Fractionated radiotherapy for surgically resected intracranial meningiomas: A multicentre retrospective cohort study.

BACKGROUND: Aside from surgical resection, the only standard of care treatment modality for meningiomas is radiotherapy (RT). Despite this, few studies have focused on identifying clinical covariates associated with failure of fractionated RT following surgical resection (fRT), and the timing of fRT following surgery still remains controversial (adjuvant versus salvage fRT). We assessed the outcomes of the largest, multi-institutional cohort of surgically resected meningiomas treated with subsequent adjuvant and salvage fRT to identify factors associated with local freedom from recurrence (LFFR) over 3-10 years post-fRT and to determine the optimal timing of fRT. METHODS: Patients with intracranial meningiomas who underwent surgery and fRT between 1997 and 2018 were included. Primary endpoints were radiographic recurrence/progression and time to progression from the completion of fRT. RESULTS: 404 meningiomas were included for analysis. Of these, 167 (41.3%) recurred post-fRT. Clinical covariates independently associated with worse PFS post-fRT included receipt of previous RT to the meningioma, having a WHO grade 3 meningioma or recurrent meningioma, the meningioma having a higher MIB1-index or brain invasion on pathology, and older patient age at diagnosis. Subgroup analysis identified higher MIB1-index as a histological factor associated with poorer LFFR in WHO grade 2 meningiomas. 179 patients underwent adjuvant RT shortly after surgery whereas 225 patients had delayed, salvage fRT after recurrence/progression. Following propensity score matching, patients that underwent adjuvant fRT had improved LFFR post-fRT compared to those that received salvage fRT. CONCLUSION: There is a paucity of clinical factors that can predict a meningioma's response to fRT following surgery. Adjuvant fRT may be associated with improved PFS post-fRT compared to salvage fRT. Molecular biomarkers of RT-responsiveness are needed to better inform fRT treatment decisions.

Outcomes and predictors of response to fractionated radiotherapy as primary treatment for intracranial meningiomas.

Background: Surgery is the primary treatment for most meningiomas. However, primary fractionated radiotherapy (fRT) remains an option for patients with larger meningiomas in challenging anatomic locations or patients at prohibitively high surgical risk. Outcome prediction for these patients is uncertain and cannot be guided by histopathology without available tumor tissue from surgery. Therefore, we aimed to assess the clinical factors that contribute to treatment failure in a large cohort of meningiomas consecutively treated with fRT as primary therapy, with the goal of identifying predictors of response. Methods: Patients treated with primary fRT for intracranial meningiomas from 1998 to 2017 were reviewed. Those who received primary surgical resection, radiosurgery, previous fRT, or had <6 months of clinical follow-up were excluded. We applied logistic regression and Cox regression modeling to ascertain key predictors of treatment failure, progression-free survival (PFS), and adverse events (AE) following fRT. Results: Our cohort included 137 meningiomas, 21 of which progressed after fRT (median PFS 3.45 years). Progressive meningiomas had a larger median gross tumor volume (GTV) compared to those that remained stable (19.1 cm3 vs 9.6 cm3, p = 2.86 × 10-2). GTV > 11.27 cm3 was independently predictive of progression and larger GTV was associated with higher risk of significant (grades 3/4) AE following fRT. Cavernous sinus and optic nerve sheath meningiomas had overall excellent outcomes post-fRT. Conclusions: We present a large cohort of meningiomas treated with primary fRT and find GTV and anatomic location to be key predictors of outcome, adding to the complex treatment considerations for this heterogeneous disease.

The role of immune checkpoint inhibitors in patients with intracranial metastatic disease.

Intracranial metastatic disease (IMD) complicates the course of nearly 2-4% of patients with systemic cancer. The prevalence of IMD has been increasing over the past few decades. Historically, definitive treatment for brain metastases (BM) has been limited to radiation therapy or surgical resection. Chemotherapies have not typically proven valuable in the treatment of IMD, with the exception of highly chemotherapy-sensitive lesions. Recent data have supported a role for systemic targeted therapies and immune checkpoint inhibitors (ICIs) in the treatment of select patients with IMD. There remains, however, a clear clinical need for further investigation to delineate the role of ICIs in patients with BM. In this review, we outline and describe recent and current efforts to identify the efficacy of ICI therapy in patients with IMD.

DNA methylation profiling of a lipomatous meningioma: illustrative case.

BACKGROUND: Lipomatous meningiomas are an extremely rare, benign meningioma subtype subcategorized under metaplastic meningioma in the most recent 2021 update to the World Health Organization classification. They make up less than 0.3% of all meningiomas and, to date, less than 70 cases have been reported in the literature, none of which have undergone molecular profiling. This study aims to promote the utility of molecular profiling to better diagnose these rare tumors. OBSERVATIONS: The authors present the first case of a lipomatous meningioma with DNA methylation profiling that both confirmed its benign biology and uncovered unique cytogenetic changes. Molecular characterization of a lipomatous meningioma confirmed its diagnosis as a distinct, benign meningioma subtype and revealed several copy number variations on chromosome 8 and in NF2 and SMARCB1. Here we discuss some of the radiological and histopathological features of lipomatous meningiomas, how they can be used to distinguish from other meningiomas and other similarly presenting tumors, and a brief literature review discussing the pathophysiology and presentation of this rare tumor. LESSONS: This study provides evidence supporting the use of molecular profiling to diagnose lipomatous meningiomas and guide their clinical management more accurately.

Post-cardiac Injury Syndrome Following Permanent Dual-Chamber Pacemaker Implantation.

Post-cardiac injury syndrome is a heterogeneous group of conditions that result from autoimmune-mediated inflammation of the pericardium, epicardium, and myocardium. Interventions such as pacemaker lead insertions, percutaneous coronary interventions, radiofrequency ablations, cardiac surgeries, and Swan-Ganz catheterizations can cause myocardial injury leading to post-traumatic pericarditis. This phenomenon can lead to chest pain, recurrent effusions, and fever along with possible complications of heart failure, arrhythmias, conduction abnormalities as well as cardiac tamponade. Herein, we present a case report of a 64-year-old female with a history of sick sinus syndrome managed with a dual-chamber pacemaker who presented with post-cardiac injury syndrome after three months of pacemaker implantation. She developed a recurrent syndrome of fever, chest discomfort, tachycardia with weakness, hemodynamic instability, hemorrhagic serositis, and cardiac tamponade. The mechanism of exudative inflammatory effusions initially remained inconclusive, as the workup for infectious and malignant processes was negative. However, post-cardiac injury syndrome akin to the Dressler syndrome related to screw-in dual-chamber pacemaker implantation remained a possibility. Her condition was acutely managed with a combination of colchicine and glucocorticoid therapy. She was placed on long-term aspirin and colchicine therapy to prevent any recurrences. This article illustrates a case of post-cardiac injury syndrome after dual-chamber pacemaker implantation, including details of evaluation, management, complications and monitoring of patient progress.

The aminoglycoside G418 hinders de novo prion infection in cultured cells.

The study of prions and the discovery of candidate therapeutics for prion disease have been facilitated by the ability of prions to replicate in cultured cells. Paradigms in which prion proteins from different species are expressed in cells with low or no expression of endogenous prion protein (PrP) have expanded the range of prion strains that can be propagated. In these systems, cells stably expressing a PrP of interest are typically generated via coexpression of a selectable marker and treatment with an antibiotic. Here, we report the unexpected discovery that the aminoglycoside G418 (Geneticin) interferes with the ability of stably transfected cultured cells to become infected with prions. In G418-resistant lines of N2a or CAD5 cells, the presence of G418 reduced levels of protease-resistant PrP following challenge with the RML or 22L strains of mouse prions. G418 also interfered with the infection of cells expressing hamster PrP with the 263K strain of hamster prions. Interestingly, G418 had minimal to no effect on protease-resistant PrP levels in cells with established prion infection, arguing that G418 selectively interferes with de novo prion infection. As G418 treatment had no discernible effect on cellular PrP levels or its localization, this suggests that G418 may specifically target prion assemblies or processes involved in the earliest stages of prion infection.

Predictors of Mortality Amongst Tocilizumab Administered COVID-19 Asian Indians: A Predictive Study From a Tertiary Care Centre.

Introduction Hyper-cytokinemia is a dreaded complication of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection and an important predictor of mortality in coronavirus disease 2019 (COVID-19). The current evidence at best is still ambiguous for use of tocilizumab in cytokine storm in COVID-19. Moreover, the factors that are associated with beneficial response from tocilizumab are unknown in COVID-19. We aimed to study the clinical outcomes especially mortality vis-à-vis clinical and laboratory characteristics of patients administered tocilizumab and identify predictors of mortality benefits amongst deceased vs recovered COVID-19 patients. Methods The present study is a retrospective observation of the demographic, clinical, and biological data of all the consecutive patients treated with tocilizumab for COVID-19 pneumonia at the COVID tertiary care centre from July 2020 to October 2020 at Ahmedabad, India. We compared the deceased group with those who recovered/discharged and evaluated patient-level demographics, clinical attributes, and laboratory investigations available to identify subgroups in whom tocilizumab reduced mortality. Results Of the 112 patients included, the mean (SD) age was 56.84 ± 13.56 years and 80 (71.4%) were male. There were 97 (86.6%) patients in the survivors and 15 (13.39%) in the deceased group. Deceased were older than the recovered group (mean: 66.14, SD: 14.41 vs mean: 55.36, SD: 12.98; p=0.04). Hypertension (33.03%) was the commonest comorbidity observed. Mortality was significantly higher in patients with cancer and type-2 diabetes (p=0.05 and p=0.01, respectively). Level of D-dimer and lactate dehydrogenase (LDH) showed trends towards significance as a predictor of mortality (p=0.07 and p=0.08, respectively) not reaching significance. D-dimer level > 5,000 nanograms per millilitre (ng/mL) was the significant predictor of subsequent deaths (p<0.0001). Fourteen patients reported adverse events of tocilizumab. Patients who developed in-hospital complications (such as septic or vasodilatory shock and/or sepsis, acute kidney injury, multiorgan dysfunction) had significantly higher mortality (p<0.0001, p=0.009, and p=0.03, respectively). Conclusion Tocilizumab might be more beneficial in younger patients without sepsis/ septic shock, acute kidney injury, multiorgan dysfunction, and who were non-ventilated. The predictors of mortality amongst Asian Indians treated with tocilizumab were older patients, the presence of type-2 diabetes, cancer, in-hospital complication (such as acute kidney injury, sepsis/septic shock, multiorgan dysfunction), higher D-dimer > 5,000 ng/mL. A larger study with pre-defined inclusion cut-offs of these variables may aid in defining patient's characteristics of Asian Indians who may benefit from tocilizumab in COVID-19.

A cell-penetrating MARCKS mimetic selectively triggers cytolytic death in glioblastoma.

Glioblastoma (GBM) is an aggressive malignancy with limited effectiveness of standard of care therapies including surgery, radiation, and temozolomide chemotherapy necessitating novel therapeutics. Unfortunately, GBMs also harbor several signaling alterations that protect them from traditional therapies that rely on apoptotic programmed cell death. Because almost all GBM tumors have dysregulated phosphoinositide signaling as part of that process, we hypothesized that peptide mimetics derived from the phospholipid binding domain of Myristoylated alanine-rich C-kinase substrate (MARCKS) could serve as a novel GBM therapeutic. Using molecularly classified patient-derived xenograft (PDX) lines, cultured in stem-cell conditions, we demonstrate that cell permeable MARCKS effector domain (ED) peptides potently target all GBM molecular classes while sparing normal human astrocytes. Cell death mechanistic testing revealed that these peptides produce rapid cytotoxicity in GBM that overcomes caspase inhibition. Moreover, we identify a GBM-selective cytolytic death mechanism involving plasma membrane targeting and intracellular calcium accumulation. Despite limited relative partitioning to the brain, tail-vein peptide injection revealed tumor targeting in intracranially implanted GBM PDX. These results indicate that MARCKS ED peptide therapeutics may overcome traditional GBM resistance mechanisms, supporting further development of similar agents.

Identification of PD-L2, B7-H3 and CTLA-4 immune checkpoint proteins in genetic subtypes of meningioma.

Meningioma is the most common brain tumor in adults. Surgical resection remains the primary treatment. No chemotherapy exists. However, gene mutations now could explain ~ 80% of meningioma and targeted therapies based on these are being investigated. Furthermore, with the recent discovery of PD-L1 in malignant meningioma, clinical trials using immunotherapy have commenced. Here, we report for the first time the expression profiles of immune checkpoint proteins PD-L2, B7-H3 and CTLA-4 in meningioma and their association to common gene mutations. PD-L2 and B7-H3 expression was significantly greater than all immune checkpoint proteins studied, and particularly elevated in patients with gene mutations affecting the PI3K/AKT/mTOR pathway. CTLA-4 expressing CD3+ lymphocytes were observed in atypical and malignant meningioma and tumors harboring a PIK3CA or SMO mutation. These results identify novel targets for immunotherapy irrespective of grade and distinguish potential patient populations based on genetic classification for stratification into checkpoint inhibitor clinical trials.

Crystal structure of N-allyl-4-methyl-benzene-sulfonamide.

The title compound, C10H13NO2S, was synthesized by a nucleophilic substitution reaction between allyl amine and p-toluene-sulfonyl chloride. The sulfonate S-O bond lengths are 1.4282 (17) and 1.4353 (17) Å, and the C-N-S-C torsion angle involving the sulfonamide moiety is -61.0 (2)°. In the crystal, centrosymmetric dimers of the title compound are present via inter-molecular N-H⋯O hydrogen bonds between sulfonamide groups. These dimers are linked into ribbons along the c-axis direction through offset π-π inter-actions.