This study has aimed to examine the incidence and histological subtypes of appendiceal neoplasms in a Southern Hungarian population. Methods: Our study included neoplastic appendix specimens processed at the University of Szeged between 2014 and 2023. Results: Neoplasms were identified in 71 cases from 3640 appendectomies (1.9%). Benign lesions were present in 37% of cases (n = 26), with the most common subtype being the sessile serrated lesion (n = 20). Mucinous and malignant neoplasms were found in 63% of cases (n = 45), most frequently low-grade appendiceal mucinous neoplasm (n = 19), followed by neuroendocrine tumour (n = 17). Notably, colorectal neoplasm was identified in 50% of benign, and 42.2% of mucinous and malignant cases during a mean follow-up of 33.4 months. Significant associations were found between histological subtype and age (p = 0.022), complete resection (p = 0.012), presence of vascular invasion (p = 0.007), and localisation of potentially associated colorectal carcinoma (p = 0.018). Additionally, tumour dignity showed significant correlations with tumour, node, metastasis (TNM) stage (p < 0.001), vascular invasion (p = 0.017), and lastly, occurrence (p = 0.031) and localisation (p = 0.003) of associated colorectal carcinoma. Conclusions: The prevalence and characteristics observed in this Southern Hungarian population were consistent with international data, although raw case numbers suggested an upward trend. The high rate of associated colorectal neoplasms underscores the importance of thorough pathological evaluation and long-term surveillance. Full article

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

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14 pages, 12846 KB

Open AccessArticle

Secondary Genetic Events and Their Relationship to TP53 Mutation in Mantle Cell Lymphoma: A Sub-Study from the FIL_MANTLE-FIRST BIO on Behalf of Fondazione Italiana Linfomi (FIL)

by Maria Elena Carazzolo, Francesca Maria Quaglia, Antonino Aparo, Alessia Moioli, Alice Parisi, Riccardo Moia, Francesco Piazza, Alessandro Re, Maria Chiara Tisi, Luca Nassi, Pietro Bulian, Alessia Castellino, Vittorio Ruggero Zilioli, Piero Maria Stefani, Alberto Fabbri, Elisa Lucchini, Annalisa Arcari, Luisa Lorenzi, Barbara Famengo, Maurilio Ponzoni, Angela Ferrari, Simone Ragaini, Jacopo Olivieri, Vittoria Salaorni, Simona Gambino, Marilisa Galasso, Maria Teresa Scupoli and Carlo Visco Show full author list Hide full author list

Cancers 2025, 17(24), 4027; https://doi.org/10.3390/cancers17244027 - 17 Dec 2025

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Abstract

Background: Mantle Cell Lymphoma (MCL) is an aggressive malignancy with variable clinical behavior, largely reflecting the underlying molecular heterogeneity. The genomic landscape of MCL encompasses gene mutations with strong prognostic implications and secondary genetic events, which are also implicated in the pathogenesis [...] Read more.

Background: Mantle Cell Lymphoma (MCL) is an aggressive malignancy with variable clinical behavior, largely reflecting the underlying molecular heterogeneity. The genomic landscape of MCL encompasses gene mutations with strong prognostic implications and secondary genetic events, which are also implicated in the pathogenesis and prognosis of the disease. Methods: We evaluated the diagnostic samples of 73 patients with relapsed/refractory MCL that were enrolled in the Fondazione Italiana Linfomi Mantle First-BIO study. All patients had available data for correlating CNVs with the presence of TP53 mutation. Time to first relapse or progression of disease (POD) was used as the primary outcome measure. Results: We identified CNVs associated with MCL, with Del 9p21.3 (CDKN2A) being the strongest predictor of shorter time to POD (p = 0.01), independently of TP53 mutation in multivariable analysis. Unsupervised clustering identified molecularly defined clusters that were associated with significantly different times to POD (p = 0.01). Pairwise log-rank tests confirmed TP53 mutated vs. wild-type (WT) as the strongest prognostic factor, with cluster assessment improving the prognostic predictivity among patients: clusters TP53-mut vs. TP53-WT, p = 0.001, HR = 3.92; and p = 0.014, HR = 2.23, respectively. In conclusion, CNV-based molecular clusters might represent a novel approach to identify patients at higher risk of treatment failure, further contributing to the prognostic predictivity of TP53 mutation. Full article

(This article belongs to the Section Molecular Cancer Biology)

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20 pages, 1180 KB

Open AccessArticle

Associations of Breast Cancer Treatments with One-Year Changes in Health-Related Fitness

by Fernanda Z. Arthuso, Ki-Yong An, Qinggang Wang, Renée L. Kokts-Porietis, Andria R. Morielli, Margaret L. McNeely, Jeff K. Vallance, S. Nicole Culos-Reed, Gordon J. Bell, Leanne Dickau, Myriam Filion, Stephanie M. Ntoukas, Jessica McNeil, Lin Yang, Charles E. Matthews, Christine M. Friedenreich and Kerry S. Courneya

Cancers 2025, 17(24), 4026; https://doi.org/10.3390/cancers17244026 - 17 Dec 2025

Cited by 1 | Viewed by 959

Abstract

Background/Objectives: Early-stage breast cancer treatments adversely affect components of health-related fitness (HRF) important for treatment tolerability, recovery, and long-term outcomes. Few studies have examined cancer treatment modality-specific effects on HRF. We examined associations of breast cancer treatment modalities, regimens, and combinations with one-year [...] Read more.

Background/Objectives: Early-stage breast cancer treatments adversely affect components of health-related fitness (HRF) important for treatment tolerability, recovery, and long-term outcomes. Few studies have examined cancer treatment modality-specific effects on HRF. We examined associations of breast cancer treatment modalities, regimens, and combinations with one-year changes in HRF. Methods: Newly diagnosed early-stage breast cancer patients were recruited between 2012 and 2019 for the Alberta Moving Beyond Breast Cancer (AMBER) cohort study. HRF assessments were completed within 90 days of diagnosis and at one year, including cardiorespiratory fitness, muscle strength and endurance, and body composition. Analysis of covariance was used to test whether HRF changes differed between treatment modalities, regimens, and combinations. All tests were 2-sided. Results: A total of 1350 participants (mean [SD] age, 55.6 [10.7] years) were included. Women who received chemotherapy (n = 797; 59%) experienced statistically significant smaller increases in upper body strength (−1.7 kg, 95% confidence interval [CI]: −3.0 to −0.5), greater declines in lower body endurance (−118.0 kg, 95%CI: −216.6 to −19.3), and greater declines in total lean mass (−0.7 kg, 95%CI: −1.1 to −0.3), bone mineral density (−0.01 g/cm², 95%CI: −0.02 to 0.00), and bone mineral content (0.04 kg, 95%CI: −0.06 to −0.02). Other treatment modalities were modestly and inconsistently associated with HRF changes. Treatment combinations that included chemotherapy had the most negative impact on cardiorespiratory fitness and body composition. Conclusions: Chemotherapy—either alone or in combination with other treatments—had the largest and broadest negative impact on HRF recovery in early-stage breast cancer at one-year follow-up. Full article

(This article belongs to the Special Issue Exercise and Cancer Treatment: The Clinical Application of Exercise Oncology)

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22 pages, 3100 KB

Open AccessArticle

Drug-Induced Partial Immunosuppression for Preclinical Human Tumor Xenograft Models

by Anton K. Gorbushin, Natalia A. Luzan, Victoriya D. Kakhanova, Anastasia A. Koshmanova, Daniil S. Grek, Ivan I. Voronkovskii, Vladislav M. Farniev, Elvira. S. Melikhova, Kirill A. Lukyanenko, Dmitriy V. Veprintsev, Evgeny V. Morozov, Maya A. Dymova, Elena V. Kuligina, Evgeny A. Pryakhin, Vladimir A. Richter, Elena V. Styazhkina, Ekaterina A. Lipetskaya, Tatiana A. Garkusha, Tatiana N. Zamay, Olga S. Kolovskaya, Andrey A. Narodov, Vadim V. Kumeiko, Maxim V. Berezovski and Anna S. Kichkailo Show full author list Hide full author list

Cancers 2025, 17(24), 4025; https://doi.org/10.3390/cancers17244025 - 17 Dec 2025

Cited by 1 | Viewed by 1352

Abstract

Background: With the rising incidence of cancer, there is a growing need for improved preclinical models to test new therapies. While patient-derived xenografts (PDX) in immunodeficient mice are the gold standard, they are costly and result in a complete absence of a functional [...] Read more.

Background: With the rising incidence of cancer, there is a growing need for improved preclinical models to test new therapies. While patient-derived xenografts (PDX) in immunodeficient mice are the gold standard, they are costly and result in a complete absence of a functional immune system, limiting their utility for studying tumor–immune interactions. This study characterizes a pharmacological partial immunosuppression protocol in immunocompetent mice as a promising alternative, evaluating its impact on the immune system and demonstrating its efficacy for growing human tumor xenografts. Methods: Mice received a regimen of cyclosporine (20 mg/kg, i.p., every 48 h for 12 days), cyclophosphamide (60 mg/kg, i.p., every 48 h for 8 days), and ketoconazole (10 mg/kg, p.o., for 12 days). The dynamics of CD3⁺, CD4⁺, CD8⁺, and CD19⁺ lymphocyte subpopulations and the CD4/CD8 index were monitored via flow cytometry on days 1, 5, 8, 12, 16, and 21. The protocol’s utility was tested by orthotopic transplantation of human glioma and lung cancer cells, and subcutaneous transplantation of breast cancer cells (MCF7). Tumor engraftment and growth were assessed using in vivo microscopy, MRI, and histology. Results: The immunosuppressive protocol induced a significant but partial reduction in CD3⁺ T-cells and CD19⁺ B-cells by day 8 (p = 0.0277). A profound and progressive decrease in the CD4/CD8 index was observed, indicating a shift towards immunosuppression. Crucially, CD8⁺ and CD4⁺ T-cells populations recovered rapidly post-therapy, demonstrating that the protocol creates a temporary and modifiable immune window rather than inducing complete ablation. The protocol enabled successful engraftment and growth of all three tested tumors in a residual immune microenvironment, confirmed by in vivo imaging and histopathological analysis. Conclusions: This drug-induced partial immunosuppression protocol effectively creates a reproducible state of transient immunodeficiency in outbred mice, suitable for various human tumor xenograft models. It represents a cost-effective and flexible alternative to genetic models, with the distinct advantage of preserving a residual immune microenvironment, making it particularly valuable for preclinical studies that require a partially intact host immune system. Full article

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

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28 pages, 3140 KB

Open AccessReview

The Impact of Senescence-Associated Secretory Phenotype (SASP) on Head and Neck Cancers: From Biology to Therapy

by Md Tanjim Alam, Mishfak A. M. Mansoor, Sarah A. Ashiqueali, Pawel Golusinski, Ewelina Golusinska-Kardach, Joanna K. Strzelczyk, Blazej Rubis, Wojciech Golusinski and Michal M. Masternak

Cancers 2025, 17(24), 4024; https://doi.org/10.3390/cancers17244024 - 17 Dec 2025

Cited by 3 | Viewed by 2913

Abstract

Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play [...] Read more.

Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play a dual role in cancer biology. While the SASP can suppress tumors by facilitating immunosurveillance, it can also promote tumor progression by fostering a pro-inflammatory milieu, stimulating angiogenesis, enhancing invasiveness, and enabling immune evasion. In Head and Neck Cancers (HNCs), a highly heterogeneous group of malignancies, SASP has emerged as a critical player in disease progression and treatment resistance. Persistent DNA damage response (DDR) signaling drives SASP and thereby contributes to the progression of head and neck cancer by modulating the tumour microenvironment. It influences the tumor microenvironment (TME) by facilitating epithelial-to-mesenchymal transition (EMT), promoting cancer stem cell-like properties, and impairing the efficacy of radiotherapy, chemotherapy, and immune checkpoint inhibitors. These effects underscore the need for targeted interventions to regulate SASP activity. This review presents a comprehensive overview of the molecular mechanisms underlying SASP generation and its effects on HNCs. We discuss the dual roles of SASP in tumor suppression and progression, its contribution to therapy resistance, and emerging therapeutic strategies, including novel senolytic and senomorphic drugs. Finally, we highlight key challenges and future directions for translating SASP-targeted therapies into clinical practice, emphasizing the need for biomarker discovery, and a deeper understanding of SASP heterogeneity. By targeting the SASP, there is potential to enhance therapeutic outcomes and improve the management of HNCs. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment in Cancer: An Impact on Therapeutic Efficacy)

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18 pages, 713 KB

Open AccessArticle

Real-World Neoadjuvant Systemic Therapy Utilization and Treatment Patterns in Patients with Early-Stage or Locally Advanced Triple-Negative Breast Cancer in Greece—The TRINITY Study

by Konstantinos Papazisis, Christos Christodoulou, Flora Zagouri, Ippokratis Korantzis, Ioannis Boukovinas, Anna Koumarianou, Angelos Koutras, Eleni Timotheadou, Giannis Mountzios, Loukas Kontovinis, Ioannis Binas, Alkistis Papatheodoridi, Eleni Zairi, Ilias Gountas, Danai Ktena, Charalampos Athanasopoulos, Athanasios Kotsakis and Emmanouil Saloustros

Cancers 2025, 17(24), 4023; https://doi.org/10.3390/cancers17244023 - 17 Dec 2025

Cited by 1 | Viewed by 893

Abstract

Background: Guidelines recommend neoadjuvant systemic therapy (NST) as the preferred treatment approach for stage II–III triple-negative breast cancer (TNBC), an aggressive form of breast cancer (BC) that lacks specific therapeutic targets. This study primarily aimed to assess the NST adoption among stage II–III [...] Read more.

Background: Guidelines recommend neoadjuvant systemic therapy (NST) as the preferred treatment approach for stage II–III triple-negative breast cancer (TNBC), an aggressive form of breast cancer (BC) that lacks specific therapeutic targets. This study primarily aimed to assess the NST adoption among stage II–III TNBC patients in Greece under real-world conditions during the pre-immunotherapy era. Methods: This multicenter, observational, retrospective chart review included 230 female patients (≥18 years) with early-stage or locally advanced TNBC across 10 public and private BC reference centers over 6.5 years. Data included demographics and clinical characteristics at diagnosis, treatment details, clinical outcomes, and survival status. Descriptive statistics followed by uni/multivariate analyses were performed. Survival outcomes were assessed using survival analysis methods. Results: Women with stage II (67.4%) or stage III (32.6%) TNBC were included, with a median age of 53.1 years (range 23.9–84.1). Patients received NST [113 (49.1%)] and non-NST [117 (50.9%)]. NST utilization was significantly associated with larger tumor size and BRCA1/2 testing and status. Overall, 43.9% underwent BRCA1/2 testing, and 32.7% of those were positive for a BRCA1/2 mutation. More than half of the patients (n = 61) achieved pathological complete response (pCR) following NST. Event rates were lower with NST (16.8%) versus without (24.8%). Utilization increased over time, peaking at 63.5% in 2020–2022. Conclusions: NST use showed moderate uptake with notable practice variations, emphasizing the need for multidisciplinary strategies to improve guideline adherence. Over half achieved pCR post-NST, setting a benchmark for TNBC care. Ongoing real-world monitoring is vital to guide long-term outcomes. Full article

(This article belongs to the Special Issue Research on Early-Stage Breast Cancer: Management and Treatment)

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22 pages, 659 KB

Open AccessReview

Insomnia in Women Surviving Breast and Gynecological Cancers—A Narrative Review to Address the Hormonal Factor

by Silvia Martella, Paola Proserpio, Maria Elena Guerrieri, Andrea Galbiati, Luigi Ferini-Strambi, Laura Cucinella, Anna Daniela Iacobone, Dorella Franchi and Rossella E. Nappi

Cancers 2025, 17(24), 4022; https://doi.org/10.3390/cancers17244022 - 17 Dec 2025

Viewed by 1690

Abstract

Female cancers, including breast and gynecological malignancies, are among the most prevalent oncological conditions worldwide. Advances in screening, diagnosis, and treatment have markedly improved survival, resulting in a growing population of female cancer survivors. Consequently, long-term health and quality of life have become [...] Read more.

Female cancers, including breast and gynecological malignancies, are among the most prevalent oncological conditions worldwide. Advances in screening, diagnosis, and treatment have markedly improved survival, resulting in a growing population of female cancer survivors. Consequently, long-term health and quality of life have become essential aspects of comprehensive cancer care. Among survivorship issues, sleep disturbances—particularly insomnia—are highly prevalent and associated with adverse outcomes including mood and cognitive impairment, fatigue, immune and cardiometabolic dysregulation, and reduced adherence to therapy. Insomnia, defined as difficulty initiating or maintaining sleep or experiencing poor sleep quality with daytime impairment, affects 6–10% of the general population and is more common in women. In cancer survivors, poor sleep quality appears to be three times more frequent, reaching 62% in breast cancer survivors, although these data may be underestimated, especially for other cancer types, due to the small sample size and heterogeneity of the studies. The pathogenesis of insomnia in female cancer patients is multifactorial, involving cancer-related inflammation, hypothalamic–pituitary–adrenal axis dysregulation, neuroimmune alterations, treatment effects, psychological distress, and behavioral factors. Hormonal disruption plays a central role, as oncological treatments are often the cause of iatrogenic menopause, leading to vasomotor symptoms, mood and cognitive disturbances, sexual dysfunction, and genitourinary complaints, all contributing to sleep disruption. Importantly, estrogens and progesterone independently regulate sleep–wake pathways via central mechanisms, influencing sleep quality even in the absence of vasomotor symptoms. Management requires a multidisciplinary approach integrating oncology, gynecology, and sleep medicine. Cognitive Behavioral Therapy for Insomnia (CBT-I) is first-line, while pharmacologic options include benzodiazepines, Z-drugs, SSRIs/SNRIs, melatonin, or new medication like DORAs. Menopausal hormone therapy (MHT) should be considered for premature menopause management in selected women without contraindications, improving both vasomotor symptoms and sleep quality. Emerging neurokinin receptor (NK-R) antagonists show promise, and ongoing trials suggest significant potential even in breast cancer survivors. Full article

(This article belongs to the Special Issue Fertility Preservation and Hormonal Health in Oncology)

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26 pages, 703 KB

Open AccessReview

HER2-Low and HER2-Ultralow Metastatic Breast Cancer and Trastuzumab Deruxtecan: Common Clinical Questions and Answers

by Nusayba A. Bagegni, Karthik V. Giridhar and Daphne Stewart

Cancers 2025, 17(24), 4021; https://doi.org/10.3390/cancers17244021 - 17 Dec 2025

Cited by 4 | Viewed by 3390

Abstract

Approximately 80% of invasive breast cancers are classified as human epidermal growth factor receptor 2 (HER2)-negative; however, many of these tumors have detectable levels of HER2 surface expression. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate with a membrane-permeable payload that is cytotoxic [...] Read more.

Approximately 80% of invasive breast cancers are classified as human epidermal growth factor receptor 2 (HER2)-negative; however, many of these tumors have detectable levels of HER2 surface expression. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate with a membrane-permeable payload that is cytotoxic to both HER2-expressing tumor cells and neighboring cells via the bystander antitumor effect. T-DXd has shown significant antitumor activity in clinical trials for patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) breast cancer. In addition, the results of the DESTINY-Breast04 trial demonstrated the clinical benefit of T-DXd in patients with HER2-low (IHC 1+ or IHC 2+/ISH−) breast cancer after receiving prior chemotherapy. DESTINY-Breast06 demonstrated the clinical benefit of T-DXd in patients with hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH−), and HER2-ultralow (IHC 0 with membrane staining) metastatic breast cancer who had not received prior chemotherapy in the advanced setting. These results validate the need for a standard-of-care diagnostic test to identify HER2-low and HER2-ultralow expression levels in patients with metastatic breast cancer to guide therapeutic decision-making. Furthermore, effective treatment sequencing strategies and adverse event management are essential for maximizing patient benefit. This review presents the identification of HER2-low and HER2-ultralow breast cancer, sequencing of T-DXd with other treatments, and management of common or clinically significant adverse events reported with T-DXd. Full article

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

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38 pages, 1669 KB

Open AccessReview

Determinants of Response to Immune Checkpoint Blockade in Pleural Mesothelioma: Molecular, Immunological, and Clinical Perspectives

by Martina Delsignore, Gaia Cassinari, Simona Revello, Luigi Cerbone, Federica Grosso, Marcello Arsura and Chiara Porta

Cancers 2025, 17(24), 4020; https://doi.org/10.3390/cancers17244020 - 17 Dec 2025

Viewed by 1289

Abstract

Diffuse pleural mesothelioma (PM) is a rare thoracic malignancy with historically limited treatment options and poor outcomes. Despite the recent breakthrough of dual immune checkpoint blockade (ICB)—notably the combination of anti-PD-1 and anti-CTLA-4 therapies—clinical responses remain variable and overall survival gains modest. Consequently, [...] Read more.

Diffuse pleural mesothelioma (PM) is a rare thoracic malignancy with historically limited treatment options and poor outcomes. Despite the recent breakthrough of dual immune checkpoint blockade (ICB)—notably the combination of anti-PD-1 and anti-CTLA-4 therapies—clinical responses remain variable and overall survival gains modest. Consequently, there is an urgent need for multidimensional biomarkers and adaptive trial designs to unravel the complexity of PM immune biology. This review provides a comprehensive overview of current evidence on how histological subtypes (epithelioid vs. non-epithelioid) influence ICB efficacy, highlighting distinct genetic landscapes (e.g., BAP1, CDKN2A, NF2 mutations) and tumor microenvironment (TME) features, including immune infiltration patterns and PD-L1 or VISTA expression, that underlie differential responses. We further examine intrinsic tumor factors—such as mutational burden and checkpoint ligand expression—and extrinsic determinants, including immune cell composition, stromal architecture, patient immune status, and microbiota, as modulators of immunotherapy outcomes. We also discuss the rationale behind emerging strategies designed to enhance ICB efficacy, currently under clinical evaluation. These include combination regimens with chemotherapy, radiotherapy, surgery, epigenetic modulators, anti-angiogenic agents, and novel immunotherapies such as next-generation checkpoint inhibitors (LAG-3, VISTA), immune-suppressive cell–targeting agents, vaccines, cell-based therapies, and oncolytic viruses. Collectively, these advancements underscore the importance of integrating histological classification with molecular and microenvironmental profiling to refine patient selection and guide the development of combination strategies aimed at transforming “cold” mesotheliomas into “hot,” immune-responsive tumors, thereby enhancing the efficacy of ICB. Full article

(This article belongs to the Special Issue Biomarkers and Targeted Therapy in Malignant Pleural Mesothelioma)

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30 pages, 2692 KB

Open AccessReview

Therapeutic Applications of Fibroblast Activation Protein (FAP)-Binding Radiopharmaceuticals: Review of Opportunities and Challenges

by Justine Maes, Bernard Pôlet, Janke Kleynhans, Filip Van Herpe, Karolien Goffin, Jeroen Dekervel, Philippe Nafteux, Baki Topal, Frederik Cleeren and Christophe M. Deroose

Cancers 2025, 17(24), 4019; https://doi.org/10.3390/cancers17244019 - 17 Dec 2025

Cited by 4 | Viewed by 2136

Abstract

Fibroblast activation protein (FAP)-binding radiopharmaceuticals have emerged as promising candidates for both diagnostic and therapeutic applications in oncology due to their selective targeting of cancer-associated fibroblasts (CAFs). This review evaluates the current literature on the therapeutic use of FAP-targeted radiopharmaceuticals in human studies, [...] Read more.

Fibroblast activation protein (FAP)-binding radiopharmaceuticals have emerged as promising candidates for both diagnostic and therapeutic applications in oncology due to their selective targeting of cancer-associated fibroblasts (CAFs). This review evaluates the current literature on the therapeutic use of FAP-targeted radiopharmaceuticals in human studies, with a focus on their safety, efficacy, and clinical applicability. Data on radionuclide type, clinical outcome, radiological and metabolic response and adverse events were extracted and summarized. The included studies demonstrated that lutetium-177,yttrium-90 and actinium-225 (in combination therapy) labeled FAP inhibitors exhibit high tumor uptake, with varying but mostly sufficient retention and a favorable safety profile. While mild adverse events such as fatigue, nausea and grade 1 or 2 hematotoxicity were observed, severe toxicities were rare. FAPI-based radionuclide therapies generally show high disease control rates, with promising results from tandem and combination strategies. The heterogeneity of tumor types and small sample sizes limited the generalizability of findings. FAP-targeted radioligand therapy appears to be a promising treatment option for patients with advanced cancer who have exhausted standard therapies. However, further large-scale, prospective clinical trials are necessary to determine optimal dosing strategies, long-term safety and efficacy across different tumor types. Emerging approaches, such as covalently binding FAP-targeted radiopharmaceuticals and the use of alpha-emitters such as actinium-225, lead-212 and bismuth-213, may further enhance treatment outcomes and warrant future investigation. Full article

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

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13 pages, 3167 KB

Open AccessArticle

In Vitro and In Vivo Efficacy of Romidepsin Alone and in Addition to Standard of Care for Treatment of Ewing Sarcoma

by Kaitlyn H. Smith, Erin M. Trovillion, Kimberly Q. McKinney, Poornima Gourabathini, Kenzie Wells, Divya Gandra, Chloe Sholler, Ingrid Votruba, Javier Oesterheld and Giselle L. Saulnier Sholler

Cancers 2025, 17(24), 4018; https://doi.org/10.3390/cancers17244018 - 17 Dec 2025

Viewed by 698

Abstract

Background: Ewing sarcoma (ES) is an aggressive malignancy and there is an unmet need for more effective treatment options for patients. Histone deacetylases (HDACs) have been shown to be involved in ES tumorigenesis and HDAC inhibitors have been investigated in the context of [...] Read more.

Background: Ewing sarcoma (ES) is an aggressive malignancy and there is an unmet need for more effective treatment options for patients. Histone deacetylases (HDACs) have been shown to be involved in ES tumorigenesis and HDAC inhibitors have been investigated in the context of ES. Our objective for this study was to investigate the efficacy and mechanism of action of HDAC inhibition in vitro and in vivo in ES models, alone and in combination with standard of care therapies. Methods/Results: HDAC inhibitors were tested for in vitro efficacy against ES cell lines and romidepsin was found to be most effective. The mechanistic changes induced by romidepsin were investigated by Western blotting and proteins involved in cell cycle progression and DNA damage repair were found to be repressed. In vitro we identified that romidepsin synergizes with doxorubicin and etoposide and that it increases the efficacy of the standard of care combinations VDC/IE. Further, the combination treatments lead to an increase in caspase 3/7 cleavage, a decrease in DNA damage repair proteins, and an accumulation of DNA damage. In vivo, the combination of romidepsin and ifosfamide/etoposide (IE) leads to a significant decrease in tumor volume compared to that of IE alone. Conclusions: Our data indicates that romidepsin improves efficacy of chemotherapeutic agents in vitro and leads to a decreased tumor volume in vivo, suggesting that the addition of romidepsin may improve upfront treatment in ES patients. Full article

(This article belongs to the Section Pediatric Oncology)

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16 pages, 534 KB

Open AccessReview

The Management of Muscle Invasive Bladder Cancer: State of the Art and Future Perspectives

by Antonio Cigliola, Brigida Anna Maiorano, Doga Dengur, Valentina Tateo, Chiara Mercinelli, Michela Piacentini, Sara Inguglia, Carlo Messina and Andrea Necchi

Cancers 2025, 17(24), 4017; https://doi.org/10.3390/cancers17244017 - 17 Dec 2025

Viewed by 1981

Abstract

Background: Muscle-invasive bladder cancer (MIBC) represents a highly aggressive malignancy associated with significant morbidity and mortality. The current standard treatment, which includes radical cystectomy and platinum-based chemotherapy, is burdened by high toxicity and a substantial risk of relapse. For this reason, over the [...] Read more.

Background: Muscle-invasive bladder cancer (MIBC) represents a highly aggressive malignancy associated with significant morbidity and mortality. The current standard treatment, which includes radical cystectomy and platinum-based chemotherapy, is burdened by high toxicity and a substantial risk of relapse. For this reason, over the past decade, novel therapeutic strategies involving immune checkpoint inhibitors (ICIs), antibody–drug conjugates (ADCs), and targeted therapies have been investigated. This review aims to summarize current clinical evidence and ongoing trials evaluating these approaches in the perioperative setting. Methods: A systematic search was conducted using PubMed, EMBASE, and Cochrane databases, along with abstracts from major oncology conferences (ASCO, ESMO, SGO). Clinical trials assessing ICIs, ADCs, and targeted therapies, either alone or in combination with each other or with chemotherapy, in MIBC, were included. Results: Several early-phase and phase III trials have investigated the perioperative management of MIBC. Various studies evaluated the addition of ICIs to standard chemotherapy, demonstrating promising results in terms of pathological complete response. In parallel, the encouraging outcomes with ICIs and ADCs alone in the neoadjuvant or adjuvant setting paved the way for their combination in integrated strategies. Biomarker-driven approaches, based on circulating tumor DNA and specific genomic alterations, are being actively explored to improve patient selection and personalize treatment. Conclusions: ICIs, ADCs, and targeted therapies are reshaping the therapeutic landscape of MIBC. While early results are promising, further data and biomarker validation are essential to establish their definitive role and guide clinical decision-making in the perioperative setting. Full article

(This article belongs to the Special Issue Advances in Neoadjuvant Therapy for Urologic Cancer)

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16 pages, 3227 KB

Open AccessArticle

Synergistic Disruption of Survival and Metastatic Potential in Esophageal Adenocarcinoma Cells Through Combined Inhibition of HIF1α and CD73

by Ian Mersich, Alexander Malmberg, Eahsanul Anik, Md Sazzad Hassan, Urs von Holzen, Brian S. J. Blagg and Aktar Ali

Cancers 2025, 17(24), 4016; https://doi.org/10.3390/cancers17244016 - 17 Dec 2025

Cited by 1 | Viewed by 709

Abstract

Background/Objectives: Hypoxia promotes esophageal adenocarcinoma (EAC) aggressiveness through stabilization of hypoxia-inducible factor-1α (HIF-1α), which regulates pro-survival, pro-metastatic, and immunosuppressive pathways, including the ectoenzyme CD73 (NT5E). Although CD73 is a known hypoxia-responsive gene, its functional integration with HIF-1α signaling in EAC remains incompletely understood. [...] Read more.

Background/Objectives: Hypoxia promotes esophageal adenocarcinoma (EAC) aggressiveness through stabilization of hypoxia-inducible factor-1α (HIF-1α), which regulates pro-survival, pro-metastatic, and immunosuppressive pathways, including the ectoenzyme CD73 (NT5E). Although CD73 is a known hypoxia-responsive gene, its functional integration with HIF-1α signaling in EAC remains incompletely understood. This study aimed to define the relationship between HIF-1α and CD73 in EAC and to evaluate the therapeutic potential of their combined inhibition. Methods: Gene expression and survival analyses were performed using CCLE and TCGA-ESCA datasets. CD73 and HIF-1α expression were evaluated in EAC patient tissues by immunohistochemistry. EAC cell lines were subjected to hypoxic conditions with genetic or pharmacologic inhibition of HIF-1α and/or CD73. Cell viability, migration, angiogenesis, VEGF secretion, and purinergic metabolite levels were assessed using luminescence assays, Boyden chamber migration assays, endothelial tube formation assays, ELISA, and targeted LC-MS/MS, respectively. Results: NT5E expression was transcriptionally upregulated by HIF-1α under hypoxia and correlated with advanced disease stage and poor overall survival in EAC patients. While CD73 inhibition alone modestly reduced EAC cell viability, combined inhibition of HIF-1α and CD73 synergistically decreased tumor cell survival, particularly under hypoxic conditions, and significantly altered extracellular adenosine metabolism. Dual targeting further suppressed migration, reduced VEGF secretion, and impaired angiogenic signaling, indicating disruption of tumor microenvironmental pathways critical for metastasis and immune evasion. Conclusions: These findings identify CD73 as a direct hypoxia-responsive effector of HIF-1α in EAC and demonstrate that dual inhibition of HIF-1α and CD73 synergistically disrupts tumor cell survival and pro-metastatic signaling. This combinatorial strategy represents a mechanistically integrated therapeutic approach to overcome hypoxia-driven resistance in esophageal adenocarcinoma. Full article

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

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1 pages, 135 KB

Open AccessCorrection

Correction: Cantile et al. Functional Interaction among lncRNA HOTAIR and MicroRNAs in Cancer and Other Human Diseases. Cancers 2021, 13, 570

by Monica Cantile, Maurizio Di Bonito, Maura Tracey De Bellis and Gerardo Botti

Cancers 2025, 17(24), 4015; https://doi.org/10.3390/cancers17244015 - 17 Dec 2025

Viewed by 294

Abstract

In the original publication [...] Full article

(This article belongs to the Collection The Role of Non-coding RNA in Cancer)

17 pages, 2901 KB

Open AccessArticle

Diagnostic Algorithm for Secondary Extramammary Paget Disease from Institutional Cases and Literature Review

by Salin Kiratikanon, Ayaka Fukui, Masahiro Hirata, Jakob M. T. Moran, Masakazu Fujimoto and Mai P. Hoang

Cancers 2025, 17(24), 4014; https://doi.org/10.3390/cancers17244014 - 17 Dec 2025

Cited by 1 | Viewed by 1126

Abstract

Background/Objectives: Although clinicopathologic correlation with integration of clinical and radiographic data is the gold standard in distinguishing primary extramammary Paget disease (EMPD) from secondary EMPD, immunoprofiling of EMPD tumors enables distinction between primary and secondary EMPD. Methods: We evaluated the immunoprofiles [...] Read more.

Background/Objectives: Although clinicopathologic correlation with integration of clinical and radiographic data is the gold standard in distinguishing primary extramammary Paget disease (EMPD) from secondary EMPD, immunoprofiling of EMPD tumors enables distinction between primary and secondary EMPD. Methods: We evaluated the immunoprofiles of previously published cases in the literature as well as 12 secondary EMPD cases from our archives in order to construct a diagnostic algorithm that enables the distinction between primary and secondary EMPD. Results: Immunoprofiles of 480 primary (published cases) and 132 secondary (120 published cases and 12 institutional cases) EMPD cases were compared. CK7, CK20, CDX2, GATA3, GCDFP15, TRPS1, and SATB2 expression was significantly different in primary EMPD versus colonic secondary EMPD (p < 0.001 for all except SATB2, p = 0.036). CK20, GCDFP15, TRPS1, p63 and uroplakin II/III expression was significantly different in primary EMPD versus urothelial secondary EMPD (p < 0.001). CK7, CDX2, SATB2, GATA3 and p63 expression was significantly different in colonic versus urothelial secondary EMPD. CK20, CDX2, and GCDFP15 expression was significantly different in colonic versus prostatic secondary EMPD. CK20 expression was significantly different in colonic versus prostatic secondary EMPD (p = 0.018). CK20, GCDFP15 and TRPS1 are helpful in the distinction of primary EMPD versus colonic and urothelial secondary EMPD (p < 0.001). Conclusions: We propose that the initial IHC panel should include TRPS1, CK7 and CK20. In TRPS1-negative cases, additional immunostains should be performed: CDX2 and SATB2 for colonic; p63, GATA3 and uroplakin II/III for urothelial; and PSA and NKX3.1 for prostatic secondary EMPD. Full article

(This article belongs to the Special Issue Histopathology and Pathogenesis of Skin Cancer)

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21 pages, 5785 KB

Open AccessArticle

The Role of High-Dose-Rate Brachytherapy (Interventional Radiotherapy) in the Reirradiation of Liver Metastases

by Paweł Cisek, Izabela Kordzińska-Cisek, Aleksandra Kozłowska and Ludmiła Grzybowska-Szatkowska

Cancers 2025, 17(24), 4013; https://doi.org/10.3390/cancers17244013 - 16 Dec 2025

Viewed by 638

Abstract

Background: This study aimed to analyse treatment outcomes, determine prognostic factors and assess the toxicity of reirradiation using high-dose-rate (HDR) brachytherapy for liver metastases in the oligometastatic stage of disease. Materials and Methods: The study included 59 patients who had previously [...] Read more.

Background: This study aimed to analyse treatment outcomes, determine prognostic factors and assess the toxicity of reirradiation using high-dose-rate (HDR) brachytherapy for liver metastases in the oligometastatic stage of disease. Materials and Methods: The study included 59 patients who had previously undergone SBRT (stereotactic body radiation therapy) or HDR brachytherapy and experienced progression within (type 1) or outside (type 2) the irradiated area, but in a different location within the liver. Patients were divided according to the type of reirradiation and the reason for treatment. Local control (LC), progression-free survival (PFS) and overall survival (OS) were analysed in relation to the following factors: age; gender; performance status; tumour type; line of systemic treatment; location of extrahepatic metastases; type of reirradiation; time since previous irradiation; indication for treatment; size and number of metastases; dose; and degree of response to treatment. Treatment toxicity and the influence of dose, irradiation volume, number of metastases, time since previous radiotherapy and dose to the non-irradiated part of the liver on hepatic toxicity were also assessed. Results: With a median follow-up period of 13 months, the median LC, PFS and OS were 9, 8 and 13 months, respectively. The respective rates of partial regression (PR), stable disease (SD) and progressive disease (PD) were 32%, 44% and 12%. The most significant factors influencing LC were the degree of tumour shrinkage, with PFS influenced by the degree of tumour shrinkage and a low number of metastases, and OS influenced by the degree of tumour shrinkage, a low number of metastases and one to two lines of systemic therapy. Treatment toxicity was low, and there was no strong correlation between the dosimetric parameters of the treatment plan and the biochemical parameters of liver function. Conclusions: Brachytherapy is a safe and effective method of re-irradiating liver metastases. However, due to the limitations of the study, further investigation is required. Full article

(This article belongs to the Special Issue Clinical Research of Brachytherapy in Cancer)

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27 pages, 4216 KB

Open AccessReview

The Evolving Molecular Landscape of Uterine Mesenchymal Tumors: Diagnostic and Therapeutic Implications

by Tong Sun

Cancers 2025, 17(24), 4012; https://doi.org/10.3390/cancers17244012 - 16 Dec 2025

Viewed by 1387

Abstract

Uterine mesenchymal tumors encompass a diverse and diagnostically challenging group of neoplasms, including smooth muscle tumors, endometrial stromal tumors (ESS), perivascular epithelioid cell tumors (PEComas), inflammatory myofibroblastic tumors (IMTs), uterine tumor resembling ovarian sex cord tumor (UTROSCT), along with many other relatively rare [...] Read more.

Uterine mesenchymal tumors encompass a diverse and diagnostically challenging group of neoplasms, including smooth muscle tumors, endometrial stromal tumors (ESS), perivascular epithelioid cell tumors (PEComas), inflammatory myofibroblastic tumors (IMTs), uterine tumor resembling ovarian sex cord tumor (UTROSCT), along with many other relatively rare entities. Traditionally classified by histomorphology and immunophenotype, these tumors are now increasingly defined by recurrent genetic alterations that refine diagnosis and elucidate tumorigenesis. For example, leiomyosarcomas display complex genomic instability with frequent TP53, RB1, and ATRX mutations. Low grade-ESS are characterized by JAZF1::SUZ12 and other related fusions, whereas high-grade tumors harbor YWHAE::NUTM2 or ZC3H7B::BCOR fusions, and BCOR internal tandem duplication (ITD) alterations. PEComas frequently contain TSC1 or TSC2 mutations, leading to aberrant activation of the mTOR pathway. Beyond their diagnostic utility, these molecular signatures increasingly inform prognosis and highlight potential therapeutic targets, including CDK4/6 inhibition, PI3K/AKT/mTOR blockade, and immunotherapy. This review summarizes the evolving molecular landscape of uterine mesenchymal tumors, underscoring the value of integrating molecular testing into clinical practice to enhance diagnostic precision and enable personalized management of these rare yet clinically significant neoplasms. Full article

(This article belongs to the Special Issue The Genomic Landscape of Gynecological Cancers)

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34 pages, 2314 KB

Open AccessReview

Targeting MARylation and DePARylation in Cancer Therapy: New Promising Therapeutic Opportunities

by Vanesa Cabeza-Fernández, Francisco Javier Ríos-Sola, David Martín-Oliva, Jerónimo Borrego-Pérez, Francisco Javier Oliver, José YéLamos and José Manuel Rodríguez-Vargas

Cancers 2025, 17(24), 4011; https://doi.org/10.3390/cancers17244011 - 16 Dec 2025

Viewed by 707

Abstract

The poly(ADP-ribose) polymerase (PARP) family constitutes a major group of proteins and enzymes essential for the maintenance of cellular homeostasis under physiological conditions and plays a pivotal role in the onset and progression of multiple pathological states. Members of the PARP family are [...] Read more.

The poly(ADP-ribose) polymerase (PARP) family constitutes a major group of proteins and enzymes essential for the maintenance of cellular homeostasis under physiological conditions and plays a pivotal role in the onset and progression of multiple pathological states. Members of the PARP family are classified into distinct subgroups based on their subcellular localization, structural organization, and ADP-ribosyltransferase activity. To date, the majority of studies have focused on DNA-dependent PARPs, owing to their well-established involvement in DNA repair mechanisms, cell cycle regulation, and diverse human pathologies. Nevertheless, over the past decade, a smaller subset of PARPs—limited in both abundance and enzymatic activity—has emerged as a critical regulator of numerous cellular processes, including embryonic development and disease progression. Within this subset, mono(ADP-ribosyl) transferases (MARTs) have gained growing attention as potential therapeutic targets in cancer, cardiovascular disorders, and neurodegenerative diseases. The ADP-ribose (ADPr) cycle, which comprises both branched poly(ADP-ribose) (PAR) polymers and mono-ADP-ribose moieties present either in free form or covalently bound to cellular substrates, is tightly regulated to ensure cellular homeostasis. This regulation relies on a finely tuned balance between ADP-ribosylation, DePARylation, and the subsequent recycling of mono-ADP-ribose. In this review, we provide a comprehensive overview of the biological roles of mono-ADP-ribosylation (MARylation) and DePARylation, with particular emphasis on their contribution to cancer-related processes. In addition, we discuss emerging evidence supporting their translational relevance and therapeutic potential. In conclusion, MARylation and DePARylation represent two increasingly recognized regulatory pathways whose expanding clinical significance highlights the need for deeper mechanistic understanding and further exploration in both basic and translational research. Full article

(This article belongs to the Special Issue PARP Inhibitors in Cancers: 2nd Edition)

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14 pages, 830 KB

Open AccessArticle

PAM50 Intrinsic Subtypes and Immunity Status in Prognosis of Triple-Negative Breast Cancer: A Retrospective Cohort Study

by Yuan Wang, Yu Song, Songjie Shen, Huanwen Wu, Xinyu Ren and Zhiyong Liang

Cancers 2025, 17(24), 4010; https://doi.org/10.3390/cancers17244010 - 16 Dec 2025

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Abstract

Background: Although triple-negative breast cancer (TNBC) patients commonly receive adjuvant chemotherapy after surgery, their prognoses vary. This study aimed to investigate how the intrinsic subtypes of TNBCs and immune status of patients affect their prognosis. Methods: A total of 111 TNBC patients were [...] Read more.

Background: Although triple-negative breast cancer (TNBC) patients commonly receive adjuvant chemotherapy after surgery, their prognoses vary. This study aimed to investigate how the intrinsic subtypes of TNBCs and immune status of patients affect their prognosis. Methods: A total of 111 TNBC patients were retrospectively analyzed at Peking Union Medical College Hospital from 2002 to 2014. All underwent surgery and received adjuvant chemotherapy per NCCN guidelines. Intrinsic subtypes (luminal A, luminal B, HER2-enriched, and basal-like) were identified using PAM50 profiling. Recurrence-of-risk (ROR) scores were classified into high, intermediate, and low. Immune status was assessed via a 17-gene panel and categorized as immune-strong or immune-weak. Statistical analyses included chi-square tests, Kaplan–Meier curves, log-rank tests, and Cox regression. Results: All four PAM50 subtypes were present, with basal-like being the most common (77%). Luminal A patients with low-to-intermediate ROR scores showed worse outcomes than other subtypes (DFS, p = 0.123; OS, p = 0.170). Unexpectedly, high-ROR patients had the longest DFS (p = 0.042). Immune-strong status correlated with improved DFS and OS in stage IIB–III patients (DFS, p = 0.029; OS, p = 0.003), and was associated with higher TILs (p = 0.015) and PD-L1 expression on tumor cells (p = 0.022). Conclusions: Multigene-based assessment of molecular subtype and immune status provides important prognostic insight into TNBC and may guide adjuvant treatment decisions, particularly in non-basal-like subtypes. Full article

(This article belongs to the Section Molecular Cancer Biology)

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17 pages, 1377 KB

Open AccessArticle

The Outcome and Impact of Academic Cancer Clinical Trials with Participation from Canadian Sites (2015–2024)

by Rebecca Y. Xu, Diana Kato, Victoria Percival, James Schoales, Stephen Sundquist, Raisa Chowdhury, Gregory R. Pond and Janet E. Dancey

Cancers 2025, 17(24), 4009; https://doi.org/10.3390/cancers17244009 - 16 Dec 2025

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Abstract

Background/Objectives: Academically sponsored cancer clinical trials (ACCTs) are essential for advancing patient-centered care, particularly in areas underserved by commercial research. The Canadian Cancer Clinical Trials Network (3CTN) was established to support high-quality multi-center ACCTs through coordinated infrastructure and funding. Over ten years, funders [...] Read more.

Background/Objectives: Academically sponsored cancer clinical trials (ACCTs) are essential for advancing patient-centered care, particularly in areas underserved by commercial research. The Canadian Cancer Clinical Trials Network (3CTN) was established to support high-quality multi-center ACCTs through coordinated infrastructure and funding. Over ten years, funders provided an average of CAD 4.3 million annually (~CAD 0.11 per capita), primarily from federal and provincial sources. This study evaluates the outcomes and impact of trials supported by 3CTN between 2015 and 2024. Methods: We conducted a descriptive analysis of 350 ACCTs that stopped recruiting and had primary completion dates within the study period. Trial characteristics, results, publication rates, and incorporation into clinical guidelines were assessed using registry data, peer-reviewed publications, and structured searches of oncology guidelines. Results: Among these 350 closed trials, 116 were Phase III studies. Of these, 36% were incorporated into clinical practice guidelines, and 7% were likely to be incorporated. Overall, 81% of trials were published in journals, and 45% posted results in public registries. Trials addressed diverse cancer types, with notable contributions in rare cancers and vulnerable populations. Conclusions: 3CTN-supported ACCTs had high completion and reporting rates, with substantial influence on clinical practice. These findings highlight how sustained infrastructure and modest public investment can deliver meaningful improvements in cancer care and inform evidence-based policy. Full article

(This article belongs to the Special Issue Advances in Clinical Trials: Outcome, Innovations, Challenges, and Ethical Practice in Cancer Research 2025–2026)

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16 pages, 1592 KB

Open AccessArticle

Comparative Analysis of Bone Marrow, cfDNA and CTCs for NGS-Based Multiple Myeloma Detection: A Pilot Study Indicating the Potential of CTCs

by Wouter De Brouwer, Robbe Heestermans, Jona Van der Straeten, Kiara Falise, Ann De Becker, Isabelle Vande Broek, Rik Schots, Marleen Bakkus and Ivan Van Riet

Cancers 2025, 17(24), 4008; https://doi.org/10.3390/cancers17244008 - 16 Dec 2025

Cited by 1 | Viewed by 870

Abstract

Background/Objectives: Minimal residual disease (MRD) persists in most multiple myeloma (MM) patients, causing relapse despite deep remissions. Repeatability of MRD detection in MM bone marrow (BM) samples is limited, underscoring the need for blood-based monitoring approaches that can allow more thorough disease [...] Read more.

Background/Objectives: Minimal residual disease (MRD) persists in most multiple myeloma (MM) patients, causing relapse despite deep remissions. Repeatability of MRD detection in MM bone marrow (BM) samples is limited, underscoring the need for blood-based monitoring approaches that can allow more thorough disease surveillance. Methods: This study compares tumor detection rates in BM-derived DNA with different blood-derived DNA sources, using next-generation sequencing of the immunoglobulin locus (NGS-IG). CD138-targeted immunomagnetic enrichment of circulating tumor cells (CTCs) followed by vacuum evaporation to concentrate DNA was used to optimize the tumor detection rate. Results: Tumor DNA was detected in 76%, 88% and 100% of cell-free DNA, peripheral blood-derived mononuclear cells, DNA and enriched CTC-DNA samples of patients with active myeloma, respectively. These data indicate that enriched CTC samples were the most informative for evaluation of disease detection with NGS-IG in patients with active myeloma. MRD detection was performed in paired BM and enriched CTC-DNA samples from 37 patients in remission. MRD positivity was found in the BM of 24 patients, with half of them (12/24) also showing the presence of MRD when enriched CTC-DNA was used. Interestingly, time to progression (TTP) of enriched CTC MRD-negative/BM MRD-positive patients was comparable to that of double MRD-negative (BM and CTC) patients. Moreover, double positive patients showed a trend to earlier relapses. Conclusions: Our data suggest that NGS-IG analysis with enriched CTC-DNA may offer improved predictive abilities for relapse in multiple myeloma compared to the currently used BM-DNA-based tumor detection method. Full article

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

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Cancers, Volume 17, Issue 24 (December-2 2025) – 150 articles

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