Quality of life with second or third line nab-paclitaxel-based regimens in advanced non-small-cell lung cancer.

Aim: Evaluate quality of life (QoL) in patients with advanced non-small cell lung cancer treated with second or third line nab-paclitaxel ± durvalumab. Patients & methods: Longitudinal QoL was assessed using Lung Cancer Symptom Scale, EuroQoL Five-Dimensions Five-Levels and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core. Results: QoL was generally stable through eight treatment cycles (both arms). Clinically meaningful improvement from baseline was noted in Lung Cancer Symptom Scale (overall constitutional score and three-item index [nab-paclitaxel + durvalumab]) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core (global health status/QoL and emotional functioning [both arms] and pain [nab-paclitaxel + durvalumab]) analyses. EuroQoL Five-Dimensions Five-Levels domains were stable/improved or completely resolved at least once in 19-56% and 9-51% of patients, respectively. Conclusion: While QoL trends were promising, additional data are required to support these regimens in this setting.

Analysis of Patients Unable to Undergo Adjuvant Chemotherapy after Surgery in Stage IIIA/B Non-Small Cell Lung Cancer: Will They Benefit from Mediastinal Radiotherapy?

Objectives The role of postoperative mediastinal radiotherapy in completely resected non-small cell lung cancer (NSCLC) and pathological N2 disease is controversial. In clinical practice, not all lung cancer patients with histologically confirmed N2 disease and a high risk for local recurrence are able to undergo postoperative concurrent radio/chemotherapy due to their physical condition or postoperative morbidities. Mediastinal radiotherapy is less compromising than a combination of radio/chemotherapy and seems likely to be tolerable for limited patients to achieve better local tumor control. Materials and Methods All patients included in this retrospective analysis were excluded from postoperative adjuvant combination chemo/radiotherapy due to their comorbidity, advanced age, or a complicated postoperative course. Three-dimensional conformal radiotherapy of the mediastinal lymph node stations (mean dose: 50 Gy; range: 50-54 Gy) in patients with R0 resection, additional boost of 10 Gy in patients with R1 or R2 resection, was performed postoperatively. Results A total of 110 patients were included in this analysis. Mean survival was 25.5 ± 19.2 months. The 1-, 3-, and 5-year survival was 75.4, 38.7, and 26.2%, respectively. Postoperative complications and the development of distant metastases did not correlate (p = 0.7). Distant metastases proved to be a significant prognostic factor of survival (p < 0.0001). Local recurrence was seen in a total of three patients (2.7%). Five-year survival of patients developing major postoperative complications was significantly inferior (p = 0.04) to those without postoperative complications. The extent of surgery had a significant impact on survival-5-year survival after lobectomy was significantly longer than after pneumonectomy (p = 0.029). R1 resection had no significant impact on the survival rates (p = 0.67). Discussion Stage III-N2 NSCLC patients with multiple comorbidities or a complicated postoperative course after surgery may benefit from modern mediastinal radiotherapy. Surgery and postoperative mediastinal radiotherapy can achieve local tumor control. Distant metastases have the highest impact on the prognosis. Pneumonectomy, however, should be avoided in stage III NSCLC, when possible.

Cabazitaxel Versus Topotecan in Patients with Small-Cell Lung Cancer with Progressive Disease During or After First-Line Platinum-Based Chemotherapy.

INTRODUCTION: Patients with small-cell lung cancer (SCLC) typically respond well to initial chemotherapy. However, relapse invariably occurs, and topotecan, the only approved second-line treatment option, has limited efficacy. Taxanes have activity in SCLC, and cabazitaxel is a second-generation taxane with potential for enhanced activity in chemorefractory malignancies. METHODS: Patients with SCLC who relapsed after initial platinum-based chemotherapy were randomly assigned to receive cabazitaxel 25 mg/m every 21 days or topotecan 1.5 mg/m on days 1-5 every 21 days. Two patient subgroups, defined by chemosensitive and chemo-resistant/refractory disease, were assessed in combination and separately. RESULTS: The safety profile of cabazitaxel and topotecan was consistent with previous studies, and despite considerable toxicity in both arms, no new safety concerns were identified. Patients receiving cabazitaxel had inferior progression-free survival compared with topotecan (1.4 versus 3.0 months, respectively; two-sided p < 0.0001; hazard ratio = 2.17, 95% confidence interval = 1.563-3.010), and results were similar in both the chemosensitive and chemorefractory subgroups. No complete responses were observed in either arm, and no partial responses were observed in the cabazitaxel group. The partial response rate in the topotecan arm was 10%. Median overall survival was 5.2 months in the cabazitaxel arm and 6.8 months in the topotecan arm (two-sided p = 0.0125; hazard ratio = 1.57, 95% confidence interval = 1.10-2.25). CONCLUSION: Cabazitaxel, a next-generation taxane, had inferior efficacy when compared with standard-dose topotecan in the treatment of relapsed SCLC. Topotecan remains a suboptimal therapy, and continued efforts to develop improved second-line treatments are warranted.

EGFR mutation status and first-line treatment in patients with stage III/IV non-small cell lung cancer in Germany: an observational study.

INTRODUCTION: EGFR mutations confer sensitivity to EGFR tyrosine kinase inhibitors (TKI) in advanced non-small cell lung cancer (NSCLC). We investigated the clinicopathologic characteristics associated with EGFR mutations and their impact on real-world treatment decisions and outcomes in Caucasian patients with advanced NSCLC. METHODS: REASON (NCT00997230) was a noninterventional multicenter study in patients (≥18 years) with stage IIIb/IV NSCLC, who were candidates for EGFR mutation testing and first-line systemic treatment, but not eligible for surgery or radiotherapy. Patients were followed up according to normal clinical practice and assessed for primary (correlation of mutation status with baseline characteristics) and secondary endpoints (first-line treatment decision). RESULTS: Baseline data were obtained for 4,200 patients; 4,196 fulfilled the inclusion criteria; EGFR mutations were detected in 431 patients; no EGFR mutations were detected in 3,590 patients; mutation status was not evaluable in 175 patients. In multivariate analysis, the odds of EGFR mutations were significantly higher (P < 0.0001) in females versus males (odds ratio: 1.85; 95% confidence interval, 1.48-2.32), never-smokers versus smokers (3.64; 2.91-4.56), and patients with adenocarcinoma versus other histologic subtypes (2.94; 2.17-4.08). The most commonly prescribed first-line systemic treatments were: EGFR-TKIs in EGFR mutation-positive NSCLC (56.6%) and combination chemotherapy in EGFR mutation-negative NSCLC (78.5%). CONCLUSIONS: This represents the largest dataset for EGFR mutations in Caucasian patients and shows EGFR mutations to be most prevalent in females with adenocarcinoma who had never smoked. IMPACT: These findings add to our understanding of the prognostic and predictive factors of NSCLC, supporting future improved treatment selection.

Impact of ischemia-reperfusion on extracellular matrix processing and structure of the basement membrane of the heart.

PURPOSE: Acute ischemic injury is a strong inductor of cardiac remodelling, resulting in structural changes of the extracellular matrix (ECM) and basement membrane (BM). In a large animal model of ischemia-reperfusion (I/R) we investigated the post-ischemic liberation of the collagen-IV-fragments Tumstatin (TUM; 28 kDa-fragment of collagen-IV-alpha-3), Arresten (ARR; 26 kDa-fragment of collagen-IV-alpha-1) and Endorepellin (LG3, 85 kDa-fragment of perlecan) which are biologically active in angiogenesis and vascularization in the post-ischemic myocardium. METHODS AND RESULTS: In this blinded study, 30 pigs were randomized to 60 min of global I/R at either 4°C or 32°C or served as control. Three transmyocardial tissue samples were collected prior to ischemia and within 30 min and 150 min of reperfusion. Tissue content of TUM, ARR and LG3 was analyzed by western blotting and immunostaining. Within 150 min of mild hypothermic I/R a significantly increased tissue content of ARR (0.17±0.14 vs. 0.56±0.56; p = 0.001) and LG3 (1.13±0.34 vs. 2.51±1.71, p<0.001) was observed. In contrast, deep hypothermic I/R was not associated with a significant release of cleavage products. Cleavage of TUM remained unchanged irrespective of temperature. Increased matrix processing following mild hypothermia I/R is further supported by a >11fold elevation of creatine kinase (2075±2595 U/l vs. 23248±6551 U/l; p<0.001) in the coronary sinus plasma samples. Immunostaining demonstrated no changes for ARR and LG3 presentation irrespective of temperature. In contrast, TUM significantly decreased in the BM surrounding cardiomyocytes and capillaries after mild and deep hypothermic I/R, thus representing structural alterations of the BM in these groups. CONCLUSION: The study demonstrates an early temperature-dependent processing of Col-IV as major component of the BM of cardiomyocytes and vascular endothelium. These observations support the protective effects of deep hypothermia during I/R. Furthermore, the results suggest an increased structural remodelling of the myocardial basement membrane with potential functional impairment during mild hypothermic I/R which may contribute to the progression to post-ischemic heart failure.

Efficacy of cineole in patients suffering from acute bronchitis: a placebo-controlled double-blind trial.

OBJECTIVE: Cineole has mucolytic, bronchodilating and anti-inflammatory properties and reduces the exacerbation rate in patients suffering from COPD, as well as ameliorates symptoms in patients suffering from asthma and rhinosinusitis. Based on these effects, we therefore postulated the hypothesis that patients with acute bronchitis would also benefit from therapy with Cineole. METHODS: As part of a double-blind, placebo-controlled, multi-center-study, a total of 242 patients with confirmed acute bronchitis was randomly selected to participate. Over a period of 10 days, all patients were administered 3 x 200 mg of Cineole, or a respective placebo, per day. The primary outcome measure was a Bronchitis Sum Score, which summarises the relevant symptoms of acute bronchitis. RESULTS: After 4 days of treatment it was notable, that the patient group treated with Cineole, showed significantly more improvements of the bronchitis-sum-score than those of the placebo group (p = 0.0383). The statistical significant difference of the individual outcome measures was especially underlined by the frequency of cough fits by p = 0.0001 after 4 days. CONCLUSIONS: The effects of Cineole in the treatment of acute bronchitis were clearly measurable and could be proven after a treatment period of merely 4 days. This study corroborates the fact that Cineole actively and significantly reduces cough frequency after four days. Therefore it has been shown to have a great socioeconomic impact. TRIAL REGISTRATION ISRCTN: ISRCTN37784439.

Phase-I study of sagopilone in combination with cisplatin in chemotherapy-naive patients with metastasised small-cell lung cancer.

BACKGROUND: Sagopilone (ZK219477) is a new and fully synthetic epothilone with activity against multi-drug resistant tumour cell lines. It has demonstrated clinical activity in several solid tumours like ovarian cancer and melanoma. Data about clinical efficacy of sagopilone in small-cell lung cancer are lacking. Here we report the first phase-I trial of sagopilone in combination with cisplatin in previously untreated metastatic small-cell lung cancer patients. METHODS: Chemonaive patients with metastatic small-cell lung cancer (SCLC) received sagopilone in four different dosing schedules ranging from 12 to 22 mg/m(2) (on day 1 as 3-h infusion) followed by a fixed dose of cisplatin of 75 mg/m(2) as 1-h infusion on day 1. Chemotherapy was administered every 3 weeks to a maximum of six cycles. The primary objective was determination of dose-limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) in this setting. Secondary objectives were assessment of objective response rates (ORR) as well as investigation of sagopilone pharmacokinetics. RESULTS: Twenty-six patients received a total of 107 treatment cycles of the platinum-sagopilone doublet. The recommended phase-II dose (RD) and schedule was found to be 19 mg/m(2) sagopilone followed by 75 mg/m(2) cisplatin. Peripheral neuropathy turned out as dose-limiting toxicity when the combination was administered over a median of four cycles. Objective responses were observed in six out of seven SCLC patients (85.7%) treated with the RD. CONCLUSIONS: Sagopilone and cisplatin can be safely combined in the first-line treatment of metastasised SCLC. This combination demonstrated preliminary efficacy and should be further evaluated within phase-II trials.

Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer.

PURPOSE: We assessed whether chemotherapy selection based on in situ ERCC1 and RRM1 protein levels would improve survival in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients were randomly assigned 2:1 to the trial's experimental arm, which consisted of gemcitabine/carboplatin if RRM1 and ERCC1 were low, docetaxel/carboplatin if RRM1 was high and ERCC1 was low, gemcitabine/docetaxel if RRM1 was low and ERCC1 was high, and docetaxel/vinorelbine if both were high. In the control arm, patients received gemcitabine/carboplatin. The trial was powered for a 32% improvement in 6-month progression-free survival (PFS). RESULTS: Of 331 patients registered, 275 were eligible. The median number of cycles given was four in both arms. A tumor rebiopsy specifically for expression analysis was required in 17% of patients. The median time from informed consent to expression analysis was 11 days. We found no statistically significant differences between the experimental arm and the control arm in PFS (6.1 months v 6.9 months) or overall survival (11.0 months v 11.3 months). A subset analysis revealed that patients with low levels for both proteins who received the same treatment in both treatment arms had a statistically better PFS (P = .02) in the control arm (8.1 months) compared with the experimental arm (5.0 months). CONCLUSION: This demonstrates that protein expression analysis for therapeutic decision making is feasible in newly diagnosed patients with advanced-stage NSCLC. A tumor rebiopsy is safe, required in 17%, and acceptable to 89% (47 of 53) of patients.

Tasisulam sodium (LY573636 sodium) as third-line treatment in patients with unresectable, metastatic non-small-cell lung cancer: a phase-II study.

INTRODUCTION: Tasisulam sodium (hereafter referred to as tasisulam) is a novel anticancer compound that induces apoptosis and exhibits antiangiogenesis activity in a broad range of cancer models, including non-small-cell lung cancer (NSCLC). METHODS: Tasisulam was administered as a 2-hour infusion every 21 days as third-line treatment in patients with advanced (stage IIIB/IV) NSCLC. RESULTS: Thirty-two patients received a Cmax target dose of 420 µg/ml. Median time to progression was 3.12 months, median progression-free survival was 2.69 months, and median overall survival was 8.48 months. There were no objective responses; 43.8% of patients achieved stable disease. A high rate of grade-4 hematologic toxicity in the first 30 patients led to exploration of a lower Cmax target dose of 380 µg/ml. The rate of grade-4 hematologic toxicity (thrombocytopenia and/or neutropenia) at the 380-µg/ml dose (n = 20) was 20% versus 34% at the 420-µg/ml dose. CONCLUSIONS: Tasisulam has only modest activity as a third-line treatment of patients with unresectable/metastatic NSCLC. The high rate of grade-4 hematologic toxicity observed with this highly albumin- bound compound in this patient population provided challenges for fixed Cmax-based dosing. Alternative dosing methods, including varying the Cmax target dose by predose albumin, are under investigation in other studies.

Experimental immediate loading of dental implants in conjunction with grafting procedures.

The aim of this study was to evaluate immediate loading (IL) of dental implants in conjunction with grafting procedures. A total of 107 IL implants were inserted in six mini pigs. Before implant placement, crestal or apical defects were created, which were treated with bone chips, phycogene hydroxyapatite (HA), bovine HA, or bovine HA enhanced with a synthetic peptide. Crestal grafts were stabilized with titanium membranes. All bridges were in function and showed signs of chewing wear after 4-month loading. Three out of 107 implants showed no osseointegration (2.7%). Most of the crestal defects showed incomplete regeneration, due to an infection of the membranes (74.3%) The difference in height between surgical and remaining defect was calculated as defect development, which was 2.3 +/- 2.08 mm for bone chips with an area of regenerated bone of 22.8 +/- 3.34% and 0.7 +/- 2.22 mm for phycogene HA with 11.3 +/- 4.36% regenerated bone. Bovine HA showed an increase of defects 1.3 +/- 2.47 mm with only 7.9 +/- 1.7% bone regeneration. Bovine HA enhanced with a peptide showed a defect development of 1.1 +/- 1.42 mm with an area of regenerated bone of 18.2 +/- 2.38%. In conclusion, local grafting procedures did not disturb the course of osseointegration for immediate loaded implants if primary stability was reached. The regeneration of apical defects was uneventful even with immediate loading. Crestal defects required membrane fixation with a careful flap elevation to avoid membrane exposure and loss of the graft.

Influence of host periosteum and recipient bed perforation on the healing of onlay mandibular bone graft: an experimental pilot study in the sheep.

PURPOSE: The aim of this study was to evaluate the role of host periosteum and recipient bed perforation on the healing of an onlay graft to the mandible based on histologic and immunohistochemical analysis. MATERIALS AND METHODS: Each of the 12 adult sheep used in the study received four iliac corticocancellous onlay bone grafts on the lateral surface of the mandible. In experiment 1, the block graft was placed in direct contact with the recipient bed and fixed with micro-screws, and in experiment 2, the recipient cortical bed was perforated before graft placement. The host periosteum around the graft was excised before flap replacement in experiment 3, and in experiment 4, a sheet of silicone membrane was placed between the graft and the recipient bed. The animals were euthanised at 4, 8, 12 and 16 weeks after surgery and the findings were analysed by routine microscopy (haematoxylin and eosin and tartrate-resistant acid phosphatase [TRAP] stains) and immunohistochemistry for proliferation and apoptotic markers (Ki67, caspase-3 and TUNEL stains). RESULTS: After 8 weeks, full graft-host integration was seen in all the experimental groups except experiment 4. After 16 weeks, pronounced graft resorption and volume reduction was observed in experiments 1 and 2, whilst experiment 3 was characterised with extensive connective tissue infiltration and severe resorption of the graft. The number of osteoclasts expressed peaked at 4 weeks in experiments 1 and 2 and at 16 weeks in experiment 3. Immunoreactivity for Ki67 by osteoblasts lining the trabecular bone of the graft's spongiosa expressed moderate level of Ki67 at 8 weeks, and thereafter declined markedly. The strongest expression of caspase-3 on the bone surface was observed after 16 weeks. DISCUSSION AND CONCLUSION: Recipient cortical bed perforation offered no advantage over non-perforated bed regarding healing and integration of a bone graft. Excision of the host overlying the periosteum was accompanied with rapid absorption of the grafts and partial or complete replacement with fibrous connective tissue. This study also demonstrated that cell death by apoptosis is a fundamental component of osteoblastic phenotypic differentiation during healing of corticocancellous bone graft.

Polarization of skylight in the O(2)A band: effects of aerosol properties.

Motivated by several observations of the degree of linear polarization of skylight in the oxygen A (O(2)A) band that do not yet have a quantitative explanation, we analyze the influence of aerosol altitude, microphysics, and optical thickness on the degree of linear polarization of the zenith skylight in the spectral region of the O(2)A band, between 755 to 775 nm. It is shown that the degree of linear polarization inside the O(2)A band is particularly sensitive to aerosol altitude. The sensitivity is strongest for aerosols within the troposphere and depends also on their microphysical properties and optical thickness. The polarization of the O(2)A band can be larger than the polarization of the continuum, which typically occurs for strongly polarizing aerosols in an elevated layer, or smaller, which typically occurs for depolarizing aerosols or cirrus clouds in an elevated layer. We show that in the case of a single aerosol layer in the atmosphere a determination of the aerosol layer altitude may be obtained. Furthermore, we show limitations of the aerosol layer altitude determination in case of multiple aerosol layers. To perform these simulations we developed a fast method for multiple scattering radiative transfer calculations in gaseous absorption bands including polarization. The method is a combination of doubling-adding and k-binning methods. We present an error estimation of this method by comparing with accurate line-by-line radiative transfer simulations. For the Motivated by several observations of the degree of linear polarization of skylight in the oxygen A (O(2)A) band that do not yet have a quantitative explanation, we analyze the influence of aerosol altitude, microphysics, and optical thickness on the degree of linear polarization of the zenith skylight in the spectral region of the O(2)A band, between 755 to 775 nm. It is shown that the degree of linear polarization inside the O(2)A band is particularly sensitive to aerosol altitude. The sensitivity is strongest for aerosols within the troposphere and depends also on their microphysical properties and optical thickness. The polarization of the O(2)A band can be larger than the polarization of the continuum, which typically occurs for strongly polarizing aerosols in an elevated layer, or smaller, which typically occurs for depolarizing aerosols or cirrus clouds in an elevated layer. We show that in the case of a single aerosol layer in the atmosphere a determination of the aerosol layer altitude may be obtained. Furthermore, we show limitations of the aerosol layer altitude determination in case of multiple aerosol layers. To perform these simulations we developed a fast method for multiple scattering radiative transfer calculations in gaseous absorption bands including polarization. The method is a combination of doubling-adding and k-binning methods. We present an error estimation of this method by comparing with accurate line-by-line radiative transfer simulations. For the O(2)A band, the errors in the degree of linear polarization are less than 0.11% for transmitted light, and less than 0.31% for reflected light. band, the errors in the degree of linear polarization are less than 0.11% for transmitted light, and less than 0.31% for reflected light.

Pneumocyte apoptosis induction during cardiopulmonary bypass: effective prevention by radical scavenging using N-acetylcysteine.

Cardiopulmonary bypass (CPB) and cardioplegic arrest are associated with pulmonary dysfunction. We sought to investigate whether pulmonary ischemia/reperfusion during standard CPB and cardioplegic arrest is associated with reactive oxygen species (ROS)-mediated pulmonary tissue injury and pneumocyte apoptosis induction, and whether ROS scavenging using N-acetylcysteine (NAC) attenuates these alterations. Twelve pigs (41 +/- 8 kg) were randomized to receive either NAC (100 mg/kg prior to CPB; n = 7) or placebo (n = 5) and subjected to CPB and 60 min of cold (4 degrees C) crystalloid cardioplegic arrest. We collected lung biopsies prior to CPB, at 60 min CPB, as well as at 30, 60, and 120 min post CPB. Lung specimens were immunocytochemically stained against nitrotyrosine, 8-isoprostaglandin-F(2)alpha, and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) as indicators for ROS-mediated tissue injury and active caspase-3, an apoptosis signal pathway key enzyme. Oxidative stress markers were judged using a scale from 1 to 4 (low to intensive staining), and caspase-3-positive pneumocytes were counted per view field. In placebo, the number of caspase-3-positive pneumocytes significantly increased over time to reach a maximum at 120 min post CPB (p = .03 vs baseline). NAC significantly prevented caspase-3 activation in pneumocytes (p = .001 vs Placebo). Pneumocyte nitrotyrosine and 8-OH-dG staining significantly increased over time (p = .003) in the placebo group, but decreased in the NAC group (p = .004). In both groups staining for 8-isoprostaglandin-F(2)alpha showed no significant changes. This yields the conclusion that standard CPB and cardioplegic arrest initiate ROS-mediated tissue injury and apoptosis in pneumocytes that can be reduced by NAC. Thus, ROS scavenging using NAC may represent a novel approach to minimize lung injury associated with CPB.

Effect of aerosol microphysical properties on polarization of skylight: sensitivity study and measurements.

We analyze the sensitivity of the degree of linear polarization in the Sun's principal plane as a function of aerosol microphysical parameters: the real and imaginary parts of the refractive index, the median radius and geometric standard deviation of the bimodal size distribution (both fine and coarse modes), and the relative number weight of the fine mode at a wavelength of 675 nm. We use Mie theory for single-scattering simulations and the doubling-adding method with the inclusion of polarization for multiple scattering. It is shown that the behavior of the degree of linear polarization is highly sensitive to both the small mode of the bimodal size distribution and the real part of the refractive index of aerosols, as well as to the aerosol optical thickness; whereas not all parameters influence the polarization equally. A classification of the importance of the input parameters is given. This sensitivity study is applied to an analysis of ground-based polarization measurements. For the passive remote sensing of microphysical and optical properties of aerosols, a ground-based spectral polarization measuring system was built, which aims to measure the Stokes parameters I, Q, and U in the visible (from 410 to 789 nm) and near-infrared (from 674 to 995 nm) spectral range with a spectral resolution of 7 nm in the visible and 2.4 nm in the near infrared. We compare polarization measurements taken with radiative transfer simulations under both clear- and hazy-sky conditions in an urban area (Cabauw, The Netherlands, 51.58 degrees N, 4.56 degrees E). Conclusions about the microphysical properties of aerosol are drawn from the comparison.

LIFEBRIDGE: a portable, modular, rapidly available "plug-and-play" mechanical circulatory support system.

PURPOSE: We describe the LIFEBRIDGE, a portable, modular, rapidly available "plug-and-play" mechanical circulatory support system, and report its experimental safety evaluation. DESCRIPTION: The modular construction consists of a disposable patient module with cardiopulmonary bypass circuit, control module, and base module with power supply, embedded PC, and user interface. The system weighs about 20 kg, has a modular design, and has semi-automatic priming that allows action within 5 minutes, and a 7-step air elimination program that prevents air embolization. EVALUATION: In eight pigs (85 +/- 10 kg) we investigated this system using central (right atrium and ascending aorta) cannulation (n = 4) or peripheral (iliac) cannulation (n = 4). Pump flows were 5.7 +/- 0.2 L/min with central and 4.1 +/- 0.2 L/min with peripheral cannulation, yielding sufficient animal perfusion and gas exchange. Using an intraaortic 8-MHz Doppler device, we demonstrated that venous air boluses of up to 100 mL were effectively removed, thus avoiding air embolization. Changing heights between animals and LIFEBRIDGE did not affect its proper action. CONCLUSIONS: This initial evaluation demonstrates that the LIFEBRIDGE is rapidly available, provides adequate perfusion and gas exchange, and operates safely even under simulated transport conditions.

Pharmacologic cerebral capillary blood flow improvement after deep hypothermic circulatory arrest: an intravital fluorescence microscopy study in pigs.

BACKGROUND: Despite meticulous investigation of bypass techniques for deep hypothermic circulatory arrest, unfavorable long-term neurologic deficits have been well documented. Our aim was to improve brain perfusion by reducing platelet plugging with a glycoprotein IIb/IIIa inhibitor (eptifibatide) in an experimental model of deep hypothermic circulatory arrest-reperfusion in pigs. METHODS: Two groups of 12 piglets each (eptifibatide group [eptifibatide + unfractionated heparin] vs UFH group [only unfractionated heparin]) underwent 10 minutes of normothermic bypass, 40 minutes of cooling during cardiopulmonary bypass (hematocrit, 30%; cardiopulmonary bypass flow, 100 mL x kg(-1) x min(-1)), 60 minutes of circulatory arrest at 15 degrees C, and a 40-minute rewarming period. Intravital fluorescence microscopy of pial vessels at set intervals was performed. RESULTS: During the cooling period, there was a tendency toward reduced functional capillary density values without statistical significance in both groups. During reperfusion, the eptifibatide group demonstrated a significantly decreased platelet adhesion and aggregation (at 30 minutes of reperfusion: functional capillary density, 104% +/- 3% vs 77% +/- 4% relative to baseline, P = .02; red blood cell velocity, 0.65 vs 0.30 mm/s, P < .004). A more rapid recovery of tissue oxygenation (P < .001) was documented. Furthermore, a significant microvascular permeability reduction was achieved compared with that seen in the UFH group (P < .02). The use of eptifibatide resulted in fewer ultrastructural changes in hippocampal tissue, which is demonstrated by histologic examination. CONCLUSIONS: Platelet plugging reduction with the glycoprotein IIb/IIIa inhibitor eptifibatide improves cerebral capillary blood flow and reduces cerebral ischemia in the setting of deep hypothermic circulatory arrest. Furthermore, significant endothelial cell injury and perivascular edema reduction can be achieved.

Effect of the Na+/H+ exchange inhibitor eniporide on cardiac performance and myocardial high energy phosphates in pigs subjected to cardioplegic arrest.

BACKGROUND: Pharmacologic Na(+)/H(+) exchange inhibition has been suggested to ameliorate cardiac performance depression associated with myocardial ischemia/reperfusion. The purpose of our experimental study was to investigate the impact of the novel Na(+)/H(+) exchange inhibitor Eniporide (EMD 96785) on cardiac performance and high energy phosphate content in a clinically relevant pig model of cardioplegic arrest. METHODS: We subjected 21 pigs (47 +/- 12 [SD] kg) to cardiopulmonary bypass (CPB) and 60 minutes cold (4 degrees C) crystalloid cardioplegic arrest (Bretschneider). The pigs were randomized to receive either systemic infusion of 3 mg/kg Eniporide before cardioplegia with added 2 micromol/L Eniporide (ENI-CP+iv; n = 7); 3 mg/kg Eniporide in cardioplegia only (ENI-CP; n = 7); or no Eniporide (control; n = 7). For cardiac performance determination we measured preload recruitable stroke work and Tau, the time constant of left ventricular (LV) isovolumic relaxation using sonomicrometry and micromanometry before CPB as well as 30, 60, and 120 minutes after weaning off CPB. LV and right ventricular myocardial adenine nucleotides (ATP, ADP, and AMP), glycogen, and water content were determined at the end of the experiments. RESULTS: Neither for standard hemodynamics including vascular pressures and cardiac index nor for cardiac performance factors did we find statistically significant differences between the groups. Similarly, myocardial adenine nucleotides, glycogene, and water content did not differ significantly between the groups. CONCLUSIONS: In this acute study we did not find significant effects of the Na(+)/H(+) exchange inhibitor Eniporide on cardiac performance and high energy phosphate content in healthy pig hearts subjected to ischemia/reperfusion induced by crystalloid cardioplegic arrest.

Cardioplegic arrest induces apoptosis signal-pathway in myocardial endothelial cells and cardiac myocytes.

OBJECTIVE: Myocardial ischemia-reperfusion is associated with free radical-mediated injury and may be involved in cardiac apoptosis. The purpose of our study was to investigate (1) if cardioplegia-induced ischemia-reperfusion initiates cardiac apoptosis signal pathway, and (2) if this is mediated by free radicals. METHODS: We subjected 13 pigs (56+/-10 kg) to 1 h of cold crystalloid cardioplegic arrest (CA) on cardiopulmonary bypass (CPB), and collected five transmural LV biopsies: prior to CPB (baseline), at 60 min CA, at 15 and 30 min reperfusion on CPB, and at 120 min post CPB. Two additional pigs were subjected to CPB but not CA and two further pigs were neither subjected to CPB nor CA and served as sham-operated time controls. LV specimens were cut at 7 microm and immunocytochemically stained against active caspase-3 and 85 kDa poly(ADP-ribose) polymerase (PARP) as apoptosis signal-pathway key enzymes, nitrotyrosine as indicator for peroxynitrite (ONOO(-))-mediated tissue injury, and 8-iso-prostaglandin-F(2)alpha as indicator for oxygen free radical-mediated lipid peroxidation. Specimen were assessed using a scale of 0 (negative) to 3 (highly positive), and cardiomyocytes were quantitatively investigated using TV densitometry. RESULTS: At 60 min CA, caspase-3 was increased by 9.2+/-3.7 gray units and remained on this level until 2 h post CPB (P