Cancers

12 pages, 254 KiB

Open AccessArticle

Healthcare Costs by Comorbidity Patterns in Lung Cancer Patients

by Alessandra Buja, Massimo Rugge, Marcello Di Pumpo, Manuel Zorzi, Federico Rea, Ilaria Pantaleo, Giovanna Scroccaro, Pierfranco Conte, Leonardo Rigon, Giorgio Arcara, Giulia Pasello and Valentina Guarneri

Cancers 2025, 17(16), 2682; https://doi.org/10.3390/cancers17162682 - 18 Aug 2025

Abstract

Introduction: Lung cancer imposes a substantial economic burden on patients, healthcare systems, and societies due to its high prevalence and costs associated with diagnosis, treatment, and palliative care. Comorbidities in lung cancer patients can further complicate clinical management and increase healthcare utilization. This [...] Read more.

Introduction: Lung cancer imposes a substantial economic burden on patients, healthcare systems, and societies due to its high prevalence and costs associated with diagnosis, treatment, and palliative care. Comorbidities in lung cancer patients can further complicate clinical management and increase healthcare utilization. This study investigated the impact of comorbidity patterns on healthcare costs in patients with lung cancer. Methods: A cohort of 1540 lung cancer patients in the Veneto region of Italy was divided into five groups based on comorbidity burden using latent class analysis: no comorbidities, only one comorbidity, and specific comorbidity classes (Class 1: cardiovascular, respiratory, and endocrine diseases; Class 2: multiorgan diseases; Class 3: socio-multifactorial neuro conditions). Using administrative data, both overall healthcare costs and lung cancer-specific costs were analyzed over three years. Results: Patients with one comorbidity class had the highest overall costs over three years from diagnosis (USD 52,039) and the highest lung-specific costs (USD 47,804). In contrast, patients in the Cardiovascular-Respiratory and Endocrine class incurred the lowest overall costs (USD 38,447). Additionally, they had the lowest lung case-specific costs (USD 33,425) over the same three-year period from diagnosis. Higher costs for inpatient medications were observed in patients without any comorbidities or with at most one. Conclusions: The findings emphasize the significant effect of comorbidity patterns on resource use in lung cancer patients. Considering comorbidity profiles is essential for economic assessments and healthcare planning, as it allows for better resource allocation and supports personalized treatment strategies. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

12 pages, 679 KiB

Open AccessArticle

Antitumor Effects of Combination Therapy with Oncolytic Vaccinia Virus and Tepotinib on Lung Cancer Cells

by Takuya Inoue, Nobuhiro Kanaji, Takafumi Nakamura, Masanao Yokohira, Yuta Komori, Yasuhiro Ohara, Hitoshi Mizoguchi, Naoki Watanabe and Norimitsu Kadowaki

Cancers 2025, 17(16), 2681; https://doi.org/10.3390/cancers17162681 - 18 Aug 2025

Abstract

Objectives: Despite advancements in molecular-targeted therapies and immune checkpoint inhibitors, the survival rate of patients with advanced lung cancer remains unsatisfactory. Therefore, new and effective treatment strategies are urgently needed. Both mesenchymal-epithelial transition (MET) inhibitors and oncolytic viruses exhibit immunomodulatory properties along with [...] Read more.

Objectives: Despite advancements in molecular-targeted therapies and immune checkpoint inhibitors, the survival rate of patients with advanced lung cancer remains unsatisfactory. Therefore, new and effective treatment strategies are urgently needed. Both mesenchymal-epithelial transition (MET) inhibitors and oncolytic viruses exhibit immunomodulatory properties along with direct antitumor effects. Materials and Methods: The antitumor effects of a combination therapy using MDRVV, a modified vaccinia virus for oncolytic virus therapy, and tepotinib, a MET inhibitor, were evaluated in vitro and in vivo using lung cancer models. Results: The combination therapy demonstrated additive cytotoxic effects on various lung cancer cell lines in vitro and significantly suppressed tumor growth in an immunocompetent mouse model. MDRVV triggered immunogenic cell death, evidenced by the release of adenosine triphosphate (ATP) and high-mobility group box-1 (HMGB-1). Additionally, the combination therapy enhanced CD4+ and CD+ T-cell infiltration more effectively than either agent alone. MDRVV exhibited antitumor effects not only in the inoculated tumors but also in distant tumors, with the most pronounced effect observed when combined with tepotinib. Conclusions: These findings suggest that combining a MET inhibitor with oncolytic vaccinia virus represents a promising and effective strategy for improving lung cancer treatment by targeting both tumor cells and the tumor microenvironment. Full article

(This article belongs to the Section Cancer Therapy)

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34 pages, 2377 KiB

Open AccessReview

Exogenous Estrogens as Breast Cancer Risk Factors: A Perspective

by Parth Malik and Tapan Kumar Mukherjee

Cancers 2025, 17(16), 2680; https://doi.org/10.3390/cancers17162680 - 18 Aug 2025

Abstract

Background: The human body’s exposure to high levels of endogenous estrogens and their metabolites, such as estradiol, estriol, 2-hydroxyestradiol, and 4-hydroxyestradiol, is implicated in the development and complications of breast cancers (BCs). Besides endogenous estrogen production, the human body is also exposed to [...] Read more.

Background: The human body’s exposure to high levels of endogenous estrogens and their metabolites, such as estradiol, estriol, 2-hydroxyestradiol, and 4-hydroxyestradiol, is implicated in the development and complications of breast cancers (BCs). Besides endogenous estrogen production, the human body is also exposed to environmental sources of estrogen and estrogen-like compounds, which include pharmaceutical estrogens, xenoestrogens, and phytoestrogens. Females consume pharmaceutical estrogens as a constituent of postmenopausal hormone replacement therapy (HRT) and oral contraceptive pills, either alone or in combination with progestins. Additionally, humans, including females, are exposed to estrogen-resembling non-native compounds called xenoestrogens, prevailing in pesticides, plastics, and personal care items via inhalation, dermal contact, and oral consumption. Several phytoestrogens, such as isoflavones and lignans, are consumed by humans as food ingredients. Methods and Results: Emerging cellular and molecular experimental evidence indicates that when binding to estrogen receptors (ERs), various pharmaceutical estrogens, including equine/synthetic forms, progestin combinations, and xenoestrogens, promote BC development and complications by triggering survival, proliferation, angiogenesis, and invasion of these cells. Conversely, other experimental observations reveal the protective and beneficial effects of phytoestrogens like genistein from soy products on BC development and complications. Conclusions: This comprehensive review article describes the implications of exposure to exogenous estrogens, such as pharmaceutical estrogens, xenoestrogens, and phytoestrogens, as risk factors in the prevention or development of BC and its complications. Full article

(This article belongs to the Special Issue Lifestyle Choices and Endocrine Dysfunction on Cancer Onset and Risk)

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Graphical abstract

21 pages, 2574 KiB

Open AccessArticle

Clinically Explainable Prediction of Immunotherapy Response Integrating Radiomics and Clinico-Pathological Information in Non-Small Cell Lung Cancer

by Jhimli Mitra, Soumya Ghose and Rajat Thawani

Cancers 2025, 17(16), 2679; https://doi.org/10.3390/cancers17162679 - 18 Aug 2025

Abstract

Background/Objectives: Immunotherapy is a viable therapeutic approach for non-small cell lung cancer (NSCLC). Despite the significant survival benefit of immune checkpoint inhibitors PD-1/PD-L1, on average; the objective response rate is around 20% as monotherapy and around 50% in combination with chemotherapy. While PD-L1 [...] Read more.

Background/Objectives: Immunotherapy is a viable therapeutic approach for non-small cell lung cancer (NSCLC). Despite the significant survival benefit of immune checkpoint inhibitors PD-1/PD-L1, on average; the objective response rate is around 20% as monotherapy and around 50% in combination with chemotherapy. While PD-L1 IHC is used as a predictive biomarker, its accuracy is subpar. Methods: In this work, we develop a machine learning (ML) method to predict response to immunotherapy in NSCLC from multimodal clinicopathological biomarkers, tumor and peritumoral radiomic biomarkers from CT images. We further learn a graph structure to understand the associations between biomarkers and treatment response. The graph is then used to create sentences with clinical hypotheses that are finally used in a Large Language Model (LLM) that explains the treatment response predicated on the biomarkers that are comprehensible to clinicians. From a retrospective study, a training dataset of NSCLC with n = 248 tumors from 140 subjects was used for feature selection, ML model training, learning the graph structure, and fine-tuning LLM. Results: An AUC = 0.83 was achieved for prediction of treatment response on a separate test dataset of n = 84 tumors from 47 subjects. Conclusions: Our study therefore not only improves the prediction of immunotherapy response in patients with NSCLC from multimodal data but also assists the clinicians in making clinically interpretable predictions by providing language-based explanations. Full article

(This article belongs to the Special Issue The Future of Machine Learning in Predicting the Treatment Responses of Cancers)

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13 pages, 1051 KiB

Open AccessArticle

Maintenance Treatment with 5-Azacitidine in Patients with Acute Myeloblastic Leukemia Ineligible for Intensive Treatment and with Response After Induction Chemotherapy: A Phase II Clinical Trial

by Alfonso Fernández Fernández, María García Fortes, Mar Tormo Díaz, María Luz Juan Marco, Rebeca Cuello García, Adolfo de La Fuente, Josefina Serrano López, Mª Ángeles Medina Pérez, Miguel Ángel Sánchez Chaparro and Regina García Delgado

Cancers 2025, 17(16), 2678; https://doi.org/10.3390/cancers17162678 - 18 Aug 2025

Abstract

Background/Objectives: After first-line treatment, elderly patients with acute myeloid leukemia (AML) often become unfit to continue intensive chemotherapy despite having achieved a response. This trial aimed to determine the efficacy of maintenance treatment with azacitidine in AML patients who are ineligible to [...] Read more.

Background/Objectives: After first-line treatment, elderly patients with acute myeloid leukemia (AML) often become unfit to continue intensive chemotherapy despite having achieved a response. This trial aimed to determine the efficacy of maintenance treatment with azacitidine in AML patients who are ineligible to continue intensive treatment after remission. Methods: A single-arm, multicenter, phase II clinical trial (EudraCT: 2010-020432-18) including patients with AML with complete (CR) or partial remission (PR) after one or two cycles of intensive induction chemotherapy and ineligible to continue intensive treatment was conducted. Efficacy was measured as the response rate, progression-free survival (PFS), and overall survival (OS), and was assessed in the intention-to-treat (ITT) population (all patients). Quality of life was also assessed. Results: Thirty-two patients were included, with a mean age of 73.3 years (SD 3.8) (53.1% male); sixteen patients (50.0%) reached the sixth treatment cycle. The best response was CR in 11 patients (68.8%) and PR in 2 patients (12.5%) at cycle six, and CR in 15 patients (46.9%) and PR in 5 patients (15.6%) overall. The median PFS was 6.7 months (95% CI 3.1–8.7), and OS was 11.5 months (95% CI 6.6–15.9). The daily function (p = 0.0296), cognitive function (p = 0.0412), and social function (p = 0.0275) scales of the EORTC QLQ-C30 questionnaire significantly improved. Thirty-one patients (96.9%) experienced adverse events; six (1.9%) were serious. Conclusions: Azacitidine is a safe and well-tolerated maintenance treatment option for AML patients unfit for intensive therapy following a response to induction, although the single-arm phase II design precludes direct causal inference. Patients achieved promising results regarding PFS and remission rates, with improved quality of life. Full article

(This article belongs to the Section Cancer Therapy)

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20 pages, 3736 KiB

Open AccessSystematic Review

Diagnostic Accuracy of Diffusion-Weighted MRI for Differentiating Benign and Malignant Thyroid Nodules: Systematic Review and Meta-Analysis

by Benjamin Noto, Carolin Bobe, Jonas Brandt, Heiner N. Raum, Nabila Gala Nacul, Burkhard Riemann and Anne Helfen

Cancers 2025, 17(16), 2677; https://doi.org/10.3390/cancers17162677 - 18 Aug 2025

Abstract

Background: Thyroid nodules are highly prevalent, affecting up to 75% of the population, yet most are benign. The limited specificity of ultrasound-based workup leads to substantial overdiagnosis and overtreatment, underscoring the need for improved imaging-based classification. Diffusion-weighted MRI (DWI), quantified via the [...] Read more.

Background: Thyroid nodules are highly prevalent, affecting up to 75% of the population, yet most are benign. The limited specificity of ultrasound-based workup leads to substantial overdiagnosis and overtreatment, underscoring the need for improved imaging-based classification. Diffusion-weighted MRI (DWI), quantified via the apparent diffusion coefficient (ADC), has emerged as a promising imaging biomarker. This meta-analysis updates pooled diagnostic performance metrics and systematically evaluates which DWI acquisition techniques, imaging parameters, and combinations with other MRI modalities are most promising for clinical translation. Methods: PubMed, Web of Science, Scopus, and ProQuest were systematically searched. Pooled sensitivity, specificity, and area under the curve (AUC) were calculated using bivariate random-effects models. The effects of b-value, magnetic field strength, echo time, and diffusion model on diagnostic accuracy and ADC values were examined through subgroup and meta-regression analyses. Results: Forty-six studies (3003 nodules) were included. Pooled sensitivity and specificity were 0.84 (95% CI: 0.81–0.86) and 0.88 (95% CI: 0.85–0.90), with an AUC of 0.912. Intravoxel incoherent motion and diffusion kurtosis imaging showed no added value over the mono-exponential model. For the mono-exponential model, a negative association between b-values and reported ADCs was observed, whereas no association was found between b-values and diagnostic accuracy. Magnetic field strength and echo time did not affect ADCs. Combining DWI with morphological imaging showed the potential to further enhance diagnostic performance. Conclusions: DWI holds strong potential to improve the diagnostic workup of thyroid nodules. Technical standardization, particularly of key acquisition parameters, should be pursued to enable clinical implementation. Full article

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

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23 pages, 4718 KiB

Open AccessArticle

Clinical Integration of NIR-II Fluorescence Imaging for Cancer Surgery: A Translational Evaluation of Preclinical and Intraoperative Systems

by Ritesh K. Isuri, Justin Williams, David Rioux, Paul Dorval, Wendy Chung, Pierre-Alix Dancer and Edward J. Delikatny

Cancers 2025, 17(16), 2676; https://doi.org/10.3390/cancers17162676 - 17 Aug 2025

Abstract

Background/Objectives: Back table fluorescence imaging performed on freshly excised tissue specimens represents a critical step in fluorescence-guided surgery, enabling rapid assessment of tumor margins before final pathology. While most preclinical NIR-II imaging platforms, such as the IR VIVO (Photon, etc.), offer high-resolution [...] Read more.

Background/Objectives: Back table fluorescence imaging performed on freshly excised tissue specimens represents a critical step in fluorescence-guided surgery, enabling rapid assessment of tumor margins before final pathology. While most preclinical NIR-II imaging platforms, such as the IR VIVO (Photon, etc.), offer high-resolution and depth-sensitive imaging under controlled, enclosed conditions, they are not designed for intraoperative or point-of-care use. This study compares the IR VIVO with the LightIR system, a more compact and clinically adaptable imaging platform using the same Alizé 1.7 InGaAs detector, to evaluate whether the LightIR can offer comparable performance for back table NIR-II imaging under ambient light. Methods: Standardized QUEL phantoms containing indocyanine green (ICG) and custom agar-based tissue-mimicking phantoms loaded with IR-1048 were imaged on both systems. Imaging sensitivity, spatial resolution, and depth penetration were quantitatively assessed. LightIR was operated in pulse-mode under ambient lighting, mimicking back table or intraoperative use, while IR VIVO was operated in a fully enclosed configuration. Results: The IR VIVO system achieved high spatial resolution (~125 µm) and detected ICG concentrations as low as 30 nM in NIR-I and 300 nM in NIR-II. The LightIR system, though requiring longer exposure times, successfully resolved features down to ~250 µm and detected ICG to depths ≥4 mm. Importantly, the LightIR maintained robust NIR-II contrast under ambient lighting, aided by real-time background subtraction, and enabled clear visualization of subsurface IR-1048 targets in unshielded phantom setups, conditions relevant to back table workflows. Conclusions: LightIR offers performance comparable to the IR VIVO in terms of depth penetration and spatial resolution, while also enabling open-field NIR-II imaging without the need for a blackout enclosure. These features position the LightIR as a practical alternative for rapid, high-contrast fluorescence assessment during back table imaging. The availability of such clinical-grade systems may catalyze the development of new NIR-II fluorophores tailored for real-time surgical applications. Full article

(This article belongs to the Special Issue Application of Fluorescence Imaging in Cancer)

14 pages, 711 KiB

Open AccessSystematic Review

Clinical Characteristics and Outcomes of SMARCA4-Mutated or Deficient Malignancies: A Systematic Review of Case Reports and Series

by Ryuichi Ohta, Natsumi Yamamoto, Kaoru Tanaka, Chiaki Sano and Hidetoshi Hayashi

Cancers 2025, 17(16), 2675; https://doi.org/10.3390/cancers17162675 - 16 Aug 2025

Abstract

Background/Objectives: SMARCA4-deficient or SMARCA4-mutated cancers are rare but highly aggressive tumors with poor differentiation, resistance to conventional treatments, and limited clinical guidance. While thoracic SMARCA4-deficient undifferentiated tumors are relatively well described, the full spectrum of SMARCA4-altered cancers across different organs and their therapeutic [...] Read more.

Background/Objectives: SMARCA4-deficient or SMARCA4-mutated cancers are rare but highly aggressive tumors with poor differentiation, resistance to conventional treatments, and limited clinical guidance. While thoracic SMARCA4-deficient undifferentiated tumors are relatively well described, the full spectrum of SMARCA4-altered cancers across different organs and their therapeutic responses remains poorly understood. This study aimed to systematically review published case reports and case series to clarify the clinical characteristics, molecular features, treatment patterns, and survival outcomes of SMARCA4-altered malignancies. Methods: We conducted a systematic review of case reports and case series published between 2015 and 2025 using PubMed, Embase, and Web of Science. Eligible studies included adult patients with immunohistochemically or genetically confirmed SMARCA4-deficient or SMARCA4-mutated tumors. Key clinical, pathological, molecular, therapeutic, and outcome-related data were extracted. Descriptive statistics were used, and exploratory subgroup analyses were performed based on tumor type and treatment modality. The review protocol was registered in PROSPERO (CRD420251088805). Results: A total of 109 studies reporting 160 individual patients were included. Most tumors arose in the thorax (40.0%), followed by gastrointestinal (17.5%) and gynecologic sites (15.6%). The median age was 58 years, with a male predominance (70.0%) and frequent smoking history (44.4%). Platinum-based chemotherapy was administered in 62.5% of cases, and immune checkpoint inhibitors (ICIs) were used in 25.6%. Among ICI-treated patients, partial responses or stable disease were observed in 80.5%. The median progression-free survival (PFS) was 4.0 months, and the median overall survival (OS) was 5.0 months. Conclusions: SMARCA4-altered cancers are clinically and molecularly diverse but uniformly aggressive, with limited therapeutic benefit from conventional chemotherapy. Immune checkpoint inhibitors may offer improved outcomes in select patients, particularly those with thoracic tumors. Early molecular profiling, rare tumor registries, and biomarker-driven trials are crucial for guiding future treatment strategies. Full article

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

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15 pages, 1415 KiB

Open AccessArticle

Long-Term Immune Response to SARS-CoV-2 Vaccination in Hematologic Malignancies: An Update of the ImV-HOng Trial of the East German Study Group for Hematology and Oncology

by Susann Schulze, Sabrina Jotschke, Robby Engelmann, Beatrice Ludwig-Kraus, Frank Bernhard Kraus, Nadja Jaekel, Christina Zahn, Christian Junghanss, Sebastian Böttcher and Haifa Kathrin Al-Ali

Cancers 2025, 17(16), 2674; https://doi.org/10.3390/cancers17162674 - 16 Aug 2025

Abstract

Purpose: Evaluate long-term immunogenicity and its association with the number of vaccines and breakthrough infections in patients with hematologic malignancies compared to a healthy cohort. Methods: This study is an amendment of a multicenter study (DRKS00027372) which described the upsurge of [...] Read more.

Purpose: Evaluate long-term immunogenicity and its association with the number of vaccines and breakthrough infections in patients with hematologic malignancies compared to a healthy cohort. Methods: This study is an amendment of a multicenter study (DRKS00027372) which described the upsurge of anti-spike-IgGs on day 120 from a blunted day-35 response in patients with hematologic neoplasms. In this amendment, 191 individuals from the original study (patients with myeloid and lymphoid neoplasms and controls) were followed beyond month 12 after first SARS-CoV-2-vaccination. The long-term humoral and cellular responses and their correlation with the number of vaccines were studied. Results: After a median follow-up of 18 months, a median of three vaccinations (range 1–5) were given. Antibody levels did not correlate with the number of vaccinations (≤2 versus ≥3) (p = 0.3). With a median of 5274 U/mL anti-spike-IgGs, the inferior day-120 antibody response in patients with lymphoid neoplasms was no longer detected. Breakthrough SARS-CoV-2-infections, mostly mild, occurred in 67% of controls and 46% of patients. Patients with lymphoid neoplasms with two vaccinations did not have more infections compared to patients with more doses (p = 0.4). There was a significant decline in the spike-specific T-cell response for CovCD4⁺ and CovCD8⁺ (p < 0.001). On last assessment, 33% of individuals lost their day-120 CovCD4⁺-positive response (p < 0.001). There was no correlation between the number of vaccinations and cellular immune response in patients and controls (p = 0.3). Conclusions: In this study, breakthrough infections were high despite repeated boosting, which by itself does not lead to an upsurge in the cellular immune response in the majority of patients. Full article

(This article belongs to the Section Infectious Agents and Cancer)

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22 pages, 3464 KiB

Open AccessArticle

Clinical and Molecular Differences Suggest Different Responses to Immune Checkpoint Inhibitors in Microsatellite-Stable Solid Tumors with High Tumor Mutational Burden

by Imran Nizamuddin, Tarik Demir, Katrina Dobinda, Ruohui Chen, Masha Kocherginsky, Peter Doukas, Neelima Katam, Carolyn Moloney and Devalingam Mahalingam

Cancers 2025, 17(16), 2673; https://doi.org/10.3390/cancers17162673 - 16 Aug 2025

Abstract

Background/Objectives: We aim to identify predictors of response to ICIs in patients with advanced solid tumors that exhibiting a TMB ≥ 10 mut/Mb. Methods: Patients treated with ICIs alone at Northwestern University between 1 January 2015 and 31 December 2020 were [...] Read more.

Background/Objectives: We aim to identify predictors of response to ICIs in patients with advanced solid tumors that exhibiting a TMB ≥ 10 mut/Mb. Methods: Patients treated with ICIs alone at Northwestern University between 1 January 2015 and 31 December 2020 were identified. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method, and groups were compared using the log-rank test. Wilcoxon rank sum tests, chi-squared tests, and Fisher’s exact tests were used for univariable analyses evaluating the impact of clinical and genetic variables on response, with significance defined as p < 0.05. Results: A total of 117 patients were classified as ICI-sensitive (n = 88) or non-ICI-sensitive (n = 29). Among evaluable patients (n = 105), the overall response rate was 34% with 14% achieving a complete response. Median PFS and OS were 8.05 months and 26.8 months, respectively. Higher PFS rates were significantly linked to the ICI-sensitive tumor group (p = 0.009), absence of liver metastasis (p = 0.015), and no prior systemic treatment (p = 0.001) in both cohorts. In non-ICI-sensitive patients, a TMB of ≥15 mut/Mb correlated with improved outcomes (p = 0.012). Mutations in the MYC pathway (p = 0.03) and the MLL2 gene (p = 0.014) were associated with poorer responses, while mutations in the TERT gene were linked to better responses (p = 0.031). Conclusions: Patients without liver metastasis, mutations in TERT, and TMB ≥ 15 mut/Mb are associated with superior response, while mutations in the MYC pathway and MLL2 are associated with worse responses. Full article

(This article belongs to the Special Issue Biomarkers for Therapy Response in Gastrointestinal Malignancies: Predicting Outcomes and Personalizing Care)

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10 pages, 453 KiB

Open AccessArticle

Clinicopathological Features and Pathogenesis of Thymoma Complicated with Alopecia Areata: A Multicenter, Matched Case Analysis

by Xin Du, Xuehan Gao, Jian Cui, Xintao Yu, Cheng Huang, Yeye Chen, Chao Guo, Ye Zhang, Chao Gao, Xiayao Diao, Lei Yu and Shanqing Li

Cancers 2025, 17(16), 2672; https://doi.org/10.3390/cancers17162672 - 16 Aug 2025

Abstract

Background: Thymoma is a malignant tumor originating from the thymic epithelium and can be associated with over 100 paraneoplastic syndromes (PNSs). Due to the low incidence of thymoma and the relative rarity of alopecia areata (AA) as an associated autoimmune disease, patients with [...] Read more.

Background: Thymoma is a malignant tumor originating from the thymic epithelium and can be associated with over 100 paraneoplastic syndromes (PNSs). Due to the low incidence of thymoma and the relative rarity of alopecia areata (AA) as an associated autoimmune disease, patients with thymoma combined with AA are relatively uncommon in clinical practice. As a result, the clinicopathological features and pathogenesis of such patients have been rarely investigated. Methods: This study retrospectively analyzed the clinical records of thymoma patients who underwent surgical treatment at Peking Union Medical College Hospital and Beijing Tongren Hospital from August 2014 to July 2019, with a focus on the clinicopathological features of thymoma patients with AA. Propensity score matching (PSM) was employed to create a 1:5 matched comparison group with thymoma patients without AA. Results: A total of 428 thymoma patients were included, among which 9 had AA. Using PSM, we matched 45 control patients without AA based on age and gender. The analysis revealed that thymoma patients with AA had a significantly higher proportion of myasthenia gravis (MG) [100.00% (9/9) vs. 66.67% (30/45), p = 0.049], although there were no significant differences between the AChR antibodies, Titin antibodies, MG severity, and the incidence of postoperative myasthenic crisis. However, the proportion of thymoma patients with AA who also had other PNSs besides MG was significantly higher [88.89% (8/9) vs. 6.67% (3/45), p < 0.001]. Additionally, CD4⁺/CD8⁺ T-cell inversion in the serum was observed at a much higher rate in thymoma patients with AA [100.00% (9/9) vs. 24.44% (11/45), p < 0.001]. Conclusions: We hypothesize that the pathogenesis of thymoma with AA differs from that of thymoma with MG, though there may be a correlation. The etiology of thymoma with AA may be attributed to abnormal autoimmune CD8⁺ T lymphocytes produced by the thymoma, which can also lead to other cytotoxic T-cell-mediated autoimmune diseases. Full article

(This article belongs to the Section Cancer Pathophysiology)

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14 pages, 4518 KiB

Open AccessArticle

Real-World Effectiveness and Safety of Photoimmunotherapy for Head and Neck Cancer: A Multicenter Retrospective Study

by Isaku Okamoto, On Hasegawa, Yukiomi Kushihashi, Tatsuo Masubuchi, Kunihiko Tokashiki and Kiyoaki Tsukahara

Cancers 2025, 17(16), 2671; https://doi.org/10.3390/cancers17162671 - 16 Aug 2025

Abstract

Background/Objectives: Photoimmunotherapy for head and neck cancer (HN-PIT) is an emerging treatment for unresectable locally advanced or recurrent head and neck cancer. However, real-world data (RWD) are limited. This study examined the safety and effectiveness of HN-PIT. Methods: This multicenter, retrospective cohort study [...] Read more.

Background/Objectives: Photoimmunotherapy for head and neck cancer (HN-PIT) is an emerging treatment for unresectable locally advanced or recurrent head and neck cancer. However, real-world data (RWD) are limited. This study examined the safety and effectiveness of HN-PIT. Methods: This multicenter, retrospective cohort study included 40 patients with unresectable locally advanced or recurrent head and neck cancers who underwent HN-PIT from January 2021 to August 2024. The primary endpoint was time to treatment failure (TTF). Secondary endpoints included the objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Results: The median TTF and 1-year treatment failure rate were 6.0 months and 23.2%, respectively. Moreover, the ORR, disease control rate, median OS, and median PFS were 75.0% (95% confidence interval [CI]: 60.0–86.0%), 95.0% (95% CI: 83.5–99.0%), 26.9 months, and 6.2 months, respectively. The incidence of grade ≥3 AEs was 17.5% (95% CI: 7.1–29.1%). Pain was the most common AE, occurring in 37 patients (92.5%), with grade III pain reported in 5 (12.5%). Mucositis occurred in 32 patients (80.0%), with grade III mucositis reported in 3 (7.5%). Hemorrhages occurred in 31 patients (77.5%), with no grade ≥III hemorrhages reported. Two patients experienced sepsis (5.0%; grades IV and V). Seventeen patients (42.5%) had laryngeal edema, with grade IV edema reported in four (10.0%). Conclusions: Our RWD shows that HN-PIT is effective with an acceptable safety profile. TTF may serve as an endpoint reflecting this treatment’s characteristics. This study provides important basic data for the development of future treatment strategies. Full article

(This article belongs to the Section Cancer Therapy)

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21 pages, 642 KiB

Open AccessReview

Prehabilitation Prior to Chemotherapy in Humans: A Review of Current Evidence and Future Directions

by Karolina Pietrakiewicz, Rafał Stec and Jacek Sobocki

Cancers 2025, 17(16), 2670; https://doi.org/10.3390/cancers17162670 - 15 Aug 2025

Abstract

Background/Objectives: Chemotherapy is an aggressive form of oncological treatment often accompanied by numerous adverse effects. A patient’s baseline status significantly influences the course of therapy, its efficacy, quality of life, and overall survival. This review aims to analyze the published peer-reviewed studies in [...] Read more.

Background/Objectives: Chemotherapy is an aggressive form of oncological treatment often accompanied by numerous adverse effects. A patient’s baseline status significantly influences the course of therapy, its efficacy, quality of life, and overall survival. This review aims to analyze the published peer-reviewed studies in this area and to assess whether they permit the formulation of preliminary recommendations for future prehabilitation protocols. Methods: An integrative review was conducted due to the limited number of relevant studies. Four databases—MEDLINE/PubMed (Medical Literature Analysis and Retrieval System Online/National Library of Medicine), Scopus, Cochrane, and Web of Science—were systematically searched for English-language articles published between 2010 and 13 January 2025, using the terms “prehabilitation,” “chemotherapy,” “drug therapy,” and “neoadjuvant.” A total of 162 records were retrieved. After duplicate removal, titles and abstracts were screened. The remaining papers were subjected to detailed analysis, resulting in ten studies with diverse methodologies being included. Results: We reviewed ten (n = 10) studies, most of which were reviews focused on breast cancer, indicating variation in the state of knowledge across different cancer types. A protein intake of 1.4 g/kg body mass helps preserve fat-free mass, with whey being more effective than casein. Omega-3 fatty acid supplementation at a dose of 2.2 g/kg may prevent chemotherapy-related neurotoxicity and support appetite and weight maintenance. Physical activity, especially when it includes strength training, improves VO₂max, preserves fat-free mass, and may reduce stress and anxiety. We identified one randomized controlled trial in which a single exercise session before the first dose of doxorubicin resulted in a smaller reduction in cardiac function. Continuous psychological support should be available. A combined behavioural and pharmacological approach appears to be the most effective strategy for smoking cessation. Conclusions: No official guidelines exist for prehabilitation before chemotherapy, and the availability of studies on this topic is very limited. The pre-treatment period represents a critical window for interventions. Further research is needed to evaluate the effectiveness and applicability of particularly single-component interventions. Full article

(This article belongs to the Special Issue Rehabilitation Opportunities in Cancer Survivorship)

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17 pages, 633 KiB

Open AccessArticle

Impact of Preoperative CT-Diagnosed Sarcopenic Obesity on Outcomes After Radical Cystectomy for Bladder Cancer

by Alberto Artiles Medina, Mariam Bajawi Carretero, Enrique López Pérez, Sara Garach Fernández, David López Curtis, Leyre Elías Pascual, José Daniel Subiela, Javier Soto Pérez-Olivares, Catalina Nieto Góngora, Fernando González Tello, Irene de la Parra Sánchez, César Mínguez Ojeda, Victoria Gómez Dos Santos and Francisco Javier Burgos Revilla

Cancers 2025, 17(16), 2669; https://doi.org/10.3390/cancers17162669 - 15 Aug 2025

Abstract

Objective: To evaluate the impact of body composition parameters, including specifically sarcopenic obesity (SO), on postoperative and oncological outcomes in patients undergoing radical cystectomy (RC) for bladder cancer, thereby addressing a paucity of data in this setting. Methods: A retrospective observational study was [...] Read more.

Objective: To evaluate the impact of body composition parameters, including specifically sarcopenic obesity (SO), on postoperative and oncological outcomes in patients undergoing radical cystectomy (RC) for bladder cancer, thereby addressing a paucity of data in this setting. Methods: A retrospective observational study was conducted in patients who underwent RC. Preoperative CT scans were analyzed using semi-automatic segmentation software to assess body composition parameters, with measurements of adipose and muscle tissue obtained at the level of the L3 vertebra. Results: A total of 249 patients were included, of whom 127 (52.5%) met the criteria for sarcopenia, 53 (21.3%) for obesity, and 14 (5.6%) for SO. Multivariate analysis identified previous abdominal surgery (OR 2.56, 95% CI 1.24–5.23, p = 0.011), total serum protein level (OR 0.57, 95% CI 0.36–0.88, p = 0.013), and SO (OR 7.01, 95% CI 1.06–37.05, p = 0.045) as independent predictors of 90-day postoperative complications. Patients with SO experienced significantly higher rates of abdominal wall complications (p = 0.03). However, in multivariate analyses, SO was not associated with overall survival (despite a p value of 0.04 at univariate analysis), cancer-specific survival, or progression-free survival. Conclusions: Preoperative CT-based assessment of body composition is a valuable tool in the surgical evaluation of patients undergoing RC. SO appears to be an independent predictor of short-term postoperative complications and should be considered when planning prehabilitation strategies. Full article

(This article belongs to the Special Issue Clinical Outcomes in Urologic Cancers)

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22 pages, 6269 KiB

Open AccessArticle

Global Hypomethylation as Minimal Residual Disease (MRD) Biomarker in Esophageal and Esophagogastric Junction Adenocarcinoma

by Elisa Boldrin, Maria Assunta Piano, Alice Volpato, Rita Alfieri, Monica Franco, Tiziana Morbin, Annalisa Masier, Stefano Realdon, Genny Mattara, Giovanna Magni, Antonio Rosato, Pierluigi Pilati, Alberto Fantin and Matteo Curtarello

Cancers 2025, 17(16), 2668; https://doi.org/10.3390/cancers17162668 - 15 Aug 2025

Abstract

Background/Objectives: Esophageal and esophagogastric junction adenocarcinoma (EADC-EGJA), which mainly develops from Barrett’s esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), has a poor prognosis and several unmet clinical needs, among which is the detection of minimal residual disease (MRD) after endoscopic/surgical [...] Read more.

Background/Objectives: Esophageal and esophagogastric junction adenocarcinoma (EADC-EGJA), which mainly develops from Barrett’s esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), has a poor prognosis and several unmet clinical needs, among which is the detection of minimal residual disease (MRD) after endoscopic/surgical resection. Long interspersed nuclear element-1 (LINE-1), a surrogate marker of global methylation, is considered an emerging biomarker for MRD monitoring. The aim of this study was to determine, by LINE-1 methylation analysis, at which carcinogenesis step global methylation is affected and whether this biomarker could be followed in longitudinal to monitor the disease behavior post-surgery. Methods: Cell-free DNA of 90 patients with non-dysplastic Barrett’s esophagus (NDBE), HGD/early EADC-EGJA, or locally advanced/advanced EADC-EGJA were analyzed for LINE-1 methylation, by Methylation-Sensitive Restriction Enzyme droplet digital PCR (MSRE-ddPCR). Twenty-six patients were longitudinally studied by repetitive blood sampling. Results: Global hypomethylation increased during carcinogenesis, with significant difference between locally advanced/advanced EADC-EGJA and NDBE patients (p = 0.028). Longitudinal cases confirmed the rareness of hypomethylation in NDBE cases. The majority of HGD/early EADC-EGJA and locally advanced/advanced EADC-EGJA patients showed methylation changes after resection according to clinical status. Conclusions: This study suggests that global hypomethylation occurs just prior to cancer invasiveness and that it is a promising biomarker to monitor MRD. Full article

(This article belongs to the Special Issue Circulating Tumour DNA and Liquid Biopsy in Oncology)

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20 pages, 598 KiB

Open AccessReview

Oral Microbiome as a Biomarker and Therapeutic Target in Head and Neck Cancer: Current Insights and Future Directions

by Saad Ahmad, Dasantha Jayamanne, Sarah Bergamin, Anna Lawless, Alexander Guminski, Adrian Lee, Alexander Yuile, Helen Wheeler, Thomas Eade, Michael Back, Mark Molloy and Byeongsang Oh

Cancers 2025, 17(16), 2667; https://doi.org/10.3390/cancers17162667 - 15 Aug 2025

Abstract

Background/Objectives: The oral microbiome has been implicated in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). This review examines the association between specific oral bacterial taxa and HNSCC. Methods: A systematic review was conducted following the Preferred Reporting Items [...] Read more.

Background/Objectives: The oral microbiome has been implicated in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). This review examines the association between specific oral bacterial taxa and HNSCC. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to examine the relationship between the oral microbiome and HNSCC. A comprehensive literature search was conducted in databases including EMBASE, Cochrane Library, Web of Science, Medline, and PubMed. Results: Following the screening of 284 articles, 21 studies met the inclusion criteria, comprising 1023 HNSCC patients (male: n = 806, 79%; female: n = 217, 21%) and 837 healthy controls (male: n = 622, 74%; female: n = 215, 25.7%). Although findings on alpha diversity were inconsistent, a significant difference in beta diversity was consistently reported between HNSCC patients and healthy controls. HNSCC patients exhibited higher relative abundances of Firmicutes and Synergistetes at the phylum level; Fusobacterium, Prevotella, Porphyromonas, Parvimonas, and Peptostreptococcus at the genus level; and Fusobacterium nucleatum, Prevotella intermedia, Lactobacillus spp., and Porphyromonas gingivalis at the species level. In contrast, healthy controls showed higher abundances of Proteobacteria and Actinobacteria at the phylum level; Streptococcus, Actinomyces, Corynebacterium, Rothia, and Veillonella at the genus level; and Haemophilus influenzae, Rothia mucilaginosa, and Streptococcus mitis at the species level in most studies. Conclusions: The findings indicate distinct alterations in oral microbiome diversity and composition among HNSCC patients, highlighting the role of microbial dysbiosis in cancer progression. Standardized protocols for oral sample collection and microbiota analysis are essential to facilitate more robust, comparable, and clinically meaningful research outcomes. Full article

(This article belongs to the Special Issue Gut Microbiome, Diet and Cancer Risk)

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21 pages, 4517 KiB

Open AccessArticle

Cancer Chemopreventive Properties of Glutelin Hydrolysate from Riceberry Bran Residues Against the Early Stage of Liver and Colon Carcinogenesis Induced by Chemicals in Rats

by Aroonrat Pharapirom, Sirinya Taya, Arpamas Vachiraarunwong, Warunyoo Phannasorn, Chonikarn Singai, Rawiwan Wongpoomchai and Jetsada Ruangsuriya

Cancers 2025, 17(16), 2666; https://doi.org/10.3390/cancers17162666 - 15 Aug 2025

Abstract

Background: Rice bran proteins and their hydrolysates exhibit anticancer activity. Our previous study demonstrated that Riceberry glutelin and its hydrolysates possessed potent in vitro antioxidant and antimutagenic properties. However, their cancer chemopreventive effects in animals remain unclear. Methods: This study investigated [...] Read more.

Background: Rice bran proteins and their hydrolysates exhibit anticancer activity. Our previous study demonstrated that Riceberry glutelin and its hydrolysates possessed potent in vitro antioxidant and antimutagenic properties. However, their cancer chemopreventive effects in animals remain unclear. Methods: This study investigated chemopreventive mechanisms in diethylnitrosamine (DEN)- and 1,2-dimethylhydrazine (DMH)-induced preneoplastic lesions, including glutathione S-transferase placental form (GST-P)-positive foci in the liver and aberrant crypt foci (ACF) in the colon of rats. Rats received GTL, GTLH, and total protein hydrolysate (TPH) at 500 mg/kg body weight, five days per week for ten weeks. Results: GTLH significantly reduced GST-P-positive foci in the liver and ACF in the colon, while GTL decreased GST-P-positive foci only in the liver. However, TPH did not affect preneoplastic lesions in both the liver and the colon. GTLH suppressed cell proliferation by reducing proliferating cell nuclear antigen (PCNA)-positive cells and promoted apoptosis, as indicated by an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in both organs. GTL also decreased PCNA-positive cells in the liver and colon. Moreover, GTLH significantly upregulated BAX and CASP3 in the liver, while only BAX in the colon was observed. Conclusions: This study highlighted the cancer chemopreventive potential of Riceberry GTLH with its underlying mechanism to reduce the number of preneoplastic lesions in the liver and colon through cell proliferation inhibition and apoptosis induction. These findings suggested that this protein hydrolysate might be used as a functional food ingredient or dietary supplement for cancer prevention. Full article

(This article belongs to the Special Issue Chemoprevention Advances in Cancer (2nd Edition))

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37 pages, 9132 KiB

Open AccessPerspective

The Evidence That Brain Cancers Could Be Effectively Treated with In-Home Radiofrequency Waves

by Gary W. Arendash

Cancers 2025, 17(16), 2665; https://doi.org/10.3390/cancers17162665 - 15 Aug 2025

Abstract

There is currently no effective therapeutic capable of arresting or inducing regression of primary or metastatic brain cancers. This article presents both pre-clinical and clinical studies supportive that a new bioengineered technology could induce regression and/or elimination of primary and metastatic brain cancers [...] Read more.

There is currently no effective therapeutic capable of arresting or inducing regression of primary or metastatic brain cancers. This article presents both pre-clinical and clinical studies supportive that a new bioengineered technology could induce regression and/or elimination of primary and metastatic brain cancers through three disease-modifying mechanisms. Transcranial Radiofrequency Wave Treatment (TRFT) is non-thermal, non-invasive and self-administered in-home to safely provide radiofrequency waves to the entire human brain. Since TRFT has already been shown to stop and reverse the cognitive decline of Alzheimer’s Disease in small studies, evidence is provided that three key mechanisms of TRFT action, alone or in synergy, could effectively treat brain cancers: (1) enhancement of brain meningeal lymph flow to increase immune trafficking between the brain cancer and cervical lymph nodes, resulting in a robust immune attack on the brain cancer; (2) rebalancing of the immune system’s cytokines within the brain or brain cancer environment to decrease inflammation therein and thus make for an inhospitable environment for brain cancer growth; (3) direct anti-proliferation/antigrowth affects within the brain tumor microenvironment. Importantly, these mechanisms of TRFT action could be effective against both visualized brain tumors and those that are yet too small to be identified through brain imaging. The existing animal and human clinical evidence presented in this perspective article justifies TRFT to be clinically tested immediately against both primary and metastatic brain cancers as monotherapy or possibly in combination with immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Emerging Research on Primary Brain Tumors)

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43 pages, 356 KiB

Open AccessArticle

A Step Toward a Global Consensus on Gastric Cancer Resectability Integrating Artificial Intelligence-Based Consensus Modelling

by Katarzyna Gęca, Franco Roviello, Magdalena Skórzewska, Radosław Mlak, Wojciech P. Polkowski and ICRGC Collaborators

Cancers 2025, 17(16), 2664; https://doi.org/10.3390/cancers17162664 - 15 Aug 2025

Abstract

Background: Surgical resection remains central to the curative treatment of locally advanced gastric cancer (GC), yet global variability persists in defining resectability, particularly in complex scenarios such as multivisceral invasion, positive peritoneal cytology (CY1), or oligometastatic disease. The Intercontinental Criteria of Resectability for [...] Read more.

Background: Surgical resection remains central to the curative treatment of locally advanced gastric cancer (GC), yet global variability persists in defining resectability, particularly in complex scenarios such as multivisceral invasion, positive peritoneal cytology (CY1), or oligometastatic disease. The Intercontinental Criteria of Resectability for Gastric Cancer (ICRGC) project was developed to address this gap by combining expert surgical input with artificial intelligence (AI)-based reasoning. Methods: A two-stage prospective survey was conducted during the 2024 European Gastric Cancer Association (EGCA) meeting. Fifty-eight surgical oncologists completed a 36-item questionnaire on resectability, strategy, and quality metrics. Subsequently, they reviewed AI-generated responses based on current clinical guidelines and completed a second round. Concordance between human and AI responses was classified as full, partial, or discordant, and changes in surgeon opinions were statistically analyzed. Results: Substantial agreement was observed in evidence-based domains. Seventy-nine percent of surgeons agreed with AI on distinguishing technical from oncological resectability. In cT4b cases, 61% supported restricting multivisceral resection to high-volume centers. Similar alignment was found in CY1 (54%) and N3 nodal disease (63%). Partial concordance appeared in areas requiring individualized judgment, such as peritonectomy or bulky-N disease. After AI exposure, surgeon responses shifted toward guideline-consistent decisions, including increased support for cytoreductive surgery only when CC0/1 was achievable and stricter classification of R2 resections as unresectable. Following AI exposure, 27.1% of surgeons changed at least one answer in alignment with AI recommendations, with statistically significant shifts observed in items related to surgical margin definition (p = 0.015), anatomical resection criteria (p < 0.05), and hospital stay benchmarks (p = 0.031). Conclusions: The ICRGC study demonstrates that AI-driven consensus modeling can replicate expert reasoning in complex surgical oncology and serve as a catalyst for harmonizing global practice. These findings suggest that AI-supported consensus modeling may complement expert surgical reasoning and promote greater consistency in decision-making, particularly in controversial or ambiguous cases. Full article

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

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