Glioblastoma (GBM) is a highly malignant brain tumor with a poor prognosis. Long noncoding RNAs (lncRNAs) significantly influence GBM pathogenesis. Although lncRNA MIR4435-2HG is known to promote tumorigenesis in various cancers, its regulatory role in GBM remains undefined. We quantified MIR4435-2HG and miR-181d-5p expression using quantitative reverse transcription polymerase chain reaction. The functional impact of the MIR4435-2HG/miR-181d-5p/MALT1/NF-κB axis was assessed in A172 and U87 MG cells through cell counting kit-8 (CCK-8), wound healing, Transwell, flow cytometry, Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), western blot, and immunofluorescence assays. Interactions between miR-181d-5p, MIR4435-2HG, and MALT1 were confirmed by dual-luciferase reporter, fluorescence in situ hybridization, RNA immunoprecipitation, and RNA pulldown experiments. Finally, a xenograft tumor model in C57BL/6 mice, combined with hematoxylin and eosin staining, immunohistochemistry, and TUNEL staining, was used to investigate the role of MIR4435-2HG in vivo. The results demonstrated that both MIR4435-2HG and MALT1 were upregulated in GBM tissues and cell lines, whereas the expression of miR-181d-5p was reduced. MIR4435-2HG promoted GBM cell proliferation and metastasis in both in vitro and in vivo experiments. Inhibition of MALT1 reversed the promotive effects of miR-181d-5p knock down on GBM cell proliferation and metastasis. Mechanistic studies revealed that MIR4435-2HG upregulates MALT1 expression and activates the NF-κB signaling pathway by sponging miR-181d-5p. In conclusion, MIR4435-2HG overexpression facilitates the malignant progression of GBM through the miR-181d-5p/MALT1/NF-κB pathway.

Lung adenocarcinoma (LUAD) is the most common histological subtype of malignant lung tumors, characterized by high incidence and mortality rates. Super-enhancers (SEs) are involved in regulating tumor transcription and promote tumorigenesis and progression. However, their role in LUAD remains underexplored. This study uses bulk, single-cell, and spatial transcriptomics analyses to uncover their tumor-promoting and tumor microenvironment-regulating features in LUAD. By integrating multi-omics data with 10 clustering algorithms, the study successfully identified molecular subtypes of SEs in LUAD. Analysis showed significant differences among patients with different subtypes in prognosis, genomic instability, and drug sensitivity. Subsequently, the Lasso + StepCox algorithm identified nine super-enhancer-related prognostic genes and built the super-enhancer-associated gene risk score (SEGRS) prognostic model. In-depth analysis revealed that SEGRS is closely linked to genomic mutations and oncogenic pathway enrichment in lung adenocarcinoma. SEGRS also plays a role in regulating the tumor microenvironment and immune response patterns. Finally, differential analysis, survival analysis, and spatial transcriptomics pinpointed the core gene HSPD1. In vitro experiments confirmed its high expression in LUAD and its role in promoting malignant progression. This work uncovers pro-tumorigenic SEs signatures in LUAD through a multi-omics and machine learning integrative approach, establishes new molecular subtypes and prognostic models, and clarifies the prognostic and cancer-promoting roles of HSPD1. These findings offer strategies and potential new targets for the precise diagnosis and treatment of LUAD.

Second malignant neoplasms (SMNs) represent a devastating late complication of central nervous system (CNS) tumor, particularly in pediatric and young adult populations. While improved treatments have increased survival rates, the risk and characteristics of SMNs in contemporary cohorts remain poorly characterized. The purpose of this study is to characterize the clinicopathological and molecular features of therapy-related high-grade gliomas(t-HGGs), and to explore their multifactorial etiology involving radiation, chemotherapy, and potential genetic susceptibility.

We analyzed seven cases of histologically confirmed SMNs developing after treatment for primary CNS tumors. We collected and analyzed key clinical information from patients, including gender, age, time to second tumor onset (latency), treatment modalities, and outcomes. Additionally, we examined imaging findings, histopathological features using hematoxylin-eosin (H&E) staining and immunohistochemistry, as well as molecular marker characteristics.

The cohort consisted of seven patients (5 males, 2 females). The median age at primary tumor diagnosis was 5 years (range: 3-21 years), and at SMN diagnosis was 12 years (range: 7-27 years), with a median latency of 6 years (range: 2-9 years). All patients received radiotherapy. Exploratory analysis revealed no significant relationship between radiation dose and latency period. Histological transformation was universal, most commonly from medulloblastoma to high-grade glioma (3/7 cases) and germ cell tumors (3/7 cases, including 2 germinomas and 1 non-germinomatous germ cell tumor (NGGCT)). Molecular analysis in sequenced cases revealed distinct profiles, including NF1/PDGFRA alterations. Outcomes were poor.

This study delineates a rare yet distinct clinicopathological entity-therapy-related high-grade glioma, which may arise from the complex interplay of prior radiotherapy, chemotherapy, and underlying genetic susceptibility. Recognition of this multifactorial etiology is critical for risk stratification and long-term surveillance.

We develop a personalized optimization framework for designing spatiotemporal radiotherapy strategies for Glioblastoma Multiforme (GBM). The tumor dynamics are described by a reaction diffusion model on patient-specific brain geometries, and the treatment objective is formulated as a PDE-constrained optimization problem in which the admissible targeting region is allowed to vary on each day of therapy. The resulting optimization requires repeated solutions of the state and adjoint equations, and we implement an adjoint-driven gradient algorithm with line search and projection to enforce clinical dose constraints. To improve robustness, the algorithm is first validated on a simplified surrogate model before being applied to full patient data. The proposed framework generates patient-specific targeting volumes informed by clinical and radiological parameters, producing a dynamic treatment region that adapts to tumor evolution rather than relying on standard fixed or population-based margins. Our results demonstrate that incorporating daily adaptability into the optimization process can lead to substantially different and potentially more effective treatment targets. This study highlights the potential of PDE-constrained optimization as a mathematical tool for personalized radiotherapy planning.

Vestibular schwannomas are the most common tumor of the cerebellopontine angle, estimated to occur in about 1 per 500 people. They most commonly present with unilateral hearing loss.

We review the epidemiology and present a comprehensive review of the preoperative work-up, including formal assessment of symptoms and imaging evaluation.

We present practices for supporting patients with prehabilitation techniques and symptom management. We then discuss available treatment options and outline the evidence for each before detailing an approach to counseling the patient.

Even with new drugs available, how best to treat unfit adults with acute myeloid leukemia (AML) remains uncertain. In a previous trial in such patients, we found high-dose cytarabine-based therapy with CLAG-M yielded higher response rates but no more toxicity than lower-intensity therapy with dose-attenuated CLAG-M. Here, we conducted a single-institution phase 2 trial (NCT04195945) randomizing 60 adults with untreated AML and medical unfitness with Treatment-Related Mortality (TRM) score of ≥13.1 (68% with ECOG performance status 3-4) 1:1 to standard-dose CPX-351 or CLAG-M. Primary endpoint was 3-month overall survival (OS); key secondary endpoints included overall response rate, rate of measurable residual disease (MRD) negativity, toxicity/mortality rates, and survival estimates. Only CLAG-M met the primary endpoint of ≥63% 3-month OS (70% vs. 60%; P = 0.41), and CLAG-M therapy was associated with a non-significantly higher complete remission (CR) plus CR with incomplete hematologic recovery rate (73% vs. 47%, P = 0.064). Nonetheless, there was no statistically significant difference in relapse-free survival following CLAG-M vs. CPX-351 (median 37.6 vs. 19.9 months; P = 0.80) or OS (median 10.5 vs. 5.8 months; P = 0.76). In patients with proliferative disease, however, OS following CLAG-M was longer (median 18.5 vs. 3.9 months; P = 0.02) suggesting a role for intensive therapy in this patient subset.

More than ten years ago, the World Health Organization's (WHO) International Agency for Research on Cancer (IARC) published a monograph concluding there was limited evidence in experimental animals for carcinogenicity of Radio Frequency Electromagnetic Field (RF EMF).

The objective of this review was to systematically evaluate the effects of RF EMF exposure on cancer in experimental animals.

Eligibility criteria: Based on pre-established Populations, Exposures, Comparators, Outcomes, and Study Type (PECOS) criteria, studies in experimental animals of the following study types were included: chronic cancer bioassays, initiation-(co-)promotion studies, and studies with tumor-prone animals.

MEDLINE (PubMed), Science Citation Index Expanded and Emerging Sources Citation Index (Web of Science), and the EMF Portal. Data abstraction and synthesis: Data are publicly available online as interactive visuals with downloadable metadata. We adapted the risk-of-bias (RoB) tool developed by Office of Health Assessment and Translation (OHAT) to include considerations pertinent to the evaluation of RF EMF exposure and cancer bioassays. Study sensitivity was assessed with a tool adopted from the Report on Carcinogens (RoC). We synthesized studies using a narrative approach. Effect size was calculated as the 1% Bayesian Average benchmark dose (BMD) of a respective study when dose response or a trend was identified (see Supplementary Data 3). Evidence Assessment: Certainty of the evidence (CoE) was assessed using the Grading of Recommendations, Assessment, Developing and Evaluations (GRADE) approach, as refined by OHAT. Evidence from chronic cancer bioassays was considered the most directly applicable to evaluation of carcinogenicity.

We included 51 studies with 10 chronic bioassays No studies were excluded based on risk of bias concerns. Studies were not considered suitable for meta-analysis due to heterogeneity in study design, species, strain, sex, exposure characteristics, and cancer outcome. No or minimal evidence of RF EMF exposure-related cancer outcomes was found in most systems or organs in any study (these included gastrointestinal/digestive, kidney, mammary gland, urinary, endocrine, musculoskeletal, reproductive, and auditory). For lymphoma (17 studies), with 5 chronic bioassays (2,186 mice, 2,500 rats) inconsistency between two chronic bioassays was not plausibly explainable, and the CoE for lymphoma was rated 'moderate'. For brain tumors (20 studies), including 5 chronic bioassays (2,575 mice, 8,840 rats), an increase in glial cell-derived neoplasms was reported in two chronic bioassays in male rats. The CoE for an increased risk in glioma was judged as high. The BMD analysis was statistically significant for only one study, and the BMD was 4.25 (95% CI 2.70, 10.24). For neoplasms of the heart (3 chronic bioassays), 3 studies were performed in rats (∼4,304 animals), and 1 in mice (∼1,386 animals). Based on 2 bioassays, statistically significant increases in malignant schwannomas were judged as high CoE for an increase in heart schwannomas in male rats. The BMDs from the two positive studies were 1.92 (95%CI 0.71, 4.145) and 0.102 (95%CI 0.056, 0.244), respectively. Ten studies reported neoplasms in the adrenal gland (5 chronic bioassays). The CoE for an increased risk in pheochromocytoma was judged as moderate. None of these findings were dose-dependent when compared to the sham controls. Fourteen studies investigated tumors of the liver with 5 of these being chronic bioassays. The CoE was evaluated as moderate for hepatoblastomas. For neoplasms of the lung (5 chronic bioassays), 4 studies were conducted in rats (∼2,176 animals) and 9 studies in mice (∼4,171 animals). In one chronic bioassay, a statistically significant positive trend was reported for bronchio-alveolar adenoma or carcinoma (combined), which was rated as moderate CoE for an increase in lung neoplasms with some evidence from 2 initiation-(co-)promotion studies.

Meta-analysis was considered inappropriate due to the heterogeneity in study methods. The GRADE/OHAT CoE framework has not been frequently applied to animal studies and experience to date suggests refinements are needed. We deferred to standard methods in environmental health where CoE is framed in the context of strength of the evidence providing positive support for carcinogenicity. High CoE can be interpreted as the true effect is highly likely to be reflected in the apparent relationship. Moderate CoE indicates the true effect may be reflected in the apparent relationship. Cancer bioassays conducted in experimental animals are commonly used to identify potential human carcinogens. We note that the two tumor types with high CoE in animals in this systematic review are the same as those identified with limited evidence in humans by the IARC Working Group. However, even in cases where the animal evidence demonstrates high CoE, the extrapolation of risk from cancer bioassays to humans is particularly complex for RF EMF. Without a better understanding of the mechanism of the carcinogenicity of RF-EMF, the choice of exposure metric for risk extrapolation (whole body versus localized), intensity or cumulative exposure whether or not a monotonic dose response holds for carcinogenic effects, and whether SAR is the appropriate dose metric for adverse effects induced by RF-EMF may be critical.

This review was partially funded by the WHO radioprotection programme. The protocol for this review was registered in Prospero reg. no. CRD42021265563 and published in Environment International 2022 (Mevissen et al., 2022).

Overcoming tyrosine kinase inhibitor (TKI) resistance improves survival in advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). We therefore examined the safety and preliminary efficacy of pelcitoclax, a B-cell lymphoma-2 (BCL-2)/BCL-extra-large (BCL-xL) inhibitor, and osimertinib in patients with EGFR-mutated advanced NSCLC.

Enrolled patients included Cohort 1 (previously progressed after third-generation TKI treatment+chemotherapy), Cohort 2 (previously progressed after first-generation or second-generation TKI treatment+chemotherapy), and Cohort 3 (TKI treatment-naive±prior chemotherapy). Patients received intravenous pelcitoclax (160 mg in dose-expansion and either 160 or 240 mg in dose-escalation) weekly and oral osimertinib 80 mg daily. Primary endpoints were safety and recommended phase 2 dose (dose-escalation), objective response rate (ORR) and safety (dose-expansion).

64 patients were enrolled (13, dose-escalation; 51, dose-expansion): 29 patients in Cohort 1, 8 in Cohort 2, and 27 in Cohort 3. One dose-limiting toxicity occurred at pelcitoclax 240 mg, and the recommended phase 2 dose was 160 mg plus osimertinib 80 mg. The ORR was 10.7% and median progression-free survival (mPFS) 2.7 months in patients previously progressed after third-generation TKI treatment+chemotherapy (Cohort 1) and 80.8% and 16.4 months in TKI treatment-naïve patients±prior chemotherapy (Cohort 3). mPFS was longer in Cohort 1 patients with high expression of BCL-xL (4.2 vs 2.7 months, p=0.058).

Pelcitoclax combined with osimertinib showed promising safety and antitumor activity in EGFR-mutated NSCLC.

NCT04001777.

Extrinsic airway compression secondary to vertebral osteophytes is a rare clinical entity. We report a case of an elderly patient presenting with pneumonia where a subsequent chest CT scan showed right main bronchus compression caused by lower thoracic vertebral osteoarthritis-related osteophytes. There were additional incidental findings of sclerotic skeletal lesions prompting a new diagnosis of metastatic prostate cancer. The pneumonia improved with antibiotic therapy. Interventional management of airway compression was not pursued in this patient given his poor functional state and advanced metastatic malignancy. The patient was later readmitted with recurrent pneumonia as expected. Clinicians should be aware of this rare entity as a potential cause of airway compression identifiable on CT chest.