Cancers doi: 10.3390/cancers18142261

Authors: Sammy Y. Gao Jonathan M. Hughes Shaun A. Nguyen Bryce S. McCaulay Jason G. Newman

Background/Objectives: Machine learning (ML) models have increasingly been applied to prognostic prediction in oral cavity squamous cell carcinoma (OCSCC), though their performance and methodological quality remain variably reported. This systematic review evaluated contemporary ML-based prognostic models for clinically relevant OCSCC outcomes, with emphasis on independently validated studies. Methods: A systematic review was conducted according to PRISMA guidelines using PubMed, Scopus, Cochrane Library, and CINAHL databases through 1 December 2025. Studies evaluating ML or artificial intelligence prognostic models in adult OCSCC patients were included. Outcomes included overall survival, recurrence, disease-free survival, recurrence-free survival, disease-specific survival, cancer-specific survival, progression, and nodal metastasis. Data extraction and risk-of-bias assessment using PROBAST + AI were performed independently by reviewers. Results: Forty studies comprising 105,619 patients met inclusion criteria. ML architectures included random forests, support vector machines, gradient boosting methods, neural networks, and deep learning frameworks. Most models incorporated clinical and pathologic variables, while many integrated radiologic, immunologic, or genomic features. For overall survival prediction, independently validated models generally demonstrated AUCs between 0.80 and 0.90. Recurrence prediction models similarly showed favorable discrimination, with most externally validated studies reporting acceptable predictive performance. Additional prognostic endpoints including disease-free survival, progression, and nodal metastasis demonstrated AUCs ranging from 0.70 to 0.90. Common methodological limitations included retrospective design, small sample size, inadequate external validation, and risk of overfitting. Conclusions: ML-based prognostic models in OCSCC demonstrate generally favorable predictive performance across survival and recurrence outcomes. However, substantial heterogeneity in methodology and limited external validation continue to restrict clinical implementation. Future work should prioritize prospective multicenter validation, standardized reporting, and reproducible modeling frameworks.

Cancers doi: 10.3390/cancers18142260

Authors: Yujin Cha Sue Youn Kim Chankyung Kim Ja Seong Bae Dong-Jun Lim So-Lyung Jung Chan Kwon Jung

Background/Objectives: Preoperative risk stratification of indeterminate thyroid nodules, particularly category IV nodules diagnosed as follicular neoplasm, remains challenging. Molecular testing may support clinical decision-making, but its cost and limited availability restrict routine use. This study evaluated whether the digitally quantified Ki-67 labeling index, alone and combined with the Korean Thyroid Imaging Reporting and Data System (K-TIRADS), could predict malignancy in thyroid core needle biopsy (CNB) specimens. Methods: We retrospectively analyzed 130 thyroid nodules sampled by ultrasound-guided CNB. The Ki-67 labeling index was digitally quantified in immunohistochemically stained CNB sections, and ultrasound features were classified according to K-TIRADS. Receiver operating characteristic curve analysis was performed in the overall cohort. Logistic regression analyses were restricted to 57 category IV nodules. Results: In the overall cohort, the Ki-67 labeling index showed excellent diagnostic performance for predicting malignancy, with an area under the curve of 0.924. The optimal cutoff was 1.73%, with 88.7% sensitivity and 83.1% specificity. In category IV nodules, K-TIRADS category and Ki-67 labeling index were independently associated with malignancy. The odds ratios were 6.02 (95% CI, 1.53–23.74) for each one-category increase in K-TIRADS and 4.44 (95% CI, 1.69–11.70) for each percentage-point increase in Ki-67. In the Ki-67-only model, a Ki-67 index of 5% corresponded to a predicted malignancy probability of 98.1%. Conclusions: Digital Ki-67 quantification, integrated with K-TIRADS, may serve as a practical adjunct for malignancy risk stratification in thyroid CNB specimens, particularly for category IV nodules. Further external validation is warranted.

Cancers doi: 10.3390/cancers18142259

Authors: Feifan Lu Ting Zhang Zhixuan Li Renqi Yao Hao Hu Rui Guan Mingjuan Xu

Background: Tertiary lymphoid structures (TLSs) are spatial immune niches in solid tumors, but their relationship to mature regulatory dendritic-cell (mregDC) states in ovarian cancer remains incompletely resolved. Methods: We integrated public gynecological-tumor single-cell RNA sequencing, representative CD11C/HLA-DRA/LAMP3/CCR7 multiplex immunofluorescence, public Xenium and multi-sample spatial transcriptomics, TCGA-OV immune deconvolution and exploratory prognostic modeling, scTenifoldKnk and CellOracle perturbation analyses, and supplementary computational drug prioritization. Results: A LAMP3+CCR7+ dendritic-cell state showed mature migratory, antigen-presentation, checkpoint, and NF-κB/TNF-associated programs. Spatial analyses linked TLS-score-defined regions to mregDC, antigen-presentation/MHC-II proxy, and interferon-associated signals, with distance-gradient analyses supporting TLS-proximal enrichment. Immune deconvolution associated the TLS/mregDC axis with an immune-infiltrated TCGA-OV contexture, whereas adjusted analyses emphasized dependence on broader immune-program richness. Perturbation analyses nominated candidate regulatory axes for experimental testing, and the supplementary drug-prioritization layer was retained only as target-class hypothesis support. Conclusions: These data support a hypothesis-generating model of a TLS-associated LAMP3+CCR7+ mregDC antigen-presentation program in ovarian cancer, while requiring raw-channel tissue validation, functional perturbation, and independent clinical testing.

Cancers doi: 10.3390/cancers18142258

Authors: Arpita Poddar Farah Ahmady-Nield Revati Sharma Seemadri Subhadarshini Mohit Kumar Jolly Suresh Ramakrishna Ali Raza Ravi Shukla George Kannourakis Aparna Jayachandran Prashanth Prithviraj

Background/Objectives: Clear cell renal cell carcinoma (ccRCC), the predominant malignant subtype of kidney cancer, is the leading cause of death among renal cell carcinoma patients. Although a subset of ccRCC patients benefit from select immune checkpoint inhibitors (ICIs), prognosis remains poor. While PD-1 and PD-L1 have been extensively studied, the prevalence and distribution of other immune checkpoints (ICs) and their relationship with epithelial-to-mesenchymal transition (EMT) remain poorly characterised. Here, we investigated the interplay between twenty ICs and EMT markers and assessed their combined prognostic relevance in ccRCC patients. Methods: Transcriptomic profiling and integrated bioinformatic analyses were performed, including differential expression, correlation analyses, survival analyses, forest plot analyses, ROC curve evaluation, and OncoPrint visualisation, complemented by analysis of single-cell RNA sequencing data, immunohistochemistry, and multiplex secretory IC (LegendPlex) assays. Results: Transcriptomic profiling of over 500 ccRCC tumours versus normal kidney tissue revealed dysregulation of ICs, particularly LAG3 and NT5E. Notably, expression of ICs, including LAG3 and NT5E, was associated with poor overall survival in 415 ccRCC patients. ICs that synergised with the EMT phenotype provided improved prognostic discrimination compared to individual ICs. Correlation analyses, single-cell RNA sequencing, and immunohistochemistry demonstrated an association between EMT-associated tumours and expression of LAG3 and NT5E. ROC analysis indicated modest prognostic performance of LAG3 and NT5E. Conclusions: Collectively, this study identifies an EMT–IC axis in ccRCC and demonstrates its relevance to tumour biology and patient outcomes, highlighting LAG3 and NT5E as potential prognostic markers and therapeutic targets that warrant further investigation.

Cancers doi: 10.3390/cancers18142257

Authors: Izabella Ryguła Violetta Rosiek Beata Kos-Kudła

Inflammation is a hallmark of cancer and contributes to tumour initiation, progression, and therapeutic resistance. Among inflammatory mediators, interleukin-1β (IL-1β) and interleukin-6 (IL-6) are central cytokines linking innate immune responses with oncogenic signalling networks. This narrative review summarizes current experimental and clinical evidence regarding the role of IL-1β and IL-6 in carcinogenesis, with particular emphasis on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). We discuss the molecular pathways associated with these cytokines, their interactions within the tumour microenvironment, and their contribution to tumour proliferation, angiogenesis, immune modulation, metastatic dissemination, and resistance to anticancer therapies. Particular attention is given to GEP-NENs, in which chronic inflammation and cytokine dysregulation may influence tumour behaviour, systemic inflammatory activity, and clinical outcomes. Accumulating evidence suggests that IL-6 may represent a promising exploratory biomarker associated with tumour burden, histological grade, disease progression, and systemic inflammation, whereas IL-1β appears to be more closely linked to local inflammatory signalling, microenvironmental remodelling, and potential susceptibility mechanisms. However, current evidence in GEP-NENs remains limited by small study cohorts, heterogeneous patient populations, variable analytical methodologies, and the lack of prospective validation. Further translational and clinical investigations are warranted to determine whether cytokine-based biomarkers and therapeutic modulation of inflammatory pathways may expand current diagnostic, prognostic, and therapeutic approaches in GEP-NENs.

Cancers doi: 10.3390/cancers18142256

Authors: Stanley P. Leong

Background/Objectives: Cancer metastasis is responsible for most cancer-related deaths, yet the precise anatomical and physiological routes by which cancer cells disseminate remain incompletely defined. This review aims to present an integrated model of lymphatic and hematogenous dissemination that provides a unified framework for understanding metastatic progression. Methods: The published literature on lymphatic biology, microvascular physiology, tumor immunology, and cancer metastasis was critically reviewed and integrated to develop a comprehensive anatomical and physiological model of cancer dissemination. Results: The proposed model identifies lymphatic dissemination as the predominant metastatic route in many solid tumors. Cancer cells enter structurally permissive initial lymphatic capillaries and are transported to the sentinel lymph node (SLN), where interactions with the tumor microenvironment may eliminate disseminated cells, maintain dormancy, or facilitate immune escape and further dissemination. Cancer cells that survive within or escape beyond the SLN subsequently travel through collecting lymphatics and the thoracic or right lymphatic duct to enter the systemic venous circulation. Following cardiopulmonary transit, surviving cells may be redistributed through the systemic arterial circulation to distant organs. A secondary pathway involves direct hematogenous intravasation through post-capillary venules, where reduced shear stress, increased endothelial permeability, and permissive endothelial biology facilitate entry into the venous circulation. Thus, lymphatic and direct venular pathways ultimately converge in the venous circulation before systemic arterial dissemination. Conclusions: This unified model integrates lymphatic and hematogenous dissemination into a coherent anatomical and physiological framework. By emphasizing the SLN as an early immunologic checkpoint and the arterial circulation as the final distribution network for disseminated cancer cells, this review provides a conceptual basis for understanding metastatic patterns and identifying biomarkers and therapeutic vulnerabilities.

Cancers doi: 10.3390/cancers18142255

Authors: Aleksandra Czyzak Gráinne O’Brien Milagrosa Lopez-Riego Lourdes Cruz-Garcia Christophe Badie

Acute myeloid leukaemia (AML) remains a highly lethal malignancy with poor prognosis in adults above 60 years old and often occurs after radiation exposure. Emerging evidence suggests that circadian rhythm disruption, prevalent in shift workers, may contribute to cancer development. Clock genes (CGs) regulate fundamental cellular processes, including the DNA damage response (DDR), cell cycle progression, and haematopoiesis. In the absence of substantial experimental data, this review examines the potential pathways linking circadian clock dysregulation to radiation-induced AML (rAML) and evaluates how temporal disruption may modulate leukaemogenesis and radiation-induced effects. The evidence was synthesised on core clock components (BMAL1, CLOCK, PER, CRY, REV-ERB, ROR), their dysregulation in AML, and their roles in radiation response. Epigenetic and post-transcriptional regulatory mechanisms, including m6A RNA modification and sirtuin-mediated chromatin remodelling, were evaluated for their contribution to circadian-regulated DNA repair capacity. Multiple CGs demonstrated aberrant expression in AML, with BMAL1 showing tissue-specific dysregulation, and PER1/2/3 was consistently downregulated in peripheral blood. Clock proteins directly regulate DNA damage checkpoints through interactions with ATM/CHK2 and p53 pathways. Circadian disruption enhances inflammatory signalling, promotes accumulation of myeloid-derived suppressor cells, and accelerates immune senescence. Moreover, radiation exposure modulates CG expression, which may alter repair fidelity and increase leukaemogenic risk. Understanding these connections in the context of disrupted circadian rhythms could help identify at-risk populations and improve shift workplace health policies.

Cancers doi: 10.3390/cancers18142254

Authors: Cosmin Vasile Obleagă Mirela-Marinela Florescu Lucian Mihai Florescu Rukie Ana Maria Ahmet Sergiu Marian Cazacu Alina Maria Mehedințeanu Michael Schenker Liliana Streba

Context: Locally advanced fungating breast cancer complicated by hemorrhage or infection represents a complex clinical condition that often requires a rapid and coordinated multidisciplinary approach. Although international guidelines, such as those developed by ESMO and NCCN, provide well-defined principles for the management of locally advanced breast cancer, they offer limited recommendations regarding the management of complicated fungating forms. Methods: We conducted a structured narrative review of the literature using the PubMed, Scopus, and Web of Science databases, including studies published between December 2019 and March 2026. Studies addressing locally advanced breast cancer and fungating forms complicated by hemorrhage or infection were included. Results: Available data are heterogeneous and derive primarily from case reports, small case series and retrospective studies. Systemic therapy remains the cornerstone of oncologic control; however, the presence of acute complications often necessitates prioritization of local interventions depending on the patient’s clinical stability. Hemorrhage may be managed through arterial embolization, hemostatic dressings or radiotherapy, whereas infection requires local wound care and targeted antibiotic therapy. These interventions aim to control acute symptoms and stabilize patients, thereby facilitating the subsequent integration of oncologic treatment. Emergency surgical intervention is reserved for selected cases, particularly when conservative measures fail to control bleeding or in the presence of persistent sepsis. Conclusions: The management of fungating breast cancer should be individualized and guided by the clinical presentation within a multidisciplinary team setting rather than by a rigid therapeutic sequence. This paper proposes a pragmatic, symptom-oriented clinical framework integrating all currently available therapeutic modalities (systemic therapy, radiotherapy, interventional radiology, surgery, and supportive care) with the aim of supporting decision-making in complex clinical scenarios.

Cancers doi: 10.3390/cancers18142253

Authors: Yan Mao Qiuling Lin Yingchun Liu Xiaoxia Wei Zihan Zhou Qiuping Wen Yanji Jiang Peiqin Chen Xiumei Liang Yuying Wei Qingyi Wei Wenjing Zhou Hongping Yu

Purpose: Nucleotide metabolism plays a critical role in cancer development, but the prognostic significance of genetic variants in nucleotide metabolism genes for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients remains unclear. Methods: We performed Cox proportional hazards regression analyses to evaluate the association between genetic variants in 94 nucleotide metabolism-related genes and overall survival (OS) in 866 HBV-HCC patients. To assess the potential biological relevance of the identified variants, the Bayesian false discovery probability and false-positive report probability were applied for multiple testing correction. Results: Two independent SNPs, DCTD rs17074255 G>A (HR = 1.22, 95% CI: 1.06–1.40, p = 0.005) and ENTPD2 rs3763662 G>A (HR = 1.18, 95% CI: 1.03–1.34, p = 0.015), were significantly associated with OS. A significant dose-dependent association between the number of risk genotypes and poorer OS was observed (Ptrend < 0.001). Luciferase reporter assays demonstrated allele-specific regulatory effects of rs3763662 on ENTPD2 expression (p < 0.001). DCTD and ENTPD2 mRNA expression levels were significantly elevated in HCC tumors in the UALCAN database and in our 103 paired samples. Higher expression levels of both genes were associated with poorer survival in the TCGA cohort (p = 0.003 and p < 0.001). Conclusions: Our findings suggest that ENTPD2 rs3763662 (supported by direct functional evidence) and DCTD rs17074255 (supported by eQTL and expression associations) may serve as potential prognostic indicators for HBV-HCC through the regulation of mRNA expression. These findings provide new insights into the role of nucleotide metabolism-related genetic variation in HBV-HCC progression and may facilitate prognostic assessment, pending replication in independent cohorts.

Cancers doi: 10.3390/cancers18142252

Authors: Shigeaki Nawa Mitsugu Fujita Masasuke Ohno Shunichiro Kuramitsu Shota Nohira Ryuta Saito

Background: The clinical outcomes of lung cancer brain metastases (LCBMs) are highly variable. Traditional pathology relies on bulk cell densities. These static measures fail to capture the spatial architecture of the tumor immune microenvironment (TIME). B7-H3 (CD276) represents a key immune checkpoint in LCBMs. We investigated whether the spatial orchestration of B7-H3-expressing cell populations is associated with patient prognosis. Methods: Multiplex immunohistochemistry (mIHC) for B7-H3 and Iba1 (a macrophage marker) was performed on surgically resected tissues from 22 patients, with single-cell segmentation and classification in QuPath. We then applied spatial point pattern and spatial autocorrelation analyses to evaluate the relative positioning of single cells, computing spatial interaction metrics, including cross-Moran’s I and the cross-K function, within a 35 μm radius. These metrics were correlated with postoperative overall survival (OS), and prognostic thresholds were determined via time-dependent ROC curve analysis. Results: Standard cell densities generally did not correlate with OS, although B7-H3+ tumor-associated macrophage (TAM) density showed a moderate positive correlation (rs=0.434, p = 0.044), of a magnitude comparable to the clinical GPA score (rs=0.464, p = 0.029). Conversely, specific spatial metrics emerged as candidate prognostic factors. High spatial mixing and clustering of B7-H3+ and B7-H3− TAMs, as shown by high cross-Moran’s I (p = 0.011) and the cross-K function (p = 0.033), associated with significantly shorter OS. This pattern suggests a coordinated local immunosuppressive network. Conversely, high spatial integration between B7-H3+ and B7-H3− tumor cells was associated with prolonged OS (p = 0.016), whereas spatial segregation of B7-H3+ tumor cells was associated with poor outcomes. Conclusions: Decoding the spatial architecture of B7-H3-expressing cell subpopulations provides superior prognostic stratification compared with standard density-based metrics. These localized spatial niches represent potential biomarkers and therapeutic targets for personalized LCBM management.

Cancers doi: 10.3390/cancers18142251

Authors: Zuzanna Korbecka Beata Jabłońska Robert Król

Background/Objectives: Renal cell carcinoma (RCC) with inferior vena cava tumor thrombus (IVCTT) is a rare and surgically complex condition traditionally managed with open nephrectomy and thrombectomy. Robot-assisted approaches are increasingly used in selected patients, but their comparative perioperative and oncological value remains uncertain. This systematic review aimed to summarize current evidence comparing robot-assisted and open nephrectomy with IVC thrombectomy in RCC. Methods: A systematic search of PubMed, Scopus, Web of Science, and Cochrane Library was performed according to PRISMA guidelines. Original clinical studies reporting perioperative or oncological outcomes of nephrectomy with IVC thrombectomy were included. Owing to substantial heterogeneity, a qualitative synthesis was performed. Results: Thirteen studies were included. Robot-assisted surgery was associated with lower estimated blood loss, reduced transfusion rates, and shorter hospital stay, although operative time was generally longer. Complication rates and oncological outcomes were broadly comparable between approaches. Robotic cohorts were typically highly selected and included mainly patients with lower-level thrombi, limited tumor burden, and procedures performed in high-volume centers. Conclusions: Robot-assisted nephrectomy with IVC thrombectomy appears feasible and safe in carefully selected patients and may improve perioperative outcomes without compromising oncological efficacy. However, open surgery remains essential for complex high-level thrombi. Tumor thrombus level, tumor burden, and institutional expertise should guide surgical approach selection.

Cancers doi: 10.3390/cancers18142250

Authors: Yinnan Zhang Boon Seng Kho Xixi Wang Huanhuan Lu Miao Zhu Rentao Zhu Yinyin Wang

Background: Hypertension is a common comorbidity and risk factor for clear cell renal cell carcinoma (ccRCC), yet the molecular mechanisms linking these two diseases remain unclear. This study aimed to investigate hypertension-related molecular signatures in ccRCC using integrated multi-transcriptomic analyses. Method: Hypertension-related differentially expressed genes (DEHRGs) in ccRCC were identified by integrating transcriptomic data from the TCGA-KIRC cohort with the GeneCards database. Functional enrichment, WGCNA, machine learning, GSVA, survival analysis, and Mendelian randomization were performed to identify and characterize hub genes. Spatial and single-cell transcriptomic analyses were used to investigate tumor heterogeneity and predict candidate therapeutic compounds, which were subsequently evaluated in vitro. Results: Four hypertension-related hub genes—SCNN1G, CASR, KCNJ1, and WNK4—were identified and were mainly involved in ion transport, electrolyte homeostasis, and blood pressure regulation. Diagnostic models based on these genes showed good discriminatory performance between tumor and normal tissues, and the nomogram showed good calibration and potential clinical benefit. Higher hypertension-related transcriptional activity was associated with significantly poorer overall survival, while MR analysis suggested a genetic association with ccRCC risk. Spatial transcriptomics revealed pronounced spatial heterogeneity of SCNN1G, CASR, KCNJ1, and WNK4, with these hub genes predominantly enriched in stromal and immune regions. Single-cell-based drug screening identified candidate compounds predicted to have antitumor activity, among which epicatechin gallate (ECG) and pseudoginsenoside-F11 showed favorable tumor selectivity. Conclusions: This study systematically characterized hypertension-related molecular signatures in ccRCC and identified SCNN1G, CASR, KCNJ1, and WNK4 as key hub genes. These genes may contribute to the molecular association between hypertension and ccRCC. They also represent promising candidate biomarkers and therapeutic targets. Integrated spatial and single-cell analyses further identified pseudoginsenoside-F11 and ECG as potential therapeutic compounds and supporting a potential molecular association between hypertension and ccRCC.

Cancers doi: 10.3390/cancers18142249

Authors: Kouta Hirotaki Hajime Oyoshi Kana Motegi Atsushi Motegi Masashi Ito Sadamoto Zenda

Accurate positioning remains a central challenge in head and neck radiotherapy because highly conformal dose distributions are delivered near multiple critical organs, and clinically relevant discrepancies may not be resolved by rigid image-guided correction alone. This narrative review synthesizes evidence on positioning management in head and neck radiotherapy, with particular emphasis on the transition from couch correction to action-oriented clinical decision-making. Peer-reviewed studies, guidelines, and key reviews published between January 2005 and April 2026 were identified using PubMed/MEDLINE and reference screening. Positioning uncertainty is often region-specific and dynamic, reflecting lower-neck and shoulder mismatch, mandibular variation, mask-fit deterioration, functional motion, and progressive anatomical changes during treatment. Thermoplastic immobilization, customized headrests, bite blocks, cone-beam computed tomography, six-degree-of-freedom correction, and adaptive workflows have improved reproducibility and verification; however, these approaches do not eliminate mismatches caused by non-rigid posture, immobilization failure, or evolving anatomy. In such situations, the key clinical task is to distinguish rigid setup deviations suitable for online correction from discrepancies requiring repositioning, re-immobilization, repeat simulation, or adaptive replanning. Emerging technologies, including artificial intelligence, dose-of-the-day estimation, corrected CBCT, synthetic CT, rapid replanning, and workflow-integrated decision support, may help close the gap between mismatch detection and intervention selection. Positioning management should therefore evolve from a correction-centered model to an action-oriented framework that links observed geometric or anatomical change to the most appropriate clinical response.

Cancers doi: 10.3390/cancers18142248

Authors: Ana Carolina Prado-Ribeiro Luciana Estevam Simonato Manoela Carrera Thaís Bianca Brandão Manoela Domingues Martins Thomas P. Sollecito

Background/Objectives: Head and neck cancer (HNC) is associated with substantial morbidity, functional impairment, and represents a substantial socioeconomic burden worldwide. Although advances in surgery, radiotherapy (RT), and systemic therapies have improved oncologic outcomes, treatment-related toxicities frequently overlap with profound economic consequences for patients and caregivers. Financial toxicity (FT), defined as the objective financial burden and subjective financial distress associated with cancer care, has emerged as a clinically relevant determinant of treatment adherence, quality of life (QoL), and survival. In HNC, FT appears particularly critical during active treatment, when multimodal therapies, nutritional compromise, work interruption, transportation costs, and supportive care needs converge. Methods: This structured narrative review synthesizes current literature regarding FT during active treatment for HNC, focusing on conceptual definitions, measurement approaches, temporal dynamics, clinical and psychosocial consequences, and health system determinants. The review was conducted according to the Scale for the Assessment of Narrative Review Articles (SANRA) framework using searches of PubMed/MEDLINE, Scopus, Embase, and Google Scholar. Results: Available evidence suggests that FT may emerge early during treatment and evolve dynamically throughout the care trajectory. Lower socioeconomic status, treatment intensity, work interruption, and limited social support have been reported in association with increased FT. FT has also been linked to worse health-related QoL, higher symptom burden, treatment interruptions, hospitalization, and reduced survival, although the limited number of studies and methodological heterogeneity preclude definitive conclusions. Emerging evidence suggests that FT may be partially modifiable through interventions such as financial counseling and patient navigation. Conclusions: Future research should prioritize prospective and interventional designs using standardized multidimensional instruments capable of capturing both objective and subjective domains of FT. Integrating routine FT assessment into supportive oncology workflows may help identify vulnerable patients and support more equitable, patient-centered HNC care.

Cancers doi: 10.3390/cancers18142247

Authors: Eudmar Marcolino Jinxia Zheng Christopher Roberts Eric Vancauwenberghe Ahmed Alhajuji Ian G. Mills Abeer M. Shaaban Sebastian Oltean Padma-Sheela Jayaraman Kevin Gaston

Background: The Proline Rich Homeodomain/Haematopoietically Expressed Homeobox (PRH/HHEX) transcription factor down-regulates the proliferation of prostate cells, and it has been suggested that this protein acts as a tumour suppressor in prostate epithelial cells. Results: Here, we show that the HHEX gene encoding PRH, located at chromosome 10q23, is often deleted in prostate cancer cells. Moreover, the gene encoding PRH displays increased CpG methylation in prostate cancer cells, and PRH mRNA levels and protein levels are decreased in high Gleason grade prostate tumours. Using a doxycycline-inducible model, we show that over-expression of PRH in prostate cancer cells reduces cell proliferation and cell migration in vitro and inhibits tumour growth and tumour initiation in a mouse xenograft model. Similarly, PRH over-expression in a syngeneic mouse model reduces tumour growth. Interestingly, the inhibition of Protein Kinase CK2 in this model results in increased PRH protein levels in vitro, decreased cell viability, and reduced tumour growth in vivo. Conclusions: PRH acts as a tumour suppressor protein in prostate cancer cells and the re-establishment of PRH activity in these cells through the inhibition of PRH phosphorylation, or through other means, could be a useful approach to prostate cancer treatment.

Cancers doi: 10.3390/cancers18142246

Authors: Eisuke Booka Takahiro Kuroda Shuhei Yasumoto Keita Misu Yuki Sakai Kenichi Sekimori Shunta Nakamura Ryoma Haneda Wataru Soneda Mayu Sakata Yoshifumi Morita Hirotoshi Kikuchi Yoshihiro Hiramatsu Hiroya Takeuchi

Background/Objectives: Thoracoscopic esophagectomy is an accepted minimally invasive approach for resectable esophageal and esophagogastric junction cancer in Japan. Whether robot-assisted minimally invasive esophagectomy (RAMIE) improves short- and long-term outcomes compared with video-assisted thoracoscopic esophagectomy (VATS) remains clinically relevant. Methods: We retrospectively reviewed patients who underwent VATS or RAMIE between January 2017 and April 2026. Patients who underwent open esophagectomy, non-gastric conduit reconstruction, or staged operation were excluded. Propensity score matching (PSM) was performed using age, sex, body mass index, histology, tumor location, clinical stage, preoperative therapy, extent of lymph node dissection, abdominal approach, and reconstruction route. Long-term outcomes were explored in a PSM cohort limited to patients treated between January 2017 and December 2023. Results: The main cohort included 369 patients (VATS, n = 186; RAMIE, n = 183). Overall complications of Clavien–Dindo (CD) grade ≥ II were comparable between VATS and RAMIE (32.8% vs. 32.8%, p = 0.999), whereas RLNP CD ≥ I (9.7% vs. 3.8%, p = 0.025) and RLNP CD ≥ II (3.8% vs. 0.5%, p = 0.034) were less frequent after RAMIE. PSM yielded 128 matched pairs; RLNP remained less frequent after RAMIE (CD ≥ I, 10.9% vs. 3.1%, p = 0.015; CD ≥ II, 4.7% vs. 0%, p = 0.013), while other short-term outcomes were comparable. In the survival PSM cohort (79 pairs), 3-year overall survival (66.0% vs. 73.4%, p = 0.203) and recurrence-free survival (62.3% vs. 59.3%, p = 0.651) did not differ significantly between VATS and RAMIE. Conclusions: RAMIE showed comparable short-term safety to VATS and was associated with lower RLNP after adjustment for clinicopathological, treatment-related, and surgical factors. Exploratory long-term analysis was limited by cohort size and follow-up duration but suggested that RAMIE did not compromise oncologic outcomes.

Cancers doi: 10.3390/cancers18142245

Authors: Gabriel Tinoco Marium Husain David Liebner James L. Chen Swati Satturwar Hans Iwenofu Valerie Grignol Joal Beane Scott Lenobel David Konieczkowski Carl Quinion Joel Mayerson

In the original publication [...]

Cancers doi: 10.3390/cancers18142244

Authors: Giorgio Cannone Luigi Lione Viola Sambataro Alessandro Bonis Vincenzo Verzeletti Alessandro Rebusso Giovanni Maria Comacchio Eleonora Faccioli Giulia Pasello Laura Bonanno Fiorella Calabrese Samuele Nicotra Marco Schiavon Andrea Dell’Amore

Background: In patients with non-small cell lung cancer (NSCLC) treated with neoadjuvant chemo-immunotherapy, pulmonary resection can be technically demanding because of hilar/mediastinal inflammation and fibrosis, potentially limiting the use of minimally invasive surgery (MIS). We report our single-center experience with MIS anatomical lung resections after neoadjuvant chemo-immunotherapy. Methods: We retrospectively collected consecutive NSCLC patients who underwent neoadjuvant chemo-immunotherapy followed by anatomical lung resection with an intended MIS approach at our institution between May 2018 and October 2025. Primary endpoints were feasibility and safety (conversion rate, intraoperative and postoperative complications, need for reoperation, and 30-day mortality). Results: Fifty-two patients were included. Mean age was 65.9 ± 8.6 years; 27 (51.9%) were male. Median Charlson Comorbidity Index was 3 (IQR 2–4). Most patients had clinical stage III disease (IIIA 40.4%, IIIB 30.8%). Conversion to open surgery occurred in 7 cases (13.5%). One intraoperative complication was recorded (1.9%). Anatomical resections were predominantly lobectomies (including combined/extended lobectomies) (88.4%); sleeve resections accounted for 11.5%, and bilobectomy for 7.7%. Postoperative complications occurred in 13 patients (25.0%); reoperation for complications was required in 1 case (1.9%). No deaths were recorded in the dataset. Pathological response showed pCR in 22 patients (42.3%) and MPR in 10 (19.2%). Conclusion: In our experience, minimally invasive anatomical lung resection after neoadjuvant chemo-immunotherapy for NSCLC is feasible, with an acceptable conversion rate and manageable morbidity, and is associated with a substantial rate of pathological response. Careful patient selection and surgical expertise remain essential.

Cancers doi: 10.3390/cancers18142243

Authors: Takeshi Nagasaka Yoshiyasu Kono Yosuke Kito Takayuki Ando Yuji Negoro Tomoyuki Abe Hidekazu Kuramochi Shogen Boku Tomohiko Mannami Junichiro Nasu Masafumi Inoue Masato Nakamura Yoshihiro Okita Yoshiaki Shindo Takeshi Yamada Tetsuya Maeda Yudai Shinohara Hiroaki Tanioka

Background: Platinum-based doublets are standard first-line therapy for advanced gastric cancer (GC) in the Western Pacific region, but oxaliplatin frequently induces persistent peripheral sensory neuropathy (PSN). Whether residual PSN compromises the feasibility and efficacy of subsequent paclitaxel (PTX)-based therapy remains unclear. Methods: The IVY study was a prospective, multicenter observational trial conducted across 16 Japanese institutions. Patients with advanced GC progressing after fluoropyrimidine–platinum therapy received second-line PTX ± ramucirumab. Baseline PSN was assessed by CTCAE, PNQ, and FACT/GOG-Ntx. The primary endpoint was the incidence of grade ≥ 3 PSN during second-line therapy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), tumor response, and patient-reported outcomes. Results: Among 156 patients (90 PSN-positive, 66 PSN-negative), grade ≥ 3 PSN occurred more frequently in the PSN-positive group (16.7% vs. 4.5%; p = 0.02). Median PFS was 4.0 vs. 3.9 months (p = 0.20), and median OS was 10.3 vs. 8.1 months (p = 0.04). In multivariable analysis, residual PSN was not an independent predictor of OS (HR = 0.68 for PSN-positive vs. PSN-negative, 95% CI [0.46–1.01]; p = 0.06). Patient-reported instruments captured greater and earlier QoL impairment in PSN-positive patients, though trajectories stabilized by 12 weeks. Conclusions: Residual PSN increases the risk of clinically relevant neurotoxicity—particularly in patients with baseline grade ≥ 2—but, in this cohort, did not appear to preclude paclitaxel-based second-line therapy when monitoring and dose modification were available. The apparent survival difference was exploratory and, after adjustment for baseline imbalance, should not be interpreted as a benefit attributable to residual PSN. Residual neuropathy should therefore prompt structured baseline assessment and early-cycle monitoring rather than routine reassurance.

Cancers doi: 10.3390/cancers18142242

Authors: Keisuke Sano Shuhei Suzuki Shuya Kandori Reo Takahashi Bunpei Isoda Ryota Yanagihashi Kazuki Hamada Kozaburo Tanuma Satoshi Nitta Kosuke Kojo Masanobu Shiga Yoshiyuki Nagumo Atsushi Ikeda Takashi Kawahara Akio Hoshi Bryan J. Mathis Ayako Okuyama Hiroyuki Nishiyama

Background/Objectives: Penile malignant tumors are rare neoplasms, and both clinicopathologic features and prognoses remain unclear in Japanese patients. Here, we investigated the prognoses of penile malignant tumors in Japan using the nationwide hospital-based cancer registry (HBCR) database. Methods: The 2015 HBCR database cohort was queried to identify patients with penile malignant tumors. Moreover, we investigated age, pathology, tumor–node–metastases classification, first-course treatment, and overall survival in these patients. Results: A total of 269 patients were analyzed from the 2015 cohort (149 squamous cell carcinoma [SCC] patients and 56 extramammary Paget disease [EMPD] patients). The median ages at diagnosis in both SCC and EMPD patients were 76.0 and 76.5 years. The median observation period was 53 months in the present study. The 5-year overall survival (OS) rates of SCC and EMPD were 56.8% and 78.5%. The 5-year OS rates of clinical stages 0–I, II, III, and IV were (respectively) 68.0%, 70.1%, 38.5%, and 11.9% in SCC patients and (respectively) 83.7%, 83.3%, not evaluated, and 0% in patients with EMPD. Conclusions: We revealed the OS of Japanese patients with penile SCC and EMPD in a large population-based study for the first time. Patients with clinical stage IV penile SCC and EMPD had extremely poor prognoses, highlighting a need for im-proved disease management in these patients.

Cancers doi: 10.3390/cancers18142241

Authors: Maria Goulielmaki Sotirios P. Fortis Anastasia Xagara Panagiota Batsaki Theodoros Loupis Giannis Vatsellas Dimitrios M. Vrachnos Alexandra Voutsina Filippos Koinis Evangelia Chantzara Katerina Oikonomaki Stavroula Samara Georgia Christopoulou Pantelis Constantoulakis Periklis Makrythanasis Anna Koumarianou Ioannis S. Pateras Vasilis Georgoulias Athanasios Kotsakis Constantin N. Baxevanis Angelos D. Gritzapis

Background: Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has improved outcomes in non-small cell lung cancer (NSCLC), although reliable biomarkers for predicting benefit are still limited. Methods: In this exploratory study, we conducted a longitudinal analysis of the peripheral T-cell receptor (TCR) β repertoire in 28 patients with unresectable stage IIIb non-small cell lung cancer (NSCLC) who received anti-PD-L1 immunotherapy following chemoradiotherapy. Blood samples were collected at baseline and three months after treatment initiation. Results: At the cohort level, global TCR repertoire features such as diversity and richness did not change significantly over time. However, when looking at individual patients, more specific patterns became evident. Patients could be broadly separated based on changes in clonotype richness, with reductions generally accompanied by lower diversity and decreased convergent TCR frequency. We also observed differences in TRBV gene usage in relation to clinical outcome, with higher TRBV20-1 and lower TRBV28 frequencies tending to associate with improved survival and delayed disease progression. Interestingly, the disappearance of dominant clonotypes from the peripheral blood during treatment was linked to longer progression-free survival (PFS). In addition, patients with higher baseline blood plasma tumor mutational burden (bTMB) showed greater clonotype richness and were more likely to exhibit this clonotype loss. The combination of high bTMB and clonotype disappearance identified a subgroup of patients with particularly favorable outcomes. Conclusions: Overall, these results suggest that early responses to PD-L1 blockade may be reflected less in global TCR repertoire shifts, including clonality and diversity measures, and more in subtle changes in clonotype composition and dynamics, since the frequencies of certain TRBV genes and the disappearance of dominant clonotypes following ICB were associated with clinical outcomes integrating TCR profiling with bTMB and could therefore help refine patient stratification and improve the understanding of immune responses in NSCLC. Nevertheless, due to the small number of recruited patients, our study is exploratory and hypothesis-generating, and further validation in larger patient cohorts is warranted.

Cancers doi: 10.3390/cancers18142240

Authors: Yohei Honda Shohei Shimajiri Takehiko Manabe Yukiko Nemoto Rintaro Oyama Natsumasa Nishizawa Hiroki Matsumiya Yusuke Nabe Masaru Takenaka Koji Kuroda Fumihiro Tanaka Hidetaka Uramoto

Background/Objectives: Published data on reliable prognostic biomarkers for pulmonary pleomorphic carcinoma (PPC), a rare, aggressive subtype of non-small cell lung cancer, are limited. Programmed death-ligand 1 (PD-L1) has been studied; however, the prognostic impact of other immunoregulatory molecules, such as CD73, CD155, and Ki-67 and their combined expression profiles, remains unclear. Methods: We retrospectively analyzed data of 47 patients who had undergone macroscopic complete resection of PPC between January 2000 and December 2022. Immunohistochemistry for PD-L1, CD73, CD155, and Ki-67 was performed. Cut-off values were determined by receiver operating characteristic analysis for cancer-specific death. The primary endpoint was the association between each biomarker and overall survival (OS) or cancer-specific survival (CSS). The secondary endpoint was the prognostic value of combined biomarker profiles, particularly PD-L1 with CD73, CD155, or Ki-67. Results: At a positivity threshold of 1%, the positivity rates were 70.2% for PD-L1, 89.4% for CD73, 91.5% for CD155, and 83.0% for Ki-67. There were no statistically significant differences in OS or CSS between groups with high expression and those with low expression for any single marker. Secondary endpoint analysis showed that low PD-L1 and low CD73 predicted significantly poorer OS (p = 0.046) and low PD-L1 and low Ki-67 predicted significantly poorer CSS (p = 0.039) compared with other combinations. Conclusions: Primary endpoint analyses showed no statistically significant association between any single marker and prognosis in PPC. In contrast, secondary endpoint findings indicated that concurrent low PD-L1 with either low CD73 or low Ki-67 identified subsets with significantly poorer outcomes. The present findings provide a basis for further investigation of biomarker combinations for prognostic assessment in this rare lung cancer. Because of the limited sample size, these findings are exploratory and require validation in larger independent cohorts.

Cancers doi: 10.3390/cancers18142239

Authors: Marco Cerbone Rosa De Vincenzo Alessia Auriola Miriam Dellino Eliano Cascardi Carmine Carriero Vincenzo Pinto Mauro Francesco Pio Maiorano Giorgio Maria Baldini Caterina Ricci Maria Teresa Evangelista Vera Loizzi Gennaro Cormio Ettore Cicinelli

Background: Colposcopy is a widely used clinical and diagnostic tool for detecting cervical intraepithelial neoplasia grade 2 or higher (CIN2+). This paper aims to analyze the diagnostic accuracy, pooled sensitivity, specificity, likelihood ratios, and overall diagnostic performance of colposcopy. Methods: A systematic review of papers on diagnostic accuracy, preregistered in PROSPERO (CRD420251028776), was conducted following PRISMA-DTA guidelines. Statistical analyses were performed using SPSS 29 and METADISC 2.0. Study quality and risk of bias were assessed using QUADAS-2. Results: A total of 49 studies, including 141,355 colposcopic examinations, were included in the final analysis. The overall sensitivity was 0.745 (95% CI: 0.684–0.797) and specificity was 0.831 (95% CI: 0.770–0.879). The diagnostic odds ratio was 14.388 (95% CI: 9.673–21.400). The positive likelihood ratio was 4.419 (95% CI: 3.260–5.991). Conversely, the negative likelihood ratio was 0.307 (95% CI: 0.249–0.378). The area under the curve was 0.8569. Significant heterogeneity was observed across studies (I2 > 93.2%). Conclusions: Colposcopy demonstrates moderate-to-high diagnostic accuracy in detecting CIN2+ lesions, with a good balance between sensitivity and specificity. However, significant variability exists among studies, highlighting the need for the implementation of standardized colposcopic criteria, improved examiner training, and adjunctive diagnostic methods such as HPV testing and ancillary techniques to enhance accuracy and reduce false positives and false negatives. Future research should focus on minimizing interobserver variability and refining diagnostic algorithms to optimize colposcopic performance.

Cancers doi: 10.3390/cancers18142238

Authors: Anastasia Savva Panayiota Christodoulou Charalambos Michaeloudes Paraskevi A. Farazi

Background/Objectives: The global health crisis of the COVID-19 pandemic in 2020 severely impacted healthcare systems, particularly affecting cancer patients, including those with lung cancer. Understanding the pandemic’s effects on lung cancer diagnosis is important for providing guidelines for future similar crises. Methods: A comprehensive search was conducted using the SCOPUS and PubMed databases, including keywords such as ‘COVID-19 pandemic,’ ‘lung cancer,’ ‘diagnosis,’ and ‘screening.’ In the initial screening phase, studies were selected based on their title and abstract, followed by the removal of duplicates. A second round of full-text screening was then performed using predefined inclusion and exclusion criteria. Specific checklists were applied to ensure methodological quality. Results: Out of 564 articles, 78 met the inclusion criteria and were grouped according to changes in lung cancer incidence, screening and diagnostic procedures, and staging during the COVID-19 pandemic compared to pre-pandemic. Multiple studies reported an average decline of 20% in newly diagnosed lung cancer cases, alongside significant decreases in screenings, follow-ups, and diagnostic procedures. In contrast, only two studies reported an increase in lung cancer incidence, and three studies reported increases in screening or diagnostic activity. Eight studies reported a shift toward more advanced-stage diagnoses and fewer early-stage detections, while four studies observed a decrease in advanced-stage lung cancer during the pandemic compared to pre-pandemic years. Conclusions: Studies show that overall, the COVID-19 pandemic disrupted lung cancer diagnosis in many countries, highlighting the need for stronger healthcare systems that can support crisis response and equitable care.

Cancers doi: 10.3390/cancers18142237

Authors: Zhongrui Wang Yu Liu Lu Qian Jiayuan Li Zuoren Yu Qian Zhao Jinhui Lü

Background: The diversity of RNA isoforms plays a critical role in regulating the development and progression of human cancers. Our previous work has demonstrated that piR-2158 exerts antitumor activity in breast cancer by repressing IL11-STAT3 signaling. Methods: The isoforms of piR-2158 were analyzed using Sanger sequencing, quantitative real-time PCR (qRT-PCR), and Gene Expression Omnibus (GEO) dataset. Cell proliferation capacity was assessed using Cell Counting Kit-8 (CCK-8) assays and Ki67 immunofluorescence staining. Cell migration was evaluated using wound healing assays. Cancer cell stemness was analyzed using mammosphere formation assay, stemness marker detection, and ALDH activity assay. Results: We identified two types of piR-2158 isoforms in mammary tissues: a 31 nt long isopiR (designated as iso-piR-2158-L) and a 28 nt short isopiR (designated as iso-piR-2158-S). Predominant expression of iso-piR-2158-L was observed in normal mammary epithelial cells and adjacent non-tumor breast tissues, whereas it was significantly downregulated in TNBC cell lines and primary tumor tissues. We experimentally demonstrated that iso-piR-2158-L and iso-piR-2158-S exert distinct effects on TNBC cell proliferation, migration, and stemness, with iso-piR-2158-L showing significantly stronger antitumor effects than iso-piR-2158-S. Subsequent mechanistic studies revealed that iso-piR-2158-L suppresses IL11 expression more effectively, compared to iso-piR-2158-S. Conclusions: Our findings reveal a piRNA isoform-based regulatory pathway that may be involved in regulating pathological transformation, tumor initiation, and progression in TNBC.

Cancers doi: 10.3390/cancers18142234

Authors: Kizuki Yuza Timothy M. Pawlik

Immune checkpoint inhibitor (ICI)-based combinations have become central systemic treatment options for advanced hepatocellular carcinoma (HCC) and are now being integrated into selected intermediate-stage settings. As tumor responses have improved, some patients who were not initially candidates for curative-intent treatment may later become candidates for resection, ablation, or liver transplantation. However, radiographic response alone does not define curative-intent candidacy, and no shared framework currently guides how post-immunotherapy response should be translated into a treatment decision. Terminology also differs regionally: Asian literature frames a resection-anchored paradigm, whereas Western practice uses transplant-anchored downstaging. This narrative review proposes a multidisciplinary framework for immunotherapy-based conversion to curative-intent treatment in HCC. We first clarify the lexicon of conversion, downstaging, bridging, neoadjuvant therapy, post-ICI transplantation, and drug-free or treatment-free status. We then summarize conversion-relevant evidence across key clinical decision settings, including transarterial chemoembolization (TACE)-unsuitable intermediate-stage disease, portal vein tumor thrombus or macrovascular invasion, borderline-resectable or locally advanced disease, and transplant downstaging or bridging. The central framework defines curative-intent transition through the intersection of three domains: technical suitability, oncologic suitability, and physiologic or liver-reserve suitability. Biomarkers, imaging response, tumor-marker kinetics, liver function, and treatment-related toxicity are discussed as inputs into candidacy rather than as response measures alone. Finally, we propose a multidisciplinary workflow and highlight lessons from pancreatic cancer, biliary tract cancer, and colorectal liver metastases. As an expert-opinion-based framework, this approach should structure multidisciplinary discussion rather than serve as validated selection criteria; harmonized terminology, prospective conversion registries, and conversion-specific endpoints are needed for prospective validation.

Cancers doi: 10.3390/cancers18142235

Authors: Faure Rodríguez-Velásquez Andrés Montoya-Durán Nicole Bonilla Jacobo Echeverri-Hoyos Jaime A. Echeverri-Franco Eduardo Tuta-Quintero

Background: Esophageal cancer is a highly lethal malignancy, the prognosis of which depends largely on early diagnosis. Artificial intelligence (AI) has emerged as a promising tool to enhance endoscopic detection and characterization of early esophageal cancer. This scoping review aims to map and synthesize the available evidence regarding the diagnostic performance and clinical utility of artificial intelligence systems applied to upper gastrointestinal endoscopy for the detection and characterization of premalignant squamous lesions and early-stage esophageal squamous cell carcinoma (ESCC). Methods: A scoping review was conducted according to Arksey and O’Malley, Levac, Joanna Briggs Institute, and PRISMA-ScR recommendations. The review question focused on patients with premalignant lesions or early ESCC, artificial intelligence-based diagnostic systems, and upper gastrointestinal endoscopy. Searches were performed in PubMed, Scopus, and Embase. Original studies reporting sensitivity, specificity, accuracy, AUC, or F1-score were included. Results: A total of 30 publications were included, consisting mainly of retrospective observational and diagnostic test studies (26/30; 86.7%), followed by randomized clinical trials (3/30; 10.0%) and a multicenter validation study (1/30; 3.3%). The studies were predominantly from China (18/30; 60%), followed by Japan (8/30; 26.7%), Taiwan (3/30; 10%), and the United Kingdom + Taiwan (1/30; 3%). Automatic lesion detection was predominant (21/30; 70.0%), followed by diagnostic classification (11/30; 36.7%), while segmentation (3/30; 10.0%), histological prediction (2/30; 6.7%), estimation of invasion depth (3/30; 10.0%), and lesion delineation (1/30; 3.3%) were evaluated less frequently, and in some cases combined within the same model. The most used endoscopic imaging modalities were narrow-band imaging (23/30; 76.7%) and white light endoscopy (20/30; 66.7%), followed by magnifying endoscopy with narrow-band imaging (5/30; 16.7%), blue light imaging (2/30; 6.7%), and hyperspectral imaging (1/30; 3.3%). Conclusions: Available studies suggest that AI has the potential to achieve high diagnostic performance under controlled conditions. However, the current evidence is derived predominantly from single-center retrospective studies using selected high-quality static images, with limited external, prospective, and real-world validation.

Cancers doi: 10.3390/cancers18142236

Authors: Bang Zhang Chenmeng Liu Xiaolan Li Yang Wan Xiaojuan Chen Ye Guo Li Zhang Yao Zou Fang Liu Yumei Chen Tianyuan Hu Yingchi Zhang Xiaofan Zhu Wenyu Yang

Background: Juvenile myelomonocytic leukemia (JMML) is a rare RAS/MAPK-driven pediatric myelodysplastic/myeloproliferative neoplasm. The phenotype and survival relevance of NRAS/KRAS alterations remain difficult to interpret because of co-mutations, evolving sequencing, incomplete germline confirmation, and post-diagnostic HSCT. Methods: We retrospectively reviewed 34 children with JMML and classifiable NRAS and/or KRAS alterations diagnosed between November 2010 and September 2022. Patients were classified as NRAS-only, KRAS-only, or NRAS/KRAS co-mutated. Direct comparisons used single-subtype cases. OS was analyzed in evaluable patients, with HSCT modeled as a time-dependent covariate. Results: The cohort included 20 NRAS-only, 12 KRAS-only, and 2 NRAS/KRAS co-mutated cases. KRAS-only cases had higher monocyte percentage (27.2% vs. 16.7%; p = 0.023) and lymphocyte percentage (48.1% vs. 39.0%; p = 0.018), whereas absolute monocyte count was comparable (4.0 vs. 4.0 × 109/L; p = 0.930). PTPN11 was the most frequent non-RAS co-mutation (7/34) and occurred in both NRAS/KRAS co-mutated cases. Methylation status was available in 11 patients and analyzed descriptively. NRAS/KRAS subtype did not significantly stratify OS (HR for KRAS-only vs. NRAS-only, 0.55; 95% CI, 0.18–1.62; p = 0.276). HbF did not significantly stratify OS, while diagnostic total hemoglobin showed only an exploratory univariable association. Exact HSCT dates were retrieved for all 11 transplanted patients; time-dependent Cox analysis showed a significant association between HSCT and better OS (HR, 0.11; 95% CI, 0.02–0.56; p = 0.007). Conclusions: NRAS/KRAS status defined a limited diagnosis-time phenotype but did not independently stratify survival. JMML survival analyses should integrate co-mutations, germline and testing-era limitations, HbF/hemoglobin risk context, and time-dependent HSCT handling.

Cancers doi: 10.3390/cancers18142233

Authors: Carolina Mendez-Guerra Rayna S. Kuthiala Andrew R. Moya Marcos R. Gonzalez Juan Pretell-Mazzini

Background/Objectives: Extra-articular resection (EAR) may be considered for sarcomas involving or extending into joints, but its oncologic outcomes are not well defined. This study evaluated oncologic outcomes following EAR for bone and soft tissue sarcomas of the knee, shoulder, or hip. Methods: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in the International Prospective Register of Systematic Reviews (ID: CRD420251140969). PubMed and Embase were searched from inception through 14 January 2026, to identify studies including patients with bone or soft tissue sarcomas involving or extending into the knee, shoulder, or hip joints who underwent EAR. Studies including other types of resections or mixed populations were excluded. Primary outcomes were local recurrence (LR) and distant metastasis (DM); secondary outcomes were 1- and 5-year overall survival (OS). Proportions were estimated using sample size-weighted pooling, with 95% confidence intervals (95% CIs) calculated using the Wilson score method. Exploratory subgroup analyses were performed by anatomic location for LR and histologic subtype for DM. Quality assessment was conducted using the Joanna Briggs Institute Critical Appraisal Checklist for case series, and the Newcastle–Ottawa Scale for cohort studies. Results: Twenty-one studies, comprising 455 patients, were included. Pooled LR was 11.65% (95% CI, 8.92–15.04), with the highest proportion in the hip (17.65%; 95% CI, 10.53–27.75), followed by the shoulder (10.90%; 95% CI, 6.66–17.13) and knee (9.81%; 95% CI, 6.32–14.80). Pooled DM was 35.26% (95% CI, 30.01–40.87), with the highest proportion in Ewing sarcoma (50.00%; 95% CI, 23.66–76.34) and the lowest in chondrosarcoma (13.79%; 95% CI, 4.51–32.57). No significant differences were found in exploratory subgroup analyses. The 1-year and 5-year OS rates were 92.13% (95% CI, 85.63–95.95) and 58.42% (95% CI, 51.28–65.23), respectively. Conclusions: EAR was associated with low reported LR and moderate survival in patients with sarcomas involving or extending into major joints. DM likely reflects underlying tumor biology. These findings should be interpreted cautiously given the lack of a comparison group, heterogeneity of included studies, and statistical limitations.

Cancers doi: 10.3390/cancers18142232

Authors: Rino S. Seedor Mizue Terai Sergei Koshkin Andrew E. Aplin Marlana Orloff Erin Sharpe-Mills Madeleine Naccarato Aurora Mills Alfredo A. Molinolo J. Silvio Gutkind Takami Sato

Background: Treatment options are limited, and outcomes remain poor for patients with metastatic uveal melanoma (MUM). We conducted an investigator-initiated, prospective, single-arm, single-institution, phase II study evaluating the combination of an FAK inhibitor (defactinib) with a RAF/MEK inhibitor (avutometinib) for the treatment of MUM. Methods: From February 2021 through January 2023, 12 patients with MUM were treated with the combination of defactinib and avutometinib. Defactinib was given 200 mg twice daily, and avutometinib was given 3.2 mg twice a week. Both drugs were given for 3 weeks on and 1 week off (28-day cycle). Disease control rate was the primary endpoint of this study. Results: Median lines of prior therapies for the patients were two. After two cycles, six patients achieved stable disease while six patients developed progressive disease (disease control rate of 50%). With a median follow-up of 20.0 months, the median progression-free survival was 3.0 months and the median overall survival was 20.0 months. The combination was quite tolerable for patients, with no patients requiring dose reduction or discontinuation. Trial enrollment was stopped early by study sponsors before the anticipated accrual of 18 patients due to no patients having a significant reduction in disease. Conclusions: This is the first study reporting on the use of an FAK inhibitor combination in MUM. Further research should seek to elucidate an optimal combination treatment strategy for MUM, such as FAK and PKC inhibitors, for improved blockade of the signaling pathways downstream of GNAQ/GNA11 driver mutations.

Cancers doi: 10.3390/cancers18142231

Authors: Muin Tuffaha Wael Hananeh Michael Starke

Background: Gastric and gastroesophageal junction adenocarcinomas remain major causes of cancer- related mortality worldwide. Although perioperative chemotherapy, HER2-directed therapy, Claudin-18.2 (CLDN18.2)-targeted treatment, immune checkpoint inhibition, and anti-angiogenic therapy have improved outcomes in selected patients, clinically actionable targets are absent, heterogeneous, or lost in many high-grade, diffuse, poorly cohesive, signet-ring-cell micropapillary, hepatoid, and sarcomatoid carcinomas. Additional histopathology-assessable biomarkers that can support both molecular imaging and targeted therapy are of considerable clinical interest. Methods: Integrin αvβ6 is an epithelial-specific adhesion receptor that is minimally expressed in most normal adult tissues but becomes markedly upregulated during epithelial carcinogenesis, tissue remodeling, invasion, and activation of transforming growth factor-β signaling. This retrospective histopathological and immunohistochemical study evaluated integrin αvβ6 expression by immunohistochemistry in 53 formalin-fixed paraffin-embedded diagnostic specimens of untreated primary gastric or gastroesophageal junction adenocarcinoma. Tumors were classified according to the WHO Classification of Tumors of the Digestive System, 5th edition. Membranous integrin αvβ6 staining intensity and the percentage of positive tumor cells were recorded, and an H-score was calculated. Expression patterns were compared descriptively with histological subtype, differentiation grade, HER2 status, and CLDN18.2 expression. Results: Integrin αvβ6 immunoreactivity was detected in 49 of 53 tumors (92.5%), the clinically more relevant moderate to strong expression (H-score > 100) was present in 27 of 53 cases (50.9%), and strong expression was present in 13 of 53 cases (24.5%). Expression was not confined to conventional intestinal-type tumors; among carcinomas containing a signet-ring-cell component, 14 of 16 assessable cases (87.5%) showed integrin αvβ6 positivity, with 8 of 16 (50.0%) showing moderate to strong staining. By comparison, HER2 positivity was identified in 4 of 53 cases (7.5%; 4 of 52 assessable cases, 7.7%), and clinically relevant CLDN18.2 positivity, defined as moderate-to-strong membranous staining in at least 75% of tumor cells, was present in 7 of 38 assessable cases (18.4%). Conclusions: Integrin αvβ6 is frequently expressed in gastric and gastroesophageal junction adenocarcinoma, with moderate to strong expression in approximately half of all cases and in half of signet ring cell-containing tumors, including aggressive histological subtypes that often lack established therapeutic targets. The precise H-Score threshold for theranostic eligibility remains to be determined. The findings support integrin αvβ6 as a promising biomarker for histopathology-based screening, PET-based whole-body target assessment, and future targeted radionuclide therapy. Integration of immunohistochemistry and integrin αvβ6- targeted PET imaging will be essential to validate integrin αvβ6 as a candidate biomarker and to optimize radionuclide selection in gastric cancer, particularly with moderate to strong expression.

Cancers doi: 10.3390/cancers18142230

Authors: Ellen M. Voigt Alexandra L. Isaacson Mariah R. Leidinger James A. Goeken Quinn Hanigan Deng Fu Guo Rachel M. Gasser Makenna Eadie Isabella Babor Benjamin W. Darbro William Paradee Kamal Rahmouni Tian Zhao Patrick Breheny Eunhyeong Lee Minah Kim David K. Meyerholz Mohammed Milhem Rebecca D. Dodd Dawn E. Quelle

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that arise from Schwann cells and lack effective therapies. RABL6A is an oncogenic Rab-like GTPase whose expression is associated with worse survival in many human cancers. It is required for human MPNST cell survival, and its expression is dramatically increased in patient MPNSTs compared to benign precursor lesions. Methods: To model elevated expression of RABL6A in vivo, we developed transgenic mice expressing Cre-inducible Rabl6a. These Rabl6a-tg mice express the murine Rabl6a cDNA with a 5′ hemagglutinin [HA] epitope sequence downstream of a CMV enhancer and separated by a lox–stop–lox cassette. Double transgenic DhhCre–Rabl6a-tg mice were generated to achieve Schwann-cell specific Cre expression from the Desert hedgehog (Dhh) promoter. De novo MPNSTs were induced by CRISPR editing of Nf1, Ink4a, and Arf genes in the mouse sciatic nerve. Results: Cre-dependent expression of transgenic Rabl6a was verified at the mRNA and protein levels in Cre-positive mouse embryo fibroblasts and tissues. Increased Rabl6a expression in DhhCre–Rabl6a-tg mice had no effect on de novo MPNST initiation but significantly accelerated tumor progression relative to DhhCre control mice. The Rabl6a phenotype was associated with increased tumor angiogenesis but not proliferation. Interestingly, many MPNSTs in the DhhCre background exhibited varying levels of rhabdomyoblastic (RMB) features. That immature muscle cell phenotype is a hallmark of malignant Triton tumors, a rare histological variant of human MPNSTs associated with worse outcomes. Conclusions: These data provide direct evidence that Rabl6a is a functional driver of MPNSTs while establishing Rabl6a-tg mice as a suitable model for investigating Rabl6a’s role in other lethal RABL6A-high tumors.

Cancers doi: 10.3390/cancers18142229

Authors: Na Young Jung Jihe Lim Hyug-Gi Kim Sung Hun Kim Bobae Choi Bo La Yun Ga Eun Park Jang-Hoon Oh Bo Kyoung Seo Min Sun Bae

Background/Objectives: Accurate visual categorization of small enhancing lesions on contrast-enhanced breast MRI remains challenging. The purpose of this study was to develop a deep learning (DL) model for detecting small (≤2 cm) invasive breast cancers using multi-institutional breast MRI data. Methods: This retrospective study included a total of 1721 women (mean age: 54 years; range, 21–87 years) with T1-stage invasive breast cancer across five hospitals. All patients underwent dynamic contrast-enhanced breast MRI before surgery between 2010 and 2020. Enhancing breast masses on early postcontrast T1-weighted images (14,917 labeled cancer images and 1443 labeled benign images) were used as the ground truth. In this multicenter cancer-enriched cohort, a DL model was developed to distinguish cancerous lesions from noncancerous lesions. MR images were independently reviewed by three breast imaging radiologists to detect subcentimeter (≤1 cm) cancers, and the readers were informed that each examination contained a single cancer. The performance of the model was evaluated using the area under the precision–recall curve (AUPRC), sensitivity, precision, and F1 score. Results: The DL model achieved an AUPRC of 0.42 in detecting small (≤2 cm) invasive breast cancers presenting as enhancing masses on MRI (sensitivity, 83.2%; precision, 33.2%; F1 score, 0.47). For subcentimeter (≤1 cm) cancers, the detection performance of the model was lower (sensitivity, 75.3%; precision, 20.8%; F1 score, 0.33) than that of the radiologists (mean sensitivity, 89.5%; mean precision, 72.9%; mean F1 score, 0.80). When the radiologists used the DL model, their mean precision in detecting subcentimeter invasive breast cancers improved from 72.9% to 83.2%, with no significant change in sensitivity (89.5% vs. 86.8%, p > 0.05). Conclusions: The DL model demonstrated potential as an assistive tool by improving radiologists’ precision for detecting small invasive breast cancers on contrast-enhanced breast MRI in this enriched reader-study setting, although it did not significantly improve their sensitivity.

Cancers doi: 10.3390/cancers18142228

Authors: Amr Sayed Ghanem Róbert Bata Marianna Móré Renáta Jávorné Erdei Attila Csaba Nagy

Introduction: Head and neck cancers are frequently diagnosed at advanced stages, resulting in poor survival despite therapeutic advances, highlighting the need for earlier identification within routine clinical care. Routinely collected electronic health record data provide a potential source of longitudinal clinical signals, although the clinical applicability of machine learning models remains limited by concerns regarding interpretability and real-world integration. Methods: This retrospective cohort study included 157,031 patients treated at the University of Debrecen Clinical Centre between 2007 and 2022, with head and neck cancer defined using ICD-10 codes C01 to C14. A total of 1397 variables, including demographic characteristics, ICD based comorbidities, and laboratory parameters, were reduced to 91 features using variance filtering and elastic net penalized Cox regression. Three survival modelling approaches were developed and compared, including CoxNet, Random Survival Forest, and XGBoost with a Cox objective. Results: The XGBoost model demonstrated the highest predictive performance with a mean concordance index of 0.916, followed by Random Survival Forest at 0.892 and CoxNet at 0.886, with acceptable calibration across models. Risk stratification showed clear separation between low, medium, and high-risk groups. Model interpretability using SHapley Additive exPlanations indicated that predictions were driven by a combination of demographic factors, laboratory markers, and clinically relevant diagnosis codes, reflecting both distal risk gradients and proximal clinical signals. Conclusions: These findings suggest that explainable machine learning applied to routine clinical data can support accurate and clinically interpretable risk stratification, with potential utility for opportunistic early identification of high-risk patients within existing healthcare pathways. Clinical Relevance: Explainable EHR-based survival models may support opportunistic identification of patients at increased head and neck cancer risk within routine clinical workflows, potentially improving triage and referral.

Cancers doi: 10.3390/cancers18142227

Authors: Kazushi Yamashita Daisuke Suzuki Katsunori Furukawa Tsukasa Takayashiki Satoshi Kuboki Shigetsugu Takano Masayuki Ohtsuka

Background/Objectives: The lymphocyte-to-monocyte ratio (LMR) is an inflammation-based prognostic score (IBPS) that can be easily calculated using routine blood tests. Handgrip strength (HGS), a key diagnostic component of sarcopenia, also predicts survival. Nonetheless, the prognostic role of combined LMR and HGS in patients with pancreatic head cancer undergoing pancreaticoduodenectomy remains unclear. This exploratory study aimed to analyze whether the combination of preoperative LMR and HGS is associated with overall survival. Methods: We retrospectively analyzed 105 patients with pancreatic head cancer who underwent pancreaticoduodenectomy at Chiba University Hospital from January 2016 to December 2020. We examined the prognostic values of IBPSs and HGS and compared combinations of preoperatively measurable factors. Results: Multivariate analysis assessing preoperatively measurable factors demonstrated that low preoperative HGS, low preoperative LMR, and high preoperative carbohydrate antigen 19-9 level were associated with poor overall survival (hazard ratio [HR]: 2.41, 95% confidence interval [CI]: 1.29–4.51, p = 0.006; HR: 2.05, 95% CI: 1.12–3.76, p = 0.020; and HR: 2.68, 95% CI: 1.25–5.76, p = 0.011, respectively). The combination of low HGS and low LMR was associated with poor overall survival, although only 12 patients were included in this subgroup. Multivariate analysis evaluating clinicopathological factors demonstrated that this combination was associated with poor overall survival (HR: 2.85, 95% CI: 1.06–7.69, p = 0.038). Conclusions: In this single-center exploratory study, the combination of preoperative LMR and HGS was associated with poor overall survival in patients with surgically resected pancreatic head cancer. Further prospective multicenter validation is required before this combined marker can be used for clinical decision-making.

Cancers doi: 10.3390/cancers18142226

Authors: Justyna Durślewicz Marek Zdrenka Łukasz Szylberg Jędrzej Borowczak

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is characterized by poor prognosis and marked molecular heterogeneity. Mitochondrial ribosomal proteins have emerged as regulators of cancer metabolism, yet the clinical significance of MRPL23 in GBM remains unclear. This study aimed to evaluate the prognostic relevance of MRPL23 expression in glioblastoma and its association with patient survival and mitochondrial functional profiles. Methods: MRPL23 protein expression was assessed by immunohistochemistry in tissue microarrays derived from 89 patients with primary glioblastoma and 36 samples of adjacent non-tumorous brain tissue. Survival analyses were performed using Kaplan–Meier estimates and Cox proportional hazards models. In silico validation was conducted using transcriptomic and proteomic data from 296 IDH-wildtype glioblastomas from The Cancer Genome Atlas. Correlation analyses were used to explore associations between MRPL23 expression and mitochondrial respiratory chain components. Results: MRPL23 protein expression was significantly upregulated in glioblastoma compared with non-tumorous brain tissue (p < 0.001). High MRPL23 expression was associated with significantly shorter overall survival in the institutional cohort (median 13.5 vs. 21 months, p = 0.013). Consistently, low MRPL23 expression in the TCGA cohort was associated with improved overall and progression-free survival. MRPL23 expression showed strong positive correlations with key mitochondrial respiratory chain proteins, including COX5B, UQCRC1, and COX4I1. Conclusions: MRPL23 is overexpressed in glioblastoma and is associated with unfavorable patient outcomes. These findings identify MRPL23 as a potential prognostic biomarker and highlight mitochondrial translation as a relevant biological process in aggressive glioblastoma.

Cancers doi: 10.3390/cancers18142225

Authors: Christoph Ebner Linda Ebner Sergej Skvortsov Heidelinde Fiegl Katharina Steger Barin Feroz Verena Wieser Katharina Leitner Irina Tsibulak Christian Marth Alain Gustave Zeimet

Objective: Squamous cell carcinoma antigen (SCC-A) is a widely used biomarker for squamous cell cervical carcinoma and pretreatment elevation is associated with poor prognosis. Normalization during chemoradiation correlates with PET-CT response and survival. This study assessed the prognostic value of SCC-A normalization for biopsy-proven pathological response and survival outcomes. Materials and Methods: This retrospective single-center cohort study included patients with locally advanced or node-positive squamous cell cervical cancer treated with definitive chemoradiation at the Medical University Innsbruck between 2008 and 2023. Eligible patients had baseline SCC-A ≥ 2 ng/mL and at least two additional measurements within 42 days of treatment. SCC-A normalization was evaluated at predefined weekly time points. Associations with biopsy-assessed residual disease, PFS, and OS were assessed. Results: Of 186 screened patients, 83 met the inclusion criteria. Within 42 days, 70% achieved SCC-A normalization, with a median time of 21 days (IQR 19–32). Among predefined time points, normalization by day 28 was associated with reduced odds of residual disease (OR 0.14; 95% CI 0.04–0.44) and improved PFS (HR 0.28; 95% CI 0.12–0.63) and OS (HR 0.37; 95% CI 0.14–0.96), remaining independently significant after multivariate adjustments. Conclusions: SCC-A normalization during chemoradiation is a non-invasive independent biomarker of treatment response. Normalization within 28 days identifies patients at low risk of residual disease, progression, and death, supporting its use for early risk stratification and response monitoring for potential treatment adaptations.

Cancers doi: 10.3390/cancers18142224

Authors: Binru Cai Duoduo Lv Qiang Qiu Wenju Xiong Heyu Tang Yixiao Bai Sicheng Zhou Yiguo Hu Rifaat Safadi Chengdi Wang Lingyun Zhou

Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide, is driven by complex interactions between genetic mutations and reversible epigenetic alterations. Among these, aberrant DNA methylation, histone modifications, and dysregulated noncoding RNAs (ncRNAs) play central roles in hepatocarcinogenesis, tumor progression, and therapy resistance. Epigenetic changes not only regulate key oncogenic pathways, including JAK/STAT and RAS, but also contribute to tumor immune evasion and heterogeneity. Unlike genetic mutations, epigenetic alterations are reversible, offering unique opportunities for therapeutic targeting. This review highlights recent advances in understanding the epigenetic landscape of HCC, identifies promising biomarkers for early detection and prognosis, and evaluates emerging epigenetic therapies (including DNMT, HDAC, and BET inhibitors as well as ncRNA-based strategies). Although these therapies have shown tumor-suppressive or treatment-sensitizing effects in preclinical models, their clinical translation remains limited by modest efficacy, small early-phase trials, treatment-related adverse events, and insufficient biomarker-guided patient selection. These insights may support more precise diagnostic and therapeutic strategies for HCC.

Cancers doi: 10.3390/cancers18142223

Authors: Simonetta Ausoni Alessandra Casarin Giuseppe Azzarello

Head and neck squamous cell carcinoma (HNSCC) is characterized by marked intratumoral heterogeneity and complex tumor–immune–stromal interactions, which shape therapeutic response and clinical outcome. Despite extensive transcriptomic efforts, bulk RNA sequencing has faced significant limitations, often failing to generate robust prognostic or predictive biomarkers, highlighting the need for approaches capable of resolving the cellular and spatial complexity of the tumor ecosystem. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have refined our understanding of HNSCC biology by enabling high-resolution mapping of malignant, stem-like, immune, and stromal compartments. Three major spatial domains have been defined in HNSCC: tumor core (TC), tumor invasion front (TIF), and leading edge (LE). Each ecosystem exhibits distinct cellular programs that promote immune evasion, tumor dissemination, and therapy resistance, particularly in high-risk clinical settings. In this Review, we integrate recent single-cell and spatial studies and propose a translational framework linking ecosystem architecture with clinical stratification across resectable locally advanced (r-LAD), unresectable locally advanced (u-LAD), and recurrent/metastatic (R/M) disease. We further discuss how spatially resolved transcriptomic approaches may support biomarker discovery and hypothesis generation for risk stratification and trial design, while emphasizing that clinical implementation remains limited by cohort size, methodological heterogeneity, and the need for large-scale prospective validation. Finally, we outline key methodological and translational challenges that must be addressed before these technologies can reliably inform precision oncology and decision-making in HNSCC.

Cancers doi: 10.3390/cancers18142222

Authors: Karl C. Reger Gabriela Schneider Keegan T. Line Alagammai Kaliappan Robert Buscaglia Nichola C. Garbett

In the original publication [...]

Cancers doi: 10.3390/cancers18142221

Authors: Takuya Miura Hisashi Kessoku Yohei Morishita Toshiki Kobayashi Yosuke Mizunari Shinichi Okada Hiroto Ohto Masato Nagaoka Hiromi Kojima

Background/Objectives: Temporal muscle thickness (TMT) has been proposed as a practical surrogate marker for skeletal muscle mass, whereas the geriatric nutritional risk index (GNRI) reflects nutritional status. However, the independent and combined prognostic value of TMT and GNRI in surgically treated head and neck squamous cell carcinoma (HNSCC) remains unclear. Methods: We retrospectively analyzed 214 patients with HNSCC who underwent curative-intent surgery. Disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards models. In the primary analyses, TMT and GNRI were entered simultaneously as continuous variables and adjusted for age, sex, clinical stage, and postoperative adjuvant treatment. For clinical interpretability, Kaplan–Meier analyses were additionally performed using a composite TMT–GNRI score. Results: In the multivariable analyses, higher TMT was independently associated with longer DFS (hazard ratio [HR] 0.83 per 1 mm increase, 95% confidence interval [CI] 0.72–0.96, p = 0.014) and OS (HR 0.73, 95% CI 0.60–0.89, p = 0.002). GNRI was significantly associated with DFS and OS in the univariate analyses; after simultaneous adjustment for TMT and clinical covariates, it remained independently associated with OS (HR 0.98 per 1-point increase, 95% CI 0.96–0.99, p = 0.015) and showed a borderline association with DFS (HR 0.984, 95% CI 0.966–1.001, p = 0.068). Kaplan–Meier analyses using the composite TMT–GNRI score demonstrated clear risk stratification, with the poorest outcomes observed in patients with concomitantly low TMT and low GNRI. Conclusions: In surgically treated HNSCC, preoperative TMT was independently associated with both DFS and OS. GNRI may provide additional prognostic information, particularly for OS.

Cancers doi: 10.3390/cancers18142220

Authors: Eliana Marostica Sunil Singhal

Background/Objectives: Intraoperative molecular imaging (IMI) enables real-time visualization of tumor biology during surgery using fluorescent probes and near-infrared imaging systems. As lung cancer screening increases detection of small and nonpalpable pulmonary nodules, conventional localization and margin assessment techniques remain limited, particularly during minimally invasive surgery. This review summarizes the technical foundations, imaging agents, clinical applications, and future directions of IMI in thoracic oncology. Methods: We performed a narrative review to synthesize current evidence regarding the technical foundations, molecular imaging agents, clinical applications, and future directions of intraoperative molecular imaging in thoracic oncology. Given the multidisciplinary scope of the field, a narrative approach was selected to integrate mechanistic, translational, and clinical evidence rather than to answer a single narrowly defined clinical question. Results: IMI generates dynamic intraoperative contrast based on preferential probe accumulation or activation within malignant tissue. Current approaches include non-specific fluorophores such as indocyanine green, activatable probes targeting tumor-associated proteases or acidic microenvironments, and receptor-targeted agents such as pafolacianine. Across prospective studies and multicenter trials, IMI improved localization of nonpalpable lesions, identified occult synchronous malignancies, and enhanced intraoperative margin assessment, frequently altering surgical management. Phase 2 and 3 studies of folate receptor-targeted imaging demonstrated clinically significant findings in a substantial proportion of patients, including lesions not detected by conventional imaging or palpation. However, performance remains dependent on tumor biology, target expression, lesion depth, and optical constraints. Conclusions: IMI represents an emerging transition from anatomy-guided toward biology-informed thoracic surgery by providing real-time molecular information during resection. Current evidence supports its role as a complementary intraoperative technology that augments conventional imaging and surgical techniques, particularly for small, peripheral, and nonpalpable lesions.

Cancers doi: 10.3390/cancers18142219

Authors: Diana Huber Florian von Strachwitz Linda Hofmann Monika Pietrowska Marta Gawin Dapi Meng-Lin Chiang Christiane Guder Ramin Lotfi Shosei Kishida Michael W. Pfaffl Barbara Wollenberg Thomas K. Hoffmann Cornelia Brunner Marie-Nicole Theodoraki

Background: Head and neck squamous cell carcinomas (HNSCCs) are highly immunosuppressive, and tumor-associated macrophages constitute a major component of HNSCC tumor microenvironments. Here, we investigate the effects of circulating small extracellular vesicles (sEVs) from HNSCC patients on primary macrophages, to elucidate systemic sEV-mediated immune regulation in HNSCC patients. Methods: sEVs were isolated from plasma by size-exclusion chromatography. Internalization of PKH26-labeled sEVs was demonstrated, and mass spectrometry analysis was performed on HNSCC sEVs and sEV-treated macrophages. NF-κB activation was investigated by Western blot and p65 translocation assay. Downstream, mRNA and protein levels of cytokines and chemotaxis of T cells were investigated. Results: Proteomic analysis revealed time-dependent modulation of the macrophage proteome and NF-κB signaling pathway, which was confirmed by Western blot and p65 translocation assay. sEVs from HNSCC patients negative for human papillomavirus type 16 (HPV) differentially modulated NF-κB signaling and sEV uptake mechanisms compared with sEVs from HPV-positive patients and healthy donors. Conclusions: Circulating sEVs derived from HNSCC patient plasma modulate macrophage proteomic profiles and NF-κB signaling. HPV16 status was associated with differential sEV-mediated macrophage regulation, suggesting a potential role of sEVs in systemic immune modulation in HNSCC.

Cancers doi: 10.3390/cancers18142218

Authors: Hyewon Hur Eun Hwa Kim Myeongjee Lee Inkyung Jung Kyung Jin Eoh

Background: Preeclampsia, a condition of high blood pressure during pregnancy, is linked to microangiopathy in various organs and may contribute to cancer development. This study aimed to evaluate cancer risk in women with newly diagnosed preeclampsia. Methods: We conducted a nationwide, population-based retrospective study using data from the Korean National Health Insurance claims database (2008–2020). Women diagnosed with preeclampsia between 2009 and 2013 were compared to a control group who underwent appendectomy but did not have preeclampsia. Participants with a prior cancer diagnosis were excluded. Cancer occurrence was assessed using the International Classification of Diseases, 10th revision codes. Results: Data from 42,380 preeclampsia patients and 105,327 controls were analyzed. Cancer incidence rates were 333.1 per 100,000 person-years in the preeclampsia group and 377.0 in controls. Preeclampsia was associated with significantly higher risks of gallbladder and biliary tract cancers (HR 5.49, 95% CI 1.23–24.50), breast cancer (HR 1.17, 95% CI 1.02–1.34), and thyroid cancer (HR 1.21, 95% CI 1.10–1.34). However, it was linked to lower risks of ovarian cancer (HR 0.44, 95% CI 0.27–0.74) and leukemia (HR 0.36, 95% CI 0.16–0.81). All hazard ratios were adjusted for age, which differed substantially between the two groups; unadjusted incidence rates and age-adjusted hazard ratios therefore differed in direction for some sites. Conclusions: Preeclampsia was associated with an increased risk of certain cancers, including breast and thyroid cancers, and with a decreased risk of ovarian cancer and leukemia. Because the control group was older than the preeclampsia group, crude incidence rates and age-adjusted hazard ratios differed in direction; the age-adjusted estimates should therefore be regarded as the primary findings. Several site-specific associations, particularly those based on small event counts (e.g., gallbladder and biliary tract cancer), should be interpreted as exploratory and warrant replication.

Cancers doi: 10.3390/cancers18142217

Authors: Ryota Matsui Jun Watanabe Kazuma Rifu Kenichi Ishibayashi Kenta Doden Kengo Hayashi Hiroto Saito Megumi Watanabe Toshikatsu Tsuji Daisuke Yamamoto Jun Kinoshita Noriyuki Inaki

Background: Malnutrition is common among patients with cancer and has been associated with unfavorable postoperative outcomes, including higher rates of complications. This study aimed to synthesize current evidence on the relationship between malnutrition, as defined by the Global Leadership Initiative on Malnutrition (GLIM) criteria, and postoperative outcomes after curative surgery for upper gastrointestinal (GI) cancers. Methods: We systematically searched the literature from database inception to 28 March 2026. Studies were eligible if they included adult patients with upper GI cancer who underwent surgical resection and had their nutritional status evaluated according to the GLIM criteria. We conducted a systematic review and random-effects meta-analysis. The primary outcomes were overall survival and overall postoperative complications, defined as events with a Clavien–Dindo grade ≥ II occurring within 30 days after surgery. Hazard ratios with 95% confidence intervals for overall survival and risk ratios with 95% CIs for postoperative complications were pooled. Results: Fourteen studies (17 reports) including a total of 7876 patients were eligible for both qualitative and quantitative synthesis. Compared with patients without malnutrition, those with GLIM-defined malnutrition showed poorer overall survival (hazard ratio: 1.96, 95% confidence interval: 1.57–2.45) and a higher risk of postoperative complications (risk ratio: 1.43, 95% confidence interval: 1.14–1.79). Conclusions: GLIM-defined malnutrition was associated with shorter overall survival and a higher incidence of postoperative complications in patients with upper GI cancer after surgery. However, because most included studies were observational and at low-to-moderate certainty of evidence, these associations should be interpreted with appropriate caution.

Cancers doi: 10.3390/cancers18142216

Authors: Marzena Janiszewska Tomasz Siudziński Krzysztof Składowski Adam J. Maciejczyk

Objectives: Our objective was to develop and evaluate a locally trained knowledge-based planning (KBP) model for head and neck (H&N), brain, and central nervous system malignancies using RapidPlan, and to determine whether standard statistical metrics such as the coefficient of determination (R2) and outlier frequency are definitive predictors of clinical utility. Methods: An institutional dataset of 594 plans was retrospectively curated into a 497-plan training set. Performance was evaluated in 370 paired plan comparisons generated with identical beam geometry. Training–validation overlap was explicitly quantified at both plan and patient levels, and a plan-level held-out sensitivity analysis was performed. Additional analyses included monitor units (MUs), subgroup assessment, clinically relevant OAR threshold achievement, and 95% confidence intervals for paired differences. Results: The validation set included 370 plans from 289 patients. At the plan level, 303 validation plans overlapped with the training model, and 67 were held-out cases; at the patient level, no fully patient-independent validation cohort was available. RapidPlan maintained target coverage while reducing OAR doses, including oral cavity Dmean (−7.62%Rx; 95% CI: −8.91 to −6.32; p < 0.001) and larynx Dmean (−7.57%Rx; 95% CI: −9.14 to −6.00; p < 0.001). The same direction of benefit was observed in the plan-level held-out subset. MU did not increase with RapidPlan and decreased from 764.2 ± 275.5 to 695.8 ± 210.3 MU (Delta = −68.4 MU; 95% CI: −89.4 to −47.4; p < 0.001). Conclusions: A high R2 was not required for clinically useful optimization objectives in this heterogeneous cohort. However, the retrospective design and patient-level overlap limit claims of full generalizability. The model should therefore be interpreted as a clinically useful standardization and decision-support tool requiring expert review rather than as a replacement for the judgment of physicists and radiation oncologists.

Cancers doi: 10.3390/cancers18142215

Authors: Haley Willem Tyler Aguilar Arthur W. Cowman Kristel Lourdault Richard Essner

Imaging techniques used for the care of cutaneous melanoma patients have greatly changed over the past century, from symptom-driven radiography toward a multimodality framework integrated for staging, directing surgery, and systemic therapy, and surveillance. Historically, clinical evaluation and skin exams have been the tenets of melanoma diagnosis and staging. In recent years, noninvasive imaging, such as dermoscopy, total-body photography and reflectance confocal microscopy, has expanded the diagnostic toolset for primary melanoma detection. Concurrently, several imaging techniques have been developed to detect metastases and follow disease progression, including computed tomography (CT), magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), lymphoscintigraphy, and single-photon emission computed tomography/computed tomography (SPECT/CT). The use of immune checkpoint inhibitors has also altered imaging interpretation by introducing atypical response patterns, including pseudoprogression, requiring immune-adapted assessment frameworks such as Immune Response Evaluation Criteria in Solid Tumors (iRECIST). While there is a strong consensus for high-risk patients, imaging techniques and surveillance schedules for low-risk patients (stage I/II) remain controversial due to limited supporting evidence and conflicting data on costs and patient benefit. The development of new technologies, including image-guided surgery, non-FDG PET tracers, phone apps, artificial intelligence-assisted image analysis, and radiomics, may further change melanoma imaging. The aim of this review is to detail the historical evolution of melanoma imaging, the development of new imaging techniques, and their role and future in clinical practice.

Cancers doi: 10.3390/cancers18142214

Authors: Xiao Zhang Yang Fu Hongsheng Wang Xiaohua Zhu Yi Yu Ping Cao Chen Shen Xiaowen Zhai

Background: Febrile neutropenia (FN) is a major complication of chemotherapy in pediatric hematological malignancies. This study compared the efficacy and safety of prophylactic pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) versus daily short-acting recombinant human granulocyte colony-stimulating factor (rhG-CSF). Methods: This single-center, open-label, randomized controlled trial was conducted at a tertiary children’s hospital in China. Pediatric patients (<18 years) with confirmed hematological malignancies (leukemia or lymphoma) were enrolled. A total of 138 chemotherapy cycles were randomized 2:1 to receive either a single dose of PEG-rhG-CSF (100 μg/kg, n = 86 cycles) or daily short-acting rhG-CSF (5 μg/kg/day, n = 45 cycles) after chemotherapy. The primary endpoint was FN incidence. Secondary endpoints included neutropenia incidence, FN duration, time to neutrophil recovery, blood product transfusions, hospital stay, and costs. Safety was assessed by monitoring adverse events (AEs) graded according to NCI CTCAE version 4.03. Results: Baseline characteristics were comparable between groups. PEG-rhG-CSF significantly reduced the incidence of FN (59.3% vs. 77.7%, OR 0.42 (0.18–0.97), p = 0.046) compared to daily rhG-CSF. The median time to neutrophil recovery was 9.8 days (95% CI: 8.1–10.7) in the PEG-rhG-CSF group and 10.3 days (95% CI: 8.6–11.1) in the control group (p = 0.45). No significant differences were observed in FN duration, transfusions, hospital stay, or costs. Subgroup analyses showed PEG-rhG-CSF significantly reduced FN in non-Hodgkin lymphoma (57.4% vs. 83.3%, OR 0.27 (0.08–0.89), p = 0.032). A total of 12 AEs (9.9% overall, mainly bone pain) were observed, with no significant difference between groups and no infection-related deaths. Conclusions: In this single-center, open-label trial, prophylactic single-dose PEG-rhG-CSF was associated with a lower incidence of FN compared to daily short-acting rhG-CSF. Safety profiles appeared broadly similar, but the sample size was insufficient to detect rare differences.

Cancers doi: 10.3390/cancers18142213

Authors: Emmanuel Massy Julien Seiller Muriel Piperno Edith Bonnelye Denis Maillet Stéphane Dalle Clara Fontaine-Delaruelle Pierre-Jean Souquet Julien Péron Cyrille B. Confavreux

Background/Objectives: Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs), including rheumatic manifestations affecting 5–10% of treated patients. Managing rheumatic irAEs is challenging, as the use of glucocorticoids (GCs) or disease-modifying antirheumatic drugs (DMARDs) raises concerns about potentially impairing ICI antitumour efficacy. The oncological safety of DMARDs used specifically for rheumatic irAE management remains poorly characterised. Our objective was to evaluate the oncological safety profile of various rheumatic irAE treatment strategies. Methods: This single-centre retrospective observational study included 55 patients out of 104 who underwent rheumatological evaluation between July 2016 and October 2022. Patients were categorised into three groups: symptomatic treatment alone (analgesics/NSAIDs, n = 11), systemic glucocorticoids (GCs) only (n = 27), and conventional synthetic or biological disease-modifying antirheumatic drugs (csDMARDs and/or bDMARDs, n = 17). Overall survival (OS) and progression-free survival (PFS) were compared using a Kaplan–Meier analysis. Results: The three most frequent rheumatic irAE patterns were undifferentiated arthritis (n = 20), rheumatoid arthritis-like presentations (n = 14), and polymyalgia rheumatica (n = 11). Patients in the DMARD group had more severe irAEs (CTCAE grade ≥3: 30% vs. 15%, p < 0.01) and a higher baseline CRP (27.5 vs. 17.4 mg/L, p < 0.05), reflecting greater disease burden at treatment initiation. No significant difference was observed between groups for OS (p = 0.22) or PFS (p = 0.31) over a median follow-up of 34 months. Conclusions: No detrimental oncological safety signal was identified across rheumatic irAE treatment strategies, including GCs combined with csDMARDs or bDMARDs. These results support the cautious use of DMARDs as GC-sparing agents when clinically indicated, consistent with current EULAR and ESMO guidelines, and underline the need for prospective trials to optimise immunosuppressive management in ICI-treated patients.

Cancers doi: 10.3390/cancers18142210

Authors: Fatemeh Sadat Tabatabaei Nicholas J. Caldwell Nattaya Teeyapun Seyed Mohammad Amin Dashti Sienna M. Durbin Matthew Strickland Jonathan N. Glickman Samuel J. Klempner

Rare subtypes of gastroesophageal malignancies represent a small but biologically meaningful fraction of upper gastrointestinal cancers. Although most therapeutic algorithms are derived from conventional squamous cell carcinoma and adenocarcinoma, uncommon entities such as variants of squamous cell carcinoma, lymphoepithelioma-like carcinoma, adenosquamous carcinoma, neuroendocrine carcinoma, and others display distinct clinicopathologic, immunologic, and molecular features that may influence prognosis and therapeutic decision-making. This review synthesizes current evidence regarding the epidemiology, histopathology, molecular alterations, and emerging therapeutic vulnerabilities across these rare subtypes. Importantly, these tumors frequently exhibit aggressive clinical behavior and are often managed by extrapolation from more common histologies due to the absence of prospective data. Increasing integration of genomic profiling, immune characterization, and biomarker-driven stratification is essential to refine diagnoses, expand precision therapeutic strategies, and improve outcomes. Recognition of these rare subtypes in routine practice is critical, as even small molecularly defined populations may carry disproportionate biological and translational significance within oncology.

Cancers doi: 10.3390/cancers18142211

Authors: Nath Pampita Babu Santha Aswani Bandari BharathwajChetty Sameena Lone Mangala Hegde Sunil C. Kaul Kazumi Hirano Renu Wadhwa Ajaikumar B. Kunnumakkara

Cancer remains one of the most frightening global health challenges, contributing substantially to morbidity and mortality across diverse populations. In recent years, naturally derived compounds have attracted considerable attention due to their potential therapeutic efficacy and fewer adverse effects. Among these, the flavokawain subclass of chalcones, comprising Flavokawains A, B, and C, obtained from various plant sources, has emerged as a promising group of bioactive phytochemicals exhibiting a broad spectrum of pharmacological activities, with notable anticancer potential. This review critically compiles and evaluates the existing preclinical evidence regarding the anticancer mechanisms of flavokawains across various cancer models. It was found that these compounds have significant potential to inhibit cancer cell proliferation, induce apoptosis, disrupt cell-cycle progression, and modulate multiple molecular pathways implicated in tumorigenesis, including phosphoinositide 3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), extracellular-signal regulated kinase/c-Jun N-terminal kinase/mitogen-activated protein kinase (ERK/JNK/MAPK) and so on. Importantly, flavokawains exert significant modulatory effects within the tumor microenvironment by suppressing angiogenesis through downregulation of vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1), attenuating epithelial-mesenchymal transition via restoration of E-cadherin and suppression of vimentin and Snail1, inhibiting matrix metalloproteinase (MMP)-mediated extracellular matrix remodeling, and disrupting cancer stem cell (CSC)-supportive niches. Preclinical toxicity profiles suggest a favorable safety margin, though further investigation is required to fully elucidate their therapeutic index. Due to their multifaceted mechanisms of action and selective cytotoxicity toward cancer cells, flavokawains are considered promising preclinical candidates for development as adjuncts or alternatives to conventional chemotherapeutic agents.

Cancers doi: 10.3390/cancers18142212

Authors: Calogero Geraci Rossella Cannarella Valentina Morello Valentina Paternò Salvatore Massimo Petrina Roberta Esposito Giulio Geraci Rosita A. Condorelli Sandro La Vignera Aldo E. Calogero

Background: Obesity has evolved from a morphometric descriptor to a chronic, relapsing, multisystem disease in which low-grade adipose-tissue inflammation, insulin resistance, endothelial dysfunction, and a prothrombotic, pro-tumorigenic milieu coexist. Venous thromboembolism (VTE) and malignancy share this substrate through a well-established bidirectional link: within twelve months of an unprovoked deep vein thrombosis (DVT), 6–15% of patients are diagnosed with occult cancer, a substantial proportion of which are already locally advanced or metastatic at detection. In this context, obesity acts as a dual amplifier of both thrombotic and oncologic risk, making the post-DVT patient with an incidentally diagnosed cancer a paradigmatic candidate for integrated management. Objective: To propose an evidence-based, unifying cardiometabolic and antithrombotic clinical framework that reconciles (i) risk-stratified screening for occult malignancy after unprovoked DVT, (ii) contemporary pharmacotherapy of obesity, and (iii) cancer-associated thrombosis (CAT) management, in the light of evidence published through 2025. Methods: Narrative synthesis based on a structured literature search (PubMed/MEDLINE, Embase, Scopus; 2000–March 2025) of current guidelines (ISTH, ASH, ESC Cardio-Oncology, EASO) and pivotal randomized evidence on GLP-1 and dual GLP-1/GIP receptor agonists (semaglutide, tirzepatide), SGLT2 inhibitors (empagliflozin, dapagliflozin), and direct oral anticoagulants (DOACs), with critical interpretation of recent meta-analytic data on oncologic signals, cardiovascular outcomes, and bleeding safety. Results: Three evidence-based pillars emerge: (1) limited screening complemented by age- and sex-specific testing in patients ≥ 50 years with unprovoked DVT, enhanced by FDG-PET/CT for high-risk phenotypes in which obesity itself degrades the sensitivity of clinical examination and conventional imaging; (2) GLP-1/GIP receptor agonist-based anti-obesity pharmacotherapy, associated in observational cohorts with a 17% relative reduction in overall cancer incidence (HR 0.83; 95% CI 0.76–0.91) and neutral-to-reassuring oncologic signals, but requiring cautious, case-by-case use in patients with active cancer because of the risk of accelerating sarcopenia and cachexia; and (3) apixaban as the preferred DOAC for cancer-associated thrombosis, with a superior efficacy-to-bleeding ratio in network meta-analyses and a reduced-dose extended strategy now validated by the API-CAT trial. Conclusions: Patients with obesity presenting with unprovoked DVT and an incidentally detected cancer embody a cardiometabolic–antithrombotic continuum. A framework integrating structured occult-cancer screening, judicious obesity pharmacotherapy, and apixaban-preferred anticoagulation—coordinated by a multidisciplinary team and illustrated here by a case-based pathway—offers the most rational, evidence-aligned approach. Prospective, dedicated trials in this specific phenotype are urgently warranted.

Cancers doi: 10.3390/cancers18142209

Authors: Kiyon Naser-Tavakolian Abin Sajan Alyssa Knight Nikhil Jacob Stephen P. Reis Ahmed Abdelal Binta Patel Michael A. Clifton Muhammad Usman Shahid Kirema Garcia-Reyes Leigh Casadaban Maarten L. J. Smits Zachary T. Berman Venkatesh P. Krishnasamy

Purpose: Percutaneous thermal ablation of hypervascular liver tumors is limited by lesion conspicuity on conventional imaging, challenges with ablative margin assessment, and unequal global access to advanced technologies such as ablation confirmation software and radioembolization. This review describes the selective intra-arterial lipiodol injection (SIALI) technique, its technical variations across institutions, and summarizes published clinical outcomes for SIALI-guided thermal ablation of hepatic malignancies. Methods: A narrative review was conducted through structured searches of the PubMed, Embase, and Cochrane databases using terms including “selective intra-arterial lipiodol injection,” “lipiodol-guided ablation,” “SIALI,” and “hepatic arterial lipiodol.” Studies were selected based on relevance to SIALI technique, clinical outcomes, and comparator techniques, including hepatic arteriography with C-arm CT-guided ablation (hepACAGA) and ablation confirmation software. Full-text peer-reviewed articles were included; conference abstracts and letters were excluded. No formal PRISMA-compliant inclusion or exclusion criteria were applied, consistent with the narrative review format. Results: Seven studies were identified, encompassing six retrospective cohort studies and one prospective randomized controlled trial, collectively comprising over 900 patients treated across institutions in Asia, Europe, and the United States. Across heterogeneous patient populations and technical approaches, SIALI-guided thermal ablation was associated with improved local tumor recurrence rates, local recurrence-free survival, and overall survival compared with conventional ultrasound- or CT-guided ablation alone in selected studies where comparator data were available, with favorable technical success rates in lesions otherwise occult on standard imaging. Conclusion: SIALI appears to be a technically feasible and potentially useful adjunct technique that may improve lesion conspicuity and enable real-time ablative margin assessment in the treatment of hypervascular liver tumors, particularly in settings without access to ablation confirmation software. The available evidence is predominantly retrospective, and prospective validation is needed before broad conclusions regarding oncologic outcomes can be drawn.

Cancers doi: 10.3390/cancers18142208

Authors: Daniel P. Steinfort Matthew Evison

Systematic endoscopic mediastinal lymph node staging is imperative to most accurately define the extent of LN involvement in patients with locally advanced (cN2) NSCLC. It provides the most accurate nodal information in comparison to imaging techniques and is the most likely investigation to differentiate N2a from N2b disease. Accumulation of evidence to validate the prognostic, and potentially the predictive value of accurately defining N2a and N2b N-status will be supported by more consistent and more comprehensive mediastinal endoscopic staging in this group, aided by more detailed (synoptic) reporting. We identify proposed solutions for enhancement of systematic staging in patients with N2 NSCLC, including routine performance of systematic lymph node assessment, with sampling of all LN > 6 mm, addition of EUS-B-FNA where possible, and use of synoptic reporting to reduce variance in care and enable performance monitoring.

Cancers doi: 10.3390/cancers18142207

Authors: Enrique Amaya Jacobo Palma Roser Fayós-Solà Rosa Meiriño Mauricio Cambeiro Ana Navarrete Pablo Cabello-García Alberto Viñals Diego Pedrero Felipe A. Calvo Javier Aristu Javier Serrano

Background/Objectives: Photon re-irradiation in previously treated head and neck cancer (HNC) is constrained by cumulative normal-tissue toxicity. Pencil-beam scanning intensity-modulated proton therapy (PBS-IMPT) allows for a sharper dose conformation than conventional photon techniques, which may widen the therapeutic window in previously irradiated tissue. Methods: Sixty-five patients with recurrent or second primary HNC were enrolled in a prospective single-institution registry and re-irradiated with PBS-IMPT between January 2020 and December 2025. Forty-five were treated with radical intent (69.2%), and 20 were treated postoperatively (30.8%), with a median prescribed dose of 66 Gy (RBE) in 30 fractions. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Locoregional control (LRC), adverse events and the prognostic impact of anatomical extent were secondary endpoints. Results: The median follow-up was 9.3 months. The median OS was 17.2 months (95% CI 13.9–NR), with a 12-month rate of 67.1%. The median PFS was 10.1 months and the median LRC was 28.1 months. Central/skull-base involvement was associated with a non-significant trend toward worse OS (14.3 vs. 35.2 months; p = 0.062) and with significantly worse PFS (9.1 vs. 14.7 months; p = 0.037) than peripheral disease, but LRC did not differ between the groups (p = 0.240). Grade ≥ 3 oral mucositis occurred in 7.7%, with no grade 4–5 acute events. Within a median follow-up of 9.3 months, late osteoradionecrosis affected 6.2%, but late toxicity data remain preliminary given the short follow-up. Ninety-two percent of patients completed treatment. Conclusions: PBS-IMPT re-irradiation provided adequate survival with low acute toxicity. T3–T4 stage at re-irradiation was the only variable retaining significance for PFS on multivariable analysis (HR 4.32, 95% CI 1.24–15.13; p = 0.022). The poor survival observed for central/skull-base disease on Kaplan–Meier curves disappeared after T-stage adjustment, indicating the higher concentration of advanced disease in that compartment. Multicentre prospective data and longer follow-up are needed.

Cancers doi: 10.3390/cancers18142206

Authors: Kiarash Mashayekhi Mark Kidd Anthony Gulati

Background/Objectives: Reliable biomarkers for longitudinal surveillance of neuroendocrine tumors (NETs) remain an unmet clinical need. Chromogranin A (CgA), the most widely used circulating biomarker, is limited by low sensitivity, substantial biologic variability, and poor concordance with radiologic progression. NETest2.0® is a blood-based multigene transcriptomic liquid biopsy designed to dynamically assess NET biologic activity. This study compared serial NETest2.0® measurements with CgA for monitoring disease progression in a real-world registry cohort. Methods: Patients with histologically confirmed NETs enrolled in the RegisterNET program (NCT02270567) who had paired blood samples and contemporaneous clinical assessment were included. NETest2.0® scores were derived from quantitative RT-PCR analysis of a 51-gene transcript panel and expressed on a 0–100 scale. Serum CgA levels were measured using standard clinical immunoassays. Imaging-based disease assessment was performed using CT, MRI, and/or 68Ga-somatostatin receptor PET/CT with RECIST 1.1 criteria applied where appropriate. Longitudinal percentage changes (Δ) between sequential measurements were evaluated using predefined NETest2.0® thresholds and compared with the conventional CgA threshold (>50%). NETest2.0 Δ thresholds of >0% and >5% were evaluated a priori: >0% as a high-sensitivity threshold capturing any upward transcriptomic drift, and >5% as a more conservative threshold intended to reduce minor biological or analytical fluctuation. Receiver operating characteristic (ROC) analysis, operating characteristics, multivariable analysis (MVA), and logistic regression analysis (LRA) were performed. Results: A total of 191 patients were analyzed. Exploratory ROC analysis demonstrated superior discrimination for progression using serial NETest2.0® changes compared with changes in CgA (AUC: 0.893 vs. 0.538; p < 0.0001). In the primary surveillance analysis, NETest2.0® thresholds of >0% and >5% achieved AUCs of 0.860 (95% CI: 0.803–0.906) and 0.822 (95% CI: 0.760–0.873), respectively, both significantly superior to CgA (AUC: 0.553, 95% CI: 0.480–0.625; both p < 0.0001). NETest2.0® >0% demonstrated the highest sensitivity (86.4%), whereas NETest2.0® >5% achieved the optimal balance of sensitivity (70.5%), specificity (93.9%), and overall accuracy (88.5%). In multivariable and logistic regression analyses, changes in NETest2.0® were the strongest independent predictor of progression (all p < 0.0001; odds ratios: 52.99–61.26), whereas CgA did not significantly contribute to progression prediction. Conclusions: Serial NETest2.0® assessment significantly outperformed CgA for monitoring NET disease activity and progression. These findings support the integration of NETest2.0®into molecularly informed surveillance strategies to complement imaging and improve longitudinal monitoring of patients with NETs.

Cancers doi: 10.3390/cancers18142205

Authors: Caterina Alati Maria Bruna Greve Gaetana Porto Giorgia Policastro Erica Bilardi Giovanna Utano Laura Giordano Martina Pitea Massimo Martino

Background: Systemic mastocytosis (SM) is a clonal mast cell (MC) neoplasm driven by somatically acquired activating mutations in the KIT receptor tyrosine kinase (CD117), resulting in pathological accumulation of morphologically atypical MCs in extracutaneous organs. The KIT D816V substitution is detectable in over 95% of cases by high-sensitivity next-generation sequencing (NGS) or allele-specific PCR. This gain-of-function variant confers ligand-independent receptor autophosphorylation, leading to constitutive activation of downstream signaling cascades that promote MC progenitor survival, clonal expansion, and resistance to apoptosis. Co-occurring somatic mutations in TET2, SRSF2, ASXL1, CBL, and RUNX1, increasingly identified in the context of clonal hematopoiesis of indeterminate potential, are associated with more aggressive phenotypes and independently confer adverse prognostic impact. Results: The 2022 WHO classification delineates indolent forms from advanced-phase SM, aggressive SM, SM with an associated hematologic neoplasm (SM-AHN), and MC leukemia, which produce progressive end-organ damage through both neoplastic tissue infiltration and uncontrolled mediator release. Formal diagnosis requires integration of histological criteria (multifocal bone marrow MC aggregates of ≥15 cells), immunophenotypic aberrancies (CD25, CD2, and/or CD30 coexpression on MCs by flow cytometry or immunohistochemistry), biochemical markers (baseline serum tryptase ≥ 20 ng/mL), and molecular confirmation of KIT D816V or equivalent pathogenic KIT mutation. The development of type I KIT inhibitors with selectivity for the D816V-mutant conformation has fundamentally restructured the therapeutic field of advanced SM. Conclusions: This review provides a thorough synthesis of SM pathobiology, WHO-defined diagnostic and classification criteria, validated prognostic tools, and the developing landscape of KIT-directed and combination therapies, with direct translational relevance for specialist practitioners managing this heterogeneous myeloid neoplasm.

Cancers doi: 10.3390/cancers18142204

Authors: Maen Abdelrahim Abdullah Esmail Nour Mustafa Ebtesam Al-Najjar Yazan Hamdaneh Zaid Alabed Hikmat Abdel-Razeq Asem Mansour

Background: Metastatic colorectal cancer (mCRC) that progresses after standard first- and second-line therapies carries a poor prognosis, and multiple third-line treatment options are available without a clearly established optimal strategy. This study aimed to comprehensively compare the efficacy and safety of currently approved third-line treatments using reconstructed individual patient data (reconstructed IPD). Methods: A systematic review and reconstructed IPD meta-analysis of phase III randomized controlled trials was conducted in accordance with PRISMA-IPD guidelines. Kaplan–Meier survival curves were digitized and reconstructed using validated methodologies. The primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS) and the incidence of grade ≥3 treatment-related adverse events (AEs). Results: A total of 3338 patients were included across five treatment groups: regorafenib (n = 650), fruquintinib (n = 739), trifluridine/tipiracil (TAS-102; n = 780), TAS-102 plus bevacizumab (n = 246), and pooled placebo (n = 923). TAS-102 plus bevacizumab demonstrated the greatest benefit (OS HR: 0.43, 95% CI: 0.35–0.50; median OS: 10.89 months; PFS HR: 0.20, median PFS: 5.51 months). Fruquintinib (OS HR: 0.67; median OS: 7.97 months; PFS HR: 0.32; median PFS: 3.70 months) and TAS-102 (OS HR: 0.70; median OS: 7.2 months; PFS HR: 0.41; median PFS: 2.09 months) showed comparable survival benefit to regorafenib (OS HR: 0.68; median OS: 7.04 months; PFS HR: 0.39; median PFS: 2.16 months), with fruquintinib demonstrating superior PFS versus regorafenib (HR: 0.71, p < 0.001). Grade ≥3 AEs were highest with TAS-102 plus bevacizumab (72.36%) and lowest with fruquintinib (34.02%), with hematologic toxicity predominating in TAS-102-based regimens and hypertension and hand–foot skin reactions more common with tyrosine kinase inhibitors. Conclusion: TAS-102 plus bevacizumab was associated with the greatest survival benefit in this indirect comparison and appears to be the most effective option for eligible patients. However, these findings should be interpreted cautiously given the absence of direct head-to-head trials. Among tyrosine kinase inhibitors, fruquintinib demonstrated superior PFS compared with regorafenib, while OS was comparable.

Cancers doi: 10.3390/cancers18142203

Authors: Jingru Xu Georges Lacaud

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by a block of differentiation and uncontrolled expansion of myeloid progenitor cells. Standard treatment includes intensive induction chemotherapy, typically with cytarabine and anthracycline, followed by consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation. However, these approaches are often associated with relapse and treatment-related toxicity. Accumulating evidence highlights a critical role for epigenetic dysregulation in driving disease initiation, progression, and therapeutic resistance. In this review, we examine an integrated framework of epigenetic regulation in AML, encompassing DNA methylation, histone post-translational modifications, chromatin remodeling, and RNA-mediated epigenetics. We discuss how alterations in key epigenetic regulators, such as DNMT3A, TET2, IDH1/2, EZH2, and histone-modifying enzymes, reshape the transcriptional and epigenetic landscape of leukemic cells. Particular emphasis is placed on epigenetically defined AML subtypes, including NPM1-mutated, DNMT3A-mutated, and KMT2A-rearranged AML, which illustrate distinct mechanisms of transcriptional and epigenetic dysregulation and confer unique therapeutic vulnerabilities. We further summarize current and emerging therapeutic strategies, ranging from conventional chemotherapy to molecularly targeted agents, epigenetic drugs, and immunotherapeutic approaches. Despite these advances, durable responses remain limited, highlighting the need to better understand epigenetic mechanisms to overcome resistance and improve patient outcomes.

Cancers doi: 10.3390/cancers18142202

Authors: Yasuto Jin Yukihisa Inoue Hiroyuki Shimada Tetsu Hara Shohei Yamashita Mio Yamamoto Osamu Matsubara

Background: Overexpression of programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) induces immune evasion by cancer cells. Nivolumab and pembrolizumab (anti-PD-1 antibodies) are used to treat advanced non-small cell lung cancer (NSCLC). However, objective response rates are limited (20–30%), indicating that individual tumor microenvironments may differ according to immune evasion processes. Therefore, the development of biomarkers predictive of responders to immune checkpoint inhibitors is necessary. Activation of the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) signaling pathway promotes lung cancer cell growth and resistance to chemotherapy, radiotherapy, targeted therapy, and PD-1/PD-L1 inhibition. The present study investigated whether NRF2 expression in NSCLC is associated with clinicopathological factors, the expression levels of intratumoral PD-L1 and CD8, and the efficacy of anti-PD-1 monotherapy. Methods: NRF2, PD-L1, and CD8 expression on tumor cells and tumor-infiltrating lymphocytes were examined by immunohistochemistry in 54 patients with advanced adenocarcinoma (N = 40) and squamous cell carcinoma (N = 14) treated with nivolumab or pembrolizumab. Histological subtypes, tumor stages, and other clinicopathological features were compared with their expression levels. Results: Weak NRF2 staining was significantly correlated with high levels of PD-L1 and CD8+ tumor-infiltrating lymphocytes, and a favorable response to treatment with nivolumab or pembrolizumab in NSCLC. Progression-free survival of patients treated with anti-PD-1 therapy differed according to the different NRF2 levels. Conclusions: NRF2 overexpression in NSCLC is associated with resistance to PD-1 blockade monotherapy.

Cancers doi: 10.3390/cancers18142201

Authors: Junjie Bao Qingyu Shi Mingbo Liu Huimin Xu Yunzhou Wu Jingya Zeng

Background: The survival benefit of primary tumor resection (PTR) in patients with synchronous metastatic primary malignant bone neoplasms (PMBNs) remains controversial. We aimed to evaluate the association between PTR and survival outcomes using a large population-based cohort with rigorous confounding control. Methods: Patients diagnosed with synchronous metastatic PMBNs (osteosarcoma, chondrosarcoma, Ewing sarcoma, and chordoma) between 2004 and 2022 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were stratified by receipt of PTR. Propensity score matching (PSM; 1:1 nearest-neighbor, caliper = 0.03) was applied to balance baseline covariates. Kaplan–Meier analysis with log-rank testing and multivariable Cox proportional hazards regression stratified by matched pairs were used to assess overall survival (OS) and cancer-specific survival (CSS). Subgroup analyses were performed across four histological subtypes. Results: A total of 1046 patients were included (resection: n = 658, 62.9%; no resection: n = 388, 37.1%). After PSM, 488 patients (244 per group) were retained. In the matched cohort, PTR was independently associated with significantly improved Overall survival (OS) (HR = 0.34, 95% CI: 0.21–0.54, p < 0.001) and cancer-specific survival (CSS) (HR = 0.35, 95% CI: 0.22–0.55, p < 0.001). Subgroup analyses demonstrated significant survival benefit in osteosarcoma and chondrosarcoma (both p < 0.001), but not in Ewing sarcoma or chordoma. Conclusions: PTR is associated with a significant survival benefit in selected patients with synchronous metastatic PMBNs, particularly those with osteosarcoma and chondrosarcoma. These findings support individualized, multidisciplinary decision-making regarding surgical intervention in this population.

Cancers doi: 10.3390/cancers18142200

Authors: Misato Nakano Asuka Tamura Sora Yorikawa Nahoko Matsuki Runa Ito Hideaki Matsuoka Mikako Saito

Background/Objectives: Extracellular vesicles (EVs) participate in tumor progression and immune regulation through the transfer of bioactive molecules. Although tumor-derived EVs are generally considered to promote metastasis, accumulating evidence suggests that their functions vary according to the biological characteristics of their cells of origin. This study investigated the mechanisms underlying the anti-metastatic effects of EVs derived from Nanog-overexpressing melanoma cells (Nanog+F10-EVs). Methods: Nanog+F10-EVs were isolated and characterized by EV marker expression. Their anti-metastatic activity was evaluated using melanoma liver metastasis models in Rag2-deficient and macrophage-depleted mice. Differential miRNA expression analysis was performed to identify candidate functional mediators. Functional studies were conducted using miR-19a-3p-overexpressing cells and EVs. Results: Nanog+F10-EVs significantly suppressed melanoma metastasis. Rag2 deficiency only modestly affected this activity, whereas macrophage depletion abolished the anti-metastatic effect, suggesting a predominant role of innate immunity. miRNA profiling identified miR-19a-3p as a candidate mediator enriched in Nanog+F10-EVs. Despite promoting tumor cell proliferation and migration, miR-19a-3p-enriched EVs partially reproduced anti-metastatic activity. Macrophage marker analysis suggested that these effects were not fully explained by classical M1/M2 polarization. Conclusions: Nanog+F10-EVs may suppress metastasis through macrophage-dependent innate immune regulation potentially mediated by miR-19a-3p and are consistent with a model of preemptive immune education.

Cancers doi: 10.3390/cancers18142199

Authors: Kamil Krystkiewicz Aleksander Kowal Agata Krajniak Michał Dziatosz Mateusz Bilski Łukasz Kuncman Marcin Tosik

Background/Objectives: Patients undergoing surgery for metastatic spinal disease often require instrumented stabilization followed by radiotherapy and postoperative magnetic resonance imaging (MRI) surveillance. Titanium implants may generate artifacts that impair assessment of the operated level, whereas carbon fiber-reinforced polyetheretherketone (CFR-PEEK) constructs may improve MRI assessability. This study compared CFR-PEEK and titanium instrumentation with respect to postoperative MRI artifact burden, early outcomes, and oncological follow-up, and introduced a study-specific artifact grading system. Methods: This retrospective single-center cohort included 78 patients treated with instrumented stabilization for metastatic spinal disease: 33 with CFR-PEEK and 45 with titanium instrumentation. Postoperative MRI suitable for artifact assessment was available in 47 patients. Implant-related artifacts were evaluated using the Oncologic Spinal Instrumentation MRI Artifact Score (O-SIMAS), a 0–5 anatomy-based grading system. Early postoperative outcomes, local recurrence, progression-free survival, overall survival, and interrater agreement were analyzed. Results: CFR-PEEK instrumentation was associated with lower postoperative MRI artifact burden than titanium instrumentation, with median O-SIMAS scores of 2.0 versus 3.0, respectively (p < 0.001). High-grade artifacts were less frequent after CFR-PEEK than after titanium instrumentation (15.8% versus 67.9%; p = 0.0008). Titanium instrumentation remained independently associated with high-grade artifacts. Early postoperative outcomes, local recurrence, progression-free survival, and overall survival did not differ significantly between groups. O-SIMAS showed substantial pairwise interrater agreement. Conclusions: CFR-PEEK instrumentation was associated with improved postoperative MRI assessability and fewer diagnostically relevant artifacts than titanium instrumentation. No oncological benefit was shown. O-SIMAS may support structured artifact assessment, but requires external validation.

Cancers doi: 10.3390/cancers18142198

Authors: Mariela A. Blum Murphy Lianchun Xiao Matheus Sewastjanow-Silva Xumei Wang Brian D. Badgwell Paul F. Mansfield Naruhiko Ikoma Cindy M. Pabon Jeffrey H. Lee Manoop S. Bhutani Brian Weston Emmanuel Coronel Grace L. Smith Emma B. Holliday Jessie Tian Anas M. Barabrah Prajnan Das Bruce D. Minsky Rebecca E. Waters Jeannelyn S. Estrella Jenny J. Li Jaffer A. Ajani

Background/Objectives: Immunotherapy (IO) has demonstrated survival benefits in metastatic gastroesophageal cancers, and current data supports perioperative IO in localized adenocarcinomas. Radiation may further enhance IO response through immunologic priming. This study evaluates the feasibility, safety, and preliminary efficacy of incorporating IO into a chemoradiation-based perioperative strategy for resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma. Methods: This single-arm, phase I/II study enrolled adults with untreated, locally advanced, resectable gastric or GEJ adenocarcinoma between February 2019 and June 2023. The treatment protocol consisted of induction chemotherapy (oxaliplatin + 5-fluorouracil), induction IO (nivolumab + ipilimumab), concurrent immune-chemoradiation (nivolumab, 5-fluorouracil, and 45 Gy IMRT/VMAT), surgical resection, and adjuvant nivolumab for residual disease. Primary endpoints were safety and feasibility; secondary endpoints included the pathologic complete response (pCR), R0 resection rate, disease-free survival (DFS), overall survival (OS), and biomarker analysis. Results: In total, 30 patients were enrolled, and 23 underwent resection. Grade 4 treatment-related toxicities occurred in three patients (10%), including acute kidney injury, myocarditis/myositis/myasthenia gravis overlap syndrome, and neutropenia. Among surgical patients, the pCR rate was 39.1% (95% CI: 19.7–61.5%), and the intention-to-treat pCR rate was 30% (95% CI: 14.7–49.4%). R0 resection was achieved in 87% of cases. Median DFS among resected patients was 40.2 months (95% CI: 21.6–NE). Median OS was 43.7 months (95% CI: 30.7–NE), with 2-, 3-, and 5-year OS rates of 73.3%, 57.5%, and 47.9%, respectively. Conclusions: This multimodality approach incorporating IO with chemotherapy and chemoradiation demonstrated a manageable safety profile and an encouraging pCR rate, supporting further evaluation.

Cancers doi: 10.3390/cancers18142197

Authors: Jun Chih Wang Daniel Rosas Luis E. Raez

Bispecific antibodies (bsAbs) have emerged as a novel therapeutic class in oncogene-driven non-small-cell lung cancer (NSCLC), designed to simultaneously target multiple signaling pathways and overcome resistance mechanisms associated with tyrosine kinase inhibitors (TKIs). Unlike small-molecule TKIs, bsAbs enable dual receptor blockade and immune effector engagement, offering a mechanistically distinct advantage in the context of tumor heterogeneity and bypass signaling. This review summarizes the structural and biological principles underlying bsAb design, with a focus on clinically approved agents such as amivantamab (EGFR/MET) and zenocutuzumab (HER2/HER3) and a growing pipeline of investigational agents. We evaluate key clinical evidence from Phase I-III trials including CHRYSALIS, PAPILLON, MARIPOSA, MARIPOSA-2 and eNRGy, and compare the efficacy, toxicity, and CNS penetration profile of bsAbs relative to TKIs and antibody–drug conjugates (ADCs). While bsAbs demonstrate meaningful clinical activity, particularly in TKI-resistant disease and molecularly defined subsets such as EGFR exon 20 insertions and NRG1 fusions, their limitations, including intravenous administration, increased immune-mediated and thromboembolic toxicity, currently preclude replacement of TKIs in most settings. Collectively, available evidence supports a complementary role for bsAbs within evolving multimodal treatment paradigms, particularly in combination strategies. Future directions include biomarker-driven patient selection, improved drug engineering and integration into adaptive therapeutic sequencing frameworks.

Cancers doi: 10.3390/cancers18142194

Authors: Lin Zhu Chunying Shen Wei Qian Peiyao Liu Tingting Xu Huijuan Liu Xin Zhou Xueguan Lu

Background: Circulating tumor HPV DNA (ctHPV DNA) has shown clinical value in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), but its relationship with tumor burden and its role in prognosis, especially when combined with clinicoradiological factors, remain to be further defined. Methods: We analyzed 103 patients with HPV-positive OPSCC enrolled in an observational biomarker study, most of whom received induction chemotherapy or chemoimmunotherapy followed by definitive radiotherapy. Blood samples were collected at pretreatment, post-radiotherapy, and follow-up time points, and ctHPV DNA levels were quantified using droplet digital PCR. Baseline clinicoradiological parameters from contrast-enhanced MR or CT and 18F-FDG PET/CT were analyzed for their association with ctHPV DNA levels and clinical outcomes. Results: Baseline ctHPV DNA correlated with primary tumor volume (VT), nodal volume (VN), total tumor volume (VT+N), and the number of involved primary tumor sites and lymph node regions, particularly LN-related features. VT and maximum LN diameter were independent predictors of baseline ctHPV DNA. Detectable follow-up ctHPV DNA was associated with inferior progression-free survival but showed low sensitivity and positive predictive value for relapse detection. Integrative stratification using baseline ctHPV DNA and VT+N identified a potential high-risk subgroup with high tumor volume but paradoxically low ctHPV DNA (VOLhighDNAlow). Exploratory RNA-seq analysis was performed to investigate potential biological features underlying this discordance, and a seven-gene signature associated with PFS was identified. Conclusions: These findings suggest that baseline ctHPV DNA reflects tumor burden and may provide additional information for upfront risk stratification in HPV-positive OPSCC, warranting further validation in larger prospective cohorts.

Cancers doi: 10.3390/cancers18142196

Authors: Felishia Tian Sarah Soyeon Oh Chul S. Hyun Han Sang Kim Jae Il Shin

Background/Objectives: eccDNA is a promising cancer biomarker in liquid biopsy. However, the reliability and reproducibility of eccDNA studies rely on the standardization of pre-analytical handling and processing of eccDNA, as well as transparent methodological reporting. Although evidence-based guidelines for cell-free DNA handling provide clear recommendations for plasma/serum processing, the extent to which eccDNA studies report and adhere to these key procedures remains uncertain. Methods: We systematically reviewed 14 studies (2017–2025) assessing eccDNA in plasma or serum from cancer patients. Each study was evaluated against 22 checklist items summarized from the NCI Biospecimen Collection and Processing Guideline, categorized into biospecimen collection, blood processing, and eccDNA processing. Items were classified as “reported,” “not reported,” or “deviated from NCI guideline,” and missing/deviation rates were calculated. Results: Publication was largely post-guideline (13/14 after 2020). Reporting gaps were widespread. Items with 100% missing were venipuncture site (14/14), freeze–thaw cycles (14/14), and fitness for downstream analysis/pre-assay QC (14/14). Other frequently missing elements included blood volume (10/14; 71%), collection tube type (7/14; 50%), date/time from draw to processing (11/14; 79%), second centrifugation parameters (8/14; 57%), storage temperature before freezing (6/14; 43%), frozen storage duration (13/14; 93%), and post-thaw handling (13/14; 93%). By contrast, the extraction method was consistently reported (0% missing), and most reported quantification (21% missing). Deviations from the NCI guideline were uncommon when items were reported, such as a blood processing delay (2/14; 14%) and the use of circulating nucleic acid kits for eccDNA extraction (1/14; 7%). Conclusions: Inconsistent reporting of pre-analytical procedures limits the reproducibility, transparency, and clinical translation of eccDNA research. We propose a concise reporting checklist informed by the NCI guideline. By focusing on the most frequently underreported aspects of key pre-analytical eccDNA procedures, the checklist provides researchers with an efficient and succinct methodological reporting framework that will enhance transparency and promote standardization in future eccDNA studies.

Cancers doi: 10.3390/cancers18142195

Authors: Nicole Goncalves Kelly Lamiman Michael Silver Ioannis Alagkiozidis

Objective: Previous studies have demonstrated that the use of laparoscopy prior to laparotomy for primary debulking surgery (PDS) in advanced ovarian cancer is linked to lower rates of suboptimal cytoreduction. However, its impact on overall survival remains uncertain. This study aimed to compare overall survival and surgical outcomes between PDS cases initiated with laparoscopy and those without. Methods: We identified patients in the National Cancer Database who underwent PDS for stage IIIC and IV epithelial ovarian cancer between 1 January 2010 and 31 December 2017. Patients were divided into two groups for analysis: cases that were initiated with laparoscopy and those that were not initiated with laparoscopy. The primary outcome was overall survival, while secondary outcomes included 90-day postoperative mortality, 30-day readmission rate, and length of hospital stay. Statistical analyses were performed using SPSS version 29.0. Results: Among 12,532 eligible patients, 529 cases (4.2%) were initiated laparoscopically. Laparoscopy utilization increased from 3.4% to 6.9% over the study period. Rates of complete gross resection were similar between groups. Postoperative outcomes, including 90-day mortality, 30-day readmission, and hospital stay, did not differ significantly. However, laparoscopy was associated with improved overall survival in patients who proceeded to PDS (60.8 vs. 51.6 months, p = 0.012). In stage-stratified analysis, a survival benefit was noted in stage IIIC (64.5 vs. 55.2 months, p = 0.026), but not in stage IV cases. Conclusions: Despite its increasing use, the overall rate of laparoscopy before PDS remains low. Laparoscopy prior to laparotomy is associated with improved overall survival in patients with stage IIIC epithelial ovarian cancer undergoing PDS.

Cancers doi: 10.3390/cancers18142193

Authors: Marta Druszcz Justyna Łapińska Igor Kusio Wiktoria Krowisz Klaudia Gładowska Weronika Pająk Jakub Kleinrok Ryszard Sitarz Agnieszka Korolczuk

The global incidence of thyroid cancer (TC) has increased significantly in recent decades. Traditionally, this trend has been attributed to overdiagnosis resulting from the widespread use of imaging and improved diagnostic techniques, but increasing evidence suggests that current epidemiological patterns may not be fully explained by diagnostic factors alone. Most importantly, increasing rates of larger and more advanced tumors have been reported in several populations. This narrative review discusses the evidence on possible drivers of rising TC incidence: obesity and metabolic dysfunction, environmental exposures such as air pollution, and endocrine-disrupting chemicals (EDCs) and ionizing radiation, as well as molecular and genetic mechanisms involved in thyroid carcinogenesis. The role of advances in diagnostics and their contribution to overdiagnosis are also discussed. Current available data support a multifactorial model with better detection coupled with changes in environmental, metabolic and biological risk factors. A better understanding of the relative contribution and interaction of these determinants may help refine diagnostic strategies, reduce unnecessary interventions, and improve the prevention and management of TC.

Cancers doi: 10.3390/cancers18142192

Authors: Simin Elif Türker Marco Demaria Boshi Wang

Pharmacological cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have reshaped the treatment landscape of HR-positive, HER2-negative (HR+/HER2−) breast cancer and are increasingly being explored across diverse malignancies. By preventing retinoblastoma (RB) phosphorylation and enforcing G1-S cell cycle arrest, these agents achieve durable tumour control with a more favourable toxicity profile than conventional chemotherapy. Beyond their canonical cytostatic effects, prolonged CDK4/6 inhibitor treatments induce cellular senescence, a stable, proliferative arrest accompanied by profound transcriptional, epigenetic, and secretory changes. This review summarises current knowledge on CDK4/6 inhibitor-induced senescence in both cancer and normal cells as a central biological mechanism that links tumour suppression and microenvironmental remodelling. Importantly, this process is highly context-dependent, differing between tumour and non-malignant cells, with a distinct senescence-associated secretory phenotype (SASP) that shapes immune responses and tissue homeostasis. We also discuss how CDK4/6 inhibitor-induced senescence influences the tumour microenvironment by modulating immune surveillance, stromal interactions, and cancer cell plasticity. Finally, we examine emerging resistance mechanisms and rational combination strategies for CDK4/6 inhibitors, including targeting compensatory signalling pathways, immune checkpoint blockades, and senescence-directed sequential therapies. Collectively, CDK4/6 inhibitor-induced senescence represents both a challenge and a therapeutic opportunity, underscoring the need to integrate cell cycle control with the modulation of cellular states.

Cancers doi: 10.3390/cancers18142191

Authors: Imjai Chitapanarux Narongchai Autsavapromporn Wimrak Onchan Somvilai Chakrabandhu Pooriwat Muangwong Apidet Duangya Tanin Lertsiriladakul Atikorn Panya Atchara Paemanee

Background: H2 gas inhalation has been proposed as a selective modulator of reactive oxygen species (ROS), potentially mitigating treatment-related oxidative damage. This study investigated the effects of adjunctive H2 gas inhalation on serum metabolomic profiles and clinical toxicities in patients with LAHNC undergoing CCRT. Methods: Twenty patients were prospectively randomized to receive either standard CCRT alone (Group A) or CCRT combined with adjunctive H2 gas inhalation (Group B). Serum samples collected before and after treatment were analyzed using untargeted ultra-high-performance liquid chromatography coupled with ion mobility quadrupole time-of-flight high-resolution mass spectrometry (UHPLC-IM-QTOF-HRMS)-based metabolomics. Results: One patient in Group B discontinued participation, leaving 19 patients for the final analysis. Patients receiving adjunctive H2 gas inhalation tended to exhibit numerically lower frequencies of moderate treatment-related toxicities, fewer chemotherapy delays, and a shorter overall treatment duration than those receiving CCRT alone. Metabolomic profiling in the CCRT-alone group revealed exploratory alterations in metabolites associated with arginine metabolism, glutathione metabolism, and purine metabolism following treatment. Ornithine, uric acid, and tetrahydrodeoxycorticosterone were among the candidate discriminative metabolites with exploratory discriminatory performance after CCRT. In contrast, patients receiving adjunctive H2 gas inhalation showed a more limited pattern of pathway mapping, with exploratory evidence from an illustrative single-hit pathway assignment suggesting possible involvement of purine metabolism. Altered uric acid levels together with changes in several lipid-related metabolites may collectively reflect metabolic responses associated with treatment-related oxidative stress during CCRT. Consistent with these findings, direct between-group comparison of within-subject changes (Δ = post − pre) indicated a numerically smaller reduction in serum uric acid levels in the adjunctive H2 gas inhalation group; however, this difference did not reach statistical significance. Conclusions: Adjunctive H2 gas inhalation during CCRT may be associated with reduced moderate treatment-related toxicities and exploratory changes in systemic metabolic profiles in patients with LAHNC. However, the study was not designed to evaluate oncological outcomes, and the metabolomic findings, particularly the pathway-level interpretations, should be considered exploratory because several pathway assignments were based on only one or a few mapped metabolites, together with the limited sample size, patient heterogeneity, and lack of independent external validation. Further validation in larger, independent cohorts using comprehensive between-group metabolomic analyses is warranted.

Cancers doi: 10.3390/cancers18142190

Authors: Ishaan Vohra Harishankar Gopakumar Anuraga Meyyappan Cody Chen Garrett Blatter Brian Martins Shyam Thakkar Neil Sharma

Endoscopic submucosal dissection (ESD) has revolutionized the management of superficial colorectal neoplasms, offering superior en bloc resection rates compared with conventional endoscopic mucosal resection (EMR). While ESD has been the standard of care in East Asian countries for over two decades, its adoption in Western countries has been considerably slower, hampered by the steep learning curve, prolonged procedural times, limited training infrastructure, and differences in disease epidemiology. However, recent years have witnessed a paradigm shift, with growing evidence from Western multicenter studies demonstrating outcomes that increasingly approach those reported from high-volume Eastern centers. The landmark RESECT-COLON randomized trial provided level-1 evidence supporting the superiority of ESD over piecemeal EMR for large colorectal polyps. Concurrently, novel training paradigms, technological innovations including traction-assisted devices and artificial intelligence (AI)-guided systems, and evolving societal guidelines from the American Gastroenterological Association (AGA), American Society for Gastrointestinal Endoscopy (ASGE), and European Society of Gastrointestinal Endoscopy (ESGE) are accelerating Western adoption. This state-of-the-art review comprehensively examines the current landscape of colorectal ESD in Western practice, highlighting the evolution of outcomes, training pathways, guideline recommendations, technological advances, and future directions. We provide a critical appraisal of the East–West outcome gap and discuss strategies to bridge this divide, positioning colorectal ESD as an increasingly viable first-line therapy for appropriate lesions in Western endoscopy centers.

Cancers doi: 10.3390/cancers18142189

Authors: Kazunori Nakaoka Hiroyuki Kato Seiji Yamada Fumino Kato Yusaku Urakawa Gakushi Koumura Hiroyuki Tanaka Takuji Nakano Sayaka Ueno Teiji Kuzuya Hiroshi Matsuoka Tamotsu Sudo Yoshiki Hirooka Eizaburo Ohno

Background: Comprehensive genomic profiling (CGP) is increasingly incorporated into the management of biliary tract tumors (BTTs); however, single-center real-world data integrating clinical utility and site-specific genomic landscape remain limited. Methods: This retrospective single-center observational study included 91 patients with BTTs who underwent CGP. The primary endpoints were the rates of potentially actionable genomic alterations, expert panel-based therapeutic options, and implementation of genomically matched therapy. Secondary endpoints included the distribution of recurrent and clinically relevant genomic alterations according to the primary tumor site. Results: The cohort included 46 patients with intrahepatic cholangiocarcinoma (iCCA), 19 with extrahepatic cholangiocarcinoma (eCCA), 24 with gallbladder cancer (GBC), and 2 with ampullary tumors. CGP was successfully performed in all 91 patients. Reportable genomic alterations were detected in 88 patients (96.7%), whereas no reportable alteration was detected in three patients (3.3%). The most frequently altered genes were TP53 (51/91, 56.0%), KRAS (21/91, 23.1%), CDKN2A (18/91, 19.8%), SMAD4 (14/91, 15.4%), and ARID1A/PBRM1 (12/91, 13.2%). Potentially actionable genomic alterations were identified in 21 patients (23.1%). Expert panel-based therapeutic options were identified in 15 patients (16.5%), and genomically matched therapy was introduced in 7 patients (7.7%). Matched therapy was introduced the most frequently in iCCA (6/46, 13%), followed by GBC (1/24, 4.2%), whereas no patient with eCCA or ampullary tumor received matched therapy. Conclusions: CGP revealed a heterogeneous genomic landscape across BTT subtypes and provided clinically actionable information in a limited but meaningful subset of patients. The practical utility of CGP was the greatest in selected molecular subsets, particularly iCCA.

Cancers doi: 10.3390/cancers18142188

Authors: Corey A. Hounschell Jared A. Forrester Ronald F. Wolf Anton Bilchik Paul Shin

Complete resection with microscopically negative (R0, or no tumor cells within 1 mm of resection surface) margins has long been considered the cornerstone of curative-intent hepatectomy for colorectal liver metastases (CRLM). R1 resection is defined as the presence of tumor cells at or within 1 mm of the inked margin. A growing body of contemporary evidence, however, shows that the traditional binary R0/R1 framework obscures biologically meaningful subcategories of positive margin. An R1 parenchymal (R1p) margin on the transected liver surface carries a distinctly adverse prognosis, whereas an R1 vascular (R1v) margin (created by intentional detachment of tumor from the adventitia of a major intrahepatic vessel along Laennec’s capsule) yields oncologic outcomes that are, in essence, equivalent to R0: modern series report five-year overall survival rates of 34–45% after R1v, comparable to matched R0 cohorts. This insight has radical implication, enabling parenchyma-preserving hepatectomy (PPH) for patients who would otherwise require major hepatectomy (i.e., trisectionectomy) for multifocal and centrally located tumors, as well as allowing patients who would otherwise be considered unresectable to undergo curative intent resection. Careful patient selection, taking into consideration anatomic variation, use of intraoperative ultrasound guidance, response to systemic therapy, and molecular tumor profiling is essential for the safe application of R1v PPH. This review synthesizes the evidence supporting the R1p/R1v distinction, places it within the broader evolution of margin paradigms in CRLM, and outlines the clinical, anatomical, and biological criteria that should guide its judicious use in the current era of precision hepatobiliary surgery.

Cancers doi: 10.3390/cancers18142184

Authors: Alessia Lucia Daverio Alessandro Coccarelli Théophraste Henry Alina Danu Laurentiu Agrigoroaie Khalil Trabelsi Tarek Kamoun Guido Rovera Silvia Morbelli Désirée Deandreis

Background/Objectives: Multiple myeloma (MM) is a complex hematologic malignancy characterized by abnormal plasma cell proliferation in the bone marrow. [18F]FDG PET/CT has emerged as a key imaging modality, demonstrating high sensitivity and specificity for the detection of metabolically active disease compared with conventional imaging techniques. This review examines the role of PET/CT imaging in evaluating therapeutic response in symptomatic myeloma, including minimal residual disease (MRD) assessment. Methods: We surveyed the literature published between 2014 and 2024 across PubMed, Scopus, Web of Science, and the Cochrane Library for peer-reviewed articles evaluating PET imaging in the assessment of treatment response in multiple myeloma. Results: [18F]FDG PET/CT provides a whole-body assessment of disease burden, extramedullary involvement detection, and early metabolic response evaluation. Standardized response assessment criteria (Deauville, IMPeTUs, IMWG) have enhanced the reproducibility and accuracy of treatment monitoring. Semiquantitative parameters including SUVmax and metabolic tumor volume (MTV) provide useful prognostic information with PET negativity correlating with improved progression-free and overall survival. The integration of PET/CT with bone marrow assessment techniques (next-generation flow cytometry and sequencing) optimizes MRD evaluation and patient stratification. Conclusions: PET/CT represents a valuable imaging tool for improving therapeutic decision making and risk stratification in MM management. Emerging radiotracers beyond FDG, including [11C]choline, [11C]methionine, and targeted agents like [68Ga]pentixafor and CD38-targeted immunoPET tracers, hold promise for enhanced diagnostic capabilities in specific clinical contexts.

Cancers doi: 10.3390/cancers18142187

Authors: Ákos Juhász Sára Eszter Surguta Laura Svajda Ivan Ranđelović Andrea Ladányi József Tóvári Mihály Cserepes

Cancer accounts for approximately ten million deaths annually. The majority of these are attributable to resistance-driven tumor progression and metastasis. Although increasingly effective, precise, and selective therapeutic strategies are being developed, cancer cells retain the capacity to dynamically alter their phenotype and evade treatment. Traditional in vitro approaches rely heavily on cell line monocultures; however, their limited clinical translatability has driven the development of more advanced model systems. Three-dimensional in vitro models, including spheroids, organoids, and bioprinted tissues, provide more physiologically relevant and rapid insights, but fail to capture systemic pharmacodynamics and anatomical complexity. Emerging in vivo models, such as genetically engineered mouse models (GEMMs) of carcinogenesis and patient-derived xenografts (PDXs), as well as their derived organoids, provide a more comprehensive understanding of tumor biology. The preservation of tumor heterogeneity, microenvironment, and drug sensitivity profiles has positioned PDX models as widely used platforms in both drug development and therapy response prediction. Despite limitations—including variable engraftment rates, genetic drift, lack of fully functional immune systems, ethical concerns, and high costs—PDX models, when integrated with complementary techniques, contribute significantly to identifying novel therapeutic targets and combinations. Moreover, they support clinical decision-making by enabling drug response prediction based on genetic landscapes and co-clinical response data.

Cancers doi: 10.3390/cancers18142185

Authors: Mirte Dekker Erick Suazo-Zepeda T. Jeroen N. Hiltermann Geertruida H. De Bock Marjolein A. Heuvelmans

Background/Objectives: Immune checkpoint inhibitors (ICIs) have broadened treatment options for non-small cell lung cancer (NSCLC), but many patients show limited response. Baseline biomarkers and indices, including C-reactive protein (CRP), albumin, Neutrophil-to-Lymphocyte Ratio (NLR), Glasgow Prognostic Score (GPS), Prognostic Nutrition Index (PNI), and Advanced Lung Cancer Inflammation Index (ALI), may predict treatment outcomes. This study evaluated whether these biomarkers associate with three-month mortality and disease progression assessed by disease control rate (DCR) using RECIST. Methods: We conducted a retrospective cohort study of consecutive patients with NSCLC from the OncoLifeS biobank (2015–2020). Three-month mortality was defined by status alive or deceased at three months after treatment start. DCR was based on CT-assessments using RECIST. Univariate and multivariable logistic regression models with backward selection and bootstrapping were developed to test biomarker associations with three-month mortality and DCR. Sensitivity analysis was performed to compare results with the standard definition of objective response rate (ORR). Results: Among 505 patients, 421 were alive and 84 deceased; 297 were responders and 208 non-responders. In the final progression model, higher GPS was associated with increased odds of 3-month progression, whereas higher ALI (OR 0.99, 95% CI 0.97–1.00) and higher PNI (OR 0.93, 95% CI 0.87–0.99) were associated with decreased odds of 3-month progression. Higher ALI (OR 0.97, 95% CI 0.94–0.99), and higher PNI (OR 0.83, 95% CI 0.78–0.89) were associated with lower odds of 3-month mortality. The mortality-model showed an AUC of 0.82 and 0.73 for the disease progression model. Sensitivity analysis with the standard RECIST definition revealed similar results. Conclusions: Higher GPS was associated with increased risk of progression, whereas higher PNI and ALI were associated with lower risk of progression and mortality. These findings warrant external validation before clinical implementation.

Cancers doi: 10.3390/cancers18142186

Authors: Han Shen Yizhou Huang Kristina M. Cook Eric Hau

Diffuse midline glioma (DMG) is one of the most aggressive paediatric brain tumours and remains almost universally fatal despite decades of research. The defining molecular feature of approximately 80% of DMG tumours is H3K27M, which disrupts PRC2 activity and profoundly remodels chromatin architecture. Increasing evidence suggests that this epigenetic alteration not only rewires transcriptional programs but also influences tumour metabolism. Several studies indicate that H3K27M-mutant tumours exhibit altered mitochondrial metabolism, oxidative phosphorylation activity, redox regulation, and cellular stress responses, although the extent of oxidative phosphorylation dependence varies between models, tumour subtypes, and cellular states. In parallel, dopaminergic signalling has been implicated in cancer stem cell maintenance, metabolic regulation, and tumour survival across multiple malignancies, including glioma. The imipridone compound ONC201/dordaviprone, initially described as a dopamine receptor D2/3 antagonist and subsequently characterised as a mitochondrial ClpP agonist, demonstrates clinical activity in H3K27M-mutant DMG and induces mitochondrial stress responses. In this review, we examine emerging connections between epigenetic dysregulation, mitochondrial metabolism, and dopamine signalling in DMG. We propose that H3K27M-driven epigenetic reprogramming may impose metabolic constraints that increase tumour reliance on mitochondrial bioenergetics and stress-buffering pathways. Within this context, dopamine signalling may function as a metabolic rheostat that contributes to mitochondrial homeostasis; however, this remains a hypothesis requiring direct experimental validation in DMG models. Pharmacologic disruption of this axis may destabilise tumour metabolism and expose therapeutically exploitable vulnerabilities in this otherwise treatment-resistant disease.

Cancers doi: 10.3390/cancers18142183

Authors: Vincenzo De Giorgi Giovanni Cecchi Virginia Marabini Ginevra Gurioli Gabriella Perillo Federica Fazzari Biancamaria Zuccaro

Background: Dermoscopy has increased the excision of very small pigmented lesions in routine practice, yet the diagnostic efficiency of excising lesions ≤ 6 mm judged suspicious for melanoma remains incompletely defined. Objectives: The objectives of this study were to quantify melanoma detection yield and number needed to excise (NNE) for pigmented lesions ≤ 6 mm excised after clinical and dermoscopic suspicion of melanoma and to describe melanoma characteristics according to lesion diameter. Methods: We performed a retrospective observational cross-sectional study at a tertiary dermatologic oncology referral center within the Tuscany Regional Health Service, Florence, Italy. All pigmented lesions excised between 1 January 2022 and 31 December 2023 were screened. Consecutive lesions were included if they were excised because melanoma or suspected melanoma was the preoperative clinicodermoscopic diagnosis; lesions removed for benign or cosmetic indications were excluded. Primary outcomes were melanoma yield and number needed to excise, overall and stratified by clinical diameter. Multivariable logistic regression was performed to assess whether lesion diameter was independently associated with melanoma diagnosis after adjustment for age, sex, and anatomical site. Results: Among 2240 included excisions, 609 melanomas were diagnosed, corresponding to an overall yield of 27.2%. Lesions ≤ 6 mm accounted for 1331 excisions and yielded 175 melanomas, with a yield of 13.1% and a number needed to excise of 7.6. Lesions > 6 mm accounted for 909 excisions and yielded 434 melanomas, with a yield of 47.7% and a number needed to excise of 2.1. Thus, 86.9% of excised lesions ≤ 6 mm were benign on histopathology. Melanomas diagnosed in lesions ≤ 6 mm showed a more favorable histopathologic profile than larger melanomas. In multivariable analysis, lesions > 6 mm had significantly higher odds of melanoma than lesions ≤ 6 mm after adjustment for age, sex, and anatomical site (adjusted odds ratio 4.77, 95% confidence interval 3.81–5.97; p < 0.001). Conclusions: In routine practice, excision of dermoscopically suspicious pigmented lesions ≤ 6 mm has markedly lower melanoma yield and higher NNE than excision of larger lesions. These findings support risk-stratified management approaches and careful consideration of excision thresholds for very small lesions.

Cancers doi: 10.3390/cancers18142182

Authors: Cynthia Villarreal-Garza César Octavio Lara-Torres Jesus Edgardo Hernandez-Hernandez Daniela Vázquez Juárez Gabriela Sofía Gómez-Macías Paula Cabrera-Galeana Fany Iris Porras-Reyes Víctor Manuel Pérez-Sánchez Antonio Nateras-Pérez Gabriela Lugo-Martinez Alejandro Aranda-Gutierrez Alejandro Mohar

Background: Pembrolizumab-containing regimens have become the standard of care across the spectrum of triple-negative breast cancer (TNBC). While their use in the neoadjuvant setting is independent of biomarker status, their application in metastatic disease remains strictly contingent upon PD-L1 expression. Given that PD-L1 prevalence can vary significantly by ethnicity and geography, the lack of specific data for the Mexican population creates a challenge for optimizing treatment in the metastatic setting. This study sought to characterize PD-L1 positivity rates in a Mexican TNBC cohort to better define the local molecular landscape. Methods: We conducted a retrospective study across two cancer centers in Mexico to assess PD-L1 positivity in a cohort of women with TNBC (stages I–IV) diagnosed between 2006 and 2021. PD-L1 expression was assessed and evaluated centrally using the 22C3 pharmDx assay, with a Combined Positive Score (CPS) of ≥1 considered positive. We explored the association between PD-L1 expression and clinicopathological features. Results: Of the 298 TNBC patients identified, 285 (96%) had sufficient tissue for CPS evaluation and thus were included in the analysis. PD-L1 positivity was observed in 29.1% of the cohort, and 13.3% of patients had a CPS ≥ 10. PD-L1 positivity was associated with higher histological grades (91.3% vs. 78.5%, p = 0.035) and TILs ≥ 30% (22.2% vs. 10.0%, p = 0.007). Additionally, pre-treatment surgical specimens were more frequently PD-L1 positive than tumor biopsies (56.6% vs. 30.7%, p < 0.001). Conclusions: This study characterizes the PD-L1 landscape in Mexican women with TNBC, reporting a 29.1% prevalence of CPS ≥ 1. The strong association between PD-L1 positivity and high TILs/histological grade highlights the role of the immune microenvironment in these aggressive phenotypes. Given the significant variability observed between specimens (biopsy vs. surgical), clinicians should consider the dynamic nature of PD-L1 expression when choosing treatment strategies.

Cancers doi: 10.3390/cancers18132181

Authors: Ana Grigoraș Bogdan Filip Mihaela-Mădalina Gavrilescu Dragos-Viorel Scripcariu Ionuț Huțanu Maria-Gabriela Aniței Viorel Scripcariu

Background/Objectives: Anastomotic leakage (AL) remains one of the most severe postoperative complications following colorectal surgery and is associated with increased morbidity, delayed adjuvant therapy, and impaired oncological outcomes in CRC patients. Increasing evidence suggests that alterations in the gut microbiome contribute to the pathogenesis of AL through effects on epithelial integrity, collagen metabolism, inflammatory pathways, and immune regulation. This review aimed to provide an updated overview of AL in CRC patients and to evaluate current evidence regarding the perioperative use of probiotics, prebiotics, and synbiotics as microbiome-modulating interventions in reducing AL after radical CRC surgery. Methods: A comprehensive literature review of randomized controlled trials (RCTs) investigating perioperative microbiome-targeted interventions in CRC patients undergoing colorectal surgery was conducted. Searches of PubMed, Embase, Cochrane Library, Scopus, and Clarivate databases identified 477 records, of which 21 RCTs met the inclusion criteria and were included in the final analysis. Results: Current evidence supports the role of probiotics in modulating postoperative immune and inflammatory responses. Four studies demonstrated a statistically significant reduction in AL incidence. Perioperative probiotic administration was additionally associated with lower rates of infectious complications, attenuation of systemic inflammatory responses, and earlier recovery of bowel function. Multi-strain formulations containing Lactobacillus and Bifidobacterium species appeared particularly promising. Overall, microbiome-targeted interventions were safe and well tolerated. However, treatment efficacy varied according to bacterial strain composition, dosage, and timing of administration. Conclusions: Perioperative microbiome modulation may contribute to restoration of gut microbial diversity and reduction in AL risk after radical CRC surgery. Multi-strain formulations containing Lactobacillus and Bifidobacterium species appear particularly promising. Nevertheless, further large-scale, standardized clinical trials are required before definitive recommendations can be established.

Cancers doi: 10.3390/cancers18132180

Authors: Yoshiaki Shoji Kazuo Koyanagi Miho Yamamoto Akihito Kazuno Yamato Ninomiya Kohei Kanamori Takatoshi Seki Kohei Tajima Rie Nakashima Masaki Mori

Background/Objectives: Currently, a definitive diagnostic strategy for predicting mediastinal lymph-node (MLN) metastasis remains poorly established in Siewert Type I and II esophagogastric junction adenocarcinoma (EGJAC). This study aimed to evaluate long-term survival and identify objective, reliable preoperative risk factors for MLN metastasis to optimize perioperative treatment and surgical approach. Methods: We retrospectively reviewed a well-defined cohort of 133 patients with Siewert Type I (33.1%) and II (66.9%) EGJAC who underwent R0 resection and complete follow-up at our institution between 2005 and 2025. Preoperative risk factors for histological MLN metastasis were evaluated using receiver operating characteristic (ROC) curve analysis and univariate/multivariate logistic regression models. Results: Thorough upper, middle, and lower MLND were completed in 57.9%, 72.9%, and 94.7% of patients, respectively. Pathological MLN metastasis was confirmed in 31.6% of patients and was significantly associated with poor overall and recurrence-free survival. ROC analysis demonstrated that an MLN short-axis diameter of ≥5 mm on CT, esophageal involvement length (EIL) in upper GI series ≥ 30 mm, and EIL in endoscopy ≥ 60 mm predict histological MLN metastasis. In univariate analysis, Siewert Type I, EIL in upper GI series ≥30 mm, EIL in endoscopy ≥ 60 mm, clinical tumor depth ≥ cT3, and CT node size ≥ 5 mm were correlated with MLN metastasis. Multivariate logistic regression analysis revealed that a clinical tumor depth of ≥cT3, EIL in upper GI series ≥ 30 mm, and a CT node size of ≥5 mm were independent predictors of MLN metastasis. Conclusions: Clinical tumor depth, EIL, and size of MLN are powerful independent preoperative risk factors for MLN metastasis in Siewert Type I/II EGJAC. Utilizing these objective indices may help identify high-risk patients requiring intensive perioperative multidisciplinary strategies.

Cancers doi: 10.3390/cancers18132179

Authors: Hadeel Halalsheh Lana Amer Mohammad Alzoubi Noor F. Al-Assaf Adam Diab Nada Odeh Iyad Sultan

Background: Systemic inflammation has been implicated in prognosis of multiple malignancies, yet evidence regarding its role in Wilms Tumor (WT) remains scarce. We investigated the prognostic significance of pre-treatment inflammatory markers in unilateral WT. Methods: We conducted a retrospective analysis of children with unilateral WT treated at our institution between November 2014 and December 2023. Clinical characteristics, treatment, and outcomes were evaluated. Inflammatory markers included a novel pan-immune-inflammation value (PIV), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR). Optimal cut-off values for Event-Free Survival (EFS) and Overall survival (OS) were determined using data-derived optimization to maximize survival curve separation (surv_cutpoint). Cox proportional hazards models were used for survival analysis, while ROC curves were used to calculate AUC values and confirm optimal cut-off points. Results: We included 91 patients (median age: 3.6 years; 62% female), of whom 34% presented with metastasis. Higher EFS was significantly associated with low PIV (cut-off 288.9), low NLR (cut-off 1.1), and high LMR (cut-off 6.3). Similarly, OS was positively associated with lower PIV (HR 8.56 for high PIV, p = 0.038) and lower NLR (HR 4.63 for high NLR, p = 0.043). ROC analysis confirmed their discriminative ability; when evaluated at the unified survival cutpoints, LMR yielded an AUC of 0.692 for 5-year mortality (at cut-off 6.3), while NLR yielded an AUC of 0.671 for 5-year events (at cut-off 1.1). Conclusions: Pre-treatment inflammatory markers demonstrate significant prognostic value in unilateral WT. Elevated NLR and PIV, along with lower LMR, correlate with poorer survival. These accessible biomarkers provide a valuable, low-cost tool for risk assessment. Our optimal thresholds differed from Western adult cohorts, emphasizing the need for population-specific reference intervals in global pediatric oncology.

Cancers doi: 10.3390/cancers18132178

Authors: Nisreen Albzour Sarah S. Lam

Background/Objectives: Manual Pap smear analysis for cervical cancer screening is limited by inter-observer variability, time constraints, and restricted expert availability. Although convolutional neural networks (CNNs) have automated cervical cell classification, they remain limited in modeling long-range spatial dependencies and often lack clinical interpretability. Methods: In this study, Vision Transformer (ViT) architectures were systematically optimized to enhance automated cervical cancer screening and improve interpretability. The Herlev dataset (917 images: 242 normal, 675 abnormal) was utilized to optimize ViT-Tiny, a lightweight ViT architecture designed for reduced computational complexity, through a comprehensive evaluation of augmentation strategies, class weighting, and hyperparameters. Results: The optimal configuration achieved a cross-validation accuracy of approximately 95% (94.89% for the best replicated configuration), in which random horizontal flipping and class weighting (0.7 × 1.3) were identified as most effective. Gradient-weighted Class Activation Mapping (Grad-CAM) analysis confirmed that model attention corresponded to clinically relevant morphological features, including nuclei regions, cell boundaries, and chromatin texture, which align with cytopathological criteria. Conclusions: These findings indicate that Vision Transformers can deliver accurate and interpretable decision support for cervical cancer screening by combining competitive classification performance with attention-based transparency relevant to medical AI. Further validation on larger, multi-center datasets remains necessary before clinical deployment.

Cancers doi: 10.3390/cancers18132177

Authors: John D. Potter Finlay A. Macrae Julian R. Sampson Saskia Haupt Toni T. Seppälä Sinead Cameron-Mackintosh Aysel Ahadova Matthias Kloor Pål Møller PLSD Collaborators PLSD Collaborators

Background/Objectives It is not established whether melanoma and lung cancer are part of the tumor spectrum of the Lynch syndromes (LS). Our first hypothesis was that, if melanoma is associated with LS, most prospectively observed cases would be carriers of pathogenic MSH2 variants (path_MSH2), as for other LS non-endodermal tumors. Our second hypothesis, which was derived from findings of the first study, was that the pattern of differences in the incidence of lung cancer in path_MMR carriers would mirror that for melanoma. Methods We used the Prospective Lynch Syndrome Database (PLSD) data and methods. Results Firstly, consistent with hypothesis, ten of 3154 path_MSH2 carriers followed for 26,309 years developed melanoma, compared with 6 of 5288 path_MLH1/MSH6/PMS2 carriers followed for 45,081 years (p = 0.04). Secondly, although the incidence of melanoma in carriers of path_MSH2 was 0.00041—similar to the populations in which the carriers resided—the average incidence rates for path_MLH1/MSH6/PMS2 carriers was 0.00012, lower than the corresponding population rates. Thirdly, the average lung cancer incidence rates in PLSD were 0.00112 in path_MSH2 carriers and 0.00032 in path_MLH1/MSH6/PMS2 carriers (p = 0.02), both lower than the population rates. Conclusions Melanomas and lung cancers—both of which are immunogenic through mechanisms independent of mismatch repair deficiency—may become even more immunogenic when they also exhibit microsatellite instability. This may lead to an increased likelihood that both tumors are eliminated by the immune system and, thus, show variable and lower incidence. These insights may help inform strategies for cancer prevention or treatment that are aimed at simultaneously interrupting multiple carcinogenic pathways.

Cancers doi: 10.3390/cancers18132176

Authors: Yoshihiro Takahashi Shin Tsunekawa

Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors that have traditionally been regarded as “immune cold” and largely refractory to PD-1/PD-L1 checkpoint blockade, with notable exceptions such as Merkel cell carcinoma (MCC). The advent of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics has enabled unprecedented dissection of the NEN tumor microenvironment (TME), but a cross-subtype synthesis is lacking. This review aims to integrate single-cell and spatial transcriptomic findings across major NEN subtypes to reframe NEN immunosuppression and delineate translational implications. To this end, we performed a structured narrative review of PubMed-indexed studies up to 30 April 2026, prioritizing original human scRNA-seq, single-nucleus RNA-seq, spatial transcriptomic, and spatial proteomic studies of NENs, supplemented by mechanistic, clinical, and biomarker-focused reports providing essential context. Across these studies, synthesis spanning pancreatic, pulmonary, gastrointestinal, cutaneous, pituitary, adrenal, and other NEN subtypes highlights conserved features beyond the PD-1/PD-L1 axis, including myeloid-dominated infiltration with alternative checkpoints (VISTA, TIM-3, Galectin-9), cancer-associated fibroblast-mediated immune exclusion, lineage-state-dependent immune visibility, and direct immunomodulation by neuroendocrine secretory products such as calcitonin gene-related peptide. We propose a four-layer framework integrating these mechanisms and linking them to emerging biomarkers and therapies, including DLL3-directed bispecifics, alternative checkpoint inhibitors, stromal-targeting agents, and peptide receptor radionuclide therapy combinations. Together, these findings indicate that single-cell and spatial transcriptomic studies reframe NEN immunosuppression as a multilayered, subtype-dependent process, providing a conceptual scaffold for biomarker-guided, subtype-adapted therapeutic strategies and prospective clinical trial design in neuroendocrine oncology.

Cancers doi: 10.3390/cancers18132175

Authors: Julian Palzer Alexander Genchev Esref Belger Clara Antonia Weigle Bengt Arne Wiemann Philipp Tessmer Mohamad Murad Marie-Luise Berres Franziska Alexandra Meister Iakovos Amygdalos Philipp Bruners Daniel Truhn Ahmed Allam Mohamed Florian Wolfgang Rudolf Vondran Felix Oldhafer Oliver Beetz

Introduction: Multidisciplinary tumor boards (MTBs) are the standard for oncologic decision-making but require substantial time and personnel resources. Large language models (LLMs) may support MTBs by generating structured, guideline-based recommendations. We evaluated concordance between MTB decisions and LLM recommendations in newly diagnosed cholangiocellular adenocarcinoma (CCA) and hepatocellular carcinoma (HCC). Method: In this retrospective single-center study, MTB protocols from 2022–2023 were screened. After exclusions, 50 CCA and 50 HCC cases were analyzed. Institutional MTB recommendations were compared with outputs from ChatGPT and Claude using identical structured clinical summaries available at the time of MTB presentation. Agreement was assessed using Cohen’s kappa, and correlation using Spearman’s rank coefficient. Results: For CCA, exact concordance between MTB and ChatGPT was 80%, with substantial agreement (k = 0.688) and strong correlation (r = 0.725; both p < 0.001). Concordance with Claude was at 56%. For HCC, concordance between MTB and ChatGPT was 66%, with substantial agreement (k = 0.604) and moderate correlation (r = 0.484; both p < 0.001). Concordance with Claude was only 38%, with fair agreement (k = 0.314, p < 0.001) and weak correlation (r = 0.086, p = 0.551). Conclusions: LLM-derived recommendations varied markedly by model. ChatGPT demonstrated substantial concordance, whereas Claude showed limited agreement. MTBs appeared more individualized, while LLM outputs were more guideline-oriented. These findings highlight the potential role of LLMs as supportive tools for structured clinical reasoning and guideline adherence. Prospective multicenter studies should evaluate real-time LLM integration into MTB workflows, efficiency, decision quality, and patient outcomes safely.

Cancers doi: 10.3390/cancers18132174

Authors: Belén Mora-Garijo Syed Rahman Hongzhi Xu Jon Chatzkel G. Daniel Grass Philippe E. Spiess Roger Li

Histological subtypes of bladder cancer are generally associated with more aggressive disease, higher stage at presentation, and worse prognosis compared to conventional urothelial carcinoma. Recent updates in classification systems have further refined the distinction between true histologic subtypes and divergent differentiation, underscoring the complexity of these tumors. Emerging molecular profiling studies have identified subtype-specific genomic alterations, including ERBB2 amplification in micropapillary subtype carcinoma, CDH1 loss in plasmacytoid subtype carcinoma, and TP53 and RB1 co-alterations in neuroendocrine bladder cancer, which may contribute to differences in tumor biology and therapeutic response. Despite these advances, the histological subtypes of bladder cancer remain underrepresented in prospective clinical trials, leading to significant gaps in evidence-based management. Treatment responses vary widely across subtypes, with some demonstrating sensitivity to platinum-based chemotherapy or immunotherapy, while others appear less responsive to conventional approaches. This review summarizes the current understanding of the epidemiology, molecular landscape, and clinical behavior of major bladder cancer subtypes and highlights emerging opportunities for personalized treatment strategies, biomarker-driven therapies, and more inclusive clinical trial design to improve outcomes in this high-risk population.

Cancers doi: 10.3390/cancers18132173

Authors: Mijail I. Zambrano Iglesias Daniel Rosas Salih Akgun Ines C. Padron Cubillan Fedor Wadi Richani Meinhardt Atif Hussein Luis E. Raez

Small cell lung cancer (SCLC) has historically been treated as a single, uniformly aggressive disease defined by neuroendocrine differentiation, near-universal loss of TP53 and RB1, and the absence of classical druggable oncogene addictions. Two converging lines of evidence are now reshaping that view. First, transcriptomic profiling has resolved SCLC into molecular subtypes—SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-I (inflamed)—with distinct immune microenvironments, surface-antigen expression patterns, and emerging therapeutic vulnerabilities, although intratumoral heterogeneity and phenotypic plasticity complicate clean subtype assignment. Second, the development of delta-like ligand 3 (DLL3)-directed therapies provides a natural experiment: the same validated surface antigen failed as an antibody–drug conjugate (rovalpituzumab tesirine, three negative randomized trials) yet succeeded as a bispecific T-cell engager (tarlatamab, which received FDA accelerated approval in 2024 and subsequent traditional FDA approval in 2025 following positive confirmatory phase 3 data). In this review, we integrate the current first-line standard of care—chemoimmunotherapy with atezolizumab- or durvalumab-based regimens followed by maintenance intensification with lurbinectedin–atezolizumab (IMforte)—with the molecular framework of subtypes and biomarkers, and we use DLL3 as a case study to propose that delivery modality is an important determinant of therapeutic success in SCLC and should be considered alongside target biology and tumor heterogeneity. Rapid proliferation, antigen heterogeneity, subtype plasticity, and a relatively less immunogenic microenvironment systematically penalize modalities dependent on payload accumulation and cell-cycle progression and reward modalities that recruit catalytic, cell-cycle-independent cytotoxic effectors. The emerging B7-H3 and SEZ6 programs—including ifinatamab deruxtecan and ABBV-706—are the next test of this framework. We discuss implications for biomarker development, trial design, and the operational challenges of subtype-guided precision oncology in a disease where tissue is scarce and biology shifts under therapy.

Cancers doi: 10.3390/cancers18132172

Authors: Kunhwa Kim Dimitrios P. Kontoyiannis Hycienth Ahaneku Deborah McCue Javier Adachi Alessandra Ferrajoli

Background: As hyperbaric oxygen therapy has been sporadically used in combination with antimicrobial treatment for refractory infections in patients with hematologic malignancies, data on its efficacy and outcomes are limited. Methods: We retrospectively analyzed 55 patients with hematologic malignancies treated with hyperbaric oxygen therapy over a 10-year period at a single tertiary care center and report on patients’ clinical features, infection types, treatment responses, and survival outcomes. Results: The most common underlying hematologic malignancy diagnosis was acute myeloid leukemia (30 patients, 55%). The most common hyperbaric oxygen therapy indications were invasive mold disease (IMD) (35 patients, 64%), BK virus-associated cystitis (17 patients, 31%), and bacterial cellulitis (3 patients, 5%). Patients underwent a median of 10 hyperbaric oxygen therapy sessions (range, 1–45). In total, 54 (98%) of the 55 patients were evaluable for response, of whom 32 (59%) patients demonstrated a response, defined as either resolution or stabilization of the infection. Among the 35 patients with IMDs, we found that 11 patients (31%) achieved a complete response, 5 (14%) had a partial response, 6 (17%) had stable disease, and 13 (37%) patients experienced progression of their infection. In contrast, among the 17 patients with BK virus-associated cystitis, 9 patients (53%) had persistent or worsening hematuria. The two evaluable patients with bacterial cellulitis responded with resolution of the infection. We reviewed the status of the hematologic malignancies at the time of hyperbaric oxygen therapy treatment and found that the 21 patients whose hematologic malignancies were in remission tended to have a higher response rate of their infection compared to patients whose hematologic malignancies were not in remission (73% vs. 46% p = 0.057). Despite the response of infections, 1-year mortality in these patients remained high at 76%. Conclusions: Based on our experience, hyperbaric oxygen therapy, in conjunction with appropriate anti-infective therapy and debridement surgery, could benefit selected patients with hematologic malignancies, especially those whose underlying disease is controlled but experience recalcitrant bacterial or fungal infections.

Cancers doi: 10.3390/cancers18132171

Authors: Vicky Betech-Antar Juan J. Rosales Fernando Mínguez Marta Romera Luis Fuertes Fernando Díez-Caballero Bernardino Miñana-López Rafael Martinez-Monge Edgar F. Guillen Macarena Rodríguez-Fraile

Background: This study aimed to determine whether incorporating radiologic contrast during the excretory (urographic) phase enhances the detection of recurrence on [68Ga]Ga-PSMA-11 PET/CT in patients with biochemical relapse (BCR) following radical prostatectomy (RP). Methods: A single-center retrospective analysis included 43 men with BCR after RP who underwent [68Ga]Ga-PSMA-11 PET/CT. Each patient underwent two comparative assessments. In the first assessment, whole-body PET images acquired at 60 min post-injection were fused with the non-contrast CT from early dynamic pelvic imaging (PET/CTd), and local recurrence and pelvic nodal involvement were evaluated according to PROMISE V2 and E-PSMA frameworks by two blinded readers. In the second assessment, the same PET dataset was fused with the excretory-phase CT urography (CT-U) obtained during the same imaging session at 60 min post-injection, and the same parameters were re-evaluated. Endpoints included surgical-bed classification, peri-ureteric nodal status, reader confidence, ureter visualization/opacification, and interpretation time. Inter- and intra-observer agreement was assessed, and discrepancies were resolved by consensus. Results: Surgical-bed positivity decreased from 12/43 (27.9%) on PET/CTd to 5/43 (11.6%) on PET/CT-U, leading to reclassification in seven patients (p = 0.016). Reader confidence improved significantly in five cases (p < 0.005). Peri-ureteric nodal status was changed in four patients (two positive-to-negative and two negative-to-positive), with overall positivity unchanged (5/43 vs. 5/43; p = 1.000). Ureter visualization improved markedly (inadequate: 31 vs. 10 cases), reducing diagnostic uncertainty by 50%. CT-U opacification was ≥50% in most cases (κ = 0.814), enabling reliable delineation of the ureteral course. Inter-reader agreement remained strong (surgical bed κ: 0.944 vs. 0.876; nodes κ: 0.896 both). Interpretation time decreased for both readers (senior: 3.12 vs. 2.10 min (−32.7%); junior: 4.06 vs. 2.42 min (−40.4%)). Conclusions: Adding an excretory-phase CT urography to [68Ga]Ga-PSMA-11 PET/CT improves diagnostic confidence, reduces interpretive uncertainty in the surgical bed, clarifies peri-ureteric nodal findings, enhances ureter visualization, and shortens interpretation time. CT-U is a practical enhancement to low-dose PET/CT protocols for BCR after RP.

Cancers doi: 10.3390/cancers18132170

Authors: Kamila Adamczuk Paulina Miziak Grzegorz Adamczuk Marzena Baran Matthias Nees Andrzej Stepulak

Despite advances in multimodal treatment, head and neck squamous cell carcinoma (HNSCC) remains a major clinical problem owing to its high recurrence rate and frequent development of treatment resistance. Abnormal histone modifications, particularly lysine methylation regulated by methyltransferases (KMTs) and demethylases (KDMs), have emerged as key drivers of HNSCC initiation, progression, and cellular plasticity. This review aims to comprehensively evaluate the role of selected KMTs and KDMs in HNSCC biology, with a focus on their contribution to resistance to immunotherapy, radiotherapy, and cytotoxic chemotherapy. We summarize and critically analyze preclinical and clinical studies investigating histone methylation dynamics in HNSCC, with particular emphasis on enzymes such as KMT2C/D, EZH2, NSD1/NSD2, SMYD3, G9a/EHMT2, LSD1, KDM2A/B, KDM3, KDM4, KDM5, KDM6, KDM7, and KDM8. Attention is given particularly to pharmacological approaches targeting these proteins: we discuss small-molecule inhibitors of EZH2, LSD1, KDM4/5/6, and other KMT/KDMs that are currently in preclinical development or in early clinical trials, and we highlight completed and ongoing studies testing EZH1/2 inhibitors and epigenetic combinations in patients with recurrent and metastatic HNSCC. The deregulation of specific KMTs and KDMs reshapes histone methylation at key residues, thereby controlling cell cycle progression, epithelial–mesenchymal transition (EMT), stem cell phenotypes, DNA damage responses, and multiple interactions with the immune system in HNSCC. Targeting disrupted histone methylation pathways may partially reverse the epigenetic reprogramming of HNSCC cells and represents a promising strategy to improve treatment efficacy in patients with advanced disease. We also summarize the preclinical evidence and the currently limited clinical data on targeting histone methylation dynamics in HNSCC and discuss their therapeutic implications.

Cancers doi: 10.3390/cancers18132169

Authors: Sung-Won Lim Bo Mi Ku Myung-Ju Ahn

Leptomeningeal metastasis (LM) is a severe and increasingly recognized complication of advanced non-small-cell lung cancer (NSCLC), particularly in patients with actionable genomic alterations. Although LM has historically been associated with poor outcomes, molecularly targeted systemic therapies with improved central nervous system (CNS) activity are reshaping its therapeutic landscape. This review summarizes current concepts in the pathogenesis, diagnosis, and risk stratification of LM, focusing on systemic treatment strategies for NSCLC harboring actionable driver alterations. We highlight the rationale and emerging evidence for next-generation tyrosine kinase inhibitors targeting EGFR, ALK, and other oncogenic drivers, and discuss their role as the cornerstone of LM management. Intrathecal chemotherapy, immunotherapy, and radiotherapy are also reviewed within a risk-adapted treatment framework. An individualized approach integrating molecular profiling, neurological status, and disease distribution is essential to optimize outcomes. Prospective studies are needed to refine systemic treatment strategies and establish evidence-based algorithms for this high-risk population.

Cancers doi: 10.3390/cancers18132168

Authors: Chase M. Walton Elif Percin Han Gyul Lee Odai Darawsha Ben A. Strickland Besim Ogretmen

Background/Objectives: T cells within solid tumors often switch from a recirculating to a tissue-resident state, which may blunt antitumor activity, but the signal driving this switch in vivo remains unclear. We asked whether alterations in sphingosine-1-phosphate (S1P) signaling in tumor or the surrounding stromal cells are associated with T cell residency in glioblastoma (GBM). Methods: We analyzed five single-cell RNA-sequencing cohorts: three human glioma datasets, an in-house mouse CT2A glioblastoma cohort, and a human melanoma tumor-infiltrating lymphocyte cohort. T cell egress and tissue-residency programs, together with stromal S1P production and degradation, were scored per cell using curated gene modules. Cell-state contrasts were quantified as Cohen’s d, and sample-level coupling as Spearman ρ. Results: In human GBM, T cell residency programs were elevated in CD4+ helper and regulatory T cells in tumors compared with low-grade glioma controls. In mouse CT2A-derived GBM tumors, stromal S1P production correlated negatively with T cell residency across four independent stromal cell types. In human GBM microglia, S1P production was reduced compared with control microglia. The same CD8+ residency phenotype was replicated in CD3-sorted GBM tumor-infiltrating lymphocytes (TILs) and in melanoma TILs. Conclusions: A loss of stromal S1P production accompanies T cell tissue residency in GBM. Thus, stromal S1P metabolism is a candidate axis for modulating T cell recirculation and TIL biology in GBM. These findings are transcriptomic associations from single-cell RNA sequencing that do not directly measure S1P metabolite levels or signaling activity and will require functional and lipidomic validation.

Cancers doi: 10.3390/cancers18132167

Authors: Ali Awada Ali Tarhini Abbas Hammoud Mohammad Kassem Joe Rizkallah Mohammad Al Hajjar Ali Dakik Michael Romanos Sary Faraj Duha Awada Lara Soueid Razane Wehbe Karim Kalout Nicole Charbel Firas Kreidieh

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but are associated with immune-related adverse events (irAEs) and variable clinical outcomes. Clinical predictors of organ-specific irAEs remain indeterminate, particularly in real-world populations. Methods: We conducted a retrospective single-center cohort study including 751 adult patients with solid tumors treated with ICIs between 2018 and 2025. Clinical, demographic, and treatment-related variables were analyzed. Multivariable logistic regression identified predictors of irAEs, while associations with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were assessed using logistic and Cox regression models. Results: The most frequent irAEs were endocrine (9.9%), dermatologic (9.1%), gastrointestinal (7.6%), and pulmonary (4.7%). Female sex independently predicted endocrine (aOR 1.98, p = 0.007) and rheumatologic irAEs (aOR 4.06, p = 0.007). Combination immunotherapy was associated with increased dermatologic (aOR 2.66, p = 0.013) and gastrointestinal irAEs (aOR 2.65, p = 0.016), while concurrent radiotherapy predicted gastrointestinal toxicity (aOR 1.82, p = 0.044). Atezolizumab was associated with higher pulmonary irAE risk (aOR 2.97, p = 0.048). Endocrine, dermatologic, gastrointestinal, and pulmonary irAEs were independently associated with improved ORR (OR range: 2.53–4.30, all p < 0.01). Conclusions: Organ-specific irAEs exhibit distinct clinical predictors and differential prognostic implications in patients receiving ICIs. Select irAEs are associated with improved treatment response and disease control, yet our results should be regarded as hypothesis-generating requiring further investigation.

Cancers doi: 10.3390/cancers18132166

Authors: Joji Kitayama

Peritoneal metastasis (PM) is the most frequent and lethal pattern of dissemination in gastrointestinal malignancies. Despite advances in systemic chemotherapy, outcomes remain poor because the unique biology of PM, characterized by poor vascularization and the peritoneal–plasma barrier (PPB), limits drug penetration and contributes to treatment resistance. To address these challenges, several locoregional treatment strategies have been developed, including cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). However, their widespread adoption is constrained by invasiveness, strict patient selection, and inconsistent survival benefits. Normothermic intraperitoneal and systemic treatment (NIPS) has emerged as a practical and less invasive alternative, particularly in East Asia. Through an implanted intraperitoneal port, NIPS enables repeated drug administration, providing sustained regional exposure while imposing minimal procedural burden. Importantly, it can be readily integrated with systemic chemotherapy, making it suitable for long-term multimodal treatment. Among available agents, paclitaxel (PTX) is particularly well suited for intraperitoneal administration because of its prolonged retention within the peritoneal cavity and limited systemic absorption. These pharmacokinetic properties allow high local drug concentrations with relatively low systemic toxicity. Consequently, PTX-based NIPS represents a biologically rational and clinically feasible treatment strategy for PM. This review summarizes the pharmacological rationale, clinical evidence, and emerging innovations in drug formulation and delivery that may further enhance the efficacy of PTX-based intraperitoneal chemotherapy for this challenging disease.

Cancers doi: 10.3390/cancers18132163

Authors: Mathias Sanchez Machado Sangnya A. Upadhyaya Saipriya Gadiraju Matthew Santhosh John Gaba Patrick J. Mcdonnell Jacobo Hincapie-Echeverri Carlos A. Barrero

Cancer immunotherapy has reshaped oncology, yet durable benefit remains limited for many patients because antitumor responses are constrained by multiple biological and clinical barriers. A targeted narrative review was conducted using peer-reviewed literature indexed in PubMed, Scopus, and Web of Science from January 2020 to April 2026, with additional landmark studies from earlier years included for essential mechanistic context. Priority was given to clinical, translational, and high-impact review articles examining combination strategies built on immune checkpoint blockade and related immune platforms. The evidence was synthesized by the main barriers each strategy aims to overcome, including poor immune priming, immune exclusion, immunosuppressive tumor microenvironments, adaptive resistance, and limited treatment durability. Across recent studies, combination immunotherapy is increasingly moving away from empiric regimen construction toward biologically rational approaches that integrate checkpoint blockade with chemotherapy, radiotherapy, antiangiogenic therapy, targeted agents, antibody–drug conjugates, bispecific antibodies, vaccines, and cellular platforms. Increasing emphasis has also been placed on integrated biomarkers that combine tumor-intrinsic, immune, spatial, and dynamic features to improve patient selection. At the same time, growing regimen complexity continues to raise challenges related to overlapping toxicity, sequencing, polypharmacy, and multidisciplinary implementation. Overall, the field is evolving toward mechanism-matched, biomarker-guided, and clinically manageable strategies that may broaden and refine the benefit of cancer immunotherapy.

Cancers doi: 10.3390/cancers18132165

Authors: Yeongsoo Jo Yoo-Seok Yoon Ho-Seong Han Jai Young Cho Jun Suh Lee Boram Lee

Background: Distal cholangiocarcinoma (dCCA) has a poor prognosis and the prognostic impact of ductal margin status, particularly carcinoma in situ (CIS) or high-grade dysplasia (HGD) at the margin, remains controversial. This retrospective single-center study evaluated whether ductal margin distance (DMD) is a stronger prognostic indicator than ductal margin status (DMS) after curative resection. Methods: We reviewed 416 patients who underwent pancreaticoduodenectomy for distal cholangiocarcinoma between 2003 and 2022. DMS was classified as negative, CIS/HGD, or invasive carcinoma (IC). The DMD was defined pathologically as the linear distance from the proximal ductal margin to IC and patients were divided into two groups using 10 mm as the cut-off. Survival was analyzed with Kaplan–Meier and Cox regression. Results: Overall, 349, 52, and 15 patients had negative, CIS/HGD, and IC margins, and 249 and 167 had DMD > 10 and ≤10 mm, respectively. Overall survival (OS) and disease-free survival (DFS) did not differ significantly according to DMS, whereas DMD ≤ 10 mm was associated with significantly worse 5-year OS (48.5% vs. 67.9%) and DFS (39.9% vs. 55.9%). On multivariable analysis, DMD ≤ 10 mm was an independent adverse prognostic factor for both OS (hazard ratio 1.669; p = 0.003) and DFS (hazard ratio 1.394; p = 0.026). Conclusions: DMD demonstrated a stronger association with prognosis than DMS in patients with negative or CIS/HGD at the ductal resection margin following dCCA resection. A DMD of ≤10 mm was significantly associated with decreased OS and DFS. Well-designed prospective studies are warranted to validate these results.

Cancers doi: 10.3390/cancers18132162

Authors: Natalia Luisy Farias Müller Maitha Al Sibani Yousef Ayoub Mariam Ayoub Abdul Kareem Pullattayil Farideh Tavangar Anna Plotkin Sophia George Katarzyna J. Jerzak Helen Mackay Rania Chehade

Background: Vulvar cancer is a rare gynecologic malignancy comprising 1–3% of all cases. No established standard exists for advanced disease, and treatment is often extrapolated from cervical cancer. Although HER2 overexpression is well defined in breast cancer and recognized across multiple solid tumors, its prevalence and significance in vulvar cancer remain unclear. Recent activity of HER2-directed antibody–drug conjugate Trastuzumab deruxtecan in solid tumors with an objective response rate (ORR) of around 37% highlights the need to better characterize HER2 expression in vulvar cancer. Methods: We performed a systematic search of Medline, Embase, and the Cochrane Library up to May 2025. Eligible studies included ≥10 vulvar cancer cases, predominantly vulvar squamous cell carcinoma (VSCC), excluding vulvar Paget’s disease, with available HER2 assessment by immunohistochemistry and/or in situ hybridization. Two reviewers independently screened the studies. A random-effects model was used to estimate pooled HER2 positivity. Heterogeneity was assessed using Cochrane’s Q and Higgins’s I2. Results: Of 506 records, nine retrospective studies including 769 patients with predominantly squamous cell carcinoma histology (98%, n = 752) met inclusion criteria. A total of 50 HER2-positive cases were observed. Median age at diagnosis of vulvar cancer was between 55 and 78, reported in three studies. Molecular profiling was limited. Among three studies with known TP53 status (n = 206), 59% of the tumors expressed TP53 (n = 122), and among two studies with known human papilloma virus (HPV) status (n = 128), 21% (n = 27) were HPV-positive. Six studies used American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2 testing guidelines in breast cancer. Pooled HER2-positive expression across ASCO/CAP-based studies was 2% (95% CI: 1%, 3%) and for non-ASCO/CAP-based studies was 21% (95% CI: 2%, 52%). Exploratory pooled estimated proportion of HER2-positive expression was 5% (95% CI: 0.4%, 14%). There was substantial heterogeneity across studies, I2 value of 91.1% [95% CI: 85.4%; 94.6%], and no significant publication bias was observed (Egger’s test p = 0.364). This study could not assess prognostic value of HER2 overexpression in VSCC. Conclusions: HER2 positivity in VSCC appears uncommon but it remains to be fully explored. Standardized assessment using contemporary ASCO/CAP breast, endometrial-specific and/or gastric criteria are needed to clarify the prevalence of HER2-positive versus HER2-low/ultralow disease to inform potential use of HER2-targeted therapy.

Cancers doi: 10.3390/cancers18132164

Authors: Qi Pan Qing Shi Yubo Zhao Tianxi Yu Shiyu Bai Haoran Zhu Wei Zhang Yaowei Li Ziyi Liu Haonan Li Ziqi Wang Zhichao Tong

Background: CDK4/6 inhibitors induce G1/S cell-cycle arrest in bladder cancer; however, adaptive resistance limits their therapeutic efficacy. The role of the m6A reader IGF2BP3 in regulating sensitivity to CDK4/6 inhibition remains largely unknown. Methods: Transcriptomic profiling was performed in palbociclib-treated bladder cancer cell lines (T24, RT112, and UMUC-3) to identify m6A regulators associated with drug response. The expression and clinical significance of IGF2BP3 were evaluated using The Cancer Genome Atlas (TCGA) data and an independent clinical cohort. Gain- and loss-of-function assays were conducted to investigate the effects of IGF2BP3 on cell proliferation and cell-cycle progression. Mechanistic studies, including RNA-binding, mRNA stability, ubiquitination, and in vivo tumorigenesis assays, were performed to elucidate the underlying regulatory network. Results: IGF2BP3 was identified as the only m6A regulator differentially expressed following palbociclib treatment. IGF2BP3 expression was significantly elevated in bladder cancer tissues compared with normal tissues and was associated with poor prognosis and Ki67 positivity. Functionally, IGF2BP3 overexpression (OE) promoted G1/S transition, increased MYC and downstream cell-cycle regulators, and partially rescued palbociclib-induced cell-cycle arrest, whereas IGF2BP3 knockdown (KD) suppressed cell proliferation in an MYC-dependent manner. Mechanistically, IGF2BP3 bound to MYC mRNA in an m6A-dependent manner and enhanced its stability. Furthermore, MKRN2 was identified as an E3 ubiquitin ligase that directly interacted with IGF2BP3, promoted its ubiquitination, and facilitated its proteasomal degradation. In vivo, MKRN2 co-overexpression attenuated IGF2BP3-driven tumor growth and synergized with palbociclib to maximally suppress tumor volume, reduce MYC and Ki67 expression, and induce apoptosis. Conclusions: These findings establish the MKRN2–IGF2BP3–MYC axis as a critical regulator of CDK4/6 inhibitor sensitivity in bladder cancer. Targeting IGF2BP3 or enhancing MKRN2 activity may represent a promising strategy to overcome adaptive resistance and improve the therapeutic efficacy of CDK4/6 inhibitors.