Mohyeldin, Ahmed

Background: Sinonasal undifferentiated carcinoma (SNUC) is an extremely rare, high-grade, and aggressive tumor of the sinonasal tract. Due to the rarity of this malignancy, current treatment guidelines are based on small and often/mainly single-center retrospective datasets. In the absence of a universally accepted standard of care for SNUC, treatment approaches vary across countries and institutions, reflecting real-world clinical practice. The primary aim of this study was to describe real-world treatment and outcomes for patients with confirmed SNUC. Methods: This was an international, multi-center, retrospective, observational cohort study that pooled patients into the largest SNUC dataset to date. Fifteen centers were enrolled to contribute data, including seven from Europe, four from the United States, three from the United Kingdom, and one from Canada. In the absence of a universally accepted standard of care for SNUC, treatment approaches varied across countries and institutions, reflecting real-world clinical practice. Patients included were those with histologically confirmed SNUC who were treated between 1997 and 2021. Results: This study yielded 485 patients treated for SNUC. The median age at diagnosis was 55.6 years (IQR: 44.5–67.6), and 63.7% were male. Most cases presented at advanced stages, with 70.8% as T4a or T4b. Overall survival (OS) outcomes were available for 412 patients, with a median follow-up of 26.0 months. The 5- and 10-year OS were 47.2% (95% CI: 40.8–53.3%) and 39.6% (95% CI: 32.5–46.6%), respectively. Advanced age, dichotomized T-stage (T4a/b vs. T1–3), M-stage, and orbital involvement were significant poor prognostic factors on univariable analysis (p’s < 0.01). On multivariable analysis, orbital involvement (HR: 2.73, 95% CI: 1.42–5.27, p = 0.003) and distance metastasis stage (HR: 3.00, 95% CI: 1.25–7.21, p = 0.014) were both independently associated with worse OS. Conclusions: This observational study presents the largest multi-center cohort analysis of SNUC to date, providing new insights into prognostic factors for a rare cancer treated at global centers of excellence. Orbital involvement and the presence of metastases are candidate independent risk factors associated with poorer OS.

Abstract Introduction Meningiomas—the most common extra-axial tumors—are benign, slow-growing dural-based lesions that can involve multiple cranial fossae and can progress insidiously for years until coming to clinical attention secondary to compression of adjacent neurovascular structures. For complex, multicompartmental lesions, multistaged surgeries have been increasingly shown to enhance maximal safe resection while minimizing adverse sequela. Here, we systematically review the extant literature to highlight the merits of staged resection. Methods PubMed, Scopus, and Web of Science databases were queried to identify articles reporting resections of intracranial meningiomas using a multistaged approach, and articles were screened for possible inclusion in a systematic process performed by two authors. Results Of 118 identified studies, 36 describing 169 patients (mean age 42.6 ± 21.3 years) met inclusion/exclusion criteria. Petroclival lesions comprised 57% of cases, with the most common indications for a multistaged approach being large size, close approximation of critical neurovascular structures, minimization of brain retraction, identification and ligation of deep vessels feeding the tumor, and resection of residual tumor found on postoperative imaging. Most second-stage surgeries occurred within 3 months of the index surgery. Few complications were reported and multistaged resections appeared to be well tolerated overall. Conclusions Current literature suggests multistaged approaches for meningioma resection are well-tolerated. However, there is insufficient comparative evidence to draw definitive conclusions about its advantages over an unstaged approach. There are similarly insufficient data to generate an evidence-based decision-making framework for when a staged approach should be employed. This highlights the need for collaborative efforts among skull base surgeons to establish an evidentiary to support the use of staged approaches and to outline those indications that merit such an approach.

Abstract Due to its anti-fibrinolytic action, tranexamic acid (TXA) can be utilized to help maintain hemostasis during surgical operations. With respect to surgery for intracranial tumors, we hypothesize that TXA could help mitigate blood loss during resection of highly vascular tumors such as meningiomas. We therefore conducted a systematic review of the literature and meta-analysis to analyze the effects of TXA administration in patients undergoing surgical resection of intracranial meningioma. Study inclusion criteria were (1) primary data articles describing use of TXA in surgical resection of meningioma. In this meta-analysis, which included four primary comparative studies, outcome measurements between TXA and non-TXA groups were compared. Primary outcomes included operative length, complications, transfusion requirements, estimated blood loss, and postoperative Hb for TXA versus non-TXA (control) groups. Pooled-comparative analysis was conducted for each of these perioperative variables and formal meta-analysis was applied toward statistically significant parameters. A total of 221 patients were analyzed (110 TXA, 111 non-TXA). Patient age (p = 0.1632), gender (p = 0.8317), and tumor location (p = -.8334) were similar for TXA and control groups. TXA was associated with decreased complication rate (logRR: -0.85; CI95% = -1.49 to -0.22; p = 0.0087), decreased transfusion requirement (logRR: -0.50; CI95% = -0.92 to -0.08; p = 0.0039), reduced blood loss (SMD: -1.76; CI95% = -3.21 to -0.31; p &lt; 0.0001), and increased postoperative Hb (SMD: 0.46; CI95% = -0.15 to 1.07; p &lt; 0.0001). In three trials, TXA was administered intravenously as a loading dose of 20 mg/kg for 20 minutes preoperatively with an intraoperative maintenance rate of 1mg/kg/hr; in one trial, administration design was identical except that infusion rate of the 20 mg/kg preoperative loading dose was unspecified. TXA may be associated with reduced complications, transfusion requirements, perioperative estimated blood loss, and increasedpostoperative Hb when administered perioperatively for surgical resection of intracranial meningiomas.

Abstract Recent literature has primarily focused on the factors influencing postoperative seizures following resection of meningioma, but many patients also suffer seizures preoperatively. This meta-analysis examined patient demographics, tumor characteristics, and preoperative symptoms to determine which factors are most associated with preoperative seizures. A literature search of Pubmed, Web of Science, and Scopus was conducted. All randomized controlled trials, case-control studies, and cohort studies reporting on preoperative seizure in patients with meningioma were included for analysis. The initial search yielded 4129 total studies, 33 of which were included for quantitative analysis. A total of 8221 patients were analyzed and the rate of preoperative seizure was 26%. Patients were classified as adult vs pediatric and male vs female for analysis. Meningiomas were classified as midline/bilateral vs left-sided vs right-sided, WHO grade 1 vs grade 2-3, greater than 4 cm3 vs less than 4 cm3, and skull base vs non-skull base location. The preoperative signs and symptoms analyzed included presence of headaches, tumor-related edematous change, and neurological deficits. Preoperative seizures were more common in pediatric patients (p&lt; .02) and males (p&lt; .0001). Patients with tumors classified as midline (p&lt; .0001), WHO grade 2-3 (p&lt; .0001), larger than 4 cm3 (p&lt; .0001), and skull base location (p&lt; .0001) were more likely to experience preoperative seizures. Preoperative headaches (p&lt; .0001) were less common in patients with preoperative seizures. Edematous change (p&lt; .0001) and neurological deficits (P&lt; .0001) were more common in patients with pre-operative seizures. On assessment of risk for study bias, no publication bias was detected. This meta-analysis displayed that over 20% of meningioma patients suffer from preoperative seizures. Notably, pediatric patients, patients with midline and skull base meningiomas, and males of all ages were more likely to experience preoperative seizure. Interestingly, patients with preoperative seizures were less likely to experience headaches.

Abstract Purpose: The epigenetic mechanisms involved in transcriptional regulation leading to malignant phenotype in gliomas remains poorly understood. Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, we investigated its role in epigenetic regulation in these tumors. Experimental Design: To investigate the role of TOP2B in epigenetic regulation in gliomas, we performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens. These experiments were complemented with assay for transposase-accessible chromatin using sequencing, gene silencing, and mouse xenograft experiments to investigate the function of TOP2B and its role in glioma phenotypes. Results: We discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with PDGFRA and MYC expression across glioma specimens, which was not seen in nontumoral human brain tissue. In vivo, TOP2B knockdown of human glioma intracranial implants prolonged survival and downregulated PDGFRA. Conclusions: Our results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas promoting a proliferative phenotype.