Surgery of high grade gliomas - pros in favor of maximal cytoreductive surgery

Background: Malignant glioma is themost common primary brain tumour inadults. More and more studies are focusedon the role of surgery in prolonged medianof survival and survival at two years. Thepurpose of this study is to add somearguments in favour of radical surgery inmalignant glioma.Material and Methods: The study is based433 cases of high grade cerebral gliomaoperated between 01.01.2000-31.12.2009 atthe Department of Neurosurgery, ClujCounty Emergency Hospital. We analyzedage, gender, type and duration ofsymptoms, type of surgery, pathologicaldiagnosis and the correlation of thesefactors with overall survival. Data for longterm follow up were available for 266patients.Results: The results shows, according totheir histological features, the fallowingdispersions: astrocitomas grade III (28%),glioblastoma multiforme (64%), high gradeoligodendrogliomas (5%) and high gradeependimomas (3%). The global survivalrate was 47 % at 12 months, 26,3% at 18months and 16,7% at 24 months. The ageand type of surgery are prognostic factorsthat significantly influenced the survival at12, 18 and 24 months (9,3 months age <65years versus 7,1 months age >65 years; 9,2months GTR versus 6,4 months STR-at 12months monitoring; 11,7 months age <65versus 7,7 months age >65; 11,5 monthsGTR versus 7,1 months STR-at 18 monthsmonitoring; 12,8 months age <65 versus 8months age >65; 12,6 months GTR versus7,5 months STR –at 24 monthsmonitoring).Conclusions: Our study shows that longterm postoperative outcome after radicalsurgical resection are better than the resultsof either partial resection or simple biopsy;in terms of duration of survival (thedifference of mean survival at 12, 18 and 24months monitoring was 2,8 months, 4,4months and 5,1 months respectively infavour of patients with gross total removal)

Who Is In Charge, and Who Should Be? The Disciplinary Role of the Commander in Military Justice Systems

BackgroundStandard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. MethodsWe randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival. ResultsA total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P&lt;0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%). ConclusionsThe addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo.

Deep-learning magnetic resonance imaging-based automatic segmentation for organs-at-risk in the brain: Accuracy and impact on dose distribution

Background and purpose: Normal tissue sparing in radiotherapy relies on proper delineation. While manual contouring is time consuming and subject to inter-observer variability, auto-contouring could optimize workflows and harmonize practice. We assessed the accuracy of a commercial, deep-learning, MRI-based tool for brain organs-at-risk delineation. Materials and methods: Thirty adult brain tumor patients were retrospectively manually recontoured. Two additional structure sets were obtained: AI (artificial intelligence) and AIedit (manually corrected auto-contours). For 15 selected cases, identical plans were optimized for each structure set. We used Dice Similarity Coefficient (DSC) and mean surface-distance (MSD) for geometric comparison and gamma analysis and dose-volume-histogram comparison for dose metrics evaluation. Wilcoxon signed-ranks test was used for paired data, Spearman coefficient(ρ) for correlations and Bland–Altman plots to assess level of agreement. Results: Auto-contouring was significantly faster than manual (1.1/20 min, p < 0.01). Median DSC and MSD were 0.7/0.9 mm for AI and 0.8/0.5 mm for AIedit. DSC was significantly correlated with structure size (ρ = 0.76, p < 0.01), with higher DSC for large structures. Median gamma pass rate was 74% (71–81%) for Plan_AI and 82% (75–86%) for Plan_AIedit, with no correlation with DSC or MSD. Differences between Dmean_AI and Dmean_Ref were ≤ 0.2 Gy (p < 0.05). The dose difference was moderately correlated with DSC. Bland Altman plot showed minimal discrepancy (0.1/0) between AI and reference Dmean/Dmax. Conclusions: The AI-model showed good accuracy for large structures, but developments are required for smaller ones. Auto-segmentation was significantly faster, with minor differences in dose distribution caused by geometric variations

Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma

BackgroundStandard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. MethodsWe randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival. ResultsA total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P&lt;0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%). ConclusionsThe addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo.

Randomized Phase II Study of Duligotuzumab (MEHD7945A) vs. Cetuximab in Squamous Cell Carcinoma of the Head and Neck (MEHGAN Study)

Background: Duligotuzumab, a novel dual-action humanized IgG1 antibody that blocks ligand binding to EGFR and HER3, inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody dependent cell mediated cytotoxicity. High tumor-expression of neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab. Methods: This multicenter, open-label, randomized phase II study (MEGHAN) evaluated drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) progressive on/after chemotherapy, and among patients with NRG1-high tumors. Patients received duligotuzumab (1100 mg IV, q2w) or cetuximab (400 mg/m2 load, 250 mg/m2 IV, q1w) until progression or intolerable toxicity. Tumor samples were assayed for biomarkers (NRG1, ERBB3, and HPV status).Results: Patients (N =121) were randomized (duligotuzumab:cetuximab; 59:62), median age 62 y; ECOG 0-2. Both arms (duligotuzumab vs. cetuximab, respectively) showed comparable progression-free survival (4.2 vs. 4.0 months; HR: 1.23 [90% CI: 0.89-1.70]), overall survival (7.2 vs. 8.7 months; HR 1.15 [90% CI: 0.81-1.63], and objective response rate (12% vs. 14.5%), with no difference between patients with NRG1-high tumors or ERBB3-low tumors. Responses in both arms were confined to HPV-negative patients. Grade ≥3 adverse events (duligotuzumab vs. cetuximab, respectively) included infections (22% vs. 11.5%) and GI disorders (17% vs. 7%) contributing to higher rates of serious adverse events (41% vs. 29.5%). Metabolic disorders were less frequent with duligotuzumab (10% vs. 16%); any grade rash-related events were less with duligotuzumab (49% vs. 67%).Conclusion: While several lines of preclinical evidence had supported the premise that the blockade of HER3 in addition to that of EGFR may improve outcomes for patients with R/M SCCHN overall or specifically in those patients whose tumors express high levels of NRG1, this study provided definitive clinical evidence refuting this hypothesis. Duligotuzumab did not improve patient outcomes in comparison to cetuximab despite frequent expression of NRG1. These data indicate that inhibition of EGFR alone is sufficient to block EGFR-HER3 signaling, suggesting that HER2 plays a minimal role in this disease. Extensive biomarker analyses further show that HPV-negative SCCHN but not HPV-positive SCCHN are most likely to respond to EGFR blockage by cetuximab or duligotuzumab

A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma

IF 5.306 (2017)International audienceBACKGROUND: We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV.PATIENTS AND METHODS: TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety.RESULTS: Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69-1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48-1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37-1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52-1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo).CONCLUSION: There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma.IMPLICATIONS FOR PRACTICE: Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy

International neural monitoring study group guideline 2018 part I: Staging bilateral thyroid surgery with monitoring loss of signal

This publication offers modern, state-of-the-art International Neural Monitoring Study Group (INMSG) guidelines based on a detailed review of the recent monitoring literature. The guidelines outline evidence-based definitions of adverse electrophysiologic events, especially loss of signal, and their incorporation in surgical strategy. These recommendations are designed to reduce technique variations, enhance the quality of neural monitoring, and assist surgeons in the clinical decision-making process involved in surgical management of recurrent laryngeal nerve. The guidelines are published in conjunction with the INMSG Guidelines Part II, Optimal Recurrent Laryngeal Nerve Management for Invasive Thyroid Cancer-Incorporation of Surgical, Laryngeal, and Neural Electrophysiologic Data. Laryngoscope, 128:S1-S17, 2018