Phase II dose escalation study of caspofungin for invasive Aspergillosis.

Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥ 4 in 2 of 8 patients or ≥ 3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin.

Diagnostic performance of digital subtraction angiography (DSA) and magnetic resonance angiography (MRA): preliminary results in vascular occlusive disease of the abdominal and lower-extremity arteries.

Fifty-nine patients with occlusive disease of the aorto-iliac and femoro-popliteal arteries were investigated prospectively by intravenous (IV) or intraarterial (IA) digital subtraction angiography (DSA) and magnetic resonance angiography (MRA). This was accomplished using a two-dimensional (2D) Inflow- (59 patients) and a 2D Phase Contrast- (RSE--rapid sequential excitation) sequence (29 patients). The spectrum of pathology included stenoses < 50%, stenoses 50-89%, stenoses 90-99%, occlusions, aneurysms and status following reconstructive surgery. MRA- and DSA-examinations were evaluated by four radiologists. The diagnoses were made by consent decisions of a radiologist and a vascular surgeon based on clinical and radiological findings. Diagnostic performance of IA-DSA was superior to all other imaging modalities. Vascular delineation of 2D Inflow-MRA was comparable to that of IV-DSA. The image quality of RSE-MRA was not adequate for diagnosis. In conclusion, 2D Inflow-MRA is a promising method for evaluating abdominal and peripheral arteriosclerotic disease. Interpretation of MR-angiograms, however, requires profound knowledge of MRA-techniques, X-ray angiography and hemodynamics.

[X-ray studies of the peripheral joints: a comparison of digital luminescence radiography (DLR) and film-screen systems]. / Röntgenuntersuchungen der peripheren Gelenke: Vergleich der digitalen Lumineszenzradiographie (DLR) mit Filmfoliensystem.

175 matched skeletal x-ray examinations were carried out by digital luminescent radiography (DLR) and conventional screen-film system combinations. In digital luminescent radiography (DLR) two differently postprocessed images were obtained from one x-ray exposure: A display with low spatial frequency enhancement was opposed to a second display with high edge enhancement. Conventional and digital images were evaluated randomly and separately by four radiologists using a questionnaire. DLR proved to be diagnostically equivalent to the conventional technique except for a diminished visibility of subtle erosions and fissures. As major advantages of DLR maybe pointed out that faulty exposures were avoided by the automatic adjustment of image brightness and that the soft tissue margins could be more easily delineated in displays with high edge enhancement than in conventional radiography. However, digital displays with high edge enhancement did not provide additional diagnostic information and led to artifacts at the edges of metal prostheses.

[Peripheral occlusive arterial diseases: comparison of diagnostic value of MRA and DSA]. / Peripheres arterielles Verschlussbleiden: Vergleich der diagnostischen Wertigkeit von MRA und DSA.

MATERIAL AND METHODS: In 59 patients with arterial flow disturbances 2-D inflow sequence of the abdominal and lower leg arteries were prospectively obtained on a 1.5 T MR-imager and were compared with additional DSA examinations. Supplementary Phase Contraste RSE ("Rapid Sequential Excitation") sequences were carried out in 29 patients. MRA and DSA angiograms were evaluated in random order by 4 readers using a questionnaire. The assessment of image quality were evaluated by variance analysis. Diagnostic performance of MRA and DSA was assessed by comparison of the readers' diagnostic assessments with reference diagnoses established by a radiologist and a vascular surgeon with full knowledge of all data concerning a patient. Image quality of inflow MRA was considered inferior to i.a. DSA (p < 0.001) and comparable with i.v. DSA (p = 0.1361). Image quality of RSE-MRA was inadequate (p < 0.001). Correspondingly, i.a. DSA was the superior and RSE-MRA the inferior imaging technique. The accuracy of inflow MRA in determining stenosis grade was 66% and that of RSE-MRA 59%.

[Quality control of outpatient imaging examinations in North Rhine-Westphalia, Part II]. / Qualitätskontrolle der ambulanten bildgebenden Diagnostik in Nordrhein-Westfalen, Teil II.

PURPOSE: In the state of North Rhine-Westphalia (NRW), Germany, a survey was conducted on radiologic examinations ordered by general practitioners (GPs). Part II of this study aims to determine the quality of the process and outcome. The reference standard is the assessment of both radiologists and physicians without board certification in radiology working at a university hospital and in outpatient facilities. MATERIALS AND METHODS: AllGPs in NRW were asked to cooperate. Participating GPs filled out a questionnaire for each patient. The patients recorded the symptoms prompting the imaging examinations. The radiologists or other physicians performing the examinations were asked to provide the images and written reports and to complete a questionnaire. A file was created for each of the 394 patients with image documentation of at least one examination. Each file, which included medical history, physical findings, imaging documentation and written report, was sequentially forwarded to a board-certified radiologist and to a physician without board certification in radiology working in a university hospital and in an outpatient facility. All physicians were requested to complete a structured questionnaire for each file. RESULTS: The referral diagnoses were rated as medically plausible in 81%, the indications for imaging found correct in 76%, the examination techniques considered appropriate in 69%, the clinical question answered in 63%, the interpretation judged medically correct in 50% and all incidental findings documented in 49%. In retrospect, 32 % of the examinations were judged superfluous. The sequence of multiple examinations performed on a particular patient was rated as appropriate in 51%. The interpretation revealed specialty-related differences. The plausibility of the referral diagnoses had a significant impact on the appropriateness of subsequent diagnostic investigations. Marked deficits showed sonography, performance by non-radiologists, self-referrals by GPs, gastroenterologic radiology and the ICD-10 coding (suspicion of cardiovascular disease). CONCLUSION: In the "best-case" scenario, the process quality proved to have moderate deficiencies and the outcome quality severe deficiencies. In consequence, GPs and radiologists should be more communicative by sharing information and exchanging opinions. GP self-referrals should be restricted. Sonography and examinations performed by physicians without board certification in radiology should undergo stricter quality controls. A more intensive interdisciplinary collaboration is needed to determine the optimum implementation of diagnostic imaging of gastroenterologic and cardiovascular diseases.

[Quality control of outpatient imaging examinations in North Rhine-Westphalia, part I]. / Qualitätskontrolle der ambulanten bildgebenden Diagnostik in Nordrhein-Westfalen, Teil I.

PURPOSE: In the state of North-Rhine Westphalia (NRW), Germany, a survey was conducted on radiologic examinations ordered by general practitioners (GPs). Part I of this study aims to collect characteristic epidemiological data and to assess structural quality. MATERIALS AND METHODS: All GPs in NRW were asked to cooperate. Participating GPs filled out a questionnaire for each patient. The patients recorded the symptoms prompting the imaging examinations. The radiologists or other physicians performing the examinations were asked to provide the images and written reports and to complete a questionnaire. Two university radiologists documented the pertinent test data from the submitted images and written records. Independently of each other, five university radiologists anonymously reviewed the image quality of each examination using structured questionnaires. RESULTS: A total of 920 patients gave their informed consent and participated. Questionnaires from 787 patients, 852 GPs and 611 radiologists or other interpreting physicians as well as the complete survey data from 530 examinations were available. Of 1503 examinations, conventional radiography made up 52 %, sonography 17 %, computed tomography (CT) 13 % and magnetic resonance imaging (MRI) 5 %. Most indications involved the musculoskeletal (37 %) and respiratory systems (24 %). Physicians without board certification in radiology interpreted 1 % of the CT examinations, 26 % of the radiographic examinations and 71 % of the sonographic examinations. Of the 174 self-referrals, 1 % involved CT, 33 % conventional radiography and 66 % sonography. Written reports were available for 95 % of all 469 examinations performed by radiologists and 74 % of all 127 examinations conducted by non-radiologists. Only 44 % of the 23 sonographic studies were self-referrals by the patient's GP. On average, the radiographic techniques were acceptable in terms of diagnostic information and radiation hygiene. Conventional radiographs were better exposed when obtained by radiologists than by non-radiologists (p = 0.038). The delineation of anatomical structures was rated as good to acceptable for MRI, CT and conventional radiography, while the image quality was rated as diagnostically insufficient for sonography (p < 0.0001). The image quality of radiographic and sonographic examinations performed by radiologists was superior in comparison to examinations performed by physicians without board certification in radiology (p < 0.0001). CONCLUSION: Examination technique and imaging quality of MRI, CT and conventional radiography performed on outpatients were in an acceptable diagnostic range, whereas the quality of sonography was inadequate.

Phase-contrast pulsatility measurements: preliminary results in normal and arteriosclerotic iliofemoral arteries. Work in progress.

Magnetic resonance (MR) flow measurements were obtained in six healthy volunteers and 30 patients with arteriosclerotic disease with a 1.5-T imager and a pulse sequence for flow quantification based on flow-induced phase shifts. The iliac arteries were investigated in eight and the femoral arteries in 28 subjects. A trigger pulse, followed by the acquisition of 30 evenly distributed data sets, was applied every second heartbeat, thus eliminating any acquisition gap in a full heart cycle. For quantitative analysis, flow velocity was plotted as a function of time. Systolic acceleration, postsystolic deceleration, and pulsatility of flow were calculated and compared with stenosis grades determined from recent intraarterial digital subtraction angiograms. The flattening of the temporal flow patterns correlated with local severity of vascular occlusive disease.

Digital luminescence radiography and conventional radiography in abdominal contrast examinations.

In 326 patients abdominal contrast radiographs were compared to digital luminescence radiographs (DLR) and conventional screen-film system ones. The digital exposure dose was 50% of the conventional. In DLR, 2 different types of postprocessed images were obtained from each data set. A display with low spatial frequency enhancement filtered to look like a conventional radiograph was compared to a display with high spatial frequency enhancement. Conventional and DLR images were evaluated randomly and separately by 4 radiologists by means of a questionnaire. DLR proved to be diagnostically equivalent to the conventional technique with the exception of a slightly diminished visibility of the mucosal pattern. High spatial frequency enhancement did not provide additional diagnostic information and should be dispensed with in abdominal examinations.

MR pulsatility measurements in peripheral arteries: preliminary results.

Phase contrast flow velocity measurements were performed in six healthy volunteers and 30 patients with arteriosclerotic disease. The iliac arteries were investigated in 8 cases and the femoral arteries in 28 cases. In the first 24 patients, 16 evenly distributed data sets were acquired during one cardiac cycle. In the last 12 patients, a trigger pulse followed by the acquisition of 30 evenly distributed data sets was applied every second heart beat. This procedure allowed data to be acquired over a full heart cycle without any acquisition gap. The measured flow velocities were displayed as function of time. Systolic acceleration, postsystolic deceleration and pulsatility of flow velocity were calculated and compared with stenosis grades determined from DSA angiograms. Flattening of the flow velocity patterns was found to correlate with the local severity of arteriosclerotic disease.

A pilot study of continuous ambulatory electrocardiography in patients donating blood for autologous use in elective coronary artery bypass grafting.

BACKGROUND: A pilot study was conducted to evaluate the impact of a single autologous blood donation on the presence or absence of myocardial ischemic episodes in patients with coronary artery disease. STUDY DESIGN AND METHODS: Fifty patients scheduled for elective coronary artery bypass grafting underwent two 24-hour periods of ambulatory electrocardiogram monitoring, one before and one after their first autologous blood donation. The presence or absence and the number, duration, and integral area of episodes of ST segment depression for each 24-hour monitoring period were determined. RESULTS: Forty-two patients had legible electrocardiogram recordings for both monitoring periods. Of these, 36 patients (86%) had at least one episode of ST segment depression during any monitoring period. The number of patients who had at least one episode of ST segment depression before donation was not significantly different from the number of those who had at least one episode after donation (31 and 33 patients, respectively; p = 0.73). CONCLUSION: Donating a unit of blood had no demonstrable effect on the presence or absence of myocardial ischemic episodes in this sample of 42 autologous blood donors with coronary artery disease. The results of this study should be validated in further trials.