Search Results (586)

Background/Objectives: Glioblastoma surveillance after surgery and chemoradiation remains challenging because MRI findings of tumor recurrence can overlap with pseudo-progression, treatment-related effects, and postoperative tissue changes. Methods: We developed a seven-channel postoperative MRI framework using a deep learning transfer method to support non-invasive glioblastoma treatment-effect assessment. The model used T1 contrast-enhanced, FLAIR, T1, RSI-Cell, ADC, T2, and cerebral blood flow volumes from 124 postoperative glioblastoma patients (164 MRI timepoints) as input. Images were processed using a 3D ResNet18 encoder pretrained on 588 postoperative glioma samples and fine-tuned using task-specific classification heads. The cohort comprised 124 patients contributing 164 postoperative MRI timepoints, all acquired at 3T on scanners from a single vendor. Performance was evaluated with nested five-fold cross-validation stratified and assigned at the patient level, so that all timepoints from a given patient fell in one-fold and the training epoch was selected on an inner split rather than on the fold being reported. Because some of the clinical labels were incomplete, the number of evaluable timepoints differed by task (recurrence versus pseudo-progression, 164; MGMT, 99; short-term survival, 139). The whole procedure was repeated under three independent random seeds and results are reported as the mean and standard deviation across seeds. Results: The strongest clinical endpoint was recurrence versus pseudo-progression, where nested cross-validation across three random seeds gave a pooled out-of-fold AUC of 0.935 (SD = 0.014), area under the precision-recall curve of 0.973, balanced accuracy of 0.880, sensitivity of 0.917, and specificity of 0.843. No other endpoint reached reliable discrimination. Radiation decision reached an AUC of 0.658 (SD = 0.039), while MGMT promoter methylation (AUC = 0.532, SD = 0.082) and short-term survival (AUC = 0.514, SD = 0.027) were indistinguishable from chance. Conclusions: In this single-center proof-of-concept study, postoperative MRI successfully distinguished tumor recurrence from pseudo-progression. However, the models did not reliably predict the other three outcomes related to molecular status, treatment planning, and prognosis. Overall, the model learned imaging features specifically associated with recurrence, rather than a more general representation of the tumor that can predict many different clinical outcomes. These findings support technical feasibility for a single endpoint rather than clinical readiness, for which external multi-center validation is required. Full article

Lymphedema is usually approached as a survivorship complication; yet, many of the injuries that produce lymphatic failure begin during cancer treatment planning. Regional nodal irradiation, chemoradiation, lymph-node surgery, systemic therapy, obesity, infection history, and baseline lymphatic reserve can converge to produce chronic swelling, fibrosis, cellulitis risk, functional limitation, and an impaired quality of life. Despite this, lymphatic drainage pathways are rarely contoured, constrained, or prospectively monitored as organs at risk in radiotherapy practice. This commentary argues that the lymphatic system should enter radiotherapy-planning discussions as a candidate toxicity structure, while cautioning against premature universal dose constraints. Evidence signals are clinically meaningful but not yet protocol-defining: in the MA.20 breast cancer trial, regional nodal irradiation increased lymphedema from 4.5% to 8.4%; in nasopharyngeal carcinoma, mean doses of approximately 58.7 Gy to level IV and 58.6 Gy to levels I–VII were proposed as thresholds associated with moderate/severe facial lymphedema; and gynecological cancer studies report wide lower-limb lymphedema incidence ranges, with radiotherapy, lymphadenectomy, number of nodes removed, and body mass index repeatedly implicated as risk factors. The immediate priority is not mandatory lymphatic sparing, but lymphatic-aware planning: a baseline risk assessment, reproducible candidate contours, dose–volume reporting, selective sparing where oncologically safe, and prospective toxicity monitoring. The author proposed a framework to reflect this argument. Making lymphatic toxicity visible, measurable, and modelled may help shift lymphedema from an accepted late effect to a potentially preventable planning endpoint. Full article

Background: Organized cervical cancer screening aims to reduce the burden of advanced disease through earlier detection. However, a substantial proportion of women continue to present with locally advanced cervical cancer (LACC) requiring definitive chemoradiation. This study evaluated temporal changes in the demographic and clinicopathological characteristics of women with LACC treated with definitive chemoradiation before and after implementation of the organized cervical cancer screening program in Serbia. Methods: This retrospective single-center cohort study included 200 consecutive women with histologically confirmed LACC treated with definitive chemoradiation at the Institute of Oncology and Radiology of Serbia. Two cohorts were analyzed: a pre-screening cohort (2010–2011, n = 100) and a post-screening cohort (2022–2023, n = 100). Demographic and clinicopathological characteristics, including age, histopathology, FIGO stage, lymph node involvement, and geographic distribution, were compared. For study purposes, all patients were retrospectively restaged according to the FIGO 2018 classification using the best available clinical, radiological, and pathological data. Results: Women in the post-screening cohort were significantly older at diagnosis than those in the pre-screening cohort (mean age 54.9 vs. 49.7 years, p = 0.0046), with a substantially higher proportion of patients older than 64 years (28% vs. 2%, p < 0.0001). Although the overall distribution of FIGO stages II–IV did not differ significantly, a marked redistribution of FIGO 2018 substages was observed (p < 0.0001), characterized by an increased proportion of stage IIIC disease and significantly more frequent lymph node involvement (63% vs. 41%, p = 0.0018). Geographic distribution remained stable, with most patients referred from the Belgrade administrative district. Conclusions: This study demonstrated clinically relevant temporal changes in the demographic and clinicopathological characteristics of women requiring definitive chemoradiation for LACC in Serbia. More than a decade after implementation of organized cervical cancer screening, tertiary referral centers continue to manage a substantial burden of patients with locally advanced disease requiring complex, resource-intensive treatment. These findings should not be interpreted as a direct evaluation of the national screening program but may provide valuable insights for healthcare planning in Serbia and other countries with similarly resource-constrained healthcare systems. Strengthening participation in organized screening, ensuring timely diagnostic evaluation, and improving HPV vaccination uptake remain essential to reduce the burden of advanced cervical cancer. Full article

Background: Locally advanced rectal cancer (LARC) treatment has shifted from the utilization of neoadjuvant chemoradiation (NACRT), followed by total mesorectal excision (TME) and adjuvant chemotherapy (AC) to the implementation of total neoadjuvant therapy (TNT). This transition was influenced by data from multiple studies reporting suboptimal compliance rates to adjuvant chemotherapy. As a result, a paradigm shift to TNT occurred, consisting of chemoradiation with chemotherapy, based on the RAPIDO and PRODIGE-23 studies. Methods: Following IRB approval, a single-institution retrospective chart review was conducted at a tertiary care academic institution for patients with LARC. Demographic, clinical, and treatment data were collected using REDCap. Patients were excluded if under 18 years of age, pregnant, or had stage 1 or metastatic rectal cancer. The primary objective was to evaluate TNT adherence; secondary objectives assessed adherence associations with demographic and clinical variables. Results: Two hundred twenty-nine patients with rectal cancer were initially included in the database, including 153 patients with LARC from 2019 to 2024. One hundred twenty-seven patients underwent TNT with an adherence rate of 87.5%. Statistically significant variables that contributed to adherence include male gender (p = 0.04) and non-use of recreational drugs (p = 0.04). Conclusions: This is the first real-world study assessing TNT adherence. The observed 87.5% adherence rate represents a significant improvement over historical data in which patients were treated with NACRT/TME/AC. Statistically significant variables that contributed to TNT adherence included male gender and non-use of recreational drugs. These factors may provide insight into gender differences and behavioral patterns that put patients in an at-risk category for non-adherence. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies despite advances in surgical techniques and systemic therapy. Although surgical resection offers the only potential for cure, recurrence is common, underscoring the critical role of multimodal treatment. Over the past two decades, numerous clinical trials have cemented adjuvant chemotherapy as a cornerstone of multimodal management in resected PDAC, with progressive evolution from single-agent regimens to modern multiagent regimens. In contrast, the role of chemoradiation remains debated, with the body of evidence demonstrating conflicting results. Ongoing clinical trials are expected to elucidate optimal treatment modalities. Emerging targeted therapies, biomarker-directed treatment approaches, and immunotherapeutic strategies also hold promise for improving outcomes in select patient populations. This narrative review summarizes the landmark trials that have shaped adjuvant therapy, examines the evolution of adjuvant treatment over time, reviews current management guidelines, and highlights promising emerging therapeutic directions likely to influence the management of localized pancreatic cancer. Full article

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

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

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

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited therapeutic options in advanced and recurrent diseases. Advanced PSCC is typically managed with multimodal therapy, including neoadjuvant chemotherapy or chemoradiation followed by surgery; however, durable responses remain uncommon, and outcomes after recurrence are poor. Cancer vaccines represent a promising immunotherapeutic strategy, as these treatments induce tumor-specific immunity and heightened immune surveillance against penile cancer cells. While therapeutic cancer vaccines have not yet demonstrated consistent clinical efficacy as monotherapy in PSCC, their integration with complementary immune-modulating approaches, particularly immune checkpoint blockade, represents a rational strategy to enhance antitumor immunity. This review summarizes the rationale for vaccine development in PSCC, with emphasis on HPV-derived antigens, neoantigens, and emerging tumor-associated targets. We examine major vaccine platforms, including viral-vector, peptide-based, nucleic acid, and dendritic cell-based approaches. We also discuss how spatial transcriptomics, single-cell RNA sequencing, artificial intelligence-assisted antigen prediction, and nanotechnology-enhanced delivery systems may support future personalized vaccine development. Overall, therapeutic vaccines remain investigational in PSCC but may become relevant within biomarker-driven, combination-based immunotherapy strategies. Full article

Glioblastoma (GBM) remains the most lethal primary brain tumor in adults, with a median overall survival of approximately 15–20 months despite multimodal treatment including surgery, chemoradiation, and Tumor Treating Fields (TTFields). While the survival benefit of TTFields was established by the EF-14 phase III trial, their biological effects extend well beyond the canonical anti-mitotic mechanism and encompass extensive interactions with the GBM tumor microenvironment (TME). This review provides an integrated mechanistic analysis of TTFields–TME interactions in GBM, with a distinctive focus on their convergence with radiotherapy. We examine how TTFields activate innate immune sensing through cGAS/STING and AIM2 inflammasome pathways, drive immunogenic cell death, reprogram tumor-associated macrophages, and prime adaptive T cell responses. We further address TTFields effects on glioma stem cells, blood–brain barrier permeability, and intracellular signaling governing invasion, angiogenesis, and autophagy. Critically, we develop the mechanistic and clinical case for TTFields-radiotherapy combinations, highlighting convergent mechanisms of DNA repair impairment, mitotic catastrophe, and innate immune activation. Practical considerations for concurrent clinical implementation are discussed alongside a research agenda centered on optimal timing, hypofractionation, and predictive biomarkers. Available evidence—largely preclinical—suggests that TTFields may act as a TME-remodeling platform whose potential is most likely to be realized through mechanistically informed combinations. Full article

Background: Para-aortic lymph node involvement is present in approximately 17–24% of women with locally advanced cervical cancer (LACC) and is one of the strongest adverse prognostic factors in this population. Current international guidelines recommend two alternative staging techniques: the International Federation of Gynecology and Obstetrics (FIGO) and European Society of Gynecologic Oncology (ESGO) endorse imaging-based staging as the primary method to define radiation fields, whereas the National Comprehensive Cancer Network (NCCN) lists pre-treatment minimally invasive para-aortic lymphadenectomy as a Category 2B recommendation. Objective: We aimed to review and critically appraise the available evidence on the oncologic impact (progression-free and overall survival) of pre-treatment surgical para-aortic staging compared with clinical imaging-based staging in women with LACC. Methods: We searched MEDLINE (Ovid), Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Scopus from inception to January 2026, complemented by manually searching the reference lists for relevant articles and prior reviews. The review focused on comparative studies of women with LACC of squamous, adenocarcinoma, or adenosquamous histology—operationally defined as FIGO 2009 stages IB2–IVA with pelvic nodal involvement or FIGO 2018 stages IB3–IVA who received definitive-intent radiotherapy with or without concurrent chemotherapy and brachytherapy, and for whom comparative survival outcomes between a surgical-staging arm and an imaging-staging arm were reported. For this manuscript, a narrative review style was planned and reported in line with SANRA (Scale for the Assessment of Narrative Review Articles) quality criteria. Results: Twelve studies were included: two randomized controlled trials and ten observational studies (nine retrospective cohorts and one population-based analysis). Surgical staging consistently increased detection of occult para-aortic disease and led to more frequent use of extended-field radiotherapy (18–44%), but it did not yield a reproducible advantage in terms of progression-free or overall survival over imaging-guided chemoradiation. Conclusions: In LACC, pre-treatment surgical para-aortic staging improves anatomic and prognostic information but has not shown a consistent survival advantage over imaging-based staging combined with contemporary chemoradiation. Current comparative evidence does not support routine surgical staging, and its use still warrants further prospective evaluation in large clinical trials. Until results from ongoing phase III trials are available, surgical staging should be considered an individualized option in highly selected cases within multidisciplinary decision-making at experienced clinical centers. Full article

Gliomas remain among the most treatment-resistant malignancies of the central nervous system. Glioblastoma (GBM), the most aggressive adult-type diffuse glioma, is associated with persistently poor survival despite maximal safe resection followed by chemoradiation. Gliomas do not grow in isolation. Work over the past twenty years has dismantled the older tumor-centric view of glioma biology, replacing it with a model in which malignant cells operate within a tumor microenvironment (TME) composed of immune, vascular, stromal, and neural elements that together govern disease behavior. What makes the glioma TME so difficult to treat is not just its composition of immune cells, vasculature, stroma, and neurons, but the fact that these elements are arranged unevenly across the tumor. Different regions harbor different cellular mixtures and signaling environments, and, as a result, different vulnerabilities to therapy. Cytoreduction has not lost its importance, far from it. However, the same surgical window now also serves a different purpose; it lets the surgeon see which tissue is biologically dangerous rather than just visually abnormal, locate the true edge of infiltration, and get therapeutics past a blood–brain barrier (BBB) that has historically locked them out of the brain. This review examines two technology domains, including: (1) optical theranostics (5-aminolevulinic acid fluorescence-guided surgery, fluorescein-guided visualization, Raman spectroscopy, and stimulated Raman histology); and (2) blood–brain barrier disrupting technologies. The direction they collectively point toward is a version of glioma surgery that is guided less by anatomy and more by the biology of the tumor itself. Full article

Glioblastoma multiforme (GBM) remains the most aggressive and therapeutically intractable primary brain tumor, with many patients experiencing rapid relapse despite maximal surgical resection followed by standard chemoradiation. This persistent failure reflects the convergence of profound tumor-intrinsic genetic heterogeneity and a highly dynamic, spatially structured, and immunosuppressive tumor microenvironment (TME). Together, these forces create strong selective pressures that fuel tumor evolution, intratumoral diversity, phenotype plasticity, diffuse invasion, and robust resistance to therapy. The TME of GBM is orchestrated through a complex interplay between diverse cellular constituents, including tumor-associated macrophages, reactive astrocytes, endothelial cells, pericytes, and GBM stem cells, and non-cellular components such as extracellular matrix remodeling, hypoxia, metabolic and nutrient gradients, and spatially patterned cytokine and chemokine signaling networks. Additionally, heterogeneity in blood–brain barrier (BBB) and blood–tumor barrier (BTB) complicates drug delivery and immune surveillance, reinforcing therapeutic resistance and regional tumor adaptation. Conventional two-dimensional cell cultures and animal models fail to sufficiently capture these multiscale, patient-specific interactions, limiting their translational predictive power. In this narrative review, we synthesize recent advances in GBM organoid technologies as physiologically relevant, three-dimensional platforms that more faithfully recapitulate TME for driving tumor evolution and treatment resistance. We compare complementary organoid strategies, including patient-derived GBM organoids that preserve native cytoarchitecture, cerebral organoid co-culture systems that reconstruct tumor–brain interactions, and advanced platforms incorporating immune and vascular features such as air–liquid interface cultures, microglia-enriched systems, and BBB/BTB-integrated models. Finally, we highlight emerging innovations such as spatial transcriptomics, organoid-on-a-chip systems, live imaging coupled with lineage tracing, genome engineering, and artificial intelligence integration that collectively position GBM organoids at the forefront of precision neuro-oncology, reproducing TME, enabling dynamic mapping of tumor evolution, and accelerating patient-specific therapeutic discovery. Full article

Trimodality therapy (TMT)—maximal transurethral resection of bladder tumor (TURBT) followed by concurrent chemoradiotherapy—can offer oncologic outcomes comparable to radical cystectomy (RC) in carefully selected muscle-invasive bladder cancer (MIBC) patients while preserving the bladder and, possibly, the quality of life. Systematic reviews and long-term series support durable bladder-intact survival in responders, yet there is still a significant percentage of patients who exhibit incomplete response or invasive intravesical recurrence requiring salvage RC. This review covers computational genomics, transcriptomics, immune contexture, radiogenomics, and digital pathology approaches for predicting response in order to avoid preventable TMT failures. We discuss clinically relevant endpoints (complete response, invasive recurrence, bladder-intact survival, and salvage RC), patient selection (carcinoma in situ, hydronephrosis, debulking feasibility, and histology), and DNA damage response (DDR) biology—highlighting ERCC2 and related pathways as determinants of chemo-radiation sensitivity. We then review reproducible transcriptomic subtype classifiers and immune deconvolution methods, emphasizing translational constraints and reporting standards. Finally, we propose an integrated hypothetical modeling framework (calibration, external validation, and decision-curve thresholds) to guide recommendations for upfront RC versus bladder preservation with intensified surveillance and timely salvage RC. Full article

Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality. Radiological distinctions between borderline resectable (BR) and locally advanced disease (LA) are increasingly recognised as imperfect when considered without dynamic assessment. Neoadjuvant therapy (NAT) improves outcomes through tumour downstaging and early treatment of occult metastatic disease, but the optimal NAT strategy, particularly in BR disease, remains uncertain. Published data evaluating combined systemic anti-cancer therapies (SACT) with or without chemoradiation (CRT) are limited and heterogeneous. Methods: This is a single-centre retrospective analysis of 44 patients with BR PDAC and a comparator cohort of 121 patients with LA PDAC treated with a total neoadjuvant approach of SACT with or without CRT and surgical resection between June 2017 and September 2022. Results: Median overall survival (OS) did not differ significantly between BR and LA disease (18 vs. 16 months, p = 0.14). Following NAT, 47.7% of BR and 18.1% of LA patients were anatomically suitable for surgical resection. Among unresected BR and LA patients, those treated with CRT in addition to SACT had a median OS of 18 and 21 months respectively. In the resected subgroup, resection margin status was the primary factor associated with survival; with R0 resection conferring a substantial OS advantage over R1, irrespective of initial BR/LA classification as diagnosis (47 vs. 22 months, p < 0.001). Conclusions: Despite anatomical differences at diagnosis, BR and LA PDAC demonstrated comparable survival outcomes when treated with total neoadjuvant strategies in this cohort. These findings challenge traditional radiological staging-based treatment paradigms and confirm that a margin-negative surgical resection offered the greatest opportunity for long-term survival for BR/LA PDAC patients. Full article