Citations

Object Rathke cleft cysts (RCCs) are benign masses arising from the embryological Rathke pouch, and are commonly treated by transsphenoidal surgery. The authors retrospectively compared RCC extent of resection—either gross-total resection (GTR) or decompression—to the primary outcome measure, which was recurrences resulting in repeat surgery, and the secondary outcome measure, which was complications. Methods Seventy-four patients presenting to the neurosurgical department with RCC were analyzed retrospectively. Sixty-eight patients had a total of 78 surgical procedures, with the diagnosis of RCC confirmed by histological investigation; of these, 61 patients had adequate operative notes for the authors to evaluate extent of resection. Groups were separated into GTR (32 patients) or decompression (subtotal resection or fenestration into the sphenoid sinus; 29 patients) based on operative notes and postoperative imaging. The mean follow-up duration was 60.5 ± 72.1 months (the mean is expressed ± SD throughout). Results The average age at the time of the initial surgery was 42.8 ± 17.4 years, and 70% of patients were female. The mean cyst diameter preoperatively was 16.9 ± 17.8 mm. Eight patients had repeat surgery, our primary outcome measure; 3 repeat operations occurred in the GTR group, and 5 in the decompression group. There was no significant difference in recurrence when comparing groups (GTR 9%, decompression 17%; p = 0.36). There were no major complications; however, analysis of postoperative minor complications revealed that 11 (34%) GTRs resulted in surgical complications, whereas the decompression cohort accounted for only 3 complications (10%) (p = 0.03), with diabetes insipidus (6) and CSF leaks (5) being the most common. Gross-total resection also resulted in an increase in postoperative hyperprolactinemia compared with decompression (p = 0.03). Conclusions It appears that RCCs require repeat surgery in 13% of cases, and attempted GTR does not appear to reduce the overall rate of recurrence. However, more aggressive resections are associated with more complications in this series.

Corticotropin releasing factor is an endogenous neuropeptide released by the hypothalamus that activates the pituitary-adrenocortical system in response to stressful stimuli. It has been demonstrated that corticotropin releasing factor increases the excitability of hippocampal neurons in both in vitro and in vivo studies, which may contribute to neurological injury during hypoxia. The purpose of this study was to determine the effects of corticotropin releasing factor and its synthetic competitive antagonist, alpha-CRF, on neuronal synaptic recovery after a hypoxic insult using the hippocampal slice. Wistar rat hippocampal brain slices (n = 120) were treated with various concentrations (10(-6) to 10(-11)) of corticotropin releasing factor or its synthetic antagonist during a 10-minute hypoxic episode. Extracellular recording of population spikes was used during and after the hypoxic insult to assess neuronal recovery. Corticotropin releasing factor provided dose-dependent neuronal protection with maximum recovery (37.95 +/- 8.71%) occurring at 10(-9) concentrations. The competitive antagonist alpha-CRF provided a similar degree of recovery at 10(-6) concentration, whereas 10(-9) molar concentration of competitive antagonist resulted in 16.84 +/- 7.68% recovery. Corticotropin releasing factor provides moderate protection to hypoxic hippocampal neurons in the brain slice preparation. The mechanism of action is unknown but appears to be a direct neuronal effect. These results support the hypothesis that corticotropin releasing factor may act as an endogenous neuroprotective hormone during hypoxia.

The aim of this experiment was to study the serial changes in brain intracellular pH, cerebral blood flow, and the oxidation/reduction level of intramitochondrial nicotinamide adenine dinucleotide fluorescence across the cortical surface during severe incomplete global ischemia. Reduced nicotinamide adenine dinucleotide fluorescence and brain intracellular pH using the pH-sensitive indicator umbelliferone were measured with in vivo panoramic fluorescence imaging of the cortical surface. Cerebral blood flow was measured with the clearance of both umbelliferone and xenon-133. Fifteen minutes of severe incomplete global ischemia was produced by temporary occlusion of the innominate, left carotid, and subclavian arteries in five fasted New Zealand White rabbits. Baseline brain intracellular pH was homogeneous over the exposed cortex, measuring 7.00 +/- 0.02, while cerebral blood flow was 48.0 +/- 2.6 ml/100 g/min. During 15 minutes of ischemia, cerebral blood flow measured 6.3 +/- 1.8 ml/100 g/min and brain pH declined to 6.61 +/- 0.02 (p < 0.005); in addition, there were acidotic foci with pH measuring 6.40 +/- 0.10. During reperfusion, there was an initial normalization of brain intracellular pH without an alkaline shift followed by a recurrent cortical acidosis of pH 6.88 +/- 0.06. There was a heterogeneous pattern of fluorescence that increased significantly following 60 minutes of reperfusion, coinciding with a postischemic hypoperfusion. The hypoperfusion was a uniform reduction in cerebral blood flow over the brain's surface, with reductions of 42.5% and 44.2% at 30 and 45 minutes, respectively. During incomplete global ischemia there is a heterogeneous pattern of brain intracellular pH and reduced nicotinamide adenine dinucleotide changes that do not correlate with changes in cortical blood flow. The acidotic foci that were approximately 0.2 pH units more acidotic than the surrounding cortex may be the result of continued glucose delivery under anaerobic conditions. The degree of reduced nicotinamide adenine dinucleotide fluorescence suggests that the cortex is most vulnerable to metabolic failure after 60 minutes of reperfusion following severe incomplete global ischemia. The heterogeneous pattern of brain intracellular pH and reduced nicotinamide adenine dinucleotide changes suggest that there may be a selective vulnerability of cortical tissue to an ischemic challenge.

Background and Purpose —During focal cerebral ischemia, the ischemic penumbra or border-zone regions of moderate cortical blood flow reductions have a heterogeneous development of intracellular cortical acidosis. This experiment tested the hypotheses that (1) this acidosis is secondary to glucose utilization and (2) this intracellular acidosis leads to recruitment of potentially salvageable tissue into infarction. Methods —Brain pH i , regional cortical blood flow, and NADH redox state were measured by in vivo fluorescent imaging, and infarct volume was assessed by triphenyltetrazolium chloride histology. Thirty fasted rabbits divided into 6 groups of 5 each were subjected to 4 hours of permanent focal ischemia in the presence of hypoglycemia (≈2.8 mmol/L), moderate hyperglycemia (≈11 mmol/L), and severe hyperglycemia (>28 mmol/L) under either normoxia or moderate hypoxia (Pa o 2 ≈50 mm Hg). Results —Preischemic hyperglycemia led to a more pronounced intracellular acidosis and retardation of NADH regeneration than in the hypoglycemia groups under both normoxia and moderate hypoxia in the ischemic penumbra. For example, 4 hours after ischemia, brain pH i in the severe hyperglycemia/normoxia group measured 6.46, compared with 6.84 in the hypoglycemia/normoxia group ( P <0.01), and NADH fluorescence measured 173% compared with 114%. Infarct volume in the severe hyperglycemia/normoxia group measured 35.1±6.9% of total hemispheric volume, compared with 13.5±4.2% in the hypoglycemia/normoxia group ( P <0.01). Conclusions —Hyperglycemia significantly worsened both cortical intracellular brain acidosis and mitochondrial function in the ischemic penumbra. This supports the hypothesis that the evolution of acidosis in the ischemic penumbra is related to glucose utilization. Furthermore, the observation that hypoglycemia significantly decreased infarct size supports the postulate that cortical acidosis leads to recruitment of ischemic penumbra into infarction.

Background and Purpose The use of intermittent reperfusion versus straight occlusion during neurovascular procedures is controversial. This experiment studied the effects of intermittent reperfusion and single occlusion on intracellular brain pH (pH i ), regional cerebral or cortical blood flow, and nicotinamide adenine dinucleotide (NADH) fluorescence during temporary focal ischemia. Methods Twenty fasted rabbits under 1.0% halothane anesthesia were divided into four groups: (1) nonischemic controls, (2) 60 minutes of uninterrupted focal ischemia, (3) 2×30-minute periods of focal ischemia separated by a 5-minute reperfusion, and (4) 4×15-minute periods of focal ischemia separated by three 5-minute reperfusion periods. Focal ischemia was produced by occlusion of both the middle cerebral and ipsilateral anterior cerebral arteries. After the final occlusion, there was a 3-hour reperfusion period in all groups. Regional cerebral and cortical blood flow, brain pH i , and NADH fluorescence were measured with in vivo panoramic fluorescence imaging. Results During occlusion, regional cerebral and cortical blood flows and NADH fluorescence values were not different among the groups. Brain pH i was significantly lower in the 4×15-minute group compared with the 1×60-minute group (6.57±0.02 versus 6.73±0.06; P <.03) but not significant when compared with the 2×30-minute group. During the short reperfusion periods, all parameters returned to normal except for NADH fluorescence levels, which remained elevated. During the postischemic final reperfusion period, there was a mild brain alkalosis of approximately 7.1 in all groups. There were no significant differences in NADH fluorescence among groups during the final reperfusion. Regional cerebral and cortical blood flow returned to near normal values in all groups. Conclusions This study demonstrates that intermittent reperfusion during temporary focal ischemia has different effects on the intracytoplasmic and the intramitochondrial compartments: worsening of brain cytoplasmic pH i but no significant differences in the oxidation/reduction level of mitochondrial NADH.

Abstract Identification of HER2 as an important cellular marker in the biology and treatment of breast cancer has highlighted the importance of reliable testing methodology. Controversy exists regarding type of test, reliability, definition of positivity, and which test may best predict for patient (pt) efficacy to anti-HER2 therapies. Purpose: To determine the concordance between HER2 results by 3 central laboratories, impact of round-robin adjudication of discordant cases, and heterogeneity in HER2 results using specimens from 3 adjuvant trials where HER2 testing was performed by local and central laboratories for enrollment. Methods: We performed a blinded round-robin exchange of randomly sampled, HER2-normal (IHC-& FISH-) and HER2-positive breast tumors among 3 central laboratories (NCCTG, BCIRG and NSABP) for confirmatory HER2 testing. The 3 laboratories performed immunohistochemistry (IHC) for HER2 using the HercepTest kit (Dako, Carpenteria, CA) and fluorescence in situ hybridization (FISH) for HER2 using the PathVysion HER2 DNA probe kit/HER2/CEN17 probe mixture (Abbott Molecular, Des Plaines, IL) on 389 tumor specimens obtained from N9831/BCIRG006 (37 IHC+/FISH+, 33 IHC+/FISH-, 36 IHC-/FISH+, 62 IHC-& FISH-) and BCIRG005 (96 IHC-& FISH-); 123 cases had ≥2 blocks examined from the same pt. HER2 positivity was defined according to FDA-approved guidelines used in the clinical trials (IHC+: 3+ complete membrane staining in &gt;10% cells; FISH+: HER2/CEN17 ratio ≥2.0). The HER2 status (IHC: 3+ vs 0-2+; FISH: amplified vs not) for each block was independently determined at each site; discordant IHC and FISH cases were adjudicated at a face-to-face meeting. Results: Independent reads were concordant across pathologists in IHC status in 351/381 (92%) cases and in FISH status in 343/373 (92%) cases. Upon adjudication, a consensus was reached on 16 and 18 of the discordant IHC and FISH cases, respectively. Among 96 BCIRG005 cases, IHC-and FISH-were confirmed in the primary block in all 96 cases. Among 59 evaluable N9831 HER2-normal cases, IHC-and FISH-were confirmed in the primary block in 57 (97%) cases (but another block tested HER2+ for 4 cases). Among 102 N9831/BCIRG006 HER2+ cases, HER2 positivity was confirmed in the primary block in 73 (72%) cases. Among 118 cases with IHC results for &gt; 1 block, the adjudicated IHC result agreed across blocks in 106 (90%) cases. Among 113 cases with FISH results for &gt;1 block, the adjudicated FISH result agreed in 107 (95%) cases. Among 53 N9831 HER2-normal cases adjudicated as IHC-& FISH-(although they all had a previous local HER2+ test), there was significant improvement in disease-free survival associated with trastuzumab given concurrently with paclitaxel after doxorubicin and cyclophosphamide compared to chemotherapy alone (HR=0.31, 95% CI 0.11-0.91; A 23 pts, 10 events; C 30 pts, 5 events). Conclusions: Excellent agreement (96%) was observed among the pathologists at adjudication, suggesting that standardized methods improve assay proficiency. HER2 heterogeneity across blocks was observed more at the protein than at the gene level. In the small subset of N9831 pts adjudicated as HER2-normal trastuzumab benefit was observed. This work was supported by NCI and Genentech. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD10-02.

The effects of the N-methyl-d-aspartate (NMDA) antagonist MK-801 on capillary beds and CBF following 1 h of transient incomplete focal cerebral ischemia were studied by examining 133 Xe CBF, capillary diameter, and area of perfused vasculature. Capillary diameter increased from a control of 5.24 ± 0.37 to 8.62 ± 0.57 μm (p < 0.001) and area of perfused vasculature from 20,943 ± 1,151 to 30,442 ± 1,691 μm 2 /×10 magnification field (p < 0.001) with MK-801 1.0 mg/kg administered 30 min prior to ischemia. After flow restoration in control animals, there was a relative hypoperfusion with eventual normalization of CBF over 60 min. Alternatively, in MK-801 1.0 mg/kg animals, there was rapid normalization of CBF upon flow restoration without the postischemic hypoperfusion observed in controls. On histological analysis, there was consistently less neuronal edema in MK-801-treated animals. These results support the hypothesis that hypoperfusion following incomplete focal cerebral ischemia may be due in part to NMDA-mediated cellular edema with subsequent extravascular capillary bed compression.

The effects of the novel dihydronaphthyridine Ca 2+ antagonist CI-951 on focal cerebral ischemia were assessed during MCA occlusion in 30 white New Zealand rabbits under 1.0% halothane anesthesia. In vivo brain pH i and focal CBF were measured with umbelliferone fluorescense. Baseline normocapnic brain pH i and CBF were 7.02 ± 0.02 and 48.4 ± 2.9 ml/100 g/min, respectively. In the severe ischemic regions, 15 min postocclusion brain pH i , and CBF were 6.62 ± 0.04 and 14.4 ± 0.7 ml/100 g/min in controls vs. 6.60 ± 0.02 and 12.9 ± 2.3 ml/100 g/min, respectively, in animals destined to receive CI-951. Twenty minutes after MCA occlusion, CI-951 was administered at 0.5 μg/kg/min and brain pH i and CBF were determined in both regions of severe and moderate ischemia for 4 h postocclusion. Control severe ischemic sites demonstrated no significant improvement in brain pH i and only mild increases in CBF over the next 4 h. CI-951 caused significant improvement in both of these parameters. Postocclusion 4 h brain pH i and CBF measured 6.69 ± 0.04 and 18.5 ± 3.2 ml/100 g/min in controls vs. 7.01 ± 0.04 and 41.7 ± 5.3 ml/100 g/min, respectively, in CI-951 animals ( p < 0.001). Similar improvements were observed in moderate ischemic sites. In animals that demonstrated postocclusion EEG attenuation, 75% of CI-951 animals had EEG recovery as compared to 18% in controls. CI-951 may be a useful therapeutic agent for focal cerebral ischemia if histological and outcome studies verify these data.