Laser speckle flowmetry method for measuring spatial and temporal hemodynamic alterations throughout large microvascular networks.

OBJECTIVES: 1) To develop and validate laser speckle flowmetry (LSF) as a quantitative tool for individual microvessel hemodynamics in large networks. 2) To use LSF to determine if structural differences in the dorsal skinfold microcirculation (DSFWC) of C57BL/6 and BALB/c mice impart differential network hemodynamic responses to occlusion. METHODS: We compared LSF velocity measurements with known/measured velocities in vitro using capillary tube tissue phantoms and in vivo using mouse DSFWCs and cremaster muscles. Hemodynamic changes induced by feed arteriole occlusion were measured using LSF in DSFWCs implanted on C57BL/6 and BALB/c mice. RESULTS: In vitro, we found that the normalized speckle intensity (NSI) versus velocity linear relationship (R(2) ≥ 0.97) did not vary with diameter or hematocrit and can be shifted to meet an expected operating range. In vivo, DSFWC and cremaster muscle preparations (R(2) = 0.92 and 0.95, respectively) demonstrated similar linear relationships between NSI and centerline velocity. Stratification of arterioles into predicted collateral pathways revealed significant differences between C57BL/6 and BALB/c strains in response to feed arteriole occlusion. CONCLUSIONS: These data demonstrate the applicability of LSF to intravital microscopy microcirculation preparations for determining both relative and absolute hemodynamics on a network-wide scale while maintaining the resolution of individual microvessels.

A phase 1 study of nifurtimox in patients with relapsed/refractory neuroblastoma.

The primary aim of this phase 1 study was to determine the maximum tolerated dose (MTD) and evaluate the safety of nifurtimox alone and in combination with cyclophosphamide and topotecan in multiple relapsed/refractory neuroblastoma pediatric patients. The secondary aim was to evaluate the pharmacokinetics of nifurtimox and the treatment response. To these ends, we performed a phase 1 dose escalation trial of daily oral nifurtimox with toxicity monitoring to determine the MTD, followed by 3 cycles of nifurtimox in combination with cyclophosphamide and topotecan. Samples were collected to determine the pharmacokinetic parameters maximum concentration, time at which maximum concentration is reached, and area under the curve between 0 and 8 hours. Treatment response was evaluated by radiographic and radionuclide (I-metaiodobenzylguanidine) imaging, measurement of urinary catecholamines, and clearance of bone marrow disease. We determined the MTD of nifurtimox to be 30 mg/kg/d. The non-dose-limiting toxicities were mainly nausea and neuropathy. The dose-limiting toxicities of 2 patients at 40 mg/kg/d were a grade 3 pulmonary hemorrhage and a grade 3 neuropathy (reversible). Overall, nifurtimox was well tolerated by pediatric patients at a dose of 30 mg/kg/d, and tumor responses were seen both as a single agent and in combination with chemotherapy. A Phase 2 study to determine the antitumor efficacy of nifurtimox is currently underway.

Appearance of the delta phalanx (longitudinally bracketed epiphysis) with MR imaging.

The delta phalanx is an unusual condition occurring in the hand or the foot that can be distinguished from a secondary ossification center on radiographic evaluation based on the well-defined phalangeal epiphyses typically evident by 24-30 months of age. MR imaging of the delta phalanx offers the advantage of visualizing sites of unossified bone before the age these findings are typically visible with radiography. We describe the case of a 15-month-old boy who presented with soft-tissue fusion of the third and fourth digits of the right hand. Radiograph and MR evaluation revealed soft-tissue intra-axial syndactyly of the third and fourth digits and a delta phalanx involving the proximal phalanx of the involved fourth digit.