Cancers doi: 10.3390/cancers18203254

Authors: Alaa A. A. Aljabali Mohammad A. Obeid Abdelrahim Alqudah Yassmen Hamzat Alaa Alqudah Lorca Alzoubi Omar Gammoh Esam Qnais Vijay Mishra Yachana Mishra Taher Hatahet Mohamed El-Tanani

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed or refractory hematological malignancies, producing deep and durable responses in B-cell acute lymphoblastic leukemia, aggressive B-cell non-Hodgkin lymphomas, and multiple myeloma. Nevertheless, antigen escape, limited in vivo persistence, T-cell exhaustion, and toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) limit broader application. This review synthesizes the mechanistic basis and clinical evidence for the currently approved CAR T-cell products and examines engineering strategies designed to overcome these barriers, including “armored” CAR T cells, multitargeted and logic-gated constructs, and modular or universal platforms intended to extend this approach beyond CD19-positive disease. Combination strategies with immune checkpoint inhibitors, radiotherapy, and other immunotherapies are discussed, together with emerging biomarkers of response and toxicity. Continued optimization of CAR design, toxicity management, and manufacturing scalability will be essential for CAR T-cell therapy to become a foundational pillar of precision oncology.

Cancers doi: 10.3390/cancers18203252

Authors: Claudia G. Chambers Grace Liles Anupam Mathur Tamer M. Sakr John M. Himmelberg Fabio Gallazi Lisa Watkinson Terry Carmack Yue Guan Susan Rottinghaus Yubin Miao Christine Lovingier Thomas Collora Gracie Miller Michael R. Lewis John D. Brockman Carolyn J. Anderson Charles J. Smith

Background/Objectives: A series of PSMA/GRPR-targeting compounds were selected based on modifications to their respective pharmacokinetic-modifying linking groups and the structure of the PSMA-binding moiety, to examine how these alterations impact binding affinity and specificity for preclinical prostate cancer models. Methods: The multi-receptor targeting heterodimers PSMA/2PSMA-X-DOTA-Y-BBN (where X is 6-aminohexanoic acid (6AHX) or polyethylene glycol-4 (PEG4) and Y is either 8-aminooctanoic acid (8AOC) or carboxy piperidine (CP)) were radiolabeled with the theranostic isotope [177Lu]Lu. Each heterodimer construct was evaluated through characterization, stability, whole-cell in vitro studies, biodistribution in tumor-bearing mice, and in vivo small animal SPECT/CT molecular imaging. Results: In vitro evaluation of 2PSMA-6AHX-DOTA-8AOC-BBN demonstrated moderate IC50 values of 200 ± 20 nM in LNCaP cells and 21 ± 1 nM in PC3 cells. Subsequent biodistribution studies demonstrated selective tumor uptake at 4 h post-intravenous injection with uptake of 9.52 ± 2.59%ID/g in GRPR[+] PC3 tumors and 6.37 ± 0.64%ID/g in PSMA[+] PC3-PIP tumors. At 24 h post-injection, high tumor-to-blood ratios (874.0 ± 276 in PC3 and 344.3 ± 85 in PC3-PIP) and tumor-to-muscle ratios (739.8 ± 277 in PC3 and 403.5 ± 66 in PC3-PIP) were observed, further supporting the theranostic feasibility of the radiolabeled heterodimer. Small animal SPECT/CT imaging confirmed tumor targeting specificity of the heterobivalent peptide. Conclusions: Evaluation in PSMA/GRPR-expressing tumor models identified 2PSMA-6AHX-DOTA-8AOC-BBN as a leading candidate, having enhanced tumor uptake and favorable pharmacokinetics in tumor-bearing mice. These investigations advance structure–activity relationship understanding and support heterobivalent radiopharmaceuticals for precision imaging and targeted prostate cancer therapy.

Cancers doi: 10.3390/cancers18203251

Authors: Arjun Dhir Brian Martins Zachary P. Yeung Neil R. Sharma Mohit Girotra

Background: Biliary tract cancers (BTCs) carry a poor prognosis driven by frequent diagnosis at advanced or metastatic stages. Inadequate tissue sampling impedes biomarker-directed selection of therapy that could potentially improve outcomes over limited chemotherapeutic options. Plasma cell-free DNA (cfDNA) yields limited sensitivity. However, given its direct contact with the tumor, bile holds promise as a locally enriched source of tumor-derived cfDNA for evaluation. Methods: Following the PRISMA-ScR guidelines, we searched PubMed/MEDLINE and EMBASE without date restrictions. Seventeen primary studies of bile cfDNA in cholangiocarcinoma (CCA), gallbladder carcinoma (GBC), pancreatic ductal adenocarcinoma (PDAC), and primary sclerosing cholangitis (PSC) were synthesized narratively. Results: Compared to plasma cfDNA, Bile cfDNA was isolated at higher concentrations and in longer fragments than plasma cfDNA; bile cfDNA demonstrated higher concordance with matched tumor tissue, capturing more actionable alterations. Pairing it with serum CA19-9 or newer bile-derived markers improved performance. Emerging data suggest a role in early detection of CCA during PSC surveillance. Conclusions: Bile cfDNA as a liquid biopsy medium offers analytic advantages over plasma for detecting and profiling biliary malignancy. Standardized collection, extraction, and reporting protocols and prospective multicenter validation are needed before routine use.

Cancers doi: 10.3390/cancers18203250

Authors: Martin P. Nilsson Jakob Eberhard Anders Johnsson Henrik Jutesten Marie-Louise Lydrup Pamela Buchwald

Background: Recent studies have indicated that the treatment of inguinal lymph node metastasis (ILNM) and para-aortic lymph node metastasis (PALNM) in colorectal cancer could be curative. However, the optimal treatment approach remains unclear. Methods: A systematic search and a narrative review were undertaken to identify manuscripts reporting at least 10 patients with colorectal cancer treated with curative intent for ILNM or PALNM. Each study cohort was categorized into one of four treatment approaches: (1) surgery without radiotherapy; (2) radiotherapy followed by universal surgery; (3) radiotherapy followed by selective surgery; (4) definitive radiotherapy. Results and Conclusions: This review supports the use of curative-intent treatment in selected colorectal cancer patients with ILNM or PALNM. Surgery without radiotherapy is the most extensively studied approach. Lower recurrence rates have been reported in some retrospective series using preoperative radiotherapy followed by universal surgery, at the cost of acceptable additional toxicity. In some small studies, definitive radiotherapy has achieved recurrence rates in the range observed in surgical series, but direct comparisons are lacking. Radiotherapy followed by selective surgery may represent a potential strategy for achieving locoregional control while avoiding surgery in selected patients, but evidence is currently limited to two small studies of ILNM. In related clinical settings, such as nonoperative management of primary rectal tumors and lateral lymph node metastasis, treatment has shifted over the past decade toward radiotherapy followed by selective surgery. It is possible that a similar evolution will occur for ILNM and PALNM as well, but stronger evidence is required before firm recommendations can be made. Systemic therapy was not the focus of this review but should be considered an essential component for most patients, in addition to radiotherapy and surgery.

Cancers doi: 10.3390/cancers18203249

Authors: Sonja Millert-Kalińska Dominik Pruski Marcin Przybylski

Objectives: This study aims to evaluate the diagnostic performance of multimodal hyperspectral spectroscopy (MHS) using the LuViva® Advanced Cervical Scan for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in women referred for further cervical assessment. Methods: This prospective, non-randomized diagnostic study included 77 women examined between September 2025 and April 2026. Participants were referred because of abnormal liquid-based cytology (LBC), high-risk human papillomavirus (HR-HPV) infection, or other indications for colposcopy. LuViva examination was performed before colposcopy with cervical biopsy. Histopathological diagnosis based on biopsy or loop electrosurgical excision procedure specimens was used as the reference standard. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for HR-HPV testing, LBC, and different LuViva positivity thresholds. Results: The mean age was 39.0 ± 8.4 years. The final histopathology showed no lesions in 30 women, LSIL in 18, HSIL in 28, and cervical cancer in one. For CIN2+ detection, HR-HPV testing demonstrated a sensitivity of 93.1% and specificity of 29.2%, whereas LBC had a sensitivity of 82.8% and specificity of 39.6%. LuViva testing showed sensitivities between 82.8% and 100%, and a specificity—when comparing with LBC—of 45.8% but 20.8% in LuViva alone. LuViva results differ significantly between women with CIN2+ and those with LSIL or no lesions. Conclusions: LuViva showed potential as an adjunctive triage tool, as no CIN2+ lesions were observed among women with a low-risk result; however, the small number of negative tests and wide confidence intervals preclude safely deferring colposcopy. The AND strategy showed a modest numerical improvement in specificity and overall accuracy compared with LBC alone but did not show an increase in sensitivity; this finding should be considered exploratory.

Cancers doi: 10.3390/cancers18203246

Authors: Isaac Amoah Hannah Ayettey Anie Daniel Tetteh Vanessa Adu Sarpong Kwaku Addai Arhin Appiah Phyllis Tawiah

Background: In Ghana, prostate cancer (PCa) was the second most frequently diagnosed cancer among men in 2022, after liver cancer. Despite increasing research interest, evidence needed to guide PCa research priorities remains fragmented. This scoping review aimed to highlight research priorities and direction on PCa in Ghana by identifying thematic areas, gaps and potential areas for future research. Methods: The scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist (PRISMA-ScR). A systematic search for relevant articles was conducted on four prominent databases: PubMed, Cochrane Library, Scopus, and ScienceDirect. Results: Data from eligible studies (n = 47) were synthesized across 15 thematic domains, including awareness, diagnosis and treatment approaches, genetics, dietary and metabolic factors, and pharmacological interventions. PCa awareness was high in some populations, but knowledge of specific disease features was variable, while screening uptake remained low. PSA was the most frequently assessed diagnostic marker, commonly evaluated alongside DRE and biopsy. Genomic studies identified potentially relevant genetic and molecular variants, although the evidence remains limited and requires further validation. Treatment patterns varied by disease stage and were also constrained by access- and resource-related factors. Epidemiological estimates differed by study design and population. Conclusions: PCa research in Ghana is broad but uneven, with significant gaps in early detection, population-level data, genomic validation and equitable access to care. Improving timely diagnosis and access to diagnostic and treatment services is important, while population-wide screening requires further evaluation of benefits, harms, cost-effectiveness, and health system capacity.

Cancers doi: 10.3390/cancers18203248

Authors: Kaiming Peng Jieming Lu Peipei Zhang Weiguang Zhang Jinlong Fang Junhuang Lin Shuchen Chen Mingqiang Kang

Background: Esophageal squamous cell carcinoma (ESCC) accounts for over 80% of esophageal cancer cases globally. Lymph node status is the strongest determinant of survival after resection, yet occult disease is found in about 17% of patients classified as node-negative. We developed a postoperative model estimating the probability of lymph node metastasis (LNM) from the resection specimen, combining nuclear features with clinicopathological variables. Methods: Of 477 consecutive ESCC patients undergoing radical esophagectomy without neoadjuvant therapy, 416 were analyzed (LNM 217, 52.2%). Nuclear features were extracted from H&E whole-slide images (20×) by QuPath optical-density detection; LASSO logistic regression selected 17. A nomogram combining the pathomics score with age, sex, tumor location, pT category and grade was validated by 10-fold cross-validation (out-of-fold, OOF) and applied without refitting to 101 patients from another institution. Results: OOF AUC was 0.821 (95% CI 0.779–0.858) for the combined model, versus 0.791 (clinical) and 0.762 (pathomics alone). The pathomics score remained an independent predictor (adjusted OR 2.47, 95% CI 1.80–3.39; p < 0.001). LNM prevalence rose across tertiles (15.8%, 55.1%, 85.6%; p < 0.001). Among 199 node-negative patients, high pathomics risk predicted worse 3-year overall survival (77.2% vs. 94.3%; p = 0.005) and progression-free survival (75.5% vs. 88.9%; p = 0.007). Externally (n = 101; LNM 24.8%), AUCs were 0.812, 0.801 and 0.697, and adding pathomics did not significantly improve discrimination. Conclusions: Within the development cohort, pathomics added modest but significant incremental value and identified node-negative patients at elevated risk. Because the model requires the resection specimen, it cannot guide preoperative treatment selection. External validation did not confirm incremental value: the clinical component; the pathomics signature did not.

Cancers doi: 10.3390/cancers18203247

Authors: Takayuki Ogino Yuki Sekido Tsunekazu Mizushima Ryota Mori Mitsunobu Takeda Masaaki Miyo Atsushi Hamabe Norikatsu Miyoshi Mamoru Uemura Hidetoshi Eguchi

Ulcerative colitis (UC) is associated with an increased risk of colorectal cancer, particularly in patients with long-standing and extensive disease. Although advances in medical therapy and surveillance have reduced colorectal cancer incidence, prolonged preservation of chronically inflamed colonic mucosa has increased the importance of understanding how cumulative inflammation promotes carcinogenesis. UC-associated neoplasia differs from sporadic colorectal cancer in its multifocality, pathological heterogeneity, and molecular evolution. Repeated inflammation, epithelial injury, and regeneration promote the accumulation of somatic and epigenetic alterations across histologically non-dysplastic mucosa, generating a cancerized field composed of genetically heterogeneous epithelial clones. Recent sequencing studies have shown that many clones selected in chronically inflamed mucosa harbor alterations that enhance adaptation to inflammatory stress but are not necessarily premalignant, indicating that field cancerization represents a dynamic evolutionary ecosystem rather than simple expansion of cancer-prone clones. Neoplastic progression requires further clonal selection as the selective environment shifts toward autonomous growth. Colitis-associated colorectal cancer is characterized by early TP53 alterations, a relatively late and less frequent involvement of APC, branching clonal evolution, and substantial copy-number alterations, particularly during progression from low- to high-grade dysplasia. Thus, colitis-associated carcinogenesis can be understood as a process in which chronic inflammation establishes a genetically altered field, followed by dynamic clonal selection and genomic evolution. Elucidating these processes may enable identification of high-risk fields and clones before invasive cancer develops and provide a biological basis for improved surveillance, risk stratification, and chemoprevention.

Cancers doi: 10.3390/cancers18193245

Authors: Kazuyuki Murase Yusuke Sugama Yohei Arihara Kohichi Takada Kunihiko Ishitani

Background/Objectives: Decision-making in advanced cancer care is intertwined with diagnostic profiling, prognostic communication, supportive care, and anticancer treatment selection. An author-developed D-S-T × B/C/E conceptual mapping scaffold—three decision/action domains (Diagnosis, Supportive care, Therapy) and three evaluative dimensions (Biological, Clinical, Existential)—was used to organise the literature, to identify coverage gaps and recurring framework categories, and, as a secondary conceptual synthesis objective, to derive a candidate integrative framework. Methods: The review was conducted according to the Joanna Briggs Institute (JBI) methodology for scoping reviews, pre-registered on OSF, and reported per PRISMA-ScR. PubMed was searched on 21 June 2026, and the final evidence set was derived solely from this search. Eligible records concerning adults with advanced cancer were dual-screened and charted using a structured form. Results: Eighty-two records (2010–2026) were included. Under the strict D-S-T × B/C/E matrix, Supportive care showed the highest joint coverage, particularly S × C (59/82, 72.0%), whereas D × B and D × E were the least represented cells (13/82 each, 15.9%). Eight recurring framework categories were inductively derived from the charted framework descriptors, led by early integrated palliative care (30/82) and prognosis-informed shared decision-making (27/82). Twenty-two records met an emergence-candidate screen defined at the synthesis stage, of which three received the maximum cross-axis coupling score of 6/6 from both reviewers. Conclusions: The advanced-cancer decision-framework literature clusters around a small number of architectures with uneven D-S-T × B/C/E coverage. Diagnosis-centred frameworks coupled with biological or existential dimensions were relatively under-represented within our mapping and represent priority targets for future primary research; the proposed Adaptive framework provides one structure in which this research could be conducted.

Cancers doi: 10.3390/cancers18193243

Authors: Julian Brack Valon Gllareva Bastian von Nettelbladt Eva Meixner Line Hoeltgen Laila Koenig Hanna Waldsperger Katharina Kozyra Habiba Sallem Alexander Neuholz Thomas Tessonnier Andrea Mairani Jürgen Debus Klaus Herfarth Semi B. Harrabi

Background/Objectives: Proton therapy is widely used in paediatric neuro-oncology because of its favourable dose distribution and reduced exposure to radiation of healthy tissue. Nevertheless, current knowledge regarding radiation-induced contrast enhancements (RICE) is largely derived from adult proton therapy cohorts, while evidence in paediatric patients remains limited and the underlying biological mechanisms are still incompletely understood. This study investigated the incidence of RICE in paediatric patients with low-grade glioma (LGG) and ependymoma and evaluated potential associations with linear energy transfer (LET) and variable relative biological effectiveness (RBE)-weighted dose distributions. Methods: In this retrospective single-centre study, paediatric patients with LGG or ependymoma were identified from a prospectively maintained institutional registry patients treated with proton therapy at the Heidelberg Ion-Beam Therapy Centre (HIT) between 2010 and 2024. Follow-up magnetic resonance imaging examinations were systematically reviewed for RICE. Lesions were contoured in RayStation and assessed dosimetrically using a fixed RBE of 1.1 and three variable RBE models. LET-weighted dose metrics and Dose(RBE) × LET products were compared between RICE regions and planning target volumes (PTVs). Overall survival and progression-free survival were estimated using Kaplan–Meier method. Results: Seventy-six patients met the inclusion criteria, including 33 patients with LGG and 43 with ependymoma. A total of 724 follow-up magnetic resonance imaging examinations were reviewed. RICE occurred in six patients (7.9%), exclusively in the ependymoma subgroup (14.0%). Higher prescribed radiation dose was significantly associated with RICE occurrence (p = 0.031). Across all variable RBE models, biologically weighted dose estimates and Dose(RBE) × LET products were consistently elevated within RICE regions compared with corresponding PTV regions, particularly at low- and intermediate-dose levels. Five-year overall survival rates were 91.7% for LGG and 86.6% for ependymoma, while corresponding progression-free survival rates were 84.4% and 69.3%, respectively. Conclusions: Variable RBE models identified biologically relevant dose heterogeneities within RICE regions that were not adequately captured by the conventional fixed RBE approach. These findings suggest that LET-associated biological dose escalation may contribute to radiation-related brain tissue changes after proton therapy and support further investigation and prospective validation of LET- and RBE-informed normal-tissue risk assessment in paediatric neuro-oncology.

Cancers doi: 10.3390/cancers18193244

Authors: Mesut Süleymanoğulları Cemre Didem Eyipınar Zarife Pancar Valentina Stefanica Nicola Luigi Bragazzi Halil İbrahim Ceylan

Background and Objectives: Anxiety is highly prevalent among breast cancer patients and significantly impairs quality of life. Although both conventional physical exercise (PE) and mind–body interventions (MBE) are used in supportive care, their relative efficacy remains unclear. This systematic review and meta-analysis compared the effects of PE and MBE on anxiety in breast cancer patients. Materials and Methods: PubMed, Web of Science, Embase, PsycINFO, and CINAHL were systematically searched through April 2026 for controlled trials comparing structured PE or MBE with control conditions. Effect sizes were pooled as standardized mean differences (SMDs; Hedges’ g) using a random-effects model with restricted maximum likelihood estimation and modified Hartung–Knapp inference. Subgroup analyses and univariable meta-regressions explored potential moderators. Results: Twenty-four reports (N = 2,197) represented 25 independent trials; 22 estimates from 21 reports entered the meta-analysis, and three reports were synthesized narratively. Interventions significantly reduced anxiety on average (SMD = −0.58, 95% CI [−1.01, −0.15], p = 0.011), with substantial heterogeneity (I² = 85.0%) and a 95% prediction interval of −2.38 to 1.22. Both PE (SMD = −0.67) and MBE (SMD = −0.46) favored intervention numerically, although both subgroup confidence intervals included no effect, with no significant difference between modalities (p = 0.697). A larger, yet non-significant, effect was observed during active treatment (SMD = −0.84, 95% CI [−1.68, 0.01]) compared with survivorship (SMD = −0.34, 95% CI [−0.62, −0.07]); the between-phase comparison was inconclusive (p = 0.291). The comparison across diagnostic stages was also inconclusive (p = 0.366). None of the seven continuous moderators met the multiplicity-adjusted significance threshold. Conclusions: Current findings suggest an average reduction in anxiety following physical and mind–body interventions in breast cancer patients. However, no statistically significant differences were observed between intervention modalities or treatment stages. Very low certainty, substantial heterogeneity and indirect subgroup comparisons limit confidence in the size and consistency of benefit. Overall, individualized interventions may have a role in oncology care, but these findings do not establish superiority, equivalence or differential efficacy between modalities or treatment phases.

Cancers doi: 10.3390/cancers18193242

Authors: Jinghui Sun Lingling Liu Rhyston Broadhurst David Wang Anand Mehta Denis C. Guttridge Leonardo M. R. Ferreira Haizhen Wang Xueliang Gao

Background/Objectives: Pancreatic cancer (PC) is a leading cause of cancer-related death in the United States and lacks efficient therapeutic options. Serine peptidase inhibitor, clade B, member 5 (SERPINB5) is non-inhibitory toward serine proteases, yet it has diverse biological functions, including regulating cell migration, cell death, gene expression, and stress responses. Mesothelin (MSLN) is a tumor-associated antigen that is broadly overexpressed on various malignant tumor cells and plays a crucial role in promoting proliferation, invasion, and metastasis. Methods: We integrated public database analyses, cell-line screening, gene knockdown and overexpression, immunoblotting, cell viability and apoptosis assays, flow cytometry, chromatin immunoprecipitation paired with quantitative PCR (ChIP-qPCR), and chimeric antigen receptor (CAR) T-cell therapy to investigate SERPINB5 and MSLN functions, developing a novel and effective therapeutic strategy for patients with pancreatic cancer. Results: Both SERPINB5 and MSLN are highly expressed and negatively associated with the overall survival of PC patients. Our mechanistic study suggests that SERPINB5 negatively regulates the mitochondrial protein dehydrogenase/reductase 2 (DHRS2) to promote PC cell survival; consequently, SERPINB5 depletion induces PC cell apoptosis. Of note, SERPINB5 depletion increases MSLN transcription by enhancing c-Myc binding to the MSLN promoter region, which in turn suppresses the mitochondrial protein DHRS2 and leads to resistance to apoptosis in PC cells. Our genetic ablation study shows that SERPINB5 and MSLN are critical for PC cell survival, and that depleting both proteins synergistically induces PC cell apoptosis. Gemcitabine (GEM) is a standard chemotherapy drug for PC treatment. Our study shows that SERPINB5-high PC cells display greater sensitivity to GEM than SERPINB5-low PC cells. GEM treatment increases mitochondrial DHRS2 protein expression, similar to the effect of SERPINB5 knockdown, whereas upregulated MSLN confers apoptotic resistance by decreasing DHRS2 levels. Conclusions: Our in vitro study demonstrates that sequential treatment with GEM followed by anti-MSLN chimeric antigen receptor (CAR)-T cells is an effective and promising strategy for patients with pancreatic cancer. Future studies using mouse models may validate the efficacy of this sequential treatment strategy in vivo.

Cancers doi: 10.3390/cancers18193241

Authors: Klaudia Gutowska Aleksandra Urban Cezary Wojtyła Sławomir Ławicki Piotr Laudański

Purpose: We aim to synthesize recent clinical and translational evidence on the relationship between endometriosis and ovarian cancer, with emphasis on publications from 2024 to 2026 and on clinically conservative risk stratification. Materials and methods: This state-of-the-art narrative review prioritizes major peer-reviewed publications from July 2024 to June 2026. Older landmark publications were used only where necessary to contextualize recent findings. Results: Recent evidence supports a selective, phenotype-dependent association instead of a generalized malignant potential of endometriosis. The strongest and most reproducible signal concerns epithelial ovarian cancer, especially clear-cell and endometrioid ovarian carcinoma, with the highest relative risks reported for ovarian endometrioma and/or deep endometriosis. The ENDOCANCER meta-analysis found increased ovarian cancer risk across odds ratio, hazard ratio and standardized incidence ratio estimates but confirmed low absolute incidence and substantial heterogeneity. Contemporary reviews, including Leone Roberti Maggiore et al. and Bogani et al., emphasize low absolute lifetime risk and the absence of evidence supporting universal oncologic surveillance. Newer clinicopathological studies distinguish endometriosis-correlated tumors supported by transitional lesions indicative of malignant transformation from incidental coexistence. Molecular data support biological plausibility through ARID1A, PIK3CA, KRAS, PTEN, mismatch repair deficiency, POLE-mutated disease and p53-abnormal phenotypes, but these markers are not ready for routine prediction in endometriosis care. Conclusions: The immediate clinical implication is individualized risk assessment in place of routine cancer screening or prophylactic surgery based solely on the increased cancer risk associated with endometriosis. Counseling should integrate endometriosis phenotype, age, menopausal status, lesion dynamics, imaging atypia, hereditary cancer risk, reproductive goals and surgical consequences.

Cancers doi: 10.3390/cancers18193240

Authors: Tancredi Didier Bazan Russo Valerio Gristina Francesco Pepe Claudia Scimone Giulia Busuito Domenico Cozzolino Claudia Sarracino Giuseppina Ratto Lorena Incorvaia Nadia Barraco Giuseppe Badalamenti Antonio Galvano Viviana Bazan Antonio Russo Giancarlo Troncone Umberto Malapelle

Immune checkpoint inhibitors (ICIs) have transformed the treatment of non-small-cell lung cancer (NSCLC), yet predicting durable benefit and detecting resistance remain major challenges. As immunotherapy expands across disease stages, minimally invasive tools are increasingly needed to monitor response and inform treatment personalization. Liquid biopsy enables serial assessment of circulating tumor DNA (ctDNA) and other blood-based biomarkers, complementing tissue analysis and imaging. This review critically synthesizes evidence across resectable, locally advanced, and metastatic NSCLC, integrating ctDNA dynamics with emerging multi-omics approaches. Its contribution is to distinguish the prognostic value of circulating biomarkers from evidence that using them to guide treatment improves patient outcomes, while identifying priorities for clinical translation. Across the reviewed studies, ctDNA clearance is associated with favorable outcomes, whereas persistent or rising ctDNA signals an increased risk of recurrence or progression, sometimes before radiological detection. Methylation, fragmentomics, plasma proteomics, and immune-cell profiling may provide complementary information on tumor-immune interactions. However, low tumor shedding, clonal hematopoiesis, assay variability, and unvalidated intervention thresholds limit routine use. The expansion of perioperative immunotherapy and emerging interest in biomarker-guided treatment adaptation make this synthesis timely. Prospective interventional trials are needed to determine whether liquid biopsy can safely guide treatment escalation, de-escalation, or discontinuation. By clarifying both the promise and the limitations of longitudinal monitoring, this review informs research aimed at detecting ineffective treatment earlier and reducing unnecessary treatment exposure while preserving cancer control.

Cancers doi: 10.3390/cancers18193239

Authors: Lidia Tarone Irene Fiore Merighi Elisa Tirtei Davide Giacobino Emanuela Maria Morello Federica Cavallo Federica Riccardo

Osteosarcoma (OSA) remains the most common primary malignant bone tumor of children and young adults, with limited survival improvements in patients with relapsed or metastatic disease despite multimodal chemotherapeutic treatment. Beyond the intrinsic heterogeneity and malignancy of tumor cells, OSA progression and therapeutic resistance are strongly influenced by the specialized bone tumor microenvironment (TME). Interactions among tumor, immune and stromal cells generate a complex ecosystem characterized by immune suppression, hypoxia and metabolic adaptation, representing a major challenge for effective (immune) therapeutic approaches. In this review, we discuss how the OSA microenvironment shapes tumor evolution and therapeutic response, with particular emphasis on the mechanisms that limit effective immune-mediated tumor control. We further examine the rationale for combining tumor-directed and microenvironment-directed immunotherapies. Within this context, B7-H3/CD276 represents a relevant example of a multifunctional molecule at the interface between tumor biology and immune regulation. B7-H3 is associated with aggressive tumor features and therapy resistance, while its immunoregulatory activities contribute to the establishment of an immune-restrictive TME. Consequently, B7-H3-targeted therapies may exert complementary mechanisms of action, either by directly eliminating B7-H3-expressing tumor cells or by modulating the TME to overcome immunosuppressive barriers. This dual activity provides rationale for combination strategies integrating B7-H3-targeting with antigen-directed immunotherapies, including those targeting the novel OSA-associated antigen, chondroitin sulfate proteoglycan 4, where effective antitumor immunity may require simultaneous modulation of the local immune context. We then discuss how advanced preclinical models, comparative oncology, and emerging biomarker-guided approaches may accelerate the clinical translation of more effective immunotherapeutic strategies for OSA.

Cancers doi: 10.3390/cancers18193238

Authors: Naohisa Kuriyama Shugo Mizuno Yuki Segi Haruna Komatusbara Kazuyuki Gyoten Takahiro Ito Aoi Hayasaki Takehiro Fujii Yusuke Iizawa Yasuhiro Murata Akihiro Tanemura Masashi Kishiwada

Objectives: The long-term impact of neoadjuvant chemotherapy (NAC) based on anatomical resectability for perihilar cholangiocarcinoma (PHC) remains unclear. We evaluated the mature long-term outcomes of our multidisciplinary treatment strategy based on anatomical resectability classification and regional lymph node (LN) status using gemcitabine plus S-1 (NAC-GS). Methods: Between September 2010 and August 2021, 110 consecutive PHC patients were classified as resectable (R; n = 47), borderline resectable (BR; n = 38), or unresectable locally advanced (UR-LA; n = 25) according to our anatomical resectability classification. NAC-GS was administered to patients with clinically positive LN metastasis and to BR and UR-LA patients. Long-term overall survival (OS), recurrence-free survival (RFS), and prognostic factors were evaluated. Results: NAC-GS was administered to 72 patients (65.5%). Curative-intent resection was achieved in 40 (85.1%), 25 (65.8%), and 6 (24.0%) patients in the R, BR, and UR-LA groups, respectively. In the overall cohort, anatomical resectability significantly stratified OS (p = 0.032). However, among patients who underwent curative-intent resection, OS and RFS were comparable across the three resectability groups. Those receiving NAC-GS showed favorable long-term survival despite having more advanced disease characteristics; however, this comparison was limited to selected patients who ultimately proceeded to surgery. Multivariable analysis identified preoperative serum carcinoembryonic antigen ≥5.5 ng/mL (HR: 3.174, p = 0.003), non-adjuvant therapy (HR: 2.222, p = 0.023) and pathological T4 (HR: 2.397, p = 0.037) as independent predictors of poor survival. Conclusions: Anatomical resectability was associated with long-term prognosis and the likelihood of achieving curative-intent resection. Selected patients who ultimately underwent curative-intent resection after NAC-GS showed favorable long-term outcomes; however, these findings do not establish a survival benefit of NAC-GS over upfront surgery. Prospective multi-institutional validation is warranted.

Cancers doi: 10.3390/cancers18193237

Authors: Peisen Zhang Changjiang Yan Meilin Sun Shaojie Ding Lingmei Li Wenfeng Cao Lu Cao

Accurate subtyping of lymphomas is critical for guiding treatment decisions and predicting patient outcomes, yet it remains challenging due to overlapping morphological features. This study aimed to develop and validate a deep learning-based diagnostic system, designated BH-LymphDS, to accurately differentiate the three most prevalent lymphoma subtypes: Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), and Hodgkin Lymphoma (HL). The system integrates a Swin Transformer backbone with a clustering-constrained attention multiple instance learning (CLAM) algorithm and a k-nearest neighbors (KNN) classifier, supporting weakly supervised learning directly from whole-slide images without manual region-level annotation. A total of 1910 whole-slide images (WSIs) from diagnostic biopsies were utilized for model development—the largest cohort to date in this field. The performance of nine distinct deep learning architectures was systematically compared. Model efficacy was rigorously evaluated through five-fold cross-validation and further validated on independent external datasets from TCIA and TCGA. Additionally, a comparative analysis was conducted against the diagnostic performance of three experienced hematopathologists. In the internal testing cohort, BH-LymphDS achieved a micro-average AUC of 0.955 and an accuracy of 92.5%. During cross-validation, the system attained a superior micro-average F1-score (0.871) compared to the average of the three hematopathologists (0.851). The Swin Transformer emerged as the optimal backbone, and gradient-weighted class activation mapping (GradCAM) confirmed that the model’s decisions were based on legitimate morphological features such as nuclear atypia and cellular growth patterns. Our findings demonstrate that an advanced AI system can satisfy the rigorous requirements for accurate lymphoma subclassification on histopathological slides. The BH-LymphDS shows strong potential as a reliable auxiliary diagnostic tool to enhance clinical workflow efficiency and diagnostic consistency.

Cancers doi: 10.3390/cancers18193236

Authors: Hirotaka Konishi Shutaro Sumiyoshi Hiroyuki Inoue Keiji Nishibeppu Toshiyuki Kosuga Yusuke Yamamoto Ryo Morimura Hitoshi Fujiwara Atsushi Shiozaki

Background: Mediastinoscopic esophagectomy is a minimally invasive approach that avoids thoracotomy and single-lung ventilation. We previously performed this procedure using hand-assisted laparoscopic surgery (HALS) and recently established a totally laparoscopic transhiatal approach. This retrospective, non-randomized study reported laparoscopic technique and compared the feasibility and surgical outcomes of these approaches. Methods: We retrospectively reviewed 262 patients who underwent radical mediastinoscopic esophagectomy using left cervical and transhiatal approaches at the Kyoto Prefectural University of Medicine between January 2020 and June 2026. HALS was performed in 202 patients and laparoscopy in 60 patients. Surgical procedures and perioperative outcomes were compared between the groups. Results: Blood loss and total operative time did not differ significantly between the groups, although the transhiatal procedure tended to require a longer operative time with laparoscopy (p = 0.09). The approach used for middle mediastinal lymphadenectomy was similar between the two groups (43% vs. 35%, p = 0.28), and the overall number of dissected lymph nodes, excluding the upper mediastinal and cervical nodes, was comparable. However, significantly more abdominal lymph nodes were dissected with laparoscopy than with HALS (17.9 vs. 15.7, p = 0.04). Laparoscopic gastric mobilization and lymph node dissection were safely performed, with no significant differences in the rate of postoperative complications or curability. Conclusions: The totally laparoscopic transhiatal technique is a feasible and safe approach for mediastinoscopic esophagectomy, with surgical outcomes comparable to those of HALS and not inferior abdominal lymph node dissection. It may be particularly advantageous for cases requiring meticulous abdominal lymphadenectomy.

Cancers doi: 10.3390/cancers18193233

Authors: Francesca Palone Luca Marchetti Marco Corso Emiliano Fratini Ilaria De Stefano Ilaria Di Sarcina Simonetta Pazzaglia Mariateresa Mancuso

Background: Radiotherapy (RT) is a cornerstone of medulloblastoma (MB) treatment, but its efficacy may be limited by intrinsic or acquired radioresistance, while radiation-related late effects remain a major concern in pediatric patients. 18β-Glycyrrhetinic acid (18β-GA), a bioactive triterpenoid derived from Glycyrrhiza glabra, has shown antitumor activity in several malignancies. This study evaluated its antitumor and radiosensitizing effects in biologically distinct MB models. Methods: DAOY cells, used as an SHH-associated, TP53-mutant model, and D283 cells, commonly considered a Group 3/Group 4-associated model, were treated with 18β-GA (2.5–5 μM), γ-radiation (2–4 Gy), or their combination. Cell viability, clonogenic survival and migration were assessed. Apoptosis was evaluated by caspase-3/7 activity and cleaved caspase-3 expression. Modulation of AMPK/NF-κB and SHH signaling was examined by immunoblotting and RT-qPCR. Results: 18β-GA reduced cell viability in a dose- and time-dependent manner and significantly reduced wound closure in DAOY cells and migratory capacity in D283 cells. D283 cells showed greater apoptotic sensitivity, accompanied by increased total and phosphorylated AMPK and reduced NF-κB p65 expression. In DAOY cells, 18β-GA reduced the expression of SHH-associated transcriptional markers, including GLI1, SOX2, CCND1, and MYC. Most importantly, 18β-GA significantly enhanced radiation response in both cell lines, producing greater reductions in viability and clonogenic survival than irradiation alone (p < 0.01). Combined treatment with 5 μM 18β-GA and 4 Gy reduced the surviving fraction to 0.013 in DAOY cells and approximately 0.01 in D283 cells (p < 0.001 versus radiation alone). This radiosensitizing effect was accompanied by increased caspase-3/7 activity and cleaved caspase-3 expression. Conclusions: 18β-GA exerts antitumor activity in biologically distinct MB models through differential modulation of SHH and AMPK/NF-κB signaling, while converging on enhanced apoptotic susceptibility and a profound loss of clonogenic survival after irradiation. These findings provide a strong rationale for further preclinical evaluation of 18β-GA as a potential radiosensitizing adjuvant in MB.

Cancers doi: 10.3390/cancers18193235

Authors: Dheeraj Sharma Shriyansh Srivastava Sathvik Belagodu Sridhar Javedh Shareef Rakesh Sahu Roja Rani Budha Mohd Tariq Mohammad Amjad Kamal

Breast cancer is a biologically heterogeneous disease that requires accurate diagnosis, risk stratification, treatment selection and longitudinal assessment. Conventional imaging and tissue biopsy remain the mainstays of clinical management. However, tissue sampling represents a specific anatomical site and time point, and may not reflect the molecular heterogeneity or evolution of disease. Liquid biopsy offers a minimally invasive complementary approach, analyzing circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and extracellular vesicles. Applications include molecular characterization, treatment-response assessment, resistance detection and minimal residual disease (MRD) evaluation, which are under investigation or in clinical use. Gene-expression profiles, mutational alterations and epigenetic marks can generate molecular signatures that offer further support for tumor classification and risk stratification, and have demonstrated clinical value in specific breast cancer populations. Advances in next-generation sequencing, digital PCR, proteomic analysis, and artificial intelligence have expanded the analytical capacity for detection and interpretation of circulating and tissue-derived biomarkers. However, biological heterogeneity, low abundance of circulating biomarkers, pre-analytical and analytical variability, standardization of assays and limited prospective evidence for some applications are still major barriers to clinical translation. In this review, we discuss the biological basis, detection technologies, clinical applications and limitations of liquid biopsies and molecular signatures in breast cancer, highlighting multi-omics integration and computational approaches. It distinguishes between promising analytical biomarkers and clinically validated applications and highlights the evidence and methodological needs for wider implementation in precision breast cancer care.

Cancers doi: 10.3390/cancers18193234

Authors: Krzysztof Gawronski Nadia Hussein Piotr Rzepecki Aneta Guzek

Background/Objectives: Neutrophil recovery after bloodstream infection (BSI) in acute leukemia is clinically important, but evaluation is complicated by early death and recurrent infectious episodes. We assessed clinical, treatment-related, and microbiological factors associated with recovery while accounting for death as a competing event. Methods: This retrospective single-center cohort included 205 microbiologically documented BSI episodes in 101 adults with acute leukemia treated between 2020 and 2025. Neutrophil recovery was defined as an absolute neutrophil count >500/µL after BSI onset. The endpoint was evaluable in 186 episodes; 116 were followed by recovery and 70 by death before recovery. Recurrent episodes were retained and within-patient dependence was addressed by patient-level clustering in marginal Fine–Gray regression. Results: In the fully adjusted model (177 episodes, 93 patients), G-CSF use was associated with a higher cumulative incidence of recovery (sHR 3.17, 95% CI 1.40–7.18; p = 0.006), as was consolidation versus induction (sHR 2.50, 95% CI 1.44–4.33; p = 0.001). Clinically relevant antimicrobial resistance was not independently associated with recovery (sHR 0.80, 95% CI 0.38–1.68; p = 0.558). A literal-first-BSI sensitivity analysis supported the overall clinical pattern. Conclusions: Neutrophil recovery after BSI was associated primarily with treatment and clinical context, while the crude adverse association with antimicrobial resistance was substantially attenuated after adjustment. These observational associations, particularly those involving G-CSF, should not be interpreted causally.

Cancers doi: 10.3390/cancers18193232

Authors: Jasmine Machhi Priya Kumthekar Stella Hartmann

Gliomas are the most prevalent and aggressive primary tumors of the central nervous system (CNS), with glioblastoma demonstrating particularly poor survival rates despite multimodal treatment approaches. The extensive molecular heterogeneity and resistance to conventional therapies highlight the urgent need for novel biomarkers and therapeutic targets. Non-coding RNAs (ncRNAs), transcripts that do not encode proteins, have emerged as crucial regulators of gene expression and cellular homeostasis in both normal and malignant contexts. Their dysregulation contributes to key oncogenic processes, including uncontrolled proliferation, apoptosis, evasion, invasion, and therapeutic resistance. Small and intermediate-sized are strong candidates for biomarkers due to their high abundance and relative stability. Previous reviews on ncRNAs highlight the numerous roles of microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in gliomas. Here, we focus specifically on small and intermediate-length non-coding RNAs, including transfer RNAs (tRNAs) and tRNA-derived fragments (tRFs or tsRNAs), small nucleolar RNAs (snoRNAs), vault RNAs (vRNAs or vtRNAs), small nuclear RNAs (snRNAs) and mitochondrial tRNAs (mt-tRNAs). Recent studies suggest that these various non-coding RNAs participate in diverse aspects of glioma biology, including regulation of gene expression and modulation of metabolic and immune pathways, and correlate with tumor grade and molecular subtype. In this review, we summarize current evidence regarding the expression profiles and functional roles of small and intermediate-length non-coding RNAs in glioma tumorigenesis, progression, and therapeutic response. The differential expression of many of these ncRNAs in gliomas implies their involvement in both tumor-suppressive and oncogenic processes. A deeper understanding of these molecules may provide valuable insights into glioma biology and reveal novel biomarkers for diagnosis, prognosis, and treatment.

Cancers doi: 10.3390/cancers18193231

Authors: Shoeb Ikhlas Amani Alsharidah Reem A. Alkhodier Sergio Senar Mohamed Boudjelal

Drug repurposing offers an efficient strategy to identify novel anticancer agents from marketed compounds. We screened a library of ~1400 approved drugs using a PPARE–PPAR-α luciferase reporter assay to uncover modulators of lipid metabolism that induce cancer cell death without direct binding to PPARα. This primary screen identified 224 compounds inhibiting reporter activity by >50%, of which 26 demonstrated ≥50% cytotoxicity in KAIMRC1 breast cancer and HCT116 colorectal cancer cells at 10 µM after 48 h incubation. AI-based DrTarget analysis classified these hits, with Group 1 comprising four previously unrecognized anticancer agents: antibiotics cefditoren pivoxil, tebipenem pivoxil, broxyquinoline, and cosmetic ingredient 1-hexadecanol. Dose–response studies across KAIMRC1, HCT116, and SW480 cells revealed IC50 values as low as ~10 µM, comparable to daunorubicin, a well-known anti-cancer drug. Apoptosis profiling confirmed activation of intrinsic/extrinsic pathways via cytochrome c, SMAC/Diablo, TRAIL-R1/DR4, and phospho-p53 modulation. Based on these findings, we propose the repurposing of Broxyquinoline, 1-Hexadecanol, Cefditoren Pivoxil, and Tebipenem Pivoxil as potential anti-cancer drugs.

Cancers doi: 10.3390/cancers18193230

Authors: Tina Y. Zhang Alex Y. Ge Shyam A. Patel Poorva Bindal Jan Cerny Andrew Gillis-Smith Muthalagu Ramanathan Sakiko Suzuki Laurie Pearson

Background: Acute myeloid leukemia (AML) predominantly affects older adults; however, patients 75 years of age and older are often not candidates for curative-intent treatments. Data on their treatment patterns, survival outcomes, and healthcare utilization are limited, and we evaluated these outcomes among patients 75 years of age and older with AML. Methods: We retrospectively analyzed 97 patients aged 75 years and older managed at our academic safety-net hospital between 2016 and 2025. Results: Median overall survival (mOS) was 95 days for all patients. Receipt of any AML-directed therapy was associated with longer mOS compared with no leukemia-directed treatment (144 days, 95% CI: 98–184 vs. 17 days, 95% CI: 7–50; p < 0.001). Among patients with 2024 ELN adverse-risk/TP53-mutated disease, mOS was 88 days (95% CI: 34-NE) with AML-directed therapy and 44 days (CI: 36-NE) without treatment (p = 0.2). Forty-four percent of patients were enrolled in a hospice at their time of death, and an additional 40% were managed with comfort measures as inpatients. Median duration of hospice or comfort care was 2 days (IQR: 1–5), with no difference based on whether patients received any AML-directed treatment. Fifty-one percent of patients died in the hospital. Conclusions: Our findings highlight real-world challenges for older adults with AML, including the need for more effective treatments for patients with TP53-mutated AML. AML-directed treatment was associated with longer survival without a decrease in the time spent in hospice care, and the risk of in-hospital mortality remains elevated for this population.

Cancers doi: 10.3390/cancers18193229

Authors: Aikaterini Anetaki Constantine Anetakis Ioannis Chaniotakis Christos Mpogiatzis Anna Goussia Dionysios J. Papachristou Mattheos Bobos

Primary bone vascular neoplasms comprise a rare and biologically heterogeneous group of endothelial tumors encompassing benign, intermediate, and malignant entities with distinct clinicopathological, molecular, and prognostic characteristics. These tumors remain diagnostically and biologically challenging because of overlapping histopathological features, heterogeneous clinical behavior, evolving molecular landscapes, and limited disease-specific evidence. Advances in bone pathology, immunophenotyping, molecular diagnostics, and genomic profiling have substantially improved tumor classification and biological characterization. Importantly, contemporary classification and molecular studies have also highlighted the biological heterogeneity of vascular lesions involving bone, distinguishing well-defined vascular neoplasms from vascular malformations and identifying additional molecularly defined entities relevant to osseous disease and differential diagnosis. Concurrently, increasing recognition of the bone microenvironment and osteoimmunology provides a broader framework for understanding interactions among endothelial, skeletal, stromal, and immune populations and the extracellular matrix, with potential relevance to angiogenesis, bone remodeling, and tumor biology. Previous authoritative syntheses have established the classification, molecular features, diagnosis, and clinical management of these neoplasms. However, comparatively limited attention has been devoted to integrating tumor-intrinsic alterations with vascular–bone crosstalk, extracellular-matrix and mechanobiological signaling, osteoimmune regulation, and emerging precision-oncology strategies. Building on these foundations, this review integrates current evidence on classification, molecular pathogenesis, the skeletal microenvironment, osteoimmunology, biomarkers, and precision oncology. Where relevant, molecularly defined vascular neoplasms and vascular anomalies involving bone are discussed to clarify classification, molecular context, and differential diagnosis without conflating these lesions with the principal WHO-defined primary vascular neoplasms of bone. Findings directly demonstrated in primary bone vascular neoplasms are distinguished from mechanistic concepts extrapolated from physiological bone biology, other bone tumors, or non-osseous vascular neoplasms. Through this evidence-calibrated approach, we propose an integrated vascular–bone–immune framework, identify key knowledge gaps, and define priorities for disease-specific translational research and more individualized patient management.

Cancers doi: 10.3390/cancers18193228

Authors: Júlio Martins Lopes Vânia Oliveira Pedro Cardoso Manuel Magalhães Paula Fidalgo António Araújo

Background/Objectives: Bone metastases from lung cancer can cause pain, pathological fracture, spinal instability, metastatic spinal cord compression and loss of independence. Lung cancer-specific evidence for orthopaedically relevant local management remains fragmented. This review assessed outcomes across spinal, appendicular and pelvic skeletal disease, while explicitly examining the anatomical distribution and limitations of the evidence. Methods: PubMed, Web of Science, Europe PMC and Scopus were searched for original studies published from January 2015 to December 2025. Eligible studies evaluated orthopaedic, surgical, minimally invasive or percutaneous skeletal interventions, including radiotherapy when combined with or directly compared with an orthopaedically relevant local strategy. Two reviewers independently screened studies, extracted data and completed the full Joanna Briggs Institute checklist applicable to each design. Findings were synthesised narratively, with evidence certainty assessed using GRADE. Results: Thirty-three studies comprising 3585 participants with lung cancer were included; 26 were retrospective observational studies. Thirty studies predominantly evaluated axial disease, mainly spinal metastases, whereas only six included appendicular lesions; these categories were not mutually exclusive. Local interventions were associated with pain relief, maintenance or recovery of ambulation, neurological improvement and local symptom control in selected patients. Comparative survival findings were inconsistent and vulnerable to selection bias and confounding by indication; no causal survival benefit of surgery was established. Complication patterns differed by intervention type. Overall certainty was low to very low and was weakest for appendicular and pelvic disease. Conclusions: Orthopaedic management can be clinically important for preserving function and controlling mechanical or neurological complications, but the evidence is substantially stronger for spinal than for extraspinal disease. Treatment should remain multidisciplinary and individualised. The proposed decision frameworks are conceptual and guideline-informed rather than validated treatment algorithms.

Cancers doi: 10.3390/cancers18193227

Authors: Piotr J. Wysocki Katarzyna Pogoda Ewa Wysocka Barbara Radecka Maciej Krzakowski

Background/Objectives: Antibody–drug conjugates (ADCs) targeting trophoblast cell-surface antigen 2 (TROP2), including sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd), have expanded treatment options for patients with advanced breast cancer. Although both agents target TROP2, they differ in molecular design, clinical evidence, toxicity profiles, and monitoring requirements. Without head-to-head trials, their relative clinical positioning remains uncertain. This review aimed to critically assess the available evidence and develop a practical framework to support individualized treatment selection between SG and Dato-DXd. Methods: This narrative critical review used a structured literature search of PubMed/MEDLINE and targeted searches of major oncology guidelines, regulatory documents, pivotal-trial publications, conference reports when full publications were unavailable, and relevant retrospective or translational studies. The evidence cutoff was 29 September 2026. Direct randomized-trial evidence, indirect clinical inference, and expert/practical considerations were explicitly distinguished. Results: SG and Dato-DXd have both demonstrated clinically meaningful activity in advanced breast cancer, but their evidence base, toxicity patterns, and practical requirements differ. Cross-trial differences in populations, treatment lines, comparator composition, follow-up, subsequent therapy, response assessment, and safety reporting preclude valid numerical comparisons of efficacy or toxicity between the two agents. SG is characterized predominantly by hematologic and gastrointestinal toxicity, whereas Dato-DXd is associated with stomatitis, ocular toxicity, and interstitial lung disease/pneumonitis. These distinctions, together with patient-specific comorbidities, prior toxicities, prior ADC exposure, logistical considerations, and local healthcare resources, may inform individualized treatment selection when both agents are clinically appropriate. Conclusions: In the absence of direct comparative trials, treatment selection between SG and Dato-DXd should not rely on cross-trial efficacy or safety comparisons. The proposed framework separates regulatory and guideline eligibility from drug-specific safety evidence, indirect clinical inference, patient preferences, and healthcare system considerations. It is intended as evidence-informed clinical guidance rather than a validated comparative treatment selection rule and requires prospective evaluation.

Cancers doi: 10.3390/cancers18193225

Authors: Hui Lionel Raphael Chen Jun Yan Ian Wee Jun Kiat Thaddaeus Tan Wei Ming Aaron Seah Anders Jacobsen Skanderup Chin-Ann Johnny Ong Han Chong Toh Kwong-Wei Emile Tan Bee Huat Iain Tan

Background: Early-onset colorectal cancer (EOCRC, diagnosed <50 years) is increasing globally and presents with advanced clinicopathological features, yet its mutational landscape compared to late-onset CRC (LOCRC) remains poorly defined. Methods: We systematically searched PubMed and Embase (January 2016–December 2025) for studies comparing somatic mutations between EOCRC and LOCRC. Two reviewers independently screened 1880 records; 43 studies met inclusion criteria. Two public datasets (TCGA, China PanCancer) were also included. Meta-analyses were conducted using random-effects models with Review Manager. Subgroup analysis was restricted to microsatellite-stable (MSS) tumors. Meta-regression evaluated study-level differences in tumor sidedness and stage distribution as sources of heterogeneity. The primary outcome was odds ratios (OR) for mutations in 10 driver genes. Results: Among 154,982 participants, 33,937 (21.9%) had EOCRC. In the overall analysis, EOCRC showed higher frequencies of TP53 (OR 1.13), SMAD4 (OR 1.15), and PTEN mutations (OR 1.77), and lower frequencies of APC (OR 0.73), KRAS (OR 0.94), and BRAF mutations (OR 0.69). In MSS-restricted analysis, differences persisted for TP53, SMAD4, APC, and KRAS, whereas PTEN and BRAF differences became non-significant. Additionally, NRAS (OR 0.74) and PIK3CA mutations (OR 0.89) were less frequent in MSS-EOCRC. Meta-regression showed that study-level differences in left-sided tumor distribution were associated with lower relative BRAF mutation frequency in EOCRC (β = −5.08, 95% CI −7.66 to −2.49, p < 0.001). Conclusions: EOCRC exhibits a different mutational profile with higher TP53 and SMAD4 and lower APC and KRAS mutations. These findings highlight the need for further research into alternative mechanisms of CRC carcinogenesis among younger adults.

Cancers doi: 10.3390/cancers18193226

Authors: Nayonika Pande Justin C. Moser Sanjay Chandrasekaran Andrew S. Brohl Rajan P. Kulkarni Vincent T. Ma

Merkel cell carcinoma (MCC) represents a rare but highly aggressive neuroendocrine skin cancer with limited systemic therapy options for patients who fail or are ineligible for immune checkpoint inhibitors (ICIs). Intratumoral (IT) immunotherapy has emerged as a promising strategy, leveraging the accessibility of tumor lesions and their inherent capacity to trigger immune responses, known as abscopal effects. This review synthesizes the current evidence on IT approaches in MCC, including Toll-like receptor agonists, cytokines, and oncolytic viruses, and highlights their distinct mechanisms of action, while emphasizing the critical need for standardized radiographic response assessment of injected and non-injected lesions. Inconsistent documentation of abscopal responses has hindered quantification of IT therapy’s systemic potential, particularly in a disease where one-third of patients present with metastases and distant relapse is common. We outline MCC-specific rationale for routine lesion-level tracking, and recommendations for IT trial designs and objectives. Rigorous assessments of abscopal data will clarify IT’s role as both rescue therapy and an ICI partner, potentially transforming outcomes in this refractory MCC.

Cancers doi: 10.3390/cancers18193224

Authors: Trilok Shrivastava Yusra Medik Nikhila Sampath Kumar Shi-Ming Tu Anuradha Kunthur

Background/Objectives: Non-clear cell renal cell carcinoma (nccRCC) comprises biologically heterogeneous renal malignancies with distinct molecular drivers, clinical behavior, and therapeutic responses. This review summarizes prognosis and systemic therapy and evaluates emerging histology-specific and biomarker-directed approaches. Methods: We analyzed overall survival by histology in the SEER 17 Registries database (2000–2022) and conducted a narrative review of trials, guidelines, and translational studies. The ICD-O-3-defined population included 43,966 adults; 43,789 with known survival time were included in survival analyses. Results: Median follow-up was 96 months. Compared with papillary RCC, adjusted HRs were 0.67 (95% CI 0.64–0.70) for chromophobe RCC, 3.73 (3.37–4.11) for collecting duct carcinoma, 0.97 (0.80–1.17) for oncocytic tumors, and 33.23 (27.47–40.20) for medullary carcinoma. VEGFR- and MET-directed therapies and immune checkpoint inhibitor combinations show activity that varies by histology. Conclusions: nccRCC should be studied and managed as a collection of distinct entities. Registry associations require cautious interpretation because of residual confounding, evolving classification, and non-proportional hazards; subtype-specific trials and molecular stratification remain priorities.

Cancers doi: 10.3390/cancers18193223

Authors: Yujing You Yan Zhang

Molecular classification has transformed the management of endometrial cancer (EC), yet the no specific molecular profile (NSMP) subtype remains a major challenge for precision oncology due to its substantial biological and clinical heterogeneity. This narrative review summarizes evidence on the molecular features, candidate prognostic biomarkers, procedural implications, and treatment data relevant to NSMP EC and proposes a conceptual framework for further study. Emerging evidence indicates that NSMP represents a heterogeneous disease spectrum rather than a uniform entity. Histological grade and estrogen receptor (ER) expression provide important prognostic refinement, while molecular alterations, including CTNNB1 mutations, ARID1A abnormalities, and L1CAM overexpression, may further discriminate risk. Current trials and guidelines increasingly support biomarker-driven treatment strategies, although prospective validation is needed. In conclusion, NSMP EC requires further refinement beyond conventional risk classification. We propose an evidence-informed three-layer conceptual framework integrating molecular classification (POLE, MMR, and p53 status), clinicopathological factors (grade and ER expression), and emerging biomarkers, including ARID1A and L1CAM. This framework is intended to organize current evidence and generate hypotheses for future validation, which may facilitate individualized prognostic assessment of NSMP EC.

Cancers doi: 10.3390/cancers18193222

Authors: Lucas Regis Clara Perez Jacques Planas Ana Celma Merce Cuadras Maria-Eugenia Semidey Richard Mast Juan Morote Enrique Trilla

Background: Active surveillance (AS) is increasingly considered for selected patients with International Society of Urological Pathology (ISUP) Grade Group (GG) 2 prostate cancer. However, candidate selection remains controversial due to histological heterogeneity and the risk of harboring adverse pathology (AP). We aimed to identify preoperative clinical, multiparametric magnetic resonance imaging (mpMRI), and histological predictors of AP, biochemical recurrence (BCR), and postoperative PSMA PET/CT positivity in men with biopsy-confirmed ISUP GG 2 disease undergoing robotic-assisted radical prostatectomy (RARP). Methods: We retrospectively analyzed 127 consecutive patients with biopsy-proven ISUP GG 2 prostate adenocarcinoma from a prospective single-center RARP database (2012–2024). All patients underwent pre-biopsy 3T mpMRI and systematic plus software-fusion targeted biopsies, with diagnostic specimens strictly lacking cribriform architecture or intraductal carcinoma. AP was defined as pathological stage ≥ pT3 and/or ISUP GG upgrading to ≥ 3 in the final surgical specimen. BCR was defined as two consecutive postoperative PSA measurements ≥ 0.2 ng/mL. Patients with BCR underwent PSMA PET/CT restaging. Univariable and multivariable logistic regression analyses evaluated independent preoperative predictors of AP, incorporating separate models for ≥ 10% and ≥ 15 biopsy Gleason pattern 4 thresholds to prevent collinearity. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and Hosmer–Lemeshow calibration tests. Results: Median patient age was 63.2 years, median PSA was 7.6 ng/mL, and median PSA density (PSAD) was 0.18 ng/mL. PI-RADS ≥ 4 lesions were identified in 71.6% of patients, and median biopsy pattern 4 proportion was 21.1%. Overall, AP occurred in 39 of 127 patients (30.7%), driven by ISUP upgrading to GG ≥ 3 in 21.3% (n = 27) and upstaging to ≥ pT3 in 17.3% (n = 22). No undergrading was observed. On univariable analysis, PSA (p = 0.028), PSAD (p = 0.011), and biopsy pattern 4 proportion ≥ 10% (p = 0.042) and ≥ 15% (p = 0.027) were significantly associated with AP. On multivariable analysis, PSAD (OR 6.75, 95% CI 3.51–12.87, p = 0.005) and biopsy pattern 4 proportion ≥ 10% (OR 2.54, 95% CI 1.15–6.54, p = 0.036) or ≥ 15% (OR 2.74, 95% CI 1.06–6.06, p = 0.023) remained independent predictors of AP. The final multivariable model demonstrated solid discrimination (AUC = 0.78, 95% CI 0.71–0.85) and satisfactory calibration (p = 0.42). At a mean follow-up of 32.3 months, BCR occurred in 23 patients (18.1%; 3-year recurrence-free survival: 81.3%). Restaging PSMA PET/CT was positive in 8 of 23 recurrences (34.8%; three local, four regional nodal, one solitary bone). Neither clinical nor radiological parameters independently predicted BCR or PSMA PET/CT positivity. Conclusions: Biopsy Gleason pattern 4 extent (<10% and <15%) and PSAD are the strongest independent preoperative predictors of organ-confined, non-upgraded pathology in ISUP GG 2 prostate cancer. Combining a low pattern 4 burden (<10%, or up to 15% in highly selected cases) with a low PSAD provides objective parameters to refine “favorable intermediate-risk” stratification by identifying patients with a lower probability of adverse pathological features.

Cancers doi: 10.3390/cancers18193221

Authors: Thomas Meyer Lea Stockfleth Kerstin Lang Heiko U. Käfferlein Thomas Brüning Eggert Stockfleth

The high—and in most countries steadily increasing—incidence of cutaneous squamous cell carcinoma (cSCC) represents a growing public health challenge. As the majority of cSCCs arise from pre-existing actinic keratosis (AKs), these lesions are recognized as the principal precursors of invasive disease. A comprehensive understanding of the molecular mechanisms driving the progression from AK to cSCC is essential for advancing prevention, facilitating early diagnosis, and enabling targeted therapies. Moreover, this knowledge provides a basis for identifying biomarkers that can predict the risk of malignant transformation. The progression from AK to cSCC is a complex, multistep process driven by the gradual accumulation of genetic, epigenetic, and microenvironmental alterations. Over the past decades, numerous molecular changes associated with this transition have been identified. However, no single biomarker has demonstrated sufficient predictive accuracy for clinical use. This reflects the pronounced molecular heterogeneity of AKs as no individual alteration is uniformly present in all lesions that undergo malignant progression. In addition, numerous proposed biomarkers are also detected in non-progressive AKs and even in non-neoplastic skin, which compromises their sensitivity and specificity for predicting progression to cSCC. Current evidence, therefore, suggests that the most promising strategy for identifying AKs at greatest risk of malignant transformation is the development of a multi-marker panel. This panel, ideally, should integrate molecular signatures encompassing genetic, epigenetic, proliferative, inflammatory, and microenvironmental markers. This review summarizes the molecular factors that currently represent the most promising candidates for inclusion in such a multi-marker panel and discusses their potential clinical utility, while emphasizing the need for validation in well-designed prospective longitudinal studies.

Cancers doi: 10.3390/cancers18193220

Authors: Daysha Ferrer-Torres Paramita Ray Noah Etzioni Max A. Hammer Archismaan Ghosh Meilan Liu Vinay Jeeyar Sachin Wani Sunnie S. Kim Benedetto Mungo Stefan Marasligiller Danielle Kim Turgeon Jules Lin Peter D. R. Higgins Jason R. Spence Kiran H. Lagisetty David G. Beer Dipankar Ray

Background/Objectives: Glutathione S-transferase theta 2 (GSTT2) is highly expressed in esophageal tissues from African American (AA) compared with European American (EA) individuals, but its localization, regulation, and relevance to esophageal adenocarcinoma progression remain unclear. Methods: Here, we combined FISH, immunofluorescence, patient-derived culture models, cell-cycle synchronization, biochemical perturbation, and transcriptomics to define GSTT2 expression in normal and neoplastic esophageal contexts. Results: In developing and adult esophageal tissues, GSTT2 mRNA and protein were broadly distributed across squamous epithelium and lamina propria, co-localizing with p63-positive basal/progenitor cells and extending into differentiated compartments, with no major ancestry-associated differences in spatial patterning. In Barrett’s esophagus, GSTT2 protein was retained in metaplastic columnar epithelium and slightly elevated in dysplastic versus adjacent non-dysplastic regions. GSTT2 mRNA was highest in normal squamous esophagus, reduced during Barrett’s-to-adenocarcinoma progression, but increased in treatment-resistant esophageal adenocarcinoma (EAC). In resistant EAC, GSTT2 co-expression shifted from homeostatic antioxidant programs to proliferation and mitotic pathways, including the G2-M checkpoint, E2F targets, and Reactome Cell Cycle, with leading-edge regulators CDK1 and CDC20. Sequence analysis identified putative APC-C and FBXW7 recognition motifs. In synchronized cells, GSTT2 abundance declined during S-G2/M and increased during mitotic exit/early G1 in cytosolic and membrane fractions. Forskolin, a dual inhibitor of FBXW7 and CDC20, stabilized GSTT2 and rescued CDC20- or FBXW7-associated loss, implicating APC-CDC20 and FBXW7 pathways in GSTT2 turnover. In EAC cells, by contrast, CDC20 was found to be a cooperative partner stabilizing GSTT2. Conclusions: These findings identify GSTT2 as a spatially widespread, ancestry-associated, cell-cycle-regulated protein with potential oncogenic roles in EAC resistance.

Cancers doi: 10.3390/cancers18193219

Authors: Hyun Min Ko Katherine Scarton Samantha C. Covey Lucio Miele Sun Young Kim

Background: Acute myeloid leukemia (AML) is characterized by substantial biological heterogeneity that is incompletely captured by current risk-classification frameworks. Podocalyxin-like 2 (PODXL2), a CD34-family transmembrane sialomucin implicated in tumor progression in solid tumors, remains poorly characterized in AML. Methods: We conducted integrated clinical, genomic, transcriptomic, regulatory network, and ex vivo drug-response analyses using two independent AML cohorts, TCGA-LAML and BeatAML. Results: Elevated PODXL2 expression was consistently associated with inferior overall survival across both cohorts, including after adjustment for established clinical risk factors. PODXL2-high AML was enriched for adverse-risk features, including ELN 2022 adverse-risk classification, poor-risk cytogenetics, and TP53 mutations, whereas IDH2 mutations were more frequent in PODXL2-low AML. Transcriptomic analyses identified a distinct PODXL2-high state characterized by enrichment of MYC and E2F target programs, cell-cycle progression, DNA repair, oxidative phosphorylation, mTORC1 signaling, and metabolic pathways. Regulatory network analyses demonstrated enhanced MYC/E2F-associated regulatory activity. PODXL2-high AML also exhibited altered differentiation-state features, characterized by reduced representation of monocyte-like and conventional dendritic cell-like malignant cell states. Ex vivo drug-response profiling identified distinct PODXL2-associated response patterns, including reduced sensitivity to OTX-015 and SRC-family kinase inhibitors. Conclusions: PODXL2 expression is associated with adverse clinical and molecular features, distinct transcriptional programs, altered differentiation states, and differential ex vivo drug-response patterns in AML. These findings identify PODXL2 expression as a marker associated with adverse clinical and molecular features and inferior survival in AML, although its prognostic discrimination as a standalone marker is modest. Further functional and prospective studies are warranted to establish its biological and clinical significance.

Cancers doi: 10.3390/cancers18193218

Authors: Chaofan Bian Yanjin Qin Hongliang Zou Wenzhe Fan Jiaping Li

Objectives: To develop and validate a CT radiomics-based machine learning model for the noninvasive prediction of HANS status in advanced HCC and to investigate the prognostic and genomic characteristics associated with HANS status. Materials and Methods: This retrospective study included patients with advanced HCC treated with TACE-based triplet therapy. Patients were followed until death or last follow-up. Tumor tissue underwent whole-exome sequencing for HANS calculation, and arterial-phase CT images were used for radiomic feature extraction. A radiomics model (HANS-Rad), a clinical model (HANS-Clin), and a combined model (HANS-RC) were developed using least absolute shrinkage and selection operator regression. Model performance was evaluated using receiver operating characteristic curve analysis. Calibration and decision curve analyses were performed to assess model reliability and clinical utility. Shapley Additive Explanations (SHAP) were used for model interpretation. Genomic analyses were conducted to explore differences between predicted HANS subgroups. Results: A total of 129 patients were included (median age, 54 years; IQR, 44–62 years; 90% men). The HANS-High group demonstrated longer overall survival compared with the HANS-Low group (median, 23.0 vs. 10.0 months; hazard ratio, 0.60; p = 0.026). The combined HANS-RC model achieved the best performance, with an area under the curve (AUC) of 0.964 in the training set and 0.869 (95% CI, 0.716–1.000) in the test set, outperforming the radiomics-only and clinical models. The model also showed favorable calibration and net benefit. Genomic analyses revealed that HANS-High tumors exhibited higher tumor mutational burden and enrichment of immune-related and oncogenic pathways, whereas HANS-Low tumors were associated with distinct mutational patterns and pathway alterations. Conclusions: A radiomics-based machine learning model using CT images enables the noninvasive prediction of HANS status in advanced HCC, with strong prognostic relevance and biologic interpretability supported by genomic analyses.

Cancers doi: 10.3390/cancers18193217

Authors: Manat Chopra David John David J. Cote Gabriel Zada

Endoscopic endonasal surgery (EES) has fundamentally changed the management of anterior skull base meningiomas by enabling access to many lesions through a direct minimally invasive corridor that avoids traditional transcranial exposure. Improvements in endoscopic optical technology, surgical instrumentation, and skull base reconstruction have steadily expanded the range of tumors that can be treated through an endonasal approach. Even so, EES is not appropriate for every lesion, making thoughtful patient selection and surgical team experience the most important determinants of surgical success. This review explores where EES fits in the contemporary management of anterior skull base meningiomas, including olfactory groove, tuberculum sellae, and planum sphenoidale meningiomas, with particular attention to its indications, limitations, and situations in which EES may not be appropriate. Evidence comparing endoscopic endonasal and transcranial approaches for anterior skull base meningiomas is reviewed, with attention to how tumor anatomy, oncologic objectives, and individual patient characteristics influence the choice of approach. A major consideration is how surgical morbidity can be minimized without compromising oncologic and safety outcomes. Current strategies to protect critical neurovascular structures, reduce the risk of cerebrospinal fluid leakage, and improve skull base durability, including advances in vascularized reconstruction techniques, are discussed. Emerging outcome data and the evolving learning curve associated with EES are also reviewed. Rather than presenting EES as a universal solution, the evidence points toward a patient-centered approach in which operative strategy and clinical decision making is guided by tumor characteristics, anatomy, and surgical goals.

Cancers doi: 10.3390/cancers18193216

Authors: Guillermo de Velasco Teresa Alonso-Gordoa Juan Francisco Rodríguez-Moreno Ignacio Duran Lucía Carril Ajuria Pablo Álvarez Ballesteros Enrique González-Billalabeitia José I. Domínguez Ana García-Casas Enrique Pérez-Navarro Sara Sánchez-Redondo Javier Molina-Cerrillo Felix Guerrero-Ramos Ray Manneh Kopp Cecilia Marinas Jesús M. Paramio Héctor Peinado Daniel Castellano Marta Dueñas

Background/Objectives: Despite advances in metastatic renal cell carcinoma (mRCC), long-term survival is poor and biomarkers are lacking. Optimal integration of cytoreductive nephrectomy (CN) in the current era remains controversial. CABOPRE, the first phase II trial assessing perioperative cabozantinib in mRCC patients eligible for CN, aimed to determine its effects in this setting, integrating tumor outcomes with molecular profiling. Methods: CABOPRE (NCT06377722) is a multicentre, single-arm, phase II study conducted in Spanish academic hospitals. Patients with resectable metastatic clear cell RCC (ccRCC) eligible for post-treatment CN received perioperative cabozantinib (60 mg/day for 12 weeks; n = 18). The primary endpoint was the objective response rate (ORR) at 12 weeks assessed by RECIST v1.1. Exploratory analyses included longitudinal plasma miRNA and spatial transcriptomic profiling to identify candidate biomarkers. The trial closed early because of slow accrual, after enrolling 18 of 50 planned patients and without completing the 26-patient first stage of the Simon two-stage design; the planned interim analysis was therefore never performed. Results: Because the two-stage design was not completed, the primary endpoint could not be formally evaluated against the prespecified decision rule. Among 15 evaluable patients, the objective response rate was 26.7% (95% CI, 7.8–55.1), with stable disease in 10 (66.7%) and progressive disease in 1 (6.7%). Cabozantinib demonstrated a manageable safety profile (Grade 1–2 adverse events). In exploratory biomarker analyses, miR-126-3p upregulation and VEGFA/CCND1 downregulation were associated with tumor shrinkage, and the adhesion molecules ITGAV and ICAM1 were upregulated in these patients. Because no direct vascular measurements were performed, these changes are described as treatment-associated and hypothesis-generating rather than as predictors of response or evidence of vascular normalization. Conclusions: The observed response rate was close to the 25% null rate, and the prespecified efficacy rule could not be applied. CABOPRE provides preliminary evidence that perioperative cabozantinib is active and represents a viable backbone for neoadjuvant combination strategies in selected patients with potentially resectable mRCC. The identified molecular heterogeneity and stromal-immune signatures provide a biological rationale for the prospective evaluation of cabozantinib-IO combinations in this setting.

Cancers doi: 10.3390/cancers18193215

Authors: Tharmentheran Pitchaimuthu Mohamad Yunus Mohd Razif Khairiyiah Sidek Syed Nabil

Background/Objectives: We aimed to assess the efficacy of a simple intervention by comparing changes in mouth opening and trismus status among HNC patients during radiotherapy treatment. It also explored its effect on the patient’s mandibular function impairment. Methods: This is a Randomised Controlled Trial in which subjects were divided into groups undergoing jaw exercise with a wooden tongue depressor versus a basic jaw exercise group. The primary outcome of this study was changes in maximal mouth opening (MMO)/maximal interincisal distance (MID) measured at baseline (before treatment), at the 10th and 20th week after initiation of radiotherapy. The secondary outcome included trismus prevalence and mandibular functionality, which were assessed in relation to trismus severity and the effectiveness of the intervention. Results: A total of 38 subjects were recruited, comprising 19 (50.0%) in the control group and 19 (50.0%) in the intervention group. There were 22 (57.9%) males and 16 (42.1%) females. Overall, the mean age of the patients was 52.5 years (22 to 74 years). Our clinical assessment showed no statistically significant differences (p = 0.835) in mouth opening among the groups, with an overall median of 0mm (IQR 7.0). Conclusions: Mouth opening did not worsen from baseline to 20 weeks after initiation of radiotherapy, and the addition of wooden tongue depressors did not confer a statistically significant benefit over basic jaw exercise alone. Trial Registration: ISRCTN96737564, registered on 26 August 2026, retrospectively registered.

Cancers doi: 10.3390/cancers18193214

Authors: Anne-Sophie Pirson Gilles Delahaut Raphaël Georis Stéphanie Deheneffe Sébastien Van der Vorst Ken Kudura

Purpose: Volumetric PET biomarkers carry substantial prognostic value in head and neck squamous cell carcinoma (HNSCC), yet their clinical implementation is hampered by segmentation heterogeneity. A fundamental and unresolved question is which segmentation method is most suitable for routine clinical use, both for a reader experienced in PET segmentation and for a reader without PET segmentation experience, such as an ENT surgeon or a radiation oncologist. This study addressed this question by assessing the intra- and interobserver reproducibility of four PET segmentation methods in MIM Maestro Software Version 7.4.2, identifying tumour-related determinants of variability, and examining concordance between PET-derived metabolic tumour volume (MTV) and CT-based gross tumour volume (GTV). Methods: Two readers with contrasting PET segmentation experience, a nuclear medicine physician experienced in PET segmentation (R1) and an ENT surgeon without prior PET segmentation training (R2), applied four methods to the primary tumours of 154 patients with HNSCC (oral cavity, oropharynx, hypopharynx or larynx) treated with definitive (chemo)radiotherapy between 2010 and 2021: fixed absolute thresholds at SUV 3.0 and 4.0, a relative threshold at 41% of the maximum standardised uptake value (SUVmax), and a gradient edge-detection algorithm (PET Edge+). R1 segmented twice with a washout of at least 4 weeks; R2 performed one session and delineated CT-GTV in the 85 patients whose PET/CT-derived CT served directly as the radiotherapy planning scan. The second session of R1 served as the reference for all interobserver and MTV–GTV analyses. Agreement was assessed by ICC (two-way mixed model), coefficient of variation, repeatability coefficient and Bland–Altman analysis; determinants of variability by a multivariable linear mixed-effects model with a random intercept per patient. Results: All four methods demonstrated excellent intraobserver (ICC 0.993 to >0.999) and interobserver (ICC 0.989–0.996) reproducibility. SUV3.0 generated significantly more relative error than SUV41% (β = +3.1%; 95% CI 0.89, 5.3). PET Edge+ was the only method for which a significant method × reader interaction was observed in this reader pair: the reader without PET segmentation experience generated more error than the reader experienced in PET segmentation (β = +7.1%; 95% CI 3.9, 10), an effect concentrated in smaller tumours (below approximately 15 mL); in the 85-patient GTV subset, where tumours were larger on average, the interobserver ICC for PET Edge+ was 0.997. GTV concordance was good for three of four methods (ICC 0.808–0.895); SUV41% showed only moderate concordance (ICC 0.572). Conclusions: All four methods provided excellent volumetric reproducibility within a single clinical software platform, but they differed in reader dependence and in agreement with CT-defined GTV. Rather than supporting a universal segmentation standard, these findings suggest that the method should be selected according to its intended application, pending multicentre confirmation.

Cancers doi: 10.3390/cancers18193212

Authors: Seva N. S. Gill Tanjot S. Kurala Serkan Bayram Jennifer M. Brown Muhammad Riaz Muhammad A. Siddiqi Thomas D. A. Cosker

Background/Objectives: Extremity leiomyosarcoma is an uncommon soft tissue sarcoma with a more favorable prognosis than other anatomical subtypes. Risk stratification currently rests on tumor grade, size, and metastatic status. Vascular invasion is an established predictor of metastasis in mixed soft tissue sarcoma cohorts but has seldom been formally examined in extremity leiomyosarcoma. We assessed its prognostic value in a single-center cohort. Methods: We retrospectively studied 62 adults who underwent resection of primary localized extremity leiomyosarcoma at a tertiary sarcoma center between January 2015 and February 2025. Vascular invasion was reported contemporaneously at original diagnostic reporting by specialist sarcoma histopathologists. Overall (OS), disease-specific (DSS), local recurrence-free (LRFS), and metastasis-free (MFS) survival were estimated by the Kaplan–Meier method and compared using log-rank tests. Death from another cause was treated as a competing event for disease-specific death and distant metastasis in a sensitivity analysis. Multivariable Cox models were refitted using Firth’s penalized likelihood, with discrimination corrected for optimism by bootstrapping. Results: Median follow-up was 59.5 months. Five-year OS, DSS, and MFS were 71.0%, 80.2%, and 74.6%. Vascular invasion was reported in 11 of 62 patients (17.7%) and was associated with inferior OS (p = 0.002), DSS (p < 0.001), and MFS (p < 0.001), but not LRFS (p = 0.631). Adjusted for grade, it was associated with inferior OS (HR 3.89, 95% CI 1.35–11.26), DSS (HR 5.48, 95% CI 1.46–20.58), and MFS (HR 5.63, 95% CI 1.69–18.80). The association persisted on separate adjustment for tumor size, depth, and neoadjuvant radiotherapy. Conclusions: Vascular invasion was associated with inferior survival in localized extremity leiomyosarcoma. With 17 deaths and 14 metastatic events, these are exploratory estimates, but they support documenting vascular invasion explicitly, as present or absent, in routine histopathological reporting so that its role can be evaluated at scale.

Cancers doi: 10.3390/cancers18193213

Authors: Adriana Roque Artur Paiva Raquel Seiça Catarina Geraldes

Immunotherapy has revolutionized the treatment of multiple myeloma (MM), but durable immune control remains limited, increasing interest in how the bone marrow (BM) microenvironment influences antitumor immunity. BM adipocytes (BMAds) are increasingly recognized as metabolically active components of the BM. This review summarizes the current evidence linking BMAds to myeloma cell survival and immune cell function, particularly T cell activity. It also discusses their potential relevance to monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapy. Preclinical studies have shown that myeloma-associated BMAds undergo lipid depletion and acquire inflammatory and senescence-associated secretory features. BM lipid exposure is associated with impaired CD8+ T-cell metabolic fitness, whereas leptin receptor activation suppresses invariant natural killer T-cell anti-myeloma activity. Evidence concerning conventional natural killer cells and other immune compartments remains limited. Available clinical evidence is predominantly cross-sectional and therefore does not establish a direct role for BMAds in resistance to current immunotherapies or clarify whether they influence therapeutic target availability or function as clinically relevant bystander targets. Patient- and treatment-related factors, including aging and obesity, may further reshape the adipocytic-stromal and immune landscape of the marrow, potentially modifying local responses to immunotherapy. Future studies combining patient-derived multicellular models with spatial and longitudinal approaches should determine how BMAd-associated metabolic, inflammatory, and adipokine signaling affect immune control and treatment outcomes in MM and whether these processes can be therapeutically modulated.

Cancers doi: 10.3390/cancers18193211

Authors: Cosimo Rupe Gioele Gioco Benedetta Corraro Anna Schiavelli Silvia Longo Francesco Pastore Mariangela Massaccesi Maria Antonietta Gambacorta Francesco Miccichè Raffaella Castagnola Jacopo Galli Stefano Settimi Luca Raffaelli Alessandra Cassano Massimo Cordaro Carlo Lajolo

Objectives: To evaluate (a) changes in caries experience, (b) changes in periodontal status, and (c) the need for dental extractions in a cohort of patients treated with radiotherapy (RT) and chemoradiotherapy (RTCT) for head and neck cancer (HNC). Methods: This prospective cohort study was approved by the local Ethics Committee (Ref. 22858/18) and registered at ClinicalTrials.gov (ID: NCT04009161). The study population consisted of patients with HNC who, prior to RT, underwent a dental examination followed by the elimination of oral foci of infection and were then enrolled in a follow-up program. The primary outcome was oral health worsening, defined as the onset of severe periodontitis and/or a DMFt score ≥ 13. Oral cavity RT dose was obtained contouring the ‘buccal mucosa’ organ at risk (OAR). Results: In total, 113 patients were included (median follow-up: 44.77 months). The sample mainly included oral, oropharyngeal, nasopharyngeal and laryngeal cancers (89/113, 78.8%). Salivary glands, hypopharynx and other sites accounted for a minority of the cases (24/113, 21.2%). Seventeen patients (34.7%) experienced worsening of oral health status over time, which was associated with smoking (OR = 4.7, 95% CI: 1.27–17.37; p = 0.02). The DMFt index increased (difference: 4.08; 95% CI: 1.60–6.56; p = 0.001), and this increase was associated with smoking (β = 2.05, 95% CI: 0.27–3.83; p = 0.02). Although worsening of periodontitis stage was not statistically significant (p = 0.35), localized deterioration was observed, with an increase in sites with PPD ≥ 5 mm (p = 0.02). Forty-nine patients (43.4%) experienced tooth loss. Mean tooth loss was 2.12 teeth per patient (p = 0.05), primarily due to caries (48.5%) and periodontitis (48.1%). Independent risk factors for tooth loss were age (p = 0.025) and an RT dose > 60 Gy to the ‘buccal mucosa’ OAR (p = 0.023). Conclusions: Patients treated with RT experienced significant deterioration in dental and periodontal health, and oral cavity dosimetric parameters might be associated with tooth loss, although this association requires confirmation in further studies.

Cancers doi: 10.3390/cancers18193209

Authors: Katharina Wiedemeyer Ingrid Ferreira David J. Adams Thomas Brenn

Cutaneous sebaceous neoplasms are rare adnexal tumours differentiated towards sebaceous glands, spanning a biological spectrum from benign (sebaceous adenoma, sebaceoma, nevus sebaceus) to outright malignant (sebaceous carcinoma). Most tumours are sporadic and solitary, with a predilection for the head and neck of elderly adults, but a clinically important subset is observed in the setting of Lynch syndrome/Muir–Torre syndrome. Recent large-scale genomic and transcriptomic studies have provided insights into the pathogenesis of these unique neoplasms, revealing a genetically heterogeneous landscape shaped by mismatch repair deficiency, UV damage, and abnormalities in several other key signalling pathways. The inclusion of nevus sebaceus within the sebaceous tumour family in the WHO 5th Edition of Skin Tumours reflects a conceptual shift, recognising nevus sebaceus as a clonal, mutation-driven neoplasm and a precursor lesion for secondary tumour development.

Cancers doi: 10.3390/cancers18193210

Authors: Alicia Castelo-Loureiro Amanda Lesmes González de Aledo Mateo Bover Larroya Zaira Molina Collado Cristina Serrano Gómez Isaías Martín Badía Jesús González Olmedo Santiago Terán Marcos Valiente Fernández Carlos Heredia-Mena Joseph Exebio-Jara Lidia Orejón García María Carnevali Frías Carlos Gómez Martín María Cruz Martín Delgado Luis Paz-Ares

The number of patients with solid tumours requiring intensive care is increasing as cancer survival improves and oncological treatments become more complex. Intensive care unit (ICU) admission decisions should not be based on cancer diagnosis, metastatic status or palliative treatment intent alone. This narrative review presents a practical, multidisciplinary framework for assessing critically ill patients with solid tumours. It integrates acute illness severity and reversibility, organ failure, baseline performance status and frailty, cancer trajectory, remaining treatment options, expected functional recovery and patient preferences. We discuss contemporary anticancer treatment toxicities, cancer-associated thromboembolic disease, older adults, palliative care, communication and ethical decision-making. We also propose an algorithm ranging from full ICU support to a time-limited ICU trial with predefined reassessment or comfort-focused care. Early joint assessment by oncology and intensive care teams, followed by dynamic reassessment, may reduce both inappropriate escalation and premature exclusion from potentially beneficial organ support. Future research should prioritize structured pathways, improved prognostic tools and outcomes beyond survival, including functional recovery, quality of life and the ability to resume meaningful cancer treatment.

Cancers doi: 10.3390/cancers18193207

Authors: Juan Gomez Rivas Pedro Gabriel Silva Helena Margot Flôres Soares da Silva Luís Severo Luís Campos Pinheiro Isabel Galante Romo Enrique Redondo-González Claudia González-Santander Jesús Moreno Sierra

Background: Oligometastatic prostate cancer (OMPC) comprises biologically and clinically distinct states with a limited number of detectable metastases. Improved systemic therapy and prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) have intensified interest in treating the primary tumor. Methods: In this narrative review we searched PubMed/MEDLINE from inception to 1 July 2026, reviewed current guidelines, and searched ClinicalTrials.gov, the ISRCTN registry and the EU Clinical Trials Register for ongoing surgical studies, prioritizing randomized trials, prospective studies, PSMA PET-staged cohorts, systematic reviews, guidelines, and studies of perioperative, functional and patient-reported outcomes. Results: Registry and institutional data generated the hypothesis that cytoreductive prostatectomy improves outcomes but are vulnerable to selection bias; prospective and PSMA PET-staged cohorts established feasibility. The phase II trial by Dai and colleagues supported radical treatment of the primary tumor but combined surgery and radiotherapy. RAMPP provided the first prostatectomy-specific randomized signal, with lower 5-year cancer-specific mortality after radical prostatectomy plus best systemic therapy than after systemic therapy alone (13% versus 23%; hazard ratio 0.39, 95% confidence interval 0.16–0.98), but accrual ended early, clinical progression was similar, overall survival was not significantly improved, systemic therapy predated contemporary intensification, and major surgery-related complications occurred in 14%. A randomized phase II trial with a predominantly surgical local-therapy arm found no progression-free or overall survival benefit, so randomized evidence is mixed. All randomized evidence concerns radical prostatectomy or local treatment irrespective of surgical approach; no trial has tested a robot-specific oncologic effect. Guidelines recommend prostate radiotherapy for selected low-volume de novo metastatic disease and restrict surgery to clinical trials. Conclusions: Cytoreductive prostatectomy, delivered mostly as robot-assisted radical prostatectomy (RARP), is feasible and may improve local control while providing complete pathology, but it remains investigational; the robotic approach is the surgical platform, not a modality with distinct oncologic efficacy. Appropriate use requires expert-center surgery, modern staging, guideline-concordant systemic therapy, multidisciplinary selection, transparent counseling and, preferably, trial participation. Future trials must establish whether prostatectomy adds meaningful benefit beyond modern systemic therapy, prostate radiotherapy and metastasis-directed treatment, while measuring morbidity, continence and quality of life.

Cancers doi: 10.3390/cancers18193208

Authors: Giovanni Leuzzi Pamela Minicozzi Paolo Verderio Chiara Maura Ciniselli Michele Ferrari Alessandro Pardolesi Alessia Stanzi Jury Brandolini Luigi Rolli Matteo Calderoni Clarissa Uslenghi Ugo Pastorino Giuseppe Lo Russo Claudia Proto Arsela Prelaj Teresa Beninato Daniele Lorenzini Piergiorgio Solli

Objectives: Chronobiology may influence outcomes in non-small-cell lung cancer (NSCLC), but its prognostic role in early-stage disease remains unclear. We evaluated the association between perioperative chronobiological variables, systemic inflammation, and long-term outcomes after complete resection for stage I NSCLC. Methods: 587 patients who underwent curative-intent resection for pathological stage I NSCLC between 2009 and 2018 were retrospectively reviewed. Chronobiological and inflammatory variables included season of surgery (spring/summer [21st March–22nd September], autumn/winter [23rd September–20th March]), time of day, day of week, and preoperative (CRP0 levels: low ≤ 3 mg/L, high > 3 mg/L) and postoperative day-3 (CRP3 levels: low ≤ 126 mg/L, high > 126 mg/L) C-reactive protein levels. The cohort was randomly divided into training (70%) and testing (30%) sets to develop and validate a prognostic model for overall survival (OS), taking into consideration the follow-up time. Disease-free survival (DFS) was analyzed as a secondary endpoint. Results: Median follow-up was 6.7 years, with 80 deaths and 108 recurrences recorded. In the training set, older age (p = 0.0049), stage IB disease (p = 0.0301), high CRP0 (p = 0.0049), and high CRP3 (p = 0.0280) were associated with worse OS, while surgery performed during autumn/winter was associated with improved OS (p = 0.0312). The multivariate Cox model including age, stage, and season of surgery showed the best prognostic performance (C-index 0.67, 95% Bonferroni-adjusted CI 0.50–0.83) and was internally validated in the testing cohort (C-index 0.69, 95%CI 0.52–0.86). The resulting linear predictor remained associated with both OS and DFS in the overall population. Conclusions: A simple model integrating age, pathological stage, and season of surgery was associated with long-term outcomes after surgery in stage I NSCLC. This model provides an exploratory framework integrating host-, tumor-, and chronobiological dimensions of prognosis. These findings require external validation and further investigation of the biological mechanisms underlying seasonal variation.

Cancers doi: 10.3390/cancers18193206

Authors: Rina Tamir Yaniv Tamar Tzur Hila Goldstein Gadi Ben-Shitrit Gabi Haran

Background: Malignancy risk in hysteroscopic polypectomy specimens rises with age and postmenopausal status, but decade-stratified absolute rates from large, unselected cohorts remain scarce, limiting the quantitative basis for pre-procedural risk counseling. Objective: To estimate decade-specific absolute malignancy rates and to determine how the documented procedural indication modifies that risk. Methods: Retrospective multicenter cohort study with SNOMED-coded histology. All hysteroscopic polypectomies at five Assuta Medical Center sites from January 2019 to April 2026 with a linked histology result constituted the analytic cohort (n = 9269; 75.1% of a base cohort of 12,339). The primary outcome was histologically confirmed endometrial malignancy, defined by SNOMED morphology and topography coding. Multivariable logistic regression adjusted for weight category, hospital site, and calendar year. Results: The overall malignancy rate was 1.63% (151/9269), increasing monotonically: 0.45% (under 50 years), 1.25% (50–59), 3.79% (60–69), and 4.58% (70 or older). Adjusted odds ratios versus the reference group were 2.02 (95% CI, 1.13–3.60), 5.77 (95% CI, 3.39–9.83), and 8.03 (95% CI, 4.51–14.30). Across all age groups, procedures with a documented postmenopausal bleeding (PMB) indication carried an overall malignancy rate of 6.32% (29/459; adjusted OR, 3.04; 95% CI, 1.96–4.72 versus incidental polyp finding); among women aged 70 or older with a documented PMB indication, the rate was 8/61 (13.1%; 95% CI, 6.8–23.8%). Procedures coded with a non-PMB uterine bleeding indication were not associated with excess malignancy risk (0.36%). Weight over 80 kg was an independent predictor of endometrial malignancy (adjusted OR, 3.05; 95% CI, 1.92–4.84). Age group and the documented PMB indication were entered as independent covariates in a single multivariable model; no significant age-by-PMB interaction was detected (likelihood ratio test p = 0.667). Conclusions: Malignancy risk rises more than tenfold from the youngest to the oldest age group. Procedures with a documented PMB indication were associated with substantially higher risk than other indications, while non-PMB bleeding was not associated with excess risk in this cohort. Age and documented procedural indication may be the most clinically useful predictors for stratifying histological examination decisions.

Cancers doi: 10.3390/cancers18193205

Authors: Hasan Göze İsmail Eren Polat Nermin Bal İsa Yalçınkaya Gokhan Burul Büşra Tuğçe Tonyalı Tahir Alper Cinli İstemi Serin

Background/Objectives: Interim 18F-FDG PET/CT is the most powerful prognostic tool in Hodgkin lymphoma but is only available after 2 cycles and does not guide initial treatment. The C-reactive protein-albumin-lymphocyte (CALLY) index is a novel composite index of inflammation, nutrition, and immunity, measurable at diagnosis, but has not been studied in Hodgkin lymphoma (HL). We tested whether baseline CALLY could predict interim PET response and survival and whether combining the two provides additional information over either alone. Methods: A retrospective study of 180 consecutive patients with newly diagnosed Hodgkin lymphoma at a single center was performed. CALLY was defined as albumin (g/L) × lymphocytes (×109/L)/CRP (mg/L). Interim PET after two cycles was scored using the Deauville scale (4–5 positive). The endpoints were progression-free survival (PFS) and overall survival (OS). Results: Median follow-up was 30.5 months, 32 patients had a PFS event, and 16 died. Interim PET was positive in 31/163 patients (19.0%). Baseline CALLY was lower in PET-positive patients compared with PET-negative patients (median 1.16 vs. 3.34; p = 0.022; area under the curve 0.635, modest discrimination). Interim PET positivity (29.8% vs. 13.0%; OR 2.84, 95% CI 1.26–6.42), 24-month PFS (66.9% vs. 89.8%; p = 0.001) and OS (84.8% vs. 95.5%; p = 0.022) were reduced below a Youden-derived threshold of 1.5. CALLY was not independently prognostic after adjustment for interim PET (PFS hazard ratio [HR] 1.86, 95% CI 0.79–4.37; p = 0.157). A three-tier exploratory model combining both factors separated 24-month PFS into 94.5% (n = 87), 79.6% (n = 53), and 41.2% (n = 17) (p < 0.001; high- vs. low-risk HR 9.48, 95% CI 3.59–25.04), although the intermediate tier was not statistically different from the low-risk tier. Conclusions: In this cohort, baseline CALLY provides a low-cost pre-treatment correlate of early metabolic response and outcome, with numerically greater discrimination than the International Prognostic Score. Its prognostic signal seems largely mediated through the interim PET response, and therefore it should complement, not replace, interim response assessment. Discrimination was modest, and the integrated model is exploratory and requires prospective multicenter validation in contemporary protocols before clinical use.

Cancers doi: 10.3390/cancers18193204

Authors: Eva M. Verdugo-Sivianes Carmen Campos-Silva José Luis García-Márquez Elena Aguado-Domínguez

Therapy-induced senescence (TIS) is a common response to anticancer treatments, characterised by stable cell cycle arrest and the acquisition of a complex senescence-associated secretory phenotype (SASP). Initially regarded as a beneficial mechanism that limits tumour growth, growing evidence indicates that TIS is a highly dynamic and heterogeneous process with context-dependent effects that can either suppress or promote tumour progression. The SASP is a central mediator of tumour plasticity, linking TIS to epithelial-to-mesenchymal transition (EMT), cancer stemness, microenvironmental remodelling, therapeutic resistance, and metastatic dissemination. These findings highlight the therapeutic potential of senotherapeutic approaches, including senolytic and senomorphic agents, as key components of one–two-punch therapeutic strategies to selectively eliminate or modulate persistent senescent cells and improve treatment outcomes. Recent advances in multi-omics technologies, artificial intelligence, and liquid biopsy are further transforming the study of senescence by enabling comprehensive molecular characterisation, biomarker discovery, patient stratification, and real-time monitoring of tumour evolution. Collectively, current evidence supports a paradigm shift in which senescence should be considered a dynamic regulator of tumour plasticity and a promising target for precision oncology strategies.

Cancers doi: 10.3390/cancers18193203

Authors: Ziyu Wang Nina Afshar Allison M. Hodge Harindra Jayasekara Stella Koutros Piet A. van den Brandt Alicja Wolk Molin Wang Tao Hou Hans-Olov Adami Agneta Åkesson Chrisa Arcan Kimberly A. Bertrand Marisa Bittoni David Bogumil Hui Cai Amanda J. Cross A. Heather Eliassen Jo L. Freudenheim Gretchen L. Gierach Edward L. Giovannucci Wen-Yi Huang Paula Jakszyn Rieko Kanehara Victoria A. Kirsh Woon-Puay Koh Candyce H. Kroenke James V. Lacey Linda M. Liao Erikka Loftfield Chaoran Ma Loic Le Marchand Maria Elena Martinez Anthony B. Miller Steven C. Moore Lorelei A. Mucci Heather M. Munro Marian L. Neuhouser Jessica L. Petrick Jenny N. Poynter Mark A. Preston Anna Prizment Samantha Rees Kim Robien Thomas E. Rohan Sven Sandin Norie Sawada Eva S. Schernhammer Marissa M. Shams-White Martha J. Shrubsole Xiao-Ou Shu Rashmi Sinha Sabina Sieri Mingyang Song Meir J. Stampfer Rachael Z. Stolzenberg-Solomon Matthew Triplette Caroline Y. Um Kala Visvanathan Trang VoPham Fenglei Wang Renwei Wang Sophia S. Wang Ying Wang Elisabete Weiderpass Lynne Wilkens Walter C. Willett Jian-Min Yuan Wei Zheng Nathaniel Rothman Brigid M. Lynch Debra T. Silverman Stephanie A. Smith-Warner Roger L. Milne

Background: Processed meat and unprocessed red meat are considered carcinogenic and ‘probably carcinogenic’ to humans, respectively, but findings for bladder cancer remain inconsistent. Objectives: We assessed associations between processed meat and unprocessed red meat intake and bladder cancer risk using data from the Pooling Project of Prospective Studies of Diet and Cancer. Methods: Associations with bladder cancer risk were assessed using individual-level data from 30 cohort studies from North America, Europe, Australia and Asia. Diet was assessed at enrolment using validated food frequency questionnaires or diet histories. Following a pre-specified analysis plan, study- and sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression, adjusted for smoking status and duration and other potential confounders, and pooled using inverse-variance-weighted random-effects meta-analysis. Results: During median follow-up across cohorts of 8–29 years, among 2,575,971 participants, 20,780 were diagnosed with bladder cancer. Processed meat intake was associated with increased bladder cancer risk (HR comparing ≥40 with <5 g/day = 1.08; 95% CI: 1.02–1.15; HR per 20 g/day = 1.02; 95% CI: 1.00–1.03). Weaker evidence of association with increased risk was also observed for unprocessed red meat (HR comparing ≥100 with <20 g/day = 1.06; 95% CI: 1.00–1.13; HR per 50 g/day = 1.01; 95% CI: 0.99–1.03). There was no evidence of heterogeneity by study, sex, or region. Conclusions: Higher intakes of processed meat and unprocessed red meat were associated with a small increase in risk of bladder cancer. These findings are consistent with existing public health recommendations to limit consumption of red and processed meat.

Cancers doi: 10.3390/cancers18193202

Authors: Shaolin Li Minghui Li Yinglang Zhang Jie Pu Jiaao Sun Chunsheng Li Changgang Guo

Metabolic reprogramming is increasingly recognised as a central determinant of bladder cancer heterogeneity, immune regulation and treatment response. This review integrates genetic, epigenetic, microenvironmental and therapeutic evidence to explain how bladder cancer redistributes carbon and nitrogen across glycolysis, lipid synthesis and oxidation, amino-acid metabolism and mitochondrial respiration. Alterations in FGFR3, PIK3CA, MYC, TP53/RB1 and KDM6A establish distinct, context-dependent metabolic dependencies, while hypoxia, extracellular-matrix mechanics and treatment selection reinforce metabolic plasticity. These programmes influence not only energy production and biosynthesis but also ferroptosis, genome stability and chromatin or RNA regulation. Lactate, adenosine, kynurenine and asparagine further connect tumour metabolism to regulatory T cells, myeloid cells, innate immune sensing and CD8-positive T cell function, thereby shaping resistance to chemotherapy and immune-checkpoint blockade. Therapeutic opportunities include targeting glycolysis, fatty-acid and cholesterol metabolism, glutamine and proline metabolism, arginine auxotrophy and metabolite-mediated immune suppression. However, pathway redundancy, cellular heterogeneity and shared metabolic requirements between tumour and immune cells constrain unselected treatment. Urine, tissue, blood and imaging metabolomics offer complementary routes to diagnosis, prognostication and real-time response monitoring, but require harmonised sampling, functional flux measurements and prospective validation. A clinically useful strategy will therefore depend on defining metabolic vulnerabilities by genotype, cell type, spatial context and treatment stage, and on pairing pharmacodynamic biomarkers with rational combinations and local delivery where appropriate.

Cancers doi: 10.3390/cancers18193201

Authors: Hualin Zhang Nguyen Phuong Dang Jason C. Ye Adam Garsa Aram S. Modrek Zhilei Liu Shen Salim Balik Zhengzheng Xu Kaley Woods Adam C. Turner David G. Brachman Thomas Chen Gabriel Zada Eric L. Chang

Purpose: Tile-based radiation therapy (TBRT) delivers adjuvant radiation to brain tumor beds using evenly spaced cesium-131 (Cs-131) sources in collagen tiles. This study evaluated TBRT as spatially fractionated radiation therapy (SFRT) across tumor sizes and source counts. Methods and Materials: Dose distributions were generated from postoperative CT scans for 18 patients treated with TBRT, using 10–32 implanted Cs-131 sources per case (median, 20). The resection cavity (RC) was contoured on CT with registered postoperative T1-weighted MRI guidance. CTV_5mm was defined as the RC plus a 5 mm expansion excluding skull and surgical tract, and CTV_5mm_Eval as CTV_5mm minus the RC. Both volumes were analyzed using SFRT dose metrics from the Radiosurgery Society SFRT/Flash working group white paper, and planar high-dose core number density (HCND_A) was used to characterize TBRT spatial fractionation. Results: The mean dose indices of D5 (dose covering 5% of the target volume), D10, D50, D90, D95 and D100 were 175.8 ± 43.3, 148.8 ± 35.1, 86.7 ± 18.5, 56.1 ± 10.5, 50.2 ± 9.0 and 33.4 ± 7.2 Gy for the CTV_5mm_Eval, respectively. The heterogeneity indices, represented by the ratio of D5/D95 and D10/D90, were 3.5 ± 0.6 and 2.7 ± 0.4, respectively, which were in the range of the linac-based Lattice therapy. HCND_A was a constant, TBRT delivered one high dose core for every 1 cm2 of tumor bed. All dose metrics in both the CTV_5mm and CTV_5mm_Eval were largely consistent across all plans. Conclusions: TBRT produced heterogeneous dose distributions comparable to conventional SFRT. A 60 Gy TBRT nominal prescription dose approximated the SFRT D90, or valley dose of the 5 mm expansion target volume, suggesting TBRT may provide an SFRT platform for tile-accessible cancers.

Cancers doi: 10.3390/cancers18193199

Authors: Sakshi Singh Anitha Kartha Aishwarya Jaiswal Dhanir Tailor Sivanandhan Dhanalakshmi

Background: Andrographolide (AG), a diterpenoid lactone and a major constituent of Andrographis paniculata, has shown promising antiproliferative effect on diverse cancer cell lines, including head and neck cancer. However, a significant anti-proliferative effect is observed only at high micromolar concentrations. Further, AG has been shown to have poor oral bioavailability. Therefore, it is essential to consider mechanism-based combinations that could synergistically enhance the therapeutic potential of this compound so that efficacy can be achieved in concentrations that are systemically achievable. Objective: The present study is aimed to evaluate the anticancer effects and associated molecular alterations of an AG and Chk1/2 inhibitor combination in head and neck squamous cell carcinoma (CAL-33) cells since the earlier studies have suggested ATM/ATR/Chk1/2-mediated activation of DNA damage checkpoints. Methods: Normal FHs74int cells and HNSCC cells (CAL-33 and FaDu) were used to assess cell proliferation and cell death. Cell cycle distribution and apoptosis were analyzed by flow cytometry and Acridine orange/EtBr, respectively, in CAL-33 cells. DNA damage in CAL-33 and FaDu cells was assessed by comet assay. Changes in the expression of proteins implicated in apoptosis, cell cycle progression, and DNA damage signaling were examined using Western blotting. Results: While AG did not show any significant changes in the growth or cell death of normal FHs74int cells, it strongly inhibited proliferation of HNSCC cells, concomitant with G2/M arrest and apoptosis. AG and AZD7762 showed an IC50 of 2.743 μM and 0.02600 μM, respectively, on cell proliferation in CAL-33 cells. Furthermore, AG caused an accumulation of intracellular ROS, which was inhibited by treatment with N-acetylcysteine. Chk1, Chk2 and γH2AX phosphorylation were induced in a dose-dependent manner by treatment with AG. The combination of AG with Chk1/2 inhibitor AZD7762 showed a synergistic effect in inhibiting cell proliferation with a CI of 0.4 through inhibition of DNA repair and premature mitotic entry, ultimately resulting in programmed cell death. Conclusions: These findings provide evidence that AG selectively targets DNA damage and repair in HNSCC CAL-33 cells via cell cycle arrest and apoptosis. Further, the anticancer potential of AG can be significantly enhanced by combination with the Chk1/2 inhibitor AZD7762, preventing repair of AG-induced DNA damage and amplifying checkpoint stress responses, resulting in enhanced apoptotic cell death. Together, these findings support the therapeutic potential of AG and highlight checkpoint kinase inhibition as a rational combination strategy for HNSCC treatment.

Cancers doi: 10.3390/cancers18193200

Authors: Benyamin Khajetash Mohammad Reza Deevband William A. Stokes Meysam Tavakoli

Head and neck cancer (HNC) presents a significant challenge due to its anatomic complexity and treatment-related complications such as sticky saliva and xerostomia, which critically impair patients’ quality of life. Recent advancements in imaging technologies, using the concept of radiomics, offer promising approaches for predicting these complications and ultimately reducing their incidence. In this regard, robust feature selection is critical in radiomics-based predictive modeling due to the high dimensionality, redundancy, and instability of extracted imaging biomarkers. This study aims to evaluate nine distinct feature selection algorithms—Boruta, Kruskal, Recursive Maximum Relevance minimum redundancy (R-MRmr), Relief, Recursive Feature Elimination (RFE), Forward Selection (FS), Backward Elimination (BE), Least Absolute Shrinkage and Selection Operator (LASSO), and Principal Component Analysis (PCA)—as a feature-transformation comparator for predicting sticky saliva and xerostomia in HNC patients using clinical, dosimetric, MRI and CT radiomics data. The study involved 250 HNC patients who underwent radiotherapy from three different institutions. From MRI and CT images, a total of 321 radiomic features (107 from each CT, T1, and T2-weighted MRI) along with 20 clinical and dosimetric features were extracted. The predictive robustness of feature selection methods was further evaluated across five machine-learning classifiers, including K-nearest neighbors (KNN), support vector machine (SVM), random forest (RF), logistic regression (LR), and eXtreme Gradient Boosting (XGBoost), were initially benchmarked using a common feature selection procedure, after which SVM was selected as the reference classifier for systematic comparison of the feature-reduction approaches. Model performance was assessed using metrics objectives such as Area Under the Curve (AUC), accuracy, sensitivity, and specificity. Among the evaluated feature selection approaches, R-MRmr and Relief generally yielded better discrimination, although performance varied according to toxicity endpoint and imaging modality. The highest AUCs were 0.85 for early sticky saliva (R-MRmr, T1-weighted MRI), 0.96 for early xerostomia (R-MRmr, T1-weighted MRI), 0.65 for late sticky saliva (Relief, combined CT+T1+T2), and 0.88 for late xerostomia (Relief, T1-weighted MRI). T1-weighted MRI frequently provided better individual-modality performance, whereas combining all three imaging modalities did not consistently improve discrimination. These findings demonstrate that the choice of feature selection strategy and imaging modality can materially influence radiomics-based toxicity prediction.

Cancers doi: 10.3390/cancers18193197

Authors: Claire Lloyd-Davies Abdul Kasem

Background: Non-palpable breast cancer management has become less invasive and more efficient, driven by advances in tumor localization and sentinel lymph node (SLN) identification. Savi Scout, using a radar-based localization system, can be implanted into the tumor before neoadjuvant systemic therapy (NST). Magtrace, a superparamagnetic iron oxide nanoparticle for SLN detection, can be administered preoperatively. This study evaluated combining Savi Scout and Magtrace for breast-conserving surgery and SLN biopsy in non-palpable breast cancer. Methods: Patients who underwent breast-conserving surgery and SLN biopsy for non-palpable breast cancer using Savi Scout and Magtrace between December 2022 and June 2026 at HCA Healthcare London Bridge Hospital were retrospectively identified. Outcomes included successful tumor localization, SLN identification, intraoperative signal detection failure, margin status, re-excision rate and staining. Results: 72 patients were identified (mean age 52 years, standard deviation ± 10), with a total of 78 breast lesions and 73 SLN biopsies. A total of 27.8% (20/72) underwent neo-adjuvant therapy with Savi Scout in situ. SLNs were identified using Magtrace in 95.9% (70/73) of SLN biopsies, with a mean of 2.7 (standard deviation ± 0.7) SLNs identified per procedure. A total of 78 Savi Scout devices were implanted, one for each lesion. Of these, 97.4% (76/78) were localizable intraoperatively, 100.0% (78/78) were retrieved and none migrated. One patient required re-excision for margin involvement. Conclusions: Combined use of Savi Scout and Magtrace is feasible, demonstrates high technical success, and offers pre-operative imaging flexibility in primary surgery for non-palpable breast cancers and post-NST patients. This study evaluates the combination of Savi Scout and Magtrace and demonstrates a practical approach for simultaneous tumor localization and SLN identification.

Cancers doi: 10.3390/cancers18193198

Authors: Shashi Kant Ahmad Alhalabi Nadeem Bilani Iktej Singh Jabbal María Herrán Theresa Abdo Saad Sabbagh Kaylee Sarna Amanda Stevenson Diana Saravia Candice Schwartz Thomas Samuel Zeina Nahleh Elizabeth Stone

Purpose: Assess the feasibility of a 6-month individualized nutrition counseling and exercise program targeting a 10% body weight loss in breast cancer (BC) survivors, with secondary endpoints assessing metabolic parameters, cardiovascular function, and quality of life. Methods: This single-arm pilot study enrolled BC survivors with body mass index (BMI) ≥ 25 kg/m2 in a counseling program with a registered dietitian, consisting of in-person and telephone visits over six months. Outcomes measured included weight, body composition, blood markers, cardiovascular function, and quality of life at 3 and 6 months. Results: A total of 78 breast cancer survivors were enrolled; 59 remained in the study at Month 3, and 54 completed the 6-month follow-up. The median age of participants was 58.5 years, and the cohort was predominantly White (72.4%). Among the 54 participants who completed 6-month follow-up, 11.1% achieved >10% weight loss and 29.6% achieved >5% weight loss. At 3 months, significant reductions were observed in BMI, body fat composition, and hemoglobin A1c (HbA1c), along with improvements in quality of life, depression, and anxiety. At 6 months, significant reductions were observed in weight, BMI, and body fat composition, with improvements in quality of life and depressive symptoms. Conclusions: This hybrid nutrition and exercise program was associated with observed improvements in weight loss and improved quality of life among BC survivors. Implications for Cancer Survivors: A low-burden, hybrid nutrition and exercise program integrated into routine oncology follow-up may help breast cancer survivors achieve weight loss while improving their quality of life.

Cancers doi: 10.3390/cancers18193196

Authors: Haoan Zhang Fuming Sun Hang Yu Xinyuan Chen Yixuan Shi Yue Teng Wenze He Yu Jin Shangdong Liu Chongyang Ding Chong Jiang Jingyan Xu

Background/Objectives: To evaluate a deep learning–based method for automatic segmentation of Hodgkin lymphoma (HL) on PET images and to explore the prognostic value of total metabolic tumor volume (TMTV) derived from segmentation. Methods: PET datasets from two independent institutions were retrospectively collected and divided into training and validation cohorts. MedNeXt was trained for HL PET segmentation and benchmarked against five representative segmentation architectures under the same data split, preprocessing pipeline, and evaluation framework. Segmentation performance was assessed using the Dice similarity coefficient (DSC), Jaccard index (JSC), 95th percentile Hausdorff distance (HD95), and average symmetric surface distance (ASSD). Bland–Altman and linear regression analyses evaluated agreement between ground-truth TMTV (gtTMTV) and predicted TMTV (pTMTV). Cox proportional hazards regression analysis was applied to assess the prognostic value of pTMTV. Results: In the validation cohort, the mean values (±standard deviation) of DSC, HD95, JSC, and ASSD were 0.702 ± 0.191, 67.998 ± 99.220, 0.561 ± 0.203, and 16.992 ± 31.659, respectively. Among the evaluated segmentation models, MedNeXt showed the best segmentation performance. Mean gtTMTV and pTMTV were 424.681 ± 498.811 cm3 and 405.871 ± 466.984 cm3, showing good agreement. pTMTV was significantly associated with progression-free survival (PFS) (p = 0.048), but not overall survival (OS) (p = 0.163). Conclusions: MedNeXt achieved reliable HL segmentation, although tumor boundary delineation requires further improvement. The derived pTMTV may serve as a prognostic indicator for PFS but showed no significant association with OS. Further validation in larger cohorts is warranted.

Cancers doi: 10.3390/cancers18193195

Authors: Jyoti Yadav Thomas Balizzakiwa Hemant Goyal

Advances in gastrointestinal (GI) cancer care have produced a growing population of long-term survivors at risk of second primary malignancies (SPMs). SPM definitions vary across studies, and SPMs remain underrepresented in cancer forecasting and prediction tools for GI cancer survivors. We conducted a narrative review across major GI cancer subtypes, summarizing site-specific SPM risk, key etiological pathways, and available prediction tools. Approximately one in ten colorectal cancer (CRC) survivors develops an SPM at ten years (pooled SIR ~1.15), a figure specific to CRC that does not generalize to other GI sites. Gastric cancer survivors carry excess risk of thyroid (O/E 2.00), esophageal, small intestinal, and pancreatic (O/E 1.60) malignancy, amplified by radiotherapy. Esophageal squamous cell carcinoma survivors show markedly elevated risk of upper aerodigestive tract tumors, consistent with field cancerization. Lynch syndrome (~16% second CRC risk at 10 years) and familial adenomatous polyposis (near-100% lifetime CRC risk without colectomy) confer some of the highest lifetime risks of metachronous GI malignancy reported to date. Most forecasting frameworks treat cancer incidence as a single event and do not adequately capture survivor-specific transitions, competing mortality, or germline susceptibility. GI cancer survivors form a distinct group whose risk is often overlooked. Harmonizing SPM definitions, extending multistate and competing-risk modeling, and integrating hereditary-risk stratification are near-term priorities for individualized surveillance.

Cancers doi: 10.3390/cancers18193194

Authors: Yudai Matsuzoe Daisuke Takeda Izumi Saito Yuki Murakami Aki Murakami Yoshiaki Tadokoro Junya Hirota Yasumasa Kakei Masaya Akashi Takumi Hasegawa

Background/Objectives: Mitophagy-associated factors have been implicated in tumor behavior and patient outcomes; however, their clinical significance depends on tumor type, stage, and microenvironmental context, and consistent conclusions remain lacking. We aimed to comprehensively assess the expression of mitophagy-associated factors in a moderate-sized cohort of patients with oral squamous cell carcinoma (OSCC) and clarify their prognostic significance. Methods: A retrospective cohort study included 197 patients with OSCC who underwent primary surgical resection between August 2013 and October 2018. Immunohistochemical expression of mitophagy-associated factors, including transcription factor EB (TFEB), nuclear factor erythroid 2-related factor 2 (NRF2), activating transcription factor 4 (ATF4), Parkin, PTEN-induced kinase 1 (PINK1), and mitochondrial ubiquitin ligase (MITOL), was evaluated. Associations between protein expression and clinicopathological parameters, local control, 5-year disease-specific survival (DSS), regional control, and distant metastasis were analyzed. Results: High expression of NRF2 and TFEB was significantly related with decreased DSS, poor regional control, and increased distant metastasis. High ATF4 expression was associated with distant metastasis and showed no association with DSS. Parkin, PINK1, and MITOL showed no significant association with patient outcomes. Explanatory multivariable analysis showed associations between high TFEB expression, vascular invasion, extranodal extension, and disease-specific mortality. Conclusions: TFEB expression showed an exploratory association with aggressive tumor behavior and poor prognosis in OSCC, warranting further investigation. However, because immunohistochemical evaluation measures protein expression rather than mitophagy flux or mitochondrial turnover, these findings represent associations between mitophagy-associated factor expression and clinical outcomes and do not directly demonstrate altered mitophagy activity.

Cancers doi: 10.3390/cancers18193193

Authors: Michele Piazzolla Doroty Sampietro Marco Donatello Delcuratolo Paolo Nicola Camillo Girotti Lucia Anna Muscarella Paola Parente

Thoracic surgery has progressively moved from open thoracotomy to video-assisted and robot-assisted approaches, reducing access-related trauma while changing the technical environment in which pulmonary resections are performed and taught. This narrative review examines the clinical evolution of open, video-assisted thoracic surgery (VATS), and robot-assisted thoracic surgery (RATS), with particular attention to the evidence supporting their perioperative and oncological outcomes, the learning curves associated with minimally invasive surgery, and the role of simulation-based training. Randomized trials now provide robust evidence that VATS improve postoperative recovery compared with thoracotomy in appropriately selected patients with predominantly early-stage non-small cell lung cancer, without compromising long-term oncological outcomes. Randomized comparisons between RATS and VATS support RATS as an oncologically acceptable minimally invasive alternative and suggest advantages in selected technical endpoints, particularly blood loss and lymph node retrieval, but do not demonstrate consistent superiority in major clinical or survival outcomes. Learning curves vary according to previous experience, case complexity, supervision, institutional volume, and the endpoint used to define competence, making fixed case-number thresholds an incomplete measure of proficiency. Simulation can improve selected technical skills and provide objective performance assessment, although evidence becomes progressively less robust when moving from simulator performance to operating room transfer and patient-level outcomes. Surgical approach, therefore, should be interpreted within a broader framework that includes patient and tumour characteristics, oncological quality, surgical expertise, institutional resources, and structured training.

Cancers doi: 10.3390/cancers18193191

Authors: Harriet Makin Sophie Van Tomme Natalie V.J. Aldhouse Samantha Wratten Helen Kitchen Chloe Carmichael Cecile Gousset Paul Cordero

Background/Objectives: Up to 95% of cancer patients report sleep disturbances or disorders. These can potentially influence cancer development and outcomes. This study aimed to review the existing literature to understand the patient experience of cancer-related sleep impairment across indications and treatments, to improve awareness and inform disease treatment/management. Methods: A targeted literature review of published qualitative studies exploring sleep impairment in oncology was conducted in MEDLINE, Embase, and PsycINFO. Concepts were extracted from the reviewed articles, and patient quotes or author descriptions/interpretations were subject to secondary analysis using semantic, qualitative, directed content analysis techniques via ATLAS.ti. Results informed the development of a patient-centric conceptual model. Results: From 482 identified publications, 22 publications were selected for in-depth review and concept extraction, collectively including 531 patients across 25 different oncology indications. Cancer-related sleep impairment frequently affected patients living with cancer, who reported difficulty obtaining good quality sleep, including difficulty falling asleep and staying asleep. Sleep problems were triggered by the emotional anxiety of life with cancer, cancer-related symptoms, treatments and side effects, and external factors. Poor sleep greatly impacted daily life for patients, with difficulties in daily life causing further sleep impairment, in a cyclical relationship. Conclusions: This study determined that there is an unmet need for treatment of sleep impairment in oncology to improve patient outcomes. The holistic conceptual model developed in this study can provide an important basis for selecting, developing, or modifying outcome measures to assess relevant sleep outcomes, facilitating discussion between patients and clinicians and improving disease treatment/management.

Cancers doi: 10.3390/cancers18193192

Authors: Ece Ulukal Karancı Gamze Emin Ahmet Oruç Esma Uğuztemur Atila Yıldırım Melek Karakurt Eryılmaz Asım Armağan Aydın

Background/Objectives: Systemic inflammation contributes to tumor growth and spread. We aimed to evaluate the association of pretreatment inflammatory indices and clinical and laboratory factors with survival in newly diagnosed grade 4 diffuse glioma. Methods: A total of 120 patients diagnosed with grade 4 diffuse glioma at four centers between 2013 and 2026 were analyzed retrospectively. Nine indices derived from complete blood counts were calculated. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan–Meier and multivariable Cox regression. The cut-off for the systemic inflammation response index (SIRI) was determined with maximally selected rank statistics. Ten machine learning models were compared with the Cox model using repeated cross-validation. Results: Median follow-up was 70 months. Median OS was 22.8 months (95% confidence interval [CI] 15.8–26.3) and median PFS was 10.9 months (95% CI 9.1–14.4). In the multivariable model, SIRI > 2.85 was independently associated with OS (hazard ratio [HR] 2.62, 95% CI 1.38–4.96, p = 0.003), and this association persisted in the isocitrate dehydrogenase (IDH)-wildtype subgroup (HR 3.06, 95% CI 1.27–7.39, p = 0.013). Hemoglobin was independently associated with PFS (HR per g/dL 0.84, 95% CI 0.73–0.96, p = 0.011). Smoking was an independent indicator of poor prognosis for both OS (HR 2.02) and PFS (HR 1.73). Ki-67 and tumor size were not associated with survival. Machine learning models did not outperform the Cox model, and their variable importance rankings were consistent with the classical analysis. Conclusions: Pretreatment SIRI, hemoglobin, and smoking were independently associated with survival in grade 4 diffuse glioma. These markers are available from routine tests and may contribute to prognostic assessment.

Cancers doi: 10.3390/cancers18193190

Authors: Fatemeh Safizadeh Tafirenyika Gwenzi Marko Mandic Michael Hoffmeister Hermann Brenner

Background/Objectives: Prospective studies have reported associations between systemic inflammatory biomarkers and colorectal cancer (CRC) risk, but whether these reflect a causal role of inflammation or responses to preclinical disease remains uncertain. Methods: Using data from 383,850 UK Biobank participants (aged 40–69 years; recruited 2006–2010), we investigated potential reverse causality by assessing these associations according to time since biomarker assessment. Baseline systemic inflammatory markers, including C-reactive protein (CRP), albumin, and blood cell-derived ratios, were assessed. Multivariable Cox models estimated associations with CRC risk across predefined follow-up intervals. Results: Over a median follow-up of 11.8 years, 4996 participants developed CRC. Inflammatory biomarkers were associated with increased CRC risk, particularly during the early follow-up. Associations weakened substantially or disappeared when early follow-up was excluded. For example, CRP was associated with a 3.03-fold higher CRC risk (highest vs. lowest quartile; 95% CI: 2.06–4.45) within the 0–1-year interval, while no association was observed during the 3–5, 6–8, or >8-year intervals. Across complete follow-up, the association remained statistically significant but much weaker (HR: 1.17; 95% CI: 1.07–1.28). Similar patterns were observed for most other biomarkers, except the platelet-to-neutrophil ratio. Conclusions: Our results suggest that the associations between inflammatory biomarkers and CRC risk may partly reflect reverse causality arising from preclinical disease.

Cancers doi: 10.3390/cancers18193189

Authors: Maximilian Sturz Gabriela Studer Christoph Glanzmann Sergejs Unterkirhers Philippe Logaritsch Olga Unterkirhere

Background/Objectives: Tumours abutting or involving the brachial plexus can cause pain and neurological deficits. We evaluated six-fraction ultra-hypofractionated radiotherapy with a simultaneous integrated boost (uhRT-SIB) in a predominantly palliative cohort. Methods: We retrospectively analysed consecutive patients treated from April 2022 to June 2026, with a data cut-off of 7 July 2026. Image-guided VMAT delivered 33 Gy and 24 Gy to the high- and lower-dose planning target volumes, respectively. Outcomes included the best documented CTCAE-based symptom response, study-defined volumetric response (>30% GTV reduction), freedom from local progression (FFLP), overall survival (OS), and neurological findings in routine clinical records. Results: Forty-four patients with 45 lesions were treated; 29/45 lesions (64.4%) contacted the plexus. The median observed follow-up was 7.8 months (range 0.6–40.6). Symptoms improved by at least one grade in 16/19 evaluable symptomatic patients (84.2%, 95% CI 62.4–94.5%). The median times to first documented benefit and best symptom grade among responders were 9 and 23 days. The first-scan volumetric response occurred in 24/30 evaluable lesions (80.0%, 95% CI 62.7–90.5%). Six- and 12-month FFLP were 84.7% (95% CI 63.9–94.0%) and 73.7% (95% CI 49.7–87.6%), respectively. The median OS was 9.6 months. No clinical diagnosis of radiation-induced brachial plexopathy was documented; neurological assessment was not standardised. Conclusions: In this predominantly palliative cohort, six-fraction uhRT-SIB was associated with symptom improvement in 84.2% of evaluable symptomatic patients, study-defined volumetric response in 80.0% of evaluable lesions, and 12-month FFLP of 73.7%. No clinical diagnosis of radiation-induced brachial plexopathy was documented during routine follow-up, although the assessment of late neurological toxicity was limited.

Cancers doi: 10.3390/cancers18193186

Authors: Piotr Wiśniewski Maciej Śledziński Marcin Barczyński Andrzej Rafał Hellmann

Background/Objectives: The management of Bethesda IV (follicular neoplasm) thyroid nodules remains controversial, in part due to wide variation in the reported risk of malignancy (ROM-BIV). Understanding this variability is essential for documenting systemic inconsistencies in ROM-BIV estimates and for developing more consistent risk-stratification strategies. This study aimed to quantify ROM-BIV variability across European centers and conduct an exploratory analysis of the trade-offs associated with hypothetical risk-based thresholds within a surgically selected cohort. Methods: We analyzed data from 15,251 patients with Bethesda IV thyroid nodules enrolled in the EUROCRINE registry. Multilevel logistic regression models were used to estimate ROM-BIV and assess variation across centers and countries, adjusting for patient- and nodule-level characteristics. Threshold analysis and decision curve analysis were employed as illustrative mappings of trade-off mechanisms within the surgically treated cohort to explore how varying risk levels affect classification outcomes. Results: Adjusted center-level ROM-BIV demonstrated marked variability, ranging from 5.5% to 65.5%. Intraclass correlation coefficients (ICCs) were 11.4% for institutions and 9.7% for countries, indicating meaningful clustering of ROM-BIV at both levels. The fixed component of the model showed limited-to-moderate discrimination (AUC-ROC 0.647; 95% CI, 0.637–0.656). Exploratory analysis illustrated the inherent trade-off between reducing potential overdiagnosis and maintaining sensitivity for malignancy detection. Decision curve analysis indicated a theoretical net benefit over default strategies, although no specific clinical threshold could be recommended based on these retrospective data. Conclusions: Substantial variability in ROM-BIV across European centers may reflect differences in institutional selection, diagnostic practices, clinical management, and reporting, rather than biological variance. These findings highlight the need for standardization of diagnostic and reporting pathways. Risk-based models must be positioned as supportive tools for individualized management and require rigorous prospective validation in unselected populations before any clinical implementation can be considered.

Cancers doi: 10.3390/cancers18193188

Authors: Mehmet Ali Tepebasili Amir Salar Nazari Ali Haluk Duzkalir Dogu Cihan Yildirim Mehmet Orbay Askeroglu Mert Veznikli Selcuk Peker

Background/Objectives: Large parasagittal meningiomas (PSMs) present significant surgical challenges due to their proximity to the superior sagittal sinus, and the optimal radiosurgical strategy for large tumors remains debated. This study compared local control (LC) and treatment-related radiological and clinical outcomes after single-session (ss-GKRS) and hypofractionated (hf-GKRS) Gamma Knife radiosurgery in PSMs ≥8 cm3. Methods: Eighty-seven patients with 87 radiologically confirmed PSMs treated between April 2006 and February 2025 were reviewed. Patients with histopathologically confirmed atypical or anaplastic meningiomas or imaging features suspicious for higher-grade disease were excluded. Fifty-nine patients underwent ss-GKRS and 28 received hf-GKRS. The median tumor volume was 11.2 cm3 (range 8–37.8 cm3). LC was defined as tumor volume regression or stability on serial MRI. Radiological complications were defined as new or worsening peritumoral T2 hyperintensity, and clinical complications as new neurological symptoms. Time to local progression was compared using the log-rank test, with an exploratory volume cut point from ROC analysis. Results: The median follow-up was 62 months (range 12–186 months). Overall crude LC was 93.1%, including 89.8% (53/59) after ss-GKRS and 100% (28/28; exact 95% CI 87.7–100%) after hf-GKRS. All six local progressions occurred in the ss-GKRS group; however, freedom from local progression did not differ significantly between the groups (log-rank p = 0.137). In an exploratory volume-stratified analysis, LC was 100% in both groups for tumors ≤11.75 cm3. Among tumors >11.75 cm3, crude LC was 71.4% (15/21) after ss-GKRS and 100% (16/16) after hf-GKRS (Fisher exact p = 0.027). Post-treatment radiological edema occurred in 39.0% after ss-GKRS versus 25.0% after hf-GKRS (p = 0.235). Conclusions: Overall freedom from local progression did not differ significantly between ss-GKRS and hf-GKRS. No local failures were observed after hf-GKRS during its shorter available follow-up, including among tumors >11.75 cm3 in an exploratory analysis. These findings support hf-GKRS as a feasible treatment option for selected larger PSMs, but neither treatment superiority nor a definitive tumor-volume threshold can be established from this retrospective cohort.

Cancers doi: 10.3390/cancers18193187

Authors: Victoria H. Ruesch Justin Thrush James F. Bena Claudia Ricotti Melissa Piliang Melissa McEnery-Stonelake Basia Marie Michalski-McNeely Jon Meine Jennifer Lucas Christine Poblete-Lopez Shlomo Koyfman Brian Gastman Allison T. Vidimos

Background/Objectives: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor, most commonly occurring on the head and neck. Incidence of MCC is rising with the aging population. Five-year overall survival (OS) for localized MCC is 50.6%; 5-year OS for patients with distant metastases is 13.5%. The purpose of this study is to determine if coordination of care for the treatment of MCC is logistically feasible, and provide a description of the patient population observed at this institution. Methods: All patients with MCC diagnosis from January 2012–June 2024 were identified at our tertiary care center. All patients with MCC were added to our non-melanoma skin cancer registry. Outcomes were compared between those treated with our “Merkel cell carcinoma in a day” (MIAD) protocol and those receiving the standard treatment protocol. Results: No significant differences were detected in the recurrence rate, transit metastasis, distant metastasis, and disease-specific death. Nodal metastasis was higher in the MIAD group (HR 4.94, 95% CI 1.08–22.6, p = 0.039, six events total). Both groups had similar times to treatment and treatment within 30 days of diagnosis. Conclusions: MCC is a rare and aggressive tumor, often exhibiting subclinical tumor spread. Mohs micrographic surgery ensures 100% peripheral and deep margin assessment, with potential for tissue sparing. With thoughtful coordination, lymphoscintigraphy can be completed on the same day as Mohs surgery followed by sentinel lymph node biopsy (SLNB) and reconstructive surgery.

Cancers doi: 10.3390/cancers18193185

Authors: Katie E. Johnston Aoife M. Twomey Samantha J. Cushen

Background: Nutrition is an important yet underexplored determinant of cancer survivorship outcomes. Emerging evidence suggests that greater adherence to the Mediterranean diet (MedD) is associated with improved health status, enhanced quality of life (QoL), and reduced mortality. However, evidence specifically targeting post-treatment breast cancer survivors remains limited, and substantial heterogeneity in MedD scoring tools and adherence thresholds restricts comparability across studies. This review aimed to (i) identify and characterise the tools used to assess MedD adherence in breast cancer survivors following completion of active treatment, including their components, scoring systems, and adherence thresholds; and (ii) map the range of health outcomes that have been examined in relation to MedD adherence in this population. Methods: A scoping review was conducted in accordance with PRISMA-ScR and Joanna Briggs Institute guidelines. PubMed, Embase, Scopus, Web of Science, and CINAHL were searched (2000–2026) for English-language intervention and observational studies reporting MedD adherence in adult female breast cancer survivors after treatment completion. Two reviewers independently extracted data, which were synthesised descriptively, including study characteristics, MedD scoring tools, adherence outcomes, and clinical, metabolic, and QoL findings. The methodological structure protocol of this scoping review was retrospectively registered in the Open Science Framework. Results: Twenty studies (16 intervention, 4 observational; 16 non-overlapping cohorts; pooled n N = 4174, excluding non-cancer comparators) met inclusion criteria. Ten MedD scoring tools were identified, most frequently MEDAS-14 (original or modified, 7/20 studies), varying in components (range 9–18), scoring approach, and adherence thresholds. Most intervention studies reported improved MedD adherence following intervention, generally as a within-group change; between-group differences in adherence were reported less often and inconsistently significant. Anthropometric outcomes (body weight, body mass index (BMI), waist circumference) were most frequently improved, but significant differences between groups were found in only a small number of controlled studies. Mortality was assessed in only one observational cohort study, which found no association with breast-cancer-specific outcomes. Conclusions: This scoping review identified considerable heterogeneity in how MedD adherence is measured in breast cancer survivors, with ten different scoring tools identified across 20 studies. Although improvements in MedD adherence appear achievable, the evidence is limited by small sample sizes, heterogeneous assessment tools, and short intervention durations. Larger, standardised longitudinal studies are needed, particularly to determine whether MedD adherence influences cancer recurrence and survival, for which current evidence remains minimal.

Cancers doi: 10.3390/cancers18193184

Authors: Zhichao Tan Yue Sun Yunxiao Zhang Zhengfu Fan Chujie Bai Shu Li Tian Gao Lu Zhang Ruifeng Xue Xinyu Wang Mengmeng Liu Hairui Wang Jiayong Liu

Background/Objectives: The anatomical distribution of inguinal lymph node (ILN) metastases may inform research on the extent of therapeutic dissection for lower-limb melanoma. Methods: Fifty-eight patients undergoing radical inguinal lymph node dissection (rILND) were retrospectively evaluated using five anatomical zones. Zone-specific node counts were reaggregated, and exploratory binary logistic regression assessed multiple-zone involvement. Results: The cohort included 48 clinically node-positive and 10 sentinel lymph node biopsy (SLNB)-positive patients. Among 816 mapped ILNs, 149 were positive. Zone I contained 102/149 positive nodes (68.5%); within-zone positivity was 102/303 (33.7%) in zone I, 27/243 (11.1%) in zone II, 13/190 (6.8%) in zone III, 3/39 (7.7%) in zone IV, and 4/41 (9.8%) in zone V. Five patients had no positive mapped ILNs. Zone I contained the only positive node in 19/20 patients (95.0%) and was the sole involved zone in 32/33 patients with single-zone involvement (97.0%). Twenty patients had multiple-zone involvement. In a two-variable complete-case model (50 patients; 18 events), ≥3 positive ILNs remained associated with multiple-zone involvement (adjusted odds ratio, 34.80; 95% confidence interval, 5.88–206.08), whereas extranodal extension did not. Conclusions: This small, selected cohort provides preliminary pathological evidence of preferential inferior-zone involvement. It does not establish sequential spread or the oncological safety of reduced rILND. External and prospective validation are required.

Cancers doi: 10.3390/cancers18193183

Authors: Emily C. Sullivan Nabil Saleem Areeba A. Hashmi Kristopher A. Knight Austre Y. Schiaffino Bustamante Ahmed A. Aljudi Brandon J. Fanelli Sunil S. Raikar

Background: Acute myeloid leukemia (AML) remains the deadliest form of leukemia in children and adults despite therapeutic advances in recent decades. Chimeric antigen receptor (CAR) T-cell therapy is one such therapeutic approach that has been explored preclinically and clinically in AML; however, its efficacy is limited by antigen heterogeneity. To overcome this roadblock, we propose a dual-targeting CAR T-cell strategy, targeting the AML-associated antigens CD33 and CD70. Methods: To recapitulate tumor heterogeneity, we genetically edited the AML cell line Molm-13 using CRISPR-Cas9 to generate distinct sublines, namely CD33+/CD70−, CD33−/CD70+, and CD33+/CD70+. Two dual-targeting CAR T-cell approaches were developed: a “pooled” product, in which CAR T cells directed towards CD33 or CD70 are combined and co-administered, and a “co-transduced” product, wherein one population of T cells is transduced with both CD33-CAR- and CD70-CAR-encoding viral vectors. Results: Pooled and co-transduced products demonstrated potent cytotoxicity against all Molm-13 populations, whereas single-antigen CAR approaches were not as effective when their respective target antigen was absent. Mice engrafted with CD33/CD70 heterogeneous Molm-13 cells were treated with pooled or co-transduced CD33/CD70 CAR T cells. Both groups exhibited a significant survival advantage over the untreated group, with the co-transduced approach showing a statistically significant advantage over the pooled group. Conclusions: In summary, engineering one T cell to express both CARs yielded superior cytotoxicity when targeting a heterogeneous AML blast population.

Cancers doi: 10.3390/cancers18193182

Authors: Lamia Sabry Aboelnasr Nanki Deol Yingran Jin Fu Mona El-Bahrawy

Background/Objectives: Differentiating benign, borderline, and malignant ovarian cystic lesions before surgery remains challenging, and many women undergo operations for lesions that prove benign. Most cystic lesions contain fluid that lies in direct contact with the lesion and forms part of the tumour microenvironment, potentially concentrating tumour-derived molecules diluted in the circulation. This review presents the current evidence on the value of ovarian cyst fluid analysis for the discovery of diagnostic and prognostic biomarkers across benign, borderline, and malignant lesions. Methods: We reviewed studies analysing ovarian cyst fluid using proteomic, glycoproteomic, metabolomic, inflammatory, and tumour-DNA approaches, together with conventional biomarkers and cytology, and considered pre-analytical and methodological factors affecting their interpretation. Results: Cyst fluid harbours proteins, glycoproteins, metabolites, cytokines, and DNA with tumour-specific mutations, frequently at concentrations exceeding those in matched serum. Multiple candidates discriminate malignant from benign lesions, and borderline lesions often show intermediate signatures. No single marker outperforms established CA125-based protocols, but multi-marker and multi-omics combinations have shown improved diagnostic performance within individual studies. Conclusions: Ovarian cyst fluid is a biologically enriched, underexploited substrate and a potential adjunct to existing diagnostic pathways. Realising its clinical potential will require standardised pre-analytics, validated multi-analyte panels, and prospective studies addressing clinical utility and reproducibility.

Cancers doi: 10.3390/cancers18193181

Authors: Ishaan Shah Srushti Naik Frank Arfuso Sudha Warrier Arun Dharmarajan Sonal M. Manohar

Triple-negative breast cancer (TNBC) is a highly aggressive and molecularly diverse subtype of breast cancer characterized by the absence of estrogen, progesterone, and human epithelial growth factor receptors. Despite advancements in therapeutic interventions, TNBC continues to remain associated with high metastatic potential, high likelihood of recurrence, and importantly, poor prognosis. Therefore, validated prognostic biomarkers are needed that can facilitate accurate prognostic assessment, drive treatment options, and lead to better clinical outcomes. This comprehensive review aims to provide a detailed overview of established and emerging prognostic biomarkers in TNBC, highlighting their biological relevance, clinical utility, and translational potential. We initially focus on the different classes of individual prognostic biomarkers and their limitations as far as prognostic stratification is concerned. We then move toward the development of multi-marker panels, further taking into account the critical factors limiting their clinical implementation. Development of standardized, clinically validated, and cost-effective multi-marker prognostic frameworks that can integrate the different aspects of tumor biology is the need of the hour. Such comprehensive approaches are expected to enhance prognostication and thereby improve outcomes in TNBC patients.

Cancers doi: 10.3390/cancers18193180

Authors: Haoyuan Xu Huankang Zhang Wanpeng Li Shixing Zheng Xiaole Song Jingjing Wang Quan Liu Dehui Wang Zhuofu Liu

Background/Objectives: Nasopharyngeal angiofibroma (NA) is generally benign, but recurrent disease and rare malignant transformation remain clinically relevant beyond adolescence. We examined adult clinical presentations, records of malignant transformation, and age-related differences in stage distribution. Methods: We retrospectively reviewed 289 surgically treated patients from January 2006 through June 2026. Radkowski stage distributions were compared between patients aged > 30 and ≤30 years using exact tests. Detailed clinical records were reviewed for 16 adults, and whole-genome sequencing (WGS) annotation summaries were examined for one tumor–blood pair. Results: Twenty-five patients (8.7%) were older than 30 years; stage was available for 287 patients. In the detailed adult subgroup, a prior pathology-slide record described focal malignant transformation with a Ki-67 index of approximately 50% in one recurrent tumor. Two other patients had database transformation entries without accompanying pathological documentation. Four recurrences and three deaths were recorded, all in stage IIIB disease. Three men had colorectal or rectal cancer histories. Low-, intermediate-, and advanced-stage tumors accounted for 36.0%, 36.0%, and 28.0% of adult cases, compared with 17.6%, 57.3%, and 25.2% of younger cases (p = 0.0493). The genomic annotations showed a C>A-predominant substitution spectrum. Conclusions: Adult NA included recurrent stage IIIB disease and a documented record of focal malignant transformation. Stage distributions differed between age groups. These clinical observations support pathological reassessment of recurrent tumors. The single-case genomic findings remain descriptive annotations.

Cancers doi: 10.3390/cancers18193179

Authors: Sicheng Qian Xinyi Zheng Jiaqi Li Jiahan Le Jiangjiang Qin Yitao Chen

Gastric cancer (GC) remains one of the most prevalent malignancies worldwide, with a high mortality rate primarily attributable to late-stage diagnosis and limited therapeutic options. Aberrant cell proliferation arising from cell cycle dysregulation is a hallmark of GC pathogenesis. Cyclins, as core regulators of cell cycle progression, exhibit dynamic protein expression patterns that are tightly controlled by the ubiquitin–proteasome system (UPS). In GC, cyclins are frequently overexpressed due to impaired ubiquitination and subsequent proteasomal degradation. This review systematically elucidates the ubiquitination-mediated regulation of distinct cyclins (Cyclins D, E, A, and B) at specific cell cycle phases—G1, S, G2, and M—and highlights the critical roles of E3 ubiquitin ligases, including SCF complexes and APC/C, in GC progression. We further discuss how dysregulated non-coding RNAs and altered E3 ligase expression contribute to aberrant cyclin ubiquitination, thereby promoting GC cell proliferation, metastasis, and poor prognosis. Importantly, emerging evidence demonstrates that bioactive compounds derived from traditional Chinese medicine (TCM) can counteract these abnormalities by directly downregulating cyclin expression, modulating E3 ligase activity, or inhibiting 26S/20S proteasome function, thus restoring cell cycle homeostasis and suppressing GC growth. This review integrates molecular mechanisms of cyclin ubiquitination with TCM-based therapeutic strategies, offering novel insights into targeted interventions for GC.

Cancers doi: 10.3390/cancers18193178

Authors: Tuba Güllü Koca Nizameddin Koca Fazıl Çağrı Hunutlu Ahmet Mert Yanık Sinem Çubukçu Rümeysa Yılmaz Tuba Ersal Vildan Gürsoy İbrahim Ethem Pınar Vildan Özkocaman Fahir Özkalemkaş

Background: Immunoglobulin isotype is recorded at diagnosis in every patient with intact-immunoglobulin multiple myeloma, but is not retained in the ISS, R-ISS, or R2-ISS. Methods: We analyzed 196 consecutive patients with IgA or IgG myeloma who underwent upfront autologous stem cell transplantation at a single center (2009–2023). The primary endpoint was progression-free survival (PFS); overall survival (OS) was the secondary endpoint. Cox models used information available at transplantation, including the induction regimen and transplant year, in the complete-case set (n = 131) and after multiple imputation (n = 196). Results: Median PFS was 14.8 versus 30.5 months and OS 43.2 versus 94.2 months in IgA versus IgG patients (both p < 0.001). IgA isotype was associated with inferior PFS (adjusted HR 1.85, 95% CI 1.13–3.02; imputed HR 1.83, 95% CI 1.22–2.73). For OS, the HR was 1.68 (0.98–2.88) in the complete-case analysis and 1.91 (1.24–2.94) after imputation, so its magnitude is uncertain. Models with maintenance gave 1.87 and 1.82. Progression documentation differed by maintenance status. Cytogenetic data were too incomplete to assess independence from genomic risk. Conclusions: In a bortezomib-era transplant cohort, IgA isotype was associated with inferior PFS; the association with OS was of uncertain magnitude. The finding is hypothesis-generating and requires validation in cohorts with complete cytogenetic characterization.

Cancers doi: 10.3390/cancers18193175

Authors: Tomasz Cwaliński Mateusz Jagielski Michał Kazanowski Jacek Piątkowski Maciej Ciesielski Marcin Januszkiewicz Zuzanna Bigus Patryk Kaczor Bartosz Kapturkiewicz Paweł Lesiak Sergii Girnyi Damian Nowiński Piotr Kurek Natale Calomino Marek Jackowski Marek Bębenek Luigi Marano

Background/Objectives: Computed tomography (CT) informs preoperative staging in colon cancer, yet its diagnostic accuracy for lymph node involvement relative to pathological staging remains uncertain. We examined nodal concordance and multicentre variation in Poland. Methods: This retrospective diagnostic accuracy study included adults who underwent upfront resection for nonmetastatic colon cancer at five centres between January 2022 and August 2025. All underwent preoperative CT; recorded cN categories were dichotomised as cN0 versus cN+ (any positive cN category), and pathological pN was the reference. We estimated accuracy, sensitivity, specificity, predictive values, and kappa with 95% confidence intervals. A centre-adjusted exploratory analysis examined the association between cT3–4 and occult pN+ among cN0 patients. Results: Of 662 otherwise eligible patients, 590 had evaluable cN and pN. CT and pathology agreed in 386 (65.4%; 95% CI, 61.5–69.2; κ = 0.276; 95% CI, 0.199–0.353). Occult pN+ occurred in 73 of 335 cN0 patients (21.8%; 95% CI, 17.7–26.5); 131 of 255 cN+ patients were pN0 (51.4%; 95% CI, 45.3–57.4). Sensitivity was 62.9% and specificity 66.7%. Centre-level cN/pN completeness ranged from 73.5% to 100%. cT3–4 was associated with occult pN+ after centre adjustment (OR, 3.10; 95% CI, 1.71–5.62). Sensitivity analyses were materially consistent. Conclusions: Routine CT nodal classification showed limited concordance with pathology. The cT3–4 association is exploratory and does not establish a prediction or treatment selection rule; cN alone should not determine treatment.

Cancers doi: 10.3390/cancers18193177

Authors: Lana Cook Gillian Prue Caitlin McShane Mei Krishnasamy Kate Furness Susan McLaughlin Gary Mitchell

Background/Objectives: Pancreatic cancer is associated with poor survival and substantial psychosocial burden, yet little is known about the psychological, emotional, and social dimensions of patients’ experiences across the illness trajectory. This review aimed to identify, analyse, and synthesise empirical qualitative literature on the psychosocial aspects of receiving, living with, dying with, or surviving pancreatic cancer. Methods: Seven bibliographic databases were searched from inception to 4 September 2025, with reference list screening and forward citation tracking undertaken. Records were managed in Covidence. Following screening of 4357 titles and abstracts and 412 full texts, 30 papers representing 28 studies were included. Methodological quality was appraised using the JBI Critical Appraisal Checklist for Qualitative Research. Data were extracted into a shared Excel workbook and synthesised using Thomas and Harden’s thematic synthesis approach. Results: Four overarching themes were developed: (1) from ambiguous symptoms to the shock and threat of diagnosis; (2) navigating care, information, and support; (3) embodied disruption, relational change, and reworking everyday life; and (4) living on borrowed time and coping with uncertainty and mortality. Across the included studies, pancreatic cancer was experienced as a profound disruption to participants’ lives, futures, and sense of selves; involved complex informational and care-navigation work; altered everyday lives; and provoked ongoing uncertainty around progression, recurrence, and survival. Conclusions: Pancreatic cancer exerts a profound psychosocial impact across early and advanced disease, with psychological, social, and emotional challenges intertwined with complex symptomatology, functional decline, uncertainty, and mortality awareness. Thus, substantial unmet psycho-oncology and supportive care needs exist for patients and their families.

Cancers doi: 10.3390/cancers18193176

Authors: Ting Wang Ting Liang Matthew Kafarski Jian Liu Yi Jing Wen Liao Hang Xing Jia Feng Tingting Bian Lei Liu Hui Sun Xiaoli Zheng Bin She Xiaosha Ren Joanne Lee Qiushi Lin Ming Chen Liang Cheng Hong Ge Xiaoqun Dong Yifei Liu

Objective: This study evaluated the diagnostic value of a combined SHOX2 and RASSF1A methylation assay (LungMe®) in differentiating malignant from benign pleural and peritoneal effusions. Methods: A total of 696 patients with pleural or peritoneal effusions were prospectively enrolled. Effusion sediment samples were analyzed by liquid-based cytology (TCT), cell block histology, and methylation-specific PCR for both SHOX2 and RASSF1A. The final diagnosis was confirmed by clinical, imaging, and pathological follow-up. Results: Lung cancer was the predominant cause of malignant pleural effusions (71.96%), while malignant peritoneal effusions mainly resulted from ovarian, gastric, and liver cancers. The optimal ΔCt cutoffs for SHOX2 and RASSF1A were ΔCt ≤ 9 and ΔCt ≤ 12, respectively. The combined methylation assay achieved a sensitivity of 79.1% and specificity of 90.4% for malignant effusions. When combined with cytology, the overall sensitivity increased from 34.7% (TCT alone) to 91.7%, with a positive predictive value (PPV) of 93.9% and a negative predictive value (NPV) of 86.7%. The assay showed high sensitivity across multiple tumor types, including 100% for esophageal and breast cancers, and ≥80% for lung cancer, gastric cancer, lymphoma, and cholangiocarcinoma. Conclusions: The combined SHOX2 and RASSF1A methylation assay has high diagnostic value for benign–malignant discrimination of pleural and peritoneal effusions, improving diagnostic sensitivity when combined with conventional cytology. Thus, within the context of this single-center study, the LungMe® assay demonstrates promise in expanding pan-cancer diagnostics, but will require further multicenter external validation and prospective clinical studies before routine clinical adoption.

Cancers doi: 10.3390/cancers18193174

Authors: Carlo Signorelli

Background: The therapeutic landscape of refractory metastatic colorectal cancer (mCRC) has expanded with antiangiogenic agents, cytotoxic therapies, immunotherapy, and biomarker-driven treatments. Randomized clinical trials (RCTs) establish efficacy and safety, while real-world evidence (RWE) can complement them by addressing generalizability, treatment delivery, safety, and outcomes in populations underrepresented in prospective studies. This narrative review examines the contribution and limitations of RWE in precision oncology and later-line therapeutic sequencing in mCRC. Methods: We reviewed evidence from randomized trials, observational studies, real-world registries, translational research, and contemporary international guidance, focusing on later-line antiangiogenic strategies, trifluridine/tipiracil-based treatment, fruquintinib, anti-EGFR rechallenge, immunotherapy in MSI-H/dMMR disease, and targeted therapies for actionable molecular alterations. Particular attention was given to RWE methodology and interpretation. Results: RWE complements randomized evidence by characterizing effectiveness and toxicity in heterogeneous populations, treatment delivery and dose modification, and implementation of biomarker-guided strategies in routine practice. Observational studies may also inform therapeutic sequencing and identify prognostic or pharmacodynamic correlates, although causal interpretation is limited by selection bias, treatment attrition, time-dependent and residual confounding. Longitudinal circulating tumor DNA (ctDNA) assessment is particularly relevant to molecular reassessment and anti-EGFR rechallenge, while broader ctDNA-guided adaptive treatment strategies remain investigational. Conclusions: Later-line mCRC management increasingly integrates molecular profiling, treatment history, patient fitness, toxicity, and therapeutic sequencing. High-quality RWE provides complementary evidence on how these strategies perform and are implemented in routine practice but should be interpreted according to study design and susceptibility to bias. Integration of rigorous RWE with randomized and prospective molecular evidence may help bridge the gap between trial efficacy and real-world effectiveness and support individualized later-line care.

Cancers doi: 10.3390/cancers18193173

Authors: Katharina Hörmandinger Elvis Ruznic Marisa Klebermass Brane Grambozov Petra Feurstein Josef Karner Georg Gruber Martin Heilmann Falk Röder Ute Ganswindt Danijela Minasch Franz Zehentmayr

Purpose: Chemoradioimmunotherapy (CRIT) with 60–66 Gy is the standard of care (SoC) for non-small-cell lung cancer (NSCLC) UICC stage III. The aim of this real-world data (RWD) study was to report the long-term impact of Durvalumab and radiation dose escalation on clinical outcomes. Material and Methods: ALLSTAR is a nationwide prospective multicentre registry for NSCLC UICC stage III, in which 12/14 Austrian centres participated (ethics approval number: 1002/2019). The basis for the current analysis is the third data extraction, which was completed on 2 June 2025. Apart from the SoC, alternative dose-fractionation and sequential CRT concepts >66 Gy were also permitted. Durvalumab maintenance treatment for one year was administered at the discretion of the tumour board at each centre. Results: Compared to prior analyses by our group, 40 individuals who completed follow-up (FUP) were added to this final analysis, leading to a total patient population of 228 (156 CRT plus Durvalumab; 72 CRT). In 156 patients, Durvalumab was added to CRT, while 72 received CRT only. The median FUP periods were 41.0 (95%-CI: 36.7–45.4) and 37.8 months (95%-CI: 31.4–44.1) for the Durvalumab and CRT cohort, respectively. Radiation dose escalation combined with Durvalumab treatment was associated with a nominally higher ITC of 37 months (95%-CI: 24.5-not reached) compared with 17.7 months (95%-CI: 14.9-not reached) in patients receiving neither dose escalation nor Durvalumab (N = 135; HR = 0.61; 95%-CI: 0.37–1.006; p-value 0.051). With Durvalumab maintenance, a median PFS of 22.8 months (95%-CI: 19.4–38.3) was observed compared to 16.5 months (95%-CI: 12.6–24.5) without (N = 228; HR = 0.61; 95%-CI: 0.42–0.88; p-value 0.0071). Median OS was 52.6 months (95%-CI: 39.5-not reached) with Durvalumab compared to 27.4 months (95%-CI: 18.7-not reached) without (N = 228; HR = 0.52; 95%-CI: 0.34–0.78; log-rank p-value < 0.002). Median time to death or distant metastasis (TTDM) was 33.3 months (95%-CI: 23.5–45) in the Durvalumab cohort compared to 18.7 months (95%-CI: 14.8-not reached) in the CRT cohort (N = 228; HR = 0.60; 95%-CI: 0.42–0.89; log-rank p-value 0.01). Median time to death or local relapse (TDLR) with Durvalumab was 30.4 months (95%-CI: 23.5–51.1) compared to 17.2 months (95%-CI: 14.8–25.7) without (N = 226; HR = 0.58; 95%-CI: 0.40–0.83; log-rank p-value < 0.003). Conclusion: This final RWD analysis implies both a beneficial effect of high-dose irradiation combined with Durvalumab on ITC and the long-lasting impact of Durvalumab on PFS, OS, TTDM, and TDLR.

Cancers doi: 10.3390/cancers18193172

Authors: Jessica S. W. Borgers Cheng-Chang Wu Theresa M. Medina Claire M. Muckle Elizabeth N. Katsnelson Phaedra A. Whitty Luke Mantle Sapna P. Patel Dexiang Gao Kimberly R. Jordan William A. Robinson Richard P. Tobin Martin D. McCarter Kasey L. Couts

Background/Objectives: Mucosal melanoma is a rare, aggressive melanoma subtype with lower response rates to immune checkpoint inhibitors than cutaneous melanoma. We previously identified reduced expression of innate immune pathogen-sensing pathway genes in mucosal melanoma, including components of the retinoic acid-inducible gene-I (RIG-I) pathway, and found that decitabine can induce re-expression of these immune genes and tumor-associated antigens. This study evaluated epigenetic immune priming with oral decitabine/cedazuridine (DEC-C) combined with nivolumab in patients with unresectable or metastatic mucosal melanoma. Methods: NCT05089370 was an open-label, single-center, single-arm phase Ib/II trial. Patients received DEC-C (35 mg decitabine/100 mg cedazuridine) orally for five days followed by nivolumab 480 mg every four weeks. The primary endpoint was safety and determination of the recommended phase II dose (RP2D). Secondary endpoints included objective response rate (ORR) and survival outcomes. Exploratory endpoints assessed immune and epigenetic correlates. Results: Eight patients were enrolled. Treatment-related adverse events occurred in seven patients (88%), with dose-limiting toxicities observed in three (38%). The RP2D was not established due to premature trial closure. At data cut-off, two patients remained on treatment with ongoing partial responses. The ORR was 25% (95% CI, 3.2–65), median progression-free survival was 3.0 months (95% CI, 2.1–not reached), and median overall survival was 7.2 months (95% CI, 4.4–not reached). Treatment significantly decreased global DNA methylation and induced RIG-I pathway genes in circulating immune cells. Conclusions: DEC-C plus nivolumab was associated with frequent treatment-related toxicities consistent with the known safety profiles of decitabine and nivolumab and demonstrated on-target epigenetic and immune activity in circulating cells. Although two partial responses were observed, the small sample size and wide confidence interval preclude conclusions regarding efficacy. These findings support future biomarker-integrated studies evaluating epigenetic immune-priming combinations in mucosal melanoma, with prospective optimization of dose, schedule, and treatment setting.

Cancers doi: 10.3390/cancers18193169

Authors: Jennifer A. Kalil René Adam Nicholas Meti Peter Metrakos

Background/Objectives: Most patients with colorectal liver metastases (CRLM) present with disease beyond upfront technical resectability. Advances in systemic therapy, surgical technique, and liver-directed therapies have expanded the proportion of patients who can achieve curative-intent treatment, yet substantial heterogeneity in practice persists. This review provides a structured synthesis of current management strategies for borderline resectable, initially unresectable, and never resectable CRLM. Methods: A structured literature search of PubMed/MEDLINE, Embase, Scopus and the Cochrane Library was performed to identify studies published between 2000 and 2026 using the eligibility criteria described in Part 1 of this review. Findings were synthesized narratively across systemic, surgical, and liver-directed treatment strategies. Results: Future liver remnant augmentation through regenerative procedures offers higher rates of conversion to resection in borderline cases. Conversion chemotherapy enables secondary resection in 12–35% of initially unresectable patients, with regimen selection guided by RAS/BRAF status, primary tumor sidedness, and performance status; however, most pivotal trials were designed for the broader metastatic colorectal cancer population, with conversion to resection rarely serving as the primary endpoint. For never resectable liver-only disease, liver transplantation demonstrates survival advantage in highly selected patients and iterative local therapy remains an area of active investigation. Across all settings, achieving complete local treatment remains the strongest determinant of long-term survival. Conclusions: Management of complex CRLM requires individualized, multidisciplinary decision-making with repeated reassessment of resectability throughout treatment. The evidence is constrained by heterogeneous resectability definitions, reliance on trials not designed for CRLM-specific endpoints, and limited data on several emerging strategies. Standardized eligibility frameworks and CRLM-specific trial designs are needed to advance the field.

Cancers doi: 10.3390/cancers18193170

Authors: Gökhan Rıza Baykal Müge Keskin Kübra Katipoğlu Ersin Gürkan Dumlu Didem Özdemir Oya Topaloğlu Reyhan Ersoy Bekir Çakır

Background/Objectives: Atypia of undetermined significance (AUS; Bethesda category III) remains a challenging thyroid cytological diagnosis because of its heterogeneous malignancy risk and limited preoperative certainty. Molecular testing can improve risk stratification but is not universally available. This study evaluated the diagnostic and incremental predictive value of preoperative complete blood count-derived systemic inflammatory indices in surgically treated Bethesda III thyroid nodules. Methods: This retrospective cohort included 352 patients who underwent thyroidectomy for Bethesda III thyroid nodules. Preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) were evaluated. Postoperative histopathology served as the reference standard. Receiver operating characteristic analysis and multivariable logistic regression were performed, followed by incremental model assessment, bootstrap internal validation, Hashimoto thyroiditis interaction analysis, and exploratory molecular subgroup analysis. Results: Among 352 patients, 197 (56.0%) had malignant histopathology. Malignant nodules showed higher NLR, PLR, SII, SIRI, and AISI and lower LMR. All six indices remained independently associated with malignancy after multivariable adjustment, with the strongest positive associations observed for SII (adjusted OR, 2.09; 95% CI, 1.60–2.72) and NLR (adjusted OR, 1.96; 95% CI, 1.51–2.54). SII demonstrated the numerically highest individual discrimination (AUC 0.687; 95% CI, 0.631–0.740), followed by NLR (AUC 0.661) and AISI (AUC 0.659); SII and NLR did not differ significantly (DeLong p = 0.182). Addition of SII increased the AUC of the clinico-ultrasonographic model from 0.695 to 0.761, with an optimism-corrected AUC of 0.721. Hashimoto thyroiditis did not significantly modify these associations. In the molecular subgroup, mutation status increased model discrimination from 0.765 to 0.824, whereas no statistically significant additional improvement with SII was detected in the exploratory molecular subgroup. Conclusions: Preoperative systemic inflammatory indices, particularly SII, provide modest but incremental predictive information beyond conventional clinical and ultrasonographic variables in surgically treated Bethesda III thyroid nodules. Their role appears complementary rather than diagnostic when used in isolation, particularly when comprehensive molecular testing is unavailable. Prospective external validation is required before clinical implementation.

Cancers doi: 10.3390/cancers18193171

Authors: Tadashi Higuchi Shinsuke Abe Satsuki Imaoka Taisei Aoki Yohei Nounaka Atsushi Tsukiyama Fumihiro Matano Shigeyuki Tahara Yasuo Murai

Background/Objectives: Accurate intraoperative identification of the tumor–brain interface is important in brain metastasis surgery, but visual assessment under white light is subjective. Narrow-band imaging (NBI) enhances hemoglobin-dependent optical contrast without an exogenous agent; whether its intraoperative appearance corresponds to tumor tissue, and whether it measurably increases tumor-to-normal image contrast, has not been established in this setting. Methods: In this retrospective, single-center, exploratory study, we evaluated 25 consecutive patients with brain metastases resected using a 4K three-dimensional exoscope equipped with NBI. In three selected patients, spatially adjacent specimens were separately sampled from grayish-appearing and whitish-appearing regions and assessed histopathologically in a non-blinded, descriptive manner. In all 25 patients, paired white-light and NBI images were retrospectively analyzed in Fiji/ImageJ using regions of interest drawn over tissue visually judged to be tumor or normal brain. Results: In the three patients with paired histology, grayish-appearing specimens contained metastatic tumor cells and whitish-appearing specimens did not; this observation derives from a small, selectively sampled subset and should be regarded as preliminary. Across all 25 patients, absolute tumor-to-normal gray-value contrast was significantly greater under NBI than white light (69.628 ± 45.338 vs. 44.287 ± 29.640; mean paired increase, 25.342; 95% CI, 9.169–41.514; p = 0.0035; Cohen’s dz = 0.647), although this increase was not observed in all patients. Conclusions: In this exploratory, non-blinded, retrospective study, NBI increased objective image contrast between visually identified tumor and normal brain relative to white light, and its grayish appearance corresponded to tumor tissue in a small histologically sampled subset. These findings support NBI as a feasible, agent-free adjunct that warrants prospective, blinded validation before its diagnostic accuracy or clinical benefit can be assessed.

Cancers doi: 10.3390/cancers18193167

Authors: Mariana Verdelho Machado

Worldwide, liver cancer is the seventh most common cancer and the third leading cause of cancer-related mortality, reflecting its dismal prognosis, with only approximately 20% of patients alive 5 years after diagnosis. At least 50% of patients ultimately require systemic treatment. In 2020, the systemic treatment landscape changed dramatically with the introduction of immune checkpoint inhibitor (ICI)-based therapies, which have demonstrated improved overall survival and longer preservation of quality of life compared with tyrosine kinase inhibitor (TKI)-based approaches. However, fewer than one third of patients achieve objective response, 10–25% experience severe immune-related adverse events, and ICI-based treatments represent a substantial economic burden for health systems. Importantly, robust and clinically validated predictive biomarkers of response to ICI remain an unmet need. This review summarizes current efforts to identify predictive biomarkers of ICI response in hepatocellular carcinoma (HCC), integrating clinical, pathological, molecular, microbiome, and imaging approaches, and discusses how these developments may shape the future of treatment selection.

Cancers doi: 10.3390/cancers18193168

Authors: Damian Kołat Julia Gałęziewska Paulina Buczek Lin-Yong Zhao Mateusz Kciuk Żaneta Kałuzińska-Kołat Małgorzata Kozłowska Agnieszka Śliwińska Renata Kontek Elżbieta Płuciennik

Background/Objectives: AP-2 transcription factors are increasingly recognized as key regulators in cancer biology. The TFAP2E gene, which encodes the AP-2ε transcription factor, remains understudied in cancer compared with other AP-2 family members. The scarcity of studies examining potential AP-2ε targets and related genes limits our understanding of its functional significance. Moreover, related studies have not incorporated a screening step to select the tumor type for justified molecular investigation. Through comparison of tumor–normal expression differences in a pan-cancer spectrum, this study prioritized ovarian serous carcinoma for downstream assessment. Methods: Expression patterns were evaluated using GENT2, GEPIA2, and TNMplot. After prioritizing ovarian serous carcinoma, TFAP2E and related signatures in TCGA-OV were analyzed using transcriptomic and clinical data from GDC and CDR, followed by comparison of findings with the GSE32062 cohort. The workflow included survival and clinicopathological analyses, outcome-independent limma-voom differential expression analysis and WGCNA, MCODE clustering, gene ontology, immune subtype and stemness assessment, PCA, CancerHallmarks enrichment, clinically adjusted Cox and competing-risk survival modeling, and HPA-derived immunostaining evaluation. Additional analyses assessed WGCNA parameter stability and preservation in GSE32062, an outcome-independent MAD-based variability screen, AP-2 family coexpression, and promoter motif enrichment. Results: TFAP2E was downregulated in ovarian cancer across the three queried resources, whereas higher expression was associated with favorable survival across multiple endpoints. Differential expression and WGCNA identified a TFAP2E-associated signature; its ontology indicated GPCR, stimulus responsiveness, and KRAS enrichment for the 933-gene module. The WGCNA pink module was stable across alternative settings, moderately preserved in GSE32062 (Zsummary = 7.86), and enriched in the outcome-independent MAD screening. GSE32062 supported concordant gene expression patterns and showed an association of TFAP2E with progression-free survival. Exploratory immune analyses showed a modestly increased proportion of C5 tumors in the higher-expression groups, whereas differences in stemness were statistically insignificant. The TFAP2E group associations with PFI and DSS in TCGA-OV and with PFS in GSE32062 remained significant after clinical adjustment; Fine-Gray sensitivity analyses gave consistent results for DSS. Immunohistochemistry provided protein-level characterization; eighteen entries differed between representative normal and tumor specimens, with lower tumor staining in fifteen. The seven-gene candidate set showed a clinically adjusted DSS association in TCGA-OV, which was not supported in the GSE32062 evaluation model. Conclusions: TFAP2E expression is associated with survival and a transcriptomic cross-cohort pattern in ovarian serous carcinoma. Covariate-adjusted and competing-risk analyses supported the association but did not establish clinical utility. The highlighted genes remain exploratory candidates for mechanistic investigation.

Cancers doi: 10.3390/cancers18193166

Authors: Jin-Ye Guan Zhuo Chen Wen-Shang Liu Jia-Long Xu Zhi-Yu Zhou Lina Song Dan Deng

Background/Objectives: Giant congenital melanocytic nevus (GCMN) is a rare developmental disorder arising from abnormal proliferation and differentiation of neural crest–derived melanocytes. It poses substantial clinical challenges due to cosmetic disfigurement, malignant potential, and the limited efficacy of current treatments. This study aimed to investigate the therapeutic effects and underlying molecular mechanisms of tunlametinib (HL-085), a novel selective MEK1/2 inhibitor, in GCMN. Methods: Primary GCMN cells and human GCMN explants were isolated, cultured, and validated to establish in vitro cellular and explant models. Following tunlametinib treatment, global transcriptional changes were analyzed using bulk RNA sequencing. Melanogenesis was assessed via Fontana–Masson staining, Western blotting, and immunofluorescence. Cell viability, apoptosis, and cell cycle distribution were evaluated using the CCK-8 assay, flow cytometry, TUNEL staining, and Western blotting for apoptosis- and cell cycle–related proteins. Results: Tunlametinib treatment significantly suppressed melanogenesis in GCMN cells and explant tissues at the phenotypic, histological, and protein levels, and reduced cell viability in a concentration-dependent manner. Transcriptomic analysis revealed marked alterations in gene expression profiles following treatment, with prominent changes in apoptosis- and cell cycle–related genes. Subsequent cellular assays and tissue staining confirmed that tunlametinib significantly increased early apoptosis and induced G1/S cell cycle arrest. Conclusions: Collectively, our findings demonstrate that tunlametinib inhibits proliferation and melanin production in GCMN cells by modulating the RAS-ERK pathway, providing a theoretical basis for its use as a targeted therapeutic strategy for GCMN.

Cancers doi: 10.3390/cancers18193165

Authors: Jennifer A. Kalil René Adam Nicholas Meti Peter Metrakos

Background/Objectives: Colorectal liver metastases (CRLMs) remain a major determinant of long-term outcome. Although hepatic resection offers the best chance of durable survival, the definition of resectability has evolved beyond technical feasibility alone. This review aims to provide a structured overview of contemporary management strategies for patients with upfront technically resectable or synchronous CRLM, with emphasis on patient selection, tumor biology, perioperative systemic therapy, margin strategy, and surgical sequencing. Methods: A structured literature search of PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library was performed to identify studies published between 2000 and 2026. Eligible studies evaluated surgical, liver-directed, or systemic treatment strategies for CRLMs and reported outcomes including overall survival, disease-free survival, recurrence, margin status, or perioperative morbidity. Given the heterogeneity of the available evidence, findings were synthesized narratively. Results: Contemporary management of CRLMs requires integration of patient fitness, technical resectability, and tumor biology. In upfront technically resectable disease, routine neoadjuvant chemotherapy has not consistently improved overall survival, whereas selected high-risk patients may benefit from short-course preoperative therapy. Margin strategy is increasingly biology-informed rather than based on a universal margin width. In synchronous disease, no single operative sequence is superior for all patients; treatment should be selected according to disease burden, operative complexity, and the need to preserve access to systemic therapy. Conclusions: Management of upfront resectable and synchronous CRLMs should be individualized through multidisciplinary assessment. Current evidence supports a risk-adapted strategy that integrates technical feasibility, patient factors, and tumor biology while recognizing persistent uncertainty regarding optimal chemotherapy timing and surgical sequencing.

Cancers doi: 10.3390/cancers18193164

Authors: Beata Pięta Karolina Gajewska Małgorzata Mikołajczyk Michalina Wiśniewska Alicja Rzymska Bartłomiej Burzyński Paweł Rzymski

Sarcopenia, low muscle mass, and low muscle radiodensity are increasingly being considered factors associated with treatment outcomes in patients with gynecological malignancies. Despite the growing body of evidence, body composition assessment is not routinely incorporated into clinical practice. The aim of this review was to present current evidence on the associations of muscle parameters with survival, complications, systemic treatment toxicity, and quality of life, as well as to discuss the opportunities and limitations of computed tomography (CT) and bioelectrical impedance analysis (BIA) in body composition monitoring. A narrative literature review was conducted using the PubMed, Scopus, and Web of Science databases, primarily covering publications from 2019 to 2026, together with earlier studies relevant to the topic. Systematic reviews, meta-analyses, and selected observational, longitudinal, and interventional studies were included. The available evidence indicates that low muscle mass and low muscle radiodensity are primarily associated with poorer overall survival and an increased risk of selected postoperative complications. Evidence regarding progression-free survival, disease recurrence, chemotherapy toxicity, and quality of life remains less consistent. Low muscle mass may occur independently of body weight and body mass index (BMI); therefore, routine anthropometric assessment may fail to identify adverse changes in body composition. CT image analysis enables quantitative assessment of muscle mass and evaluation of muscle radiodensity, whereas BIA may serve as a complementary tool for repeated body composition monitoring. However, its use is limited by the effects of hydration status, edema, and ascites, as well as by the lack of validated cut-off values for patients with gynecological malignancies. Body composition assessment should be interpreted in conjunction with evaluations of muscle strength, physical performance, nutritional status, treatment toxicity, and quality of life. Prospective studies are needed to determine whether body composition monitoring and the implementation of targeted supportive care improve treatment tolerance and clinical outcomes.

Cancers doi: 10.3390/cancers18193163

Authors: Marcel A. Kamp Martina Kern Nazife Dinc Birgitt van Oorschot Lukas Radbruch Christiane von Saß

Background: Randomised trials indicate that early integration of specialised palliative care improves quality of life and, in some studies, survival in advanced cancer, yet its implementation in inpatient oncology remains inconsistent. This study quantifies the coded utilisation of specialised inpatient palliative care in German hospitals and interprets adoption patterns using the diffusion of innovations theory. Methods: We conducted a cross-sectional analysis of nationwide hospital cases reimbursed under the German diagnosis-related groups (DRG) system in 2023. The analysis included the most common solid malignancies and assessed the utilisation of specialised inpatient palliative care overall and stratified by metastatic status, tumour entity, comorbidities, and treating medical specialties. Results: Specialised inpatient palliative care was provided in 5.4% of hospital cases involving the most common malignant tumours. Among patients with organ metastases, utilisation increased to a median rate of 15.0% of hospital cases, with the highest rates observed in cases with brain (17.8%), bone (17.0%), and pleural metastases (16.1%). Palliative care involvement correlated positively with in-hospital mortality. Interpreted cautiously through the diffusion of innovations theory, which frames the 15 to 20% band as a heuristic landmark rather than a validated threshold, utilisation even in the metastatic subgroup reaches only the lower edge of this band, indicating that uptake remains confined to innovators and early adopters and has not extended to the early majority. Conclusions: Specialised inpatient palliative care remains underutilised in German oncology, reaching 5.4% of all cases and a median of 15.0% even in metastatic disease. Interpreted cautiously through the diffusion of innovations theory, which frames the 15 to 20% band as a heuristic landmark, uptake appears confined to early adopters and has not yet reached the early majority.

Cancers doi: 10.3390/cancers18193162

Authors: Wenfang Liu Maryam Tahir Anil V. Parwani Qingqing Ding Zaibo Li

SOX17 is a developmental transcription factor that regulates endoderm formation, vascular development, germ cell specification, and tissue differentiation. Recent studies have identified SOX17 as a highly informative immunohistochemical marker and lineage-associated regulator in gynecologic pathology. This review summarizes the physiological functions of SOX17, its expression in normal and neoplastic tissues, and its expanding diagnostic and translational applications. SOX17 demonstrates high sensitivity for most ovarian and endometrial epithelial carcinomas while exhibiting substantially greater specificity than PAX8 because it is consistently absent in the vast majority of renal, thyroid, breast, pulmonary, gastrointestinal, and other nongynecologic carcinomas. These characteristics make SOX17 particularly valuable for supporting Müllerian origin in metastatic tumors and cytology specimens. Emerging evidence also supports its utility in diagnostically challenging settings, including mesonephric-like adenocarcinoma, seminomatous germ cell tumors, yolk sac tumors, angiosarcoma, and selected mesothelial proliferations, where awareness of potential diagnostic pitfalls is essential. Beyond its diagnostic role, SOX17 functions in a context-dependent manner, acting either as a tumor suppressor or as a lineage-survival transcription factor through interactions with signaling pathways such as Wnt/β-catenin and the PAX8 transcriptional network. These biological insights underscore its role in lineage maintenance, angiogenesis, and tumor progression and suggest potential therapeutic relevance. Collectively, current evidence establishes SOX17 as a lineage biomarker with both diagnostic and biologic relevance.

Cancers doi: 10.3390/cancers18193161

Authors: Cuthbert Mario Mahenge Rand Talal Akasheh Xuan V. Nguyen Ting-Yuan David Cheng

Background/Objectives: Prognoses for patients with clear cell renal cell carcinoma (ccRCC) are associated with complex interactions between tumor and patient characteristics. This cross-sectional study investigated associations between body composition and tumor proteomics and their interaction with survival among patients with ccRCC. Methods: Data from 178 patients in the TCGA-KIRC project were analyzed to assess adipose and skeletal muscle tissue areas at the third lumbar vertebra of diagnostic computed tomography scan images. Patients were classified into four body composition types: high muscle with low adiposity; high muscle with high adiposity; low muscle with low adiposity; and low muscle with high adiposity. Proteins with differential expression (p < 0.05) were screened for interactions with body composition type on survival. Linear regression was used to assess associations, and Cox regression models—adjusted for age, tumor stage, sex, race, and ethnicity—were utilized for survival analysis. Results: Patients with low muscle with low adiposity exhibited worse survival than those having high muscle with high adiposity (hazard ratio, 3.74 [95% CI, 1.69–8.27]). Low muscle with low adiposity was also associated with increased expression of P-cadherin and decreased expression of DIRAS3 (p < 0.05; false discovery rate–corrected p < 0.1), both associated with poor survival in the entire TCGA-KIRC cohort. Among patients having low muscle with high adiposity, high (vs. low) PREX1 expression was associated with 15.8-fold (95% CI, 3.08–80.78) increased mortality. Conclusions: Body composition is associated with differential protein expressions and survival in ccRCC. Therefore, body composition and its associated tumor proteomics may serve as prognostic biomarkers and therapeutic targets in ccRCC.

Cancers doi: 10.3390/cancers18193160

Authors: Maria A. Sukhanova Zakhar A. Akulov Zelimkhan G. M. Berikkhanov Alexey L. Shestakov Aleksey G. Kotelnikov Andrey M. Nikolaev Vadim S. Razumovsky Evgeniy A. Tarabrin Milena Yu. Ivanova Mehrshad Ebrahimnezhad Sergey Yu. Muraviev

Colorectal cancer (CRC) is traditionally viewed as the result of the sequential accumulation of molecular alterations and the clonal expansion of transformed cells. However, the state of morphologically non-neoplastic mucosa preceding the development of neoplasia remains considerably less well characterized. This narrative review aims to integrate evidence on biliary and lipid metabolism, intestinal transit, microbial metabolism, and field cancerization and to formulate a testable model of early metabolic remodeling in the distal colon. We propose that a chronically altered biliary–metabolic environment, combined with prolonged luminal and mucosa-associated exposure, may promote lipid–metabolic remodeling of morphologically non-neoplastic mucosa. This state is considered not as a new disease entity but as a potential tissue phenotype capable of altering the barrier, metabolic, and regenerative properties of the epithelium. Subsequent exposure to nitrogen-containing products of microbial metabolism may sustain repeated cycles of injury and regeneration, thereby creating conditions for clonal selection. Following the emergence of a neoplastic clone, the same local environment may potentially assume a different biological role and become part of a metabolic niche that supports further clonal expansion. The proposed model extends the concept of field cancerization by incorporating a metabolic dimension and generates a series of spatial and temporal predictions amenable to experimental and prospective clinical testing. Validation of this model may provide a basis for investigating morphologically non-neoplastic mucosa as potential tissue at risk and for developing earlier preventive and diagnostic approaches.

Cancers doi: 10.3390/cancers18193159

Authors: Saman Zeeshan Caila McVey Shafaq Majeed Zeeshan Ahmed Mark Nichols

Background: Small-cell lung cancer (SCLC) is a rare but highly aggressive malignancy defined by rapid progression, early metastasis, and profound therapeutic resistance. Its extensive heterogeneity across genomic, transcriptomic, epigenetic, proteomic, and microenvironmental levels continues to undermine precision medicine. Emerging evidence highlights the complex role of epidermal growth factor receptor (EGFR) alterations, histologic transformation from EGFR-mutant non-small cell lung cancer (NSCLC) to SCLC, and the influence of distinct transcriptional subtypes on clinical behavior. Methods: This review synthesizes current literature encompassing nucleic-acid-based determinants of resistance, SCLC molecular architecture, transformation biology, and subtype evolution, integrating findings from genomic, transcriptomic, epigenetic, proteomic, imaging, and clinical studies. We additionally evaluated artificial intelligence (AI) and machine learning (ML) methodologies with potential to unify multi-omics, radiomics, and clinical variables to model subtype plasticity, clonal evolution, and therapy-induced rewiring. Results: The evidence demonstrates that traditional single-layer analyses are insufficient to capture the multiscale architecture of SCLC biology or the nonlinear interactions driving resistance, whereas AI-enabled multi-omics approaches offer advantages in enhancing subtype classification, supporting early detection, and improving prediction of therapeutic response. Key barriers such as tissue scarcity, limited biomarker availability, and extreme intratumoral heterogeneity remain significant challenges, though increasingly addressable through integrative computational frameworks. Conclusion: AI-driven systems-level integration reframes SCLC as a dynamically evolving, multilayered disease process, where nucleic-acid alterations are central to subtype evolution and treatment resistance, providing a conceptual model to guide biomarker discovery and therapeutic development. By leveraging AI-enabled multi-omics and radiomics, this framework has the potential to advance personalized clinical management and overcome longstanding diagnostic and therapeutic challenges in SCLC.

Cancers doi: 10.3390/cancers18193158

Authors: Katia Beider Olga Ostrovsky Arnon Nagler

Multiple myeloma (MM) is increasingly understood as a spatially organized and dynamically evolving disease, in which malignant plasma-cell behavior is shaped by local immune, stromal, vascular, and metabolic contexts. Single-cell, spatial, and multi-omic technologies have resolved tumor-cell heterogeneity, bone marrow niche remodeling, immune dysfunction, and therapy-induced selection at unprecedented resolution, yet an integrated synthesis linking marrow architecture, extramedullary dissemination, circulating tumor cells, metabolic reprogramming, chimeric antigen receptor T (CAR-T) cell and T-cell-redirecting immunotherapy, and stem-cell transplantation remains lacking. Here, we review how malignant subclones occupy distinct marrow regions, focal lesions, and extramedullary sites with different transcriptional, antigenic, immune-interactive, and metabolic states. We discuss how spatial transcriptomics and multiplexed imaging reveal immune exclusion, stromal support, oxidative and glycolytic niches, and region-specific antigen heterogeneity. We further examine how circulating tumor cells serve as liquid readouts of tumor burden, high-risk genomics, and clonal evolution. Emphasis is placed on CAR T-cell and T-cell engager therapies, where response and resistance depend on antigen retention, effector-cell fitness, clonal T-cell expansion, myeloid suppression, and spatial accessibility. Finally, we consider autologous hematopoietic stem-cell transplantation as a clinical model of cytoreduction, lymphodepletion, and incomplete immune reconstitution. We propose that MM progression and relapse should be interpreted through an integrated spatial-temporal framework, in which therapeutic outcome reflects the interaction between malignant plasma-cell plasticity, immune competence, stromal persistence, metabolic adaptation, and residual disease localization.

Cancers doi: 10.3390/cancers18193157

Authors: Dan M. Visarion Ioana Petrescu Viorel M. Pruna Radu M. Gorgan

Background: Brain metastases are the most common malignant intracranial tumors and remain associated with poor survival despite advances in multimodal treatment. This study aimed to evaluate the associations between clinical, radiological, surgical, and perioperative characteristics and outcomes in patients undergoing surgical resection of brain metastases. Materials and Methods: This retrospective single-center cohort study included 378 consecutive adult patients who underwent resection of histopathologically confirmed brain metastases between 2015 and 2023. Overall survival was estimated using the Kaplan–Meier method, and differences between groups were assessed using the log-rank test. Factors associated with overall survival were evaluated using univariable and multivariable Cox proportional hazards regression. Binary logistic regression was used to evaluate factors associated with 30-day mortality. Results: Median overall survival was 11.3 months, the one-year survival rate was 45.5%, and 18 patients (4.8%) died within 30 days after surgery. In the adjusted logistic regression model, preoperative KPS < 80, hydrocephalus, postoperative hematoma, and postoperative pneumonia were associated with higher odds of 30-day mortality. In the multivariable Cox regression analysis, increasing age, preoperative KPS < 80, tumor volume ≥ 9 cm3, hydrocephalus, wound complications, and postoperative KPS deterioration were independently associated with shorter overall survival. Subtotal versus total resection was not significantly associated with overall survival after adjustment. Conclusions: Several preoperative and postoperative characteristics were associated with early mortality and overall survival in this surgically selected cohort. These findings emphasize the importance of careful patient selection, preservation of functional status, optimization of perioperative care, and prevention of postoperative complications.

Cancers doi: 10.3390/cancers18193156

Authors: Na Qian Songyao Sun Cong Ouyang Wenlong Xie Shuhui Chen Huizheng Xie Songyu Li Xinyu Wang Yumeng Wang Zihua Li Lili Wang Kuaiying Wu Jiajun Cui

Background/Objectives: Our previous study identified ZBTB1 as a novel tumor suppressor in estrogen receptor-positive (ER+) breast cancer. Moreover, The Cancer Genome Atlas (TCGA) data analysis showed a much lower level of ZBTB1 in triple-negative breast cancer than in ER+ breast cancer. Triple negative breast cancer (TNBC) lacks effective targeted therapies and largely depends on chemotherapy, while chemotherapy resistance remains a major clinical challenge. This study aimed to explore the role of ZBTB1 in TNBC progression and chemotherapy resistance. Methods: We performed clinical survival analysis, in vitro and in vivo functional experiments, mass spectrometry screening, and mechanistic validation in TNBC and Adriamycin-resistant TNBC cells. Results: We found that ZBTB1 protein is downregulated in TNBC and this downregulation correlates with shorter patient survival. ZBTB1 regulates glycolysis and chemotherapy resistance in TNBC cells. Mechanistically, ZBTB1 interacts with c-Myc and suppresses its transcriptional activity in MDA-MB-231 and MDA-MB-453 but not in Adriamycin-resistant cells (MDA-MB-231/ADR and MDA-MB-453/ADR). LncRNA SAP30L-AS1 is required for maintaining the ZBTB1–c-Myc interaction in TNBC cells. SAP30L-AS1 is significantly depleted in Adriamycin-resistant cells, which disrupts the binding between ZBTB1 and c-Myc. Functional validation revealed that SAP30L-AS1 modulates glycolysis and chemotherapy resistance in TNBC cells in a ZBTB1-dependent manner. Conclusions: Collectively, our data indicate the key role of ZBTB1 in TNBC and ZBTB1 may serve as a novel approach for TNBC treatments.

Cancers doi: 10.3390/cancers18193155

Authors: Maro Ohanian Fieke W. Hoff Vikas Kundra Dimitrios P. Kontoyiannis Graciela N. Nogueras-Gonzalez Javier Adachi Dawid Schellingerhout Samuel Shelburne Sherry Pierce Saadia A. Faiz Yesid Alvarado Tapan Kadia Koji Sasaki

Background: Compared to chest X-ray, computed tomography (CT) imaging of the chest is more sensitive and specific for identifying pulmonary abnormalities. However, patients with acute leukemia routinely undergo chest X-ray before beginning chemotherapy, and the benefit of obtaining baseline chest CT remains unclear. Methods: In this retrospective study, 50 patients with newly diagnosed acute leukemia who underwent chest X-ray and chest CT without contrast before beginning induction chemotherapy were included. CT imaging reports were independently evaluated by two hematologist–oncologists for infection concern and actionability, and these assessments were compared to the actions taken by the treating physicians. Results: Regardless of the presence of chest X-ray abnormalities, chest CT identified abnormalities in 94% of patients (47/50), a significantly higher detection rate than that for chest X-ray, which demonstrated abnormalities in only 66% of patients (33/50) (p < 0.001). Of the 17 patients with normal chest X-ray findings, 14 (82%) had abnormal chest CT findings. Of these 14 patients, 10 had actionable abnormalities, and four had non-clinically significant findings. All 33 patients with abnormal chest X-ray findings also had abnormal chest CT findings, and three patients with normal chest X-ray findings also had normal chest CT findings. Of the 30 patients with normal or minimal chest X-ray findings compared to chest CT findings, 26 patients (87%) had chest CT findings that were actionable, prompting more aggressive care and/or closer monitoring. On multivariate analysis, patients with both abnormal chest X-ray and chest CT findings had worse overall survival than patients without both abnormal chest X-ray and chest CT findings (p = 0.005). Conclusions: These findings highlight a diagnostic gap, potentially supporting prospective studies on routine chest CT imaging for patients with newly diagnosed acute leukemia.

Cancers doi: 10.3390/cancers18193153

Authors: Adrianna Romanowicz Marta Łukaszewicz-Zając Agnieszka Kulczyńska-Przybik Kamil Safiejko Marcin Juchimiuk Barbara Mroczko

Introduction: Epidemiological trends indicate that the global colorectal cancer (CRC) mortality will surpass 2.2 million deaths annually by the year 2050; therefore, the identification of novel circulating indicators that may support CRC diagnosis remains an important area of research. Objectives: The diagnostic relevance of circulating chemokines in CRC remains insufficiently understood. This study aimed to evaluate the diagnostic potential of selected serum C-X-C motif chemokines, CXCL13, CXCL14, and CXCL16, and to compare their diagnostic utility with CEA. Patients and Methods: This study included 62 individuals: 42 patients with CRC and 20 healthy volunteers. Serum chemokines levels were measured using a multiplex bead-based immunoassay (Luminex), and CEA levels via chemiluminescent microparticle immunoassay (CMIA). Results: Significant differences between patients with CRC and healthy controls were observed for serum CXCL13 concentrations. Spearman’s analysis revealed a significant negative correlation between CXCL13 and CXCL14. CXCL14 showed the highest diagnostic sensitivity among the chemokines, similar to CEA, while combining CXCL13 or CXCL14 with CEA further increased sensitivity. CXCL13 showed the highest positive predictive value (PPV) among all tested proteins, while its negative predictive value (NPV) and diagnostic accuracy (ACC) exceeded those of CXCL14 and CXCL16. CXCL13 demonstrated the highest AUC among the investigated chemokines and remained independently associated with CRC status in multivariable analysis. CXCL13 combined with CEA yielded the numerically highest overall AUC, although the improvement over CEA alone was not statistically significant. Conclusions: CXCL13 serves as a valuable complementary biomarker, providing crucial additive insights that might augment diagnostic frameworks of patients with CRC. These findings support further evaluation of chemokines as potential adjuncts to established diagnostic biomarkers in larger, independent screening-like study cohorts.