Citrate anticoagulation in pediatric continuous venovenous hemofiltration

Regional citrate anticoagulation has become a common alternative to systemic heparinization in adult continuous venovenous hemofiltration (CVVH) practice. We report our experience with the technique in critically ill children. We carried out a retrospective chart review of a 22-bed pediatric intensive care unit. CVVH with pre-filter citrate and systemic calcium replacement infusions was performed according to a strict protocol in nine consecutive critically ill children. All charts were reviewed for patient characteristics and CVVH circuit parameters, including filter survival. All complications were noted. Nurse specialists were interviewed about the practical management of citrate anticoagulation. All patient measurements of blood urea nitrogen, creatinine, sodium, ionized calcium (iCa), potassium, and bicarbonate were collected over the CVVH period. In seven patients, 12 simultaneous citrate measurements were taken from patient blood, pre-filter blood, and hemofiltrate fluid. Nine patients (mean age 8.8±6.8 years) were treated with CVVH and regional citrate anticoagulation for 1–14 days (mean 5.2±4.0 days). Of 19 filters used, 15 were replaced non-electively (mean filter survival 55.6±22.0 h). Control of azotemia and hyperkalemia was good. Sodium and iCa levels were well maintained. Bicarbonate levels were elevated in four patients without adverse effects. The mean systemic citrate level at equilibrium was 1.6±0.23 mmol/l. No systemic bleeding complications were observed. In children, regional citrate anticoagulation provides equivalent filter survival to heparin without bleeding complications. With good staff preparation, it is simple to perform and safe with respect to metabolic side effects.     

Tracking Readiness and Motivation for Change in Individuals with Eating Disorders Over the Course of Treatment

Ambivalence about recovery is a key aspect of the symptom presentation of individuals with eating disorders and increased attention has focused on understanding readiness for change in this group. This research examined shifts in global and symptom-specific readiness and motivation for change during residential eating disorders treatment. Forty-two participants completed the Readiness and Motivation Interview (RMI) prior to treatment, at week 7, and following the 12–15 week program. Demographic and symptom severity measures were completed at pre and at post. Overall, increases in readiness to change behavioral symptoms occurred prior to increases in readiness to change cognitive symptoms. Shifts in locus of control for change were less pronounced during treatment, and occurred only for the cognitive symptom domain. Subgroup analyses revealed that relative to the other eating disorder diagnostic groups (bulimia nervosa and eating disorder not otherwise specified), readiness for change in individuals with anorexia nervosa shifted less over the course of treatment.     

Immunoprofile of cervical and endometrial adenocarcinomas using a tissue microarray

Adenocarcinomas of the uterine cervix show a wide range of morphological features, and can be confused with endometrial adenocarcinoma in biopsy or curetting specimens. The objective of this study was to use tissue microarray technology to evaluate the immunoprofile of a large set of uterine adenocarcinomas with an extended panel of antibodies, comparing the profile of primary cervical and endometrial adenocarcinomas. A tissue microarray was constructed using paraffin-embedded, formalin-fixed tissues from 141 hysterectomy specimens. Duplicate 0.6-mm cores were obtained from 57 cervical adenocarcinomas (16 in situ and 41 invasive) and 84 endometrial adenocarcinomas. Tissue array sections were immunostained with 21 commercially available antibodies [B72.3, CD 99, carcinoembryonic antigen (CEA), c-kit, pancytokeratin, CK 5/6, CK 7, CK8/18, CK19, CK 20, CK 22, EMA, estrogen receptor (ER), KP-1, melan-A, p53, PLAP, S-100, synaptophysin, TTF-1, and vimentin] utilizing the avidin-biotin (ABC) technique. Hierarchical clustering analysis of the tumors was done based on the immunostaining results. Only ER ( P<0.001), CEA ( P=0.04), vimentin ( P<0.001), and CK 8/18 ( P=0.002) showed a significantly different frequency of positivity in endometrial relative to cervical adenocarcinomas. ER, vimentin, and CK 8/18 were more likely to be expressed in endometrial adenocarcinomas, while cervical adenocarcinomas more frequently expressed CEA. We were able to identify immunoprofiles that were highly specific for endocervical adenocarcinoma (ER(-), vimentin(-), CK 8/18(-), CEA(+)) or endometrial adenocarcinoma (ER(+), vimentin(+), CK 8/18(+), CEA(-)), but most tumors showed an intermediate, non-specific immunophenotype. Hierarchical clustering analysis was useful in the interpretation of these intermediate immunophenotypes. Papillary serous adenocarcinoma of the endometrium was less likely to express vimentin ( P=0.002) than endometrioid carcinoma of the endometrium.     

A phase I study of T900607 given once every 3 weeks in patients with advanced refractory cancers; National Cancer Institute of Canada Clinical Trials Group (NCIC–CTG) IND 130

Background: T900607 is a novel tubulin active agent which disrupts microtubule polymerization by a unique mechanism of action. This phase I trial was conducted to determine the maximum tolerated dose, recommended phase II dose, pharmacokinetic properties and toxicities of this agent. Patients and methods: Patients with advanced and/or metastatic solid malignancies were enrolled, for an open dose escalation of T900607 administered intravenously over 30 minutes every 21-days. Results: Thirty patients were enrolled on 7 dose levels ranging from 15 to 270 mg/m². No DLTs were seen until 270 mg/m², the sixth dose level, with 1 patient experiencing Grade 3 thrombocytopenia, 1 grade 4 troponin increase and 1 grade 5 myocardial infarction in an expanded cohort of 6 patients. The dose was decreased to 180 mg/m² with increased cardiac monitoring and at this dose 3/4 patients experienced cardiac toxicity. Further animal cardiotoxicity studies failed to reveal any cardiac effects and the study was reopened at 130 mg/m²; of 6 enrolled patients, 1 had grade 3 drug related lethargy considered to be a DLT and this dose was considered the RP2D. No objective responses were seen but stable disease was reported in 7/20. Pharmacokinetic analysis showed that AUC and C_max increased with dose with considerable intrapatient variability, a short half life of < 1 hour, and no apparent dose dependency clearance. Conclusions: The recommended phase II dose for T900607 is 130 mg/m² given as an intravenous infusion over 60 minutes on a 21-day cycle. Cardiac toxicity was seen with this schedule.This study was supported by grants from the National Cancer Institute of Canada and Tularik Inc., 1120 Veterans Blvd, San Francisco, CA 94080.     

Antiproteinuric effects of enalapril and losartan: a pilot study

In this randomized double-blind crossover trial we compared the antiproteinuric effects of enalapril and losartan in six children with proteinuria and underlying renal injury. The primary endpoint was reduction in proteinuria during therapy. The study had two 8-week on-drug arms, with a 4-week washout period between. Baseline proteinuria was similar, enalapril 87 mg/m² per hour and losartan 77 mg/m² per hour. The mean reduction in proteinuria with enalapril was 48% (37%–57%) with a standard error of the mean of 3%; with losartan it was 31% (14%–52%) with a standard error of the mean of 7%. Although there was a significant reduction in proteinuria with the use of both drugs, the difference in reduction of proteinuria, 48% versus 31%, was not considered clinically significant. Potassium remained below 4.5 mmol/l in all patients. No patient's creatinine rose more than the standard deviation of our assay. Blood pressure (BP) control was acceptable in four of the six patients; two patients had persistently elevated or increased BP on each drug. Side effects were minimal; none requiring withdrawal, one requiring dose reduction. Studies have shown that angiotensin converting enzyme inhibitors can reduce proteinuria in children with renal disorders. No studies to date have examined the reduction of proteinuria achieved by angiotensin receptor blockers. Our study, although small, suggests that angiotensin receptor blockers may reduce proteinuria as effectively, and as safely, as angiotensin converting enzyme inhibitors.Editorial comment Despite its limitations, this pilot study highlights the need for and may stimulate a double-blind prospective trial to compare the antiproteinuric effects of angiotensin blockers and angiotensin converting enzyme inhibitors in children.     

Clinical utility of soluble interleukin-2 receptor in hemophagocytic syndromes: a systematic scoping review

The serum-soluble interleukin-2 receptor (sIL-2r) level is considered an important diagnostic test and disease marker in hemophagocytic syndromes/hemophagocytic lymphohistiocytosis (HPS/HLH). However, this cytokine receptor is rarely measured in clinical practice and has been excluded from recent diagnostic/classification criteria such as the HScore and macrophage activation syndrome (MAS) 16. We performed a systematic scoping review of 64 articles (1975–2016) examining the clinical utility of sIL-2r in HPS/HLH. Twenty-two articles describe sIL-2r as a sensitive diagnostic marker for HLH, but only three distinct datasets actually address sensitivity. The original HLH-2004 Guidelines reported sensitivity of 93% and specificity of 100% for sIL-2r ≥ 2400, based on a pediatric dataset (n = 152) which is published for the first time in this review. Two pediatric studies reported sensitivity of 89% for sIL-2r ≥ 2400 in diagnosis of MAS complicating juvenile idiopathic arthritis (JIA) (n = 27) and 88% for secondary HLH in acute liver failure (n = 9). Twenty articles described sIL-2r as a dynamic marker of disease activity that falls with response to treatment, and 15 described high initial sIL-2r levels >10,000 U/mL as a poor prognostic marker. The ability of sIL-2r to distinguish between subtypes of HPS/HLH was inconsistent. This review confirms the importance of soluble IL-2r as a diagnostic and disease marker in HPS/HLH, but also reveals the need for more primary data about its performance characteristics, particularly in adults. More emphasis should be made in including this simple, inexpensive test in clinical practice and studies of HPS/HLH.     

Renal hyperperfusion injury resulting in transient proteinuria post renal artery angioplasty for fibromuscular dysplasia

Renovascular hypertension (RVH) can be treated utilizing medical, surgical or endovascular techniques. We present a case in which severe exacerbation of pre-existing proteinuria followed percutaneous transluminal angioplasty of a highly stenotic renal artery to relieve RVH caused by fibromuscular dysplasia. We propose that the worsening proteinuria post-angioplasty was caused by a transient renal hyperperfusion injury that overcame the glomerular autoregulatory mechanisms, thereby leading to raised intraglomerular pressures and loss of proteins through the glomerular filtration barrier until the vascular autoregulatory ability of the glomeruli was successfully re-established.