Citations

Summary Outcomes for high‐risk paediatric classic Hodgkin lymphoma (cHL) improved with the addition of brentuximab vedotin (Bv) to doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (AVEPC) chemotherapy. We evaluated the prognostic implications of distant extra‐nodal sites contributing to stage IV disease. On AHOD1331 (NCT02166463), patients aged 2–21 years with high‐risk cHL (stage IIB with bulk/IIIB/IVA/IVB) were randomized to 5 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE‐PC) versus Bv‐AVEPC. Patients with stage IV disease, determined by protocol‐defined and centrally reviewed Positron Emission Tomography ‐ Computed Tomography (PET‐CT), were identified. Baseline characteristics and progression‐free survival (PFS) were compared by pattern of stage IV involvement (lung, bone, bone marrow, multiple sites and others). A total of 340 patients (median age 15 years) with stage IV disease were included. Of these patients, 173 (51%) received ABVE‐PC and 167 (49%) Bv‐AVEPC. PFS was highest with lung‐only involvement (4‐year PFS 88.6%) and lowest with bone marrow‐only involvement (4‐year PFS 71.9%). Compared to ABVE‐PC, Bv‐AVEPC improved PFS among all stage IV patients (hazard ratio [HR] 0.53, 90% confidence interval (CI) 0.33–0.85) and in the lung‐only and bone‐only subgroups. However, no PFS benefit was observed in those with bone marrow‐only involvement. Among paediatric patients with stage IV cHL, Bv‐AVEPC improved PFS across most patterns of stage IV disease, except in those with bone marrow involvement. These results will guide efforts to improve outcomes among children with stage IV cHL.

Abstract Objective. Modern stereotactic neurosurgery increasingly relies on bilateral and multi-trajectory workflows (e.g. deep brain stimulation (DBS), stereoelectroencephalography (sEEG)), which can exceed the reach and flexibility of conventional frame-based systems. Building on our skull-mounted Navinetics D1 platform, we present a stereotactic frame (Navinetics E1) intended to expand the reachable work envelope, enable independent bilateral targeting, and preserve mechanical accuracy and patient comfort. Approach. We designed the Navinetics E1 stereotactic frame using a center-of-arc architecture with five degrees of freedom per hemisphere ( X, Y, Z , Arc, Collar) and two operating modes: Double Arm (independent left/right arms for simultaneous bilateral targeting) and Single Arm (mechanically coupled arms). The system was designed in CAD and fabricated via carbon fiber-reinforced polylactic acid (PLA-CF) additive manufacturing. Collision-aware MATLAB simulations quantified work volume and admissible approach directions. Mechanical targeting accuracy was evaluated on a ground truth fixture (GTF) platform, with mixed-effects modeling to assess target- and trajectory-dependent effects. Operative feasibility was assessed through an intraoperative entry-point replication test relative to the D1 system. Main results. Compared to the D1, the E1 frame significantly expanded key geometric ranges, including, most notably, 0°–360° Collar rotation and posterior Y -axis reach, thereby increasing the work volume and trajectory range by factors of 3.39 and 8.42, respectively. Mean GTF targeting deviation was 0.78 ± 0.38 mm in Single Arm mode and 1.23 ± 0.36 mm (right) and 1.65 ± 0.47 mm (left) in Double Arm mode. Entry-point replication across 17 clinical cases achieved 76.5% success in overlapping the reference points, providing preliminary evidence of feasibility under real operative conditions. Significance. The E1 frame extends a compact skull-mounted platform to support broader stereotactic reach and trajectory while enabling independent bilateral workflows. These features may reduce intraoperative reconfiguration for complex DBS and sEEG cases. Future work will focus on increasing structural stiffness, improving angular readout/setting, and developing MRI-compatible implementations.

ABSTRACT Background Transvenous lead extraction (TLE) is a commonly performed and generally safe procedure, though procedural complexity and risk can vary based on clinical and procedural factors. Objective This study aims to identify clinical and procedural factors associated with histologic evidence of subclinical vascular injury, defined by elastin positivity on extracted leads and its clinical significance. Methods Patients undergoing TLE with a lead dwell time of ≥ 1 year were included. Extracted leads with tissue were analyzed histologically using Verhoeff–Van Gieson staining to assess the presence of elastin. Demographic data, procedural and lead characteristics, and indication for extraction were obtained. Established extraction risk scores were calculated to determine efficacy in predicting subclinical vascular injury. Results The cohort included 49 patients with 92 leads extracted. A total of 25 patients (51%) had elastin‐positive leads. Complete procedural success occurred in 95.9% of cases. The multivariate regression model did not identify any independent predictors of elastin presence, including age (OR = 1.00; 95% CI 0.95–1.05; p = 0.89), female gender (OR = 3.04; 95% CI 0.67–13.65; p = 0.14), lead dwell time (OR = 1.13; 95% CI 0.98–1.29; p = 0.07). Additionally, no scoring system, such as the CCF, EROS, MB, SAFeTY, and LECOM, predicted the presence of elastin. Conclusion Subclinical venous injury was common following TLE, yet did not predict adverse clinical outcomes, reinforcing that TLE performed in experienced centers carries a favorable safety profile. Future studies in larger cohorts are needed to further characterize the clinical utility of subclinical vascular injury.

PURPOSE Precision medicine has revolutionized oncology; however, tumor biomarkers are not reflective of the heterogeneous cancer population. We evaluated NRG Oncology prostate cancer (PCa) clinical trials for demographic differences among patients with optional biospecimen collection (BC) consent and biospecimen submission (BSub). METHODS Data from 19 NRG PCa clinical trials closed before 2015 were analyzed. Patients who consented to BC and completed BSub were evaluated by race, ethnicity, median income, area deprivation index (ADI; categorized as highest v lowest three quartiles), age at enrollment, site, and year of enrollment. T/chi-square tests were used for continuous/categorical variables, respectively, followed by logistic regression. RESULTS Of the 15,648 randomized patients eligible for BC, 11,796 (75%) had specimens submitted. In all, 4,598 (82.2%) of 5,597 eligible patients consented for optional BC in nine clinical trials with a separate BC consent process (consent rates by race/ethnicity: 74.1% Black, 72.8% Hispanic/Latino, 83.8% White). A smaller proportion of Black and Hispanic/Latino patients consented to optional BC compared with those who did not (12.1% v 19.5% Black, P < .0001; 3.5% v 5.8% Hispanic, P = .0006). In univariable logistic regression models, high ADI (more socioeconomic disadvantage) was associated with a decreased likelihood for optional BC consent (odds ratio [OR], 0.67 [95% CI, 0.55 to 0.82]; P = .02), but not a decreased likelihood for BSub (OR, 0.74 [95% CI, 0.53 to 1.04]; P = .08). Multivariable models demonstrated that Black/Hispanic/Latino patients were less likely to consent to optional BC, and Black patients were less likely to have BSub ( P < .05 for all). CONCLUSION White/non-Hispanic patients and those with less socioeconomic disadvantage were more likely to consent to optional BC, whereas Black patients were less likely to have BSub. Targeted solutions are needed to improve biorepository representation so that precision medicine approaches better reflect the cancer population.

Primary enlargement of the cerebrospinal fluid (CSF)–filled brain ventricles, known as congenital cerebral ventriculomegaly (CCV), is a hallmark of congenital hydrocephalus. CCV is also enigmatically but frequently associated with autism and other neurodevelopmental disorders. To gain insight into the developmental genetic regulation of the human CSF-ventricular system, we conducted an integrated, multiomic study of about 2700 trio-based exomes from patients with primary CCV. We found that about 25% of cases were associated with rare, damaging de novo variants in mutation-intolerant genes, many of which are linked to other dominant Mendelian disorders. Thirty-five exome-wide significant CCV genes and dozens of other high-confidence CCV genes converged on pathways involved in ATP-dependent Brahma-related gene 1/Brahma-associated factor chromatin remodeling, histone H3 lysine 4 methylation, and phosphoinositide 3-kinase signaling. Knockout of selected CCV genes in mouse models supported that de novo variants in CCV genes caused ventriculomegaly by impairing both CSF dynamics and cortical cytoarchitecture through dysregulation of neuroprogenitor cell growth and maturation in the ventricular and subventricular zones. These findings indicated that genetic and epigenetic programs coordinate the “hand-in-glove” development of the CSF-ventricular system with that of the cerebral cortex and establish a genetic connection between CCV and neurodevelopmental disorders, potentially explaining why some patients with hydrocephalus continue to exhibit CCV and neurodevelopmental disorders despite CSF shunting. We suggest that combined brain imaging and whole-exome sequencing could enable early detection of, and intervention for, autism and other neurodevelopmental disorders.

Glioblastoma (GBM) is a devastating cancer with a dismal prognosis. Current treatment includes temozolomide (TMZ), which is more effective in about 50% of GBMs that have O 6 - methylguanine DNA methyltransferase ( MGMT ) promoter methylation. MGMT is a DNA repair protein that reverses TMZ-induced DNA damage. EGFR is a prime oncogene in GBM. Here, we report that EGFR inhibition induced the down-regulation of MGMT in GBM cells, revealing a previously unidentified link between EGFR signaling and response to TMZ. EGFR inhibition led to activation of two transcription factors, activator protein-1 (AP-1), which repressed MGMT transcription, and nuclear factor κB (NF-κB), which up-regulated MGMT transcription. EGFR inhibition also induced AP-1–mediated transcription of miR-616. miR-616 inhibited both MGMT translation and NF-κB activation. Thus, the overall effect of EGFR inhibition was down-regulation of MGMT expression. In addition, we provided an explanation for the prior failure of clinical trials that used concomitant EGFR tyrosine kinase inhibitors (TKIs) and TMZ. TMZ up-regulated MGMT, and concomitant treatment with EGFR TKIs and TMZ failed to down-regulate MGMT. However, pretreatment with EGFR TKIs followed by TMZ efficiently down-regulated MGMT and enhanced TMZ sensitivity in experimental models. Posttreatment tumor tissues from two clinical trials were used to validate these findings. We demonstrated that EGFR inhibitors induced down-regulation of MGMT in posttreatment resected tumor tissues from patients with GBM and the failure of EGFR inhibition to down-regulate MGMT if TMZ was used concomitantly. These data support using EGFR TKIs before TMZ treatment as a therapeutic approach in MGMT unmethylated GBM.

Abstract Introduction Acute interstitial nephritis is an important differential diagnosis in patients with deteriorating kidney function. Diagnosis currently requires kidney biopsy, an invasive procedure associated with risks. We hypothesized that urinary T cells may serve as a non-invasive biomarker for acute interstitial nephritis. Methods A total of 320 patients undergoing clinically indicated kidney biopsy were enrolled in a discovery cohort at Charité Berlin (n = 80), an internal validation cohort at Charité (n = 100), and an external validation cohort at The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou (n = 140). Urinary immune cells were assessed by flow cytometry. Renal T cell infiltration was evaluated by immunofluorescence in kidney biopsy specimens from the discovery and internal validation cohorts, including 16 patients with acute interstitial nephritis and 9 patients without acute interstitial nephritis. Additionally, CXCL9 was measured by ELISA in 102 urine samples from these cohorts. Results Across all cohorts, 27 patients (8.4%) were diagnosed with acute interstitial nephritis. In the discovery cohort, multiple urinary T cell subsets were increased in acute interstitial nephritis, with activated CD4 + effector memory T cells expressing CD38 and HLA-DR showing the strongest diagnostic performance. This marker outperformed urinary monocytes, eosinophils, and CXCL9 and was validated in both independent cohorts. Across all cohorts, the area under the receiver operating characteristic curve was 0.84 and increased to 0.91 after exclusion of 8 patients receiving corticosteroids. A cutoff of 211 activated CD4 + effector memory T cells per 100 mL urine yielded a sensitivity of 78% and a specificity of 81%. Urinary activated CD4 + effector memory T cell counts correlated with renal CD4 + and CD4 + CD38 + T cell infiltration in acute interstitial nephritis. Conclusions Urinary activated CD4 + effector memory T cells expressing CD38 and HLA-DR represent a promising non-invasive biomarker for the diagnosis of acute interstitial nephritis. Lay Summary Acute interstitial nephritis is a frequent cause of acute kidney injury and is usually diagnosed by kidney biopsy, an invasive procedure that carries risks. We investigated whether immune cells in urine could help identify AIN in a less invasive manner. In this multicenter study, urine samples from 320 patients undergoing kidney biopsy in Germany and China were analyzed. We found that a specific population of activated T cells was markedly increased in the urine of patients with AIN compared with patients with other kidney diseases. This urinary marker outperformed other immune cell types and the inflammatory cytokine CXCL9 and was successfully validated in independent cohorts from both Germany and China. Importantly, urinary activated T cell counts correlated with immune cell infiltration within the kidney. These findings suggest that urinary activated T cells may serve as a non-invasive biomarker to support the diagnosis of AIN and facilitate earlier clinical decision-making.

Ring-closing carbonyl-olefin metathesis (COM) reactions provide a straightforward method for producing cyclic alkenes from precursors containing carbonyl functional groups tethered to nucleophilic alkenes. Within the last decade, many methods for carrying out Lewis acid- or organocatalyzed COM reactions were reported; however, Brønsted–Lowry acid-catalyzed COM reactions are less developed. Herein, we report that phosphoric acid derivatives and N-triflylphosphoramides mediate COM reactions, although the substrate scope is limited to biaryl compounds that cyclize to produce phenanthrene products. We also disclose the synthesis and characterization of a previously non-fully characterized phosphoric acid derivative and a novel phosphoramide.