Pulmonary metastasectomy for pediatric solid tumors

Most pediatric thoracic malignancy is pulmonary disease secondary to solid tumors of childhood. The management of isolated pulmonary metastases in adulthood is well documented. Little has been published to document the long-term outcome of pulmonary metastasectomy in childhood. A retrospective study was undertaken to assess the results of surgery for isolated pulmonary metastases. Twenty children underwent surgery over 12 years (mean follow-up 8 years). Five had Wilms tumor (mean age 51 months), eight had osteogenic sarcoma (mean age 141 months), three had rhabdomyosarcoma (mean age 92 months), two had hepatoblastoma (mean age 30 months) and two had teratoma (mean age 72 months). Four had bilateral synchronous metastases and thoracotomies, and one had bilateral metachronous metastases and thoracotomies. Nineteen children were discharged well within 10 days of surgery. There was one early complication: a death due to pneumonia. Four children subsequently died postoperatively with cranial metastases (mean 29 months postoperatively). The remaining 16 children remain alive and well. As part of the combined therapy, these results would support an aggressive surgical approach to this disease. Preoperative assessment should include contrast enhanced computed tomogram of the head and chest as well as chest X-ray taken immediately preoperatively to exclude metastases. Bilateral synchronous and metachronous thoracotomy is well tolerated in childhood.     

Dopamine D4 ligands and models of receptor activation: 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole and related heteroarylmethylarylpiperazines exhibit a substituent effect responsible for additional efficacy tuning

A series of subtype selective dopamine D(4) receptor ligands from the hetroarylmethylphenylpiperazine class have been discovered that exhibit a remarkable structure-activity relationship (SAR), revealing a substituent effect in which regiosubstitution on the terminal arylpiperazine ring can modulate functional or intrinsic activity. Other structure-dependent efficacy studies in the dopamine D(4) field have suggested a critical interaction of the heteroarylmethyl moiety with specific protein microdomains in controlling intrinsic activity. Our studies indicate that for some binding orientations, the phenylpiperazine moiety also plays a key role in determining efficacy. These data also implicate a kinetic or efficiency term, contained within measured functional affinities for agonists, which support a sequential binding and conformational stabilization model for receptor activation. The structural similarity between partial agonist and antagonist, within this subset of ligands, and lack of bioisosterism for this substituent effect are key phenomena for these hypotheses.     

The role of parotid biopsy in the diagnosis of pediatric Sjögren syndrome

OBJECTIVES: To describe our experience with primary and secondary Sj?gren syndrome (SS) in the pediatric population and to evaluate the effectiveness of parotid gland biopsy in the diagnosis of pediatric SS. DESIGN: Case series review of 6 pediatric patients evaluated during a 4-year period with varied head and neck manifestations of SS. SETTING: Tertiary care children's hospital. PATIENTS: Six children (4 boys and 2 girls) ranging in age from 6 to 12 years, who were diagnosed as having primary or secondary SS. INTERVENTION: Six minor salivary gland and 4 parotid gland biopsies for pathologic examination. MAIN OUTCOME MEASURES: Pathologic examination of salivary tissue consistent with SS. RESULTS: All 6 patients underwent minor salivary gland biopsy, 2 (33%) were consistent with SS, while the remaining 4 (67%) were nondiagnostic. The 4 patients with nondiagnostic minor salivary gland biopsy results went on to have parotid biopsies, of which all 4 had histologic findings consistent with SS. No complications were encountered. CONCLUSION: Parotid gland biopsy is an effective and safe means of obtaining salivary gland tissue for histologic evaluation of SS in the pediatric population.     

Utility and outcomes of fine-needle aspiration biopsy in Hodgkin's disease

We present our 10-year experience, including clinical utilization and outcomes, with fine-needle aspiration biopsy (FNAB) in Hodgkin's disease (HD). Eighty-six cases from 68 patients with HD that were evaluated by FNAB were identified over a 10-year period. Medical records of these 68 patients were reviewed. Thirty-seven patients with primary HD underwent 41 aspirates. A diagnosis of HD was yielded in 12 and suggested in 13 cases (sensitivity 86.2%, false-positive 0%). Nine were diagnosed as atypical lymphoid cells, four as hyperplasia/other, and three as unsatisfactory. With these diagnoses, six patients began treatment without tissue exam. Thirty-five patients with suspected recurrent HD underwent 45 FNABs. Recurrent HD was confirmed in 15 and suggested in 12 aspirates (sensitivity 81.3%, false-suspicious 14.3%). With these diagnoses, 22 patients began treatment for recurrence without tissue exam. FNAB is useful both for establishing a primary diagnosis and confirming recurrence in HD and thus has a high utilization at our institution. In many instances, patients can begin therapy, negating the need for formal tissue exam.     

Superior mesenteric artery syndrome in scoliosis surgery: weight percentile for height as an indicator of risk

A retrospective analysis of charts identified cases of superior mesenteric artery (SMA) syndrome occurring after scoliosis surgery over a 23-year period. Despite numerous reports on this potentially fatal complication of scoliosis surgery, no method exists to stratify patients for risk of developing disease after spine surgery. A study of charts was performed to identify all cases of SMA syndrome occurring after scoliosis surgery from 1972 to 1995. An upper gastrointestinal study with findings specific for the syndrome was requisite for inclusion. Patients' weight and height at the time of diagnosis of SMA syndrome were recorded. Based on standard national data tables, a percentile for weight, percentile for height, and a weight percentile for height were derived for each patient. The syndrome occurred after posterior spinal fusion in six patients (three boys, three girls). The average weight percentile for height, available in five of the six patients, was 3%, significantly different from both age-matched controls in the general population and from age-matched controls undergoing posterior spinal fusion for adolescent idiopathic scoliosis. This study, the largest reported from a single institution, suggests that a weight percentile for height of 5% is the degree of asthenia that allows compromise of the duodenum. The percentile identifies patients at risk for SMA syndrome for the purposes of increasing postoperative vigilance for gastrointestinal complaints, decreasing the threshold for diagnostic workup, and guiding perioperative dietary supplementation.     

Biphenylsulfonamide endothelin receptor antagonists. 4. Discovery of N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]- 2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940), a highly potent and orally active ET(A) selective antagonist

We have previously disclosed the selective ET(A) receptor antagonist N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (1, BMS-193884) as a clinical development candidate. Additional SAR studies at the 2'-position of 1 led to the identification of several analogues with improved binding affinity as well as selectivity for the ET(A) receptor. Following the discovery that a 3-amino-isoxazole group displays significantly improved metabolic stability in comparison to its 5-regioisomer, the 3-amino-isoxazole group was combined with the optimal 2'-substituent leading to 16a (BMS-207940). Compound 16a is an extremely potent (ET(A) K(i) = 10 pM) and selective (80,000-fold for ET(A) vs ET(B)) antagonist. It is also 150-fold more potent and >6-fold more selective than 1. The bioavailability of 16a was 100% in rats and the systemic clearance and volume of distribution are higher than that of 1. In rats, intravenous 16a blocks big ET pressor responses with 30-fold greater potency than 1. After oral dosing at 3 micromol/kg, 16a displays enhanced duration relative to 1.     

TNF blockade in the treatment of rheumatoid arthritis: infliximab versus etanercept

There is accumulating evidence that tumour necrosis factor (TNF) plays a major role in the pathogenesis of rheumatoid arthritis (RA). Recent biotechnological advances have allowed for the development of agents that directly target TNF, a pro-inflammatory cytokine. In the last 2 years, the US FDA and the EU's Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of IgG1 and the extracellular domain of the TNF receptor (p75). Infliximab is a chimeric monoclonal antibody (mAb) composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well-tolerated in RA patients. This review evaluates the available TNF inhibitors, summarises pertinent clinical trials and underscores differences between the two agents in terms of molecular structure, efficacy, safety data, antigenicity and pharmacokinetics.     

CI-1017, a functionally M1-selective muscarinic agonist: design, synthesis, and preclinical pharmacology

The five muscarinic receptor subtypes (M1-M5) are characterized by seven helices that define a transmembrane cavity which serves as the binding pocket for agonists and antagonists. The five cavities appear to be topographically different enough to permit subtype selectivity among antagonists but not among classical agonists which tend to be smaller in size than antagonists. It was reasoned that synthesis of muscarinic agonists longer/larger than their classical counterparts might result in subtype selectivity. M1 subtype selectivity was found in a class of 1-azabicyclo[2.2.1]heptan-3-one, O-(3-aryl-2-propynyl) oximes. One of these, CI-1017, improved spatial memory of hippocampally deficient mice and nbM-lesioned rats at doses of 1.0-3.2 and 0.1-0.3 mg/kg, respectively, while producing parasympathetic side effects only at very high doses (100-178 mg/kg). Additionally, CI-1017 inhibited production of amyloidogenic A beta and increased secretion of soluble APP. Thus, CI-1017, besides treating AD symptomatically, may also retard its progression. CI-1017 has recently completed phase I clinical trials.     

Excretory urography with iohexol: evaluation in children

A multicenter clinical study was conducted using iohexol, a second-generation nonionic contrast medium, for excretory urography performed in 130 children. Doses of iohexol (300 mg iodine/ml) ranged between 150 and 660 mgI/kg (0.5 and 2.2 ml/kg). Iohexol was tolerated well, and no significant adverse reactions occurred. Sixty-five iohexol urograms were evaluated to determine the minimum dose for adequate visualization of the kidneys and collecting systems. A dose greater than 300 mgI/kg (1.0 ml/kg) always resulted in a urogram of diagnostic quality, while visualization was insufficient for diagnosis in 10% of studies done with doses of 150-300 mgI/kg (0.5-1.0 ml/kg). Another 65 iohexol urograms were compared in a blinded manner with a similar number of studies performed using iothalamate meglumine at comparable iodine concentration and dose. Visualization of calyces and pelvoinfundibular structures achieved with iohexol was rated better with statistical significance, but there was no difference in visualization of the renal parenchyma or ureters. Use of iohexol in excretory urography may be advantageous in children who are at greatest risk for an adverse reaction to contrast media or in those most likely to benefit from use of a low osmolality contrast agent.