A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy.

Disulfiram, a generic alcohol aversion drug, has promising preclinical activity against glioblastoma (GBM). This phase I study aims to evaluate its safety, maximum tolerated dose (MTD), pharmacodynamic effect, and preliminary efficacy when combined with adjuvant temozolomide in GBM patients after standard chemoradiotherapy. Patients received disulfiram 500-1000 mg once daily, in combination with 150-200 mg/m(2) temozolomide. A modified 3 + 3 dose-escalation design was used to determine the MTD. The pharmacodynamic effect of proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cells. The MTD was determined based on the dose-limiting toxicities (DLTs) within the first month of therapy. Twelve patients were enrolled to two dose levels: 500 and 1000 mg. Two DLTs of grade 3 delirium occurred after 15 days of administration at 1000 mg per day. Other possible grade 2-3 DSF-related toxicities included fatigue, ataxia, dizziness, and peripheral neuropathy. The toxicities were self-limiting or resolved after discontinuing DSF. The MTD was determined to be 500 mg per day. Limited proteasome inhibition was observed at week 4 and showed an increased trend with escalated disulfiram. Median progression-free survival with 500 mg of DSF was 5.4 months from the start of disulfiram and 8.1 months from the start of chemoradiotherapy. Disulfiram can be safely combined with temozolomide but can cause reversible neurological toxicities. The MTD of disulfiram with adjuvant temozolomide appears to produce limited proteasome inhibition on peripheral blood cells.

Effective and safe mannitol administration in patients undergoing supratentorial tumor surgery: A prospective, randomized and double blind study.

OBJECTIVES: Although osmotic diuresis with mannitol is commonly used to provide brain relaxation, there is no consensus regarding its optimal dose and combination with loop diuretics. The aim of the present study is to evaluate the effects of mannitol and combination of furosemide with different doses of mannitol on brain relaxation and on blood electrolytes, lactate level, urine output, fluid balance and blood osmolarity in patients undergoing supratentorial tumor surgery. PATIENTS AND METHODS: This prospective, randomized, double blind, placebo-controlled study included 51 patients (ASA I-III) scheduled for elective supratentorial craniotomy. Different doses and combinations of diuretics were administered after the bone flap removal. The Group 1 received mannitol at 0.5gkg-1 and furosemide at 0.5mgkg-1, the Group 2 received mannitol at 1gkg-1 and furosemide at 0.5mgkg-1, and the Group 3 received mannitol at 0.5gkg-1 and placebo. The primary end-point of the present study is to evaluate the effects of mannitol and combination of furosemide with different doses of mannitol on brain relaxation and the secondary end-points are to evaluate their effects on blood electrolytes, lactate level, urine output, fluid balance and blood osmolarity. RESULTS: This study shows that mannitol alone (0.5gkg-1), and the combinations of furosemide (0.5mgkg-1) with different doses of mannitol (0.5gkg-1-1gkg-1) provides adequate brain relaxation. However, administration of furosemide with low or high doses of mannitol may cause reduction in the sodium and chloride levels as well as rise in the lactate level. Moreover it may cause high urine output and negative intra-operative fluid balance. CONCLUSION: Administration of 0.5gkg-1 mannitol provides adequate brain relaxation without causing systemic side effects in patients undergoing supratentorial tumor surgery. This study is registered to clinical trials (Clinical Trials.gov identifier NCT02712476).

Carbogen and nicotinamide combined with unconventional radiotherapy in glioblastoma multiforme: a new modality treatment.

PURPOSE: A new radiotherapy schedule to treat glioblastoma multiforme after surgery, combining nicotinamide and carbogen. METHODS AND MATERIALS: We analyzed 36 patients with glioblastoma multiforme treated after surgery with radiotherapy, Nicotinamide and Carbogen as follows: 7 patients were treated with accelerated fractionation: two fractions/day, 1.5 cGy/fraction, 6 h interval, 5 days/week, total dose 60 Gy in 4 weeks; 8 patients were treated with the same irradiation scheduling plus Nicotinamide at the dose of 4 g and 2 g in capsules, respectively, 1 h before the first and the second irradiation fraction; 21 patients were treated with accelerated radiotherapy, Nicotinamide, and Carbogen (inhaled 10 min before radiotherapy and during the whole course of irradiation). On the basis of surgical removal our patients were subdivided in three groups: totally resected, with residual tumor <50%, or >50%. Radiotherapy with accelerated fractionation was completed in the scheduled time without side effects on the whole group of patients and Carbogen inhalation did not cause significant change of cardiopulmonar parameters. The toxicity observed was predominant in the gastrointestinal tract and was related to Nicotinamide. RESULTS: The median survival time (M.S.T.) was 10 months, as reported by others authors with conventional treatment, but in patients without surgical residual tumor and submitted to the complete treatment schedule, the survival at 35 months was around 25%. CONCLUSIONS: We conclude that this method is feasible with acceptable toxicity; analyzing the survival curves appears to be a trend towards an improvement in survival in the subgroup of patients with gross total removal treated with the combination of Carbogen, Nicotinamide, and accelerated fractionation.

Effect of intraoperative glucose fluctuation and postoperative IL-6, TNF-α, CRP levels on the short-term prognosis of patients with intracranial supratentorial neoplasms.

OBJECTIVE: To investigate the effect of intraoperative glucose fluctuation and postoperative interlukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) levels on the short-term prognosis of patients with intracranial supratentorial neoplasms. MATERIALS AND METHODS: Eighty-six patients undergoing intracranial excision were selected in The Second Hospital of Jilin University. According to the condition of glucose fluctuation, the patients were divided into group A (glucose fluctuation <2.2 mmol/L, n=57) and group B (glucose fluctuation ≥2.2 mmol/L, n=29). Glucose was assessed by drawing 2 mL blood from internal jugular vein in two groups in the following time points, namely fasting blood glucose 1 d before operation (T0), 5 min after anesthesia induction (T1), intraoperative peak glucose (T2), intraoperative lowest glucose (T3), 5 min after closing the skull (T4), immediately after returning to intensive care unit (ICU) (T5) and 2 h after returning to ICU (T6). 1 d before operation and 1, 3 and 6 d after operation, serum IL-6 and TNF-α levels were detected with enzyme-linked immunosorbent assay (ELISA), and CRP level with immunoturbidimetry. Additionally, postoperative adverse reactions were monitored. RESULTS: There was no statistical significance between two groups regarding the operation time, anesthesia time, amount of intraoperative bleeding and blood transfusion (P>0.05). The glucose levels in both groups at T1~T6 went up conspicuously compared with that at T0 (P<0.01), and those in group B at T2, T4, T5 and T6 were significantly higher than in group A (P<0.01). Serum IL-6, TNF-α and CRP levels in both groups 1, 3 and 6 d after operation increased markedly compared with 1 d before operation (P<0.01), but the increased range in group A was notably lower than in group B (P<0.05 or P<0.01). Postoperative incidences of hypoglycemia, hyperglycemia and myocardial ischemia in group A were significantly lower than in group B (P<0.05), and respiratory support time obviously shorter than in group B (P<0.01). CONCLUSIONS: The glucose fluctuation of patients undergoing intracranial excision is related to postoperative IL-6, TNF-α and CRP levels and those with small range of glucose fluctuation have better prognosis.

[Changes in the cytokine profile in patients with supratentorial meningiomas].

To evaluate prospects of immunocorrection in the treatment of patients with supratentorial meningiomas, we studied blood serum levels of interleukins 2, 4, 6, 10, 17, interferons α, Β, γ, heat shock proteins HSP60, HSP70 using ELISA. A study included 32 patients with supratentorial meningiomas in the presurgical period and a control group of 38 patients with lumbar disc hernias. We found the multidirectional changes in the cytokine profile that demonstrated the existence of immune imbalance in patients with meningiomas. There was the increase in the levels of Β-interferon, HSP60, interleukin 6 with the simultaneous decrease in α- and γ-interferons levels. The imbalance of cytokines in patients with meningiomas can have a negative impact on a clinical picture of the disease and worsen results of surgical treatment of tumors. To prevent secondary infectious complications after surgery, we recommend to administer glucocorticoids to decrease levels of interleukin 6 and α-interferon in the presurgical period.

[Carbon dioxide measurement in neuroanesthesia]. / La capnometria in neuroanestesia.

The study examined the arterial PCO2 minus end tidal PCO2 gradient during neuroanaesthesia. Ten patients with supratentorial tumours undergoing neurosurgical operations were included in the study. All patients were monitored continuously: ECG, intraarterial pressure, CVP, temperature, expired FtCO2 (Gas analyzer 93O-Siemens); arterial PCO2 was measured intermittently. The APCO2-EtPCO2 gradient was very variable in all patients (0.6-8.3 mmHg) not related to significant changes of ventilation, mean arterial pressure, CVP or body temperature. Our results suggest a critical review of EtCO2 monitoring for providing early warning of critical events during anaesthesia.

[Hyperoxia-induced liberation of big-endothelin into jugular venous blood of electric neurosurgical patients]. / Hyperoxie-induzierte Freisetzung von BIG-Endothelin in das jugularvenöse Blut elektiver neurochirurgischer Patienten.

The use of hyperoxia in emergency situations is generally accepted, but the routine and uncritical application of higher oxygen concentrations is criticized. The influence of short-term application of hyperoxia on cerebral oxygenation, cerebral lactate and BIG-endothelin (BIG-ET) was studied. After approval by the Ethics Committee of the University of Leipzig, 22 patients (hyperoxia group n = 16, normoxia, control group n = 6) undergoing an elective craniotomy were included in the study. After induction of a total intravenous anaesthesia (sufentanil and propofol), a fibre-optic catheter was inserted into the bulb of the jugular vein. The inspiratory concentration of oxygen was raised from 0.4 to 1.0 for 15 minutes. Before, during and after hyperoxia, a blood gas analysis and analysis of lactate and BIG-ET were performed from arterial and jugularvenous blood. Hyperoxia caused a significant increase in jugularvenous oxygen saturation (sjO2) from 60.4 +/- 8.8% to 68.6 +/- 10.4% and jugularvenous oxygen content (cjvO2) from 10.27 +/- 2.06 vol% to 11.76 +/- 2.16 vol%. These changes were reversible after the end of hyperoxia. The jugularvenous lactate decreased significantly (9%) from 1.20 +/- 0.48 mmol/l to 1.10 +/- 0.45 mmol/l after the end of hyperoxia. Hyperoxia led to a significant increase in jugularvenous BIG-ET from 3.35 +/- 0.61 pg/ml to a maximum of 3.82 +/- 0.95 pg/ml and a decrease in the arterio-jugularvenous difference of BIG-ET from 0.19 +/- 0.53 pg/ml to a minimum -0.11 +/- 0.32 pg/ml. The changes in lactate and BIG-ET were also seen after the end of the hyperoxia. In the control group (normoxia, FiO2 0.4), no significant changes in sjO2, oxygen content, lactate and BIG-ET were observed. The increase in jugularvenous BIG-ET and the decrease in the arterio-jugularvenous difference of BIG-ET following hyperoxia indicate a higher cerebral release of BIG-ET.