Brief communication: radiographic contrast infusion and catecholamine release in patients with pheochromocytoma.

BACKGROUND: Contrast-enhanced computed tomography (CT) is useful for localizing pheochromocytoma. However, in patients with suspected pheochromocytoma, CT is often canceled or not performed because of the strong belief that intravenous contrast may induce hypertensive crisis. OBJECTIVE: To examine whether intravenous low-osmolar contrast administration during CT induces catecholamine release that increases blood pressure or heart rate. DESIGN: Prospective study. SETTING: Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: 22 patients with pheochromocytoma (15 nonadrenal and 7 adrenal) and 8 unmatched control participants without pheochromocytoma. MEASUREMENTS: Plasma catecholamine levels, blood pressure, and heart rate. RESULTS: Plasma catecholamine levels within and between groups did not significantly differ before and after intravenous administration of low-osmolar CT contrast. Patients with pheochromocytoma experienced a clinically and statistically significant increase in diastolic blood pressure that was not accompanied by corresponding increases in plasma catecholamine levels. The difference became non-statistically significant after adjustment for use of alpha- and beta-blockers. LIMITATION: The study lacked a placebo group, and the sample was relatively small. CONCLUSION: Intravenous low-osmolar contrast-enhanced CT can safely be used in patients with pheochromocytoma who are not receiving alpha- or beta-blockers. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health.

Coronary-cameral fistula with double-chambered right ventricle: appearance on cardiac magnetic resonance imaging and 3D printed anatomic modeling.

The present case illustrates cardiac magnetic resonance imaging (MRI) and three-dimensional (3D) printed anatomic model findings of a coronary-cameral fistula (CCF) and double-chambered right ventricle (DCRV). A pregnant woman presented with palpitations and near syncope. A non-contrast cardiac MRI showed CCF connecting to a DCRV. Post-delivery, the patient had a contrast-enhanced MRI and 3D printed anatomic model to better evaluate her aberrant anatomy.

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition.

BACKGROUND: Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation. METHODS: We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare. RESULTS: All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events. CONCLUSIONS: Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations. (ClinicalTrials.gov number, NCT00069329 [ClinicalTrials.gov].).

Nitric oxide activation of peroxisome proliferator-activated receptor gamma through a p38 MAPK signaling pathway.

Both nitric oxide (NO*) and peroxisome proliferator-activated receptors (PPARs) protect the endothelium and regulate its function. Here, we tested for crosstalk between these signaling pathways. Human umbilical vein and hybrid EA.hy926 endothelial cells were exposed to S-nitrosoglutathione (GSNO) or diethylenetriamine NONOate (DETA NONOate). Electrophoretic mobility shift assays using PPAR-response element (PPRE) probe showed that NO* caused a rapid dose-dependent increase in PPARgamma binding, an effect that was confirmed in vivo by chromatin immunoprecipitation. Conversely, N(G)-monomethyl-L-arginine, a NOS inhibitor, decreased PPARgamma binding. NO*-mediated PPARgamma binding and NO* induction of cyclooxygenase-2 (COX-2), diacylglycerol (DAG) kinase alpha (DGKalpha), and heme oxygenase-1 (HO-1), genes with well-characterized PPRE motifs, were cGMP independent. NO* dose dependently activated p38 MAPK, and p38 MAPK inhibition with SB202190 or knockdown with siRNA was shown to block NO* activation of PPARgamma. Likewise, p38 MAPK and PPARgamma inhibitors or knockdown of either transcript all significantly blocked NO* induction of PPRE-regulated genes. PPARgamma activation by p38 MAPK may contribute to the anti-inflammatory and cytoprotective effects of NO* in the vasculature. This crosstalk mechanism suggests new strategies for preventing and treating vascular dysfunction.

Usual Care and Informed Consent in Clinical Trials of Oxygen Management in Extremely Premature Infants.

OBJECTIVE: The adequacy of informed consent in the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT) has been questioned. SUPPORT investigators and publishing editors, heads of government study funding agencies, and many ethicists have argued that informed consent was adequate because the two oxygen saturation target ranges studied fell within a range commonly recommended in guidelines. We sought to determine whether each oxygen target as studied in SUPPORT and four similar randomized controlled trials (RCTs) was consistent with usual care. DESIGN/PARTICIPANTS/SETTING: PubMed, EMBASE, Web of Science, and Scopus were searched for English articles back to 1990 providing information on usual care oxygen management in extremely premature infants. Data were extracted on intended and achieved oxygen saturation levels as determined by pulse oximetry. Twenty-two SUPPORT consent forms were examined for statements about oxygen interventions. RESULTS: While the high oxygen saturation target range (91 to 95%) was consistent with usual care, the low range (85 to 89%) was not used outside of the SUPPORT trial according to surveys and clinical studies of usual care. During usual care, similar lower limits (< 88%) were universally paired with higher upper limits (≥ 92%) and providers skewed achieved oxygen saturations toward the upper-end of these intended ranges. Blinded targeting of a low narrow range resulted in significantly lower achieved oxygen saturations and a doubling of time spent below the lower limit of the intended range compared to usual care practices. The SUPPORT consent forms suggested that the low oxygen saturation arm was a widely practiced subset of usual care. CONCLUSIONS: SUPPORT does not exemplify comparative effectiveness research studying practices or therapies in common use. Descriptions of major differences between the interventions studied and commonly practiced usual care, as well as potential risks associated with these differences, are essential elements of adequate informed consent.

Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health.

CONTEXT: Ectopic ACTH secretion (EAS) is difficult to diagnose and treat. We present our experience with EAS from 1983 to 2004. SETTING: The study was performed at a tertiary care clinical research center. PATIENTS: Ninety patients, aged 8-72 yr, including 48 females were included in the study. INTERVENTIONS AND OUTCOME MEASURES: Tests included 8 mg dexamethasone suppression, CRH stimulation, inferior petrosal sinus sampling (IPSS), computed tomography, octreotide scan, magnetic resonance imaging, and/or venous sampling. Therapies, pathological examinations, and survival were noted. RESULTS: Eighty-six to 94% of patients did not respond to CRH or dexamethasone suppression, whereas 66 of 67 had negative IPSS. To control hypercortisolism, 62 patients received medical treatment, and 33 had bilateral adrenalectomy. Imaging localized tumors in 67 of 90 patients. Surgery confirmed an ACTH-secreting tumor in 59 of 66 patients and cured 65%. Nonthymic carcinoids took longest to localize. Deaths included three of 35 with pulmonary carcinoid, two of five with thymic carcinoid, four of six with gastrinoma, two of 13 with neuroendocrine tumor, two of two with medullary thyroid cancer, one of five with pheochromocytoma, three of three with small-cell lung cancer, and two of 17 with occult tumor. Patients with other carcinoids and ethesioneuroblastoma are alive. CONCLUSIONS: IPSS best identifies EAS. Initial failed localization is common and suggests pulmonary carcinoid. Although only 47% achieved cure, survival is good except in patients with small-cell lung cancer, medullary thyroid cancer, and gastrinoma.

Nitric oxide post-transcriptionally up-regulates LPS-induced IL-8 expression through p38 MAPK activation.

Nitric oxide (NO(.-)) contributes to vascular collapse in septic shock and regulates inflammation. Here, we demonstrate in lipopolysaccharide (LPS)-stimulated human THP-1 cells and monocytes that NO(.-) regulates interleukin (IL)-8 and tumor necrosis factor alpha (TNF-alpha) by distinct mechanisms. Dibutyryl-cyclic guanosine 5'-monophosphate (cGMP) failed to simulate NO(.-)-induced increases in TNF-alpha or IL-8 production. In contrast, dibutyryl-cyclic adenosine monophosphate blocked NO(.-)-induced production of TNF-alpha (P=0.009) but not IL-8. NO(.-) increased IL-8 (5.7-fold at 4 h; P=0.04) and TNF-alpha mRNA levels (2.2-fold at 4 h; P=0.037). However, nuclear run-on assays demonstrated that IL-8 transcription was slightly decreased by NO(.-) (P=0.08), and TNF-alpha was increased (P=0.012). Likewise, NO(.-) had no effect on IL-8 promoter activity (P=0.84) as measured by reporter gene assay. In THP-1 cells and human primary monocytes treated with actinomycin D, NO(.-) had no effect on TNF-alpha mRNA stability (P>0.3 for both cell types) but significantly stabilized IL-8 mRNA (P=0.001 for both cell types). Because of its role in mRNA stabilization, the p38 mitogen-activated protein kinase (MAPK) pathway was examined and found to be activated by NO(.-) in LPS-treated THP-1 cells and human monocytes. Further, SB202190, a p38 MAPK inhibitor, was shown to block NO(.-)-induced stabilization of IL-8 mRNA (P<0.02 for both cell types). Thus, NO(.-) regulates IL-8 but not TNF-alpha post-transcriptionally. IL-8 mRNA stabilization by NO(.-) is independent of cGMP and at least partially dependent on p38 MAPK activation.

Vitamin C pharmacokinetics: implications for oral and intravenous use.

BACKGROUND: Vitamin C at high concentrations is toxic to cancer cells in vitro. Early clinical studies of vitamin C in patients with terminal cancer suggested clinical benefit, but 2 double-blind, placebo-controlled trials showed none. However, these studies used different routes of administration. OBJECTIVE: To determine whether plasma vitamin C concentrations vary substantially with the route of administration. DESIGN: Dose concentration studies and pharmacokinetic modeling. SETTING: Academic medical center. PARTICIPANTS: 17 healthy hospitalized volunteers. MEASUREMENTS: Vitamin C plasma and urine concentrations were measured after administration of oral and intravenous doses at a dose range of 0.015 to 1.25 g, and plasma concentrations were calculated for a dose range of 1 to 100 g. RESULTS: Peak plasma vitamin C concentrations were higher after administration of intravenous doses than after administration of oral doses (P < 0.001), and the difference increased according to dose. Vitamin C at a dose of 1.25 g administered orally produced mean (+/-sd) peak plasma concentrations of 134.8 +/- 20.6 micromol/L compared with 885 +/- 201.2 micromol/L for intravenous administration. For the maximum tolerated oral dose of 3 g every 4 hours, pharmacokinetic modeling predicted peak plasma vitamin C concentrations of 220 micromol/L and 13 400 micromol/L for a 50-g intravenous dose. Peak predicted urine concentrations of vitamin C from intravenous administration were 140-fold higher than those from maximum oral doses. LIMITATIONS: Patient data are not available to confirm pharmacokinetic modeling at high doses and in patients with cancer. CONCLUSIONS: Oral vitamin C produces plasma concentrations that are tightly controlled. Only intravenous administration of vitamin C produces high plasma and urine concentrations that might have antitumor activity. Because efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated.

The prevalence of pain in a pediatric and young adult cancer population.

The prevalence and nature of pain in the population of children and young adults with malignancy treated by the Pediatric Branch of the National Cancer Institute were assessed over a 6 month period. One hundred and thirty-nine patients were evaluated during 161 in-patient days and 195 out-patient clinic visits. Approximately 50% of the patients assessed in the hospital and 25% of the patients assessed in the out-patient clinic were found to be experiencing some degree of pain at the time of assessment. Therapy-related pain predominated in both in-patients and out-patients; only one-third of the pain experienced by in-patients and less than 20% of the pain experienced by out-patients was due to tumor. Tumor pain was due primarily to bony invasion. In order to control pain in those individuals experiencing pain, narcotic analgesics were being used by one-half of the in-patients and one-third of the out-patients. Overall pain control was good, with the medium visual analogue scale score being 26 mm on a 0-100 mm scale. During the study period 7 patients were identified to have chronic pain for greater than 1 year following eradication of all known tumor from the site of pain. One was receiving massive doses of narcotics (120 mg/day of methadone) apparently out of proportion to his underlying pain.

Staging and functional characterization of pheochromocytoma and paraganglioma by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography.

BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are rare tumors of the adrenal medulla and extra-adrenal sympathetic chromaffin tissues; their anatomical and functional imaging are critical to guiding treatment decisions. This study aimed to compare the sensitivity and specificity of (18)F-fluorodeoxyglucose positron emission tomography with computed tomography ((18)F-FDG PET/CT) for tumor localization and staging of PPGLs with that of conventional imaging by [(123)I]-metaiodobenzylguanidine single photon emission CT ((123)I-MIBG SPECT), CT, and magnetic resonance imaging (MRI). METHODS: A total of 216 patients (106 men, 110 women, aged 45.2 ± 14.9 years) with suspected PPGL underwent CT or MRI, (18)F-FDG PET/CT, and (123)I-MIBG SPECT/CT. Sensitivity and specificity were measured as endpoints and compared by the McNemar test, using two-sided P values only. RESULTS: Sixty (28%) of patients had nonmetastatic PPGL, 95 (44%) had metastatic PPGL, and 61 (28%) were PPGL negative. For nonmetastatic tumors, the sensitivity of (18)F-FDG was similar to that of (123)I-MIBG but less than that of CT/MRI (sensitivity of (18)F-FDG = 76.8%; of (123)I-MIBG = 75.0%; of CT/MRI = 95.7%; (18)F-FDG vs (123)I-MIBG: difference = 1.8%, 95% confidence interval [CI] = -14.8% to 14.8%, P = .210; (18)F-FDG vs CT/MRI: difference = 18.9%, 95% CI = 9.4% to 28.3%, P < .001). The specificity was 90.2% for (18)F-FDG, 91.8% for (123)I-MIBG, and 90.2% for CT/MRI. (18)F-FDG uptake was higher in succinate dehydrogenase complex- and von Hippel-Lindau syndrome-related tumors than in multiple endocrine neoplasia type 2 (MEN2) related tumors. For metastases, sensitivity was greater for (18)F-FDG and CT/MRI than for (123)I-MIBG (sensitivity of (18)F-FDG = 82.5%; of (123)I-MIBG = 50.0%; of CT/MRI = 74.4%; (18)F-FDG vs (123)I-MIBG: difference = 32.5%, 95% CI = 22.3% to 42.5%, P < .001; CT/MRI vs (123)I-MIBG: difference = 24.4%, 95% CI = 11.3% to 31.6%, P < .001). For bone metastases, (18)F-FDG was more sensitive than CT/MRI (sensitivity of (18)F-FDG = 93.7%; of CT/MRI = 76.7%; difference = 17.0%, 95% CI = 4.9% to 28.5%, P = .013). CONCLUSIONS: Compared with (123)I-MIBG SPECT and CT/MRI, both considered gold standards for PPGL imaging, metastases were better detected by (18)F-FDG PET. (18)F-FDG PET provides a high specificity in patients with a biochemically established diagnosis of PPGL.

An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers.

Metastasis is a major cause of mortality in cancer patients. However, the mechanisms governing the metastatic process remain elusive, and few accurate biomarkers exist for predicting whether metastasis will occur, something that would be invaluable for guiding therapy. We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-ΔN) that drives metastasis. mRNA encoding CPE-ΔN was found to be elevated in human metastatic colon, breast, and hepatocellular carcinoma (HCC) cell lines. In HCC cells, cytosolic CPE-ΔN was translocated to the nucleus and interacted with histone deacetylase 1/2 to upregulate expression of the gene encoding neural precursor cell expressed, developmentally downregulated gene 9 (Nedd9)--which has been shown to promote melanoma metastasis. Nedd9 upregulation resulted in enhanced in vitro proliferation and invasion. Quantification of mRNA encoding CPE-ΔN in HCC patient samples predicted intrahepatic metastasis with high sensitivity and specificity, independent of cancer stage. Similarly, high CPE-ΔN mRNA copy numbers in resected pheochromocytomas/paragangliomas (PHEOs/PGLs), rare neuroendocrine tumors, accurately predicted future metastasis or recurrence. Thus, CPE-ΔN induces tumor metastasis and should be investigated as a potentially powerful biomarker for predicting future metastasis and recurrence in HCC and PHEO/PGL patients.

The Thr92Ala 5' type 2 deiodinase gene polymorphism is associated with a delayed triiodothyronine secretion in response to the thyrotropin-releasing hormone-stimulation test: a pharmacogenomic study.

BACKGROUND: The common Thr92Ala D2 polymorphism has been associated with changes in pituitary-thyroid axis homeostasis, but published results are conflicting. To investigate the effects of the Thr92Ala polymorphism on intrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion, we designed prospective pharmacogenomic intervention aimed to detect differences in T3 levels after thyrotropin (TSH)-releasing hormone (TRH)-mediated TSH stimulation of the thyroid gland. METHODS: Eighty-three healthy volunteers were screened and genotyped for the Thr92Ala polymorphism. Fifteen volunteers of each genotype (Thr/Thr, Thr/Ala, and Ala/Ala) underwent a 500 mcg intravenous TRH stimulation test with serial measurements of serum total T3 (TT3), free T4, and TSH over 180 minutes. RESULTS: No differences in baseline thyroid hormone levels were seen among the study groups. Compared to the Thr/Thr group, the Ala/Ala group showed a significantly lower TRH-stimulated increase in serum TT3 at 60 minutes (12.07 ± 2.67 vs. 21.07 ± 2.86 ng/dL, p = 0.029). Thr/Ala subjects showed an intermediate response. Compared to Thr/Thr subjects, the Ala/Ala group showed a blunted rate of rise in serum TT3 as measured by mean time to 50% maximum delta serum TT3 (88.42 ± 6.84 vs. 69.56 ± 6.06 minutes, p = 0.028). Subjects attained similar maximal (180 minutes) TRH-stimulated TT3 levels. TRH-stimulated TSH and free T4 levels were not significantly different among the three genotype groups. CONCLUSIONS: The commonly occurring Thr92Ala D2 variant is associated with a decreased rate of acute TSH-stimulated T3 release from the thyroid consistent with a decrease in intrathyroidal deiodination. These data provide a proof of concept that the Thr92Ala polymorphism is associated with subtle changes in thyroid hormone homeostasis.

Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes.

OBJECTIVE: In patients with long-standing type 1 diabetes, we investigated whether improved beta-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote beta-cell growth and/or limit beta-cell apoptosis and 2) weaken the anti-beta-cell autoimmunity. RESEARCH DESIGN AND METHODS: For this study, 20 individuals (mean age 39.5 +/- 11.1 years) with long-standing type 1 diabetes (21.3 +/- 10.7 years) were enrolled in this prospective open-label crossover trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide. RESULTS: In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels >or=0.05 ng/ml (0.02 nmol/l) were found. Residual beta-cells responded to physiological (mixed-meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 +/- 2.9 kg body wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 +/- 0.11 vs. 0.55 +/- 0.13 units x kg(-1) x day(-1) without exenatide; P = 0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion. CONCLUSIONS: In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving beta-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining beta-cells.

Selective serotonin reuptake inhibitors: measurement of effect on platelet function.

Selective serotonin reuptake inhibitors (SSRIs) reduce platelet serotonin and are associated with increased gastrointestinal bleeding, an effect that is enhanced when taken with NSAIDs or aspirin. The best method to evaluate hemorrhagic events in patients taking SSRIs has not been determined. Platelet aggregation, which is not widely available, shows SSRI inhibition of platelet function; we tested whether a platelet function analyzer could detect SSRI inhibition of platelet function. Two groups of outpatients with mood disorders were recruited; each patient was taking a stable dose of either an SSRI or bupropion for at least 6 weeks. They were tested using the platelet function analyzer-100 (PFA-100; Dade International Inc, Miami, Fla) concomitantly with platelet aggregation. Fifty-eight patients were analyzed. We detected significant differences between the groups using aggregation methods with arachidonic acid (aggregation, P = 0.00001; release, P = 0.009) and collagen (aggregation, P = 0.016; release, P = 0.006). The PFA-100 did not detect differences between the groups or results outside the reference range. The PFA-100 does not detect the inhibitory effects of SSRIs on platelet function, but it can be used to direct evaluation of bleeding in a patient taking an SSRI. Abnormal PFA-100 results suggest additional evaluation for von Willebrand disease, other platelet inhibitory medications, or underlying intrinsic platelet dysfunction.

Gender-related differences in the clinical presentation of malignant and benign pheochromocytoma.

Signs and symptoms associated with pheochromocytomas are predominantly caused by catecholamine excess, but tend to be highly variable and non-specific. In this study, we evaluated 23 male and 35 female pheochromocytoma patients for symptoms and signs of pheochromocytoma with special regard to gender-related differences in presentation. Total symptom score comparison between genders showed significant differences (12.0 vs. 7.8, P-value 0.0001). Female patients reported significantly more headache (80% vs. 52%), dizziness (83% vs. 39%), anxiety (85% vs. 50%), tremor (64% vs. 33%), weight change (88% vs. 43%), numbness (57% vs. 24%), and changes in energy level (89% vs. 64%). Females and males displayed comparable biochemical phenotypes (60% and 65% noradrenergic phenotype, respectively). Use of alpha- and/or beta-blockade between males and females did not differ significantly. Subgroup analyses and multiple regression analysis revealed gender differences to be irrespective of benign or malignant disease, use of adrenoceptor-blockade, age and biochemical phenotype. We conclude female patients have significantly more self-reported pheochromocytoma signs and symptoms than male patients irrespective of biochemical phenotype and tumor presentation which may be related to distinct catecholamine receptor sensitivity. Clinicians should be aware of these complaints in female pheochromocytoma patients and offer adequate treatment if indicated.

A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome.

OBJECTIVE: Familial cold autoinflammatory syndrome (FCAS) is caused by mutations in the CIAS1 gene, leading to excessive secretion of interleukin-1beta (IL-1beta), which is associated with cold-induced fevers, joint pain, and systemic inflammation. This pilot study was conducted to assess the safety and efficacy of rilonacept (IL-1 Trap), a long-acting IL-1 receptor fusion protein, in patients with FCAS. METHODS: Five patients with FCAS were studied in an open-label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injection, were evaluated 6 and 10 days later for clinical efficacy, and remained off treatment until a clinical flare occurred. At the time of flare, patients were again treated with 300 mg of rilonacept and then given maintenance doses of 100 mg/week. Patients whose FCAS was not completely controlled were allowed a dosage increase to 160 mg/week and then further to 320 mg/week during an intrapatient dosage-escalation phase. Safety, disease activity measures (daily diary reports of rash, joint pain and/or swelling, and fevers), health quality measures (Short Form 36 health survey questionnaire), and serum markers of inflammation (erythrocyte sedimentation rate [ESR], high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA], and IL-6) were determined at 3, 6, 9, 12, and 24 months after initiation of rilonacept and were compared with baseline values. RESULTS: In all patients, clinical symptoms typically induced by cold (rash, fever, and joint pain/swelling) improved within days of rilonacept administration. Markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (P < 0.01, P < 0.001, and P < 0.001, respectively) at doses of 100 mg. Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain. Furthermore, levels of the acute-phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR. All patients continued taking the study drug. The drug was well-tolerated. Weight gain in 2 patients was noted. No study drug-related serious adverse events were seen. CONCLUSION: In this study, we present 2-year safety and efficacy data on rilonacept treatment in 5 patients with FCAS. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the good tolerability suggest that this drug may be a promising therapeutic option in patients with FCAS, and the data led to the design of a phase III study in this patient population.

Leukoreduction filtration of whole-blood units from sickle trait donors: effects of a metered citrate anticoagulant system.

BACKGROUND: Polymerization of hemoglobin (Hb) S is exacerbated by acidic and hyperosmotic citrate anticoagulant solutions and often results in occlusion of leukoreduction filters by red blood cells (RBCs) from sickle cell trait (Hb AS) donors. This study evaluates a blood collection instrument that adds citrate anticoagulant in a metered fashion, thus mitigating adverse citrate effects. STUDY DESIGN AND METHODS: Collection of whole blood by a metered anticoagulant system was compared to traditional phlebotomy in 12 Hb AS and 12 non-sickle trait (Hb AA) donors. Each donated twice; on one occasion, units were filtered after 4-hour storage at 20 to 24 degrees C, and on the other, units were stored at 1 to 6 degrees C for 24 hours before filtration. RESULTS: Filtration times, RBC recoveries, and residual white blood cell (WBC) counts met defined criteria more often in Hb AS units collected by a metered anticoagulant system (9 of 12, 8 of 12, and 4 of 12, respectively) compared to traditional phlebotomy (1 of 12, 2 of 12, and 0 of 12, respectively). Overall, Hb AS units filtered better after storage at 1 to 6 degrees C for 24 hours, with units collected by a metered anticoagulant system undergoing filtration most effectively (5 of 6 had >85% RBC recovery, 3 of 6 had <5 x 10(6) residual WBC). Units exhibited similar changes in RBC storage parameters. CONCLUSION: Use of a metered anticoagulation instrument demonstrates potential for successful leukoreduction and acceptable storage of Hb AS units; however, the system needs further modifications and improvements before it can be utilized to collect and leukoreduce Hb AS blood.

Search for predictors of nontherapeutic INR results with warfarin therapy.

BACKGROUND: The effectiveness and safety of warfarin require maintaining an international normalized ratio (INR) within the therapeutic range. OBJECTIVE: To identify predictors of nontherapeutic INR results in patients receiving warfarin. METHODS: A retrospective study was conducted using 350 ambulatory care patients from a broad geographic region, all receiving long-term warfarin therapy and followed in a tertiary-care cardiology clinic. Possible predictors of nontherapeutic INR results (gender, age, body weight, body mass index, height, race, tobacco use, alcohol use, warfarin dose, therapeutic indication, regimen intensity, INR monitoring frequency/category, interacting medications, adverse events) were assessed with logistic regression models. Subset analysis involved 146 patients concurrently monitored with capillary whole blood INR (CoaguChek). RESULTS: As measured on venous specimens, 52% (182/350) of the patients had subtherapeutic INR results and 13% (44/350) had supratherapeutic INR results despite frequent (< or =4 wk) monitoring in 75% of the patients. Due to the small sample size, supratherapeutic INR results could not be further analyzed. Of 19 predictors tested, only daily warfarin dose (p < 0.02) and regimen intensity (p < 0.03) were significant independent and additive predictors of subtherapeutic results. Patients on the high-intensity regimen (INR 2.5-3.5) and receiving warfarin < or =6 mg/day had >50% risk of having subtherapeutic INR results. Subtherapeutic CoaguChek results were independent predictors of subtherapeutic venipuncture INR results in the subset (p = 0.001). CONCLUSIONS: In the absence of readily identifiable predictors, only higher warfarin dosing and/or more frequent monitoring (possibly with point-of-care/home monitoring devices) may minimize the time that INRs are subtherapeutic, especially in patients receiving low-dose and/or high-intensity anticoagulation therapy.