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Ketogenic diets as an adjuvant therapy for glioblastoma (KEATING): a randomized, mixed methods, feasibility study.
Martin-McGill, KJ, Marson, AG, Tudur Smith, C, Young, B, Mills, SJ, Cherry, MG, Jenkinson, MD
Journal of neuro-oncology. 2020;(1):213-227
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Abstract
PURPOSE We conducted a feasibility study to investigate the use of ketogenic diets (KDs) as an adjuvant therapy for patients with glioblastoma (GBM), investigating (i) trial feasibility; (ii) potential impacts of the trial on patients' quality of life and health; (iii) patients' perspectives of their decision-making when invited to participate in the trial and (iv) recommending improvements to optimize future phase III trials. METHODS A single-center, prospective, randomized, pilot study (KEATING), with an embedded qualitative design. Twelve newly diagnosed patients with GBM were randomized 1:1 to modified ketogenic diet (MKD) or medium chain triglyceride ketogenic diet (MCTKD). Primary outcome was retention at three months. Semi-structured interviews were conducted with a purposive sample of patients and caregivers (n = 15). Descriptive statistics were used for quantitative outcomes and qualitative data were analyzed thematically aided by NVivo. RESULTS KEATING achieved recruitment targets, but the recruitment rate was low (28.6%). Retention was poor; only four of 12 patients completed the three-month diet (MCTKD n = 3; MKD n = 1). Participants' decisions were intuitive and emotional; caregivers supported diet implementation and influenced the patients' decision to participate. Those who declined made a deliberative and considered decision factoring diet burden and quality of life. A three-month diet was undesirable to patients who declined and withdrew. CONCLUSION Recruitment to a KD trial for patients with GBM is possible. A six-week intervention period is proposed for a phase III trial. The role of caregivers should not be underestimated. Future trials should optimize and adequately support the decision-making of patients.
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Effect of Vitamin D Supplementation on Postcraniotomy Pain After Brain Tumor Surgery: A Randomized Clinical Trial.
Hajimohammadebrahim-Ketabforoush, M, Shahmohammadi, M, Khoundabi, B, Shariatpanahi, ZV
World neurosurgery. 2019;:e105-e111
Abstract
OBJECTIVE To determine the effect of vitamin D supplementation on postoperative pain and analgesic requirement in brain tumor surgery. METHODS A total of 60 patients with vitamin D serum levels ≤20 ng/dL were randomly assigned to 2 groups equally. The study group (n = 30) received intramuscular injection of 300,000 IU vitamin D before surgery. RESULTS Preoperative serum level of vitamin D was 15.9 ± 3.8 ng/dL and 14.5 ± 3.6 ng/dL in the study and control groups, respectively (P = 0.13). Serum level of vitamin D on day 5 of surgery was 22.5 ± 4.3 and 13.7 ± 3.8 in the study and control groups, respectively (P < 0.001). A percentage of 50% had pain scores >4 on the first postoperative day, which decreased with time. The median (interquartile range) of the visual analogue scale score during the 3 postoperative days was 3 (5), 3 (5), 1 (3), and 5 (7), 2 (5), 1 (3) in the study and control groups, respectively, with no significant difference. There was no difference in analgesic consumption between the 2 groups. Analysis through the generalized estimating equation model indicated that patients who had received vitamin D for a longer time before the operative time had an insignificantly less pain score. CONCLUSIONS On the basis of the study results, one half of our patients reported moderate-to-severe pain scores on the first day after surgery. The pain in the study group was insignificantly less than that in the control group, but it seems that chronic high level of vitamin D may lead to promising results.
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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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Comparison of normal saline and balanced crystalloid (plasmalyte) in patients undergoing elective craniotomy for supratentorial brain tumors: A randomized controlled trial.
Dey, A, Adinarayanan, S, Bidkar, PU, Bangera, RK, Balasubramaniyan, V
Neurology India. 2018;(5):1338-1344
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Abstract
BACKGROUND The choice of fluid is important in neurosurgical patients, who may be dehydrated due to the administration of diuretics in order to reduce cerebral edema. Normal saline, the infused fluid routinely used in neurosurgical patients, can cause hyperchloremic metabolic acidosis. A balanced crystalloid (BC) may help to maintain the metabolic status more favorably in these patients, without adversely affecting brain relaxation. METHODS We conducted a prospective, randomized controlled trial on patients undergoing elective craniotomy for supratentorial tumor resection under general anesthesia. 44 patients were randomly allocated into two groups of 22 each to receive either normal saline or BC (Plasmalyte) as the maintenance fluid, intra-operatively. The metabolic parameters and osmolality were measured at regular intervals. Brain relaxation score was assessed by the operating surgeon. The patients were monitored with serum neutrophil gelatinase-associated lipocalin (NGAL), blood urea and serum creatinine for assessing the degree of acute kidney injury. RESULTS The metabolic profile was better maintained with the BC. The brain relaxation score was comparable between the two groups. The postoperative NGAL, urea and creatinine values were significantly higher in the normal saline group compared to the BC group. CONCLUSION The balanced crystalloid maintains metabolic status more favorably than normal saline in neurosurgical patients. Hyperchloremic metabolic acidosis, and the other problems which occur as a consequence of normal saline infusion may be circumvented by choosing a balanced crystalloid electrolyte solution. Neither of the crystalloids appeared to have any adverse effect on brain relaxation.
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Arsenic Trioxide as a Radiation Sensitizer for 131I-Metaiodobenzylguanidine Therapy: Results of a Phase II Study.
Modak, S, Zanzonico, P, Carrasquillo, JA, Kushner, BH, Kramer, K, Cheung, NK, Larson, SM, Pandit-Taskar, N
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2016;(2):231-7
Abstract
UNLABELLED Arsenic trioxide has in vitro and in vivo radiosensitizing properties. We hypothesized that arsenic trioxide would enhance the efficacy of the targeted radiotherapeutic agent (131)I-metaiodobenzylguanidine ((131)I-MIBG) and tested the combination in a phase II clinical trial. METHODS Patients with recurrent or refractory stage 4 neuroblastoma or metastatic paraganglioma/pheochromocytoma (MP) were treated using an institutional review board-approved protocol (Clinicaltrials.gov identifier NCT00107289). The planned treatment was (131)I-MIBG (444 or 666 MBq/kg) intravenously on day 1 plus arsenic trioxide (0.15 or 0.25 mg/m(2)) intravenously on days 6-10 and 13-17. Toxicity was evaluated using National Cancer Institute Common Toxicity Criteria, version 3.0. Response was assessed by International Neuroblastoma Response Criteria or (for MP) by changes in (123)I-MIBG or PET scans. RESULTS Twenty-one patients were treated: 19 with neuroblastoma and 2 with MP. Fourteen patients received (131)I-MIBG and arsenic trioxide, both at maximal dosages; 2 patients received a 444 MBq/kg dose of (131)I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide; and 3 patients received a 666 MBq/kg dose of (131)I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide. One did not receive arsenic trioxide because of transient central line-induced cardiac arrhythmia, and another received only 6 of 10 planned doses of arsenic trioxide because of grade 3 diarrhea and vomiting with concurrent grade 3 hypokalemia and hyponatremia. Nineteen patients experienced myelosuppression higher than grade 2, most frequently thrombocytopenia (n = 18), though none required autologous stem cell rescue. Twelve of 13 evaluable patients experienced hyperamylasemia higher than grade 2 from transient sialoadenitis. By International Neuroblastoma Response Criteria, 12 neuroblastoma patients had no response and 7 had progressive disease, including 6 of 8 entering the study with progressive disease. Objective improvements in semiquantitative (131)I-MIBG scores were observed in 6 patients. No response was seen in MP. Seventeen of 19 neuroblastoma patients continued on further chemotherapy or immunotherapy. Mean 5-year overall survival (±SD) for neuroblastoma was 37% ± 11%. Mean absorbed dose of (131)I-MIBG to blood was 0.134 cGy/MBq, well below myeloablative levels in all patients. CONCLUSION (131)I-MIBG plus arsenic trioxide was well tolerated, with an adverse event profile similar to that of (131)I-MIBG therapy alone. The addition of arsenic trioxide to (131)I-MIBG did not significantly improve response rates when compared with historical data with (131)I-MIBG alone.
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A comparison of equivolume, equiosmolar solutions of hypertonic saline and mannitol for brain relaxation in patients undergoing elective intracranial tumor surgery: a randomized clinical trial.
Dostal, P, Dostalova, V, Schreiberova, J, Tyll, T, Habalova, J, Cerny, V, Rehak, S, Cesak, T
Journal of neurosurgical anesthesiology. 2015;(1):51-6
Abstract
BACKGROUND Hyperosmolar solutions have been used in neurosurgery to modify brain bulk and prevent neurological deterioration. The purpose of the study was to compare the effects of equivolume, equiosmolar solutions of mannitol and hypertonic saline (HTS) on brain relaxation and postoperative complications in patients undergoing elective intracranial tumor surgery. METHODS In this prospective, randomized study, patients with American Society of Anesthesiologists physical status I to III scheduled to undergo a craniotomy for intracranial tumors were enrolled. Patients received a 3.75 mL/kg intravenous infusion of either 3.2% HTS (group HTS, n=36) or 20% mannitol (group M, n=38). The surgeon assessed the condition of the brain using a 4-point scale after opening the dura. Recorded measures included duration of surgery, blood loss, urine output, volume and type of infused fluids, hemodynamic variables, electrolytes, glucose, creatinine, predefined postoperative complications, and length of intensive care unit and hospital stays. RESULTS Brain relaxation conditions in group HTS (score 1/2/3/4, n=10/17/2/7) were better than those in group M (score 1/2/3/4, n=3/18/3/14, P=0.0281). Patients in group M had higher urine output, received more crystalloids during surgery, and displayed lower central venous pressure and lower natremia at the end of surgery than did patients in group HTS. No significant differences in postoperative complications or lengths of intensive care unit and hospital stays were observed between the groups. CONCLUSIONS Our results suggest that HTS provides better brain relaxation than mannitol during elective intracranial tumor surgery.
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Role of a Combination of Seven Micronutrients in the Management of Glioblastoma Multiforme.
Rooprai, HK, Ashkan, K, Brazil, L, Selway, RP, Lodhi, R, Aitchison, KJ, Gullan, RW, Beaney, R
Clinical oncology (Royal College of Radiologists (Great Britain)). 2015;(6):370-1
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The effect of gabapentin premedication on postoperative nausea, vomiting, and pain in patients on preoperative dexamethasone undergoing craniotomy for intracranial tumors.
Misra, S, Parthasarathi, G, Vilanilam, GC
Journal of neurosurgical anesthesiology. 2013;(4):386-91
Abstract
BACKGROUND In patients undergoing craniotomy, the incidence of postoperative nausea and vomiting (PONV) is 55% to 70% and that of moderate to severe postoperative pain is 60% to 84%. We hypothesized that gabapentin plus dexamethasone would be superior, compared with placebo and dexamethasone in reducing the incidences of PONV and pain after craniotomy. METHODS Patients undergoing craniotomy received either placebo (group D) or gabapentin (600 mg) (group GD) premedication orally, 2 hours before induction of anesthesia. In addition, all patients received 4 mg of intravenous dexamethasone on the morning of surgery and continued receiving it after every 8 hours. The 24-hour incidence of nausea, emesis, or PONV (nausea, emesis, or both) (primary outcome) and postoperative pain scores (secondary outcome) were analyzed with the χ test and the Wilcoxon rank-sum test as applicable. RESULTS A significant difference was observed between the groups in the incidence of nausea (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.07, 0.80; P=0.02), PONV (OR, 0.3; 95% CI, 0.08, 0.8; P=0.02), and the requirement for antiemetics (OR, 0.30; 95% CI, 0.09, 0.9; P=0.03). The number of emetic episodes were also reduced in group GD, but this did not assume statistical significance (OR, 0.34; 95% CI, 0.10, 1.1; P=0.06). However, there was no significant difference in either the postoperative pain scores or the opioid consumption between the 2 groups. CONCLUSIONS A dosage of 600 mg of gabapentin plus 4 mg of dexamethasone significantly reduced the 24-hour incidence of nausea and PONV. However, there was no reduction in either the postoperative pain scores or opioid consumption.
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Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial.
Brown, PD, Pugh, S, Laack, NN, Wefel, JS, Khuntia, D, Meyers, C, Choucair, A, Fox, S, Suh, JH, Roberge, D, et al
Neuro-oncology. 2013;(10):1429-37
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Abstract
BACKGROUND To determine the protective effects of memantine on cognitive function in patients receiving whole-brain radiotherapy (WBRT). METHODS Adult patients with brain metastases received WBRT and were randomized to receive placebo or memantine (20 mg/d), within 3 days of initiating radiotherapy for 24 weeks. Serial standardized tests of cognitive function were performed. RESULTS Of 554 patients who were accrued, 508 were eligible. Grade 3 or 4 toxicities and study compliance were similar in the 2 arms. There was less decline in delayed recall in the memantine arm at 24 weeks (P = .059), but the difference was not statistically significant, possibly because there were only 149 analyzable patients at 24 weeks, resulting in only 35% statistical power. The memantine arm had significantly longer time to cognitive decline (hazard ratio 0.78, 95% confidence interval 0.62-0.99, P = .01); the probability of cognitive function failure at 24 weeks was 53.8% in the memantine arm and 64.9% in the placebo arm. Superior results were seen in the memantine arm for executive function at 8 (P = .008) and 16 weeks (P = .0041) and for processing speed (P = .0137) and delayed recognition (P = .0149) at 24 weeks. CONCLUSIONS Memantine was well tolerated and had a toxicity profile very similar to placebo. Although there was less decline in the primary endpoint of delayed recall at 24 weeks, this lacked statistical significance possibly due to significant patient loss. Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed in patients receiving WBRT. RTOG 0614, ClinicalTrials.gov number CT00566852.
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A randomised controlled trial of Hartmann's solution versus half normal saline in postoperative paediatric spinal instrumentation and craniotomy patients.
Coulthard, MG, Long, DA, Ullman, AJ, Ware, RS
Archives of disease in childhood. 2012;(6):491-6
Abstract
OBJECTIVE To compare the difference in plasma sodium at 16-18 h following major surgery in children who were prescribed either Hartmann's and 5% dextrose or 0.45% saline and 5% dextrose. DESIGN A prospective, randomised, open label study. SETTING The paediatric intensive care unit (650 admissions per annum) in a tertiary children's hospital in Brisbane, Australia. PATIENTS The study group comprised 82 children undergoing spinal instrumentation, craniotomy for brain tumour resection, or cranial vault remodelling. INTERVENTIONS Patients received either Hartmann's and 5% dextrose at full maintenance rate or 0.45% saline and 5% dextrose at two-thirds maintenance rate. PRIMARY OUTCOME MEASURE plasma sodium at 16-18 h postoperatively; secondary outcome measure: number of fluid boluses administered. RESULTS Mean postoperative plasma sodium levels of children receiving 0.45% saline and 5% dextrose were 1.4 mmol/l (95% CI 0.4 to 2.5) lower than those receiving Hartmann's and 5% dextrose (p=0.008). In the 0.45% saline group, seven patients (18%) became hyponatraemic (Na <135 mmol/l) at 16-18 h postoperatively; in the Hartmann's group no patient became hyponatraemic (p=0.01). No child in either fluid group became hypernatraemic. CONCLUSIONS The postoperative fall in plasma sodium was smaller in children who received Hartmann's and 5% dextrose compared to those who received 0.45% saline and 5% dextrose. It is suggested that Hartmann's and 5% dextrose should be administered at full maintenance rate postoperatively to children who have undergone major surgery in preference to hypotonic fluids.