Efficacy and safety assessment of prolonged maintenance with subcutaneous rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma: results of the phase III MabCute study.

Rituximab plus chemotherapy induction followed by rituximab maintenance for up to 2 years confers a long-term benefit in terms of progression-free survival in patients with indolent non-Hodgkin lymphoma. It is not known whether further prolonged maintenance with rituximab provides additional benefit. The phase III MabCute study enrolled 692 patients with relapsed or refractory indolent non-Hodgkin lymphoma. Patients who responded to induction with rituximab plus chemotherapy and were still responding after up to 2 years' initial maintenance with subcutaneous rituximab were randomized to extended maintenance with subcutaneous rituximab (n=138) or observation only (n=138). The primary endpoint of investigator-assessed progression-free survival in the randomized population was un-addressed by the end of study because of an insufficient number of events (129 events were needed for 80% power at 5% significance if approximately 330 patients were randomized). In total, there were 46 progression-free survival events, 19 and 27 in the rituximab and observation arms, respectively (P=0.410 by stratified log-rank test; hazard ratio 0.76 [95% confidence interval: 0.37- 1.53]). The median progression-free survival was not reached in either randomized arm. There were no new safety signals; however, adverse events were seen slightly more frequently with rituximab than with observation during extended maintenance. Maintenance for up to 2 years with rituximab after response to initial induction therefore remains the standard of care in patients with relapsed or refractory indolent non- Hodgkin lymphoma. (Clinicaltrials.gov identifier: NCT01461928).

Density and shape as CT predictors of intracerebral hemorrhage growth.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) growth predicts mortality and functional outcome. We hypothesized that irregular hematoma shape and density heterogeneity, reflecting active, multifocal bleeding or a variable bleeding time course, would predict ICH growth. METHODS: Three raters examined baseline sub-3-hour CT brain scans of 90 patients in the placebo arm of a Phase IIb trial of recombinant activated Factor VII in ICH. Each rater, blinded to growth data, independently applied novel 5-point categorical scales of density and shape to randomly presented baseline CT images of ICH. Density and shape were defined as either homogeneous/regular (Category 1 to 2) or heterogeneous/irregular (Category 3 to 5). Within- and between-rater reliability was determined for these scales. Growth was assessed as a continuous variable and using 3 binary definitions: (1) any ICH growth; (2) >or=33% or >or=12.5 mL ICH growth; and (3) radial growth >1 mm between baseline and 24-hour CT scan. Patients were divided into tertiles of baseline ICH volume: "small" (0 to 10 mL), "medium" (10 to 25 mL), and "large" (25 to 106 mL). RESULTS: Inter- and intrarater agreements for the novel scales exceeded 85% (+/-1 category). Median growth was significantly higher in the large-volume group compared with the small group (P<0.001) and in heterogeneous compared with homogeneous ICH (P=0.008). Median growth trended higher in irregular ICHs compared with regular ICHs (P=0.084). Small ICHs were more regularly shaped (43%) than medium (17%) and large (3%) ICHs (P<0.001). Small ICHs were more homogeneous (73%) compared with medium (37%) and large (17%) ICHs (P<0.001). Adjusting for baseline ICH volume and time to scan, density heterogeneity, but not shape irregularity, independently predicted ICH growth (P=0.046) on a continuous growth scale. CONCLUSIONS: Large ICHs were significantly more irregular in shape, heterogeneous in density, and had greater growth. Density heterogeneity independently predicted ICH growth using some definitions.

A free weekly iron-folic acid supplementation and regular deworming program is associated with improved hemoglobin and iron status indicators in Vietnamese women.

BACKGROUND: Anemia due to iron deficiency is recognized as one of the major nutritional deficiencies in women and children in developing countries. Daily iron supplementation for pregnant women is recommended in many countries although there are few reports of these programs working efficiently or effectively. Weekly iron-folic acid supplementation (WIFS) and regular deworming treatment is recommended for non-pregnant women living in areas with high rates of anemia. Following a baseline survey to assess the prevalence of anemia, iron deficiency and soil transmitted helminth infections, we implemented a program to make WIFS and regular deworming treatment freely and universally available for all women of reproductive age in two districts of a province in northern Vietnam over a 12 month period. The impact of the program at the population level was assessed in terms of: i) change in mean hemoglobin and iron status indicators, and ii) change in the prevalence of anemia, iron deficiency and hookworm infections. METHOD: Distribution of WIFS and deworming were integrated with routine health services and made available to 52,000 women. Demographic data and blood and stool samples were collected in baseline, and three and 12-month post-implementation surveys using a population-based, stratified multi-stage cluster sampling design. RESULTS: The mean Hb increased by 9.6 g/L (95% CI, 5.7, 13.5, p < 0.001) during the study period. Anemia (Hb<120 g/L) was present in 131/349 (37.5%, 95% CI 31.3, 44.8) subjects at baseline, and in 70/363 (19.3%, 95% CI 14.0, 24.6) after twelve months. Iron deficiency reduced from 75/329 (22.8%, 95% CI 16.9, 28.6) to 33/353 (9.3%, 95% CI 5.7, 13.0) by the 12-mnth survey, and hookworm infection from 279/366 (76.2%,, 95% CI 68.6, 83.8) to 66/287 (23.0%, 95% CI 17.5, 28.5) over the same period. CONCLUSION: A free, universal WIFS program with regular deworming was associated with reduced prevalence and severity of anemia, iron deficiency and hookworm infection when made available to Vietnamese women over a 12-month period.

Vitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from sub-Saharan Africa.

Among African immigrants in Melbourne, Victoria, Australia, we demonstrated lower geometric mean vitamin D levels in immigrants with latent tuberculosis infection than in those with no Mycobacterium tuberculosis infection (P=.007); such levels were also lower in immigrants with tuberculosis or past tuberculosis than in those with latent tuberculosis infection (P=.001). Higher vitamin D levels were associated with lower probability of any M. tuberculosis infection (P=.001) and lower probability of tuberculosis or past tuberculosis (compared with latent tuberculosis infection; P=.001).

Anemia, iron deficiency, meat consumption, and hookworm infection in women of reproductive age in northwest Vietnam.

Iron deficiency anemia poses an important public health problem for women of reproductive age living in developing countries. We assessed the prevalence of iron deficiency and anemia and associated risk factors in a community-based sample of women living in a rural province of northwest Vietnam. A cross-sectional survey, comprised of written questionnaires and laboratory analysis of hemoglobin (Hb), ferritin, transferrin receptor, and stool hookworm egg count, was undertaken, and the soluble transferrin receptor/log ferritin index was calculated. Of 349 non-pregnant women, 37.53% were anemic (Hb < 12 g/dL), and 23.10% were iron deficient (ferritin < 15 ng/L). Hookworm infection was present in 78.15% of women, although heavy infection was uncommon (6.29%). Iron deficiency was more prevalent in anemic than non-anemic women (38.21% versus 14.08%, P < 0.001). Consumption of meat at least three times a week was more common in non-anemic women (51.15% versus 66.67%, P = 0.042). Mean ferritin was lower in anemic women (18.99 versus 35.66 ng/mL, P < 0.001). There was no evidence of a difference in prevalence (15.20% versus 17.23%, P = 0.629) or intensity (171.07 versus 129.93 eggs/g, P = 0.412) of hookworm infection between anemic and non-anemic women. Although intensity of hookworm infection and meat consumption were associated with indices of iron deficiency in a multiple regression model, their relationship with hemoglobin was not significant. Anemia, iron deficiency, and hookworm infection were prevalent in this population. Intake of meat was more clearly associated with hemoglobin and iron indices than hookworm. An approach to addressing iron deficiency in this population should emphasize both iron supplementation and deworming.

The improvement in survival of expanded criteria donor kidneys with transplantation era.

BACKGROUND: To compensate for the shortage of donor kidneys, use of expanded donor criteria (ECD) has been adopted by many transplant centres. Multiple criteria on which to score such kidneys have been proposed but the evidence base for the definitions is derived from retrospective and registry data only. We aimed to see if analysis of ECD in our population would indicate the need to change our donor selection process. METHODS: Data on primary kidney transplants (minimum follow-up two yr) from 1989 to 2004 were reviewed (n = 635). The primary study endpoint was overall graft survival. Published ECD, including the United Network for Organ Sharing (UNOS) ECD criteria were assessed as potential prognostic variables, in a multivariable Cox proportional hazards model. RESULTS: Patients transplanted after 1996 had improved graft survival compared to those transplanted pre-1996 HR = 0.51 (0.35-0.76), p = 0.0001. Pre-1996 UNOS defined ECD kidneys had a markedly increased risk of graft failure compared to live donor kidneys HR = 3.52 (1.9-6.35), p < 0.001. Post-1996 ECD kidneys had similar prognosis compared to live donor kidneys HR 0.38 (0.1-1.59), p = 0.184. The observed improvement in graft survival was not explained by changes in donor source, cause of end stage renal failure (ESRF), human leukocyte antigen mismatch, recipient age or any histological parameter on implantation biopsy. CONCLUSIONS: The explanation for improved overall graft survival and marked improved survival of ECD kidneys is unclear, but introduction of mycophenolate and subsequent falls in calcineurin inhibitor doses over the study period could be potential factors. These results provide some justification for our current selection and management of ECD kidneys.

Improving antibiotic prescribing for adults with community acquired pneumonia: Does a computerised decision support system achieve more than academic detailing alone?--A time series analysis.

BACKGROUND: The ideal method to encourage uptake of clinical guidelines in hospitals is not known. Several strategies have been suggested. This study evaluates the impact of academic detailing and a computerised decision support system (CDSS) on clinicians' prescribing behaviour for patients with community acquired pneumonia (CAP). METHODS: The management of all patients presenting to the emergency department over three successive time periods was evaluated; the baseline, academic detailing and CDSS periods. The rate of empiric antibiotic prescribing that was concordant with recommendations was studied over time comparing pre and post periods and using an interrupted time series analysis. RESULTS: The odds ratio for concordant therapy in the academic detailing period, after adjustment for age, illness severity and suspicion of aspiration, compared with the baseline period was OR = 2.79 [1.88, 4.14], p < 0.01, and for the computerised decision support period compared to the academic detailing period was OR = 1.99 [1.07, 3.69], p = 0.02. During the first months of the computerised decision support period an improvement in the appropriateness of antibiotic prescribing was demonstrated, which was greater than that expected to have occurred with time and academic detailing alone, based on predictions from a binary logistic model. CONCLUSION: Deployment of a computerised decision support system was associated with an early improvement in antibiotic prescribing practices which was greater than the changes seen with academic detailing. The sustainability of this intervention requires further evaluation.

A pilot study of resistance to aspirin in stroke patients.

Aspirin resistance has been shown to be a significant risk factor for recurrent cardiovascular ischaemic events. However, there are a lack of data correlating aspirin resistance and risk of cerebrovascular ischaemic events. This pilot study aimed to determine the prevalence of aspirin resistance in an Australian stroke population and to correlate aspirin resistance with an increased risk of ischaemic stroke. Fifty patients treated with aspirin for 2 years were tested for aspirin resistance using the Ultegra Rapid Platelet Function Assay (Accumetrics, San Diego, CA, USA) on admission to Royal Melbourne Hospital for ischaemic stroke. The 2-year history of ischaemic stroke and transient ischaemic attack (TIA) were assessed. Prevalence of aspirin resistance among our patients was 30%. Univariate analysis suggested a non-significant trend towards increased rate of previous ischaemic stroke or TIA and aspirin resistance (odds ratio, OR=3.88; 95% confidence interval 0.54-29.87; p=0.18). This study shows that aspirin resistance is prevalent within the Australian ischaemic stroke population.

Predictors of early cardiac morbidity and mortality after ischemic stroke.

BACKGROUND AND PURPOSE: In the first 3 months after acute ischemic stroke, 2% to 6% of patients die from cardiac causes. This may reflect preexisting cardiac disease, cardiac dysfunction related to the acute neurohumoral and autonomic stress response to stroke, or both. Delineation of a high-risk group could facilitate prevention strategies. We aimed to describe the temporal profile of cardiac risk after stroke and develop a predictive model of serious cardiac adverse events (SCAEs) using baseline variables. METHODS: We used data from the one trial in the Virtual International Stroke Trials Archive that matched prespecified criteria. Survival analysis was used to describe the temporal profile of cardiac events after stroke. Prognostic determinants were assessed with multivariable logistic regression, and a risk score was derived from the key predictor variables. RESULTS: Of 846 ischemic stroke patients, 35 (4.1%) died from cardiac causes and 161 (19.0%) suffered at least one SCAE. The hazard of cardiac death was highest (0.001/d) in the second week. Hazard of a first SCAE peaked at 0.02/d between day 2 and 3. The 5 factors most predictive of SCAEs were a history of heart failure (OR 3.33 [2.28, 4.89], P<0.001), diabetes (OR 2.11 [1.39, 3.21], P<0.001), baseline creatinine >115 micromol/L (OR 1.77 [1.16, 2.70], P=0.008), severe stroke (OR 1.98 [1.34,2.91], P=0.001), and a long QTc or ventricular extrasystoles on ECG (OR 1.93 [1.31, 2.85], P=0.001). Risk of SCAEs ranged from 6.3% (no predictors) to 62.2% (> or =4 predictors). CONCLUSIONS: Serious cardiac events are common in the acute period after stroke. Patients at highest risk are identifiable and may benefit from more aggressive strategies to improve survival.

'MRI-negative PET-positive' temporal lobe epilepsy (TLE) and mesial TLE differ with quantitative MRI and PET: a case control study.

BACKGROUND: 'MRI negative PET positive temporal lobe epilepsy' represents a substantial minority of temporal lobe epilepsy (TLE). Clinicopathological and qualitative imaging differences from mesial temporal lobe epilepsy are reported. We aimed to compare TLE with hippocampal sclerosis (HS+ve) and non lesional TLE without HS (HS-ve) on MRI, with respect to quantitative FDG-PET and MRI measures. METHODS: 30 consecutive HS-ve patients with well-lateralised EEG were compared with 30 age- and sex-matched HS+ve patients with well-lateralised EEG. Cerebral, cortical lobar and hippocampal volumetric and co-registered FDG-PET metabolic analyses were performed. RESULTS: There was no difference in whole brain, cerebral or cerebral cortical volumes. Both groups showed marginally smaller cerebral volumes ipsilateral to epileptogenic side (HS-ve 0.99, p = 0.02, HS+ve 0.98, p < 0.001). In HS+ve, the ratio of epileptogenic cerebrum to whole brain volume was less (p = 0.02); the ratio of epileptogenic cerebral cortex to whole brain in the HS+ve group approached significance (p = 0.06). Relative volume deficits were seen in HS+ve in insular and temporal lobes. Both groups showed marked ipsilateral hypometabolism (p < 0.001), most marked in temporal cortex. Mean hypointensity was more marked in epileptogenic-to-contralateral hippocampus in HS+ve (ratio: 0.86 vs 0.95, p < 0.001). The mean FDG-PET ratio of ipsilateral to contralateral cerebral cortex however was low in both groups (ratio: HS-ve 0.97, p < 0.0001; HS+ve 0.98, p = 0.003), and more marked in HS-ve across all lobes except insula. CONCLUSION: Overall, HS+ve patients showed more hippocampal, but also marginally more ipsilateral cerebral and cerebrocortical atrophy, greater ipsilateral hippocampal hypometabolism but similar ipsilateral cerebral cortical hypometabolism, confirming structural and functional differences between these groups.

Practicality, safety and accuracy of computed tomography coronary angiography in the evaluation of low TIMI-risk score chest pain patients: a pilot study.

OBJECTIVES: The present pilot study aimed to assess the practicality, safety and accuracy of performing CT coronary angiography (CT-CA) in the evaluation of acute chest pain of patients with low thrombolysis in myocardial infarction (TIMI) risk scores. METHODS: The present prospective observational study was undertaken in a university teaching hospital between November 2004 and December 2005. Participants were a convenience sample of patients admitted to hospital for investigation of chest pain with TIMI risk scores <3. Consenting patients underwent CT-CA within 48 h of presentation. Outcomes of interest were practicality (proportion of diagnostic quality scans obtained and preparation time for CT-CA), rate of serious adverse events, and accuracy at the patient level using selective coronary angiography as the reference standard. RESULTS: Thirty-four patients were recruited. Diagnostic quality scans were obtained in 26/34 or 76% of patients (four failed CT-CA and four non-diagnostic scans). The median CT preparation time was 1.9 h (range 0.17-4.0). No serious adverse events were found. Fourteen of those 26 patients with diagnostic CT-CA subsequently had selective coronary angiography, of which nine were positive. The sensitivity and specificity of CT-CA in identifying patients with significant coronary artery disease were 9/9 (100%; 95% confidence interval 72-100%) and 4/5 (80%; 95% confidence interval 28-100%), respectively. CONCLUSIONS: The majority of acute chest pain patients with low TIMI risk scores were successfully scanned with a 16-slice CT to produce CT-CA studies with good diagnostic quality and accuracy. No major adverse events were found. The place of CT-CA in diagnostic workup for chest pain remains to be defined.

Identifying severe community-acquired pneumonia in the emergency department: a simple clinical prediction tool.

OBJECTIVE: To identify independent predictors of severe pneumonia in a local population, and create a simple severity score that would be useful in the ED. METHODS: Data on the clinical features of patients presenting to hospital with community-acquired pneumonia were collected. Multivariate logistic regression was used to identify independent predictors of death, requirement for ventilatory or inotropic support, and these combined. These predictors were used to modify an existing severity score, and its performance was tested in a second cohort of patients. RESULTS: A total of 392 patients in the derivation, and 330 in the validation cohorts. Independent predictors of 'death and/or requirement for ventilatory or inotropic support' were: systolic blood pressure (BP) <90 mmHg (OR 3.49 [95% CI 1.12-10.38]); acute confusion (OR 5.48 [95% CI 2.74-10.99]); oxygen saturations < or =90% (OR 3.49 [95% CI 1.77-6.89]); and respiratory rate > or =30/min (OR 2.65 [95% CI 1.35-5.21]). Age >65 years was not an independent predictor in this patient group (OR 0.52 [95% CI 0.23-1.16]). This information was used to propose that severe pneumonia could be predicted by two or more of: acute confusion; oxygen saturations < or =90%; respiratory rate > or =30/min; and either systolic BP <90 mmHg; or diastolic BP < or =60 mmHg. In a separate cohort, the performance of this score was similar to other tools. CONCLUSION: This provides a practical tool that can be used to 'flag' impending patient demise. Its advantages are that it is simple, uses predictive variables, does not require invasive testing, and removes bias regarding patient age. Like other tools, its accuracy is not perfect, and it should only be used to augment clinical judgement.

Frequency and temporal profile of poststroke hyperglycemia using continuous glucose monitoring.

OBJECTIVE: Poststroke hyperglycemia (PSH) is common and has adverse effects on outcome. In this observational study, we aimed to describe the frequency and temporal profile of PSH using a continuous glucose monitoring system (CGMS) in patients with and without diabetes. RESEARCH DESIGN AND METHODS: Fifty-nine patients with acute hemispheric ischemic stroke were prospectively studied with the CGMS, regardless of medication, admission plasma glucose value, and diabetes status. The CGMS records interstitial glucose every 5 min for 72 h. RESULTS: On admission, 36% of patients had preexisting diabetes. At the earliest analyzed time point of 8 h from stroke onset, 50% of nondiabetic subjects and 100% of diabetic patients were hyperglycemic (> or =7 mmol/l). This early-phase hyperglycemia was followed by a decrease in glucose 14-16 h poststroke when only 11% of nondiabetic and 27% of diabetic patients were hyperglycemic. A late hyperglycemic phase 48-88 h poststroke was observed in 27% of nondiabetic and 78% of diabetic patients. Thirty-four percent of nondiabetic and 86% of diabetic patients were hyperglycemic for at least a quarter of the monitoring period. Multivariate regression analysis demonstrated that diabetes, insular cortical ischemia, and increasing age independently predicted higher glucose values. CONCLUSIONS: Poststroke hyperglycemia is common and prolonged despite treatment based on current guidelines. There are early and late hyperglycemic phases in nondiabetic as well as diabetic patients. Treatment protocols with frequent glucose measurement and intensive glucose-lowering therapy for a minimum of 72 h poststroke need to be evaluated.

A randomized, double-blinded, placebo-controlled phase II trial of recombinant human leukemia inhibitory factor (rhuLIF, emfilermin, AM424) to prevent chemotherapy-induced peripheral neuropathy.

PURPOSE: To determine whether recombinant human leukemia inhibitory factor (rhuLIF, AM424, emfilermin) can prevent or ameliorate the development of chemotherapy-induced peripheral neuropathy (CIPN) after treatment with carboplatin (AUC 6) and paclitaxel (175 mg/m(2) over 3 hours). EXPERIMENTAL DESIGN: Randomized double-blind placebo-controlled phase II clinical trial. Eligible patients had solid tumors for which treatment with carboplatin/paclitaxel was appropriate. The primary end point was a standardized composite peripheral nerve electrophysiology (CPNE) score, based on nerve velocities and amplitudes, measured at baseline and after four cycles of chemotherapy. Secondary efficacy end points included CPNE score at last cycle and at exit evaluation, vibration perception threshold, H-reflex latency, symptom scores, and quantitative assessment of neurologic signs. Study drug was given s.c. daily for 7 days starting the day before chemotherapy. Patients were randomized to receive low-dose rhuLIF (2 microg/kg), high-dose rhuLIF (4 microg/kg), or placebo. RESULTS: Patients (n = 117) were randomized across seven neurology test centers. Thirty-six patients received low dose rhuLIF (2 microg/kg), 39 received high dose rhuLIF (4 microg/kg) and 42 received placebo. rhuLIF was well tolerated with 95% compliance and no adverse effects on quality of life. No differences between groups in CPNE or any of the individual neurologic testing variables were observed between baseline and cycle 4 or by the secondary efficacy variables. CONCLUSIONS: rhuLIF is not effective in preventing CIPN caused by carboplatin and paclitaxel. CPNE is a reliable and valid tool that was sensitive to the onset and progression of CIPN.

Clinical-diffusion mismatch predicts the putative penumbra with high specificity.

BACKGROUND AND PURPOSE: Perfusion-diffusion (PWI-DWI) mismatch may represent the ischemic penumbra. The complexities associated with perfusion-weighted imaging (PWI) have restricted its use. Mismatch between stroke severity, assessed with the National Institutes of Health Stroke Scale (NIHSS), and the volume of the diffusion-weighted imaging (DWI) lesion (clinical-diffusion mismatch; CDM) has been suggested as a surrogate for PWI-DWI mismatch. We compared CDM with PWI and DWI in acute stroke. METHODS: Seventy-nine hemispheric stroke patients were imaged within 24 hours of symptom onset and subacutely (3 to 5 days). CDM was defined as NIHSS > or =8 and DWI < or =25 mL. DWI lesion and PWI (Tmax+4s) volumes were measured by planimetric techniques. Acute PWI-DWI mismatch was examined as a continuous variable (mismatch volume=PWIvol-DWIvol) and a categorical variable (mismatch=PWIvol-DWIvol/DWIvol x 100>20%). Early infarct expansion was calculated as DWI(subacute vol/DWI(acute vol). RESULTS: In the 54 sub-6-hour patients, CDM detected PWI-DWI mismatch with a specificity of 93% (95% confidence interval [CI], 62% to 99%), a positive predictive value of 95% (95% CI, 77% to 100%), but a sensitivity of only 53% (95% CI, 34% to 68%). Alternate DWI and NIHSS cutpoints did not improve test performance characteristics. In addition, subacute DWI expansion was significantly greater in patients with CDM (P=0.01) compared with those without. CONCLUSIONS: CDM (NIH > or =8, DWI < or =25 mL) predicts the presence of PWI-DWI mismatch with high specificity and low sensitivity. CDM also predicts DWI expansion. CDM may be a useful selection tool in acute stroke therapies, including thrombolysis.

Apparent diffusion coefficient thresholds do not predict the response to acute stroke thrombolysis.

BACKGROUND AND PURPOSE: Apparent diffusion coefficient (ADC) thresholds for tissue infarction have been identified in acute stroke. IV tissue plasminogen activator (tPA) is associated with tissue salvage. We hypothesized that tPA would lower the ADC threshold for infarction. METHODS: ADC and mean transit time (MTT) maps were generated for 26 patients imaged within 6 hours of stroke onset (12 tPA and 14 conservatively managed controls). MTT maps and day-90 T2-weighted images were coregistered to ADC maps. Relative ADC (rADC) values were calculated for initial diffusion-weighted imaging (DWI) lesions, infarct growth regions (final infarct volume-the acute DWI lesion volume), and hypoperfused salvaged regions (HS; MTT map abnormality-the final infarct volume). When relevant, the DWI lesion was subdivided into DWI reversal and DWI infarct regions. RESULTS: Mean DWI lesion rADC was 0.79 in tPA and 0.74 in untreated patients (P=0.097). Mean rADC in HS and infarct growth regions were similar in tPA patients (0.950 and 0.946) and untreated patients (0.957, P=0.76; 0.970, P=0.08, respectively). The rADC in HS tissue was directly correlated with the time to treatment with tPA (r=0.685; P=0.029). DWI reversal was seen in 67% of tPA-treated patients and in 36% of those conservatively managed (Fisher exact test; P=0.238). In the 13 patients with DWI reversal, the mean rADC in these regions (0.81+/-0.07) was significantly higher than in the acute DWI region that infarcted (0.74+/-0.07; P=0.02), although no absolute thresholds could be identified. CONCLUSIONS: The peri-DWI lesion region contains tissue with intermediate ADC values. The fate of this tissue is variable and cannot be predicted based on the ADC alone. DWI expansion occurs in bioenergetically normal tissue, and this is attenuated by tPA in a time-dependent fashion.

Photodynamic therapy of high grade glioma - long term survival.

Haemetaporphyrin derivative (HpD) mediated photodynamic therapy (PDT) has been investigated as an adjuvant treatment for cerebral glioma. This study records the survival of patients at the Royal Melbourne Hospital with residences in the State of Victoria, utilizing the Victorian Cancer Registry database for patients treated with adjuvant PDT following surgical resection of the tumour. For primary (newly diagnosed) tumours, median survival from initial diagnosis was 76.5 months for anaplastic astrocytoma (AA) and 14.3 months for glioblastoma multiforme (GBM). Seventy-three percent of patients with AA and 25% with GBM survived longer than 36 months. For recurrent tumour, median survival from the time of surgery was 66.6 months for AA and 13.5 months for GBM. Fifty-seven percent of patients with recurrent AA and 41% of patients with recurrent GBM survived longer than 36 months. Older age at the time of diagnosis was associated with poorer prognosis. Laser light doses above the sample median of 230 J/cm2 were associated with better prognosis in the 136 patients studied (primary tumour patients - (HR=0.50[0.27,0.95],p=0.033); recurrent tumour patients (HR=0.75[0.42,1.31],p=0.312). There was no mortality directly associated with the therapy, three patients had increased cerebral oedema thought to be related to photodynamic therapy that was controlled with conventional therapies.

Perihematomal edema in primary intracerebral hemorrhage is plasma derived.

BACKGROUND AND PURPOSE: The mechanisms of perihematomal injury in primary intracerebral hemorrhage (ICH) are incompletely understood. An MRI study was designed to elucidate the nature of edema and blood flow changes after ICH. METHODS: Perihematomal blood flow and edema were studied prospectively with perfusion-weighted MRI (PWI) and diffusion-weighted MRI in 21 ICH patients. MRI and computed tomography (CT) images were coregistered to ensure perfusion and diffusion changes were outside of the hematoma. Edema volumes were measured on T2-weighted images. Apparent diffusion coefficient (ADC) values of the edematous regions were calculated. RESULTS: Mean patient age was 64.2 years (45 to 89), and median National Institutes of Health stroke scale score was 12 (3 to 24). Median time to MRI was 21 hours (4.5 to 110). Average hematoma volume on CT was 26.1 (4 to 84) mL. PWI demonstrated perihematomal relative mean transit time (rMTT) was significantly correlated with hematoma volume (r=0.60; P=0.004) but not edema volume. Perihematomal oligemia (rMTT >2 s) was present in patients with hematoma volumes of >15 mL (average rMTT 4.6+/-2.0 s). Perihematomal edema was present in all patients. ADC values within this region (1178+/-213x10(-6) mm2/s) were increased 29% relative to contralateral homologous regions. Increases in perihematomal ADC predicted edema volume (r=0.54; P=0.012) and this was confirmed with multivariate analysis. CONCLUSIONS: Acute perihematomal oligemia occurs in acute ICH but is not associated with MRI markers of ischemia and is unrelated to edema formation. Increased rates of water diffusion in the perihematomal region independently predict edema volume, suggesting the latter is plasma derived.

Insular cortical ischemia is independently associated with acute stress hyperglycemia.

BACKGROUND AND PURPOSE: Acute poststroke hyperglycemia has been associated with larger infarct volumes and a cortical location, regardless of diabetes status. Stress hyperglycemia has been attributed to activation of the hypothalamic-pituitary-adrenal axis but never a specific cortical location. We tested the hypothesis that damage to the insular cortex, a site with autonomic connectivity, results in hyperglycemia reflecting sympathoadrenal dysregulation. METHODS: Diffusion-weighted MRI, glycosylated hemoglobin (HbA1c), and blood glucose measurements were obtained in 31 patients within 24 hours of ischemic stroke onset. Acute diffusion-weighted imaging (DWI) lesion volumes were measured, and involvement of the insular cortex was assessed on T2-weighted images. RESULTS: Median admission glucose was significantly higher in patients with insular cortical ischemia (8.6 mmol/L; n=14) compared with those without (6.5 mmol/L; n=17; P=0.006). Multivariate linear regression demonstrated that insular cortical ischemia was a significant independent predictor of glucose level (P=0.001), as was pre-existing diabetes mellitus (P=0.008). After controlling for the effect of insular cortical ischemia, DWI lesion volume was not associated with higher glucose levels (P=0.849). There was no association between HbA1c and glucose level (P=0.737). CONCLUSIONS: Despite the small sample size, insular cortical ischemia appeared to be associated with the production of poststroke hyperglycemia. This relationship is independent of pre-existing glycemic status and infarct volume. Neuroendocrine dysregulation after insular ischemia may be 1 aspect of a more generalized acute stress response. Future studies of poststroke hyperglycemia should account for the effect of insular cortical ischemia.

Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial.

BACKGROUND: Alzheimer disease (AD) may be caused by the toxic accumulation of beta-amyloid (Abeta). OBJECTIVE: To test this theory, we developed a clinical intervention using clioquinol, a metal-protein-attenuating compound (MPAC) that inhibits zinc and copper ions from binding to Abeta, thereby promoting Abeta dissolution and diminishing its toxic properties. METHODS: A pilot phase 2 clinical trial in patients with moderately severe Alzheimer disease. RESULTS: Thirty-six subjects were randomized. The effect of treatment was significant in the more severely affected group (baseline cognitive subscale score of the Alzheimer's Disease Assessment Scale, >/=25), due to a substantial worsening of scores in those taking placebo compared with minimal deterioration for the clioquinol group. Plasma Abeta42 levels declined in the clioquinol group and increased in the placebo group. Plasma zinc levels rose in the clioquinol-treated group. The drug was well tolerated. CONCLUSION: Subject to the usual caveats inherent in studies with small sample size, this pilot phase 2 study supports further investigation of this novel treatment strategy using a metal-protein-attenuating compound.