Citations

Medulloblastoma, the most common embryonal tumor of the central nervous system, affects both children and adults. It poses a significant therapeutic challenge in that age-dependent differences exist, not only in their pathobiology, but in the efficacy of chemotherapy and radiotherapy. This is particularly the case in very young children, whose still developing nervous system exhibits a low tolerance to radiotherapy. We review the epidemiology, clinical presentation, radiologic features, and current therapeutic concepts relative to this unique neoplasm. Efforts are made to highlight clinical controversies. ( J Child Neurol 1992;7:142-155).

Abstract Background: Urinary excretion of albumin indicates kidney damage and is recognized as a risk factor for progression of kidney disease and cardiovascular disease. The role of urinary albumin measurements has focused attention on the clinical need for accurate and clearly reported results. The National Kidney Disease Education Program and the IFCC convened a conference to assess the current state of preanalytical, analytical, and postanalytical issues affecting urine albumin measurements and to identify areas needing improvement. Content: The chemistry of albumin in urine is incompletely understood. Current guidelines recommend the use of the albumin/creatinine ratio (ACR) as a surrogate for the error-prone collection of timed urine samples. Although ACR results are affected by patient preparation and time of day of sample collection, neither is standardized. Considerable intermethod differences have been reported for both albumin and creatinine measurement, but trueness is unknown because there are no reference measurement procedures for albumin and no reference materials for either analyte in urine. The recommended reference intervals for the ACR do not take into account the large intergroup differences in creatinine excretion (e.g., related to differences in age, sex, and ethnicity) nor the continuous increase in risk related to albumin excretion. Discussion: Clinical needs have been identified for standardization of (a) urine collection methods, (b) urine albumin and creatinine measurements based on a complete reference system, (c) reporting of test results, and (d) reference intervals for the ACR.

Background— We previously reported the feasibility of an acute, orally delivered, newly developed, conjugated form of human B-type natriuretic peptide (hBNP) in normal animals. The objective of the present study was to extend our findings and to define the chronic actions of an advanced oral conjugated hBNP (hBNP-054) administered for 6 days on sodium excretion and blood pressure. We also sought to establish the ability of this new conjugate to acutely activate cGMP and to reduce blood pressure in an experimental model of angiotensin II (ANG II) –mediated hypertension. Methods and Results— First, we developed additional novel conjugated forms of oral hBNP that were superior to our previously reported hBNP-021 in reducing blood pressure in 6 normal dogs. We then tested the new conjugate, hBNP-054, chronically in 2 normal dogs to assess its biological actions as a blood pressure–lowering agent and as a natriuretic factor. Second, we investigated the effects of acute oral hBNP-054 or vehicle in 6 dogs that received continuous infusion of ANG II to induce hypertension. After baseline determination of mean blood pressure (MAP) and blood collection for plasma hBNP and cGMP, all dogs received continuous ANG II infusion (20 ng · kg −1 · min −1 , 1 mL/min) for 4 hours. After 30 minutes of ANG II, dogs received oral hBNP-054 (400 μg/kg) or vehicle in a random crossover fashion with a 1-week interval between dosing. Blood sampling and MAP measurements were repeated 30 minutes after ANG II administration and 10, 30, 60, 120, 180, and 240 minutes after oral administration of hBNP-054 or vehicle. In the chronic study in normal dogs, oral hBNP-054 effectively reduced MAP for 6 days and induced a significant increase in 24-hour sodium excretion. hBNP was not present in the plasma at baseline in any dogs, and it was not detected at any time in the vehicle group. However, hBNP was detected throughout the duration of the study after oral hBNP-054, with a peak concentration at 30 minutes of 1060±818 pg/mL. In the acute study, after ANG II administration, plasma cGMP was not activated after vehicle, whereas it was significantly increased after oral hBNP-054 ( P =0.01 between the 2 groups). Importantly, MAP was significantly increased after ANG II throughout the acute study protocol. However, although no changes occurred in MAP after vehicle administration, oral hBNP-054 reduced MAP for >2 hours (from 138±1 mm Hg after ANG II to 124±2 mm Hg at 30 minutes, 124±2 mm Hg at 1 hour, and 130±5 mm Hg at 2 hours after oral hBNP-054; P <0.001). Conclusions— This study reports for the first time that a novel conjugated oral hBNP possesses blood pressure–lowering and natriuretic actions over a 6-day period in normal dogs. Furthermore, hBNP-054 activates cGMP and reduces MAP in a model of acute hypertension. These findings advance the concept that orally administered chronic BNP is a potential therapeutic strategy for cardiovascular diseases such as hypertension.

Purpose No biomarkers have been identified to predict outcome with the use of an antiangiogenesis agent for cancer. Vascular endothelial growth factor (VEGF) genetic variability has been associated with altered risk of breast cancer and variable promoter activity. Therefore, we evaluated the association of VEGF genotype with efficacy and toxicity in E2100, a phase III study comparing paclitaxel versus paclitaxel plus bevacizumab as initial chemotherapy for metastatic breast cancer. Patients and Methods DNA was extracted from tumor blocks of patients from E2100. Three hundred sixty-three samples were available to evaluate associations between genotype and outcome. Genotyping was performed for selected polymorphisms in VEGF and VEGF receptor 2. Testing for associations between each polymorphism and efficacy and toxicity was performed. Results The VEGF-2578 AA genotype was associated with a superior median overall survival (OS) in the combination arm when compared with the alternate genotypes combined (hazard ratio = 0.58; 95% CI, 0.36 to 0.93; P = .023). The VEGF-1154 A allele also demonstrated a superior median OS with an additive effect of each active allele in the combination arm but not the control arm (hazard ratio = 0.62; 95% CI, 0.46 to 0.83; P = .001). Two additional genotypes, VEGF-634 CC and VEGF-1498 TT, were associated with significantly less grade 3 or 4 hypertension in the combination arm when compared with the alternate genotypes combined (P = .005 and P = .022, respectively). Conclusion Our data support an association between VEGF genotype and median OS as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer.

Background and objectives Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. Methods Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. Results We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of “clinically isolated syndromes” (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. Conclusions Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.

Cardiac fibromas are the 2nd most common benign cardiac tumor occurring in children and bear a striking morphologic resemblance to soft tissue or desmoid fibromatosis. Since activating mutations in beta-catenin are common in desmoid fibromatosis as well as other spindle cell proliferations, the aim of our study was to determine if such mutations could be identified in cardiac fibroma. Nine cardiac fibromas from patients with surgical resection were examined for beta-catenin mutations by immunoperoxidase staining for beta-catenin protein and DNA sequencing of a region in exon 3 of the beta-catenin gene, where relatively conserved mutations have been described in desmoid fibromatosis. The mean age of the patients was 7.6 years (range: 10 weeks to 27 years), and 6 of the patients were male. No nuclear staining for beta-catenin was seen in the fibroma cells by immunoperoxidase methods. The beta-catenin exon 3 sequence data showed no mutations in any of the 9 tumors. We conclude that despite their morphologic similarity, cardiac fibroma and desmoid fibromatosis do not share this common molecular pathway of neoplastic growth.

Purpose To assess the effectiveness of depot octreotide for the prevention of diarrhea during pelvic radiation therapy. Patients and Methods Patients receiving pelvic radiation therapy (planned minimum dose, 45 Gy; 1.7 to 2.1 Gy daily) were eligible for the study. From May 10, 2002, through October 14, 2005, 125 patients were randomly allocated in a double-blind fashion to receive octreotide (100 μg, administered subcutaneously on day 1, followed by depot octreotide, 20 mg, administered intramuscularly on days 2 and 29; n = 62) or to receive a placebo (n = 63). Results Grade 0, 1, 2, and 3 diarrhea were observed in 18%, 31%, 31%, and 21% of patients in the octreotide arm, respectively, and in 25%, 32%, 22%, and 21% of patients in the placebo arm, respectively (P = .64). Grade 0, 1, 2, and 3 abdominal cramps were observed in 32%, 45%, 21%, and 2% of patients receiving octreotide, respectively, and in 51%, 24%, 21%, and 5% of patients receiving the placebo, respectively (P = .053). Some patient-reported symptoms were worse in the octreotide group, including nocturnal bowel movements (70% v 45%; P = .004), clustering of bowel movements (90% v 69%; P = .004), and bleeding with bowel movements (57% v 35%; P = .01). Conclusion As administered in this study, octreotide did not decrease diarrhea during pelvic radiation therapy. Some gastrointestinal symptoms were worse in patients treated with octreotide. Octreotide is not indicated for prevention of diarrhea during pelvic radiation therapy.