Host defense against viruses probably depends on targeted death of infected host cells and then clearance of cellular corpses by macrophages. For this process to be effective, the macrophage must presumably avoid its own virus-induced death. Here we identify one such mechanism. We show that mice lacking the chemokine Ccl5 are immune compromised to the point of delayed viral clearance, excessive airway inflammation and respiratory death after mouse parainfluenza or human influenza virus infection. Virus-inducible levels of Ccl5 are required to prevent apoptosis of virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo. The protective effect of Ccl5 requires activation of the Ccr5 chemokine receptor and consequent bilateral activation of G(alphai)-PI3K-AKT and G(alphai)-MEK-ERK signaling pathways. The antiapoptotic action of chemokine signaling may therefore allow scavengers to finally stop the host cell-to-cell infectious process.

Purpose: Most centrally located early lung cancers (CLELC) <1.0 cm in diameter do not invade beyond the bronchial cartilage, and photodynamic therapy (PDT) with Photofrin is currently recommended as a treatment option for such lesions. NPe6 is a second-generation photosensitizer, and because it has a longer absorption band (664 nm) than Photofrin (630 nm), we hypothesized that NPe6-PDT would exert a strong antitumor effect against cancer lesions >1.0 cm in diameter, which are assumed to involve extracartilaginous invasion and to be unsuitable for treatment with Photofrin-PDT.Experimental Design: Between June 2004 and December 2008, 75 patients (91 lesions) with CLELC underwent NPe6-PDT after the extent of their tumors had been assessed by fluorescence bronchoscopy for photodynamic diagnosis and tumor depth had been assessed by optical coherence tomography.Results: Seventy cancer lesions ≤1.0 cm in diameter and 21 lesions >1.0 cm in diameter were identified, and the complete response rate was 94.0% (66 of 70) and 90.4% (19 of 21), respectively. After the mass of large tumors and deeply invasive tumors had been reduced by electrocautery, NPe6-PDT was capable of destroying the residual cancer lesions.Conclusion: NPe6-PDT has a strong antitumor effect against CLELCs >1.0 cm in diameter that have invaded beyond the bronchial cartilage, thereby enabling the destruction of residual cancer lesions after mass reduction of large nodular-or polypoid-type lung cancers by electrocautery. The PDT guidelines for lung cancers should therefore be revised because use of NPe6-PDT will enable expansion of the clinical indications for PDT. Clin Cancer Res; 16(7); 2198-204. ©2010 AACR.

Patients with large cell neuroendocrine carcinoma (LCNEC) of the lung are considered to have poor prognosis. However, the benefit of adjuvant chemotherapy for these patients has not been established. In this study, we retrospectively evaluated the efficacy of perioperative chemotherapy for patients with completely resected LCNEC in a single-center setting. From 1999 through 2007, 45 patients with surgically resected LCNEC or mixed LCNEC containing at least one portion of the neuroendocrine differentiation or morphology in non-small cell lung carcinoma were enrolled as participants of this study. Survival rates were calculated by the Kaplan-Meier method. Differences between survival curves were computed with the log-rank test. For multivariate analysis, the Cox's proportional hazards regression model was used to evaluate variables that were significant predictors of survival. Of 1397 patients undergoing surgical resection for primary lung cancer from 1999 to 2007, 45 (3.2%) were classified as LCNEC. Thirty-six (80%) patients were men, and nine (20%) were women. Twenty-four (92%) of 26 patients were present or past smokers. Twenty-three (41%) of 45 patients received perioperative chemotherapy, including seven induction chemotherapies and 16 adjuvant chemotherapies. Survival of patients who underwent perioperative adjuvant chemotherapy was significantly higher than that of those who received surgery alone (P = 0.04). The 5-year survival rate of patients who underwent perioperative adjuvant chemotherapy was 87.5%, whereas that of patients who underwent surgery alone was 58.5%. Even in stage I cases, perioperative adjuvant chemotherapy still favors survival compared with surgery alone. In the Cox proportional hazard multivariate analysis, surgery with or without chemotherapy showed an independent prognostic influence on overall survival (P = 0.0457). Patients who received surgery alone were 9.5 times more likely to die than patients who underwent surgery plus chemotherapy. In conclusion, perioperative chemotherapy will be needed to improve survival in patients with LCNEC. As the population of LCNEC is small, it has been difficult to conduct randomized controlled trials to show the survival benefit of adjuvant chemotherapy. This should be, therefore, evaluated further in prospective multi-institutional phase II trials.

Central venous catheterization for pressure monitoring and drug administration is often important in the anesthetic management of infants undergoing cardiovascular surgery. We examined the effects of patient age, weight, and central venous pressure and the experience of the anesthesiologist on the rate of successful catheterization and catheterization time of the internal jugular vein (IJV) in a prospective study. We studied 106 infants undergoing IJV catheterization for cardiovascular surgery over a 7-mo period at our institution. We catheterized the IJV by the high approach. The direct venipuncture or the Seldinger method was used according to the patient's weight. Overall successful catheterization rate was 97.2%, and the average catheterization time was 353 +/- 21 s (mean +/- SEM). Complications included arterial puncture in 12 cases (11.3%), hematoma formation in four cases (3.8%), and catheter malposition in two cases (1.9%), but pneumothorax was not observed. When a patient was younger than 3 mo or weighed less than 4.0 kg, successful catheterization rate decreased significantly to 81.3% and 78.6%, respectively. Catheterization time was inversely correlated with both age and weight, whereas central venous pressure did not affect either successful catheterization rate or catheterization time. We were unable to demonstrate that the experience of the anesthesiologist plays a significant role in the success or complication of the catheterization procedure. Our results indicate that IJV catheterization by the high approach is a reliable and useful technique in infants, and that the weight and age of the patient significantly influence the rate of successful catheterization.

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