Medicine and Pharmacology

Abstract: Cancer remains the most frequently cited disease relevance in basic and medical biology research. Yet the path from academic discovery to clinical application is often poorly understood, and significant gaps persist between academia and industry in both mindset and knowledge of the drug development process. This article outlines the essential components of contemporary preclinical cancer drug development to better equip academic researchers and strengthen the competitiveness of cancer-focused proposals. Our goal is to help bridge the translational divide, streamline the progression of academic innovations toward industry, and ultimately improve the success rate of candidate therapeutics by reducing attrition in the preclinical-to-clinical transition.

Abstract: Background and Objectives: Insomnia is a prevalent yet underrecognized symptom in patients with prostate cancer, and evidence in patients receiving systemic treatment is limited. We assessed the prevalence of insomnia and its associated factors in this population. Materials and Methods: In this two-center, cross-sectional study, insomnia was assessed with the Turkish version of the Insomnia Severity Index (ISI) in patients with metastatic prostate cancer receiving systemic treatment. Insomnia was defined as an ISI score ≥ 8 and clinical insomnia as an ISI score ≥ 15. Results: Among 110 patients, insomnia was present in 52 (47.3%) and clinical insomnia in 15 (13.6%). Pain (adjusted OR, 7.06; 95% CI, 2.31–21.59; p = 0.001) and a higher last prostate-specific antigen (PSA) level (OR per 10-fold increase, 1.47; 95% CI, 1.02–2.12; p = 0.040) were independently associated with insomnia. Clinical insomnia was more frequent in patients with visceral metastasis (50.0% vs. 9.4%; p = 0.008). Insomnia did not differ by treatment group or time on androgen deprivation therapy. Conclusions: Nearly half of these patients have insomnia, associated mainly with pain and active disease. Routine insomnia screening and pain management are warranted.

Abstract: The blood–brain barrier (BBB) limits systemic treatment of glioblastoma and brain metastases. Electroporation-based therapies apply short, high-intensity electric pulses that transiently permeabilize cell membranes or ablate tissue. Electrochemotherapy (ECT) combines reversible electroporation with chemotherapy, markedly enhancing bleomycin cytotoxicity, whereas irreversible electroporation (IRE) and its high-frequency variant (H-FIRE) induce non-thermal ablation and transiently disrupt the BBB in preclinical models. This narrative review critically examines the current evidence and identifies priorities for clinical translation. The available data remain predominantly preclinical. In rat gliomas, ECT delivered through a dedicated intracranial electrode achieved complete tumor eradication in 69% of treated animals, with effects largely confined to the target region. IRE and H-FIRE have proved technically feasible in dogs with spontaneous intracranial tumors, and H-FIRE has prolonged survival in rodent glioma models. Clinical experience is minimal: a non-invasive approach combining transcranial magnetic stimulation with bleomycin was withdrawn before patient enrollment, and the only identified trial of intracranial ECT for brain metastases was terminated for slow recruitment without published results. Major barriers include the lack of human safety and efficacy data, of intracranial electrodes approved for clinical use, and of validated treatment-planning workflows, together with uncertain recruitment feasibility. We also discuss how intracranial ECT might complement central nervous system (CNS)-active systemic therapies in patients with limited intracranial progression and controlled extracranial disease. Although most evidence derives from glioma models, we propose that selected patients with brain metastases recurring after stereotactic radiosurgery represent a rational population for initial pilot studies.

Abstract: Cells with similar endpoint measurements can have different biochemical response histories. Time-lapse single-cell Förster resonance energy transfer (FRET) imaging can distinguish these histories and test their relationship to metabolic function and cancer-cell fate. We connect FRET biophysics, biosensor design, and quantitative measurement to interpret cellular heterogeneity in metabolic dysfunction and cancer drug resistance. We emphasize corrected sensitized emission FRET imaging, distinguish corrected ratios from physical transfer efficiency, and describe controls for reporter specificity, temporal fidelity, and reproducibility. In metabolism, FRET imaging can reveal graded or bistable behavior and characterize sensitivity, response amplitude, history dependence, and coupling between signaling and substrate handling. In cancer, time-lapse signaling measurements paired with independent cell-fate outcomes can distinguish incomplete inhibition, adaptive recovery, and survival despite sustained pathway suppression. Cell culture, organoid, and intravital studies illustrate these capabilities and limits. Linking calibrated response histories to independent functional outcomes provides a robust foundation for candidate dynamic biomarkers. Integrating trajectory features with molecular profiles using machine learning could identify candidate predictors of treatment response. Future studies should test whether these dynamic features improve compound selection, combination design, and treatment schedules beyond baseline activity, initial inhibition, and endpoint measurements, with validation in independent patient-derived and in vivo models.

Abstract: Folate receptor-α (FRα) is overexpressed in a subset of high-grade endometrial cancers, but the activity and molecular effects of the FRα-targeting antibody–drug conjugate mirvetuximab soravtansine (MIRV) in this disease are undefined. Mice bearing two FRα-positive high-grade recurrent high-grade endometrial cancer patient-derived xenografts (PDXs; UT42, UT150) were randomized to a single tail vein injection of MIRV (5 mg/kg) or phosphate-buffered saline (control); a separate UT150 cohort received a second dose on Day 9. Tumors harvested 24 hours after treatment underwent microarray profiling and Hallmark, KEGG, and Gene Ontology pathway scoring. MIRV significantly inhibited tumor growth in both models, and a second dose produced more durable suppression (P<0.03). FRα protein expression was maintained after MIRV treatment. In both models, MIRV induced E2F target (z = 8.1 and 4.5) and G2/M checkpoint (z = 4.4 and 3.9) programs, consistent with DM4-induced mitotic arrest. MIRV also suppressed hypoxia (z = −6.4 and −11.6), epithelial–mesenchymal transition (EMT; z = −4.6 and −10.1), glycolysis and interferon-γ response programs. Genes reduced in both models (n = 117; 66 expected by chance) were enriched for TNFα/NF-κB, IL2–STAT5, EMT, and hypoxia signaling (FDR ≤ 0.002). These exploratory findings support evaluating MIRV-based combinations, including with anti-angiogenic agents, in endometrial cancer.

Abstract: Background: Metabolic reprogramming of tumor-associated macrophages (TAMs) drives tumor immune evasion, yet the spatial and subtype-level organization of TAM metabolism remains under-characterized. Methods: We re-analyzed public spatial metabolomics, spatial transcriptomics, and single-cell datasets using autocorrelation-corrected spatial statistics, patient-level testing, and replication across breast, lung, colorectal, liver, and brain tumor data. Results: TAMs formed the most spatially clustered transcriptional module in breast tumor sections. TAM-dense regions were robustly coupled to iron handling (ρ = 0.568), surviving gene-overlap, cell-abundance, and erythrocyte/vascular-exposure controls, whereas apparent glycolysis and lipid-uptake links did not survive spatial or abundance correction. In lung adenocarcinoma, subtype comparisons were confounded by tissue origin; within tumor tissue, two differences persisted across patients (higher lipid uptake in C1QC⁺ and higher iron handling in FOLR2⁺ TAMs). A reported SPP1⁺-versus-C1QC⁺ polarity recurred at cell level across cancer types but not at patient level. Mitochondrial DNA tracing detected clonally expanded, metabolically hyperactive TAMs in two of four evaluable samples. Conclusions: TAM metabolism is spatially organized and subtype-specific, with iron handling as the most robust territorial coupling, supporting spatially stratified, subtype-aware design of metabolism-targeting trials.

Abstract: BACKGROUND: [¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) has demonstrated clinical efficacy in metastatic androgen pathway modulator-naïve (mAPMN) and metastatic castration-resistant prostate cancer (mCRPC), however treatment responses remain heterogeneous. PURPOSE: To evaluate the prognostic value of PSMA PET-derived imaging biomarkers and genomic alterations in relation to biochemical response and clinical outcomes in systemic therapy-naïve patients with mAPMN PCa receiving [¹⁷⁷Lu]Lu-PSMA RLT as first-line systemic therapy. METHODS: Systemic therapy-naïve patients with mAPMN PCa treated exclusively with [¹⁷⁷Lu]Lu-PSMA-RLT were retrospectively analyzed. Standardized uptake value (SUV) parameters (SUVmax, SUVmean, SUVpeak) and PSMA total tumor volume (PSMA-TTV) were derived from baseline and post-treatment [68Ga]Ga-PSMA-11 PET scans, with imaging response defined as a ≥30% reduction. Prostate-specific antigen (PSA) response, PSA-PFS and androgen deprivation therapy (ADT)-free survival were assessed. Available germline and somatic genomic alterations were analyzed for associations with outcomes. RESULTS: 26 patients were analyzed. Reductions ≥30% in SUVmax and PSMA-TTV were associated with prolonged PSA-PFS (27.1 vs. 9.4 months, p=0.01; 27.1 vs. 5.5 months, p< 0.001, respectively) and ADT-free survival (39.0 vs. 19.9 months, p=0.03; 23.9 vs. 13.8 months, p=0.028, respectively). In multivariable analysis, ΔPSMA-TTV ≥30% was independently associated with prolonged PSA-PFS (HR 0.23, 95% CI 0.08-0.68; p=0.008). Of 17 genomically profiled patients, nine had somatic alterations, most frequently involving TP53, MYC, NF1. Patients with altered DNA damage repair (DDR) pathway had lower baseline PSA (0.78 vs. 12.3 ng/mL; p=0.03) and SUVpeak (7.9 vs. 16.7; p=0.03). No other associations with genetic alteration status were observed. CONCLUSIONS: In systemic therapy-naïve patients with mAPMN PCa, reductions of ≥30% in SUVmax and PSMA-TTV following PSMA-RLT were associated with favorable outcomes, with ΔPSMA-TTV independently associated with prolonged PSA-PFS. PSMA PET-derived parameters may support treatment response assessment, whereas no prognostic association with genomic alterations was identified in this cohort.

Abstract: RARγ is oncogenic in many cancers including some cases of acute myeloid leukemia, cholangiocarcinoma, and colorectal, gastric, head and neck, hepatocellular, ovarian, pancreatic, prostate, renal, and thyroid cancers (reviewed in [1]). From immuno-histological studies, high level expression was seen for tissue samples from patients with cholangiocarcinoma with lymph node metastases, stage III–IV ovarian cancer, pancreatic cancer, and high-grade prostate cancer. High expression of RARγ in colorectal cancer correlated with the expression of multidrug resistance 1 and a reduced sensitivity to chemotherapeutics. For thyroid cancer, high expression has been linked to the promotion of tumor invasiveness and metastasis. Examination of the survival curves for patients regarding the level of expression of RARγ has shown that high ex-pression is a predictor of poor overall survival outcomes for patients with AML, cholangiocarcinoma, and gastric, ovarian and pancreatic cancers. Active RARγ enhances cell proliferation and plays a role in the maintenance of stem cells. Both these roles are commensurate with RARγhaving a role in aggressive cancer.

Abstract: Introduction: Molecular tumor boards (MTBs) interpret molecular findings and connect patients with cancer to therapeutic options, including clinical trials. A recent European scoping review examines MTB implementation, while earlier global reviews address treatment attrition and clinical effectiveness. This scoping review will map global evidence on MTB-supported access to therapeutic trials and subsequent participation, including pathways, barriers, facilitators, and gaps across geographical and economic settings. Methods: The review will follow Arksey and O’Malley’s five core stages, incorporating selected refinements from Levac and colleagues and JBI guidance. Review and search reporting will follow PRISMA-ScR and PRISMA-S, respectively. PubMed, Embase, Scopus, CINAHL, and APA PsycINFO will be searched from inception, supplemented by citation and targeted grey literature searches. Searches will combine MTB and oncology terminology without requiring enrollment or outcome terms. No date, geographical, country-income, or language restrictions will apply. Eligible empirical sources will describe an MTB and provide substantive information on at least one therapeutic-trial access or participation stage, barrier, or facilitator. Neither a complete patient pathway nor a measured enrollment outcome will be required. Two reviewers will independently screen titles, abstracts, and full texts. A charting form will be piloted on at least five sources; one reviewer will chart each source, and a second will verify all entries. Results and Analysis: Descriptive and narrative synthesis will map countries, income groups, MTB models, trial identification, matching, referral, screening, enrollment, and subsequent participation. Country income and reported local resources will be recorded separately. Counts, denominators, matching definitions, follow-up periods, and evidence sources will be retained. Treatment initiation, withdrawal, discontinuation, and completion will be mapped when reported; response and survival will provide secondary context. Findings will identify evidence gaps and approaches that may inform future UAE pathways. Ethics and Dissemination: Ethics approval is not anticipated because the review will use publicly available information without collecting identifiable participant data. Findings will be disseminated through peer-reviewed publications, professional meetings, and a practical evidence summary.

Abstract: Objective: Immune checkpoint inhibitors (ICIs) have transformed advanced melanoma treatment, but optimal dosing intensity and treatment duration remain uncertain. This narrative review critically evaluates dose, schedule, and duration de-escalation with an emphasis on the directness and limitations of clinical evidence. Methods: A narrative literature review was conducted using a structured search of PubMed/MEDLINE, Embase, and CENTRAL from January 2015 through 12 September 2026, supplemented by targeted identification of pivotal clinical trials, observational cohorts, pharmacokinetic studies, systematic reviews, clinical guidelines, and relevant congress reports. Evidence was critically evaluated and synthesised qualitatively. Results: CheckMate 511 demonstrated lower grade 3-5 treatment-related toxicity with NIVO3+IPI1 than NIVO1+IPI3 without establishing efficacy non-inferiority. Me-ta-analyses across malignancies support a more favourable toxicity profile but provide indirect evidence for melanoma. EORTC 1612-EBIN used NIVO3+IPI1 in both groups and did not directly test dose reduction. Extended-interval anti-PD-1 schedules are exposure-matched alternatives, while very-low-dose therapy remains investigational. DANTE and Safe Stop illustrate the distinct evidence for fixed-duration and re-sponse-guided discontinuation. Conclusions: ICI de-escalation requires strategy-specific interpretation. Reduced-dose ipilimumab has reproducible safety signals but unproven efficacy equivalence; ex-tended dosing intervals maintain validated exposure; very-low-dose regimens require prospective testing; and shorter treatment remains an individualised decision without a universal stopping threshold.

Abstract: Several studies suggest that, in small cell lung cancer (SCLC), increasing age is associated with a lower incidence of brain metastases. This is conventionally explained by younger patients living long enough to develop them, an interpretation that fits poorly with the rapid course and short survival of SCLC. We propose a biological alternative grounded in the mechanics of brain-metastatic colonization. Because early colonization depends on the arrest of circulating tumour cells at microvessels, their perivascular survival, and outgrowth by co-option of the existing vasculature within a supportive perivascular niche, we hypothesize that the aging brain becomes a relatively resistant soil: microvascular rarefaction, endothelial senescence, chronic hypoperfusion and senescence of the perivascular niche reduce the competence of the brain to host metastatic colonization. We further propose that macroscopic cerebral atrophy is a radiologic surrogate of this reduced competence and should therefore be inversely associated with brain-metastatic incidence. The hypothesis is falsifiable, testable in matched radiologic cohorts and age-controlled experimental models, and clinically consequential for the selection of patients for prophylactic cranial irradiation.

Abstract: Adoptive cell therapy (ACT) has transformed the treatment of hematological malignancies but largely fails against solid tumors; the biological basis of this divide has rarely been quantified across cancer types. We analyzed uniformly reprocessed RNA-seq data (Toil pipeline) from TCGA (9,359 tumors, 33 cancer types), TARGET (734 pediatric tumors), and GTEx (7,862 normal samples). A 132-gene panel yielded T/natural killer (NK) infiltration, functional, metabolic, and stromal scores, integrated into a composite Solid Tumor Immune Accessibility Score (STIAS); six public single-cell datasets provided cellular validation. Median T- and NK-cell infiltration was about 30% lower in solid than in hematological tumors—a gap reflecting tissue of origin rather than recruitment failure. Single-cell analysis revealed per-cell enrichment of exhausted T-cell programs in solid tumors (23.6% versus 8.9%) and NKG2A upregulation on colorectal-tumor NK cells, while the dominant cohort-level barriers were stromal (extracellular matrix 3.79-fold) and metabolic (IDO pathway 1.27-fold). STIAS classified 14.5% of solid tumors as hematological-like “Accessible” phenotypes—reproduced in the pediatric TARGET cohort and enriched for the C2 (IFN-γ–dominant) immune subtype (26.4% versus 3.5%)—with each 0.1-unit increase associating with 46% and 40% higher hazard of death and progression. A bidirectional target atlas validated epithelial antigens (MUC1, ERBB2, CLDN18, CEACAM5, FAP, CD73) at the protein level and mapped hematological off-tumor risks; hematological-lineage signals (CD38, BCMA) proved predominantly immune-infiltrate-derived. Stromal–metabolic barriers dominate the solid tumor–specific axes of ACT resistance; STIAS-guided stratification and microenvironment reprogramming may extend cellular immunotherapy to solid malignancies.

Abstract: Background/Objectives: Abdominal radical trachelectomy (ART) preserves fertility in early-stage cervical cancer, but little is known about its outcomes outside North America, Western Europe, and East Asia. We report complications, surgical margins, and disease-free survival (DFS) in the first ART cohort from Vietnam. Methods: In this single-center retrospective cohort study, 21 consecutive patients with FIGO 2018 stage IA1–IB1 cervical cancer (tumor ≤2 cm) underwent ART with fertility-preserving intent. Complications were graded by the Clavien–Dindo system and DFS was estimated by the Kaplan–Meier method. Given the small sample, exact 95% confidence intervals and the rule of three were used. Results: No intraoperative complication occurred (0/21; 95% CI 0.0–16.1%). Five patients (23.8%) had a complication within 30 days, mostly grade II, and two (9.5%) had a grade IIIb complication. The endocervical margin was positive in one patient (4.8%). Median follow-up was 39 months (IQR 19–73). No recurrence or death occurred, and DFS was 100% at 1, 3, and 5 years, although only 7/21 patients had reached 5 years. Conclusions: In this selected cohort, ART had acceptable early safety and no recurrences. With wide confidence intervals and immature 5-year data, the findings show feasibility but do not prove safety.

Abstract: Glioblastoma (GBM) remains one of the most aggressive primary brain tumors, with limited therapeutic options and a high rate of recurrence, highlighting the need for novel treatment strategies. Ixazomib (IXA), an orally bioavailable proteasome inhibitor, has demonstrated antitumor activity in preclinical models of GBM; however, the molecular mechanisms underlying its effects remain incompletely characterized. In the present study, we investigated the anti-glioblastoma activity of IXA with particular emphasis on apoptosis induction and cell cycle regulation across distinct GBM cell models. IXA treatment elicited substantial cytotoxic effects accompanied by activation of apoptotic signaling. Concurrent activation of caspase-8 and caspase-9 in several cell models indicated the involvement of both extrinsic and intrinsic apoptotic pathways. In parallel, IXA markedly altered cell cycle progression, although the nature and extent of these effects differed between cell lines, reflecting the molecular heterogeneity characteristic of GBM. These findings indicate that the cellular response to proteasome inhibition is strongly dependent on the molecular context of individual GBM models. Together with recent evidence demonstrating the proteasome dependence of recurrent GBM and the activity of IXA in patient-derived organoid and xenograft models, our results support further investigation of ixazomib as a potential therapeutic agent for GBM. In particular, elucidating cell-specific determinants of apoptotic and cell-cycle responses may facilitate the development of rational combination strategies aimed at enhancing the therapeutic efficacy of proteasome inhibition in glioblastoma.

Abstract: Background: Metabolic reprogramming toward aerobic glycolysis, commonly referred to as the Warburg effect, is a hallmark of cancer. Such metabolic alterations may lead to aberrant expression and release of glycolytic and mitochondrial proteins, which can act as tumor-associated antigens and elicit humoral immune responses. However, whether patients with esophageal carcinoma (EC) develop a broad autoantibody response against these metabolic proteins, and whether such an autoantibody profile has diagnostic or prognostic relevance, has not been systematically investigated. Objective: To determine (1) whether serum autoantibodies against 18 proteins involved in glucose metabolism and mitochondrial pathways are broadly elevated in patients with EC and have diagnostic potential; (2) whether combining selected autoantibodies improves diagnostic discrimination; and (3) whether individual or combined autoantibody profiles show exploratory associations with postoperative overall survival. Methods: Serum autoantibody levels against 18 metabolic proteins (SLC2A1, ASPSCR1, GK2, ALDOA, TPI1, GAPDH, PGK1, PGK2, ENO1, PGAM1, PKM, PDHB, PCK1, LDHA, SDHB, FH, IDH, and ATP5B) were measured in 191 patients with EC and 96 healthy donors using AlphaLISA. For diagnostic combination analysis, a multivariable logistic regression model combining ENO1-Ab, PDHB-Ab, and ALDOA-Ab was evaluated in the complete-case cohort. In 91 surgically treated patients, exploratory overall survival analyses were performed using Kaplan–Meier curves and log-rank tests after dichotomization of antibody levels. Results: All 18 autoantibodies were significantly elevated in patients with EC compared with healthy donors (all P < 0.05), with individual AUC values ranging from 0.593 for SDHB-Ab to 0.735 for ENO1-Ab. The three-autoantibody model combining ENO1-Ab, PDHB-Ab, and ALDOA-Ab achieved an AUC of 0.812 (95% CI, 0.751–0.873), with a sensitivity of 68.1% and a specificity of 83.9%, and showed significantly greater diagnostic discrimination than the individual autoantibodies evaluated in the same cohort. In exploratory postoperative overall survival analyses, PCK1-Ab and SDHB-Ab showed significant differences in overall survival by log-rank testing. Several combined autoantibody profiles were also associated with survival differences, including high ENO1-Ab/low PGAM1-Ab, high SDHB-Ab/low FH-Ab, high ALDOA-Ab/high TPI1-Ab, and high PCK1-Ab/high SDHB-Ab versus low PCK1-Ab/low SDHB-Ab. Conclusions: The consistent elevation of autoantibodies against all 18 evaluated metabolic proteins suggests the presence of a broad humoral immune response to metabolic antigens in patients with EC. A three-autoantibody model combining ENO1-Ab, PDHB-Ab, and ALDOA-Ab improved diagnostic discrimination compared with individual markers. Exploratory analyses also identified individual and combined autoantibody profiles associated with postoperative overall survival, warranting further validation in independent cohorts.

Abstract: Protein glycosylation alterations in cancer have been recognized for their potential as a diagnostic tool. This review aims to explore the structural diversity and functional significance of glycans, as well as the relationship between aberrant glycosylation and cancer. Currently used glycomic biomarkers and their translational features in selected types of cancer are described in detail. The potential of liquid biopsy glycomics as an oncological tool is discussed, presenting different analytical strategies for glycan analysis, including total serum N-glycan analysis, O-glycosylation, and proteoglycan analysis. These strategies utilize chromatographic methods and high-resolution mass spectrometry, offering high precision and useful information. Other approaches include in situ fluorescence imaging, as well as lectin- and antibody-based methods for the detection of specific glycoforms, which have gained attention for their relative simplicity in use and clinical interpretation. With the rapid development of novel technologies for glycan detection and characterization, as well as bioinformatics tools and databases, it is expected that exploring the molecular mechanisms of glycosylation in cancer will become more accessible in everyday clinical implementation. Integrating knowledge of altered glycosylation patterns, proteomics, genomics, and metabolomics (and other omics approaches) with clinical data has potential to contribute to a more comprehensive biomolecular characterization of malignant diseases.

Abstract: Background: Survival after childhood cancer is strikingly unequal across the development spectrum, yet population-based cancer registries, the gold standard for survival measurement, are absent or incomplete in most low- and middle-income countries (LMICs), precisely where the burden is concentrated. The World Health Organization (WHO) Global Initiative for Childhood Cancer (GICC) targets at least 60% survival by 2030, but no registry-free, annually updatable, internationally comparable tracer of childhood cancer care-system performance is currently in routine use. We evaluated the mortality-to-incidence ratio (M/I), computed from Global Burden of Disease (GBD) estimates, as such a tracer.Methods: We extracted deaths and incident cases (ages 0–19 years, both sexes, 1990–2023) for leukemia, retinoblastoma, and a 14-cause aggregate aligned with the International Classification of Childhood Cancer from GBD 2023. M/I was computed as deaths divided by incidence, with Monte Carlo propagation of uncertainty intervals (UIs). A cure gap index was defined as the ratio of low-SDI to high-SDI M/I. External validity was assessed by reconciliation against registry-based survival anchors (CONCORD-3; China's National Childhood Cancer Surveillance annual report) and against the expected direction of the socio-demographic index (SDI) gradient, under an explicit construct-difference framework. Sensitivity to incidence under-ascertainment was quantified with scenario corrections (u = 0–43%).Results: Global leukemia M/I declined monotonically from 62.7% in 1990 to 46.6% (95% UI 37.1–60.1) in 2023 (estimated annual percentage change [EAPC] −0.975% per year). In 2023, M/I fell monotonically across SDI quintiles for all three calibers (leukemia 66.99% in low-SDI vs 24.35% in high-SDI countries; retinoblastoma 93.57% vs 7.23%; 14-cause aggregate 55.67% vs 19.15%), and across 21 GBD regions leukemia M/I ranged 6.5-fold, from 72.5% (Oceania) to 11.2% (Western Europe). The cure gap index widened from 1.38× to 2.75× for leukemia (average +2.47% per year, decelerating to about +1.3% per year over the most recent decade) and from 3.07× to 12.95× for retinoblastoma. Criterion reconciliation was direction-consistent throughout: the GBD-modeled retinoblastoma M/I for China (8.6%) lay within 1.0 percentage point (pp) of the registry-implied case fatality (9.6%), and regional implied survival (1 − M/I) tracked the CONCORD-3 anchors across their full range (49.8–95.2%), including a near-exact agreement for Andean Latin America (49.77% vs Ecuador 49.8%, a 0.03 pp difference) that we treat as partly endogenous corroboration rather than independent validation. Under a 43% global-average under-ascertainment scenario the inequality persisted (corrected gap indices 1.57×–7.38×), and it persisted even at the western African regional rate of 57% (leukemia gap index 1.18×).Conclusion: The M/I is a smooth, annually updatable, registry-free tracer whose levels, gradients, and trends corroborate independent survival evidence. It cannot replace registry-based survival, but it can monitor the cure gap, and its widening, in the many settings where registries do not yet exist.

Abstract: Background: Retinoblastoma is the most common primary intraocular malignancy of childhood and is nearly universally curable where effective services exist: three-year survival is 99.5% in high-income countries versus 57.3% in low-income countries. Because its occurrence is largely non-modifiable while its outcome is highly treatment-dependent, retinoblastoma is among the most sensitive tracers of childhood cancer cure capacity. We quantified its global burden, trends, and diagnosis–outcome gap. Methods: We analysed Global Burden of Disease (GBD) Study 2023 estimates (results release v8352) for retinoblastoma (cause_id 1009). Deaths and incident cases at ages 0–19 years — the sum of the <5, 5–9, 10–14, and 15–19-year bands — were extracted for the global level, 21 regions, and five Socio-demographic Index (SDI) quintiles over 1990–2023, with a national map for 204 countries in 2022. The mortality-to-incidence ratio (M/I) served as a proxy for cure. Reporting follows GATHER. Results: In 2023, retinoblastoma caused 3,226 deaths (95% uncertainty interval [UI] 1,493–6,569) at ages 0–19 years, down 31.8% from 1990; the crude death rate declined significantly (estimated annual percentage change [EAPC] −1.48% per year, 95% CI −1.60 to −1.36), while the incident case count rose significantly (EAPC +0.63%, 95% CI 0.40 to 0.87). The global M/I fell from 87.4% to 55.5%, yet the low-to-high SDI M/I ratio widened from 3.1-fold to 13.0-fold — the widest disparity among 14 childhood cancers by point estimate (95% UI 3.02–39.65). Children under 5 years accounted for 87.7% of deaths (95% UI 67.1–96.1). The cross-SDI mortality gradient (18.8-fold) far exceeded the incidence gradient (1.5-fold). Conclusions: Residual retinoblastoma mortality is concentrated almost entirely in children under 5 years in low-SDI settings and is consistent with an outcome-driven divide rooted in diagnostic delay and treatment access. Community-level recognition of leukocoria offers the highest-leverage intervention, and the M/I provides a measurable indicator for monitoring the WHO Global Initiative for Childhood Cancer.

Abstract: Background/Objectives: The LUNAR trial demonstrated the benefit of Tumor Treating Fields (TTFields) therapy in patients with metastatic NSCLC (mNSCLC) after platinum-based chemotherapy. However, real-world outcomes in patients treated with contemporary systemic regimens have yet to be empirically demonstrated. Methods: In this retrospective single-institution study, patients with mNSCLC treated with TTFields (150 kHz) after platinum-based chemotherapy between 2018 and 2026 were included. Progression-free survival (PFS) and overall survival (OS) were estimated from TTFields therapy initiation using the Kaplan–Meier method. Results: Sixteen patients were included. The median age was 73 years, 63% were male, 69% had adenocarcinoma histology, and 69% were PD-L1 positive. At TTFields therapy initiation, 94% had ECOG performance status ≤ 2, 19% had brain metastases, 31% had liver metastases, and 94% had prior ICI exposure. Median PFS was 11.8 months, and median OS was 19.9 months. OS did not differ significantly between the ICI-based and docetaxel-based groups (not reached vs. 13.5 months; p = 0.60) but PFS was shorter (3.9 months vs. not reached; p = 0.046). Treatment-related dermatitis was limited to grade 1–2 events, and no grade 3 or higher device-related toxicities were observed. Conclusions: TTFields therapy demonstrated encouraging real-world OS outcomes and favorable tolerability in this first report of a contemporary post-platinum NSCLC population, supporting further prospective evaluation of optimal timing and integration with modern systemic therapies.

Abstract: Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, represents a promising therapeutic vulnerability in recalcitrant tumors. However, standard two-dimensional (2D) monolayer models fail to reproduce the physiological architecture and metabolic constraints governing redox homeostasis in solid tumors. Here, we evaluated erastin-induced ferroptosis in OVCAR-8 (OV-8) and PA1 ovarian cancer cells cultured as 2D monolayers and three-dimensional (3D) spheroids. In 2D culture, erastin induced comparable concentration-dependent cytotoxicity in both lines, which was attenuated by deferoxamine and ferrostatin-1 (FES), and accompanied by glutathione depletion, malondialdehyde (MDA) accumulation, and upregulation of CHAC1 and HMOX1. Strikingly, 3D culture revealed a profound phenotypic divergence: OV-8 spheroids remained sensitive—displaying disrupted architecture, elevated MDA, and loss of cell viability that was rescued by ferrostatin-1—whereas PA1 spheroids acquired significant resistance to erastin. NMR-based metabolomic profiling of 2D cultures revealed that erastin induced concurrent depletion of intracellular glucose and lactate in PA1 cells, reflecting diminished glycolytic dependence and potential redirection toward NADPH-generating pathways. Concomitant glutamine depletion and glutamate accumulation suggest enhanced glutaminolysis for NADPH generation and antioxidant support. Conversely, OV-8 cells accumulated structural and alternative amino acids. These findings demonstrate that 3D tumor architecture reveals cell-line-specific redox and metabolic adaptations obscured in 2D culture, underscoring the importance of physiologically relevant models for evaluating ferroptosis-targeted therapeutics.