Background: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib (also known as Tarceva or OSI-774) has shown promising response rates in malignant gliomas. We investigated ...the association between expression of EGFR and downstream signaling components and the response of malignant gliomas to erlotinib in a phase I trial of erlotinib administered either alone or with the alkylating agent temozolomide. Methods: Expression of EGFR and ligand-independent EGFRvIII mutant proteins and of phosphorylated protein kinase B (PKB)/Akt in specimens from glioma patients were assessed by immunohistochemistry. EGFR gene amplification was evaluated by fluorescence in situ hybridization. Mutations in PTEN and EGFR were assessed by polymerase chain reaction amplification and sequencing. Response was evaluated by sequential magnetic resonance imaging every 2 months. The Cochran–Mantel–Haenzel test was used to assess associations between biomarker status and response. All statistical tests were two-sided. Results: Of 41 glioma patients, eight responded to treatment. Response to erlotinib was associated with EGFR expression (P = .07) and EGFR amplification (P = .08). These associations were stronger and statistically significant among the 29 patients initially diagnosed with glioblastoma multiforme (P = .03 and P = .02, respectively). Among six responders with sufficient tumor tissue, none had EGFRvIII mutations. None of the 22 tumors with high levels of phosphorylated PKB/Akt responded to erlotinib treatment, whereas eight of the 18 tumors with low levels of phosphorylated PKB/Akt responded to erlotinib treatment (P<.001). The level of phosphorylated PKB/Akt was also associated with time to progression (P<.001). Conclusions: Among glioma patients, those with glioblastoma multiforme tumors who have high levels of EGFR expression and low levels of phosphorylated PKB/Akt had better response to erlotinib treatment than those with low levels of EGFR expression and high levels of phosphorylated PKB/Akt.
To study patterns of recurrence in patients with focal primary glioblastoma treated on Northern California Oncology Group protocol 6G-82-2 including surgery, focal external beam radiotherapy (59.4-60 ...Gy) with oral hydroxyurea followed by temporary brain implant with high-activity iodine-125 sources (50 Gy), and six cycles of chemotherapy with procarbazine, lomustine, and vincristine.
Serial brain imaging scans were available for review in 25 of 34 patients with glioblastoma who underwent brain implant boost. Of 381 scans performed between the date of diagnosis and the date of death or last follow-up, 362 (95%) were re-reviewed. Disease progression was scored as local (within 2 cm of the implant site), separate within the brain parenchyma (> or = 2 cm from the implant site), subependymal, or systemic. Both initial and subsequent failures were scored.
Three patients are 5-year survivors, without evidence of disease, at 267, 292, and 308 weeks. Of the 22 initial sites of failure, 17 (77%) were local, three (14%) were separate brain lesions (one of which was due in retrospect to multicentric disease at diagnosis), one (5%) subependymal, and one (5%) systemic. Five patients with local failure later had other sites of failure, including a separate brain lesion in 1, subependymal spread in 3, and both in 1. One patient with separate brain failure later had local progression and then subependymal spread.
Although there was a significant risk of separate brain lesions or subependymal spread over time, local tumor progression was the predominant pattern of failure.
The determine the value of radiographically assessed response to radiation therapy as a predictor of survival in patients with glioblastoma multiforme (GBM), the authors studied a cohort of 301 ...patients who were initially treated according to uniform clinical protocols. All patients had newly diagnosed supratentorial GBM and underwent the maximum safe resection followed by external- beam radiation treatment (60 Gy in standard daily fractions or 70.4 Gy in twice-daily fractions of 160 cGy). The radiation response and survival rates were assessable in 222 patients. The extent of resection and the immediate response to radiation therapy were highly correlated with survival, both in a univariate analysis and after correction for age and Karnofsky performance scale (KPS) score in a multivariate Cox model (p< 0.001 for radiation response and p=0.04 for extent of resection). A subgroup analysis suggested that neuroimaging obtained within 3 days after surgery served as a better baseline for assessment of radiation response than images obtained later. Imaging obtained within 3 days after completion of a course of radiation therapy also provided valid radiation response scores. The impact of the radiographically assessed radiation response on survival time was comparable to that of age or KPS score. This information is easily obtained early in the course of the disease, may be of value for individual patients, and may also have implications for the design and analysis of trials of adjuvant therapy for GBM, including volume-dependent therapies such as radiosurgery or brachytherapy.
OBJECTIVE:--The aim of the present study was to investigate the effect of intravenous C-peptide infusion on ocular blood flow in patients with type 1 diabetes under euglycemic conditions. RESEARCH ...DESIGN AND METHODS--The study was performed in a randomized, placebo-controlled, double-masked, two-way, crossover design in 10 type 1 diabetic patients. C-peptide was intravenously administered at two different dosages (dosage 1: 25 pmol · kg⁻¹ · min⁻¹ bolus followed by 5 pmol · kg⁻¹ · min⁻¹ continuous infusion; dosage 2: six times higher than dosage 1), each for 60 min. Physiologic saline solution was used as a control for C-peptide on a different study day. On both study days, euglycemic clamps were performed. To assess retinal blood flow, laser Doppler velocimetry (blood flow velocities) and retinal vessel analyzer (vessels diameters) measurements were performed. Laser interferometric measurements of fundus pulsation were used to assess pulsatile choroidal blood flow. Blood velocities in the ophthalmic artery were measured using color Doppler imaging. RESULTS:--Eight patients (two female and six male) completed the study according to the protocol and without adverse events. One patient developed an anaphylactic reaction to C-peptide, which resolved without sequelae. The following results originate from the remaining eight subjects. Systemic hemodynamic parameters remained stable during both study days. Infusion of C-peptide did not affect any ocular hemodynamic parameter. CONCLUSIONS:--The data of the present study indicate that exogenous C-peptide exerts no effect on ocular hemodynamic parameters in type 1 diabetic patients under euglycemic conditions. The maximum detectable change in these parameters was <25%.
The diagnosis of type 1 von Willebrand disease (VWD) presents a diagnostic challenge in children. In fact, 25% or more of children with VWD may be diagnosed only after they experience postoperative ...bleeding. We previously described a 4-variable composite score that has 92.5% sensitivity and 95% specificity for diagnosing VWD in children with known VWD when 2 of 4 criteria are positive: (1) Tosetto bleeding score ≥ 1; (2) family history of VWD; (3) personal history of iron deficiency anemia; and/or (4) positive James early bleeding score. The purpose of this study was to prospectively validate a composite score of ≥ 2 for identifying children with VWD.
Children without a previously diagnosed bleeding disorder presenting for hematology evaluation were enrolled. Sensitivity, specificity, positive, and negative predictive value of the composite score was determined.
A total of 193 subjects were enrolled from 12 participating centers were included in the analysis. Forty-seven children had type 1 VWD, including 11 with von Willebrand Ristocetin Cofactor (VWF):RCo < 30 IU/dL, 14 subjects with a VWF:RCo 30 to 39 IU/dL, and 22 with a VWF:RCo 40 to 49 IU/dL. Including all 4 variables, a composite score of ≥ 2 had a sensitivity of 63.6% to 76.0%, specificity of 33.5% to 35.1%, negative predictive value of 76.9% to 93.8%, and positive predictive value of 5.5% to 25%.
The negative predictive value of the composite score was robust, especially at lower VWF:RCo suggesting that VWD testing could be eliminated in nearly a third of children referred for VWD testing.
Recently, ferroic materials with giant caloric responses emerged as a possible environmental-friendly alternative for the currently used cooling devices. In our work, we have performed the ...Born-Oppenheimer molecular dynamics calculations for both para- and ferroelectric phases of multicaloric (NH4)2SO4. The simulations were performed in the NVT ensemble with several conditions applied for three different supercell sizes. Time and space correlations between the ion motions were analyzed using various strategies to study the interaction changes along the obtained trajectories. The investigation of thermally induced evolution of complicated H-bond system in ammonium sulfate structure was performed using calculated power spectra. The results of simulations collated with the obtained X-ray diffraction data enabled us to describe the mechanism of (NH4)2SO4 phase transition as the one of a mixed displacive and order-disorder nature. According to the origin of such structural transformation, the giant inverse barocaloric effect in ammonium sulfate is caused by the reverse H-bond system reorganization induced by hydrostatic pressure in the vicinity of the critical temperature. The spontaneous polarization observed in the ferroelectric phase is a secondary effect of symmetry change and it partially results from the disorder relaxation of both distorted NH4+ cations in low temperatures. The proposed investigation scheme should be useful in the studies of other ferrocaloric materials and H-bonded ferroelectrics.
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Summary
Background
Inhibitor formation complicates haemophilia treatment and requires immune tolerance induction to rid inhibitors over 5 BU. In the prospective, randomized International Immune ...Tolerance Study, immune tolerance induction was equally effective with high‐dose (HD) (200 IU kg−1 day−1) and low‐dose (LD) (50 IU kg−1 3× per week) factor VIII, but haemorrhages were twofold higher in the LD arm. This finding was unexpected as inhibitors neutralize FVIII activity. We hypothesized that the thrombin generation assay (TGA), a global measure of clot formation, might predict bleeding better than FVIII levels.
Methods
We evaluated TGA using relipidated tissue factor (TF) on 83 thawed, recalcified corn trypsin inhibitor/citrate plasma samples from 31 subjects (17 HD, 14 LD) who participated on the ITI study, and who had sufficient sample available and appropriate informed consent.
Results
There were no significant differences in peak thrombin, estimated thrombin potential, maximum rate or lag time between HD and LD arms; between pre‐, during and post‐ITI time points, or after FVIII spiking. In 19 subjects (12 HD, 7 LD) with anti‐FVIII<1.0 BU, the prevalence of non‐neutralizing antibody (NNA) and neutralizing antibody (NA) was 89.5% (17/19), and the latter strongly correlated with anti‐VIII titer, r = 0.73 95% CI: 0.55, 0.88.
Conclusion
In haemophilia inhibitor patients, thrombin generation is present, but does not predict bleeding risk. Following tolerance induction, NNA remains detectable in the majority.
BACKGROUND: Acquired copper deficiency in the pediatric population is a rare event but given the hematologic and potentially irreversible neurologic consequences, prompt recognition and treatment is ...important. Copper is an essential cofactor in enzymatic reactions essential to proper hematologic, skeletal, neurologic and vascular function. Copper is found in a variety of foods including meats, nuts, legumes, and whole grains while lacking in highly processed foods. Copper requirements in children over the age of 4 is 15 mg/day, which is readily acquired in a typical diet. Copper deficiency is known to occur in patients with the rare X-linked mutation in the ATP7A copper transport protein, known as Menkes Syndrome, and in older individuals with gastrointestinal bypass surgery who lose the ability to absorb copper through the duodenum and proximal jejunum, however, it is rarely reported in other conditions. Pediatric patients with autism spectrum disorders or developmental delay with a limited dietary repertoire are at risk for copper deficiency thus a high index of suspicion must exist in order to diagnose the disorder.
CASE PRESENTATION: A 15 y/o boy with a prior diagnosis of global developmental delay and oral aversion presented with parental concerns for worsening fatigue, weakness and gait instability. Symptoms had been slowly progressive and accompanied by weight loss. His longstanding feeding difficulties had been refractory to intensive feeding programs yet he continued to feed orally (with no prior attempts at enteral/parenteral nutrition). A daily diet consisted only of 50-60 oz of milk and 25-30 individual servings of butterscotch pudding (1680-1880 calories/day, 0.7mg iron/day).
Upon presentation he was afebrile with global muscle weakness. Growth parameters were at the 25th and 2nd percentiles for height and weight, respectively. Initial complete blood count demonstrated white blood cell count of 3.3, absolute neutrophil count of 760, hemoglobin of 4.4 with MCV of <50, reticulocyte count of 0.5, platelet count of 392. Review of his peripheral blood smear revealed microcytic, hypochromic red cells without marked fragmentation, anisopoikilocytosis or ringed sideroblasts; there were no morphologic abnormalities of his leukocytes or platelets. Iron studies demonstrated ferritin of 45, total iron binding capacity of 514, and 2% iron saturation. He had no evidence of B12 or folate deficiency. Stool guaiac was negative for occult blood loss. He was hospitalized to receive transfusion of red blood cells and begin IV iron therapy due to his inability to tolerate oral repletion.
Over the the next 2 months he demonstrated some improvement in his anemia but had worsening leukopenia, neutropenia and a declining platelet count. He had worsening neurologic function with increasing need for assistance in his activities of daily living. Due to lack response to IV iron and worsening cytopenias, additional evaluation was performed which revealed a serum copper level of 6 (range 60-190), and cerulosplasmin of 2.1 (range 22-58).
Once a diagnosis of copper deficiency was made, the patient promptly began a course of parenteral copper repletion. He received IV copper 35mcg/kg/day x 3 days then weekly intravenous infusions. Given his malnutrition, a G-tube was placed to begin oral copper repletion and enteral nutrition. Within 3 weeks his copper level improved as well as his blood counts. Unfortunately, although his blood counts and copper levels normalized, his neurologic status remains below his old baseline although he has made gains in his gross and fine motor abilities.
DISCUSSION: Children with limited dietary repertoires are at risk for otherwise rare nutritional deficiencies such as copper deficiency. It is not uncommon that nutritional deficiencies may become more prominent when children reach puberty and have increased dietary requirements not only of calories, but also of micronutrients and trace elements. This patient's clinical course demonstrates the need to have a high index of suspicion of concomitant nutritional deficiencies other than those routinely evaluated such as iron, B12 and folate given his finding of both iron and copper deficiency. Review of his blood smear at presentation was consistent with iron deficiency and did not demonstrate typical hallmarks of copper deficiency such as ringed sideroblasts.
Malec:Bioverativ: Consultancy, Other: Research funding; Shire: Consultancy, Other: Research funding.
Intracranial hemorrhage (ICH) in the newborn period is a potential cause of serious morbidity and mortality in individuals with hemophilia. The incidence of ICH is estimated to be 2% to 4%; however, ...depending on the mode of delivery, it may be considerably higher. Considering the varying sensitivities and costs of various imaging modalities, there remains controversy surrounding universal cranial imaging. Cost-utility analysis is the ideal tool to display the consequences of a decision made.
We constructed a decision tree to evaluate the direct and indirect costs, possible outcomes, and probabilities of ICH in neonates with hemophilia. We created 3 decision analysis models to evaluate the cost-utility of different screening modalities for ICH: ultrasound, computed tomography, and magnetic resonance imaging. Within each model, 3 different strategies were compared: screen all neonates; screen only neonates born by instrumented delivery; and not screen any neonates. A societal perspective was used for all models. The base case models were later reanalyzed in sensitivity analysis to account for uncertainties.
Total costs for screening all neonates, screening only neonates born by instrumented delivery, and not screening any neonates were $9501, $9297, and $9347, respectively, for US, and $9761, $9351, and $9353, respectively, for CT. Screening instrumented deliveries using MRI had an incremental cost-effectiveness ratio of $12,440.
Screening newborns born by an instrumented delivery appears to be the most cost-effective strategy irrespective of the imaging modality. Subsequent studies will require a longer time frame to factor in possible late effects of radiation, anesthesia, and the high cost of factor replacement and hospital admission.
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