Citations

Abstract Rationale In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case–control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10−95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10−87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

OBJECTIVE Lateral lumbar interbody fusion including anterior-to-psoas oblique lumbar interbody fusion has conventionally relied on pedicle screw placement (PSP) for construct stabilization. Single-position surgery with lumbar interbody fusion in the lateral decubitus position with concomitant PSP has been associated with increased operative efficiency. What remains unclear is the accuracy of PSP with robotic guidance when compared with the more familiar prone patient positioning. The present study aimed to compare robot-assisted screw placement accuracy between patients with instrumentation placed in the prone and lateral positions. METHODS The authors identified all consecutive patients treated with interbody fusion and PSP in the prone or lateral position by a single surgeon between January 2019 and October 2022. All pedicle screws placed were analyzed using CT scans to determine appropriate positioning according to the Gertzbein-Robbins classification grading system (grade C or worse was considered as a radiographically significant breach). Multivariate logistic regression models were constructed to identify risk factors for the occurrence of a radiographically significant breach. RESULTS Eighty-nine consecutive patients (690 screws) were included, of whom 46 (477 screws) were treated in the prone position and 43 (213 screws) in the lateral decubitus position. There were fewer breaches in the prone (n = 13, 2.7%) than the lateral decubitus (n = 15, 7.0%) group (p = 0.012). Nine (1.9%) radiographically significant breaches occurred in the prone group compared with 10 (4.7%) in the lateral decubitus group (p = 0.019), for a prone versus lateral decubitus PSP accuracy rate of 98.1% versus 95.3%. There were no significant differences in BMI between prone versus lateral decubitus cohorts (30.1 vs 29.6) or patients with screw breach versus those without (31.2 vs 29.5). In multivariate models, the prone position was the only significant protective factor for screw accuracy; no other significant risk factors for screw breach were identified. CONCLUSIONS The present data suggest that pedicle screws placed with robotic assistance have higher placement accuracy in the prone position. Further studies will be needed to validate the accuracy of PSP in the lateral position as single-position surgery becomes more commonplace in the treatment of spinal disorders.

Medulloblastoma is the most common malignant brain tumor in children. Over the last few decades, significant progress has been made in revealing the key molecular underpinnings of this disease, leading to the identification of distinct molecular subgroups with different clinical outcomes. In this review, we provide an update on the molecular landscape of medulloblastoma and treatment strategies. We discuss the four main molecular subgroups (WNT-activated, SHH-activated, and non-WNT/non-SHH groups 3 and 4), highlighting the key genetic alterations and signaling pathways associated with each entity. Furthermore, we explore the emerging role of epigenetic regulation in medulloblastoma and the mechanism of resistance to therapy. We also delve into the latest developments in targeted therapies and immunotherapies. Continuing collaborative efforts are needed to further unravel the complex molecular mechanisms and profile optimal treatment for this devastating disease.

H3 K27–altered diffuse midline gliomas (DMGs) are frequently biopsied to obtain tissue diagnosis, inform clinical decision-making, and determine clinical trial eligibility. Tissue yield from biopsies is typically low, leaving little material available for research. To advance understanding of disease biology and promote preclinical testing of novel therapeutics, collecting viable cellular material from treatment-naive tumors is of paramount importance. Here, the authors report the feasibility of a practicable technique for creating DMG cell lines and patient-derived xenografts (PDXs) without the need for additional biopsy specimens. Tumor cells are obtained by probe washing immediately after completion of biopsy. Wash fluid is collected, and viable cells are expanded in vitro. Cultured cells are used to establish PDX rodent models. A total of 5 patient samples were collected by this technique. Viable tumor cells were obtained from 3 of the 5 samples, and cell lines suitable for experiments were obtained within 6–8 months. Orthotopic implantation and flank engraftment was successful in 1 of the 3 established cell lines. Animals harboring intracranial tumors were euthanized due to disease burden 6–7 months after stereotactic injection. Flank tumors formed within 4–5 months and were serially passaged. Molecular and tissue analyses confirmed retention of H3 K27M expression and loss of H3 K27me3 in all cell lines and PDXs.

Inhibition of the interaction between MDM2 and p53 has emerged as a promising strategy for combating cancer, including the treatment of glioblastoma (GBM). Numerous MDM2 inhibitors have been developed and are currently undergoing rigorous testing for their potential in GBM therapy. Encouraging results from studies conducted in cell culture and animal models suggest that MDM2 inhibitors could effectively treat a specific subset of GBM patients with wild-type TP53 or functional p53. Combination therapy with clinically established treatment modalities such as radiation and chemotherapy offers the potential to achieve a more profound therapeutic response. Furthermore, an increasing array of other molecularly targeted therapies are being explored in combination with MDM2 inhibitors to increase the effects of individual treatments. While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients.

Primary brain and central nervous system (CNS) tumors are a diverse group of neoplasms that occur within the brain and spinal cord. Although significant advances in our understanding of the intricate biological underpinnings of CNS neoplasm tumorigenesis and progression have been made, the translation of these discoveries into effective therapies has been stymied by the unique challenges presented by these tumors’ exquisitely sensitive location and the body’s own defense mechanisms (e.g., the brain–CSF barrier and blood–brain barrier), which normally protect the CNS from toxic insult. These barriers effectively prevent the delivery of therapeutics to the site of disease. To overcome these obstacles, new methods for therapeutic delivery are being developed, with one such approach being the utilization of nanoparticles. Here, we will cover the current state of the field with a particular focus on the challenges posed by the BBB, the different nanoparticle classes which are under development for targeted CNS tumor therapeutics delivery, and strategies which have been developed to bypass the BBB and enable effective therapeutics delivery to the site of disease.

OBJECTIVE While single-position surgery (SPS) eliminates the need for patient repositioning, the placement of screws in the unconventional lateral position poses unique challenges related to asymmetry relative to the surgical table. Use of robotic guidance or intraoperative navigation can help to overcome this. The aim of this study was to compare the relative accuracies offered by these various navigation modalities for pedicle screws placed in lateral SPS. METHODS According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the PubMed/Medline, Embase, and Cochrane Library databases were queried for studies reporting pedicle screw placement accuracy using fluoroscopic, CT-navigated, O-arm, or robotic guidance in lateral SPS, and a systematic review and meta-analysis was performed. Included studies all compared evaluated screw placement accuracy in lateral SPS using a single navigation method. Quality assessment was performed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system; risk of bias was assessed using the Newcastle-Ottawa Scale and the Joanna Briggs Institute checklist. The primary outcome, rate of pedicle screw breach, was analyzed using random-effects meta-analysis. RESULTS Eleven studies were included comprising 548 patients who underwent the placement of instrumentation with 2488 screws. For the fluoroscopic, CT-navigated, O-arm, and robotic guidance cohorts, there were 3, 2, 3, and 3 studies, respectively. Breach rates by modality were as follows: fluoroscopic guidance (6.6%), CT navigation (4.7%), O-arm (3.9%), and robotic guidance (3.9%). Random-effects meta-analysis showed a significant difference between studies, with an overall breach rate of 4.9% (95% CI 3.1%–7.5%; p < 0.001); however, testing for subgroup differences failed to show a significant difference between guidance modalities (QM = 0.69, df = 3; p = 0.88). Heterogeneity between studies was significant (I2 = 79.0%, τ2 = 0.41, χ2 = 47.65, df = 10; p < 0.001). CONCLUSIONS Robotic guidance of screws is noninferior to alternative guidance modalities in lateral SPS; however, additional prospective studies directly comparing different guidance types are merited.

Abstract Convection-enhanced delivery (CED) is a potentially promising strategy to administer therapeutics directly into the brainstem of children harboring H3 K27-altered diffuse midline glioma (DMG). While early-phase clinical trials have demonstrated the safety of this technique, efficacy has yet to be achieved. Here, we describe how different variations of CED may be exploited to extend survival in a DMG murine patient-derived orthotopic xenograft model. Either 1-day (8 µL/hr) or 7-day (1 µL/hr) continuous CED infusions were performed to deliver an equivalent volume of the aurora kinase inhibitor alisertib to the mouse brainstem. Bioluminescence and magnetic resonance images were acquired to monitor tumor progression, validate CED catheter positioning, and analyze infusion-related imaging changes. Both infusion regimens significantly prolonged survival versus control (median survival benefit of 6.5 and 8 days, p=0.03 and p=0.01, for 1-day and 7-day CED, respectively). Postmortem examination of brains revealed no signs of tissue necrosis, cavitary lesions, or cellular (inflammatory) infiltrate at the site of infusion. However, the tumor parenchyma surrounding the cannula tract was markedly hypocellular in treated animals. Alisertib induced a robust increase in H3 K27 trimethylation along with decreased H3 K27M and Ki-67. Our findings indicate that CED of alisertib is well tolerated and effective, in both the acute and prolonged setting, underscoring the potential of this approach in the management of DMG.

Abstract Diffuse midline glioma with H3 K27 alterations (DMG) is the most aggressive primary malignant brain tumor in the pediatric population. Radiation therapy (RT) is the standard-of-care; however, it has not demonstrated a significant improvement in overall survival or stalled disease progression, and children usually succumb to disease within 12-15 months of diagnosis. Consequently, finding efficient treatments for DMG remains one of the most critical unmet needs in modern neuro-oncology. Interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is a cell-surface receptor upregulated in ~80% of DMG versus normal brain, posing a potentially promising therapeutic target. Immunotherapies harnessing IL-13Rα2 to selectively delivery cytotoxic payloads, such as pseudomonas exotoxin A (PE), to tumor cells have been previously demonstrated to be safe in DMG patients and efficacious in preclinical models of DMG with high IL-13Rα2 expression using convection-enhanced delivery (CED). Furthermore, there is evidence that PE-based therapies can sensitize cells to RT. In this study, we utilized in vitro and in vivo models of DMG to evaluate clinically-relevant combination treatments of RT and the IL-13/PE immunotoxin GB-13 (IL13.E13K-PE4E). GB-13 improved the effectiveness of low-dose RT in multiple DMG cell lines by promoting caspase activation, which boosted apoptotic cell death. Intratumoral administration of GB-13 via chronic CED decreased tumor burden and prolonged survival in both DMG patient-derived orthotopic xenograft and genetically engineered mouse models. When GB-13 and RT were administered concurrently, this impact became even more prominent, informing future preclinical and clinical investigation of a potentially efficacious therapeutic approach in a subset of DMG.