Dieter Ukena

Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer

BACKGROUND Preoperative chemotherapy improves survival in patients with stage III non-small-cell lung cancer (NSCLC) amenable to resection. We aimed to assess the additional effect of preoperative chemoradiation on tumour resection, pathological response, and survival in these patients. METHODS Between Oct 1, 1995, and July 1, 2003, patients with stage IIIA-IIIB NSCLC and invasive mediastinal assessment from 26 participating institutions of the German Lung Cancer Cooperative Group (GLCCG) were randomly assigned to one of two treatment groups. The intervention group were scheduled to receive three cycles of cisplatin and etoposide, followed by twice-daily radiation with concurrent carboplatin and vindesine, and then surgical resection (those with positive resection margins or unresectable disease were offered further twice-daily radiotherapy). The control group were scheduled to receive three cycles of cisplatin and etoposide, followed by surgery, and then further radiotherapy. The primary endpoint was median progression-free survival (PFS) in patients eligible for treatment after randomisation. Secondary endpoints in patients eligible for treatment after randomisation were overall survival (OS) and the proportion of patients undergoing surgery. Secondary endpoints in patients with tumour resection were the proportion with negative resection margins, the proportion with complete resection, the proportion with histopathological response, and the proportion with mediastinal downstaging. Additionally, exploratory (not prespecified) post-hoc analyses in terms of PFS and OS were done on patients not amenable to resection and on further subgroups of patients undergoing resection. Analyses were by intention to treat. This trial is registered on the ClinicalTrials.gov website, number NCT 00176137. FINDINGS 558 patients were randomly assigned. 34 patients did not meet inclusion criteria and were excluded. Of 524 eligible patients, 142 of 264 (54%) in the interventional group and 154 of 260 (59%) in the control group underwent surgery; 98 of 264 (37%) and 84 of 260 (32%) underwent complete resection. In patients with complete resection, the proportion of those with mediastinal downstaging (45 of 98 [46%] and 24 of 84 [29%], p=0.02) and pathological response (59 of 98 [60%] and 17 of 84 [20%], p<0.0001) favoured the interventional group. However, there was no difference in PFS (primary endpoint) between treatment groups-either in eligible patients (median PFS 9.5 months, range 1.0-117.0 [95% CI 8.3-11.2] vs 10.0 months, range 1.0-111.0 [8.9-11.5], 5-year PFS 16% [11-21] vs 14% [10-19], hazard ratio (HR) 0.99 [0.81-1.19], p=0.87), in those undergoing tumour resection, or in patients with complete resection. In both groups, 35% of patients undergoing surgery received a pneumonectomy (50/142 vs 54/154). In patients receiving a pneumonectomy, treatment-related mortality increased in the interventional group compared with the control group (7/50 [14%] vs 3/54 [6%]). INTERPRETATION In patients with stage III NSCLC amenable to surgery, preoperative chemoradiation in addition to chemotherapy increases pathological response and mediastinal downstaging, but does not improve survival. After induction with chemoradiation, pneumonectomy should be avoided. FUNDING German Cancer Aid (Bonn, Germany).

Xanthine derivatives as antagonists at A1 and A2 adenosine receptors

SummaryA variety of alkylxanthines has been comparatively examined as antagonists of A1 adenosine receptors in rat fat cells, rat and bovine cerebral cortex and of A2 adenosine receptors in human platelets. With few exceptions all xanthine derivatives with 7-position substituents such as diprophylline, proxyfylline, pentoxifylline and etofylline were less potent antagonists than xanthine itself which hadKi-values of 170 μmol/l (A1) and 93 μmol/l (A2). Theophylline, caffeine and 3-isobutyl-1-methylxanthine were more potent than xanthine but nearly equipotent antagonists at both receptor subtypes. 8-Phenyl substituents considerably increased the antagonist potency at A1 and A2 receptors. 1,3-Diethyl-8-phenylxanthine was the most potent A2 antagonist (Ki 0.2 μmol/l) in human platelets. At A1 receptors 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX) was the most potent antagonist in all three tissues withKi-values from 0.3 to 8.6 nmol/l. Several 8-phenylxanthine derivatives were remarkably selective antagonists at A1 receptors. 8-Phenyltheophylline was approximately 700 times more potent as antagonist at A1 receptors (bovine brain) than at A2 receptors (human platelets), and PACPX was even 1,600 times more potent as A1 adenosine receptor antagonist. These compounds offer a possibility for a subtype-selective blockade of adenosine receptors.

18F-FDG PET for Mediastinal Staging of Lung Cancer: Which SUV Threshold Makes Sense?

18F-FDG PET is the most accurate noninvasive modality for staging mediastinal lymph nodes in lung cancer. Besides using visual image interpretation, some institutions use standardized uptake value (SUV) measurements in lymph nodes. Mostly, an SUV of 2.5 is used as the cutoff, but this choice was never deduced from respective studies. Receiver operating characteristic (ROC) analyses demonstrated that SUV thresholds of more than 4 resulted in the highest accuracy. But these high cutoffs imply high false-negative rates (FNRs). The aim of our evaluation was to determine an optimal SUV threshold and to compare its diagnostic performance with the results of visual interpretation. Methods: This retrospective study included 95 patients with suspected lung cancer who underwent mediastinoscopy/mediastinal lymphadenectomy after 18F-FDG PET (90–150 min after 250 MBq of 18F-FDG). Maximum SUV was measured in 371 lymph node regions biopsied afterward and visually interpreted using a 6-level score (− − − through + + +). Diagnostic performance was assessed by ROC analysis. FNR and false-positive rate (FPR), the sum of both error rates (FNR + FPR), and diagnostic accuracy were plotted against a hypothetical SUV threshold to determine the optimum SUV threshold. Results: SUVs in metastatic lymph nodes were higher (mean ± SD, 7.1 ± 4.5; range, 1.4–26.9; n = 70) than in tumor-free lymph node stations (2.4 ± 1.7; range, 0.6–14.9; n = 301; P < 0.01). Inflammatory lymph nodes exhibited slightly increased SUVs (2.7 ± 2.0; range, 0.8–14.9; n = 146). The plot of error rates featured a minimum of the sum FNR + FPR for an SUV of 2.5. With increasing SUV threshold, the FPR decreased most prominently up to that value whereas a continuous rise of FNR was noticed. Highest diagnostic accuracy was achieved with an SUV of 4.5. The areas under the ROC curves demonstrated that visual interpretation tends to be more accurate than SUV quantification (visual, 0.930 ± 0.022; SUV, 0.899 ± 0.025; P = 0.241). Using an SUV of 2.5 as the threshold, the resulting sensitivity, specificity, and negative predictive value were 89%, 84%, and 96%, respectively. Conclusion: For mediastinal staging, the choice of an SUV of 2.5 as the threshold is justified because FNR + FPR is minimized. The resulting high negative predictive value of 96% allows the omission of mediastinoscopy in patients with negative mediastinal findings on 18F-FDG PET images. For the experienced observer, visual analysis should be relied on primarily, with calculation of the SUV used, at most, as a secondary aid. For the less experienced observer, the SUV may be of greater value.

Adenosine receptor-blocking xanthines as inhibitors of phosphodiesterase isozymes

The pharmacological actions of methylxanthines such as theophylline and caffeine may be due to blockade of adenosine receptors and/or inhibition of phosphodiesterase (PDE) activities. In the last years, potent xanthines have been developed that display some selectivity for A1 and A2 adenosine receptors. Little is known about the PDE inhibitory potency of these xanthines. The aim of the present study was to determine the potencies of A1 and A2 receptor selective xanthines as inhibitors of several PDE isozymes, the PDE I-V subtypes. The IC50 values of 8-phenyl- and 8-cycloalkyl-1,3-dialkylxanthines for inhibition of PDE isozymes from different sources are up to 10,000-fold higher than their antagonistic potencies at adenosine receptors. However, the A1 receptor selective antagonists 1,3-diethyl-8-phenylxanthine and 1,3-dipropyl-8-cyclopentylxanthine are comparatively potent inhibitors of PDE IV activity with IC50 values in the 10 microM range and are, therefore, nearly as potent as the PDE IV selective inhibitor, rolipram. The A2 receptor selective 1,3-dipropyl-7-methylxanthine is about 10-300-fold more potent as an adenosine receptor antagonist than as a PDE inhibitor. The results indicate that some of these novel xanthines can be used as selective adenosine receptor antagonists without interference due to inhibitory effects on PDEs.

Bronchial and bronchovascular sleeve resection for treatment of central lung tumors.

BACKGROUND To improve postoperative pulmonary reserve, we have employed parenchyma-sparing resections for central lung tumors irrespective of pulmonary function. The results of lobectomy, pneumonectomy, and sleeve resection were analyzed retrospectively. METHODS From October 1995 to June 1999, 422 typical lung resections were performed for lung cancer. Of these, 301 were lobectomies (group I), 81 were sleeve resections (group II), and 40 were pneumonectomies (group III). RESULTS Operative mortality was 2% in group I, 1.2% in group II, and 7.5% in group III (group I and II vs. group III, p<0.03). Mean time of intubation was 1.0+/-4.1 days in group I, 0.9+/-1.3 days in group II, and 3.6+/-11.2 days in group III (groups I and II vs. group III, p<0.01). The incidence of bronchial complications was 1.3% in group I, none in group II, and 7.5% in group III (group I and II vs group III, p<0.001). After 2 years, survival was 64% in group I, 61.9% in group II, and 56.1% in group III (p = NS). Freedom from local disease recurrence was 92.1% in group I, 95.7% in group II, and 90.9% in group III after 2 years (p = NS). CONCLUSIONS Sleeve resection is a useful surgical option for the treatment of central lung tumors, thus avoiding pneumonectomy with its associated risks. Morbidity, early mortality, long-term survival, and recurrence of disease after sleeve resection are similar to those seen after lobectomy.

Demonstration of Ri-type adenosine receptors in bovine myocardium by radioligand binding.

SummaryAdenosine has been shown to have negative inotropic, chronotropic and dromotropic effects on the heart. The pharmacological profiles of these effects suggest that they are mediated via Ri (A1) adenosine receptors, but a direct demonstration of these receptors is still missing. In the present study we report direct labelling of these receptors with (-)N6-[125I]-p-hydroxyphenylisopropyladenosine ([125I]HPIA). The radioligand bound in a saturable and reversible manner to a crude membrane preparation, the Bmax-value was 30.5 fmol/mg protein and the KD-value 1.1 nmol/l. A similar affinity of the ligand was obtained in kinetic and competition experiments. Competition experiments with a variety of adenosine analogues gave a pharmacological profile characteristic of Ri adenosine receptors with high affinities of N6-substituted derivatives and a marked stereospecificity for N6-phenylisopropyladenosine (PIA). Purification of the membrane preparation by density gradient centrifugation resulted in a 30-fold increase in the number of binding sites which was paralleled by a similar increase in the number of binding sites for [3H]ouabain. Guanine nucleotides decreased binding of [125I]HPIA in a dose-dependent manner, but the IC50-values were considerably higher than those reported in other tissues. Finally, binding of [125I]HPIA appeared to be entropy-driven which has been shown to be characteristic of agonist binding to Ri adenosine receptors. These results suggest the presence of Ri adenosine receptors in ventricular myocardium which may be responsible for the mediation of the effects of adenosine and its analogues.

Asthmatherapie bei Kindern und Erwachsenen

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Characterization of PAF receptors on human neutrophils using the specific antagonist, WEB 2086 Correlation between receptor binding and function

The antagonism of PAF effects by WEB 2086 and the receptor binding of [3H]WEB 2086 were investigated in isolated human neutrophils. WEB 2086 inhibited PAF‐induced β‐glucuronidase release and [3H]WEB 2086 bound specifically to high‐affinity sites on the cells. Close concordance between affinity constants for WEB 2086 from functional and radioligand‐binding studies suggests that WEB 2086 interacts with the neutrophil PAF receptors and that [3H]WEB 2086 may be a useful ligand in investigation of these receptors.

Effects of several 5'-carboxamide derivatives of adenosine on adenosine receptors of human platelets and rat fat cells

SummaryThe effects of several 5′-carboxamide derivatives of adenosine on stimulatory (Ra) adenosine receptors of human platelets and inhibitory (Ri) adenosine receptors of rat fat cells have been compared. 5′-N-Cyclopropylcarboxamidoadenosine (CPCA) and 5′-N-ethylcarboxamidoadenosine (NECA) most potently inhibited ADP-induced aggregation of human platelets as shown by IC50-values of 0.24 and 0.34 μmol/l. 5′-N-Methylcarboxamidoadenosine (MECA; IC50 0.81 μmol/l) and 5′-N-carboxamidoadenosine (NCA; IC50 2.1 μmol/l) were less potent, whereas adenosine, 2-chloroadenosine and (-)N6-phenylisopropyladenosine [(-)PIA] exhibit IC50-values of about 1.5 μmol/l. Nearly the same rank order of potency was obtained for stimulation of adenylate cyclase activity of platelet membranes and for inhibition of [3H]NECA binding to human platelets. In order to examine the effects of the carboxamide analogues on Ri adenosine receptors of rat fat cells inhibition of lipolysis and adenylate cyclase were studied. (-)PIA was the most potent inhibitor of lipolysis as shown by an IC50 of 0.5 nmol/l, followed by CPCA (IC50 1.1 nmol/l) and NECA (IC50 1.3 nmol/l), whereas MECA (IC50 17.9 nmol/l) and NCA (IC50 20.1 nmol/l) were much less potent than NECA in inhibiting lipolysis. Similar results were obtained for inhibition of adenylate cyclase activity of fat cell membranes and for competition with [3H]PIA binding to fat cell membranes. The relative potencies of the adenosine analogues at both receptor subclasses were calculated from the ratio of the IC50-values for inhibition of platelet aggregation and of lipolysis. (-)PIA showed the highest selectivity for Rireceptors as indicated by a 2,900-fold lower IC50 for the antilipolytic than for the antiaggregatory effect. The Ra/Ri activity ratio for NECA was about 260, for CPCA 220, for NCA 105 and for MECA 45. These results indicate that all 5′-carboxamide adenosine derivatives are more potent agonists at Ri receptors than at Ra receptors. Since MECA has a higher selectivity for Ra receptors than NECA, it may be useful for the characterization of stimulatory adenosine receptors in different tissues.

[3H]WEB 2086 labels platelet activating factor receptors in guinea pig and human lung

The radiolabelled platelet activating factor (PAF) receptor antagonist, [3H]WEB 2086, bound to specific sites on membrane fractions from homogenised guinea pig and human lungs. The sites on guinea pig and human membranes bound [3H]WEB 2086 with dissociation constants (KD) of 16.8 and 22.6 nM and binding capacities (Bmax) of 203 and 157 fmol/mg protein, respectively. In both species, binding was displaced competitively by PAF, suggesting that the sites labelled by [3H]WEB 2086 are PAF receptors.