Successful challenges using native E. coli asparaginase after hypersensitivity reactions to PEGylated E. coli asparaginase.

PURPOSE: Asparaginase is an essential component of pediatric acute lymphoblastic leukemia (ALL) therapy. However, asparaginase-induced hypersensitivity reactions can compromise its efficacy either by directly influencing the pharmacokinetics of asparaginase or by leading to a discontinuation of asparaginase treatment. Here, we report successful challenges using native Escherichia coli asparaginase after previous hypersensitivity reactions to both PEGylated E. coli asparaginase and Erwinia asparaginase. PATIENTS AND METHODS: The two patients included in this case report were diagnosed with B-precursor ALL at St. Jude Children's Research Hospital and were treated with a common regimen. Both patients developed hypersensitivity reactions to PEGylated E. coli asparaginase and Erwinia asparaginase early in treatment, and they were challenged with native E. coli asparaginase. Serum samples were collected for estimating the pharmacokinetic parameters of each patient during native E. coli asparaginase therapy. RESULTS: Challenges with native E. coli asparaginase were successful, and asparaginase serum concentrations above therapeutic levels were attained in both patients. CONCLUSIONS: These two cases suggest that some patients can be given native E. coli asparaginase after hypersensitivity reactions to PEGylated asparaginase and achieve therapeutic concentrations of the drug in serum.

Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing: 2014 update.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B Genotype and Abacavir Dosing were originally published in April 2012. We reviewed recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplementary Material online and included additional resources for applying CPIC guidelines to the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org).

Minimally invasive parathyroidectomy: 50 consecutive cases.

OBJECTIVE: To determine the effectiveness and outcomes of minimally invasive parathyroidectomy. DESIGN: Prospective, non-randomised, non-blinded trial. SETTING: Affiliated university teaching hospitals of the Northern Clinical School, University of Sydney, New South Wales, May 1998 to October 1999. PATIENTS: 50 consecutive patients who underwent minimally invasive parathyroidectomy for primary hyperparathyroidism, and 150 consecutive patients undergoing open parathyroidectomy over the same period. RESULTS: Minimally invasive parathyroidectomy was successfully completed and resulted in cure (normocalcaemia) in 42 of 50 patients (84%). Seven patients (14%) required conversion to an open procedure, all of which also resulted in normocalcaemia, giving an overall cure rate of 98%. One patient had persistent hyperparathyroidism after minimally invasive parathyroidectomy which was cured at subsequent open reoperation. Three patients had a temporary recurrent laryngeal nerve palsy. Open parathyroidectomy was successful in 147 of 150 patients (98%) at initial operation; one patient had a temporary recurrent laryngeal nerve palsy. Intraoperative measurement of parathyroid hormone levels by a quick technique in 23 of the patients (13 having minimally invasive and 10 open procedures) correctly identified the presence of multiple-gland disease. CONCLUSION: Minimally invasive parathyroidectomy is a feasible procedure, although there are concerns about the complication rate.

Characteristics of tumor cell bioactivity in oncogenic osteomalacia.

Oncogenic osteomalacia is a condition where renal phosphate wasting occurs causing defective mineralisation, in the presence of a tumor. Cultures of cells were established from a hemangiopericytoma resected from a patient with oncogenic osteomalacia. Conditioned media from the cells inhibited phosphate uptake in opossum kidney cells and stimulated of cAMP in rat osteosarcoma cells, a standard parathyroid hormone (PTH)-like assay. This cAMP stimulation was suppressed by the PTH analogue, 3-34 bPTH and also by heat and trypsin treatment of the media. Tests of conditioned media for PTH and parathyroid hormone related protein (PTHrP) immunoreactivity were negative, however, and no hybridisation to probes for PTH, PTHrP or human stanniocalcin was detected in tumor cell RNA on Northern blot. These data support the hypothesis that tumors responsible for oncogenic osteomalacia produce a humoral substance that reduces renal phosphate reabsorption and provide evidence that the factor may act via PTH/PTHrP receptors.

Abrasive particles in tobacco products: a possible factor in dental attrition.

Tobacco products are known to cause oral soft-tissue lesions, but they may also directly affect the teeth. Abrasive particles contained in tobacco products may contribute to dental attrition. We studied tobacco samples from 16 brands of cigars, eight brands of snuff, four brands of chewing tobacco and several unprocessed tobacco leaves used as cigar wrappers. Insoluble particulate matter made up about 0.5 percent of the weight of an average tobacco sample.

A soft tissue simulated cast for implant prosthesis.

A master cast that simulates the mucosa around implant fixtures and abutments facilitates implant prosthesis fabrication. It is helpful if this simulation is not altered during laboratory procedures. A technique is described for a master cast that includes a removable mucosal component. This technique can be applied when either implant or abutment analogs are positioned in the cast.

The CT appearances of jejunojejunal intussusception.

A case of jejunojejunal intussusception is presented, in which a malignant melanoma deposit acted as the lead point. The diagnosis was made on CT and the appearances are described.

Interactions between 1,25-dihydroxyvitamin D3 and vitamin D2: effects of pharmacologic doses in normal individuals.

To determine whether the administration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) affects the conversion of a pharmacologic dose of vitamin D2 to 25-hydroxyvitamin D (25OHD), 20 normal subjects received two separate doses of vitamin D2--one with and the other without the concomitant administration of 1,25(OH)2D3. Serum 1,25(OH)2D rose in response to 1,25(OH)2D3 administration and fell when vitamin D2 was given alone. Serum osteocalcin rose in response to 1,25(OH)2D3 administration. Serum 25OHD rose in response to vitamin D2 administration regardless of whether the subjects also received 1,25(OH)2D3. The data from this study in humans support the suggestion that the effects of 1,25(OH)2D3 on serum 25OHD concentrations are mediated through mechanisms other than impairment of production.

Clinical experiences with human parathyroid hormone 1-34.

Human parathyroid hormone (PTH) 1-34 was given to nine normal subjects and to 10 patients with hypoparathyroidism. There were no side effects associated with the protocol employed. In normal subjects, five statistically significant changes occurred during the period of observation: plasma cyclic adenosine monophosphate (cAMP) rose by a factor of 3 (at 30 min), nephrogenous cyclic AMP rose approximately 40-fold (at 60 min), urinary phosphate rose by a factor of 2 (at 120 min), urine calcium levels fell by 50% between 60 and 120 min, and plasma prolactin rose by a factor of 1.4 (at 60 min). The cAMP responses were significantly blunted in five patients with chronic hypocalcemia, chronic hyperphosphatemia, and detectable serum immunoreactive PTH levels. On the basis of this test these patients were designated as suffering from pseudohypoparathyroidism. The acute phosphaturic and hypocalciuric responses were apparently intact in these five individuals. Human PTH 1-34 is likely to replace bovine material in the delineation of syndromes associated with PTH resistance.

Serum osteocalcin concentrations in Paget's disease of bone.

Total body scintiscans, serum alkaline phosphatase estimations, and serum osteocalcin radioimmunoassays were performed in 49 consecutive patients with Paget's disease of bone. Eleven were receiving calcitonin (salmon synthetic) at the time of the study. The serum alkaline phosphatase activities were elevated in all but one patient, with the highest value almost 50 times the upper limit of the reference range. Serum osteocalcin concentrations were elevated in 53% of patients and normal in the rest. The highest serum osteocalcin value was 4.2 times the upper limit of the reference range. The correlation coefficient between the extent of skeletal involvement and serum osteocalcin level was .70, while that between skeletal involvement and serum alkaline phosphatase level was .55. In spite of the better correlation between bone scintiscans and serum osteocalcin level, osteocalcin measurements are diagnostically less useful than serum alkaline phosphatase estimations in patients with Paget's disease of bone.

Some problems associated with adenylate cyclase bioassays for parathyroid hormone.

A renal adenylate cyclase system was assessed for its suitability in the performance of parathyroid hormone (PTH) bioassays. Membrane preparations from 1 week old chicks were found to be more sensitive to PTH than material from humans, dogs or rats. Because of the presence of non-specific inhibitors and stimulators of adenylate cyclase in human serum, each serum sample was assayed in the presence and in the absence of a specific PTH inhibitor and the difference was used to calculate PTH activity. Calcium, an inhibitor of adenylate cyclase, was either removed from serum samples by pretreatment with Chelex resin or chelated during assay by means of EGTA. Human and bovine PTH (1-34) stimulated adenylate cyclase in this system to the same extent. The lower limit of detectability was 19.5 pg/ml (final concentration). The intra-assay coefficient of variation at a final concentration of 45 pg/ml was 18%. The index of precision was 0.08 +/- 0.04 (n = 7). When synthetic human PTH (1-34) was infused into three normal volunteers, the mean biological half-life of this material was found to be 3.2 min. PTH-like bioactivity could be routinely detected in sera from normal rats, while such activity was significantly decreased in rats subjected to thyroparathyroidectomy.

An adenylate cyclase bioassay for parathyroid hormone: some clinical experiences.

An adenylate cyclase bioassay for parathyroid hormone (PTH) was evaluated in peripheral sera of ten normal subjects, 15 patients with various types of hypoparathyroidism, nine patients with malignancy-associated hypercalcaemia and 60 patients with primary or secondary hyperparathyroidism. The lower limit of detectability was 150 pg/ml in terms of synthetic human PTH (1-34). PTH-like bioactivity was not detected in normal subjects, in patients with surgical hypoparathyroidism, in patients with idiopathic hypoparathyroidism or in patients with malignancy-associated hypercalcaemia. Serum from one untreated pseudohypoparathyroid patient consistently contained PTH-like bioactivity. Bioactivity was detected in sera from 50% of patients with primary or secondary hyperparathyroidism. In two patients with secondary hyperparathyroidism calcium infusions suppressed this activity within 5 min. Both in primary and in secondary hyperparathyroidism there was a significant positive correlation between levels of PTH-like bioactivity, PTH immunoreactivity and the histological severity of the disease.