Cancers

10 pages, 230 KiB

Open AccessCommunication

Evolving Indications for Liver Transplantation for Hepatocellular Carcinoma Following the Milan Criteria

by Takashi Kokudo and Norihiro Kokudo

Cancers 2025, 17(3), 507; https://doi.org/10.3390/cancers17030507 (registering DOI) - 3 Feb 2025

Background/Objectives: Since their introduction in the 1990s, the Milan criteria have been the gold standard of indication for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Nevertheless, several institutions have reported wider indication criteria for LT with comparable survival outcomes. Methods: This [...] Read more.

Background/Objectives: Since their introduction in the 1990s, the Milan criteria have been the gold standard of indication for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). Nevertheless, several institutions have reported wider indication criteria for LT with comparable survival outcomes. Methods: This paper summarizes the recent indications for LT for HCC through a literature review. Results: There are several criteria expanding the Milan criteria, which can be subdivided into the “based on tumor number and size only”, “based on tumor number and size plus tumor markers”, and “based on tumor differentiation” groups, with the outcomes being comparable to those of patients included within the Milan criteria. Besides the tumor size and number, which are included in the Milan criteria, recent criteria included biomarkers and tumor differentiation. Several retrospective studies have reported microvascular invasion (MVI) as a significant risk factor for postoperative recurrence, highlighting the importance of preoperatively predicting MVI. Several studies attempted to identify preoperative predictive factors for MVI using tumor markers or preoperative imaging findings. Patients with HCC who are LT candidates are often treated while on the waiting list to prevent the progression of HCC or to reduce the measurable disease burden of HCC. The expanding repertoire of chemotherapeutic regiments suitable for patients with HCC should be further investigated. Conclusions: There are several criteria expanding Milan criteria, with the outcomes being comparable to those of patients included within the Milan criteria. Full article

(This article belongs to the Section Transplant Oncology)

9 pages, 228 KiB

Open AccessPerspective

Targeting Methionine Addiction of Osteosarcoma with Methionine Restriction to Overcome Drug Resistance: A New Paradigm for a Recalcitrant Disease

by Yusuke Aoki, Yutaro Kubota, Noriyuki Masaki, Yasunori Tome, Michael Bouvet, Kotaro Nishida and Robert M. Hoffman

Cancers 2025, 17(3), 506; https://doi.org/10.3390/cancers17030506 (registering DOI) - 3 Feb 2025

Abstract

Chemotherapy resistance in osteosarcoma results in a very poor patient prognosis, with the 5-year survival rate of approximately 20%, which not improved for over three decades; thus, the development of novel therapeutic strategies is required. Methionine addiction is a fundamental and general hallmark [...] Read more.

Chemotherapy resistance in osteosarcoma results in a very poor patient prognosis, with the 5-year survival rate of approximately 20%, which not improved for over three decades; thus, the development of novel therapeutic strategies is required. Methionine addiction is a fundamental and general hallmark of cancer, termed the Hoffman effect. Cancer cells need larger amounts of exogenous methionine in order to grow compared to normal cells, despite their ability to synthesize normal or greater amounts of methionine from homocysteine, due to increased transmethylation reactions in cancer cells. Methionine restriction therapy, including recombinant methioninase (rMETase), arrests cancer cells in the late-S/G2 phase of the cell cycle by targeting methionine addiction. First-line chemotherapy for osteosarcoma, including methotrexate (MTX), doxorubicin (DOX), and cisplatinum (CDDP), targets cells in the S/G2-phase, where cancer cells are also inhibited by methionine restriction, resulting in the synergy of methionine restriction to overcome drug resistance. In the present review, we describe the synergistic efficacy of conventional chemotherapy and methionine restriction therapy, including rMETase, in overcoming the drug resistance of osteosarcoma. The clinical potential of this new paradigm to overcome the drug resistance of osteosarcoma is discussed. Full article

(This article belongs to the Special Issue Overcoming Chemoresistance in Cancer: Identifying Biomarkers and Novel Targets)

16 pages, 2586 KiB

Open AccessArticle

Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer: A Nationwide Analysis of Eligibility, Utilization, and Outcomes

by Ilkka Nikulainen, Antti P. Salminen, Mikael Högerman, Heikki Seikkula, Peter J. Boström and The Finnish National Cystectomy Database Research Group

Cancers 2025, 17(3), 505; https://doi.org/10.3390/cancers17030505 (registering DOI) - 3 Feb 2025

Abstract

Objectives: To investigate neoadjuvant chemotherapy (NAC) eligibility, utilization, and survival outcomes for muscle-invasive bladder cancer patients undergoing radical cystectomy (RC) in a Finnish population. Materials and Methods: Data from the Finnish National Cystectomy Database (2005–2017) was combined with Finnish Cancer Registry survival data. [...] Read more.

Objectives: To investigate neoadjuvant chemotherapy (NAC) eligibility, utilization, and survival outcomes for muscle-invasive bladder cancer patients undergoing radical cystectomy (RC) in a Finnish population. Materials and Methods: Data from the Finnish National Cystectomy Database (2005–2017) was combined with Finnish Cancer Registry survival data. NAC utilization rates were reported, and downstaging rates were calculated based on final pathological staging. Logistic regression analyzed NAC usage and complete response (CR) predictors. Results: Since 2011, 29% of 1157 patients received NAC. Its usage remained consistent, and the number of eligible patients not receiving NAC decreased during the study period. Among NAC patients, pathology T-category was pT0 (34%), pT1-Ta-Tis (16%), pT2 (23%), pT3 (20%), and pT4 (7%) tumors, with pN0 in 82%. In the RC + NAC group, the 5-year overall survival (OS) rates were 89% for patients with no residual disease (pT0N0), 82% for those with organ-confined residual disease (pT1, Tis, Ta, T2/N0), and 49% for patients with non-organ-confined residual disease (pT3+/N+). The corresponding cancer-specific survival (CSS) rates were 93%, 86%, and 57%, respectively. Patients with organ-confined residual disease after NAC had survival outcomes comparable to those who underwent RC alone. Higher age; odds ratio (OR) 0.93, [95% Confidence Interval (CI): 0.90–0.95] and Charlson Co-morbidity Index–score [OR 0.88 (0.79–0.98)] reduced the likelihood of receiving NAC, while a smaller center size increased the probability [OR 1.82 (1.02–3.28)]. More treatment cycles [OR 0.70, (95% CI: 0.51–0.93)] and a favorable GFR [OR 0.38 (0.16–0.88)] were associated with achieving CR. Conclusion: We report that NAC is well-utilized across Finland, with CR rates comparable to recent trials. Additionally, our survival rates are reasonable, and even with organ-confined residual disease after NAC, survival outcomes are similar to those who underwent RC alone. Full article

(This article belongs to the Special Issue State-of-the-Art Treatment on Chemotherapy and Immunotherapy for Urological Cancer)

21 pages, 4327 KiB

Open AccessArticle

Interval Analysis-Based Optimization: A Robust Model for Intensity-Modulated Radiotherapy (IMRT)

by Andrés Camilo Sevilla-Moreno, María Eugenia Puerta-Yepes, Niklas Wahl, Rafael Benito-Herce and Gonzalo Cabal-Arango

Cancers 2025, 17(3), 504; https://doi.org/10.3390/cancers17030504 (registering DOI) - 3 Feb 2025

Abstract

Background: Cancer remains one of the leading causes of mortality worldwide, with radiotherapy playing a crucial role in its treatment. Intensity-modulated radiotherapy (IMRT) enables precise dose delivery to tumors while sparing healthy tissues. However, geometric uncertainties such as patient positioning errors and [...] Read more.

Background: Cancer remains one of the leading causes of mortality worldwide, with radiotherapy playing a crucial role in its treatment. Intensity-modulated radiotherapy (IMRT) enables precise dose delivery to tumors while sparing healthy tissues. However, geometric uncertainties such as patient positioning errors and anatomical deformations can compromise treatment accuracy. Traditional methods use safety margins, which may lead to excessive irradiation of healthy organs or insufficient tumor coverage. Robust optimization techniques, such as minimax approaches, attempt to address these uncertainties but can result in overly conservative treatment plans. This study introduces an interval analysis-based optimization model for IMRT, offering a more flexible approach to uncertainty management. Methods: The proposed model represents geometric uncertainties using interval dose influence matrices and incorporates Bertoluzza’s metric to balance tumor coverage and organ-at-risk (OAR) protection. The

θ

parameter allows controlled robustness modulation. The model was implemented in matRad, an open-source treatment planning system, and evaluated on five prostate cancer cases. Results were compared against traditional Planning Target Volume (PTV) and minimax robust optimization approaches. Results: The interval-based model improved tumor coverage by 5.8% while reducing bladder dose by 4.2% compared to PTV. In contrast, minimax robust optimization improved tumor coverage by 25.8% but increased bladder dose by 23.2%. The interval-based approach provided a better balance between tumor coverage and OAR protection, demonstrating its potential to enhance treatment effectiveness without excessive conservatism. Conclusions: This study presents a novel framework for IMRT planning that improves uncertainty management through interval analysis. By allowing adjustable robustness modulation, the proposed model enables more personalized and clinically adaptable treatment plans. These findings highlight the potential of interval analysis as a powerful tool for optimizing radiotherapy outcomes, balancing treatment efficacy and patient safety. Full article

(This article belongs to the Special Issue The Future of Radiation Research in Cancers, 2nd Edition)

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11 pages, 1989 KiB

Open AccessSystematic Review

A Meta-Analysis of First-Line Treatments for Unresectable Pleural Mesothelioma: Indirect Comparisons from Reconstructed Individual Patient Data of Six Randomized Controlled Trials

by Andrea Messori, Sabrina Trippoli, Eugenia Piragine, Sara Veneziano and Vincenzo Calderone

Cancers 2025, 17(3), 503; https://doi.org/10.3390/cancers17030503 (registering DOI) - 3 Feb 2025

Abstract

Background: In unresectable pleural mesothelioma, pemetrexed+cisplatin as first line is considered the standard of care, but novel treatments have been recently proposed. Methods: Our objective was to compare, albeit indirectly, the results of randomized controlled trials on overall survival (OS). The IPDfromKM method [...] Read more.

Background: In unresectable pleural mesothelioma, pemetrexed+cisplatin as first line is considered the standard of care, but novel treatments have been recently proposed. Methods: Our objective was to compare, albeit indirectly, the results of randomized controlled trials on overall survival (OS). The IPDfromKM method was employed for reconstruct individual patient data (IPD) from the graphs of Kaplan–Meier curves. Cox statistics was run to estimate hazard ratios (HRs). Results: After a literature search on Medline (via PubMed) and Scopus databases, six randomized controlled trials were identified in which five new treatments (nivolumab plus ipilimumab, bevacizumab plus pemetrexed plus cisplatin, chemotherapy plus pembrolizumab, ONCOS-102 plus pemetrexed plus cisplatin/carboplatin and cediranib plus pemetrexed+cisplatin with maintenance with cediranib) were evaluated. In five trials, pemetrexed plus cisplatin was the standard of care given to the control arms. Nivolumab plus ipilimumab, bevacizumab plus pemetrexed plus cisplatin and chemotherapy plus pembrolizumab showed a significantly better OS compared with controls. ONCOS-102 plus pemetrexed plus cisplatin/carboplatin did not significantly improve OS. In contrast, OS worsened with cisplatin alone and with cediranib plus pemetrexed+cisplatin with maintenance with cediranib. Discussion: Our analysis indicates that, in patients with unresectable pleural mesothelioma, three of the five novel treatments provided a significant survival benefit compared with the standard of care. Further research is needed to confirm the OS benefit found in our analysis with some treatments, whereas cisplatin alone and cediranib plus pemetrexed+cisplatin with maintenance with cediranib do not seem to deserve further research. Full article

(This article belongs to the Special Issue Research on Clinical Treatment of Mesothelioma)

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10 pages, 1306 KiB

Open AccessArticle

Serosal Patching with Glubran^®2 on the Pancreatic Stump for Reducing Postoperative Pancreatic Fistulae After Robot-Assisted Distal Pancreatectomy: A Single-Center Retrospective Study

by Ahmad Mahamid, Eden Gerszman, Esther Kazlow, Aasem Abu Shtaya, Natalia Goldberg, Dvir Froylich and Riad Haddad

Cancers 2025, 17(3), 502; https://doi.org/10.3390/cancers17030502 (registering DOI) - 3 Feb 2025

Abstract

Background: Postoperative pancreatic fistulae (POPFs) are a significant cause of morbidity following left pancreatectomy. We hypothesized that incorporating serosal patching with the application of a synthetic sealant, a modified cyanoacrylate (Glubran^®2), to the pancreatic stump, would decrease the incidence rate of [...] Read more.

Background: Postoperative pancreatic fistulae (POPFs) are a significant cause of morbidity following left pancreatectomy. We hypothesized that incorporating serosal patching with the application of a synthetic sealant, a modified cyanoacrylate (Glubran^®2), to the pancreatic stump, would decrease the incidence rate of clinically significant POPFs. Methods: This is a retrospective study of consecutive patients who underwent robot-assisted left pancreatectomy. The primary outcome was clinically significant POPFs within 90 days of surgery. Secondary outcomes included the incidence rate of POPFs (all the grades), 90-day morbidity, and 90-day mortality. Results: We compared outcomes between Glubran^®2 sealant with serosal patching (GSP, n = 6) and Glubran^®2 sealant without serosal patching (GNSP, n = 12) groups. The GSP group had significantly lower incidence rates of clinically significant POPFs (grades B/C) (p = 0.034) and overall POPFs (all the grades) (p = 0.046). No significant differences in 90-day postoperative morbidity were observed between the two groups (p = 0.56), and no 90-day mortality occurred in either group. Conclusions: Incorporating serosal patching along with Glubran^®2 sealant in the management of the pancreatic stump during left pancreatectomy demonstrates promising results in reducing the incidence rate of clinically significant POPFs. This finding highlights the need for further research with larger sample sizes in order to confirm the observed outcomes and explore the long-term implications for postoperative complications and recovery in patients undergoing this procedure during pancreatic surgery. Full article

(This article belongs to the Special Issue Robotic Surgery for Gastrointestinal (GI) Malignancies)

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12 pages, 601 KiB

Open AccessArticle

Lesion Conspicuity in Contrast-Enhanced Mammography: A Retrospective Analysis of Tumor Characteristics

by Chiara Bellini, Tommaso Susini, Kassandra Toncelli, Martina Pandolfi, Giuliano Migliaro, Francesca Pugliese, Bianca Vanzi, Ludovica Incardona, Giulia Bicchierai, Federica di Naro, Diego de Benedetto, Sofia Vidali, Silvia Pancani, Vittorio Miele and Jacopo Nori Cucchiari

Cancers 2025, 17(3), 501; https://doi.org/10.3390/cancers17030501 (registering DOI) - 3 Feb 2025

Abstract

Background/Objectives: The aim of this study is to evaluate the impact of tumor characteristics on lesion conspicuity in contrast-enhanced mammography (CEM) and identify factors associated with different levels of conspicuity. Methods: In this retrospective study, we analyzed 552 patients with breast cancer who [...] Read more.

Background/Objectives: The aim of this study is to evaluate the impact of tumor characteristics on lesion conspicuity in contrast-enhanced mammography (CEM) and identify factors associated with different levels of conspicuity. Methods: In this retrospective study, we analyzed 552 patients with breast cancer who underwent CEM. Lesion conspicuity was categorized into three levels: 1 (low), 2 (moderate), and 3 (high). Tumor characteristics included age, histological subtype, hormone receptor status, HER2 status, Ki67 index, tumor grade, and molecular subtype. Univariate and multivariate analyses were conducted to assess associations between lesion conspicuity and these factors. Results: Of the 552 cases, the majority showed mass enhancement (78.1%), followed by non-mass enhancement (NME) (16.8%), and a combination of mass and NME (4.0%). Lesion conspicuity was significantly associated with enhancement type on CEM (p < 0.001). High conspicuity (score 3) was predominantly observed in masses (84.8%) compared to NME (7.6%). Larger tumor dimensions (median 20 mm) were also associated with higher conspicuity (p < 0.001). Molecular subtypes differed significantly in conspicuity, with Luminal A tumors showing lower conspicuity compared to HER2-positive and triple-negative breast cancers (p = 0.025). In multivariate analysis, lesion conspicuity was strongly associated with enhancement type (p < 0.001) and tumor dimensions (p < 0.001), while histological subtype and molecular characteristics had no significant independent impact. Conclusions: Lesion conspicuity in CEM is primarily influenced by the type of enhancement and tumor size. Mass-forming lesions, particularly larger ones, are more conspicuous, while NME tends to result in lower conspicuity. These findings suggest that enhancement patterns and tumor dimensions are key factors to consider when interpreting CEM in breast cancer diagnosis. Full article

(This article belongs to the Special Issue Imaging in Breast Cancer Diagnosis and Treatment)

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19 pages, 2200 KiB

Open AccessArticle

HepatoPredict Accurately Selects Hepatocellular Carcinoma Patients for Liver Transplantation Regardless of Tumor Heterogeneity

by Rita Andrade, Judith Perez-Rojas, Sílvia Gomes da Silva, Migla Miskinyte, Margarida C. Quaresma, Laura P. Frazão, Carolina Peixoto, Almudena Cubells, Eva M. Montalvá, António Figueiredo, Augusta Cipriano, Maria Gonçalves-Reis, Daniela Proença, André Folgado, José B. Pereira-Leal, Rui Caetano Oliveira, Hugo Pinto-Marques, José Guilherme Tralhão, Marina Berenguer and Joana Cardoso

Cancers 2025, 17(3), 500; https://doi.org/10.3390/cancers17030500 (registering DOI) - 2 Feb 2025

Abstract

Background/Objectives: Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths rising worldwide. This is leading to an increased demand for liver transplantation (LT), the most effective treatment for HCC in its initial stages. However, current patient selection criteria are limited in predicting [...] Read more.

Background/Objectives: Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths rising worldwide. This is leading to an increased demand for liver transplantation (LT), the most effective treatment for HCC in its initial stages. However, current patient selection criteria are limited in predicting recurrence and raise ethical concerns about equitable access to care. This study aims to enhance patient selection by refining the HepatoPredict (HP) tool, a machine learning-based model that combines molecular and clinical data to forecast LT outcomes. Methods: The updated HP algorithm was trained on a two-center dataset and assessed against standard clinical criteria. Its prognostic performance was evaluated through accuracy metrics, with additional analyses considering tumor heterogeneity and potential sampling bias. Results: HP outperformed all clinical criteria, particularly regarding negative predictive value, addressing critical limitations in existing selection strategies. It also demonstrated improved differentiation of recurrence-free and overall survival outcomes. Importantly, the prognostic accuracy of HP remained largely unaffected by intra-nodule and intra-patient heterogeneity, indicating its robustness even when biopsies were taken from smaller or non-dominant nodules. Conclusions: These findings support the usage of HP as a valuable tool for optimizing LT candidate selection, promoting fair organ allocation and enhancing patient outcomes through integrated analysis of molecular and clinical data. Full article

(This article belongs to the Special Issue Advances and Future Developments in Liver Transplantation for Cancers: 2nd Edition)

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18 pages, 1911 KiB

Open AccessArticle

Low Phosphatidylserine+ Cells Within the CD34+/CD45dim/CD117(c-kit)+ Subpopulation are Associated with Poor Outcomes in Metastatic Colorectal Cancer

by Davide Brocco, Pasquale Simeone, Pietro Di Marino, Domenico De Bellis, Francesca D’Ascanio, Giulia Colasante, Antonino Grassadonia, Michele De Tursi, Rosalba Florio, Mauro Di Ianni, Alessandro Cama, Nicola Tinari and Paola Lanuti

Cancers 2025, 17(3), 499; https://doi.org/10.3390/cancers17030499 (registering DOI) - 2 Feb 2025

Abstract

Background: Colorectal cancer is among the most prevalent causes of tumor-related deaths worldwide. Antiangiogenic therapy represents a cornerstone of metastatic CRC treatment, and biomarkers are advocated for the optimization of this therapeutic strategy. Methods: In this observational prospective study, we employed an optimized [...] Read more.

Background: Colorectal cancer is among the most prevalent causes of tumor-related deaths worldwide. Antiangiogenic therapy represents a cornerstone of metastatic CRC treatment, and biomarkers are advocated for the optimization of this therapeutic strategy. Methods: In this observational prospective study, we employed an optimized flow cytometry protocol to investigate the prognostic and predictive potential of blood circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPCs), and related subsets in a cohort of patients with metastatic colorectal cancer (n = 40). Results: Computational FC analysis revealed a differential enrichment of blood cell clusters with a CD34+/CD45dim/CD117(c-kit)+ phenotype between responders and non-responders both to antiangiogenic and non-antiangiogenic treatments. Intriguingly, our results show that a high percentage of annexin V-negative cells in a putative circulating progenitor population with a CD34+/CD45dim/CD117+ phenotype was correlated with a reduced response to systemic anticancer treatments (p = 0.015) and worse overall survival (log-rank p = 0.03). In addition, we observed increased blood concentrations of CD34+/CD45dim/CD117+/annexin V- cells in patients with a higher number of metastatic sites (p = 0.03). Conclusions: Overall, these findings hold promise for the identification of novel circulating biomarkers to develop more personalized treatment approaches in patients with metastatic colorectal cancer. Full article

(This article belongs to the Special Issue Oncogenetics of Colorectal Cancer)

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26 pages, 3054 KiB

Open AccessReview

Metabolic Singularities in Microsatellite-Stable Colorectal Cancer: Identifying Key Players in Immunosuppression to Improve the Immunotherapy Response

by Teresa Gorría, Marina Sierra-Boada, Mariam Rojas, Carolina Figueras, Silvia Marin, Sergio Madurga, Marta Cascante and Joan Maurel

Cancers 2025, 17(3), 498; https://doi.org/10.3390/cancers17030498 (registering DOI) - 2 Feb 2025

Abstract

Although immune checkpoint inhibitor (ICI) therapy is currently the standard of care in microsatellite-unstable (MSI) metastatic colorectal cancer (CRC), ICI therapy, alone or in combination with other therapies, is not a treatment approach in microsatellite-stable (MSS) CRC, which is present in 95% of [...] Read more.

Although immune checkpoint inhibitor (ICI) therapy is currently the standard of care in microsatellite-unstable (MSI) metastatic colorectal cancer (CRC), ICI therapy, alone or in combination with other therapies, is not a treatment approach in microsatellite-stable (MSS) CRC, which is present in 95% of patients. In this review, we focus on metabolic singularities—at the transcriptomic (either bulk or single cell), proteomic, and post-translational modification levels—that induce immunosuppression in cancer and specifically in MSS CRC. First, we evaluate the current efficacy of ICIs in limited and metastatic disease in MSS CRC. Second, we discuss the latest findings on the potential biomarkers for evaluating ICI efficacy in MSS CRC using strict REMARK criteria. Third, we review the current evidence on metabolic patterns in CRC tumors and immune cell metabolism to advance our understanding of metabolic crosstalk and to pave the way for the development of combination strategies to enhance ICI efficacy. Full article

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

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12 pages, 246 KiB

Open AccessArticle

by Magdalena Konieczny, Jolanta Sawicka, Izabela Gąska, Elżbieta Kaczmar, Magdalena Babuśka-Roczniak and Dorota Bądziul

Cancers 2025, 17(3), 497; https://doi.org/10.3390/cancers17030497 (registering DOI) - 2 Feb 2025

Abstract

Background/Objective: The study aimed to evaluate disease acceptance and quality of life in women with breast cancer before and after receiving neoadjuvant chemotherapy. Methods: The study included 211 women diagnosed with breast cancer who underwent neoadjuvant treatment. The following measures were utilized: the [...] Read more.

Background/Objective: The study aimed to evaluate disease acceptance and quality of life in women with breast cancer before and after receiving neoadjuvant chemotherapy. Methods: The study included 211 women diagnosed with breast cancer who underwent neoadjuvant treatment. The following measures were utilized: the EORTC QLQ-C30 and QLQ-BR23 modules for quality of life assessment, the Acceptance of Illness Scale (AIS) questionnaire for evaluating disease acceptance, and a proprietary questionnaire. Assessments were conducted one week before the first chemotherapy session and three weeks after completing the chemotherapy. Statistical analysis was performed using STATISTICA v. 13. Results: The respondents exhibited an average acceptance of their disease, both before (28.2 pts) and after chemotherapy (25.5 pts). A decline in disease acceptance was observed in nearly 59.2% of the patients following chemotherapy. Higher levels of disease acceptance were associated with a better quality of life. The quality of life for the studied women decreased after neoadjuvant chemotherapy, particularly in the following areas: physical functioning (p = 0.0000), social functioning (p = 0.0000), body image assessment (p = 0.0000), sexual satisfaction (p = 0.0000), nausea and vomiting (p = 0.0000), fatigue (p = 0.0000), loss of appetite (p = 0.0000), insomnia (p = 0.0000), pain (p = 0.0000), hair loss (p = 0.0000), and side effects of systemic treatment (p = 0.0000). Conclusions: Post-neoadjuvant chemotherapy, a decline in disease acceptance and quality of life was observed among women with breast cancer in comparison with their pre-treatment status. Higher levels of disease acceptance were associated with a better quality of life. These findings may facilitate the creation of a more tailored care approach for women during and after chemotherapy. Full article

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

17 pages, 908 KiB

Open AccessReview

Antibody–Drug Conjugates Targeting CD30 in T-Cell Lymphomas: Clinical Progression and Mechanism

by Yi Jiang, Sai Dong and Yang Wang

Cancers 2025, 17(3), 496; https://doi.org/10.3390/cancers17030496 (registering DOI) - 2 Feb 2025

Abstract

CD30 is overexpressed in many T-cell lymphoma (TCL) entities, including subsets of peripheral T-cell lymphomas (PTCL) and cutaneous T-cell lymphomas (CTCL). The antibody–drug conjugate brentuximab vedotin (BV), targeting CD30-positive cells, has been approved for the treatment of relapsed or refractory (R/R) systemic anaplastic [...] Read more.

CD30 is overexpressed in many T-cell lymphoma (TCL) entities, including subsets of peripheral T-cell lymphomas (PTCL) and cutaneous T-cell lymphomas (CTCL). The antibody–drug conjugate brentuximab vedotin (BV), targeting CD30-positive cells, has been approved for the treatment of relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (sALCL), and primary cutaneous anaplastic large cell lymphoma or mycosis fungoides in patients who have received previous systemic therapy. However, many patients still experience disease progression after BV monotherapy. Extensive efforts have been dedicated to investigating effective combinations of BV. A phase III clinical study demonstrated that the combination of BV with cyclophosphamide, doxorubicin, and prednisone (CHP) is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for CD30-positive PTCL. This study led to the approval of BV with CHP as the first-line therapy for CD30-positive PTCL (sALCL in Europe). We summarize the encouraging combination applications of BV in this review. Ongoing studies on combination therapies of BV are also listed, highlighting potential directions for the future application of BV. We focus on dissecting the underlying mechanisms of BV, discussing its effects on both tumor cells and the tumor microenvironment. Exploring resistance mechanisms in TCL provide valuable insights for optimizing BV-based therapies in the future. Full article

(This article belongs to the Special Issue Cutaneous T Cell Lymphomas: From Pathology to Treatment)

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16 pages, 1335 KiB

Open AccessReview

The Relationship Between Response Rate and Survival Benefits in Randomized Immunotherapy Studies

by Aditi Jain and Justin Stebbing

Cancers 2025, 17(3), 495; https://doi.org/10.3390/cancers17030495 (registering DOI) - 2 Feb 2025

Abstract

Understanding the relationship between the Objective Response Rate (ORR) and survival outcomes, notably Progression-Free Survival (PFS) and Overall Survival (OS), is relevant for assessing the efficacy of regimens in oncology. We evaluate the relationship between ORR, PFS and OS in immuno-oncology (IO) trials. [...] Read more.

Understanding the relationship between the Objective Response Rate (ORR) and survival outcomes, notably Progression-Free Survival (PFS) and Overall Survival (OS), is relevant for assessing the efficacy of regimens in oncology. We evaluate the relationship between ORR, PFS and OS in immuno-oncology (IO) trials. Data from 68 clinical trials submitted to the FDA were evaluated, examining immunotherapy regimens, notably immune checkpoint inhibitors such as anti-programmed death (ligand)-1 [anti-PD-(L)1], cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors and combination therapies [e.g., IO + IO, anti-PD-L1 + chemotherapy, anti-PD-L1 + CTLA-4, anti-PD-L1 + TKI (tyrosine kinase inhibitors)]. Studies were included based on their reporting of ORR, PFS, and OS. Of the 68 clinical trials reviewed, 55 were included in the analysis. The correlation between ORR and PFS was moderate across most immunotherapy regimens, indicating that ORR can serve as a useful predictor of short-term disease control. However, the correlation between ORR and OS was weaker, especially in trials including combination therapies, indicating that ORR alone may not reliably predict long-term survival outcomes. ORR predicts PFS better in first-line treatment but declines in later lines and remains a weak OS predictor overall. Differing degrees of correlation between ORR and survival metrics, particularly across treatment lines and combinations, are observed. While ORR can serve as a surrogate marker for PFS in IO trials, its utility in predicting OS is restricted and the interpretation of the relationship between ORR and PFS or OS is a key limitation. Rather, a decline in PFS with increasing ORR may reflect trial differences rather than a direct relationship. Future analyses should adopt better methodologies to capture these dynamics and focus on improving surrogate endpoints for immunotherapy to improve clinical trial design and patient outcomes. Full article

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

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11 pages, 828 KiB

Open AccessArticle

Defining the Role of Adjuvant Radiotherapy for Biliary Tract Cancers: A Site-Specific Propensity-Matched Analysis

by Yongwoo David Seo, Belkacem Acidi, Andrew Newton, Antony Haddad, Yi-Ju Chiang, Rainna Coelho, Timothy E. Newhook, Ching-Wei D. Tzeng, Yun Shin Chun, Ethan B. Ludmir, Eugene J. Koay, Milind Javle, Jean Nicolas Vauthey and Hop S. Tran Cao

Cancers 2025, 17(3), 494; https://doi.org/10.3390/cancers17030494 (registering DOI) - 2 Feb 2025

Abstract

Background: Biliary tract cancers (BTCs) have distinct tumor biology but share a poor prognosis, with a 5-year-survival-rate of 5–19%. Surgical resection is the only potential cure, but recurrences are common. The role of adjuvant radiotherapy (XRT) remains unclear. Methods: Using the [...] Read more.

Background: Biliary tract cancers (BTCs) have distinct tumor biology but share a poor prognosis, with a 5-year-survival-rate of 5–19%. Surgical resection is the only potential cure, but recurrences are common. The role of adjuvant radiotherapy (XRT) remains unclear. Methods: Using the National Cancer Database (2006–2018), we analyzed resected non-metastatic BTCs. Patients who survived beyond 90 days post-surgery were included, while those with R2 resections or neoadjuvant therapy were excluded. Propensity matching was performed based on predictors of adjuvant radiation, age, and sex. Survival outcomes were compared between no adjuvant therapy, chemotherapy alone, and XRT ± chemotherapy. Results: Among 21,275 patients, including 5308 intrahepatic cholangiocarcinoma (IHC), 2689 perihilar cholangiocarcinoma (PHC), 3092 distal cholangiocarcinoma (DCC), and 10,186 gallbladder cancer (GBC) cases, adjuvant XRT did not improve survival for IHC. For PHC and DCC, XRT improved survival over no adjuvant therapy (PHC: 31.2 vs. 26.3 months, p = 0.004; DCC: 33.7 vs. 27.0 months, p = 0.015) but not over chemotherapy alone. For GBC, XRT significantly improved survival compared to both no adjuvant therapy and chemotherapy (30.2 vs. 26.6 and 24.6 months; p = 0.05 and p = 0.001). Conclusions: XRT provides a survival benefit for GBC, especially in node-positive and R1-resected patients. For PHC and DCC, XRT improves outcomes compared to no therapy, but its benefit over chemotherapy is uncertain. No benefit was observed for IHC. Full article

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

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21 pages, 4995 KiB

Open AccessReview

Dermoscopy of Basal Cell Carcinoma Part 1: Dermoscopic Findings and Diagnostic Accuracy—A Systematic Literature Review

by Irena Wojtowicz and Magdalena Żychowska

Cancers 2025, 17(3), 493; https://doi.org/10.3390/cancers17030493 (registering DOI) - 1 Feb 2025

Abstract

Introduction: Basal cell carcinoma (BCC) is the most common malignant skin tumor. While rarely fatal, it can cause local tissue damage. Part I of the review summarizes the dermoscopic features of BCC and the diagnostic accuracy of dermoscopy in the diagnosis of BCC. [...] Read more.

Introduction: Basal cell carcinoma (BCC) is the most common malignant skin tumor. While rarely fatal, it can cause local tissue damage. Part I of the review summarizes the dermoscopic features of BCC and the diagnostic accuracy of dermoscopy in the diagnosis of BCC. Methods: A search of the PubMed database was performed for studies reporting on the diagnostic accuracy of dermoscopy or dermoscopic findings in BCC, either pigmented or non-pigmented, located anywhere on the body, of any histopathologic subtype, size and at any age of onset. Results: BCC was found to present with a wide range of dermoscopic features, including white structures (shiny white lines, shiny white areas, rosettes), yellow structures (milia-like cysts, yellow lobular-like structures), multiple aggregated yellow-white globules (MAY globules), blue structures (blue ovoid nests), vascular structures (arborizing vessels, short fine telangiectasias), multiple small erosions/ulcerations, features of regression (pepper-like structures, white scar-like areas) and pigmented structures (spoke-wheel areas, maple leaf-like areas (MLLAs), blue/gray dots). Dermoscopy showed a sensitivity of 67.6–98.6% and a positive predictive value (PPV) of 85.9–97% in identifying BCC. The physician’s experience and training improve the accuracy, however, BCCs on the trunk and extremities, particularly of superficial subtypes, may still constitute a challenge. Conclusions: Dermoscopy, especially when performed by a trained physician, increases the accuracy of early BCC detection. Full article

(This article belongs to the Special Issue Dermoscopy in Skin Cancer)

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19 pages, 3644 KiB

Open AccessArticle

Inter-Reader Agreement in LR-TRA Application and NLR Association in HCC Patients Treated with Endovascular vs. Ablative Procedures

by Davide Giuseppe Castiglione, Annamaria Porreca, Daniele Falsaperla, Federica Libra, Emanuele David, Roberta Maiuzzo, Mirko Domenico Castiglione, Cristina Mosconi, Stefano Palmucci, Pietro Valerio Foti, Antonio Basile and Massimo Galia

Cancers 2025, 17(3), 492; https://doi.org/10.3390/cancers17030492 (registering DOI) - 1 Feb 2025

Abstract

Objectives: This study aimed to assess the performance of the LI-RADS tumor response algorithm in analyzing inter-reader agreement in patients with hepatocellular carcinoma (HCC) treated with Microwave Ablation (MWA) and Transarterial Embolization (TAE) and the relationship between inter-reader agreement and Neutrophils to Lymphocytes [...] Read more.

Objectives: This study aimed to assess the performance of the LI-RADS tumor response algorithm in analyzing inter-reader agreement in patients with hepatocellular carcinoma (HCC) treated with Microwave Ablation (MWA) and Transarterial Embolization (TAE) and the relationship between inter-reader agreement and Neutrophils to Lymphocytes ratio dynamic variations at different time points to explore how inflammation influences tumor response and its interpretation on imaging. Methods: A retrospective analysis was conducted on 78 HCC patients treated with MWA or TAE. Two independent radiologists evaluated pre- and post-treatment imaging and assigned categories according to the LR-TRA. Inter-reader agreement was assessed with a focus on subgroup analysis considering the different locoregional treatments. NLR values, measured at baseline (T0), 72 h (T1), and 30 days post-procedure (T2), were compared with patients with concordant and discordant LR-TRA assessments. This analysis aimed to identify any association between NLR dynamics and inter-reader agreement on treatment response. Results: The inter-reader agreement in the LR-TRA application was “substantial” in the cases of MWA treatment evaluation (κ = 0.65), and “moderate” in the cases of TAE treatment evaluation (κ = 0.51). The differences in inter-reader agreement were found to be expressions of different levels of NLR mean values in the different time frames evaluated. Three days after treatment, NLR increased significantly in TAE groups. At 30 days, NLR had returned close to baseline levels but with NLR persisting higher in the TAE group. There was a statistically significant difference in NLR between the “mismatch” group (those with discrepant LR-TRA readings) and the “match” group at 3 days (p = 0.004) and late evaluation (30+ days). Conclusions: This study has shown that NLR levels can predict inter-reader discrepancies in LR-TRA assessment and may be translated into different levels of difficult imaging interpretation. Combining LR-TRA and NLR is promising for a more comprehensive assessment of tumor response and inflammatory dynamics. Full article

(This article belongs to the Special Issue Tumor Microenvironment Dynamics in Hepatocellular Carcinoma)

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28 pages, 18048 KiB

Open AccessArticle

EBV-Induced LINC00944: A Driver of Oral Cancer Progression and Influencer of Macrophage Differentiation

by Sawarot Srisathaporn, Tipaya Ekalaksananan, Chukkris Heawchaiyaphum, Sirinart Aromseree, David G. Maranon, Noelia H. Altina, Thawaree Nukpook, Jeffrey Wilusz and Chamsai Pientong

Cancers 2025, 17(3), 491; https://doi.org/10.3390/cancers17030491 (registering DOI) - 1 Feb 2025

Abstract

Oral squamous cell carcinoma (OSCC) is a significant global health concern. Epstein–Barr virus (EBV) infection as well as long non-coding RNA (lncRNAs) associated EBV infection, have been linked to OSCC development and are known to influence cancer progression. LINC00944 is associated with various [...] Read more.

Oral squamous cell carcinoma (OSCC) is a significant global health concern. Epstein–Barr virus (EBV) infection as well as long non-coding RNA (lncRNAs) associated EBV infection, have been linked to OSCC development and are known to influence cancer progression. LINC00944 is associated with various cancers and immune cells, but its role in oral cancer remains underexplored. This study investigated the role of EBV-induced LINC00944 in OSCC and its impact on the tumor microenvironment. The LINC00944 expression was analyzed from a database of head and neck squamous cell carcinoma (HNSCC) tissues, and its expression in EBV-positive and EBV-negative OSCC cell lines was examined via qRT-PCR. We overexpressed LINC00944 in SCC25 and ORL-48T oral cancer cell lines and evaluated its impact on migration and invasion ability using wound healing and transwell experiments. Additionally, we studied its influence on macrophage differentiation. The results showed that LINC00944 expression was higher in HNSCC than in normal tissues and was linked to EBV-positive OSCC cell lines. LINC00944 overexpressed-OSCC cell lines significantly increased cellular motility and invasiveness. Additionally, LINC00944 was secreted in a cultured medium, delivered to macrophages, and promoted macrophage differentiation into the M1 subtype. Predicted interactions suggested that LINC00944 targets miRNAs that regulate NFKB1 and RELA. In conclusion, EBV-induced LINC00944 contributes to OSCC progression by enhancing tumor cell migration, invasion, and macrophage differentiation, potentially regulating these processes through NFKB1 and RELA. These findings provide valuable directions for LINC00944’s future studies on its mechanisms and suggest that it could be a target of study in EBV-associated OSCC. Full article

(This article belongs to the Section Cancer Therapy)

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12 pages, 875 KiB

Open AccessArticle

Synergistic Inhibition of Drug Resistant KRAS Mutant Non-Small Cell Lung Cancer by Co-Targeting AXL and SRC

by Soumavo Mukherjee, Dhananjay Suresh, Ajit Zambre, Sairam Yadavilli, Shreya Ghoshdastidar, Anandhi Upendran and Raghuraman Kannan

Cancers 2025, 17(3), 490; https://doi.org/10.3390/cancers17030490 (registering DOI) - 1 Feb 2025

Abstract

Abstract: Background/Objectives: KRAS-mutated NSCLC has been targeted using monoclonal antibody (mAb) or tyrosine kinase inhibitor (TKI) therapies. However, in time, these mutations appear to develop resistance against the targeted antibodies and TKI treatments. One possible explanation is the activation of pro apoptotic [...] Read more.

Abstract: Background/Objectives: KRAS-mutated NSCLC has been targeted using monoclonal antibody (mAb) or tyrosine kinase inhibitor (TKI) therapies. However, in time, these mutations appear to develop resistance against the targeted antibodies and TKI treatments. One possible explanation is the activation of pro apoptotic pathways through the AXL–SRC–Akt axis. In this study, we identify AXL as the bypass resistant gene and investigate its role with KRAS and SRC activity. Methods: In this study, we use Dasatinib and SGI-7079 to co-inhibit SRC and AXL respectively. In vitro studies were conducted using four cell lines, and AXL suppression was achieved using siRNA and in CRISPR-Cas9 mediated knockout models. Subsequently, we studied gene-protein expression analysis using Western blot, apoptotic markers using a cytochrome release assay and cytotoxicity using an MTT assay. A549 xenografts were studied for in vivo validation of our proposed hypothesis. Results: The results suggest that dual inhibition of AXL and SRC significantly reversed this resistance, both in in vivo and in vitro studies. Conclusions: Co-inhibition of AXL and SRC synergistically reduced KRAS activity and induced apoptosis in NSCLC. Full article

(This article belongs to the Special Issue Imaging and Molecular Biology as Biomarkers for Lung Cancer)

12 pages, 586 KiB

Open AccessArticle

A Prognostic Symptom Model Incorporating Patient-Reported Symptoms for Transplant-Ineligible Patients with Multiple Myeloma

by Amaris K. Balitsky, Rinku Sutradhar, Hsien Seow, Anastasia Gayowsky, Alissa Visram, Jason Tay, Irwindeep Sandhu and Hira Mian

Cancers 2025, 17(3), 489; https://doi.org/10.3390/cancers17030489 (registering DOI) - 1 Feb 2025

Abstract

Introduction: Patients with transplant-ineligible (TIE) multiple myeloma (MM) have high rates of symptom burden. The aim of this study was to develop and validate a prognostic model to predict symptoms in patients with TIE MM. Methods: In this population-based, retrospective cohort study, using [...] Read more.

Introduction: Patients with transplant-ineligible (TIE) multiple myeloma (MM) have high rates of symptom burden. The aim of this study was to develop and validate a prognostic model to predict symptoms in patients with TIE MM. Methods: In this population-based, retrospective cohort study, using multiple administrative health care databases linked using a unique encrypted patient identifier in Ontario, Canada, symptoms were identified using the patient self-reported Edmonton Symptom Assessment System (ESAS) at each clinic visit. The primary outcome was the presence of moderate-to-severe (ESAS score 4–10) symptoms (specifically symptoms of pain, tiredness, depression, and impaired well-being) within one year from the index date. Using the entire cohort, a multivariable logistic regression model with baseline covariates was developed to predict the risk of experiencing each of the above symptoms, categorized as moderate to severe within 1 year post-index date. Internal validation of the model was assessed via bootstrap validation methods. Results: A total of 1535 TIE adults with MM met the inclusion criteria. The median age was 75, with 25.2% of patients aged 80 years or older. In the multivariate analysis, baseline symptoms continued to be most associated with future symptom burden. Baseline severe pain (OR 9.84, 95% CI 6.29–15.7) was most associated with patients experiencing moderate–severe pain one year post-index date. Similarly, baseline severe tiredness (OR 17.34, 95% CI 9.00–33.42), baseline severe depression (OR 28.07, 95% CI 15.96–49.38), and baseline severely impaired well-being (OR 4.12, 95% CI 2.30–7.37) were the biggest predictors of patients experiencing moderate–severe tiredness, depression, and impaired well-being, respectively, at one year after the index date. Conclusions: Patients with MM experience persisting symptoms of pain, tiredness, depression, and impaired well-being, with baseline symptoms being the biggest predictor of future symptom burden. Full article

(This article belongs to the Special Issue Medical Complications and Supportive Care in Patients with Cancer (2nd Edition))

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