A phase II study of cediranib as palliative treatment in patients with symptomatic malignant ascites or pleural effusion.

Malignant ascites and pleural effusion are challenging clinical problems, with a major impact on quality of life. We conducted a randomized phase II trial to assess the palliative value of cediranib, an oral vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). After a baseline paracentesis or thoracentesis (on day 0), patients with symptomatic malignant ascites and/or pleural effusion were randomized between immediate treatment with cediranib (Immediate Cediranib) or delayed treatment with cediranib (Delayed Cediranib) on day 29, or after a new puncture was needed. The primary objective of the study was the puncture-free survival, defined as the time from study start (day 1) to the first need for paracentesis or thoracentesis, or time to death, whichever event occurred first. Twelve patients were enrolled. The median puncture-free survival was 45 days (range 10-368) in the Immediate Cediranib patients and 7 days (range 4-13) in the Delayed Cediranib patients (P = 0.011). The change in puncture-free interval (the puncture-free survival after study start minus the puncture-free interval before study start) increased with a median of 31 days in the Immediate Cediranib patients and shortened with a median of 3 days in the Delayed Cediranib patients (P = 0.015). The most common adverse events were fatigue and anorexia. In conclusion, cediranib increased the puncture-free survival and puncture-free interval with an acceptable toxicity profile. This is the first study in which an oral VEGFR TKI showed beneficial palliative effects in patients with malignant effusions.

Comparison of two region of interest definition methods for metabolic response evaluation with [18F]FDG-PET.

AIM: In therapy response monitoring by [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), different tumor delineations are used, resulting in different values for change in glucose metabolic rate (DMRglu). We propose a technique to compare metabolic rates in a region of interest (ROI) based on fixed volumes rather than on fixed thresholds. This method involves change in lesion size. METHODS: In 49 patients with colorectal carcinoma (CRC) and 50 patients with non-small cell lung carcinoma (NSCLC) scheduled for chemotherapy, FDG-PET was performed at baseline and during chemotherapy. A ROIfixed thresholds was determined by using a 50% threshold on both baseline and follow-up FDG-PET. A ROIfixed volumes was determined by using a 50% threshold, determined on the series with the largest tumor volume. This ROIfixed volumes is used on consecutive scans. Predictive effects of both methods were investigated by survival analysis for overall and progression free survival. RESULTS: In CRC, only ROIfixed volumes based DMRglu showed significant predictive ability. In NSCLC, both techniques showed significant predictive ability. During multivariate analysis, ROIfixed volumes determined DMRglu was an independent predictor for both overall and progression free survival in NSCLC whereas ROIfixed thresholds determined MRglu was not. After dichotomization at the median DMRglu, median survival ratio was higher in ROIfixed volumes than ROIfixed thresholds for CRC (overall survival: 1.78 vs 1.25, progression free survival: 1.57 vs 1.21) and NSCLC (overall survival: 2.01 vs 2.01, progression free survival: 2.93 vs 2.13). CONCLUSION: ROIfixed volumes based DMRglu shows better correlation with survival than DMRglu determined from a ROIfixed thresholds.

Comparison of two region of interest definition methods for metabolic response evaluation with [¹8F]FDG-PET.

AIM: In therapy response monitoring by [¹8F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), different tumor delineations are used, resulting in different values for change in glucose metabolic rate (ΔMR(glu)). We propose a technique to compare metabolic rates in a region of interest (ROI) based on fixed volumes rather than on fixed thresholds. This method involves change in lesion size. METHODS: In 49 patients with colorectal carcinoma (CRC) and 50 patients with non-small cell lung carcinoma (NSCLC) scheduled for chemotherapy, FDG-PET was performed at baseline and during chemotherapy. A ROI(fixed thresholds) was determined by using a 50% threshold on both baseline and follow-up FDG-PET. A ROI(fixed volumes) was determined by using a 50% threshold, determined on the series with the largest tumor volume. This ROI(fixed volumes) is used on consecutive scans. Predictive effects of both methods were investigated by survival analysis for overall and progression free survival. RESULTS: In CRC, only ROI(fixed volumes) based ΔMR(glu) showed significant predictive ability. In NSCLC, both techniques showed significant predictive ability. During multivariate analysis, ROI(fixed volumes) determined ΔMR(glu) was an independent predictor for both overall and progression free survival in NSCLC whereas ROI(fixed thresholds) determined MRglu was not. After dichotomization at the median ΔMR(glu), median survival ratio was higher in ROI(fixed volumes) than ROI(fixed thresholds) for CRC (overall survival: 1.78 vs 1.25, progression free survival: 1.57 vs 1.21) and NSCLC (overall survival: 2.01 vs 2.01, progression free survival: 2.93 vs 2.13). CONCLUSION: ROI(fixed volumes) based ΔMR(glu) shows better correlation with survival than ΔMR(glu) determined from a ROI(fixed thresholds).

Transesophageal endoscopic ultrasound-guided fine-needle aspiration for the mediastinal staging of extrathoracic tumors: a new perspective.

BACKGROUND: Several extrathoracic tumors metastasize to the mediastinum. Mediastinoscopy is the standard method to obtain tissue proof of mediastinal spread, but drawbacks are its invasiveness, requirement for general anesthesia and costs. Transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is indicated in lung cancer staging guidelines as a minimally invasive alternative for surgical staging. The diagnostic values in patients with suspected mediastinal metastases and various (previous) extrathoracic malignancies were assessed. PATIENTS AND METHODS: Consecutive patients with suspected mediastinal metastases (on computed tomography or positron emission tomography) and an (previous) extrathoracic malignancy underwent EUS-FNA. RESULTS: Seventy-five patients with current (n = 14) or previously diagnosed (n = 61) extrathoracic malignancies were evaluated. EUS-FNA detected mediastinal malignancies in 43 patients (57%) [metastases of extrathoracic tumors, n = 36 (48%); second malignancy (lung cancer), n = 7 (9%)]. Mediastinal metastases were found at subsequent surgical staging in seven patients or during follow-up (one patient). In seven patients, an alternative diagnosis was established. Sensitivity, specificity, accuracy and negative predictive value of EUS-FNA for mediastinal staging were 86%, 100%, 91% and 72%, respectively. CONCLUSION: EUS-FNA is a minimally invasive mediastinal staging method for patients with extrathoracic malignancies to confirm nodal metastatic spread and therefore may qualify as an alternative for surgical staging.

A rare cause of chylothorax and lymph edema.

Chylothorax is a form of pleural effusion rarely caused by metastasis of solid tumors. Because chylothorax causes complaints by local compression of the lung, as well as weight loss resulting from loss of triglycerides, it needs thorough investigation. We present the case of gastric carcinoma presenting with a chylothorax and unilateral lymph edema. Although rare, the differential diagnosis of chylothorax should include gastric cancer even in the absence of upper abdominal complaints.

Pulmonary hypertension: its diagnosis and management, a multidisciplinary approach.

Pulmonary hypertension is a devastating complication of various, but rare diseases and can also occur as an isolated entity. It causes morbidity and mortality in all patients. Ongoing research has provided some insight into the pathophysiology and clinical manifestations, and new therapeutic options have recently become available for some types of pulmonary hypertension. In order to provide optimal care for an individual patient it is mandatory to establish the type and severity of the pulmonary hypertension in each patient. The diagnostic protocol used in our hospital is presented along with a description of two case histories. An algorithm of the different therapeutic strategies now available is given as well as recommendations for follow-up.

Pleural small cell carcinoma in pre-existent asbestos related pleural disease.

Extrapulmonary small cell carcinoma (SCC) is a very rare disease, and a primary pleural manifestation is extremely rare. A case of SCC of the pleura in a 66-year-old man with pre-existent asbestos-related pleural plaques is presented. This is the first case of pleural SCC in a patient with asbestos-induced pleural disease and the third reported case of a pleural SCC. The SCC developed in an area with pre-existent pleural thickening, underlining the need for careful analysis of alterations in the manifestation of pleural disease in patients with asbestos exposition.

The effect of hypoxia on shortening contractions in rat diaphragm muscle.

Hypoxia is known to reduce isometric contractile properties of isolated rat diaphragm bundles. Its effect on isotonic contractile properties (i.e. force-velocity relationship and power output) has not been studied. We hypothesized that hypoxia reduces velocity of shortening and consequently power output of the unfatigued muscle, and shortens endurance time during isotonic contractions. Force-velocity relationship, power output, and fatigue resistance of rat diaphragm muscle bundles were measured during hypoxia (PO2: 6.6 +/- 0.2 kPa) and compared with hyperoxia (PO2: 91.8 +/- 0.7 kPa). Force was clamped from 1 to 100% of maximal tetanic force (Po). Fatigue during isotonic contractions was induced by repeated stimulation every 2 s at a clamp level of 33% of Po. Hypoxia did not affect isometric force generation compared with hyperoxia, nor contraction or relaxation time. In contrast, maximum shortening velocity decreased significantly (hypoxia: 4.2 +/- 0.3, hyperoxia: 6.0 +/- 0.2 Lo/s, P < 0.05). The force-velocity curve shifted downwards (P < 0.05). Hypoxia lowered power output at each load compared with hyperoxia (P < 0.05). The isotonic endurance time was shorter during hypoxia compared with hyperoxia (80 +/- 2 vs. 130 +/- 3 s, P < 0.05). These data show that hypoxia depresses isotonic contractile properties and power output, and reduces endurance time during repeated isotonic contractions.

Free radicals in hypoxic rat diaphragm contractility: no role for xanthine oxidase.

Recent evidence indicates that hypoxia enhances the generation of oxidants. Little is known about the role of free radicals in contractility of the rat diaphragm during hypoxia. We hypothesized that antioxidants improve contractility of the hypoxic rat diaphragm and that xanthine oxidase (XO) is an important source of free radicals in the hypoxic diaphragm. The effects of N-acetylcysteine (NAC; 18 mM), Tiron (10 mM), and the XO inhibitor allopurinol (250 microM) were studied on isometric and isotonic force generation during hypoxia (PO(2) approximately 7 kPa). NAC and Tiron decreased maximal force generation, slowed the shortening velocity, and decreased the power output. Fatigue rate was decreased in the presence of either NAC or Tiron. Allopurinol did not alter the contractility or fatigability of the diaphragm. During hyperoxia (PO(2) approximately 85 kPa), neither NAC nor allopurinol affected the contractility or fatigability of the diaphragm. Thus free radicals play a significant role in diaphragm contractility during hypoxia. Whether antioxidants exert a beneficial or harmful effect on muscle performance depends on the contraction pattern of the muscle. Free radicals generated by XO do not play a role in diaphragm contractility during either hypoxia or hyperoxia.

Effects of anabolic steroids on diaphragm impairment induced by methylprednisolone in emphysematous hamsters.

This study was designed to investigate whether the administration of the anabolic steroid nandrolone decanoate is able to antagonize the loss in diaphragm function induced by long-term administration of a low-dose of methylprednisolone in emphysematous hamsters. Normal and emphysematous male hamsters were randomized to receive either saline or methylprednisolone 0.2 mg x kg(-1) x day(-1) for 9 months, with or without nandrolone decanoate 1 mg x kg(-1) x week(-1) i.m. during the final 3 months. Diaphragm contractile properties and myosin heavy chain composition were determined. Compared to control hamsters, the force generating capacity of isolated diaphragm strips decreased by approximately 12% in the emphysema group and by approximately 22% in the emphysema plus methylprednisolone group. Addition of nandrolone decanoate to the emphysema plus methylprednisolone hamsters significantly improved force generation. The atrophy of type IIa and IIx diaphragm fibres in the emphysema plus methylprednisolone group was completely reversed to the level of control hamsters by the addition of nandrolone decanoate. In conclusion, nandrolone decanoate in part reversed the loss in diaphragm force-generating capacity in emphysematous hamsters treated with methylprednisolone, and reversed type IIa and IIx fibre atrophy completely.

Effect of beta-adrenoceptor activation on [Ca2+]i regulation in murine skeletal myotubes.

The present study used real-time confocal microscopy to examine the effects of the beta2-adrenoceptor agonist salbutamol on regulation of intracellular Ca2+ concentration ([Ca2+]i) in myotubes derived from neonatal mouse limb muscles. Immunocytochemical staining for ryanodine receptors and skeletal muscle myosin confirmed the presence of sarcomeres. The myotubes displayed both spontaneous and ACh-induced rapid (<2-ms rise time) [Ca2+]i transients. The [Ca2+]i transients were frequency modulated by both low and high concentrations of salbutamol. Exposure to alpha-bungarotoxin and tetrodotoxin inhibited ACh-induced [Ca2+]i transients and the response to low concentrations of salbutamol but not the response to higher concentrations. Preexposure to caffeine inhibited the subsequent [Ca2+]i response to lower concentrations of salbutamol and significantly blunted the response to higher concentrations. Preexposure to salbutamol diminished the [Ca2+]i response to caffeine. Inhibition of dihydropyridine-sensitive Ca2+ channels with nifedipine or PN-200-110 did not prevent [Ca2+]i elevations induced by higher concentrations of salbutamol. The effects of salbutamol were mimicked by the membrane-permeant analog dibutyryl adenosine 3', 5'-cyclic monophosphate. These data indicate that salbutamol effects in skeletal muscle predominantly involve enhanced sarcoplasmic reticulum Ca2+ release.

beta2-adrenoceptor agonists reduce the decline of rat diaphragm twitch force during severe hypoxia.

The aim of the present study was to investigate the in vitro effects of the short-acting beta2-adrenoceptor agonist salbutamol and the long-acting beta2-adrenoceptor agonist salmeterol on hypoxia-induced rat diaphragm force reduction. In vitro diaphragm twitch force (Pt) and maximal tetanic force (Po) of isolated diaphragm muscle strips were measured for 90 min during hyperoxia (tissue bath PO2 83.8 +/- 0.9 kPa and PCO2 3.9 +/- 0.1 kPa) or severe hypoxia (PO2 7.1 +/- 0.3 kPa and PCO2 3.9 +/- 0.1 kPa) in the presence and absence of 1 microM salbutamol or 1 microM salmeterol. During hyperoxia, salbutamol and salmeterol did not significantly alter the time-related decreases in Pt and Po (to approximately 50% of initial values). Salbutamol had no effects on Po or the Pt-to-Po ratio. Salmeterol treatment significantly reduced Po and increased the Pt-to-Po ratio during hyperoxia (P < 0.05 compared with control value). Hypoxia resulted in a severe decrease in Pt (to approximately 30% of initial value) and Po after 90 min. Both salbutamol and salmeterol significantly reduced the decline in Pt during hypoxia (P < 0.05). The reduction in Po was not prevented. Salbutamol increased Pt rapidly but transiently. Salmeterol had a delayed onset of effect and a longer duration of action. Addition of 1 microM propranolol (a nonselective beta-adrenoceptor antagonist) did not alter Pt, Po, or the Pt-to-Po ratio during hypoxia but completely blocked the inotropic effects of salbutamol and salmeterol, indicating that these effects are dependent on beta2-adrenoceptor agonist-related processes.

Salbutamol enhances isotonic contractile properties of rat diaphragm muscle.

The effects of the beta2-adrenoceptor agonist salbutamol (Slb) on isometric and isotonic contractile properties of the rat diaphragm muscle (Diamus) were examined. A loading dose of 25 microg/kg Slb was administered intracardially before Diamus excision to ensure adequate diffusion. Studies were then performed with 0.05 microM Slb in the in vitro tissue chamber. cAMP levels were determined by radioimmunoassay. Compared with controls (Ctl), cAMP levels were elevated after Slb treatment. In Slb-treated rats, isometric twitch and maximum tetanic force were increased by approximately 40 and approximately 20%, respectively. Maximum shortening velocity increased by approximately 15% after Slb treatment, and maximum power output increased by approximately 25%. During repeated isotonic activation, the rate of fatigue was faster in the Slb-treated Diamus, but both Slb-treated and Ctl Diamus fatigued to the same maximum power output. Still, endurance time during repetitive isotonic contractions was approximately 10% shorter in the Slb-treated Diamus. These results are consistent with the hypothesis that beta-adrenoceptor stimulation by Slb enhances Diamus contractility and that these effects of Slb are likely mediated, at least in part, by elevated cAMP.

Long-term effects of clenbuterol on diaphragm morphology and contractile properties in emphysematous hamsters.

The aim of the present study was to investigate the effect of chronic long-term clenbuterol treatment (1 mg/kg subcutaneously twice a day for 12 wk) on diaphragm morphology and function in emphysematous (EH) and normal hamsters (NH). Clenbuterol increased body weight, diaphragm weight, and skeletal muscle weight in both EH and NH to a similar extent. In the diaphragm, clenbuterol significantly increased myosin heavy chain type I, IIa, and IIx muscle fiber cross-sectional areas by approximately 35-55% in both EH and NH. This response to clenbuterol treatment was not significantly different between EH and NH diaphragm. In EH, twitch force (Pt), maximal tetanic force, and force-frequency curve were significantly reduced compared with NH. In EH, clenbuterol increased Pt by approximately 10%, restoring Pt to NH level. A similar improvement was observed in the force-frequency characteristics. Clenbuterol did not alter contractile properties in NH. In conclusion, long-term clenbuterol treatment resulted in an increased size of all diaphragm muscle fiber types in both NH and EH. Clenbuterol completely abolished the reduced force generation induced by emphysema.

Effects of salbutamol on intracellular calcium oscillations in porcine airway smooth muscle.

Relaxation of airway smooth muscle (ASM) by beta-adrenoceptor agonists involves reduction of intracellular Ca2+ concentration ([Ca2+]i). In porcine ASM cells, acetylcholine induces [Ca2+]i oscillations that display frequency modulation by agonist concentration and basal [Ca2+]i. We used real-time confocal microscopy to examine the effect of salbutamol (1 nM to 1 microM), a beta 2-adrenoceptor agonist, on [Ca2+]i oscillations in freshly dissociated porcine ASM cells. Salbutamol decreased the frequency of [Ca2+]i oscillations in a concentration-dependent fashion, completely inhibiting the oscillations at 1 microM. These effects were mimicked by a cell-permeant analog of adenosine 3',5'-cyclic monophosphate. The inhibitory effect of salbutamol was partially reversed by BAY K 8644. Salbutamol reduced [Ca2+]i even when sarcoplasmic reticulum (SR) Ca2+ reuptake and Ca2+ influx were blocked. Lanthanum blockade of Ca2+ efflux attenuated the inhibitory effect of salbutamol on [Ca2+]i. The [Ca2+]i response to caffeine was unaffected by salbutamol. On the basis of these results, we conclude that beta 2-adrenoceptor agonists have little effect on SR Ca2+ release in ASM cells but reduce [Ca2+]i by inhibiting Ca2+ influx through voltage-gated channels and by enhancing Ca2+ efflux.

Inotropic effects of salbutamol on rat diaphragm contractility are potentiated by foreshortening.

The aim of this study was to investigate whether the positive inotropic effects of the beta 2-adrenoceptor agonist salbutamol are increased by foreshortening of the diaphragm, and to determine the mechanism of action of these effects. Diaphragm strips were studied either at optimal resting length (Lo) or at approximately 70% Lo. In an initial experiment (Experiment I) salbutamol was added to the tissue baths in concentrations of 10 micrograms/L or 80 micrograms/L. In a second experiment (Experiment II), the effect of salbutamol (80 micrograms/L) was measured in the presence of 1 microM ryanodine, a sarcoplasmatic reticulum (SR) Ca(2+)-release inhibitor. Each experiment had a time-matched control group. Foreshortening reduced twitch force (Pt), maximal tetanic force (Po), and force-frequency curves. Salbutamol increased Pt and Po both at Lo and approximately 70% Lo. These inotropic effects were significantly greater after foreshortening. The force-frequency curve was shifted upward by salbutamol at both lengths. Force-frequency curves relative to maximal percent of Po were depressed by salbutamol at stimulation frequencies of 80 to 160 Hz. Ryanodine blocked the inotropic effect of salbutamol at both muscle lengths, indicating that these inotropic effects are probably mediated by increased SR Ca2+ release.