A Phase II Study of the Central European Society of Anticancer-Drug Research (CESAR) Group: Results of an Open-Label Study of Gemcitabine plus Cisplatin with or without Concomitant or Sequential Gefitinib in Patients with Advanced or Metastatic Transitional Cell Carcinoma of the Urothelium.

INTRODUCTION: This phase II trial evaluated the efficacy and safety of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib, in combination with first-line chemotherapy in advanced urothelial cancer. METHODS: Chemotherapy-naïve patients with advanced or metastatic urothelial carcinoma were randomized 1:1:1 to receive six cycles of chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8, and cisplatin 70 mg/m2 on day 1 of every cycle) concomitantly with gefitinib 250 mg/day (arm A); or with sequential gefitinib (arm B); or alone (arm C). The primary endpoint was the time to progression (TTP). RESULTS: A total of 105 patients received study treatment. Median TTP for arms A, B, and C were 6.1, 6.3, and 7.8 months, respectively. There were no significant differences between treatment arms for any outcomes measured. The most common adverse events were nausea and vomiting. CONCLUSION: Gefitinib in combination with chemotherapy did not improve efficacy in advanced urothelial cancer.

Impact and safety of adjuvant chemotherapy on pulmonary function in early stage non-small cell lung cancer.

BACKGROUND: Pulmonary function may decline after induction chemotherapy and predict perioperative complications in non-small cell lung cancer (NSCLC). The influence of adjuvant chemotherapy is largely indeterminate. OBJECTIVE: To assess whether adjuvant chemotherapy alters pulmonary function and impacts on treatment-related adverse events. METHODS: In a trial on adjuvant chemotherapy (the TREAT trial), 132 patients with R0-resected NSCLC were randomised to 4 cycles of cisplatin-vinorelbine (CVb, n = 65) or cisplatin-pemetrexed (CPx, n = 67). Pulmonary function tests (forced expiratory volume in 1 s, FEV1, forced vital capacity, FVC, total lung capacity, TLC, diffusing capacity for carbon monoxide, DLCO, and blood gas analyses, BGA) were analysed before and 30 days after the last chemotherapy, and changes were calculated (Δ = mean differences). RESULTS: Overall, FVC increased significantly (Δ +290 ml, n = 76; p < 0.0001), while TLC did not change (Δ +220 ml, n = 41; p = 0.174). For CPx, FEV1 increased significantly (Δ +150 ml, n = 47; p = 0.0017), but not for CVb (Δ +30 ml, n = 30). DLCO decreased only for CVb (-8%, n = 6) but not for CPx (-0.39%, n = 17; p = 0.58). BGA did not change (p = 0.99). In a Cox regression analysis, baseline pulmonary function did not influence treatment failure. CONCLUSIONS: Adjuvant chemotherapy seems not to result in a decrease of pulmonary function parameters. A significant FVC increase was probably due to ongoing postoperative improvement. Decline of DLCO was noted with CVb but not with CPx. Pulmonary function does not impact on treatment failure.

Differential effects of CLDR and PDR brachytherapy on cell cycle progression in a syngeneic rat prostate tumour model.

PURPOSE: The study consisted of two treatment arms comparing the effects of CLDR (continuous low dose rate) and PDR (pulsed dose rate) brachytherapy on cell cycle progression in a radioresistant rat prostate tumour model. MATERIALS AND METHODS: Interstitial PDR and CLDR brachytherapy (both 192-Ir, 0.75 Gy/h) were administered to Dunning prostate R3327-AT1 carcinomas transplanted subcutaneously into the thigh of Copenhagen rats. Increasing doses of up to 20 as well as up to 40 Gy were applied. Cell cycle distributions of the aneuploid tumour cell subpopulations were determined at 4 h (3 Gy), 24 h (18 Gy), 48 h (20 and 36 Gy), as well as during the subsequent redistribution period (20 and 40 Gy) at 72, 96, and 120 h. Tumours either implemented with an empty tubing system (n=5) or under undisturbed growth (n=5) served as controls. Three animals were irradiated per time point and exposure condition. At least two flow cytometrical analyses were carried out per animal. RESULTS: The aneuploid cells possessed a constant DNA-Index of 1.9+/-0.06. In contrast to sham-treated controls, the aneuploid cell fraction with G2/M DNA content was significantly increased (p<0.05) after initiation of both, CLDR and PDR brachytherapy. However, CLDR resulted in an earlier accumulation of tumour cells in G2/M (24 h: 28% CLDR vs. 19% PDR, p<0.05) with a concomitant reduction of cells in G1, whereas PDR yielded delayed, but then more pronounced cell cycle changes, particularly expressed during the redistribution period after both 20 and 40 Gy. CONCLUSION: CLDR and PDR brachytherapy showed differential effects on cell cycle progression. The induction of a significantly earlier but also less persistent G2/M cell cycle arrest after CLDR compared to PDR brachytherapy implies that a substantially higher fraction of tumour cells are irradiated in G2/M after CLDR.

Influence of different breathing maneuvers on internal and external organ motion: use of fiducial markers in dynamic MRI.

PURPOSE: To investigate, with dynamic magnetic resonance imaging (dMRI) and a fiducial marker, the influence of different breathing maneuvers on internal organ and external chest wall motion. METHODS AND MATERIALS: Lung and chest wall motion of 16 healthy subjects (13 male, 3 female) were examined with real-time trueFISP (true fast imaging with steady-state precession) dMRI and a small inductively coupled marker coil on either the abdomen or thorax. Three different breathing maneuvers were performed (predominantly "abdominal breathing," "thoracic breathing," and unspecific "normal breathing"). The craniocaudal (CC), anteroposterior (AP), and mediolateral (ML) lung distances were correlated (linear regression coefficient) with marker coil position during forced and quiet breathing. RESULTS: Differences of the CC distance between maximum forced inspiration and expiration were significant between abdominal and thoracic breathing (p < 0.05). The correlation between CC distance and coil position was best for forced abdominal breathing and a marker coil in the abdominal position (r = 0.89 +/- 0.04); for AP and ML distance, forced thoracic breathing and a coil in the thoracic position was best (r = 0.84 +/- 0.03 and 0.82 +/- 0.03, respectively). In quiet breathing, a lower correlation was found. CONCLUSION: A fiducial marker coil external to the thorax in combination with dMRI is a new technique to yield quantitative information on the correlation of internal organ and external chest wall motion. Correlations are highly dependent on the breathing maneuver.

Improved vascular opacification in cerebral computed tomography angiography with 80 kVp.

PURPOSE: We sought to intraindividually compare computed tomography angiographies (CTAs) acquired at 80 kVp and 120 kVp with respect to vessel contrast, noise level, and radiation dose. MATERIAL AND METHODS: CTA was performed on a single-slice CT scanner using tube voltages of 80 kVp and 120 kVp in 29 patients with arteriovenous malformations. Mean Hounsfield Units (HU) were evaluated for different vessels and brain parenchyma. To determine contrast-to-noise ratios (CNRs), noise levels were estimated from phantom measurements. RESULTS: The calculated effective dose to male/female patients was 0.4/0.5 mSv for 80 kVp and 0.7/0.8 mSv for 120 kVp. CT density in blood vessels was between 297 and 458 HU for 80 kVp and 152 and 229 HU for 120 kVp (P<0.0001). Despite an increased noise level in the low-voltage images, the CNR was 26-59% higher at 80 kVp than at 120 kVp (P<0.05). CONCLUSION: The use of a reduced tube potential leads to improved CNR in CTA of the cerebral vasculature and a markedly reduced radiation exposure to patients.

Focal gene induction in the liver of rats by a heat-inducible promoter using focused ultrasound hyperthermia: preliminary results.

OBJECTIVE: We sought to examine high-intensity focused ultrasound (HIFU)-induced hyperthermia in the liver of a rat model to focally induce green-fluorescent protein (GFP). MATERIALS AND METHODS: A total of 25 Copenhagen rats were included in this study. Rats were divided into groups treated with an adenovirus coding for green fluorescent protein (GFP) under the control of a hsp70B promoter and a CMV promoter. Ad-CMV-GFP-treated rats served as positive control. Untreated controls only subjected to MRI +/- HIFU-treatment served to find out optimal power of HIFU in the target area of the liver. Temperature was noninvasively monitored by temperature sensitive magnetic resonance imaging (MRI). RESULTS: Rats treated with Ad-hsp70B-GFP demonstrated localized gene induction within the liver parenchyma, in good correlation with MRI and histology. Applying an acoustic power of 1.92 W a relatively uniform focal temperature up to 42 +/- 5 degrees C within the liver parenchyma could be documented. 3 x 10(9) plaque-forming units proved to account for a very homogeneous liver infection. Number of fluorescent cells in the region of hyperthermia was similar to the control group treated with Ad-CMV-GFP. CONCLUSION: Using the introduced parameters spatially controlled gene induction within a parenchymal organ such as the liver in rats using HIFU under control of MRI is feasible.

Computer-assisted quantitative assessment of power Doppler US: effects of microbubble contrast agent in the differentiation of breast tumors.

RATIONALE AND OBJECTIVES: To objectively quantify the effects of a microbubble contrast agent to differentiate breast tumors with power doppler ultrasound and to compare these results with color doppler ultrasound (CD US). METHODS: In 47 patients a microbubble contrast agent was injected intravenously. Computer-assisted quantitative assessment of the color pixel density was performed to evaluate the increase in Doppler signals. Results were compared to previously published results of a color Doppler ultrasound study. RESULTS: Peak color pixel density at contrast-enhanced power Doppler ultrasound was higher for carcinomas than for benign tumors (P < 0.03). Time to peak enhancement was shorter in carcinomas than in benign tumors (P < 0.01). For both parameters, diagnostic accuracy of power Doppler ultrasound was 69 and 78%, and for color Doppler ultrasound 62 and 76%, respectively. CONCLUSIONS: Quantitative assessment of contrast-enhanced power Doppler ultrasound showed significant differences in malignant and benign breast tumors. Diagnostic accuracy of contrast-enhanced power Doppler ultrasound was higher compared to color Doppler ultrasound.

External beam radiotherapy in the treatment of male breast carcinoma: patterns of failure in a single institute experience.

AIMS AND BACKGROUND: We analyzed our own results in the treatment of male breast cancer patients with respect to local control, overall survival and possible prognostic factors for local and distant control. METHODS: Thirty-one patients with 32 carcinomas of the male breast were treated with radiotherapy. Twenty-five patients received radiotherapy to the chest wall including or not regional lymphatics after initial mastectomy (n = 23) or after surgery for local recurrence (n = 2). Median total dose was 60 Gy to the chest wall and 46 Gy to regional lymphatics. Seven patients with metastatic disease were referred for palliative radiotherapy. RESULTS: Overall survival after postoperative radiotherapy was 40% after a median follow-up of 4.3 years. Actuarial 3-, 5- and 10-year survival was 82.6%, 56.5% and 43.5%, respectively. Five-year progression-free survival was 62.5%. Survival was significantly affected by the presence of lymph node metastases (P <0.001). Local recurrence was seen in one patient after 29 months. CONCLUSIONS: Postoperative radiotherapy is important in the management of male breast cancer to improve local control and progression-free survival, resulting in one local failure in our analysis. The presence of lymph node metastases significantly impairs survival.

Evaluation of therapeutic potential of heavy ion therapy for patients with locally advanced prostate cancer.

PURPOSE: To investigate the feasibility of raster scanned heavy charged particle therapy in the treatment of prostate cancer (PCa,) with special regard to the influence of internal organ motion on the dose distribution. METHODS AND MATERIALS: The CT data of 8 patients with PCa who underwent three-dimensional conformal radiotherapy (RT) were chosen. In addition to the routine treatment planning scan, three to five additional positioning control CT scans were performed. The organs at risk and the target volumes were defined on all CT scans. Primary and boost carbon ion plans were calculated to deliver 66 Gy to the clinical target volume/planning target volume, with an additional 10 Gy to the gross tumor volume (GTV). To estimate the influence of internal organ motion on plan quality, the dose was recalculated on the basis of the control CT scans. The comparative analysis was based on the dose-volume histogram-derived physical parameters. RESULTS: The average 90% target coverage was 99.1% for the GTV. The maximal dose to the rectum was 71.8 Gy. The average rectal mean dose was 19 Gy. The volume of the rectum receiving 70 and 68 Gy was 0.1 and 0.3 cm3. The average difference in the 90% coverage for the GTV on control CT cubes was 3.6%. The maximal rectal dose increased to 76.2 Gy. The deviation in the mean rectal dose was <1 Gy on average. The rectal volume receiving 70 and 68 Gy increased to 2.5 and 3.3 cm3. CONCLUSION: The investigation demonstrated the feasibility of raster scanned carbon ions for PCa RT. Excellent coverage of the target volume and optimal sparing of the rectum were acquired. The combination of photon intensity-modulated RT and a carbon ion boost to the GTV is the most rational solution for the gain of clinical experience in heavy ion RT for PCa patients.

Fractionated stereotactic radiotherapy in low-grade astrocytomas: long-term outcome and prognostic factors.

PURPOSE: To evaluate outcome after fractionated stereotactic radiotherapy (RT) of patients with World Health Organization Grade 2 astrocytoma in terms of progression-free survival, overall survival, toxicity, quality of life, and prognostic factors. METHODS AND MATERIALS: Between 1984 and 2000, 143 patients with histologically proven Grade 2 astrocytoma were treated with fractionated stereotactic RT at our institution. The evaluation of the quality of life and toxicity was based on neurologic examinations and the Karnofsky performance score. Univariate analysis was performed on seven potential prognosticators and multivariate analysis on four prognosticators. RESULTS: The median follow-up was 44 months. The actuarial overall survival and progression-free survival was 58% and 39% at 5 years, respectively. Out-of-field recurrences occurred in 1 patient (1.2%). We did not observe a dose-response relationship. Overall survival and progression-free survival were significantly correlated with the absence of contrast media enhancement before RT (p <0.01). Toxicity was mild and included severe side effects of European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group Grade 3 in only 4 patients (2.8%). The Karnofsky performance score improved in most patients. CONCLUSION: Fractionated stereotactic RT is effective and has low toxicity in the treatment of Grade 2 gliomas. The rate of field border recurrences was not increased compared with after conventional RT. Exceeding the tumor dose did not improve the tumor control rate but did enhance toxicity. Pretherapeutic contrast media enhancement should be interpreted as a sign of higher grade tumor elements.

Measurement of tumor diameter-dependent mobility of lung tumors by dynamic MRI.

BACKGROUND AND PURPOSE: To assess the influence of tumor diameter on tumor mobility and motion of the tumor bearing hemithorax during the whole breathing cycle in patients with stage I non-small-cell lung cancer (NSCLC) using dynamic MRI. PATIENTS AND METHODS: Breathing cycles of thirty-nine patients with solitary NSCLCs were examined using a trueFISP sequence (three images per second). Patients were divided into three groups according to the maximal tumor diameter in the transverse plane (<3, 3-5 and >5 cm). Continuous time-distance curves and deep inspiratory and expiratory positions of the chest wall, the diaphragm and the tumor were measured in three planes. Motion of tumor-bearing and corresponding contralateral non-tumor bearing regions was compared. RESULTS: Patients with a tumor >3 cm showed a significantly lower diaphragmatic motion of the tumor bearing compared with the non-tumor bearing hemithorax in the craniocaudal (CC) directions (tumors 3-5 cm: 23.4+/-1.2 vs 21.1+/-1.5 cm (P<0.05); tumors >5 cm: 23.4+/-1.2 vs 20.1+/-1.6 cm (P<0.01). Tumors >5 cm in the lower lung region showed a significantly lower mobility compared with tumors <3 cm (1.8+/-1.0 vs 3.8+/-0.7 cm, P<0.01) in the CC directions. CONCLUSIONS: Dynamic MRI is a simple non-invasive method to differentiate mobility of tumors with different diameters and its influence on the surrounding tissue. Tumor diameter has a significant influence on tumor mobility and this might be taken into account in future radiotherapy planning.

Treatment of brain metastases in patients with non-small cell lung cancer (NSCLC) by stereotactic linac-based radiosurgery: prognostic factors.

A restrospective study of patients with brain metastases from non-small cell lung cancer (NSCLC) is performed to identify patients who benefit from radiosurgery and to determine prognostic factors for survival. Eighty-six consecutive patients with a total of 110 brain metastases from NSCLC were treated with linac-based radiosurgery. Six patients with eight brain metastases who received radiosurgery as a focal boost to whole brain radiotherapy where excluded. Median age at treatment was 60 years. Median dose was 20 Gy/80%-isodose. A chi(2)-test was used to identify potential prognostic factors for local control of brain metastases and survival of the patients. Median follow-up was 6 months (range 1 1/2-77 months) with 17/80 patients still alive. Median actuarial survival was significantly longer (P<0.004) in patients with metachronous onset of brain metastases in comparison to synchronous onset (8.3 vs. 3.3 months). Survival was significantly increased after radiosurgery in the absence of extracranial tumor progression (P<0.03). Eleven patients (14%) developed new brain metastases after radiosurgery after a latency of median 5 months. Actuarial local control rate was 96% after 3 months. Local control was significantly increased with a prescribed dose > or=18 Gy/80%-isodose (P<0.01). We conclude that especially patients with poor prognostic factors and a limited number of brain metastases may be palliatively treated with radiosurgery alone. This approach allows to effectively control CNS manifestation of the disease and can be integrated into chemotherapeutic protocols.

Evaluation of chest motion and volumetry during the breathing cycle by dynamic MRI in healthy subjects: comparison with pulmonary function tests.

RATIONALE AND OBJECTIVES: To investigate diaphragm and chest wall motion during the whole breathing cycle using magnetic resonance imaging (MRI) and a volumetric model in correlation with spirometry. MATERIALS AND METHODS: Breathing cycles of 15 healthy volunteers were examined using a trueFISP sequence (5 slices in 3 planes, 3 images per second). Time-distance curves were calculated and correlated to spirometry. A model for vital capacity (VC), continuous time-dependent vital capacity (tVC), and investigating the influence of horizontal and vertical parameters on tVC was introduced. RESULTS: Time-distance curves of the breathing cycle using MRI correlated highly significant with spirometry (P < 0.0001). VC calculated by the model was similar to VC measured in spirometry (5.00 L vs. 5.15 L). tVC correlated highly significantly with spirometry (P < 0.0001). Vertical parameters had a more profound influence on tVC change than horizontal parameters. CONCLUSIONS: Dynamic MRI is a simple noninvasive method to evaluate local chest wall motion and respiratory mechanics. It widens the repertoire of tools for lung examination with a high temporal resolution.

Contrast-enhanced three-dimensional pulmonary perfusion magnetic resonance imaging: intraindividual comparison of 1.0 M gadobutrol and 0.5 M Gd-DTPA at three dose levels.

RATIONALE AND OBJECTIVES: To compare 1.0 M gadobutrol and 0.5 M Gd-DTPA for contrast-enhanced three-dimensional pulmonary perfusion magnetic resonance imaging (3D MRI). MATERIALS AND METHODS: Ten healthy volunteers (3 females; 7 males; median age, 27 years; age range, 18-31 years) were examined with contrast-enhanced dynamic 3D MRI with parallel acquisition technique (FLASH 3D; reconstruction algorithm: generalized autocalibrating partially parallel acquisitions; acceleration factor: 2; TE/TR/alpha: 0.8/1.9 milliseconds/40 degrees; FOV: 500 x 375 mm; matrix: 256 x 86; slab thickness: 180 mm; 36 partitions; voxel size: 4.4 x 2 x 5 mm; TA: 1.48 seconds). Twenty-five consecutive data sets were acquired after intravenous injection of 0.025, 0.05, and 0.1 mmol/kg body weight of gadobutrol and Gd-DTPA. Quantitative measurements of peak signal-to-noise ratios (SNR) of both lungs were performed independently by 3 readers. Bolus transit times through the lungs were assessed from signal intensity time curves. RESULTS: The peak SNR in the lungs was comparable between gadobutrol and Gd-DTPA at all dose levels (15.7 vs. 15.5 at 0.1 mmol/kg bw; 12.9 vs. 12.5 at 0.05 mmol/kg bw; 7.6 vs. 8.9 at 0.025 mmol/kg bw). A dose of 0.1 mmol/kg achieved the highest peak SNR compared with all other dose levels (P < 0.05). A higher peak SNR was observed in gravity dependent lung (P < 0.05). Despite different injection volumes, transit times of the contrast bolus did not differ between both agents. CONCLUSION: Higher concentrated gadolinium chelates offer no advantage over standard 0.5 M Gd-DTPA for contrast-enhanced 3D MRI of lung perfusion.

Asbestos-related pleural disease: value of dedicated magnetic resonance imaging techniques.

OBJECTIVES: We sought to compare respiratory-gated high-spatial resolution magnetic resonance imaging (MRI) and radial MRI with ultra-short echo times with computed tomography (CT) in the diagnosis of asbestos-related pleural disease. METHODS: Twenty-one patients with confirmed long-term asbestos exposure were examined with a CT and a 1.5-T MR unit. High-resolution respiratory-gated T2w turbo-spin-echo (TSE), breath-hold T1w TSE, and contrast-enhanced fat-suppressed breath-hold T1w TSE images with an inplane resolution of less than 1 mm were acquired. To visualize pleural plaques with a short T2* time, a pulse sequence with radial k-space-sampling was used (TE = 0.5 milliseconds) before and after administration of Gd-DTPA. CT and MR images were assessed by 4 readers for the number and calcification of plaques, extension of pleural fibrosis, extrapleural fat, detection of mesothelioma and its infiltration into adjacent tissues, and detection of pleural effusion. Observer agreement was studied with the use of kappa statistics. RESULTS: The MRI protocol allowed for differentiation between normal pleura and pleura with plaques. Interobserver agreement was comparable for MRI and CT in detecting pleural plaques (median kappa = 0.72 for MRI and 0.73 for CT) and significantly higher with CT than with MRI for detection of plaque calcification (median kappa 0.86 for CT and 0.72 for MRI; P = 0.03). Median sensitivity of MRI was 88% for detection of plaque calcification compared with CT. For assessment of pleural thickening, pleural effusion, and extrapleural fat, interobserver agreement with MRI was significantly higher than with CT (median kappa 0.71 and 0.23 for pleural thickening, 0.87 and 0.62 for pleural effusion, and 0.7 and 0.56 for extrapleural fat, respectively; P < 0.05). For detection of mesothelioma, median kappa was 0.63 for MRI and 0.58 for CT. CONCLUSION: High-resolution MR sequences and radial MRI achieve a comparable interobserver agreement in detecting pleural plaques and even a higher interobserver agreement in assessing pleural thickening, pleural effusion, and extrapleural fat when compared with CT.

Assessment of irradiated brain metastases by means of arterial spin-labeling and dynamic susceptibility-weighted contrast-enhanced perfusion MRI: initial results.

RATIONALE AND OBJECTIVES: To assess if preradiation and early follow-up measurements of relative regional cerebral blood flow (rrCBF) can predict treatment outcome in patients with cerebral metastases and to evaluate rrCBF changes in tumor and normal tissue after stereotactic radiosurgery using arterial spin-labeling (ASL) and first-pass dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion MRI. METHODS: In 25 patients with a total of 28 brain metastases, DSC MRI and ASL perfusion MRI using the Q2TIPS sequence were performed with a 1.5-T unit. Measurements were performed prior to and at 6 weeks, 12 weeks, and 24 weeks after stereotactic radiosurgery. Follow-up examinations were completely available in 25 patients for Q2TIPS and 17 patients with 18 metastases for DSC MRI. The rrCBF of the metastases and the normal brain tissue was determined by a region-of-interest analysis. rrCBF values were correlated with the treatment outcome that was classified according to tumor volume changes at 6 months. RESULTS: The alteration of the rrCBF at the 6-week follow-up was highly predictive for treatment outcome. A decrease of the rrCBF value predicted tumor response correctly in all metastases for Q2TIPS and in 13 of 16 metastases for DSC MRI. The pretherapeutic rrCBF was not able to predict treatment outcome. The rrCBF values in normal brain tissue affected by radiation doses less than 0.5 Gy remained unchanged after therapy. CONCLUSION: These preliminary results suggest that ASL and DSC MRI techniques determining rrCBF changes in brain metastases after stereotactic radiosurgery allow the prediction of treatment outcome.

Comparison of arterial spin-labeling techniques and dynamic susceptibility-weighted contrast-enhanced MRI in perfusion imaging of normal brain tissue.

OBJECTIVES: To evaluate relative cerebral blood flow (rCBF) in normal brain tissue using arterial spin-labeling (ASL) methods and first-pass dynamic susceptibility-weighted contrast-enhanced (DSC) magnetic resonance imaging (MRI). METHODS: Sixty-two patients with brain metastases were examined on a 1.5 T-system up to 6 times during routine follow-up after stereotactic radiosurgery. Perfusion values in normal gray and white matter were measured using the ASL techniques ITS-FAIR in 38 patients, Q2TIPS in 62 patients, and the first-pass DSC echo-planar (EPI) MRI after bolus administration of gadopentetate dimeglumine in 42 patients. Precision of the ASL sequences was tested in follow-up examinations in 10 healthy volunteers. RESULTS: Perfusion values in normal brain tissue obtained by all sequences correlated well by calculating Pearson's correlation coefficients (P < 0.0001) and remained unchanged after stereotactic radiosurgery as shown by analysis of variance (P > 0.05). CONCLUSION: Both ASL and DSC EPI MRI yield highly comparable perfusion values in normal brain tissue.

Cytokine/chemokine messenger-RNA expression profiles in ulcerative colitis and Crohn's disease.

To define mediator profiles in inflamed and noninflamed areas in inflammatory bowel disease (IBD) we analyzed the expression of 35 messenger-RNAs (mRNAs) encoding cytokines, chemokines, and some related molecules in transmural gut tissues (n=138) from patients with ulcerative colitis (UC), Crohn's disease (CD), and inflammatory and normal controls by real-time quantitative reverse transcription polymerase chain reaction. Using sample collectives with a comparable degree of inflammation, most parameters investigated showed similarly increased mRNA expression levels in both active UC and CD. This included proinflammatory cytokines, but also interferon (IFN) gamma and several IFN-gamma inducible chemokines. Only macrophage inflammatory protein (MIP)-2alpha mRNA was expressed at higher levels in inflamed UC vs. CD. IH revealed that MIP-2alpha protein was produced mainly by intestinal epithelial cells. Importantly, in histologically noninflamed/inactive IBD samples mRNAs for several mediators were significantly enhanced, accompanied by elevated levels of migration-inhibition factor related protein (MRP) 14 transcripts. CD14 positive macrophages were found especially in noninflamed/inactive UC, many of which coexpressed the RFD-7 antigen. Our results indicate a substantial overlap in cytokine/chemokine mRNA expression in UC and CD. Elevated mediator expression is evident in noninflamed/inactive areas in both diseases. Local recruitment of MRP-14 positive leukocytes might contribute to this phenomenon. In inactive UC a phenotypically altered population of macrophages expressing CD14 might play an additional role.

Treatment of advanced gastric cancer with etoposide, folinic acid, and fluorouracil in the clinical setting: efficacy of therapy and value of serum tumor markers.

The combination of etoposide, folinic acid, and 5-fluorouracil (5-FU) (ELF regimen) has been proved to be an active chemotherapy in patients with advanced gastric cancer. The aim of this study was to confirm the efficacy in the clinical setting and to correlate response with different parameters like serum tumor markers. We treated 60 patients with advanced gastric cancer with 120 mg/m2 etoposide, 300 mg/m2 folinic acid, and 500 mg/m2 5-FU, on d 1-3. The cycle was repeated on d 21. Objective response was obtained in 23% of all patients with measurable disease. Stable disease was obtained in 37%. The tumor-growth-control rate in patients with proximal carcinoma was significantly higher than in those with distal carcinoma (85% vs 48%, p = 0.04). Median survival for all patients was 8.0 mo (95% confidence interval [CI] 7.0-8.5). In responsive patients, survival was more than two-fold longer than in patients with progressive disease. The administration of ELF could be performed safely on an outpatient basis. Toxicity was rather mild. The most frequently elevated serum tumor marker was CA 72-4 (55% of the patients). An elevated level of carcinoembryonic antigen before treatment was significantly correlated with progressive disease. A more than two-fold elevation of at least one marker under treatment was significantly correlated to progressive disease (p < 0.002). A reduction of at least one marker under treatment was significantly correlated to tumor growth control (p < 0.00015). The results of the present trial confirm the efficacy and low toxicity of the ELF regimen in advanced gastric carcinoma. Serum tumor markers proved suitable parameters for assessing response to treatment.

Multicenter randomized open-label phase III study comparing efficacy, safety, and tolerability of conventional carboplatin plus etoposide versus dose-intensified carboplatin plus etoposide plus lenograstim in small-cell lung cancer in "extensive disease" stage.

BACKGROUND: The combination of carboplatin and etoposide (CE) is one of the most effective regimens in the treatment of small-cell lung cancer (SCLC). The aim of this study was to investigate whether dose-intensified CE with the supplementation of granulocyte-colony-stimulating factor (G-CSF) is more effective than conventional CE in terms of survival with acceptable toxicity. METHODS: In a 2-arm multicentric prospective open label study, adult patients with SCLC in "extensive disease" stage were randomized either to conventional CE (carboplatin AUC 5 on day 1 IV and etoposide 140 mg/m IV on days 1-3, q28 days) or to dose-intensified therapy (carboplatin AUC 5 on day 1 IV and etoposide 190 mg/m days 1-3 IV with lenograstim 263 microg subcutaneously on days 4-13, q21 days). Primary end point was overall survival; secondary endpoints were toxicity, quality of life, and disease-free survival. RESULTS: Seventy-nine patients were included. Thirty-seven received conventional CE and 42 received the dose-intensified regimen. Median survival in the conventional group and the dose-intensified group were 11.2 months [confidence interval (CI) 9.1-15.2] and 11.7 months (CI 8.8-14.7), respectively. Progression-free survival was 6.7 (CI 5.8-7.5) and 7.4 months (CI 6.2-9.0), respectively. There was no statistically significant difference between these groups. Grade 3/4 neutropenia occurred in 69.4% in the conventional arm versus 37.5% in the dose-intensified group (P = 0.009). CONCLUSION: Dose-intense CE with GM-CSF support can be administered safely but does not prolong overall or progression-free survival compared with standard therapy.