Phase II trial of PTK787/ZK 222584 (vatalanib) administered orally once-daily or in two divided daily doses as second-line monotherapy in relapsed or progressing patients with stage IIIB/IV non-small-cell lung cancer (NSCLC).

BACKGROUND: The objective of this multicenter, prospective uncontrolled phase II trial was to determine efficacy, safety and tolerability of vatalanib, an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor receptors, in the second-line treatment of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC-proven tumor progression during or after one platinum-based chemotherapy regimen received a fixed dose of 1250 mg vatalanib either once-daily dosing (QD) or two divided daily dosing (TDD: 500 mg a.m. + 750 mg p.m.) until disease progression or unacceptable toxicity. Primary end point was the disease control rate (DCR) at 12 weeks. RESULTS: Fifty-four and 58 patients were enrolled to the QD and TDD arms. DCR at 12 weeks was 35% in the QD and 37% in the TDD arm. The best overall response included one (2%) patient with confirmed partial response with QD and three (5%) with TDD. Median progression-free survival and overall survival were 2.1/7.3 months in the QD arm and 2.8/9.0 months with TDD arm. This therapy showed a moderate toxicity profile for the majority of patients. CONCLUSIONS: In the chosen patient population, vatalanib QD and TDD dosing demonstrated potential benefits in tumor size reduction, DCR, and survival.

Mediastinal radiotherapy after multidrug chemotherapy and prophylactic cranial irradiation in patients with SCLC--treatment results after long-term follow-up and literature overview.

INTRODUCTION: Curative therapy for patients with small-cell lung cancer (SCLC) is based on multidrug chemotherapy combinations and radiotherapy. After a long time follow-up, the aim of the study was to evaluate the efficacy and toxicity of sequential chemo-radiotherapy and the effect of prophylactic cranial irradiation (PCI). METHODS: From 1995-2005, 96 patients with SCLC (64 limited-disease [LD], 32 extensive-disease [ED]; median age 61 years [range 39-79]) were treated at our department with varying chemotherapy regimens and sequential mediastinal radiotherapy (50 Gy + 10 Gy boost in case of residual disease after chemotherapy). Afterwards, 15 patients with LD, good general condition and at least partial response after local treatment received PCI (30 Gy). RESULTS: After a median follow-up of 78.6 months, 20 patients remained alive (20.8%, median survival time 18.2 months). The 2-/5-year overall survival rates were 33.8% and 12.6%, the 2-/5-year loco-regional control rates were 30.3% and 24.5%, respectively. Distant metastases occurred in 43 patients (24 cerebral). Cerebral metastasis occurred in 6.7% and 27.2% of the patients with PCI and without PCI respectively. Only tumor stage showed a statistically significant impact on overall survival and loco-regional control in multivariate analysis. Radiotherapy was well tolerated. Grade 3/4 toxicity occurred in seven patients. Prognosis of patients with SCLC remains poor. Administration of PCI in selected patients bears a decrease in the incidence of cerebral metastases. Alternative chemotherapy schemes as well as irradiation schemes and techniques should be the substance of future randomized trials.

Population pharmacokinetics of melphalan and glutathione S-transferase polymorphisms in relation to side effects.

Melphalan is associated with severe side effects such as mucositis, diarrhea, and myelosuppression. We investigated how much the individual severity of these side effects is predicted by pharmacokinetics. In addition, we studied glutathione S-transferase GSTM1, GSTT1, and GSTP1 polymorphisms in relation to adverse events. A high interindividual pharmacokinetic variability was observed in 84 patients. There was a linear correlation between creatinine and melphalan clearance (P=0.0004). Patients treated with a dose > or = 70 mg/m(2) had a 23-fold increased risk to develop mucositis (P<0.001) and a 12-fold increased risk to develop diarrhea (P<0.001) compared with lower doses. The GSTP1 codon 105 polymorphism may be relevant for development of mucositis and the GSTT1 deletion may predict diarrhea, but these findings require confirmation. Melphalan-induced side effects were significantly dependent only on dose. Therapeutic drug monitoring or genotyping for GST does not appear to be very helpful in optimizing therapy with melphalan.

Detection of pulmonary nodules at spiral CT: comparison of maximum intensity projection sliding slabs and single-image reporting.

The aim of this study was to compare numbers of pulmonary nodules detected with maximum intensity projections using a slab thickness of 15 mm (MIP 15) and 30 mm (MIP 30) with single image (SI) presentation of chest CT scans. Two readers reviewed MIP 15, MIP 30, and SI presentations of 10-mm (n = 8) and 5-mm collimation (n = 10) helical CT scans and recorded size, location, and diagnostic confidence (definite, probable) of pulmonary nodules. Readers 1 and 2 recorded more nodules with MIP 15 than with SI: 10-mm collimation, 77/64 and 60/56; 5-mm collimation, 64/60 and 40/36; and more "definite" nodules (10-mm collimation: 68/57 and 51/42; 5-mm collimation: 43/36 and 34/30). MIP 15 also detected more nodules than MIP 30 at 10-mm collimation: 77/72 and 60/50; with no major differences at 5-mm collimation: 64/66 and 40/38; and more "definite" nodules (10-mm collimation: 68/58 and 51/36; 5-mm collimation: 43/39 and 34/29). There were only minor differences between SI and MIP 30. Reading time and image number per study were reduced with MIP presentations by a factor of 1.4-5.3. There were no significant differences in the number of nodules detected with SI, MIP 15, and MIP 30, but MIP presentation reduced reporting time and filming cost when compared with SI reporting. For detection of nodules MIP 15 was slightly superior to MIP 30.

Developmental expression of corticotropin-releasing factor in the postnatal murine cerebellum.

Corticotropin-releasing factor (CRF) is present in climbing and mossy fibers and both have a distinct pattern of distribution in the adult cerebellar cortex. The intent of this developmental study is to determine when the lobular pattern of CRF distribution emerges, and to analyze the morphogenesis of CRF immunoreactive climbing and mossy fibers in individual cerebellar lobules. Between postnatal day (P)0 and P3, CRF-immunoreactive (IR) punctate elements are present throughout the cerebellum. By P3, there is a decrease in the density of staining in the white matter and punctate elements become concentrated within the developing cortex. Between P3 and P7 CRF-IR, varicosities circumscribe Purkinje cell bodies, and are present in the internal and external granule cell layers. Between P10 and P12, there is a major reduction in the density of CRF-IR puncta, especially in the internal and external granule cell layers. Varicosities remain around Purkinje cell bodies and some extend into the molecular layer. During this interval, CRF-IR profiles are first evident in axonal configurations characteristic of developing climbing fibers, although there are lobular differences in the degree of maturation of this afferent system. Axonal enlargements characteristic of immature mossy fibers can first be seen at P10 in lobules IX and X; they cannot be differentiated until P12-14 in more rostral or lateral lobules. CRF-IR fibers in lobules IX and X, the vestibulocerebellum, develop into mature climbing and mossy fibers before any other area of the cerebellum. In other lobules of the cerebellum the gradient of maturation for these axonal phenotypes is from medial to lateral and posterior to anterior. Between P10 and P12, CRF-IR climbing fibers are present in all lobules of the cerebellum. After P12, few climbing fibers are observed in the anterior lobe of the cerebellum at midvermal levels; those present are only faintly immunolabeled. Based on its early expression and uniform distribution between P0 and P10, CRF could have a role in cerebellar development. After this age, as climbing and mossy fiber terminal phenotypes mature, and the differential adult patterns of distribution emerge, CRF likely begins to function as a neuromodulator as has been shown in the adult cerebellum.

[Cost minimization analysis for the definitive therapy of hyperthyroidism: comparison of goiter resection with radioiodine therapy]. / Kostenminimierungsstudie zur definitiven Therapie der Hyperthyreose: Vergleich zwischen Strumaresektion und Radiojodtherapie.

AIM: Cost-analysis of strumaresection and radioiodine treatment in patients with hyperthyreosis. METHOD: Matched by age, sex, comorbidity, volume of goiter, and entity of hyperthyreosis 18 patients of a clinic of surgery, and 28 patients of a clinic of nuclear medicine were analysed by the reimbursed costs, and by a retrospective calculation of the real costs. RESULTS: Based on the rate for the reimbursed costs the radioiodine treatment (6450 DM) was more favourably than the strumaresection (7562 DM); based on the calculation of the real costs including regional specialities there was a minimal difference in favour of the strumaresection (5185 DM versus 5562 DM) because of the selection of large goiters (median 53 ml), the longer hospitalisation after radioiodine treatment due to legal reasons (12.5 days), and the frequent controls before and after the radioiodine treatment. Most important cost-factor of the radioiodine treatment was the volume of goiter, most important cost-factor of the strumaresection was the age of the patient. The treatment of Graves disease was more expensive than that of autonomy in surgery as well as in nuclear medicine. CONCLUSION: In order to achieve cost-minimization, radioiodine treatment should be prefered in cases of small goiters or in older patients.

The distribution of corticotropin-releasing factor (CRF), CRF binding sites and CRF1 receptor mRNA in the mouse cerebellum.

The purpose of the present study is to determine the distribution of CRF containing afferents, and correlate these findings with the distribution of CRF binding sites and the neuronal localization of mRNA for the CRF1 receptor in the cerebellum of a single species, the mouse. Corticotropin releasing factor (CRF) has been localized within climbing fibers and mossy fibers throughout the cerebellar cortex of the mouse using immunohistochemistry. CRF immunoreactive, axonal varicosities also are present within all four of the cerebellar nuclei. 125I-labeled CRF binding sites are evident throughout all three layers of the cerebellar cortex (molecular, Purkinje and granule cell layers), but are not seen within the cerebellar nuclei. In situ hybridization histochemistry was employed using an antisense riboprobe corresponding to the full length sequence of the rat mRNA for the CRF1 receptor. Positive signal is present throughout the cerebellum in Purkinje cells and the granule cell layer. CRF1 receptor mRNA also is expressed within all four of the cerebellar nuclei. Further experiments are required to reconcile the lack of CRF binding sites in the cerebellar nuclei with the positive mRNA receptor expression and the presence of immunoreactive axonal varicosities. In previous physiological experiments, iontophoretic application of CRF enhances spontaneous as well as quisqualate-induced activity of Purkinje cells in slice preparations of the mouse cerebellum. When the results of the anatomical techniques are compared to the physiological data, there is convergent evidence to suggest that CRF influences the firing rate or responsiveness of Purkinje cells directly via release of the peptide from the climbing fiber system and indirectly via the mossy fiber-granule cell-parallel fiber circuit. Taken together, these anatomical and physiological data provide strong evidence to suggest that, in the adult cerebellum, CRF functions as a neuromodulator.

A comparison of the genotoxic effects of carboplatin and cisplatin in Escherichia coli.

cis-Diammine(1,1,-cyclobutanedicarboxylato)platinum(II) (carboplatin) is a second generation platinum anticancer agent with antineoplastic properties like that of its parent compound, cis-diamminedichloroplatinum(II) (cisplatin) but with substantially less deleterious side effects in treated patients with cisplatin. We compared their genotoxic effects in Escherichia coli and found carboplatin to be less cytotoxic (measured as loss of colony forming ability) that cisplatin in that equitoxic doses required greater than 60 time more carboplatin. However, solutions of carboplatin containing chloride ion became more cytotoxic to E. coli after a 24 h incubation period than similar freshly made solutions. Two platinum conversion products which were neither present in freshly made solutions nor in solutions lacking chloride were resolved by thin-layer chromatography (TLC). One of the conversion products migrated like cisplatin and its occurrence in carboplatin solutions was associated with cisplatin-like properties, enhanced cytotoxicity and ability to induce the SOS responses in E. coli. The SOS-inducing abilities were determined by induction of a sulA::lacZ fusion. Likewise, adducts formed in end-labeled oligonucleotides treated with carboplatin appeared identical to those caused by cisplatin when carboplatin was preincubated in chloride-containing solutions but not by carboplatin in freshly made solutions. It is likely that responses evoked by carboplatin in biological systems are partly due to activation of carboplatin by its conversion of cisplatin.

Ontogeny and effect of activity on proenkephalin mRNA expression during development of the chick spinal cord.

Numerous studies have shown in the adult nervous system that mRNA expression can be regulated by neuronal activity. To examine the effect of activity during embryogenesis, the ontogeny of proenkephalin mRNA expression and expression following activity blockade was investigated during development of chick spinal cord. A cDNA fragment (ca. 0.5 kb) coding for chick proenkephalin was cloned and sequenced. With this cDNA, a cRNA probe was made to examine proenkephalin mRNA expression in the spinal cord during embryogenesis. Proenkephalin mRNA was expressed in spinal cord in clusters of cells located in the developing dorsal horn and intermediate lamina at the earliest stages examined (stage 22; E4). Proenkephalin-positive cells in the intermediate lamina were located immediately adjacent to the ventricular zone. At stage 28 (E6) an additional cluster of proenkephalin mRNA-positive cells was seen at the lateral border of the developing intermediate lamina. At stage 33 (E7.5-5-8) the pattern of hybridization positive cells was similar to earlier stages, but individual cells could be identified. At stage 39 (E13) densely labeled cells were seen throughout the dorsal horn and intermediate laminae including the column of Terni. To determine whether neural activity affects proenkephalin mRNA expression, d-tubocurarine (an inhibitor of neural activity) was injected into developing embryos. Following administration of d-tubocurarine a dramatic decrease was seen in proenkephalin mRNA hybridization in the dorsal horn and intermediate lamina of the spinal cord. This study demonstrates in vivo that changes in the level of neural activity can alter gene expression during embryogenesis and suggests that activity is required for expression of nervous system-specific genes.