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1.
Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study.
Altwairgi, AK, Alghareeb, WA, AlNajjar, FH, Alhussain, H, Alsaeed, E, Balbaid, AAO, Aldanan, S, Orz, Y, Alsharm, AA
Investigational new drugs. 2021;(1):226-231
Abstract
Glioblastoma is a fast-growing primary brain tumor observed in adults with the worst prognosis. Preclinical studies have demonstrated the encouraging anticancer activity of statins. This study evaluated the efficacy of atorvastatin in combination with standard therapy in patients with glioblastoma. In this prospective, open-label, single-arm, phase II study, patients were treated with atorvastatin in combination with the standard glioblastoma therapy comprising radiotherapy and temozolomide. The primary endpoint was progression-free survival (PFS) at 6 months (PFS-6). Among 36 patients enrolled from January 2014 to January 2017, the median age was 52 (20-69) years; 22% of the patients were aged ≥60 years, and 62% were male. Patients received atorvastatin for a median duration of 6.2 (0.3-28) months. At a median follow-up of 19 months, the PFS-6 rate was 66%, with a median PFS of 7.6 (5.7-9.4) months. In terms of Grade ≥ 3 hematological adverse events, thrombocytopenia and neutropenia occurred in 7% and 12% of patients, respectively. In multivariate analyses, high baseline low-density lipoprotein levels were associated with worse survival (P = 0.046). Atorvastatin was not shown to improve PFS-6. However, this study identified that high low-density lipoprotein levels are an independent predictor of poor cancer-related outcomes. Future clinical trials testing statins should aim to enroll patients with slow-growing tumors.Clinical trial information: NCT0202957 (December 12, 2013).
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Feasibility and Biological Activity of a Ketogenic/Intermittent-Fasting Diet in Patients With Glioma.
Schreck, KC, Hsu, FC, Berrington, A, Henry-Barron, B, Vizthum, D, Blair, L, Kossoff, EH, Easter, L, Whitlow, CT, Barker, PB, et al
Neurology. 2021;(9):e953-e963
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Abstract
OBJECTIVE To examine the feasibility, safety, systemic biological activity, and cerebral activity of a ketogenic dietary intervention in patients with glioma. METHODS Twenty-five patients with biopsy-confirmed World Health Organization grade 2 to 4 astrocytoma with stable disease after adjuvant chemotherapy were enrolled in an 8-week Glioma Atkins-Based Diet (GLAD). GLAD consisted of 2 fasting days (calories <20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates ≤20 g/d) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, insulin-like growth factor-1, and magnetic resonance spectroscopy at baseline and week 8. RESULTS Twenty-one patients (84%) completed the study. Eighty percent of patients reached ≥40 mg/dL urine acetoacetate during the study. Forty-eight percent of patients were adherent by food record. The diet was well tolerated, with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity, including hemoglobin A1c, insulin, and fat body mass, decreased significantly, while lean body mass increased. Magnetic resonance spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate [bHB] and acetone) in both lesional and contralateral brain compared to baseline. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB R s = 0.52, p = 0.05). Subgroup analysis of isocitrate dehydrogenase-mutant glioma showed no differences in cerebral metabolites after controlling for ketonuria. CONCLUSION The GLAD dietary intervention, while demanding, produced meaningful ketonuria and significant systemic and cerebral metabolic changes in participants. Ketonuria in participants correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records. TRIAL REGISTRATION INFORMATION ClinicalTrials.gov Identifier: NCT02286167.
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Deep learning features from diffusion tensor imaging improve glioma stratification and identify risk groups with distinct molecular pathway activities.
Yan, J, Zhao, Y, Chen, Y, Wang, W, Duan, W, Wang, L, Zhang, S, Ding, T, Liu, L, Sun, Q, et al
EBioMedicine. 2021;:103583
Abstract
BACKGROUND To develop and validate a deep learning signature (DLS) from diffusion tensor imaging (DTI) for predicting overall survival in patients with infiltrative gliomas, and to investigate the biological pathways underlying the developed DLS. METHODS The DLS was developed based on a deep learning cohort (n = 688). The key pathways underlying the DLS were identified on a radiogenomics cohort with paired DTI and RNA-seq data (n=78), where the prognostic value of the pathway genes was validated in public databases (TCGA, n = 663; CGGA, n = 657). FINDINGS The DLS was associated with survival (log-rank P < 0.001) and was an independent predictor (P < 0.001). Incorporating the DLS into existing risk system resulted in a deep learning nomogram predicting survival better than either the DLS or the clinicomolecular nomogram alone, with a better calibration and classification accuracy (net reclassification improvement 0.646, P < 0.001). Five kinds of pathways (synaptic transmission, calcium signaling, glutamate secretion, axon guidance, and glioma pathways) were significantly correlated with the DLS. Average expression value of pathway genes showed prognostic significance in our radiogenomics cohort and TCGA/CGGA cohorts (log-rank P < 0.05). INTERPRETATION DTI-derived DLS can improve glioma stratification by identifying risk groups with dysregulated biological pathways that contributed to survival outcomes. Therapies inhibiting neuron-to-brain tumor synaptic communication may be more effective in high-risk glioma defined by DTI-derived DLS. FUNDING A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
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Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma.
Kaley, TJ, Panageas, KS, Pentsova, EI, Mellinghoff, IK, Nolan, C, Gavrilovic, I, DeAngelis, LM, Abrey, LE, Holland, EC, Omuro, A, et al
Annals of clinical and translational neurology. 2020;(4):429-436
Abstract
PURPOSE Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well-tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti-tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose. METHODS Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg. RESULTS We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose-limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1). CONCLUSION Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.
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A novel three-dimensional template combined with MR-guided 125I brachytherapy for recurrent glioblastoma.
He, X, Liu, M, Zhang, M, Sequeiros, RB, Xu, Y, Wang, L, Liu, C, Wang, Q, Zhang, K, Li, C
Radiation oncology (London, England). 2020;(1):146
Abstract
BACKGROUND At present, the treatment of recurrent glioblastoma is extremely challenging. In this study, we used a novel three-dimensional non-coplanar template (3DNPT) combined with open MR to guide 125I seed implantation for recurrent glioblastoma. The aim of this study was to evaluate the feasibility, accuracy, and effectiveness of this technique. METHODS Twenty-four patients of recurrent glioblastoma underwent 3DNPT with open MR-guided 125I brachytherapy from August 2017 to January 2019. Preoperative treatment plan and 3DNPT were made according to enhanced isovoxel T1-weighted MR images. 125I seeds were implanted using 3DNPT and 1.0-T open MR imaging guidance. Dosimetry verification was performed after brachytherapy based on postoperative CT/MR fusion images. Preoperative and postoperative dosimetry parameters of D90, V100, V200, conformity index (CI), external index (EI) were compared. The objective response rate (ORR) at 6 months and 1-year survival rate were calculated. Median overall survival (OS) measured from the date of brachytherapy was estimated by Kaplan-Meier method. RESULTS There were no significant differences between preoperative and postoperative dosimetry parameters of D90, V100, V200, CI, EI (P > 0.05). The ORR at 6 months was 75.0%. The 1-year survival rate was 58.3%. Median OS was 12.9 months. One case of small amount of epidural hemorrhage occurred during the procedure. There were 3 cases of symptomatic brain edema after brachytherapy treatment, including grade three toxicity in 1 case and grade two toxicity in 2 cases. The three patients were treated with corticosteroid for 2 to 4 weeks. The clinical symptoms related to brain edema were significantly alleviated thereafter. CONCLUSIONS 3DNPT combined with open MR-guided 125I brachytherapy for circumscribed recurrent glioblastoma is feasible, effective, and with low risk of complications. Postoperative dosimetry matched the preoperative treatment plan. The described method can be used as a novel implantation technique for 125I brachytherapy in the treatment of recurrent gliomas. TRIAL REGISTRATION The study was approved by the Institutional Review Board of Shandong Provincial Hospital Affiliated to Shandong University (NSFC:NO.2017-058), registered 1st July 2017.
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A novel lecithin-based delivery form of Boswellic acids as complementary treatment of radiochemotherapy-induced cerebral edema in patients with glioblastoma multiforme: a longitudinal pilot experience.
Di Pierro, F, Simonetti, G, Petruzzi, A, Bertuccioli, A, Botta, L, Bruzzone, MG, Cuccarini, V, Fariselli, L, Lamperti, E
Journal of neurosurgical sciences. 2019;(3):286-291
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is an extremely challenging neurological disease for which the development of more effective therapeutic options and of adjuvant/complementary treatment is needed. We investigated the effects of an innovative phytosome-based delivery form of boswellic acids extract (Monoselect AKBA™) on radiochemotherapy-induced cerebral edema in patients with primary GBM. METHODS Patients with de novo GBM treated with surgery, radiotherapy and chemotherapy with temozolomide were enrolled in this longitudinal study and received boswellia-based product 4500 mg/die for a maximum of 34 weeks. Cerebral edema was assessed at 4, 12, 22 and 34 weeks post-surgery, together with steroids consumption and patients' psychological status. RESULTS A total of 20 patients were included in the study. The percentage of patients with reduced edema was constant during the study, while the percentage of those with reduced or stable edema tended to increase over time. Of note, two patients achieved a considerable reduction in brain edema, which led to a more favorable and beneficial surgical resection. In addition, a good percentage of patients assumed a stable/reduced steroids dose or were dexamethasone free during the study. Lastly, patients' QoL and psychological state were maintained throughout the study. CONCLUSIONS Complementary treatment with Monoselect AKBA™ might exert a beneficial effect in reducing radiochemotherapy-induced cerebral edema, thanks to the anti-inflammatory properties of the boswellia serrata extract. The reduction in brain edema might diminish dexamethasone assumption, thus minimizing steroids-induced side effects, and in few cases may allow a complete surgical excision of the tumor mass.
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11C-methionine-PET for differentiating recurrent brain tumor from radiation necrosis: radiomics approach with random forest classifier.
Hotta, M, Minamimoto, R, Miwa, K
Scientific reports. 2019;(1):15666
Abstract
Differentiating recurrent brain tumor from radiation necrosis is often difficult. This study aims to investigate the efficacy of 11C-methionine (MET)-PET radiomics for distinguishing recurrent brain tumor from radiation necrosis, as compared with conventional tumor-to-normal cortex (T/N) ratio evaluation. We enrolled 41 patients with metastatic brain tumor or glioma treated using radiation therapy who underwent MET-PET. The area with a standardized uptake value > 1.3 times that of the normal brain cortex was contoured. Forty-two PET features were extracted and used in a random forest classifier and the diagnostic performance was evaluated using a 10-fold cross-validation scheme. Gini index was measured to identify relevant PET parameters for classification. The reference standard was surgical histopathological analysis or more than 6 months of follow-up with MRI. Forty-four lesions were used for the analysis. Thirty-three and 11 lesions were confirmed as recurrent brain tumor and radiation necrosis, respectively. Radiomics and T/N ratio evaluation showed sensitivities of 90.1% and 60.6%, and specificities of 93.9% and 72.7% with areas under the curve of 0.98 and 0.73, respectively. Gray level co-occurrence matrix dissimilarity was the most pertinent feature for diagnosis. MET-PET radiomics yielded excellent outcome for differentiating recurrent brain tumor from radiation necrosis, which outperformed T/N ratio evaluation.
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Intraoperative Molecular Imaging with Second Window Indocyanine Green Facilitates Confirmation of Contrast-Enhancing Tissue During Intracranial Stereotactic Needle Biopsy: A Case Series.
Li, C, Sullivan, PZ, Cho, S, Nasrallah, MP, Buch, L, Isaac Chen, HC, Lee, JYK
World neurosurgery. 2019;:e1211-e1218
Abstract
BACKGROUND Stereotactic needle biopsy provides a minimally invasive option for the diagnosis of intracranial lesions but is limited by inconclusive diagnoses on frozen pathology. For rapid pathology, 5-aminovelunic acid and sodium fluorescein have previously demonstrated potential as diagnostic adjuvants. Stereotactic biopsy with near-infrared (NIR) fluorophores has not been reported. We identified 5 representative cases using NIR fluorescent dye indocyanine green (ICG) administered in a high dose, delayed manner. METHODS Five patients underwent second window indocyanine green (SWIG)-guided stereotactic biopsy for diagnosis of suspected glioma or tumor recurrence. Up to 5 mg/kg ICG was administered approximately 24 hours prior to surgery. Biopsies were conducted in the standard fashion, targeting regions of suspected tumor using intraoperative frameless navigation. Samples were examined intraoperatively under standard visible light and for fluorescence using conventional NIR imaging platforms. Findings were correlated with frozen and final tumor pathology for all cases. RESULTS A total of 10 biopsy specimens were obtained. Three did not fluoresce and did not demonstrate tumor on preliminary or final pathology, including a non-gadolinium-enhancing sample taken proximal to the final target. The remaining 7 fluoresced, of which 6 contained tumor and 1 contained necrosis. Fluorescence was also noted in a patient with radiation treatment effect. Overall fluorescence characteristics were highly concordant with preliminary and final diagnoses. CONCLUSIONS SWIG provides rapid intraoperative confirmation of pathologic brain tissue by permeating neoplastic or inflammatory brain tissue via a mechanism similar to that of gadolinium enhancement. SWIG-guided stereotactic biopsy can improve surgical efficiency by enhancing confidence in acquisition of target tissue.
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Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma.
Ronellenfitsch, MW, Zeiner, PS, Mittelbronn, M, Urban, H, Pietsch, T, Reuter, D, Senft, C, Steinbach, JP, Westphal, M, Harter, PN
Acta neuropathologica communications. 2018;(1):81
Abstract
Glioblastoma (GB) is the most frequent primary brain tumor in adults with a dismal prognosis despite aggressive treatment including surgical resection, radiotherapy and chemotherapy with the alkylating agent temozolomide. Thus far, the successful implementation of the concept of targeted therapy where a drug targets a selective alteration in cancer cells was mainly limited to model diseases with identified genetic drivers. One of the most commonly altered oncogenic drivers of GB and therefore plausible therapeutic target is the epidermal growth factor receptor (EGFR). Trials targeting this signaling cascade, however, have been negative, including the phase III OSAG 101-BSA-05 trial. This highlights the need for further patient selection to identify subgroups of GB with true EGFR-dependency. In this retrospective analysis of treatment-naïve samples of the OSAG 101-BSA-05 trial cohort, we identify the EGFR signaling activity markers phosphorylated PRAS40 and phosphorylated ribosomal protein S6 as predictive markers for treatment efficacy of the EGFR-blocking antibody nimotuzumab in MGMT promoter unmethylated GBs. Considering the total trial population irrespective of MGMT status, a clear trend towards a survival benefit from nimotuzumab was already detectable when tumors had above median levels of phosphorylated ribosomal protein S6. These results could constitute a basis for further investigations of nimotuzumab or other EGFR- and downstream signaling inhibitors in selected patient cohorts using the reported criteria as candidate predictive biomarkers.
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Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02.
Nghiemphu, PL, Ebiana, VA, Wen, P, Gilbert, M, Abrey, LE, Lieberman, F, DeAngelis, LM, Robins, HI, Yung, WKA, Chang, S, et al
Journal of neuro-oncology. 2018;(1):79-86
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Abstract
Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.