Docetaxel-carboplatin chemotherapy combined with cetuximab in patients with locally advanced or metastatic non small-cell lung cancer (NSCLC)--results of the nonrandomised phase II study TaxErb.

This open label, single arm phase II study was designed to evaluate the efficacy and safety of the addition of cetuximab to first line chemotherapy with carboplatin and weekly docetaxel in patients with advanced non small-cell lung cancer (NSCLC). From February 2007 to December 2008 74 patients with NSCLC (stage IIIB and IV), ECOG PS ≤2 and no prior systemic chemotherapy were enrolled and treated with carboplatin (area under the curve=5 on day 1) and docetaxel (35 mg/m(2) on days 1, 8, and 15). Cycles were repeated every 4 weeks for a minimum of 4 and a maximum of 6 cycles. Cetuximab (400mg/m(2) on day 1 with subsequent doses of 250 mg/m(2) weekly) was administered until progression or intolerable toxicity up to a maximum treatment duration of 12 months. The primary endpoint was the overall response rate (CR+PR) according to RECIST. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Patients received a median of 4 cycles of docetaxel-carboplatin-chemotherapy. The median number of administrations of cetuximab was 14. Sixty-seven patients were evaluable for response. Partial response was seen in 29/67 patients corresponding to an overall response rate (ORR) of 43.3% (95%CI, 28.5-53.7). No patient experienced complete response. The clinical benefit rate (PR+SD) was 79.1%. The 1-year rates for PFS and OS were 11.2% and 64.4%, respectively. Median PFS was 4.8 months (95%CI, 3.70-5.31) and median OS 12.9 months (95%CI 8.26-∞). Adverse events were mainly grades 1-2. Skin toxicity (76% of pts), dyspnea (36.5%) and anemia (31.1%) were most frequent. Results from this phase II study suggest that the addition of cetuximab to first-line doublet carboplatin and weekly docetaxel results in a considerable clinical efficacy with an acceptable toxicity profile for patients with advanced or metastatic NSCLC.

Effectiveness of bi-atrial pacing for reducing atrial fibrillation after coronary artery bypass graft surgery.

Atrial fibrillation (AF) is common after cardiac surgery and adds significant cost and morbidity. The use of prophylactic pacing strategies to prevent post-operative AF has been controversial. We previously performed a pilot study which suggested that the combination of beta-blockers and bi-atrial pacing (BAP) may reduce AF after cardiac surgery. We prospectively randomized 118 patients to continuous BAP for up to 96 hours post-operatively versus standard therapy. All patients were treated with beta-blockers as tolerated. Patients were paced in the AAI mode at a rate of 100 pulses per minute. The primary endpoint of the study was the occurrence of sustained AF (>10 minutes). There was a significant reduction in the incidence of AF in the BAP group among patients undergoing coronary artery bypass graft surgery with or without aortic valve replacement (35 % vs. 19 % AF; OR=0.38, 95 % CI 0.15, 0.93; p <0.05). Including patients undergoing isolated aortic valve surgery (n=7), there remained a strong trend toward a reduction of AF with pacing (no atrial pacing [NAP] vs. BAP; 35 % vs. 21 % AF; OR=0.48, 95 % CI 0.21, 1.11; p=0.08). Patients age 70 or greater benefited most from pacing (NAP vs. BAP; 55 vs. 25 % AF; p<0.05), while those less than 70 years of age did not (17 vs. 18 % p=NS). There was a significant reduction in the amount of time spent in the intensive care unit among patients receiving BAP (50+/-40 vs. 37+/-25 h; p<0.05).BAP together with beta-blockade after coronary artery bypass graft surgery reduces the incidence of post-operative atrial AF. Elderly patients (age 70 or greater) appear to benefit most, and may be a group to whom this therapy should be targeted.

Dynamics of immature secretory granules: role of cytoskeletal elements during transport, cortical restriction, and F-actin-dependent tethering.

Secretory granules store neuropeptides and hormones and exhibit regulated exocytosis upon appropriate cellular stimulation. They are generated in the trans-Golgi network as immature secretory granules, short-lived vesicular intermediates, which undergo a complex and poorly understood maturation process. Due to their short half-life and low abundance, real-time studies of immature secretory granules have not been previously possible. We describe here a pulse/chase-like system based on the expression of a human chromogranin B-GFP fusion protein in neuroendocrine PC12 cells, which permits direct visualization of the budding of immature secretory granules and their dynamics during maturation. Live cell imaging revealed that newly formed immature secretory granules are transported in a direct and microtubule-dependent manner within a few seconds to the cell periphery. Our data suggest that the cooperative action of microtubules and actin filaments restricts immature secretory granules to the F-actin-rich cell cortex, where they move randomly and mature completely within a few hours. During this maturation period, secretory granules segregate into pools of different motility. In a late phase of maturation, 60% of secretory granules were found to be immobile and about half of these underwent F-actin-dependent tethering.

Successful coronary artery bypass surgery in a patient with AIDS.

We report the case of a 47-year-old man with AIDS who underwent a successful quadruple coronary artery bypass operation. The improving prognosis of patients with HIV/AIDS, in addition to the reported incidence of plasma lipid abnormalities in patients receiving protease inhibitors, are laying the groundwork for a larger population in which premature coronary artery disease develops. Operative risk, immunosuppressive effect of cardiopulmonary bypass, and practical considerations in the care of these patients are discussed.

Unusual primary tumors of the heart.

Primary tumors of the heart, with the exception of atrial myxomas, occur rarely; tumors metastatic to or directly invasive of the heart are far more common. About 75% of primary tumors are benign, and 75% of these are atrial myxomas. The benign tumors include rhabdomyomas, fibromas, papillary fibroelastomas, hemangiomas, pericardial cysts, lipomas, hamartomas, teratomas, mesotheliomas, and paragangliomas or pheochromocytomas. The last 3 may also be malignant. The malignant tumors consist of various sarcomas: myxosarcoma, liposarcoma, angiosarcoma, fibrosarcoma, leiomyosarcoma, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, undifferentiated sarcoma, reticulum cell sarcoma, neurofibrosarcoma, and malignant fibrous histiocytoma. Cardiac tumors produce a large variety of symptoms through any of 4 mechanisms. Their mass can obstruct intracardiac blood flow or interfere with valve function. Local invasion can lead to arrhythmias or pericardial effusions with tamponade. Bits of tumor can embolize, causing systemic deficits when the tumors are on the left side of the heart. Finally, the tumors may cause systemic or constitutional symptoms. Some tumors, of course, produce no symptoms and become evident as incidental findings. The most useful diagnostic tool is the echocardiogram, which in almost all cases precisely locates the tumor and defines its extent. The echocardiographic appearance may also allow quite accurate prediction of the tumor type and whether it is malignant or benign. Magnetic resonance imaging serves as the next most important test where the density of T1 and T2 images may allow tumor cell type identification. With few exceptions, these tumors require operative excision. Most benign tumors can be resected completely; a few, because of their large size, cannot be, and only tumor debulking may be possible. Heart transplantation should be considered for these patients. Many of the malignant tumors cannot be resected completely, either because of the extent of local spread and invasion or because of the frequent distant metastases. Transplantation may also be an option for those with extensive local disease. The long-term results for resected benign tumors are excellent; the long-term results for sarcomas are very poor, and there are few survivors. For patients with unresectable sarcomas, radiation and chemotherapy may be used, but without great expectation of successful results.

Off-pump versus on-pump coronary artery bypass surgery: a case-matched comparison of clinical outcomes and costs.

BACKGROUND: Results of off-pump coronary artery bypass (OPCAB) surgery have demonstrated trends toward fewer complications, faster recoveries and lower costs compared with on-pump coronary artery bypass (ONCAB) surgery. The validity of such comparisons, however, may be impacted by differences in preoperative risk factors between the two surgeries. METHODS: A total of 76 OPCAB surgery patients were case-matched (by age, sex and Society of Thoracic Surgeons' risk scores) with an equal number of patients who underwent ONCAB surgery by the same surgeon. Postoperative clinical parameters (time on mechanical ventilation, number of blood transfusions, peak cardiac enzyme levels and metabolic acidosis) and outcomes data (intensive care unit and overall in-hospital lengths of stay, perioperative myocardial infarction, atrial fibrillation, stroke, reoperation for bleeding and mortality) were analyzed, and the variable and total costs for each patient were calculated. RESULTS: OPCAB patients required less mechanical ventilation and fewer blood transfusions and had lower peak creatinine phosphokinase levels, as well as a reduced incidence of metabolic acidosis. There were trends toward both shorter intensive care unit and overall in-hospital lengths of stay for OPCAB patients. The average total cost for this group was 20.5% less than for ONCAB patients. There were no differences in rates of atrial fibrillation, myocardial infarction, reoperation for bleeding, stroke or mortality. CONCLUSIONS: By reducing the need for mechanical ventilation, transfusions and intensive care unit and overall in-hospital lengths of stay, OPCAB surgery decreases the use of limited and costly resources without increasing risks. These advantages do not appear to be related to patient selection.

Evaluation of right atrial and biatrial temporary pacing for the prevention of atrial fibrillation after coronary artery bypass surgery.

OBJECTIVES: The purpose of this study was to determine if atrial pacing is effective in reducing postoperative atrial fibrillation (AF). BACKGROUND: Atrial fibrillation after coronary artery bypass grafting (CABG) is a common problem for which medical management has been disappointing. Atrial-based pacing has become an attractive nonpharmacologic therapy for the prevention of AF. METHODS: Sixty-one post-CABG patients (mean age = 65 years) were randomized to one of three groups: no atrial pacing (NAP), right atrial pacing (RAP) or biatrial pacing (BAP). Each patient had one set of atrial wires attached to both the right and left atria, respectively, at the conclusion of surgery. Patients in the RAP and BAP groups were continuously paced at a rate of 100 pulses per minute for 96 h or until the onset of sustained AF (>10 min). All patients were monitored with Holter monitors or full disclosure telemetry to identify the onset of AF. The primary end point of the study was the first onset of sustained AF. RESULTS: There was no significant difference in the proportion of patients developing AF in the three groups (NAP = 33%; RAP = 29%; BAP = 37%; p > 0.7). However, for the subset of patients on beta-adrenergic blocking agents after CABG, there was a trend toward less AF in the paced groups. There were no serious complications related to pacing, although in three patients the pacemaker appeared to induce AF by pacing during atrial repolarization. CONCLUSIONS: Continuous right or biatrial pacing in the postoperative setting is safe and well tolerated. We did not find that post-CABG pacing prevented AF in this pilot study; however, the role of combined pacing and beta-blockade merits further study.

The disulfide-bonded loop of chromogranin B mediates membrane binding and directs sorting from the trans-Golgi network to secretory granules.

The disulfide-bonded loop of chromogranin B (CgB), a regulated secretory protein with widespread distribution in neuroendocrine cells, is known to be essential for the sorting of CgB from the trans-Golgi network (TGN) to immature secretory granules. Here we show that this loop, when fused to the constitutively secreted protein alpha1-antitrypsin (AT), is sufficient to direct the fusion protein to secretory granules. Importantly, the sorting efficiency of the AT reporter protein bearing two loops (E2/3-AT-E2/3) is much higher compared with that of AT with a single disulfide-bonded loop. In contrast to endogenous CgB, E2/3-AT-E2/3 does not undergo Ca2+/pH-dependent aggregation in the TGN. Furthermore, the disulfide-bonded loop of CgB mediates membrane binding in the TGN and does so with 5-fold higher efficiency if two loops are present on the reporter protein. The latter finding supports the concept that under physiological conditions, aggregates of CgB are the sorted units of cargo which have multiple loops on their surface leading to high membrane binding and sorting efficiency of CgB in the TGN.

Thoracoscopic lobectomy with endoarterial vascular control: an experimental study in swine.

BACKGROUND: Video-assisted lobectomy lacks vascular control and presents the potential for serious hemorrhage in a closed cavity. The use of a lighted, flow-directed balloon catheter in the pulmonary artery as an endovascular control device was evaluated. METHODS: A modified light-bearing Swan-Ganz catheter was placed in the left or right pulmonary artery using fluoroscopy. The lit catheter was identified easily through the arterial wall at thoracoscopy. Its inflation allowed the control of proximal blood flow as required. Fully thoracoscopic lobectomy was carried out by isolating and dividing the lobar branches of the pulmonary artery, the pulmonary vein, and the bronchus in anesthetized swine. RESULTS: Forty-two video-assisted anatomic lobectomies were completed in 30 pigs with balloon catheter control of the pulmonary artery. The balloon effectively controlled experimental hemorrhage caused by puncturing arterial branches (n = 4). It allowed the transection of unlooped lobar arteries (n = 42) and the main interlobar pulmonary artery (n = 3). Catheter displacement back to the heart occurred in 5 animals and balloon catheter technical failures occurred in 3. CONCLUSIONS: The lighted, flow-directed balloon catheter was an effective means of avoiding acute hemorrhage and achieving vascular control in a swine lobectomy model.

Targeting of green fluorescent protein to neuroendocrine secretory granules: a new tool for real time studies of regulated protein secretion.

Human chromogranin B (hCgB), a soluble marker protein of neuroendocrine secretory granules, was fused to green fluorescent protein (GFP). Two GFP-mutants with different folding properties, S65T and EGFP, were used to produce two recombinant proteins, hCgB-GFP(S65T) and hCgB-EGFP, respectively. After transient expression only hCgB-EGFP elicited green fluorescence in the neuroendocrine cell line PC12. Pulse-chase experiments with [35S]sulfate followed by subcellular fractionation showed that hCgB-EGFP was sorted with high efficiency to immature secretory granules (ISG). Confocal microscopy revealed that fluorescent hCgB-EGFP colocalized largely with synaptotagmin, a membrane marker of secretory granules and synaptic-like microvesicles, and significantly with endogenous rat chromogranin B (rCgB), a soluble marker of secretory granules. Upon stimulation of transfected cells with 5 mM Ba2+ or by depolarization with 50 mM K+ hCgB-EGFP underwent regulated exocytosis. The dynamics of green fluorescent secretory granules beneath the plasma membrane (PM) of living PC12 cells were visualized by confocal microscopy. The majority of these vesicles did not move within 8.5 sec as if they were docked. In contrast, in NGF-induced cells most of the secretory granules beneath the somatic PM moved within the same time period whereas only little movement was observed in the neurites. These findings indicate that in differentiated PC12 cells the majority of the docking zones are not in the soma but are distributed along the neurites. In conclusion, the fusion protein hCgB-EGFP provides a powerful tool to study in real time vesicular traffic in the regulated pathway of protein secretion.

Prevention of lower extremity ischemia during cardiopulmonary bypass via femoral cannulation.

Prolonged cardiopulmonary bypass requiring femoral arterial cannulation may lead to ipsilateral leg ischemia. A technique described of femoral cannulation via an end-to-side femoral artery graft allows distal femoral perfusion and eliminates the complication of leg ischemia.

Heparin and protamine stimulate the production of nitric oxide.

Heparin has been shown to decrease total vascular resistance while protamine stimulates endothelium-dependent vasodilation. This study was undertaken to determine whether heparin and/or protamine could enhance endothelium-derived relaxing factor (EDRF), as determined by nitric oxide (NO) production. Porcine carotid artery endothelial cells (PAECs) were seeded on multiwell plates, grown to confluence, and exposed to heparin (1-20 U/ml) or protamine (50-200 microg/ml) for 24 hours. With the addition of the NO synthase inhibitor, N(G)-monomethyl-L-arginine (NMMA), to heparin and/or protamine, the medium samples were collected in one hour. In a parallel clinical study, plasma samples were collected from patients undergoing cardiopulmonary bypass (CPB). The NO production was measured as reflected by the formation of nitrite (NO2-) and nitrate (NO3-), the stable end-metabolites of NO. NO production by PAECs was significantly increased by heparin > or = 5 U/ml or protamine > or = 50 microg/ml in a concentration-dependent manner. The increase of NO production was prevented by the addition of NMMA. In CPB patients, plasma NO2-/NO3- concentration was significantly increased after heparin administration compared to the preoperative value, at which time the mean plasma heparin level was 4.9+/-0.5 U/ml. Following slow protamine infusion, there was no significant difference in plasma NO2-/NO3- concentration compared to preoperative value. In conclusion NO production increases following exposure of PAECs to heparin and/or protamine. In patients, NO concentration significantly increased after heparin administration by IV bolus, but not with a slow infusion of protamine after CPB.

Reduction of bleeding after heart operations through the prophylactic use of epsilon-aminocaproic acid.

UNLABELLED: Excessive postoperative bleeding after heart operations continues to be a source of morbidity. This prospective double-blind study evaluated epsilon-aminocaproic acid as an agent to reduce postoperative bleeding and investigated its mode of action. One hundred three patients were randomly assigned to receive either 30 gm epsilon-aminocaproic acid (51 patients) or an equivalent volume of placebo (52 patients). In a subset of these patients (14 epsilon-aminocaproic acid, 12 placebo), tests of platelet function and fibrinolysis were performed. RESULTS: By multivariate analysis, three factors were associated with decreased blood loss in the first 24 hours after operation: epsilon-aminocaproic acid versus placebo (647 ml versus 839 ml, p = 0.004), surgeon 1 versus all other surgeons (582 ml versus 978 ml, p = 0.002), and no intraaortic balloon versus intraaortic balloon pump use (664 ml versus 1410 ml, p = 0.02). No significant differences in platelet function could be demonstrated between the two groups. Inhibited fibrinolysis, as reflected by less depression of the euglobulin clot lysis and no rise in D-dimer levels, was significant in the epsilon-aminocaproic acid group compared with the placebo group. CONCLUSION: The intraoperative use of epsilon-aminocaproic acid reduces postoperative cardiac surgical bleeding.

Ischemic preconditioning improves post-ischemic skeletal muscle function.

Ischemic preconditioning (IP), using one or more brief periods of ischemia before a sustained ischemia, represents a new approach to reduce tourniquet ischemia-induced skeletal muscle damage. The aim of this study was to investigate the effect of IP on skeletal muscle function and high-energy phosphate tissues levels in a rodent model. IP protocols using one, two, or three preconditioning cycles were compared. IP was found to significantly improve force, performance, endurance, and contractility of postischemic skeletal muscle. The efficacy of IP-induced protection was correlated with the number of preconditioning cycles. Preconditioning with three cycles resulted in a more effective protection as compared to one or two cycles. Three cycles of IP significantly improved force (409 +/- 63 versus 240 +/- 47 mN), performance (2546 +/- 481 versus 1081 +/- 242 mN*sec), endurance (46.7 +/- 5.0 versus 29.6 +/- 3.4 sec) and contractility (59.9 +/- 4.2 versus 38.7 +/- 5.1) in postischemic m.extensor dig. long. when compared to nonpreconditioned muscles. In contrast, high-energy phosphate tissue levels remained unchanged after three cycles of preconditioning. Altogether, this study describes, for the first time, the efficacy of IP to improve postischemic muscle function. The respective clinical potential warrants further exploration.

Effects of verapamil on skeletal muscle function following ischemia and reperfusion.

Verapamil (VRP) improves ischemic tolerance of different organs including brain, kidney, liver and heart. We report here on the effects of preischemic VRP treatment on skeletal muscle function following 3 h of tourniquet ischemia and 2 h of reperfusion using a rodent model. Postischemic and contralateral limbs were evaluated. Fast (musculi peronei)- and slow-twitch muscles (musculus soleus) of both limbs were excised and electrically stimulated in vitro. VRP pretreatment was found to significantly decrease tetanic peak tension of both contralateral nonischemic m. soleus and mm. peronei. Furthermore, VRP improved fatigability of slow-twitch muscles of both ischemic and contralateral limbs [increase of fatigue index from 0.04 +/- 0.009 (0 mg/kg) to 0.10 +/- 0.019 (4 mg/kg)], but not of fast-twitch muscles. These data indicate that the effects of VRP on postischemic skeletal muscle function depend on fiber composition.

Somatic embryogenesis and shoot regeneration from excised adventitious roots of the rootstock Rosa hybrida L. 'Moneyway'.

Plants were regenerated from excised adventitious roots of the rose rootstock 'Moneyway' via a three step procedure: callus induction, induction of somatic embryos and shoot development. Callus was induced on excised roots after incubation for 4 weeks in the dark on SH-medium (Schenk and Hildebrandt) containing 50 µM 2,4-dichlorophenoxyacetic acid. For embryo induction, calluses were transferred to hormone-free SH-medium and incubated for 8 weeks. The use of Gelrite instead of agar during callus induction stimulated somatic embryogenesis (up to 16% of the explants formed organized structures), whereas the presence of 6-benzylaminopurine in this phase inhibited subsequent regeneration. Yellow solid calluses with embryo-like cotyledons or primordia and friable calluses with embryos were selected, and upon incubation in the light shoots developed. Shoot development was faster and more frequent on solid callus than on friable callus (64% and 21% of the calluses finally formed one or more shoots, respectively). Eleven out of thirteen regenerants developed similarly to control shoots. Finally this regeneration method is compared with other systems for somatic embryogenesis and opportunities for the production of transgenic rose rootstocks and rose cultivare are discussed.

Simultaneous repair of multiple traumatic aortic tears.

A 34-year-old man suffered simultaneous tears of his distal ascending and mid-descending thoracic aorta secondary to blunt trauma. Repairs of both injuries were performed via a median sternotomy approach followed by a left lateral thoracotomy using two separate methods of cardiopulmonary bypass.

Mitral valve replacement with complete retention of native leaflets.

Although both mitral leaflets contribute equally to the preservation of left ventricular function after mitral valve replacement, most surgeons routinely excise the anterior mitral leaflet. Possible disadvantages of leaflet retention are left ventricular outflow tract obstruction and interference with prosthetic valve motion. In 31 patients undergoing mitral valve replacement, all mitral valvular and subvalvular tissue was completely retained using a technique that involved reefing the native leaflets into the valve sutures. Fifteen Carpentier-Edwards porcine and 16 St. Jude Medical valves were implanted. Two patients died of causes unrelated to this technique. In the others, echocardiography demonstrated either no or an insignificant left ventricular outflow tract gradient, and, in most, no valvular tissue could be seen in the left ventricular outflow tract. No interference with prosthetic leaflet mobility occurred. The salutary results of mitral valve replacement with complete leaflet retention recommend its use.