Plasma disposition of capecitabine and its metabolites 5��DFCR and 5��DFUR in a standard and dose-intensified monotherapy regimen

Purpose

In view of a potential gain in anticancer activity in advanced colorectal cancer (ACRC), there has been considerable interest in using a higher than the approved standard dose of capecitabine (CCB) combined with oxaliplatin. This pharmacokinetic study was designed to evaluate whether CCB is metabolized at the same extent when administered as a monotherapy in two different dose regimens, comparing standard dose (CCB 1) and intensified dose (CCB 2).

Patients and methods

Seven patients suffering from ACRC received subsequently two CCB schedules: In the standard schedule, 1,250?mg/m² CCB p.o. twice daily for 2?weeks was administered, after a pause of 1?week, a dose-intensified CCB 2 schedule was given: 1,750?mg/m² CCB p.o. twice daily for 1?week to be followed by 1?week rest. Due to this paired cross over design a direct comparison for each single patient was feasible.

Results

In both schedules, mean peak plasma concentrations of CCB occurred at about 50?min, those of metabolites shortly later (range 54?C80?min). Peak plasma concentrations were about 10% (CCB, DFCR) and 40% (DFUR) higher in the CCB 2 regimen. According to the higher dose of CCB in the dose-intensified regimen (+40%), the AUC_last values increased by 34% (CCB), 20% (DFCR) and 58% (DFUR), respectively.

Conclusion

The results indicate that higher doses of CCB are metabolized approximately dose-dependent compared to the standard dose. No indices for a saturation of metabolizing processes or any significant delay of elimination rate was observed. The immediate 5FU precursor DFUR was formed at a 50% higher extent (expressed as AUC_last values) than in the standard CCB 1 schedule. From the pharmacokinetic point of view, this increased formation rate suggests clinical importance in regard to metabolic activation of CCB.     

Bildgebung molekularer Strukturen der Brust mit neuen Techniken der Sonographie

Sonography has become one of the most important imaging methods in breast diagnostics. Through the development of high-frequency transducers and the use of ultrasound contrast agents, the number of indications for sonography of the breast has continued to increase in recent years. Visualization of very small vessels under 100 µm enables sensitive detection and quantification of tissue perfusion. Thus, breast ultrasound can play an essential role in answering questions about certain pathologies. Further technical advances, such as automated breast ultrasound systems, provide an essential step for standardization of investigations. Targeted ultrasound is a new important development of this technique. Specific markers which are conjugated with the surface of contrast medium microspheres allow targeted molecular endothelial structures to be selectively visualized and quantified. These developments will strengthen the role of sonography in the future as a non-invasive and easy to use method.     

Synthesis and PET studies of [11C-cyano]letrozole (Femara), an aromatase inhibitor drug

IntroductionAromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone into estrone and estradiol, respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole; Femara) is a high-affinity aromatase inhibitor (K_i=11.5 nM) that has Food and Drug Administration approval for breast cancer treatment. Here we report the synthesis of carbon-11-labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon.MethodsLetrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile) were prepared in a two-step synthesis from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [¹¹C]cyano group was introduced via tetrakis(triphenylphosphine)palladium(0)-catalyzed coupling of [¹¹C]cyanide with the bromo precursor. Positron emission tomography (PET) studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. Log D, the free fraction of letrozole in plasma and the [¹¹C-cyano]letrozole fraction in arterial plasma were also measured.Results[¹¹C-cyano]Letrozole was synthesized in 60 min with a radiochemical yield of 79–80%, with a radiochemical purity greater than 98% and a specific activity of 4.16±2.21 Ci/μmol at the end of bombardment (n=4). PET studies in the baboon revealed initial rapid and high uptake and initial rapid clearance, followed by slow clearance of carbon-11 from the brain, with no difference between brain regions. Brain kinetics was not affected by coinjection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9%, and log D was 1.84.Conclusion[¹¹C-cyano]Letrozole is readily synthesized via a palladium-catalyzed coupling reaction with [¹¹C]cyanide. Although it is unsuitable as a PET radiotracer for brain aromatase, as revealed by the absence of regional specificity and saturability in brain regions such as amygdala, which are known to contain aromatase, it may be useful in measuring letrozole distribution and pharmacokinetics in the brain and peripheral organs.     

Validation of image quality in full-field digital mammography: Is the replacement of wet by dry laser printers justified?

OBJECTIVE: Dry laser printers have replaced wet laser printers to produce hard copies of high-resolution digital images, primarily because of environmental concerns. However, no scientific research data have been published that compare the image quality of dry and wet laser printers in full-field digital mammography (FFDM). This study questions the image quality of these printers. MATERIALS AND METHODS: Objective image quality parameters of both printers were evaluated using a standardized printer test image, i.e., optical density and detectability of specific image elements (lines, curves, and shapes). Furthermore, mammograms of 129 patients with different breast tissue composition patterns were imaged with both printers. A total of 1806 subjective image quality parameters (brightness, contrast, and detail detection of anatomic structures), the detectability of breast lesions, as well as diagnostic performance according to the BI-RADS classification were evaluated. In addition, the presence of film artifacts was investigated. RESULTS: Optical density values were equal for the dry and the wet laser printer. Detection of specific image elements on the printer test image was not different. Ratings of subjective image quality parameters were equal, as were the detectability of breast lesions and the diagnostic performance. Dry laser printer images showed more artifacts (164 versus 27). However, these artifacts did not influence image quality. CONCLUSION: Based on the evidence of objective and subjective parameters, a dry laser printer equals the image quality of a wet laser printer in FFDM. Therefore, not only for reasons of environmental preference, the replacement of wet laser printers by dry laser printers in FFDM is justified.     

Role of chest radiography in predicting the extent of airway disease in patients with suspected pulmonary embolism

An independent evaluation of the chest radiographs and ventilation-perfusion (VP) scintigrams of 119 patients (121 studies) was performed to assess the ability of radiographic findings to indicate the extent of ventilation abnormalities in patients suspected of having pulmonary embolism (PE). VP scans were obtained with krypton-81m in 72 cases and with xenon-133 in 49. All scintigrams showing ventilation abnormalities in greater than 50% of the lung were considered indeterminate for PE, owing to an increased likelihood of false-negative interpretations, as reported in previous studies. Indeterminate VP studies were found in all 21 patients who had radiographic findings of widespread obstructive pulmonary disease (OPD), in 35% with radiographic findings of focal OPD (P less than .001), and in only 18% with no OPD seen radiographically (P less than .001). VP scintigraphy is likely to be indeterminate for PE when widespread OPD is seen by chest radiography and ventilation imaging may not be warranted in these patients.     

Image quality of a wet laser printer versus a paper printer for full-field digital mammograms

OBJECTIVE: The purpose of our study was to compare the image quality of a wet laser printer with that of a paper printer for full-field digital mammography (FFDM). MATERIALS AND METHODS: For both a wet laser printer and a paper printer connected to an FFDM system, image quality parameters were evaluated using a standardized printer test image (luminance density, dynamic range). The detectability of standardized objects on a phantom was also evaluated. Furthermore, 640 mammograms of 80 patients with different breast tissue composition patterns were imaged with both printers. Subjective image quality parameters (brightness, contrast, and detection of details of anatomic structures-that is, skin, subcutis, musculature, glandular tissue, and fat), the detectability of breast lesions (mass, calcifications), and the diagnostic performance according to the BI-RADS classification were evaluated. RESULTS: Both the luminance density and the dynamic range were superior for the wet laser printer. More standardized objects were visible on the phantom imaged with the wet laser printer than with the paper printer (13/16 vs 11/16). Each subjective image quality parameter of the mammograms from the wet laser printer was rated superior to those of the paper printer. Significantly more breast lesions were detected on the wet laser printer images than on the paper printer images (masses, 13 vs 10; calcifications, 65 vs 48; p < 0.05). With the paper printer images, BI-RADS 4 and 5 categories were underestimated for 10 (43.5%) of 23 patients. CONCLUSION: For FFDM, images obtained from a wet laser printer show superior objective and subjective image quality compared with a paper printer. As a consequence, the paper printer should not be used for FFDM.     

Serial lung scintigraphy: utility in diagnosis of pulmonary embolism

Pairs of sequential perfusion lung scans and pulmonary angiograms obtained in 45 patients were reviewed to investigate the utility of short-term, sequential scintigraphy in the diagnosis of pulmonary embolism (PE). Forty-six sequential scan pairs were reviewed; 13 were ventilation-perfusion (V-P) pairs. Angiograms were obtained within 48 hours of either the first (65%) or second (35%) perfusion scan in each pair. Sequential scintigraphic patterns were classified as showing change (i.e., improvement in defects, new defects), no change, or as being indeterminate. A changing perfusion pattern was associated with a high (20/23) likelihood of PE, but seven of 16 patients with stable perfusion patterns also had PE. The sensitivity of a changing perfusion pattern for PE was 0.74 (20/27) and its specificity was 0.75 (9/12). In two of six patients who had serial V-P studies that showed changing perfusion defects, there were matched changes in regional ventilation and angiograms were negative. The findings suggest that short-term serial perfusion lung scanning may aid the scintigraphic diagnosis of PE in certain circumstances. Serial V-P imaging is needed, however, to maximize diagnostic specificity.     

Four new flavones and a new isoflavone from Iris bungei

Four new irisflavones A-D (1-4) and irilin D (5) have been isolated from the underground parts of Iris bungei along with known isoflavones, irilins A-B (6-7) and tlatancuayin (8). The structures of the new compounds were determined using NMR and mass spectroscopic methods and were found to be 2',5,7-trihydroxy-3,6-dimethoxyflavone (1), 2',5-dihydroxy-3,6,7-trimethoxyflavone (2), 2',5,6'-trihydroxy-3,6,7-trimethoxyflavone (3), 3,3',5-trihydroxy-2',7-dimethoxyflavone (4), and 3',4',5,7-tetrahydroxy-6-methoxyisoflavone (5). The structures of irisflavones 1, 3, and 4 were confirmed by single-crystal X-ray diffraction studies.