ICORG 10-14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study (Neo-AEGIS).

BACKGROUND: Neoadjuvant therapy is increasingly the standard of care in the management of locally advanced adenocarcinoma of the oesophagus and junction (AEG). In randomised controlled trials (RCTs), the MAGIC regimen of pre- and postoperative chemotherapy, and the CROSS regimen of preoperative chemotherapy combined with radiation, were superior to surgery only in RCTs that included AEG but were not powered on this cohort. No completed RCT has directly compared neoadjuvant or perioperative chemotherapy and neoadjuvant chemoradiation. The Neo-AEGIS trial, uniquely powered on AEG, and including comprehensive modern staging, compares both these regimens. METHODS: This open label, multicentre, phase III RCT randomises patients (cT2-3, N0-3, M0) in a 1:1 fashion to receive CROSS protocol (Carboplatin and Paclitaxel with concurrent radiotherapy, 41.4Gy/23Fr, over 5 weeks). The power calculation is a 10% difference in favour of CROSS, powered at 80%, two-sided alpha level of 0.05, requiring 540 patients to be evaluable, 594 to be recruited if a 10% dropout is included (297 in each group). The primary endpoint is overall survival, with a minimum 3-year follow up. Secondary endpoints include: disease free survival, recurrence rates, clinical and pathological response rates, toxicities of induction regimens, post-operative pathology and tumour regression grade, operative in-hospital complications, and health-related quality of life. The trial also affords opportunities for establishing a bio-resource of pre-treatment and resected tumour, and translational research. DISCUSSION: This RCT directly compares two established treatment regimens, and addresses whether radiation therapy positively impacts on overall survival compared with a standard perioperative chemotherapy regimen Sponsor: Irish Clinical Research Group (ICORG). TRIAL REGISTRATION: NCT01726452 . Protocol 10-14. Date of registration 06/11/2012.

Cortical arteriovenous fistula associated with skull fracture. Case report.

The case is reported of a patient who presented with a skull fracture and delayed neurological deterioration due to a cortical arteriovenous fistula at the fracture site. The clinical course and surgical therapy are described. Theories as to the pathogenesis of this lesion as well as a discussion of other intracranial vascular injuries are presented.

Treatment of intraoperative middle cerebral artery occlusion with pentobarbital and extracranial-intracranial bypass. Case report.

A patient with a meningioma of the medial sphenoid wing underwent inadvertent intraoperative occlusion of the middle cerebral artery. Neurological deficit and infarction were presumably prevented by immediate administration of pentobarbital followed by extracranial-intracranial bypass.

Perioperative antibiotic prophylaxis for prevention of postoperative neurosurgical infections. A randomized clinical trial.

The authors report the results of a randomized, prospective study to assess the effectiveness of perioperative antibiotic prophylaxis in preventing postoperative infections following clean neurosurgical operations. The study group comprised 846 patients treated between October, 1979, and June, 1984. Antibiotics, including cefazolin and gentamicin, were administered only in the immediate preoperative and intraoperative periods. Sixteen patients, none of whom developed infections, were excluded from final statistical analysis because they had inadvertently been entered into the study while failing to meet entry criteria. Fifteen wound infections (3.64%) developed in the group of 412 patients who did not receive antibiotics, whereas only four infections (0.96%) were identified among the 418 patients who received antibiotics. The difference is statistically significant (p = 0.008) and represents a 74% reduction in infection rate with antibiotics. An analysis of subgroups of surgical procedures revealed a dramatic decrease in craniotomy infections from 6.77% to 0% (p = 0.003). Of the four infections that occurred among the antibiotic-treated patients, three were in cases where foreign bodies had been implanted. No complications of antibiotic usage were identified. The rates of infection in areas of the body other than the surgical wound were no different in the antibiotic-treated and nontreated groups. All wound infections in both antibiotic-treated and nontreated patients involved similar types of Gram-positive organisms, suggesting that antibiotic prophylaxis did not produce infections with resistant or unusual organisms. This study, combined with other recently published analyses, suggests that routine perioperative antibiotic prophylaxis can significantly reduce the incidence of postoperative neurosurgical infections.

Pentobarbital changes compartmental contribution to cerebral blood flow.

Barbiturates were administered to normal dogs, establishing an isoelectric electrocorticogram. Cortical cerebral blood flows (CBF) and deeper CBF's were respectively measured by krypton-85 (85Kr) and xenon-133 (133 Xe). Following barbiturate administration, the two methods of measuring CBF showed a poor coefficient of variation (r=0.12, p less than 0.05). The cortical flows decreased less than the fast compartment flows. A shifting of percentage contribution of flow to the slow compartment (60% increase, p less than 0.001) was observed after barbiturate infusion. A selective shunting of blood flow to the slower areas may explain the lowering of intracranial pressure and protection of the deep white matter observed by many authors who use barbiturates in clinical an experimental situations.

Reversal of intracerebral steal by STA-MCA anastomosis.

A major factor determining the severity of neurological deficits caused by cerebral ischemia is the ability of the vasculature to provide collateral circulation to the ischemic areas. By establishing a major conduit by means of extracranial-intracranial anastomosis, the increased perfusion pressure through the collateral arterioles may reduce morbidity in these patients. Twenty-seven patients were selected for superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis based on clinical and angiographic evidence of lesions of the internal carotid arterial system. Cerebral blood flows (CBF's) were determined by the xenon-133 inhalation method using 16 symmetrically placed scintillator probes; two-compartment analysis was used to compute a mean flow for the compartment. An average mean flow was computed for each hemisphere, and for four regions with the lowest mean CBF in each hemisphere. The CBF was measured preoperatively and within 8 weeks postoperatively. The average mean flow was 29 ml/100 mg/min in the symptomatic hemisphere, and 30 ml/100 gm/min in the asymptomatic hemisphere. In 11 patients, the mean flow for the symptomatic hemisphere increased by 24% postoperatively, and for the asymptomatic hemisphere by 23%. Regions with lowest CBF showed an increase of 32% in the symptomatic hemisphere, and of 35% in the asymptomatic hemisphere. The low-flow regions differed from the total hemisphere (symptomatic: p less than 0.02; asymptomatic: p less than 0.05). Areas of lowest blood flow preoperatively had the greatest increase in flow postoperatively. Postoperative elevation of CBF in the contralateral hemisphere is consistent with an "intracerebral steal" before surgery. The postoperative elevation of flow in the asymptomatic hemisphere is related to improved perfusion pressure in the symptomatic hemisphere.

Anaerobic spinal epidural abscess. Case report.

An acute spinal epidural abscess is reported from which a pure growth of the anaerobe Fusobacterium necrophorum was isolated. The mode of infection and pathogen makes it unique. The literature concerning the bacteriology of epidural abscess and the implications of anaerobic epidural infection are discussed.

Effect of extracranial-intracranial bypass and pentobarbital on acute stroke in dogs.

Ninety-three mongrel dogs underwent intracranial carotid and middle cerebral artery occlusions. They were then randomized into four groups: 1) the untreated control group (no surgical or medical therapy) showed significant neurological deficit, 16% mortality, and 17% mean hemisphere infarction; 2) in the bypass group (superficial temporal to middle cerebral artery (STA-MCA) anastomosis completed within 3 hours of occlusion), neurological deficit was diminished, mortality was 7%, and mean infarction 5.66%; 3) in the pentobarbital group (single dose of pentobarbital, 35 mg/kg administered intravenously 30 minutes after occlusion), neurological deficit was essentially the same as in the previous group, there was no mortality, and mean infarction was 5.52%; and 4) in the pentabarbital/bypass group (pentabarbital dose plus STA-MCA bypass), neurological deficit was slightly lower than in previous treatment groups, there was no mortality , and mean hemisphere infarction was 1.78%. Extracranial-intracranial bypass produced an immediate 31.6% increase in regional cortical blood flow. The combination of pentobarbital postocclusive therapy and early extracranial-intracranial bypass beneficial synergism.

Qualitative measurement of cerebral infarction using ultraviolet fluorescence.

A reliable method of macroscopically determining the volume of cerebral infarction using ultraviolet fluorescence was developed in an animal model. Cerebral infarction was induced in 40 dogs by occluding the distal internal carotid and middle cerebral arteries. No barbiturates were administered. Intravenous sodium fluorescein was given before the animal was killed. Following fixation, 1 cm coronal sections were evaluated with ultraviolet light of 366 nm wavelength. The area of induced fluorescence for each section was determined using a grid overlay. Microscopic examination revealed that the areas of ischemic cell necrosis corresponded to areas of maximal fluorescence. This is an easily reproducible method to determine the volume of cerebral infarction.

Medical management of neurocysticercosis with Praziquantel.

This paper summarizes the experience with Praziquantel, a new broad spectrum antihelmintic for the treatment of neurocysticercosis.

Method for continuous conjunctival oxygen monitoring during carotid artery surgery.

A new device for measuring conjunctival oxygen tension (PcjO2) was used for intraoperative monitoring during carotid endarterectomy. The PcjO2 measures local tissue oxygenation and, thus, reflects the oxygen delivery to the areas supplied by the internal carotid artery. PcjO2 was found to be sensitive to manipulation, clamping, and obstruction of the carotid artery; it provided a useful monitoring system for assessment of the cerebral circulation during carotid surgery.

Measurement of cerebral blood flow by washout of microwave induced heating.

A method is described for measurement of cerebral blood flow utilizing the washout of microwave delivered heating. Using a microwave source attenuated to achieve a brain temperature elevation of 0.5-0.75 degrees C after a 2 second exposure in the rat, cerebral blood flow was calculated from the temperature washout curve monitored by a small thermistor implanted in the brain. The results obtained with this method were comparable to those obtained using the [14C] butanol method. To our knowledge this represents the first description of a method to deliver a blood flow "indicator" atraumatically directly into brain tissue.

Ischemic brain edema: comparative effects of barbiturates and hypothermia.

The effect of pentobarbital and hypothermia on the development of ischemic brain edema was studied in 23 rhesus monkeys undergoing transorbital middle cerebral artery occlusion. Fifteen additional animals served as unclipped controls. Regional cortical cerebral blood flow (rCBF), arteriovenous oxygen content difference (AVDO2), and regional cortical metabolic rate of O2 (rCMRO2) were measured hourly until sacrifie 11 hours postocclusion, at which time ischemic cerebral edema was measured. In 8 animals no treatment followed the occlusion, and these developed edema. In 7 animals pentobarbial 14 mg/kg was administered intravenously 30 min after occlusion and 7 mg/kg every 2 hours thereafter. In this group ischemic brain edema was negligible. In 8 animals, hypothermia to 25.9 +/- 0.5 degrees C was started 30 min after occlusion and maintained until sacrifice; ischemic brain edema was not significantly altered from untreated-clipped animals. On the basis that both pentobarbital and hypothermia produced similar changes in rCBF, AVDO2, and rCMRO2, but only pentobarbital prevented edema, it is postulated that the mode of action of barbiturates in preventing ischemic brain edema is not entirely related to their known effect on blood flow and metabolism.

Effects of vasoconstriction and distal dilation on carotid stenoses in the dog.

Traditionally, arterial stenoses have been assumed to be inflexible, static obstructive lesions that could not acutely change their configuration or cross-sectional area. However, recent clinical and experimental observations have shown that coronary arterial stenoses can respond to vasoconstriction and intraluminal pressure changes. This experimental study evaluated whether similar dynamic changes could occur in a carotid artery stenosis. The effects of dilation distal to a circumferential snare were examined in 6 mongrel dogs. To eliminate collateral flow, the distal carotid artery was occluded and blood flow diverted through a 16 or 20 gauge needle. With no stenosis, distal dilation increased flow from 29.0 +/- 2.0 to 90.1 +/- 3.8 ml/min, (p less than 0.01). With moderate stenosis, the flow increase (25.5 +/- 1.3 to 56.4 +/- 3.7 ml/min, p less than 0.01 following dilation was attenuated. With severe stenosis, flow paradoxically decreased (20.4 +/- 1.0 to 11.4 +/- 1.0 ml/min, (p less than 0.01). This flow decrease was associated with a large stenotic resistance increase (2.13 +/- 0.51 to 18.93 +/- 5.58 mm Hg/ml . min-1, (p less than 0.01). In eight additional experiments, an in vitro preparation was used to examine the effects of vasoconstriction on stenotic severity. Vasoconstriction, induced by ergonovine, methoxamine, angiotensin, or vasopressin, resulted in a significant flow decrease and stenotic resistance increase. Thus, both vasoconstriction and intraluminal pressure were shown to affect stenotic severity, and thereby influence blood flow. These data illustrate hemodynamic factors which may be important in patients with severe carotid artery stenosis.

Rapid, transient drop in brain glucose after intravenous phloretin or 3-0-methyl-D-glucose.

Rats were injected intravenously with either phloretin (100 mg/kg) or 3-0-methyl glucose (2 g/kg) to reduce the carrier-mediated flux of glucose into brain. Plasma glucose and brain free glucose (BFG), lactate, and glycogen were measured over a 16 min time course. Injection of these substances caused a rapid drop in BFG to 60% of control at one minute and a minimum (50% of control values) at 4 min., followed by a gradual rise to control levels at 16 min. While plasma glucose fell, and then increased after injection, brain lactate and glycogen content was unaffected. Repeated injections of phloretin eventually caused a drop in brain glycogen; but with either competitor, BFG never fell below 50% of normal values. The i.v. injection of the glucose analog, 3-0-methyl glucose (the less toxic of the two drugs) is proposed as a possible means of cutting off the potentially hazardous supply of blood glucose to the postischemic brain.

Hemodynamic and clinicopathologic verification of a stroke model in the dog.

Twenty-five mongrel dogs had intracranial internal carotid and proximal middle cerebral artery occlusions. The animals were followed for one week and subsequently sacrificed. This method of clipping produced a mean drop in cortical cerebral blood flow of 48.4% as measured by the 85Kr washout technique. Cerebral blood flow was not affected by the brain retraction necessary for clip placements. Mortality in the first week was 16% and neurological deficits were observed in 73% of the animals. Infarction was present in 80% of the animals, and the mean percent infarction of the affected hemisphere was 17.00 +/0 3.98SE. This is a useful stroke model in an animal which is easily available, inexpensive, and suitable for microvascular intracranial surgery research.

Attenuation of ischemic brain edema by pentobarbital after carotid ligation in the gerbil.

The efficacy of pentobarbital in the treatment of ischemic cerebral edema was evaluated in 160 gerbils. Animals underwent carotid ligation under ether or pentobarbital (50 mg/kg) anesthesia. The pentobarbital anesthetized group received an additional dose of 30 mg/kg 4 h after ligation. Animals were evaluated for neurologic deficit at 4 and 8 h post-ligation, then sacrificed. Water content of each hemisphere and swelling percentage were calculated from the wet and dry weights of the hemispheres. Swelling percentage in animals anesthetized with ether was 6.374 +/- 0.89 SE, whereas gerbils who underwent sham carotid ligation showed a negligible (0.491 +/- 0.15) swelling percentage (p less than 0.01). Pentobarbital animals had a swelling percentage of 3.359 +/- 0.68. This represents a significant edema reduction compared to ether-anesthetized animals (p less than 0.01). Neurologic deficit was decreased by 56.7% (17/60 vs 30/60) in pentobarbital animals compared with ether animals (p less than 0.025). Mortality at 8 hours was reduced by 75% (2/60 vs 8/60) in pentobarbital animals (p less than 0.05).