Preclinical Study of a Combination of Erlotinib and Bevacizumab in Early Stages of Unselected Non-Small Cell Lung Cancer Patient-Derived Xenografts.

BACKGROUND: The differential outcomes of clinical studies of the targeted therapies for non-small cell lung cancer (NSCLC) indicate that better stratification of patients is required. This could be achieved with the help of patient-derived xenografts (PDX) of epidermal growth factor receptor (EGFR) wild-type patients resistant to erlotinib treatment. OBJECTIVE: To explore the potential of patient-derived NSCLC xenografts to optimize therapy using 24 well-characterized early-stage NSCLC PDX. METHOD: Patient tumor tissue was transplanted subcutaneously into nude mice. After engraftment, tumors were expanded and the sensitivity was tested. Gene expression analysis was used to identify differentially expressed genes between erlotinib responder (n = 3) and non-responder (n = 21). Tumor tissue was analyzed with TaqMan PCR, immunohistochemistry and ELISA to examine the response of the models. RESULTS: Gene expression analysis revealed vascular endothelial growth factor A (VEGFA) to be up-regulated in erlotinib non-responder. Because of that, the combination of erlotinib with bevacizumab was evaluated in one erlotinib-sensitive and four erlotinib-resistant PDX. Combination treatment was superior to monotherapy, leading to the highest and significant inhibition of tumor growth in all models investigated. A decline of VEGFA protein and an increase of VEGFA-mRNA were observed after bevacizumab treatment. Bevacizumab treatment resulted in a distinct decrease of blood vessel number. CONCLUSION: This study showed that with the help of preclinical PDX models, drug combinations for therapy improvement can be identified on a rational basis. It was observed that a dual blockage of EGFR and VEGFA was more effective than a monotherapy for the treatment of NSCLC in selected PDX models. PDX could be employed to optimize the treatment of cancer patients.

Deficits 10-years after Achilles tendon repair.

The purpose of this study was to determine the long-term impact of surgical repair and subsequent 6-week immobilization of an Achilles tendon rupture on muscle strength, muscle strength endurance and muscle activity. 63 patients participated in this study on average 10.8 ± 3.4 years after surgically repaired Achilles tendon rupture and short-term immobilization. Clinical function was assessed and muscle strength, strength endurance and muscle activity were measured using a dynamometer and electromyography. Ankle ROM, heel height during heel-raise tests and calf circumference were smaller on the injured than on the contralateral side. Ankle torques during the concentric dorsiflexion tasks at 60 °/sec and 180 °/sec and ankle torques during the eccentric plantarflexion task and during the concentric plantarflexion task at 60 °/sec for the injured leg were significantly lower than those for the contralateral leg. The total work during a plantarflexion exercise at 180 °/sec was 14.9% lower in the injured compared to the contralateral leg (p < 0.001). Muscle activity for the gastrocnemius muscle during dorsiflexion tasks was significantly higher in the injured than in the contralateral limb. Limited ankle joint ROM and increased muscle activity in the injured leg suggest compensatory mechanisms to account for differences in muscle morphology and physiology caused by the injury.

Novel therapies in non-small cell lung cancer.

Over the last years, several new systemic cancer therapy strategies have been introduced to turn the growing insights of molecular aberrations involved in the development and progression of lung cancer into better treatment options fort the patients. This review presents some of the most important biological targets and biomarkers relevant in the treatment of non-small cell lung cancer. Especially EGFR mutations, anti-angiogenesis, multi kinase inhibition, vascular disrupting agents, vaccines, m-TOR inhibitors, TRAIL inhibition and several biomarkers are highlighted including current study results.

Adjuvant therapy for lung cancer.

To improve outcome of patients with lung cancer, the leading cause of cancer mortality worldwide, a multidisciplinary approach is required. Only approximately 30% of all lung cancer patients present with early stage disease (IA-IIIA). For non-small cell lung cancer (NSCLC) complete surgical resection is currently considered to be the optimal treatment, but high rates of recurrence even after complete resection require to investigate regimes of additional therapy. In the last years, evidence for adjuvant chemotherapy in stage II and III of NSCLC was shown, supported by large clinical trials and meta-analyses, while for stage IB disease the role of adjuvant chemotherapy remains controversial. Further there is actually no evidence to support the routine use of adjuvant radiation or radio-chemotherapy in completely resected patients. For small cell lung cancer (SCLC) a multimodality adjuvant approach is feasible in early stages, his definitive value however should be evaluated in further randomized trials. Current efforts are directed toward identification of prognostic and predictive markers to individualize treatment stratification, a realistic goal for the future. The current status and future perspectives of adjuvant therapy in lung cancer are reviewed in this manuscript.

Smoking and cancer-related gene expression in bronchial epithelium and non-small-cell lung cancers.

Tobacco smoking is the leading cause of lung cancer worldwide. Gene expression in surgically resected and microdissected samples of non-small-cell lung cancers (18 squamous cell carcinomas and nine adenocarcinomas), matched normal bronchial epithelium, and peripheral lung tissue from both smokers (n = 22) and non-smokers (n = 5) was studied using the Affymetrix U133A array. A subset of 15 differentially regulated genes was validated by real-time PCR or immunohistochemistry. Hierarchical cluster analysis clearly distinguished between benign and malignant tissue and between squamous cell carcinomas and adenocarcinomas. The bronchial epithelium and adenocarcinomas could be divided into the two subgroups of smokers and non-smokers. By comparison of the gene expression profiles in the bronchial epithelium of non-smokers, smokers, and matched cancer tissues, it was possible to identify a signature of 23 differentially expressed genes, which might reflect early cigarette smoke-induced and cancer-relevant molecular lesions in the central bronchial epithelium of smokers. Ten of these genes are involved in xenobiotic metabolism and redox stress (eg AKR1B10, AKR1C1, and MT1K). One gene is a tumour suppressor gene (HLF); two genes act as oncogenes (FGFR3 and LMO3); two genes are involved in matrix degradation (MMP12 and PTHLH); three genes are related to cell differentiation (SPRR1B, RTN1, and MUC7); and five genes have not been well characterized to date. By comparison of the tobacco-exposed peripheral alveolar lung tissue of smokers with non-smokers and with adenocarcinomas from smokers, it was possible to identify a signature of 27 other differentially expressed genes. These genes are involved in the metabolism of xenobiotics (eg GPX2 and FMO3) and may represent cigarette smoke-induced, cancer-related molecular targets that may be utilized to identify smokers with increased risk for lung cancer.

Pumpless extracorporeal lung assist using an arterio-venous shunt. Applications and limitations.

We report the use of a pumpless extracorporeal lung assist (PECLA) in 70 patients with severe pulmonary failure of various causes. The device was used under rescue conditions in patients with preserved cardiac function. By establishing a shunt between femoral artery and vein using the arterio-venous pressure gradient as the driving force for the blood flow through the oxygenator, PECLA proved to be extremely effective in terms of oxygenation and carbon dioxide removal.

[Percutaneous transfemoral implantation of a new, flexible thoracic aorta endoprosthesis using a percutaneous suture system for vascular suture--initial experiences]. / Perkutane transfemorale Implantation einer neuen, flexiblen thorakalen Aortenendoprothese unter Verwendung eines perkutanen Nahtsystems zum Gefässverschluss--erste Erfahrungen.

PURPOSE: To evaluate the transfemoral placement of a new, flexible stent-graft into the thoracic aorta and the suture-mediated closure of the femoral access. PATIENTS AND METHODS: Five patients were treated endovascularly with a stent-graft for an aneurysm (n = 3) or acute dissection (n = 2) of the thoracic aorta via a femoral 24 F sheath. The femoral access site was closed with two suture-mediated closure devices after placement of the stent-graft. RESULTS: The aneurysm or the false lumen was excluded from perfusion by the placement of the stent-graft in all patients. Hemostasis at the femoral access site was successful in all patients with the percutaneous suture device. A minor stenosis of the femoral artery was found angiographically in four patients after suture-mediated closure. Besides a reversible renal failure due to the medically induced hypotension for the treatment of an acutely ruptured aneurysm, no complications resulted from the stent-graft placement or the percutaneous suture. CONCLUSION: The percutaneous transfemoral placement of stent-grafts in the thoracic aorta using a suture-mediated closure of the access site is technically feasible. Long-term results of the technique have to be awaited.

Mechanical stimulation by external application of cyclic tensile strains does not effectively enhance bone healing.

OBJECTIVE: To determine whether an externally induced interfragmentary movement enhances the healing process of a fracture under flexible fixation. DESIGN: Randomized, prospective in vivo animal study with control group. Twenty-four skeletally mature Merino sheep were randomly assigned to six groups of four animals, which received cyclic interfragmentary movements of 0.2 and 0.8 millimeters and stimulation frequencies of 1, 5, and 10 Hertz, respectively. Twelve animals did not receive any externally applied stimulation and served as a control group. SETTING: Unrestricted stall activity with weight bearing reduced by tenotomy of the Achilles tendon. INTERVENTIONS: Osteotomy of the tibial diaphysis with three-millimeter gap width fixed with a six-pin, monolateral, double-bar external fixator. Interfragmentary movement of the osteotomy gap was externally induced by a motor-driven actuator unit. Five hundred cycles inducing nonuniform tensile strains within the gap were performed each day. MAIN OUTCOME MEASUREMENTS: Nine weeks after surgery, the animals were killed, and bone mineral density and callus cross-sectional area were measured with quantitative computed tomography. Callus projectional area was assessed by radiographs, and mechanical stability was determined with a three-point bending test. RESULTS: External stimulation with nonuniform cyclic tensile strains did slightly affect but not significantly enhance the fracture healing process. Varying the stimulation frequency had no influence on the healing process. The stimulation with 0.8 millimeter displacement magnitude resulted in a larger periosteal callus, but a decreased bone mineral density compared with the 0.2-millimeter displacement magnitude. The stimulation had no significant influence on the mechanical properties of the healing bone. CONCLUSIONS: Induced cyclic tensile strains did not produce a relevant enhancement of bone healing under flexible fixation.

[Individual isokinetic strength training in patients with gonarthrosis]. / Individuelles isokinetisches Krafttraining bei Patienten mit Gonarthrose.

PROBLEM: To date, therapy of osteoarthritis of the knee is aimed at relieving pain and changing behavior patterns, which usually leads to reduced activity. The weakening of the quadricep's musculature leads to an increase in both joint instability and arthritis. Walking time is prolonged and the pain-induced reaction of knee angle velocity is onset by increased stress on other joints. The progressive muscle atrophy correlates to the degree of pain. The aim of this study was to demonstrate an improvement in strength and pain based on 4-week isokinetic strength training in gonarthritis patients. METHOD: During a conservative hospitalization period, isokinetic strength training was performed by 19 randomized patients with gonarthritis in addition to regular physiotherapy. Another 19 patients functioned as a control group. The work was examined at 60 degrees/s and 180 degrees/s and rated using a pain questionnaire at the start and end of the investigation. RESULTS: In addition to the expected increase of strength and strength endurance in the test group, the degree of pain could also be statistically significantly decreased compared to the control group. Activities of daily living, such as climbing stairs and standing-up, were also performed more easily. CONCLUSIONS: The therapeutic strategy for patients with osteoarthritis of the knee should be reconsidered to include less expensive therapeutic sport measures. Anglo-american and Scandinavian studies support this statement. Overuse and pain can be avoided by precise and low-dose strength training. Objective and reproducible measurements in the patients are essential to make individual training possible.

Short atrioventricular delay dual-chamber pacing early after coronary artery bypass grafting in patients with poor left ventricular function.

OBJECTIVE: To investigate the effect of short atrioventricular (AV) delay dual-chamber pacing on mean arterial pressure (MAP) and stroke volume index (SVI) in patients with poor left ventricular (LV) function after cardiac surgery. DESIGN: A prospective study. SETTING: A university hospital, single-center study. PARTICIPANTS: The study group consisted of 20 patients aged 63 +/- 9 years with a left ventricular ejection fraction (LVEF) less than 30%. The control group consisted of 20 patients aged 61 +/- 10 years, with an LVEF greater than 50%. INTERVENTIONS: Immediately after routine coronary artery bypass grafting (CABG) the AV delay was shortened from 160 to 40 milliseconds in atrial-paced (DDD) mode and from 100 to 40 milliseconds in atrial-sensed ventricular stimulation (VDD) mode. MAP was on-line monitored and SVI was calculated by thermodilution. In one patient with an LVEF of 18% (case study), transmitral flow velocity and LV isovolumetric relaxation time were assessed using Doppler echocardiography during VDD pacing at 40-, 80-, and 120-millisecond AV delay. RESULTS: Short-AV delay DDD pacing decreased MAP in the control group (84.3 +/- 9 v 75.7 +/- 9 mmHg; p < 0.05) and SVI in both groups (study group, 35.9 +/- 7 v 31.7 +/- 7 mL/m2; control group, 35.3 +/- 6 v 31.0 +/- 6 mL/m2; p < 0.05). Shortening the AV delay had no influence on MAP and SVI during VDD pacing. During the echocardiographic case study, AV delay shortening distinctly modified ventricular filling patterns. Optimal LV filling and transmitral flow were achieved with an intermediate AV delay of 80 milliseconds. CONCLUSION: Dual-chamber pacing with nonphysiologic short AV delay failed to improve acute hemodynamics in patients with poor LV function after CABG. Short AV delay VDD pacing was superior to DDD pacing in both normal and impaired LV function. The use of Doppler echocardiography enabled optimization of the AV delay on the basis of LV filling patterns.

Clinical results with single lead VDD pacing.

OBJECTIVE: For patients with atrioventricular block single lead atrial synchronous ventricular pacing (VDD) may have advantages compared to conventional dual chamber pacing (DDD) since it eliminates the need for an atrial lead. The purpose of this study was to investigate the clinical performance of a novel VDD pacemaker and the reliability of atrial sensing via the "floating' atrial electrode. METHODS: 31 patients (10 females; age 64 +/- 13 years) underwent an implantation of a VDD pacemaker system (Intermedics UNITY). The patients were analyzed with regard to implantation parameters, complications and postoperative atrial sensing performance using the diagnostic data of the pacemaker memory. The mean follow-up was 6.3 (1-18) months. RESULTS: The implantation procedure did not differ from that of conventional single chamber pacemakers. Dislocation of a ventricular electrode was the only complication observed. The P wave at implantation was 1.6 +/- 0.9 mV and dropped to 0.9 +/- 0.4 mV at predischarge. During follow-up the atrial sensing threshold remained stable. The atrial sensing performance (percentage of atrial synchronous ventricular complexes) after reprogramming the highest atrial sensitivity was 99.7%. Two patients (6%) developed atrial fibrillation. 29 patients (94%) remained in VDD mode as primarily intended. CONCLUSIONS: From these results it is concluded that VDD pacing represents an excellent alternative in patients with atrioventricular block and intact sinus node function. The atrial sensing was found to be reliable.

[Radiation exposure in digital micturition cystourethrography in children. How much exposure by fluoroscopy?]. / Strahlenbelastung bei der digitalen Miktionszysturethrographie bei Kindern. Welchen Anteil hat die Durchleuchtung?

OBJECTIVE: Determination of the proportion of the dose-area product caused by fluoroscopy at voiding cystourethrography in children, using digital image intensifier technology. PATIENTS AND METHODS: Using computer-assisted dosimetry, we determined the dose-area product and the respective proportions of the dose-area product caused by fluoroscopy and radiography as well as the number of radiographs taken at a given examination of 40 children (8 children less than 2 years old, 15 children between 2 and 6 years old and 17 children between 6 and 15 years old). RESULTS: The computer software program correctly differentiated between fluoroscopy and radiography in 80% of cases. Incorrect results were primarily observed in newborns and young children. The total radiation dose ranged in relation to patient age from 22 to 651 cGy x cm2. Fluoroscopy was responsible for an average 78% of the applied radiation dose. CONCLUSION: Computer-assisted dosimetry is useful in determining the proportion of the dose-area product caused by fluoroscopy in older children undergoing voiding cystourethrography. When image intensifier technology is used, this accounts for more than 75% of the total radiation dose. The method is not suitable for use in small children.

Quantitative assessment of experimental fracture repair by peripheral computed tomography.

An experimental fracture model was used to assess bone mineral density at the fracture site by peripheral computed tomography and to compare the model with biomechanical, histological, and radiographic methods for the quantification of the fracture repair process. Transverse osteotomies in the mid-diaphysis of 28 tibia of sheep were externally fixed and mineral densities, cross-sectional areas, flexural rigidities, tissue composition, and projected callus area were calculated after 9 weeks of healing time. BMD measured by pQCT was strongly correlated with histologically determined percentages of mineralized tissue in the osteotomy gap (R = 0.71) and in the periosteal callus (R2 = 0.62). The percentage of mineralized tissue in the osteotomy gap was the best predictor of the flexural rigidity of the tibiae (R2 = 0.74). Because of high correlations with the histological findings, the volumetric BMD at the level of the osteotomy gap was also strongly correlated with the biomechanical findings (R2 = 0.70). Neither the cross-sectional area in pQCT nor the projected callus area in plane film radiography were positively correlated to the flexural rigidity of the tibiae. Quantitative computed tomography proved to be a successful estimator for the prediction of the mechanical stability of healing bones. The noninvasive procedure is a reliable tool for the quantification of the fracture repair process in experimental studies and may be useful for treatment decisions in particular clinical situations.