Everolimus for renal cell carcinoma: predictive factors for response and future directions

Mammalian target of rapamycin (mTOR) inhibitors have emerged as a major addition to the therapeutic armamentarium for renal cell carcinoma. Temsirolimus extended survival when employed as frontline therapy for poor-risk advanced renal cell carcinoma. Everolimus has demonstrated improved progression-free survival for all risk groups of RCC in the salvage setting following other anti-angiogenic agents. Preliminary data indicates that baseline activation of the mTOR signaling pathway and increased FDG-PET uptake as well as early pharmacodynamic modulations of the mTOR pathway and down-modulation of FDG-PET uptake may predict for the activity of mTOR inhibitors. Ongoing trials are attempting to validate these data with everolimus therapy for metastatic RCC and may enable the goal of personalized therapy.     

Lymphangiomas in children: MR imaging

Seventeen lymphangiomas in 15 patients were imaged with magnetic resonance (MR) to define the nature, extent, and anatomic relationships of these lesions. The MR and pathologic findings were then compared to determine the histologic basis for the signal-intensity characteristics of these lesions. The signal intensity of 13 lesions was similar to or slightly less than that of muscle on T1-weighted images and greater than that of fat on T2-weighted images. This appearance correlated with the presence of ectatic lymphatic channels containing clear fluid on histologic section. Four lymphangiomas had high signal intensity, approximately equal to that of fat, on T1-weighted images, reflecting the presence of clotted blood or small cystic spaces with a higher ratio of fat to fluid. Sixteen of 17 lesions had visible septations on MR images. The authors' experience suggests that most lymphangiomas have a characteristic appearance on MR images. The information obtained with MR imaging can help in providing a preoperative diagnosis, in planning surgical resection, and in defining recurrence.     

Localization of calcitonin gene-related peptide within the genitofemoral nerve in immature rats.

BACKGROUND/PURPOSE: Calcitonin gene-related peptide (CGRP) has been proposed to influence migration and testicular descent by release from the genitofemoral nerve. The site of CGRP within the nerve has been controversial, with conflicting views on whether CGRP is synthesised and released from the motor nerves. METHODS: The genitofemoral nerve (GFN) was retrogradely labelled by fluorescent dye (DAPI) in 25 Sprague-Dawley rats (days 5, 16, and 31, n = 8 in each group; day 35, n = 1). Spinal cords and dorsal root ganglia (DRG) were removed two to three days later and sectioned for immunofluorescence. Substance P and CGRP-containing cells were labelled with fluorescein-linked antibodies. Specimens were examined by double fluorescence to identify cells with both markers. RESULTS: The motor nucleus of the GFN contained 119 cells on day 7 and 284 cells by days 19 through 34. A prominent band of CGRP-containing fibers, arising from the dorsal horn, synapsed with the GFN motor nucleus itself. CGRP-labelled GFN cells were found in the DRG by double labelling. CONCLUSIONS: CGRP from the GFN may affect gubernacular migration by release from the sensory nerves, rather than motor nerves as previously thought. The GFN motor nucleus receives CGRP-containing innervation from the dorsal horn, which may form part of the cremasteric reflex.     

Assessment of complex peptide degradation pathways via structured multicompartmental modeling approaches: the metabolism of dynorphin A1-13 and related fragments in human plasma.

Peptide metabolic pathways in blood or other tissues are often complex because multiple enzyme systems are involved in the degradation of parent drug and its metabolites. Michaelis-Menten-type studies with isolated enzymes have been frequently employed for evaluating the metabolism of peptides. Alternatively, studies with selective enzyme inhibitors or the evaluation of the area under the drug- or metabolite-time profiles have been employed. We tested in this study the usefulness of a multicompartmental pharmacokinetic approach for the assessment of the apparent first-order metabolism of dynorphin A1-13 up to the fourth metabolite generation in human plasma. This multicompartmental kinetic analysis proved instrumental in clarifying ambiguous degradation pathways not easily detectable by the other methods of assessment (enzyme inhibition studies and noncompartmental analysis) because of the lack of specific enzyme inhibitors or specificity problems of the analytical technique employed. The proposed multicompartmental fitting approach was also highly suitable to verify the overall metabolic pathways suggested by the other methods up to the fourth metabolite by testing whether the rate constants obtained by these methods are suitable to describe the overall degradation profile after Dyn A1-13 degradation. Local sensitivity analysis for the degradation of DYNA 1-13 revealed that the model was, however, not able to adequately identify on its own all of the parameters involved in the degradation of dynorphin A1-13. Thus, the method proved beneficial in evaluating and testing the correctness of the overall degradation pathways suggested by other methods.     

Deep venous thrombosis of the leg: US findings

In a prospective study, 121 consecutive patients with a clinical diagnosis of deep venous thrombosis of the leg were examined with real-time ultrasonography. The findings were correlated with the results of venography. The common femoral vein and the popliteal vein were evaluated for intraluminal echoes and compressibility, and the common femoral vein was also evaluated for an increase in diameter in response to the Valsalva maneuver. The superficial femoral vein and the calf veins were not evaluated. The results indicate that compressibility of the common femoral and popliteal veins is the best indication of deep venous thrombosis, with a sensitivity of 96% and a specificity of 97%. The accuracy of detection was not improved by including data from thrombus visualization or the response of the common femoral vein to the Valsalva maneuver.     

The sensory contribution of a single vibrissa's cortical barrel

The sensory contribution of the cortex containing the cortical barrel of the C1 vibrissa was studied in rats using the ablation-behavior method. Three independent experiments were performed, each requiring stimulus transduction by the C1 vibrissa but varying in their perceptual demands. The first required detection of sinusoidal oscillations of the vibrissa generated by an oscillating airstream directed vertically onto the vibrissa tip. The second required detection of a change in rate of the oscillation. The third required the blinded rat to jump a gap in an elevated runway after palpating the far side with its vibrissa. Psychophysical determinations of the single vibrissa system's thresholds before and after ablation of the cortex containing its barrel show that normal sensitivity either for detecting an oscillation or for detecting a change in oscillation frequency are not dependent on either the contralateral or the ipsilateral cortical barrelfield. In contrast to the lack of effect of barrelfield ablation on the spatial and temporal acuity of the vibrissa, the third experiment shows that a rat's ability to collect situation-relevant information with the vibrissa is lost after ablation of the cortex containing its contralateral barrel but not after ablation of the cortex containing its homologous ipsilateral barrel. The results of repeated retesting of an individual rat's ability to make a jump-no jump decision on the basis of vibrissa-transduced information at each stage of a series of successive single-vibrissa removals and unilateral barrelfield ablations show that the loss of the cortex containing the vibrissa's contralateral barrel is tantamount to loss of the vibrissa itself.