C. P. Heussel

Adenovirus-Mediated Wild-Type p53 Gene Transfer in Patients Receiving Chemotherapy for Advanced Non–Small-Cell Lung Cancer: Results of a Multicenter Phase II Study

PURPOSEnTo study the additional benefit from adenoviral p53 gene therapy in patients undergoing first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC).nnnPATIENTS AND METHODSnTwenty-five patients with nonresectable NSCLC were enrolled in an open-label, multicenter phase II study of three cycles of regimen A, carboplatin (area under the curve, 6; day 1) plus paclitaxel (175 mg/m(2), day 1), or regimen B, cisplatin (100 mg/m(2), day 1) plus vinorelbine (25 mg/m(2), days 1, 8, 15, and 22) in combination with intratumoral injection of 7.5 x 10(12) particles of SCH 58500 (rAd/p53, day 1). Responses of individual tumor lesions were assessed after each cycle, and gene transfer was examined in posttreatment tumor biopsies using reverse transcriptase polymerase chain reaction.nnnRESULTSnThere was no difference between the response rate of lesions treated with p53 gene therapy in addition to chemotherapy (52% objective responses) and lesions treated with chemotherapy alone (48% objective responses). Subgroup analysis according to the chemotherapy regimens revealed evidence for increased mean local tumor regressions in response to additional p53 gene therapy in patients receiving regimen B, but not in patients receiving regimen A. There was no survival difference between the two chemotherapy regimens, and the median survival of the cohort was 10.5 months (1-year survival, 44%). Transgene expression was confirmed in tumor samples from 68% of patients, and toxicities attributable to gene therapy were mild to moderate.nnnCONCLUSIONnIntratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.

Diffusion-weighted MRI of the lung with hyperpolarized helium-3: a study of reproducibility.

To determine the reproducibility of several parameters of the ADC measurement by calculating the scan‐to‐scan intrasubject variability.

3He MRI in healthy volunteers: preliminary correlation with smoking history and lung volumes

MRI with hyperpolarized helium‐3 (3He) provides high‐resolution imaging of ventilated airspaces. The first aim of this 3He‐study was to compare observations of localized signal defects in healthy smokers and non‐smokers. A second aim was to describe relationships between parameters of lung function, volume of inspired 3He and signal‐to‐noise ratio. With Ethics Committee approval and informed consent, 12 healthy volunteers (seven smokers and five non‐smokers) were studied. Imaging was performed in a 1.5u2005T scanner using a two‐dimensional FLASH sequence at 30V transmitter amplitude (TR/TE/αu2005=u200511 ms/4.2 ms/<10°). Known amounts of 3He were inhaled from a microprocessor‐controlled delivery device and imaged during single breath‐holds. Images were evaluated visually, and scored using a prospectively defined ‘defect‐index’. Signal‐to‐noise ratio of the images were correlated with localization, 3He volumes and static lung volumes. Due to poor image quality studies of two smokers were not eligible for the evaluation. Smokers differed from non‐smokers in total number and size of defects: the ‘defect‐index’ of smokers ranged between 0.8 and 6.0 (medianu2005=u20051.1), that of non‐smokers between 0.1 and 0.8 (medianu2005=u20050.4). Intraindividually, an anteroposterior gradient of signal‐to‐noise ratio was apparent. Signal‐to‐noise ratio correlated with the estimated amount of hyperpolarization administered (ru2005=u20050.77), but not with static lung volumes. We conclude that 3He MRI is a sensitive measure to detect regional abnormalities in the distribution of ventilation in clinically healthy persons with normal pulmonary function tests. Copyright

Hyperpolarised 3He MRI versus HRCT in COPD and normal volunteers: PHIL trial

The aim of the present study was to apply hyperpolarised (HP) 3He magnetic resonance imaging (MRI) to identify patients with chronic obstructive pulmonary disease (COPD) and α1-antitrypsin deficiency (α1-ATD) from healthy volunteers and compare HP 3He MRI findings with high-resolution computed tomography (HRCT) in a multicentre study. Quantitative measurements of HP 3He MRI (apparent diffusion coefficient (ADC)) and HRCT (mean lung density (MLD)) were correlated with pulmonary function tests. A prospective three centre study enrolled 122 subjects with COPD (either acquired or genetic) and age-matched never-smokers. All diagnostic studies were completed in 94 subjects (52 with COPD; 13 with α1-ATD; 29 healthy subjects; 63 males; and 31 females; median age 62u2005yrs). The consensus assessment of radiologists, blinded for other test results, estimated nonventilated lung volume (HP 3He MRI) and percentage diseased lung (HRCT). Quantitative evaluation of all data for each centre consisted of ADC (HP 3He MRI) and MLD measurements (HRCT), and correlation with forced expiratory volume in 1u2005s (FEV1)/forced vital capacity (FVC) indicating airway obstruction, and the diffusing capacity of the lung for carbon monoxide (DL,CO) indicating alveolar destruction. Using lung function tests as a reference, regional analysis of HP 3He MRI and HRCT correctly categorised normal volunteers in 100% and 97%, COPD in 42% and 69% and α1-ATD in 69% and 85% of cases, respectively. Direct comparison of HP 3He MRI and CT revealed 23% of subjects with moderate/severe structural abnormalities had only mild ventilation defects. In comparison with lung function tests, ADC was more effective in separating COPD patients from healthy subjects than MLD (p<0.001 versus 0.038). ADC measurements showed better correlation with DL,CO than MLD (ru200a=u200a0.59 versus 0.29). Hyperpolarised 3He MRI correctly categorised patients with COPD and normal volunteers. It offers additional functional information, without the use of ionising radiation whereas HRCT gives better morphological information. We showed the feasibility of a multicentre study using different magnetic resonance systems.

Assessment of pulmonary hypertension by CT and MR imaging

In the recent World Health Organization (WHO) classification the group of pulmonary arterial hypertension (PH) comprises the classic primary pulmonary hypertension and several conditions with definite or very high risk factors to develop pulmonary arterial hypertension. Therapeutic advances drive the need for a comprehensive pre-therapeutic evaluation for optimal treatment. Furthermore, follow-up examinations need to be performed to monitor changes in disease status and response to therapy. Up to now, the diagnostic imaging work-up of PH comprises mainly echocardiography, invasive right heart catheterization and ventilation/perfusion scintigraphy. Due to technical advances helical computed tomography (CT) and magnetic resonance imaging (MRI) became more important in the evaluation and for differential diagnosis of pulmonary arterial hypertension. Both modalities are reviewed and recommendations for clinical use are given.

Paired inspiratory/expiratory spiral CT and continuous respiration cine CT in the diagnosis of tracheal instability

Abstract. In tracheo- and bronchomalacia, localisation and determination of collapse is necessary for planning of surgical procedure. We compared inspiratory and expiratory spiral CT, cine CT, bronchoscopy, exemplary cine MR, and evaluated the clinical relevance. Twenty-nine patients (2 follow-ups; mean age 61xa0years, age range 27–85xa0years) with suspected or verified tracheal stenosis or collapse (post-tracheotomy: n=17; neoplasm: n=5; other: n=7) underwent paired breath-hold inspiratory and expiratory spiral CT. Forty-five additional cine CT were performed at 1–4 levels (mean 1.5) during continuous respiration (increment 100xa0ms) to clarify respiratory collapse. The tracheal cross-sectional diameters of both techniques were calculated. Comparison with bronchoscopy, follow-up, and influence upon therapy were evaluated retrospectively. Exemplary comparison with cine MR (8 frames/s) was done in 3 cases. In addition to bronchoscopy, further information concerning localisation, extent, collapse, stability of the tracheal wall, distal portions of the stenosis and extraluminal compressions were obtained. A significantly higher degree and more pathological collapses (>50%) were seen using cine CT (38%) compared with paired spiral CT (13%; degree: p<0.0001; number: p<0.001). The findings changed the further therapeutic procedure in 16 of 29 patients. Further stenoses were excluded and bronchoscopy was verified in another 13 of 29. Temporal resolution of cine CT and cine MR is sufficient; however, spatial resolution of cine MR is inferior. Paired inspiratory and expiratory spiral CT localises tracheal stenoses and demonstrates relevant extraluminal compression. Significantly improved evaluation of respiratory collapse and further information of localised tracheal instability is obtained by cine CT. Cine MR promises more functional information especially due to free choice of imaging plane.

Pneumonia in neutropenic patients.

Radiologists have a special role in the management of neutropenic patients. The appropriate investigational technique, frequently targeted differential diagnosis, and the special needs of these patients, need to be understood. Early detection of a focus is the major goal in febrile neutropenic patients. As pneumonia is the most common focus, chest imaging is a special radiological task. The sensitivity of chest X-ray, especially in supine position, is known to be low; therefore, the very sensitive high-resolution CT (HRCT) became gold standard in neutropenic hosts and will probably be replaced by thin-section multislice CT (MSCT) in the near future. Costs of high-resolution CT are low in comparison to antibiotics. An infiltrate needs to be localised, so that a physician can utilise this information as a guidance for invasive procedures for further microbiological work-up. The radiological characterisation of infiltrates gives a first and rapid hint to differentiate between different sorts of infectious (typical bacterial, atypical bacterial, fungal) and non-infectious aetiologies. Follow-up investigations need careful interpretation according to disease and concomitant treatment. Due to an increased incidence of fungal infiltrates even with appropriate therapy, follow-up of an infiltrate must use further parameters in addition to lesion size. Temporary exclusion of infectious involvement of the lung with high accuracy remains of special interest for clinicians.

Update on diagnostic strategies of pulmonary embolism.

Abstract. Acute pulmonary embolism is a frequent disease with non-specific findings, high mortality, and multiple therapeutic options. A definitive diagnosis must be established by accurate, non-invasive, easily performed, cost-effective, and widely available imaging modalities. Conventional diagnostic strategies have relied on ventilation-perfusion scintigraphy complemented by venous imaging. If the results are inconclusive, pulmonary angiography, which is regarded as the gold standard, is to be performed. Recently, marked improvements in CT and MRI and shortcomings of scintigraphy led to an update of the diagnostic strategy. Spiral CT is successfully employed as a second-line procedure to clarify indeterminate scintigraphic results avoiding pulmonary angiography. It can also be used as a first-line screening tool if service and expertise is provided. Venous imaging is indicated if CT is inconclusive. The MRI technique can be applied as an alternative second-line test if spiral CT is not available or is contraindicated. It has the greatest potential for further developments and refinements. Echocardiography should be used as a first-line bedside examination in critical patients. If inconclusive stabilized patients undergo spiral CT, unstable patients should be referred for pulmonary angiography. Chronic thromboembolic pulmonary hypertension is a rare sequela of acute pulmonary embolism which can be cured surgically. Morphology, complications, and differential diagnoses are better illustrated by spiral CT and MRA, whereas invasive acquisition of hemodynamic data is the sole advantage of angiography.

19F-MRI of perflubron for measurement of oxygen partial pressure in porcine lungs during partial liquid ventilation.

A method for in vivo measurement of oxygen partial pressure (pO2) in porcine lungs during partial liquid ventilation (PLV) with perflubron (PFOB) was developed. A pulse sequence for high‐resolution MRI of the distribution of PFOB in the lung after intratracheal administration was developed as well. Moreover, quantitative measurements of longitudinal relaxation time T1 of 19F resonances for assessment of regional pO2 are described. Due to the need to acquire data during a single expiratory breathhold, only low SNRs were achieved in vivo. Therefore, simulations were performed to investigate the influence of background noise on T1 values calculated from data with low SNR. Based on these simulations, a postprocessing strategy was developed to correct for systematic errors by background noise prior to quantitative analysis. Results of a pilot study in pigs under conditions of PLV are presented. Magn Reson Med 47:82–89, 2002.

Focal airtrapping at expiratory high-resolution CT: comparison with pulmonary function tests

Abstract. This study was undertaken to determine prevalence, extent, and severity of focal airtrapping at expiratory high-resolution CT, and to compare focal airtrapping with age, gender, pulmonary function tests, and blood gas analysis. Two-hundred seventeen patients with and without pulmonary disease underwent paired inspiratory/expiratory high-resolution CT. Six scan pairs with corresponding scan levels were visually assessed for focal – not diffuse – airtrapping using a four-point scale. Pulmonary function tests and blood gas analysis were available for correlation in all patients (mean interval 5 days). Focal airtrapping with lower lung predominance was observed in 80 % of patients. Twenty-six of 26 patients with restrictive lung function impairment exhibited focal airtrapping (mean score 2.4), whereas only 72 of 98 (74 %) patients with obstruction did (mean score 1.5; p < 0.05). Fifty-eight of 70 (83 %) patients with normal lung function (mean score 1.8) and 19 of 23 (83 %) patients with mixed impairment (mean score 1.8) had focal airtrapping. Focal airtrapping showed negative correlations with static lung volumes (–0.27 to –0.37; p < 0.001) in all patients and moderate positive correlations with dynamic parameters (0.3–0.4; p < 0.001) in patients with obstruction. No significant correlations were found with age, gender, and blood gas analysis. Visual assessment of focal – not diffuse – airtrapping at expiratory high-resolution CT does not correlate with physiological evidence of obstruction as derived from pulmonary function tests since the perception of focal airtrapping requires an adequate expiratory increase in lung density.