Mirtazapine in combination.

INTRODUCTION: Depression is undoubtedly a particularly important disease in terms of personal suffering and death as well as social, family, and economic costs. Pharmacological treatment is a reasonably effective therapeutic approach;however, a delayed therapeutic response and the persistence of depressive symptoms represent serious drawbacks to clinical recovery.Although the pharmacological action of anti depressants begins a few hours after the start of treatment, an antidepressant response usually takes between 2 and 6 weeks.The persistence of depressive symptoms after the first weeks of treatment is indicative of a poor prognosis in terms of chronicity and a return to normal social function.The combination of mirtazapine with other antidepressants may significantly lessen these drawbacks.Its antagonist effect on the presynaptic receptors reduces the latency of the antidepressant response. Moreover, its robust noradrenergic effect enhances the serotoninergic effects of the most common antidepressants. In addition, the side effects of mirtazapine can be partially neutralized by the pharmacodynamic activity of other antidepressants, while mirtazapine can ameliorate the serious adverse effects, such as sexual dysfunction, of other medications.

Patients with non-small-cell lung cancer harbouring a BRAF mutation: a multicentre study exploring clinical characteristics, management, and outcomes in a real-life setting: EXPLORE GFPC 02-14.

Background: Mutations in BRAF are rare oncogene mutations, found in 2% of non-small-cell lung cancers (nsclcs). Little information is available about the management of patients with BRAF-mutated nsclc, except for those included in clinical trials. We undertook the present study to assess the clinical characteristics, management, and outcomes of those patients in a real-life setting. Methods: This retrospective multicentre observational study included all patients with BRAF-mutated nsclc diagnosed between January 2012 and December 2014. Results: Patients (n = 59) from 24 centres were included: 57.6% men; mean age: 64.5 ± 14.5 years; 82% with a performance status of 0-1 at diagnosis; smoking status: 40.3% current, 32.6% former; 93% with adenocarcinoma histology; 75% stage iv; 78% with V600E mutations; 2 with EGFR and 2 with ALK co-mutations. Of the stage iv patients, 79% received first-line therapy (14.2% anti-BRAF), and 48% received second-line treatment (23.8% anti-BRAF). Response rate and progression-free survival were, respectively, 51.7% and 8.7 months [95% confidence interval (ci): 6.4 months to 15.2 months] for first-line therapy and 35.3% and 4.1 months (95% ci: 2 months to 10.9 months) for second-line treatments. The 2-year overall survival was 58.5% (95% ci: 45.8% to 74.8%). Outcomes in patients with stage iv nsclc harbouring BRAF V600E mutations (n = 32) did not differ significantly from those of patients with other BRAF mutations. Conclusions: In this real-world analysis, most nsclc patients with a BRAF mutation were men and current or former smokers. Survival appears to be better in these BRAF-mutated patients than in nsclc patients without an oncogenic driver.

Impact of Continuing First-Line EGFR Tyrosine Kinase Inhibitor Therapy Beyond RECIST Disease Progression in Patients with Advanced EGFR-Mutated Non-Small-Cell Lung Cancer (NSCLC): Retrospective GFPC 04-13 Study.

UNLABELLED: Retrospective studies suggested a benefit of first-line tyrosine kinase inhibitor (TKI) treatment continuation after response evaluation in solid tumors (RECIST) progression in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. The aim of this multicenter observational retrospective study was to assess the frequency of this practice and its impact on overall survival (OS). The analysis included advanced EGFR-mutated NSCLC patients treated with first-line TKI who experienced RECIST progression between June 2010 and July 2012. Among the 123 patients included (67 ± 12.7 years, women: 69 %, non smokers: 68 %, PS 0-1: 87 %), 40.6 % continued TKI therapy after RECIST progression. There was no difference between the patients who did and did not continue TKI therapy with respect to progression-free survival (PFS1: 10.5 versus 9.5 months, p = 0.4). Overall survival (OS) showed a non-significant trend in favor of continuing TKI therapy (33.0 vs. 21.2 months, p = 0.054). Progressions were significantly less symptomatic in the TKI continuation group than in the discontinuation group (18 % vs. 37 %, p < 0.01). Univariate analysis showed a higher risk of death among patients with PS >1 (HR 4.33, 95 %CI: 2.21-8.47, p = 0.001), >1 one metastatic site (HR 1.96, 95 %CI: 1.06-3.61, p = 0.02), brain metastasis (HR 1.75, 95 %CI: 1.08-2.84, p = 0.02) at diagnosis, and a trend towards a higher risk of death in cases of TKI discontinuation after progression (HR 1.62, 95 %CI: 0.98-2.67, p = 0.056 ). In multivariate analysis only PS >1 (HR 6.27, 95 %CI: 2.97-13.25, p = 0.00001) and >1 metastatic site (HR 2.54, 95 %CI: 1.24-5.21, p = 0.02) at diagnosis remained significant. This study suggests that under certain circumstances, first-line TKI treatment continuation after RECIST progression is an acceptable option in EGFR-mutated NSCLC patients. CLINICAL TRIAL INFORMATION: NCT02293733.

Mitochondrial dysfunction after experimental traumatic brain injury: combined efficacy of SNX-111 and U-101033E.

We recently demonstrated that posttraumatic administration of the N-type calcium channel blocker SNX-111 (S) and a novel blood-brain barrier penetrating antioxidant U-101033E (U), significantly alleviated mitochondrial dysfunction induced by traumatic brain injury (TBI) in rats. The present study was designed to determine whether a combination of S and U, which act on different biochemical mechanisms of secondary brain injury, would be more efficacious than either drug alone. Brain mitochondria from injured and uninjured hemispheres were isolated and examined at 12 h post TBI induced by a severe controlled cortical impact injury. S at 1.0 mg/kg significantly increased both State 3 and 4 rates and produced a slight increase in P/O ratio, and there was virtually no change in RCI. U at 1.0 mg/kg did not show any protection. However, the combined treatment of S at 1.0 mg/kg and U at 1.0 mg/kg eliminated the uncoupling effect of S, and restored not only State 3 rates and P/O ratios but also RCI to near sham values. These results provide further evidence that both reactive oxygen species and perturbation of cellular calcium homeostasis participate in the pathogenesis of TBI-induced mitochondrial dysfunction, and support the idea of using combined therapy with lower drug doses.

Hyperacute measurement of intracranial pressure, cerebral perfusion pressure, jugular venous oxygen saturation, and laser Doppler flowmetry, before and during removal of traumatic acute subdural hematoma.

OBJECT: The poor prognosis for traumatic acute subdural hematoma (ASDH) might be due to underlying primary brain damage, ischemia, or both. Ischemia in ASDH is likely caused by increased intracranial pressure (ICP) leading to decreased cerebral perfusion pressure (CPP), but the degree to which these phenomena occur is unknown. The authors report data obtained before and during removal of ASDH in five cases. METHODS: Five patients who underwent emergency evacuation of ASDH were monitored. In all patients, without delaying treatment, a separate surgical team (including the senior author) placed an ICP monitor and a jugular bulb catheter, and in two patients a laser Doppler probe was placed. The ICP prior to removing the bone flap in the five patients was 85, 85, 50, 59, and greater than 40 mm Hg, resulting in CPPs of 25, 3, 25, 56, and less than 50 mm Hg, respectively. Removing the bone flap as well as opening the dura and removing the blood clot produced a significant decrease in ICP and an increase in CPP. Jugular venous oxygen saturation (SjvO2) increased in four patients and decreased in the other during removal of the hematoma. Laser Doppler flow also increased, to 217% and 211% compared with preevacuation flow. CONCLUSIONS: Intracranial pressure is higher than previously suspected and CPP is very low in patients with ASDH. Removal of the bone flap yielded a significant reduction in ICP, which was further decreased by opening the dura and evacuating the hematoma. The SjvO2 as well as laser Doppler flow increased in all patients but one immediately after removal of the hematoma.

Impaired cerebral mitochondrial function after traumatic brain injury in humans.

OBJECT: Oxygen supply to the brain is often insufficient after traumatic brain injury (TBI), and this results in decreased energy production (adenosine triphosphate [ATP]) with consequent neuronal cell death. It is obviously important to restore oxygen delivery after TBI; however, increasing oxygen delivery alone may not improve ATP production if the patient's mitochondria (the source of ATP) are impaired. Traumatic brain injury has been shown to impair mitochondrial function in animals; however, no human studies have been previously reported. METHODS: Using tissue fractionation procedures, living mitochondria derived from therapeutically removed brain tissue were analyzed in 16 patients with head injury (Glasgow Coma Scale Scores 3-14) and two patients without head injury. Results revealed that in head-injured patients mitochondrial function was impaired, with subsequent decreased ATP production. CONCLUSIONS: Decreased oxygen metabolism due to mitochondrial dysfunction must be taken into account when clinically defining ischemia and interpreting oxygen measurements such as jugular venous oxygen saturation, arteriovenous difference in oxygen content, direct tissue oxygen tension, and cerebral blood oxygen content determined using near-infrared spectroscopy. Restoring mitochondrial function might be as important as maintaining oxygen delivery.

Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: dose-response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury.

OBJECT: Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobehavioral endpoints, it might prove useful as an outcome measure to establish therapeutic time windows and dose-response curves in preclinical drug testing. This idea was tested in a model of TBI in rats. METHODS: Animals treated with the selective N-type voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical impact displayed significant improvement in brain mitochondrial function. When a single intravenous bolus injection of 4 mg/kg Ziconotide was given at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points, but more so between 2 and 6 hours postinjury. The authors evaluated the effects on mitochondrial function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum dose. CONCLUSIONS: The authors established these time-window profiles and dose-response curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Establishing similar time-window profiles and dose-response curves by using neurobehavioral endpoints would have required using 114 rats in much more elaborate experiments.

Bedside invasive monitoring techniques in severe brain-injured patients.

In patients with severe brain injury, brain edema, elevated intracranial pressure, and cerebral ischemia are accountable for a significant morbidity and mortality. New invasive methods of monitoring attempt to foresee the physiopathological mechanisms responsible for the production of secondary brain injuries. The available methods for monitoring severely brain-injured patients, their potential usefulness, advantages, and disadvantages are reviewed.

Microsurgical anatomy of the posterior choroidal arteries.

In this study, we analysed the microanatomy of the medial and lateral posterior choroidal arteries, which supply vital central nervous system structures to the brainstem and choroids plexus. We traced the anatomical course of the medial and lateral posterior choroid arteries, their origin, diameter, number of branches, length, and anatomical variations. Twenty-six human unfixed brains were injected through the vertebral and carotid arteries with silicon rubber. Fifty-one out of a total of 129 vessels were medial posterior, and 78 were lateral posterior choroidal arteries. We divided the medial posterior choroidal artery into three segments: around the brainstem, quadrigeminal-pineal, and choroidal. The mean length of the medial posterior choroidal artery was 77.6 +/- 15 mm on the right side, and 77.1 +/- 15 mm on the left; the mean outer diameter observed was 0.8 +/- 0.5 mm on the right side, and 0.8 +/- 0.4 mm on the left. The number of branches arising from the medial posterior choroidal arteries averaged 25 +/- 9. In the lateral posterior group, the mean length observed was 49.5 +/- 26 mm on the right, and 58.0 +/- 23 mm on the left. There were instances of duplication and triplication of the lateral posterior choroidal vessels. The outer diameter averaged 0.72 mm on the right, and 0.6 mm on the left. The posterior choroidal arteries are clearly an important vascular component. A comprehensive knowledge of their anatomy will aid the neurosurgeon during surgery of the brainstem, pineal region, and third ventricle, and will limit complications resulting from injury to these arteries.

Literature review: sinus pericranii.

Sinus pericranii is a rare circumscribed fluctuating vascular swelling of the scalp that communicates with the intracranial venous system. It has been associated with other intracranial vascular malformations. The tumour is usually round, fluctuant, nonpulsatile, and disappears with compression. Its size increases during manoeuvers that increase the intracranial pressure. Approximately 100 cases were reported in the literature. The antecedents, different surgical procedures, differential diagnoses, and associated malformations were reviewed.

Spinal cord sarcoidosis: a diagnostic dilemma.

Sarcoidosis is a chronic disorder of unknown etiology characterized by the development of non-caseating granulomas with derangement of the normal tissue architecture. Compromise of the spinal cord is one of the rarest neurologic manifestations of the disease, which may be clinically and radiologically indistinguishable from a spinal cord malignant tumor. However, neurosarcoidosis can be treated with steroids. This study reviews the clinical, radiological, and pathological features of the sarcoid compromise of the spinal cord, emphasizing the difficulties commonly encountered in making a diagnosis.

Early hemodynamic changes at the microcirculatory level and effects of mannitol following focal cryogenic injury.

Changes in cerebral blood flow due to infusion of hyperosmolar solutions are of considerable importance in states of raised intracranial pressure. The present study was aimed to evaluate the effects of mannitol on the cerebral microcirculation, in a model of vasogenic brain edema. A right fronto-parietal craniotomy was performed in 30 adult Sprague-Dawley rats. Vasogenic edema was produced by placing dry-ice over the dura for 1 min. The cortical blood flow was monitored for 120 min using a laser-Doppler flowmeter (Perimed, Stockholm, Sweden), and graphics were recorded using a personal computer. Animals were randomly divided into three groups: group 1 (control group) received no mannitol; group 2 was treated with a bolus injection of 20% mannitol (1 mg kg-1); group 3 received the same dose over a 30 min infusion. Mean blood pressure, temperature, and respiratory rate were continuously monitored. At the end of the procedure, an intravenous injection of Evan's blue 2% was given. Results were compared by using repeated measures of analysis of variance and a two-sample t-test at each time. After the production of a cryogenic injury, we found a marked decrease in the cerebral blood flow, whereas mannitol partially reversed that effect. There was not significant difference between groups 2 and 3; however, there was a significant difference between mannitol and control groups after 15 min. During the early phase of vasogenic edema, early use of mannitol did not increase the blood flow, but stabilized it, preventing further decrease. Laser-Doppler flowmetry is a valuable method for continuous estimation of hemodynamic changes in the cerebral microcirculation.

Burr hole cover for ventriculoperitoneal shunts and ventriculostomy: technical note.

In patients who have undergone intracranial procedures, bone gaps or burr holes often result in small but undesirable scalp or skin depressions. The authors designed a burr hole cover for hydrocephalus shunt system or external ventricular drainage, which is shaped to alleviate the deformity of the burr hole by filling the bone defect and allowing the passage of the ventricular catheter. The specifications of this device and its clinical application are described.

Microsurgical anatomy of the supratentorial arachnoidal trabecular membranes and cisterns.

We examined the microsurgical anatomy of the supratentorial subarachnoid cisterns with a surgical microscope in 20 brains prepared using the immersion technique. The adult brains were immersed in Ringer's solution and air was injected into the subarachnoid cisterns while the brains remained submerged in solution. We identified nine trabecular membranes that limit the 15 cisterns. We specifically looked at the anatomical relationship between the supratentorial trabecular membranes and cisterns to their corresponding vessels and cranial nerves. The cistern divisions and the dispositions of trabecular membranes were closely related to the vascular division patterns of the principal brain arteries. A clear and thorough understanding of the neuroanatomical structures of the subarachnoid cisterns is important because they provide natural pathways to neurovascular and cranial nerve structures. These pathways allow access to intracranial arteries, veins, and nerves during microvascular procedures without disturbing surrounding important brain structures.

Microsurgical anatomy of the suboccipital segment of the vertebral artery.

The craniocervical regions of seven cadavers (14 sides) injected with silicone rubber were dissected under a Zeiss OPMI surgical microscope. The present study provides a detailed description of the suboccipital segment of the vertebral artery, with particular attention to its loops, branches, supporting osteofibrous structures, adjacent nerves, and surrounding venous structures. Several ligaments fixating the vertebral artery to surrounding structures, which have not been described in previous anatomical studies, were found. The authors propose an anatomically based subdivision of the suboccipital segment of the vertebral artery into five subsegments: infraforaminal, foraminal, supraforaminal, horizontal, and intramembranous. Measurements of surgically and clinically important features were obtained. Surgical approaches to this region are suggested based on a more informed understanding of the local anatomy.

Microsurgical anatomy of the arachnoidal trabecular membranes and cisterns at the level of the tentorium.

A clear and thorough understanding of the neuroanatomical structures of the subarachnoid cisterns is important because they provide natural pathways to intracranial arteries, veins, and nerves during microvascular procedures without disturbing surrounding important brain structures. Using a surgical microscope, we examined the microsurgical anatomy of the trabecular membranes and subarachnoid cisterns in 20 adult cadaver brains. The brains were immersed in Ringer's solution and air was injected into the subarachnoid cisterns while the brains remained submerged in solution. We identified seven trabecular membranes that limit six cisterns. We specifically looked at the anatomical relationship between the trabecular membranes and cisterns and their corresponding vessels and cranial nerves. The cistern divisions and the dispositions of trabecular membranes were closely related to the vascular division patterns of the principal brain arteries.

Microsurgical anatomy of the infratentorial trabecular membranes and subarachnoid cisterns.

The understanding of the anatomy of the subarachnoid cisterns and trabecular membranes is of paramount importance in the surgical treatment of pathology of the posterior fossa. Aneurysms, arteriovenous malformations, and some tumors should be approached through the subarachnoid space. The subarachnoid cisterns provide natural pathways to approach neurovascular and cranial nerve structures. The microsurgical anatomy of the infratentorial subarachnoid cisterns was studied in twenty adult brains, using the 'immersion technique'. Air was injected into the subarachnoid cisterns and brains were dissected under the operative microscope. Six main compartmental trabecular membranes were identified in the infratentorial level. They divide the subarachnoid space into six cisterns. Cisternal divisions and the disposition of the trabecular membranes were closely related to the vascular divisional patterns of the principal arteries. Thorough knowledge of the microsurgical anatomy of the subarachnoid space will aid neurosurgeons during the surgical approach of many vascular and tumoral lesions located in the posterior fossa.

Evaluation of expanded polytetrafluoroethylene (ePTFE) versus polydioxanone (PDS) for the repair of dura mater defects.

A comparative animal experimental study was performed to test the potential application of expanded polytetrafluoroethylene (ePTFE) vs. polydioxanone (PDS) as dural substitutes. Sixty male Sprague-Dawley rats underwent a right frontoparietal craniotomy, opening of the dura mater, and a small cortical lesion. The dural defect was covered with a piece of ePTFE or PDS. Animals were sacrificed at 30 days or 90 days. Following decalcification, heads including scalp, skull, and underlying brain were sectioned, stained with hematoxylin-eosin, and histologically analyzed. Dural defects repaired with ePTFE, showed minimal reactive changes and no adhesions to the brain surface. No foreign body type giant cell reaction was seen, and the graft became enclosed in a thin sheet of connective tissue. Dural defects repaired with PDS, showed some giant cell infiltration and ingrowth of collagen fibers. Both substitutes provided satisfactory biological function and biocompatibility. Expanded PTFE advantages included relative suppression of tissue ingrowth, ensheathment by connective tissue, and a high tearing strength. Although both materials show promise for use in dural grafting, further clinical studies are necessary to determine their potential applications as a human dural substitute.

Microanatomy of the perforators of the anterior communicating artery complex.

We describe the microanatomy of the perforating arteries arising from the anterior communicating artery complex (5 mm distal of the anterior cerebral artery, the anterior communicating artery, and 5 mm proximal of the distal anterior cerebral artery). Thirteen unfixed human brains were used in this study. The origin and number of perforators are described, as is the site of brain penetration, and results are correlated with previous studies. The hemodynamics of blood flow in relation to the formation of an anterior communicating artery aneurysm and different surgical approaches are mentioned. The neuropsychological outcome after aneurysm clipping with regards to the pattern of blood supply from the anterior cerebral artery complex is also discussed.

Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111).

We have recently demonstrated in a rat model that traumatic brain injury induces perturbation of cellular calcium homeostasis with an overload of cytosolic calcium and excessive calcium adsorbed on the mitochondrial membrane, consequently the mitochondrial respiratory chain-linked oxidative phosphorylation was impaired. We report the effect of a selective N-type calcium channel blocker, SNX-111 on mitochondrial dysfunction induced by a controlled cortical impact. Intravenous administration of SNX-111 at varying times post injury was made. The concentration titration profile revealed SNX-111 at 4 mg kg-1 to be optimal, and the time window to be administration at 4 h post-injury, in line with that reported on the effect of SNX-111 in experimental stroke. Under optimal conditions, SNX-111 significantly improved the mitochondrial respiratory chain-linked functions, such as the electron transfer activities with both succinate and NAD-linked substrates, and the accompanied energy coupling capacities measured as respiratory control indices (RCI) and ATP synthesis (P/O ratio), and the energy linked Ca2+ transport. In order to assess the applicability of these data to the clinical setting, we have initiated studies with brain tissue which has to be resected during surgical treatment. Five patients suffered from brain trauma, one from intracranial hypertension due to stroke (noninfarcted tissue was taken), and one from epilepsy. Our data revealed that brain mitochondria derived from the patient with intracranial hypertension and the patient with epilepsy were tightly coupled with good respiratory rates with glutamate and malate as substrates, and high P/O ratios. The rates of respiration and ATP synthesis were severely impaired in the brain mitochondria isolated from traumatized patients. These results indicate that investigation of brain mitochondrial functions can be used as a measure for trauma-induced impairment of brain energy metabolism. The time window for the effect of SNX-111 in mitochondrial function and the (preliminary) similarity between mitochondrial dysfunction in experimental animals and humans make the drug appear to be well suited for clinical trials in severe head injury.