Polymorphisms in the apoptotic pathway gene BCL-2 and survival in small cell lung cancer.

INTRODUCTION: We investigated the single-nucleotide polymorphism C-938A in the apoptotic gene BCL-2 to assess the potential impact as a genetic marker for response to chemotherapy and outcome prediction in small cell lung cancer (SCLC) patients. Such a marker might help optimize lung cancer treatment in a tailored approach. METHODS: DNA derived from peripheral blood lymphocytes of 188 Caucasian SCLC patients treated at the Thoraxklinik Heidelberg was genotyped. Chemotherapy response, time to progression (TTP), and overall survival (OS) were evaluated using multivariable regression (unconditional logistic for response and Cox proportional hazard for TTP and OS) with odds ratios and hazard ratios (HRs) and their 95% confidence intervals (CIs) as quantitative outcome measures, respectively. RESULTS: Small cell lung cancer patients carrying the BCL-2 -938CC genotype showed significantly worse TTP than patients carrying the BCL-2 -938AA genotype (HR = 1.86; 95% CI = 1.10-3.13, p = 0.021). The same adverse effect was shown for OS (HR = 2.38; 95% CI = 1.38-4.12, p = 0.002). Also, patients with limited disease (HR = 2.57; 95% CI = 1.18-5.60, p = 0.017) showed worse OS with the BCL-2 -938CC genotype. CONCLUSION: BCL-2 -938CC genotype shows significantly worse outcome in small cell lung cancer patients. This genetic marker might particularly impact on treatment strategies using BCL-2 antisense approaches.

Estimation of pulmonary motion in healthy subjects and patients with intrathoracic tumors using 3D-dynamic MRI: initial results.

OBJECTIVE: To estimate a new technique for quantifying regional lung motion using 3D-MRI in healthy volunteers and to apply the technique in patients with intra- or extrapulmonary tumors. MATERIALS AND METHODS: Intraparenchymal lung motion during a whole breathing cycle was quantified in 30 healthy volunteers using 3D-dynamic MRI (FLASH [fast low angle shot] 3D, TRICKS [time-resolved interpolated contrast kinetics]). Qualitative and quantitative vector color maps and cumulative histograms were performed using an introduced semiautomatic algorithm. An analysis of lung motion was performed and correlated with an established 2D-MRI technique for verification. As a proof of concept, the technique was applied in five patients with non-small cell lung cancer (NSCLC) and 5 patients with malignant pleural mesothelioma (MPM). RESULTS: The correlation between intraparenchymal lung motion of the basal lung parts and the 2D-MRI technique was significant (r = 0.89, p < 0.05). Also, the vector color maps quantitatively illustrated regional lung motion in all healthy volunteers. No differences were observed between both hemithoraces, which was verified by cumulative histograms. The patients with NSCLC showed a local lack of lung motion in the area of the tumor. In the patients with MPM, there was global diminished motion of the tumor bearing hemithorax, which improved significantly after chemotherapy (CHT) (assessed by the 2D- and 3D-techniques) (p < 0.01). Using global spirometry, an improvement could also be shown (vital capacity 2.9 +/- 0.5 versus 3.4 L +/- 0.6, FEV1 0.9 +/- 0.2 versus 1.4 +/- 0.2 L) after CHT, but this improvement was not significant. CONCLUSION: A 3D-dynamic MRI is able to quantify intraparenchymal lung motion. Local and global parenchymal pathologies can be precisely located and might be a new tool used to quantify even slight changes in lung motion (e.g. in therapy monitoring, follow-up studies or even benign lung diseases).

Polymorphisms in ABCG2, ABCC3 and CNT1 genes and their possible impact on chemotherapy outcome of lung cancer patients.

The prognosis of lung cancer patients treated with chemotherapy is poor, motivating the search for predictive factors. Single nucleotide polymorphisms (SNPs) in membrane transporter genes could influence the pharmacokinetics of cytostatic drugs and therefore affect treatment outcome. We examined 6 SNPs with known or suspected phenotypic effect: ABCG2 G34A, C421A; ABCC3 C-211T, G3890A, C3942T and CNT1 G565A. For 349 Caucasian patients with primary lung cancer [161 small cell lung cancer (SCLC), 187 nonsmall cell lung cancer (NSCLC) and 1 mixed] receiving first-line chemotherapy 3 different endpoints were analyzed: response after the 2nd cycle (R), progression-free survival (PFS) and overall survival (OS). The prognostic value of the SNPs was analyzed using multivariable logistic regression, calculating odds ratios (ORs) when comparing genotype frequencies in responders and nonresponders after the 2nd cycle. Hazard ratios (HRs) for PFS and for OS were calculated using Cox regression methods. In all lung cancer patients, none of the investigated polymorphisms modified response statistically significant. The only significant result in the histological subpopulations was in SCLC patients carrying the ABCC3 -211T allele who showed significantly worsened PFS (HR: 1.79; 95% confidence interval (CI) 1.13-2.82). In an exploratory subgroup analysis significantly worse OS was seen for carriers of the ABCG2 421A-allele treated with platinum-based drugs (HR: 1.60; 95% CI 1.04-2.47; n = 256). In conclusion, this study prioritizes ABCC3 C-211T and ABCG2 C421A as candidate transporter SNPs to be further investigated as possible predictors of the clinical outcome of chemotherapy in lung cancer patients.

Assessment of morphological MRI for pulmonary changes in cystic fibrosis (CF) patients: comparison to thin-section CT and chest x-ray.

OBJECTIVES: As pulmonary complications are life limiting in patients with cystic fibrosis (CF), repeated chest imaging [chest x-ray, computed tomography (CT)] is needed for follow up. With the continuously rising life expectancy of CF patients, magnetic resonance imaging (MRI) as a radiation-free imaging modality might become more and more attractive. The goal of this study was to prospectively assess the value of MRI for evaluation of morphologic pulmonary CF-changes in comparison to established imaging modalities. MATERIALS AND METHODS: Thirty-one CF patients (19 female, 12 male; mean age 16.7 years) with stable lung disease were examined by MRI: HASTE, coronal/transversal (TR/TE/alpha/TA: infinite/28 ms/180 degrees /18 s), multi-detector computed tomography (MDCT) (30 patients): 120 kV, dose modulated mAs, and chest x-ray (21 patients). Image evaluation: random order, 4 chest radiologists in consensus; chest x-ray: modified Chrispin-Norman score; CT and MRI: modified Helbich score. The maximal attainable score for chest x-ray was 34, for MRI and CT 25. Median scores, Pearson correlation coefficients, Bland-Altman plots, and concordance of MRI to CT on a lobar and segmental basis were calculated. RESULTS: The median MRI and MDCT scores were 13 (min 3, max 20) respectively 13.5 (min 0, max 20). The median chest x-ray score was 14 (min 5, max 32). Pearson correlation coefficients: MRI/CT = 0.80, P < 0.0001; MRI/chest x-ray = 0.63, P < 0.0018; chest x-ray/CT = 0.75, P < 0.0001. The median lobe related concordance was 80% for bronchiectasis, 77% for mucus plugging, 93%, for sacculation/abscesses, and 100% for collapse/consolidation. CONCLUSIONS: Morphologic MRI of the lung in CF patients demonstrates comparable results to MDCT and chest x-ray. Because radiation exposure is an issue in CF patients, MRI might have the ability to be used as an appropriate alternative method for pulmonary imaging.

Proton MRI appearance of cystic fibrosis: comparison to CT.

Cystic fibrosis (CF) is the most frequent inherited disorder leading to premature death in the Caucasian population. As life expectancy is limited by pulmonary complications, repeated imaging [chest X-ray, multislice high-resolution computed tomography (MS-HRCT)] is required in the follow-up. Magnetic resonance imaging (MRI) of the lung parenchyma is a promising new diagnostic tool. Its value for imaging lung changes caused by CF compared with CT is demonstrated. MRI performs well when compared with CT, which serves as the gold standard. Its lack in spatial resolution is obvious, but advantages in contrast and functional assessment compensate for this limitation. Thus, MRI is a reasonable alternative for imaging the CF lung and should be introduced as a radiation-free modality for follow-up studies in CF patients. For further evaluation of the impact of MRI, systematic studies comparing MRI and conventional imaging modalities are necessary. Furthermore, the value of the additional functional MRI (fMRI) information has to be studied, and a scoring system for the morphological and functional aspect of MRI has to be established.

Assessment of differential pulmonary blood flow using perfusion magnetic resonance imaging: comparison with radionuclide perfusion scintigraphy.

OBJECTIVES: We sought to assess the agreement between lung perfusion ratios calculated from pulmonary perfusion magnetic resonance imaging (MRI) and those calculated from radionuclide (RN) perfusion scintigraphy. MATERIALS AND METHODS: A retrospective analysis of MR and RN perfusion scans was conducted in 23 patients (mean age, 60 +/- 14 years) with different lung diseases (lung cancer = 15, chronic obstructive pulmonary disease = 4, cystic fibrosis = 2, and mesothelioma = 2). Pulmonary perfusion was assessed by a time-resolved contrast-enhanced 3D gradient-echo pulse sequence using parallel imaging and view sharing (TR = 1.9 milliseconds; TE = 0.8 milliseconds; parallel imaging acceleration factor = 2; partition thickness = 4 mm; matrix = 256 x 96; in-plane spatial resolution = 1.87 x 3.75 mm; scan time for each 3D dataset = 1.5 seconds), using gadolinium-based contrast agents (injection flow rate = 5 mL/s, dose = 0.1 mmol/kg of body weight). The peak concentration (PC) of the contrast agent bolus, the pulmonary blood flow (PBF), and blood volume (PBV) were computed from the signal-time curves of the lung. Left-to-right ratios of pulmonary perfusion were calculated from the MR parameters and RN counts. The agreement between these ratios was assessed for side prevalence (sign test) and quantitatively (Deming-regression). RESULTS: MR and RN ratios agreed on side prevalence in 21 patients (91%) with PC, in 20 (87%) with PBF, and in 17 (74%) with PBV. The MR estimations of left-to-right perfusion ratios correlated significantly with those of RN perfusion scans (P < 0.01). The correlation was higher using PC (r = 0.67) and PBF (r = 0.66) than using PBV (r = 0.50). The MR ratios computed from PBF showed the highest accuracy, followed by those from PC and PBV. Independently from the MR parameter used, in some patients the quantitative difference between the MR and RN ratios was not negligible. CONCLUSIONS: Pulmonary perfusion MRI can be used to assess the differential blood flow of the lung. Further studies in a larger group of patients are required to fully confirm the clinical suitability of this imaging method.

Contrast-enhanced 3D MRI of lung perfusion in children with cystic fibrosis--initial results.

This paper is a feasibility study of magnetic resonance imaging (MRI) of lung perfusion in children with cystic fibrosis (CF) using contrast-enhanced 3D MRI. Correlation assessment of perfusion changes with structural abnormalities. Eleven CF patients (9 f, 2 m; median age 16 years) were examined at 1.5 T. Morphology: HASTE coronal, transversal (TR/TE/alpha/ST: 600 ms/28 ms/180 degrees /6 mm), breath-hold 18 s. Perfusion: Time-resolved 3D GRE pulse sequence (FLASH, TE/TR/alpha: 0.8/1.9 ms/40 degrees ), parallel imaging (GRAPPA, PAT 2). Twenty-five data sets were acquired after intravenous injection of 0.1 mmol/kg body weight of gadodiamide, 3-5 ml/s. A total of 198 lung segments were analyzed by two radiologists in consensus and scored for morphological and perfusion changes. Statistical analysis was performed by Mantel-Haenszel chi-square test. Results showed that perfusion defects were observed in all patients and present in 80% of upper, and 39% of lower lobes. Normal lung parenchyma showed homogeneous perfusion (86%, P<0.0001). Severe morphological changes led to perfusion defects (97%, P<0.0001). Segments with moderate morphological changes showed normal (53%) or impaired perfusion (47%). In conclusion, pulmonary perfusion is easy to judge in segments with normal parenchyma or severe changes. In moderately damaged segments, MRI of lung perfusion may help to better assess actual functional impairment. Contrast-enhanced 3D MRI of lung perfusion has the potential for early vascular functional assessment and therapy control in CF patients.

Monitoring of lung motion in patients with malignant pleural mesothelioma using two-dimensional and three-dimensional dynamic magnetic resonance imaging: comparison with spirometry.

PURPOSE: To monitor lung motion in patients with malignant pleural mesothelioma (MPM) before and after chemotherapy (CHT) using 2-dimensional (2D) and 3-dimensional (3D) dynamic MRI (dMRI) in comparison with spirometry. METHODS AND MATERIALS: Twenty-two patients with MPM were examined before CHT, as well as after 3 and 6 CHT cycles (3 months and 6 months) using 2D dMRI (trueFISP; 3 images/s) and 3D dMRI (FLASH 3D, 1 slab (52 slices)/s) using parallel imaging in combination with view-sharing technique. Maximum craniocaudal lung dimensions (2D) and lung volumes (3D) were monitored, separated into the tumor-bearing and nontumor-bearing hemithorax. Vital capacity (VC) was measured for comparison using spirometry. RESULTS: Using 2D technique, there was a significant difference between the tumor-bearing and the nontumor-bearing hemithorax before CHT (P < 0.01) and after 3 CHT cycles (P < 0.05), whereas difference was not significant in the second control. In the tumor-bearing hemithorax, mobility increased significantly from the status before versus after 3 CHT cycles (4.1 +/- 1.1 cm vs. 4.8 +/- 1.4 cm, P < 0.05). Using 3D technique, at maximum inspiration, the volume of the tumor-bearing hemithorax was 0.6 +/- 0.4 L and of the nontumor-bearing hemithorax 1.25 +/- 0.4 L before CHT. In the follow-up exams, these volumes changed to 1.05 +/- 0.4 L (P < 0.05) and 1.4 +/- 0.5 L, respectively. Using spirometry, there was no significant change in VC (1.9 +/- 0.4 L vs. 2.2 +/- 0.7 L vs. 2.2 +/- 0.9 L). CONCLUSION: dMRI is capable of monitoring changes in lung motion and volumetry in patients with MPM not detected by global spirometry. Thus, dMRI is proposed for use as a further measure of therapy response.

Therapy monitoring using dynamic MRI: analysis of lung motion and intrathoracic tumor mobility before and after radiotherapy.

A frequent side effect after radiotherapy of lung tumors is a decrease of pulmonary function accompanied by dyspnea due to developing lung fibrosis. The aim of this study was to monitor lung motion as a correlate of pulmonary function and intrathoracic tumor mobility before and after radiotherapy (RT) using dynamic MRI (dMRI). Thirty-five patients with stage I non-small-cell lung carcinoma were examined using dMRI (trueFISP; three images/s). Tumors were divided into T1 and T2 tumors of the upper, middle and lower lung region (LR). Maximum craniocaudal (CC) lung dimensions and tumor mobility in three dimensions were monitored. Vital capacity (VC) was measured and correlated using spirometry. Before RT, the maximum CC motion of the tumor-bearing hemithorax was 5.2 +/- 0.9 cm if the tumor was located in the lower LR (middle LR: 5.5 +/- 0.8 cm; upper LR: 6.0 +/- 0.6 cm). After RT, lung motion was significantly reduced in the lower LR (P < 0.05). Before RT, the maximum CC tumor mobility was significantly higher in tumors of the lower LR 2.5 +/- 0.6 vs. 2.0 +/- 0.3 cm (middle LR; P < 0.05) vs. 0.7 +/- 0.2 cm (upper LR; P < 0.01). After RT, tumor mobility was significantly reduced in the lower LR (P < 0.01) and in T2 tumor patients (P < 0.05). VC showed no significant changes. dMRI is capable of monitoring changes in lung motion that were not suspected from spirometry. This might make the treatment of side effects possible at a very early stage. Changes of lung motion and tumor mobility are highly dependent on the tumor localization and tumor diameter.

The role of new imaging techniques in diagnosis and staging of malignant pleural mesothelioma.

This review highlights the different imaging modalities for the detection of malignant pleural mesothelioma. The chest film is the initial diagnostic tool of choice because it is easy to perform, inexpensive, and widely available. Unfortunately, it demonstrates malignant pleural mesothelioma in later stages of disease and is not suitable for an early sensitive and specific diagnosis. Computed tomography is capable of distinguishing the different forms of pleural abnormalities. The knowledge of computed tomography findings is important for differentiation of malignant pleural diseases from benign diseases. Contrast-enhanced magnetic resonance imaging in three planes can be clinically useful to differentiate pleural mesothelioma from other malignancies or from benign pleural diseases. Furthermore, magnetic resonance imaging offers the possibility to differentiate invasion of the diaphragm from transdiaphragmatic tumor growth, and, in patients who are surgical candidates and who have questionable areas of local tumor extension on computed tomography, magnetic resonance imaging may provide additional information to plan or avoid surgery. Improvements in the detection of regional and distant metastases are needed to identify patients most likely to benefit from aggressive combined modality treatment regimes. In this context, positron emission tomography is a metabolic imaging technique that offers the possibility to evaluate active malignant cells. Drawbacks to this technique include false-positive findings, which may occur at sides of inflammation, and lesser anatomic detail information. A complete and accurate staging of malignant pleural mesothelioma is essential to evaluate the efficacy of new therapeutic strategies. This implies the need to be familiar with the most recently developed staging system from the International Mesothelioma Interest Group.