Dataset Information

Phase 0 Clinical Trial of Everolimus in Patients with Vestibular Schwannoma or Meningioma.

ABSTRACT: Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of patients with neurofibromatosis type 2 (NF2) with vestibular schwannoma. To assess the pharmacokinetics, pharmacodynamics, and potential mechanisms of treatment resistance, we performed a presurgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for vestibular schwannoma or meningiomas. Eligible patients with meningioma or vestibular schwannoma requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately before and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and postoperative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/mL and 9.4 ng/mL, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range, 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared with control tissues from untreated patients (P = 0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited antitumor effect of everolimus observed in clinical studies for patients with NF2 and will inform the design of future preclinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.

SUBMITTER: Karajannis MA

PROVIDER: S-EPMC8419097 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Phase 0 Clinical Trial of Everolimus in Patients with Vestibular Schwannoma or Meningioma.

Karajannis Matthias A MA Mauguen Audrey A Maloku Ekrem E Xu Qingwen Q Dunbar Erin M EM Plotkin Scott R SR Yaffee Anna A Wang Shiyang S Roland J Thomas JT Sen Chandranath C Placantonakis Dimitris G DG Golfinos John G JG Allen Jeffrey C JC Vitanza Nicholas A NA Chiriboga Luis A LA Schneider Robert J RJ Deng Jingjing J Neubert Thomas A TA Goldberg Judith D JD Goldberg Judith D JD Zagzag David D Giancotti Filippo G FG Blakeley Jaishri O JO

Molecular cancer therapeutics 20210617 9

Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of patients with neurofibromatosis type 2 (NF2) with vestibular schwannoma. To assess the pharmacokinetics, pharmacodynamics, and potential mechanisms of treatment resistance, we performed a presurgical (phase 0) clinical trial of everolimus in patients und ...[more]

PMID: 34224367

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Project description:BackgroundGiven concerns about risks associated with the growing use of mobile phones over recent decades, the authors analyzed temporal trends in incidence rates of nonmalignant meningioma and vestibular schwannoma in the United States.MethodsThe incidence of nonmalignant meningioma and vestibular schwannoma among adults in the Surveillance, Epidemiology, and End Results 18 registries during 2004 through 2017 was evaluated according to the method of diagnosis: microscopically (MC) or radiographically confirmed (RGC). Annual percent changes (APCs) and 95% CIs were estimated using log-linear models.ResultsOverall meningioma rates (n = 108,043) increased significantly from 2004 to 2009 (APC, 5.4%; 95% CI, 4.4%-6.4%) but subsequently rose at a slower pace through 2017 (APC, 1.0%; 95% CI, 0.6%-1.5%). Rates for MC meningiomas changed little from 2004 to 2017 (APC, -0.3%; 95% CI, -0.7%, 0.1%) but rose rapidly for RGC meningiomas until 2009 (APC, 9.5%; 95% CI, 7.8%-11.1%) and rose more modestly thereafter (APC, 2.3%; 95% CI, 1.5%-3.0%). Overall vestibular schwannoma rates (n = 17,475) were stable (APC, 0.4%; 95% CI, -0.2%, 1.0%), but MC vestibular schwannoma rates decreased (APC, -1.9%; 95% CI, -2.7%, -1.1%), whereas RGC vestibular schwannoma rates rose (2006-2017: APC, 1.7%; 95% CI, 0.5%-3.0%). For each tumor, the trends by diagnostic method were similar for each sex and each racial/ethnic group, but RGC diagnosis was more likely in older patients and for smaller tumors. Meningioma trends and the proportion of RGC diagnoses varied notably by registry.ConclusionsOverall trends obscured differences by diagnostic method in this first large, detailed assessment, but the recent stable rates argue against an association with mobile phone use. Variation among registries requires evaluation to improve the registration of these nonmalignant tumors.Lay summaryThe etiology of most benign meningiomas and vestibular schwannomas is poorly understood, but concerns have been raised about whether mobile phone use contributes to risk of developing these tumors. Descriptive studies examining temporal trends could provide insight; however, globally, few registries collect these nonmalignant cases. In the United States, reporting benign meningiomas and vestibular schwannomas became required by law in 2004. This was the first large, systematic study to quantify and characterize incidence trends for meningioma and vestibular schwannoma according to whether the tumors were diagnosed microscopically or only radiographically. Differential trends across registries and by diagnostic method suggest that caution should be used when interpreting the patterns.

Project description:AimVestibular schwannomas (VSs) are generally considered benign tumors, and malignant transformation of VSs (MTVSs) are rare findings. The clinical features, treatment strategy, outcomes and prognostic factors remain unclear. We endeavored to analyze the natural history, management, outcomes and prognostic factors of MTVSs.Materials and methodsThe clinical features, radiologic findings, pathological investigations and surgical outcomes of 4 patients with MTVSs treated at the authors' institution between 2010 and 2019 were retrospectively collected. Related literature published until December 2019 (63 articles, 67 patients) was evaluated. The authors also made a pooled analysis to evaluate the risk factors for overall survival (OS) time.ResultsOf the 4 cases in our series, 3 cases were malignant transformation following previous treatment (surgery and radiosurgery) and 1 was primary MTVS. Of the 71 MTVSs from the literature, 27 were male and 39 were female, with the mean age of 47.2 ± 17.5 years old. Twelve patients (18.5%) were diagnosed with NF2 (15.4%) or NF1 (3.1%). Forty-three (61.4%) patients underwent previous treatment (surgery and/or radiotherapy) prior to the pathological diagnosis of MTVSs. The mean size of the MTVSs was 35.1 ± 13.2mm. The mean Ki-67 index was 30.6% ± 18.8%. Twenty-four (49.0%) patients underwent gross total resection, 25 (51.0%) patients underwent incomplete resection. Twenty-five (44.6%) underwent adjuvant radiotherapy (RT) postoperatively. During the average follow-up of 9.9 ± 9.5 months (range, 0-40 months), 37 (82.2%) patients developed a local recurrence or metastasis. Forty-seven (73.4%) patients died of tumor progression or postoperative complications. The overall 1-year and 2-year survival rate was 42.3% and 18.6% respectively. Log-rank testing for Kaplan-Meier survival analysis identified that size (P = 0.047) and adjuvant radiotherapy (P=0.001) were significant prognostic factors for OS. Multivariate analysis revealed that adjuvant RT was the only prognostic factor for longer OS (P = 0.005).ConclusionsMTVSs are rare, fatal disease, prone to recur and metastasize rapidly, resulting in death in most of the cases. We found that GTR did not improve the survival in MTVSs but postoperative adjuvant RT can significantly improve the OS, and we recommend early postoperative RT in MTVSs regardless of extent of resection.

Project description:ObjectiveThe Koos grading scale is a frequently used classification system for vestibular schwannoma (VS) that accounts for extrameatal tumor dimension and compression of the brain stem. We propose an artificial intelligence (AI) pipeline to fully automate the segmentation and Koos classification of VS from MRI to improve clinical workflow and facilitate patient management.MethodsWe propose a method for Koos classification that does not only rely on available images but also on automatically generated segmentations. Artificial neural networks were trained and tested based on manual tumor segmentations and ground truth Koos grades of contrast-enhanced T1-weighted (ceT1) and high-resolution T2-weighted (hrT2) MR images from subjects with a single sporadic VS, acquired on a single scanner and with a standardized protocol. The first stage of the pipeline comprises a convolutional neural network (CNN) which can segment the VS and 7 adjacent structures. For the second stage, we propose two complementary approaches that are combined in an ensemble. The first approach applies a second CNN to the segmentation output to predict the Koos grade, the other approach extracts handcrafted features which are passed to a Random Forest classifier. The pipeline results were compared to those achieved by two neurosurgeons.ResultsEligible patients (n = 308) were pseudo-randomly split into 5 groups to evaluate the model performance with 5-fold cross-validation. The weighted macro-averaged mean absolute error (MA-MAE), weighted macro-averaged F1 score (F1), and accuracy score of the ensemble model were assessed on the testing sets as follows: MA-MAE = 0.11 ± 0.05, F1 = 89.3 ± 3.0%, accuracy = 89.3 ± 2.9%, which was comparable to the average performance of two neurosurgeons: MA-MAE = 0.11 ± 0.08, F1 = 89.1 ± 5.2, accuracy = 88.6 ± 5.8%. Inter-rater reliability was assessed by calculating Fleiss' generalized kappa (k = 0.68) based on all 308 cases, and intra-rater reliabilities of annotator 1 (k = 0.95) and annotator 2 (k = 0.82) were calculated according to the weighted kappa metric with quadratic (Fleiss-Cohen) weights based on 15 randomly selected cases.ConclusionsWe developed the first AI framework to automatically classify VS according to the Koos scale. The excellent results show that the accuracy of the framework is comparable to that of neurosurgeons and may therefore facilitate management of patients with VS. The models, code, and ground truth Koos grades for a subset of publicly available images (n = 188) will be released upon publication.

Dataset Information

Phase 0 Clinical Trial of Everolimus in Patients with Vestibular Schwannoma or Meningioma.

Publications

Phase 0 Clinical Trial of Everolimus in Patients with Vestibular Schwannoma or Meningioma.

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