Phase II study of sunitinib in patients with non-small cell lung cancer and irradiated brain metastases.

INTRODUCTION: Brain metastases frequently cause significant morbidity in patients with non-small cell lung cancer (NSCLC). Sunitinib is a multitargeted inhibitor of tyrosine kinase receptors, including vascular endothelial growth factor receptors and platelet-derived growth factor receptors, which has single-agent antitumor activity in refractory NSCLC. This phase II study evaluated the antitumor activity and safety of sunitinib in patients with pretreated NSCLC and irradiated brain metastases. METHODS: Patients received sunitinib 37.5 mg on a continuous daily dosing schedule. The primary end point was progression-free survival. Secondary end points included overall survival, patient-reported outcomes, and safety, including risk of intracranial hemorrhage (ICH) associated with focal neurological deficit. RESULTS: Sixty-four patients received sunitinib (median age 61 years), most (83%) had received prior systemic therapy, 63% had adenocarcinoma, and 19% had squamous cell carcinoma; most (55%) were never-smokers. Median progression-free survival was 9.4 weeks (90% confidence interval [CI]: 7.5-13.1), and median overall survival was 25.1 weeks (95% CI: 13.4-35.5). The most common treatment-emergent (all-causality) nonhematologic toxicities (any grade) were fatigue (38%) and decreased appetite and constipation (both 25%). The most common grade 3/4 nonhematologic toxicities were dyspnea (9%) and fatigue (8%). Lymphopenia (20%) and neutropenia (13%) were the most common grade 3/4 hematologic abnormalities. Serious neurologic adverse events occurred in six patients (9%), and none were treatment-related. No cases of ICH were reported. CONCLUSIONS: Sunitinib administration on a continuous daily dosing schedule in patients with NSCLC and brain metastases was safe and manageable, with no increased risk of ICH.

Epidemiology and treatment costs of bone metastases from lung cancer: a French prospective, observational, multicenter study (GFPC 0601).

INTRODUCTION: The aim of this prospective, observational, multicenter study was to examine the epidemiology and management costs of bone metastatic disease (BMD) in patients with lung cancer. METHODS: The analysis included all patients with BMD from lung cancer diagnosed between May 2006 and May 2007 in 40 centers. We analyzed their management and the direct costs of BMD from the health care provider's perspective, using a Markov model. Skeletal-related event (SRE) was defined as pathological fractures, spinal cord compression, or hypercalcemia (clinical SRE [cSRE]) for an initial analysis; a second analysis included palliative radiotherapy and surgery (therapeutic SRE [tSRE]). RESULTS: Among the 554 patients enrolled (62 ± 11 years, 76.5% males, 69.3% performance status 0/1, 91% non-small cell lung cancer), 24.7% had a cSRE and 26.7% a tSRE at baseline and 9% and 39% during follow-up, respectively; 81.8% received at least one chemotherapy cycle. The median survival time was 5.8 months, and the 1- and 2-year survival rates were 22% and 7%, respectively; there was no significant difference in overall survival between the patients with and without SRE at enrollment. The main BMD treatments were opiate therapy (77.7%), biphosphonates (52.3%), radiotherapy (42.1%), and surgery (9.2%). The mean monthly BMD treatment costs in euros were €190, €374, and €4672 for asymptomatic patients, symptomatic patients, and patients with SRE, respectively. The average first-year BMD management cost in euros was €3999 ± 4135 (95% confidence interval: 374-15,886), and 49.5% of this cost was attributable to patients with SRE. CONCLUSIONS: This analysis confirms the poor prognosis of BMD from lung cancer and underlines the burden of SRE in overall treatment costs.

Feasibility of assessing [(18)F]FDG lung metabolism with late dynamic PET imaging.

PURPOSE: The aim of this work was to non-invasively establish the feasibility of assessing 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) lung metabolism with the use of a late dynamic positron emission tomograpy (PET) acquisition, i.e., beyond 2 h after injection. PROCEDURES: The present method has been probed in 11 patients without any respiratory disease, under fasting conditions, by assessing mean values of (18)F-FDG lung metabolism. A kinetic model analysis has been implemented on a simple calculation sheet. An arbitrary (population based) input function has been used in each individual, which was obtained from literature data. RESULTS: In the healthy lung, no (18)F-FDG release was found, and the mean values (±SD) of the (18)F-FDG uptake rate constant and of the fraction of the free tracer in blood and interstitial volume were: K = 0.0016 min(-1) (±0.0005), and F = 0.18 (±0.10), respectively. These results were in very close agreement with literature data that were obtained by both three-compartment model analysis and Patlak graphical analysis (gold standards), and that used an invasive blood sampling. Furthermore, K and the standard uptake value index have been compared. CONCLUSION: We conclude that assessing lung metabolism of (18)F-FDG in humans with the use of late dynamic PET imaging is feasible. The arbitrary input function of this non-invasive feasibility study could be replaced in further experiments by an input function obtained by arterial sampling. It is suggested that this method may prove useful to quantify (18)F-FDG lung metabolism under pathological conditions.

Assessment of dual-time-point 18F-FDG-PET imaging for pulmonary lesions.

OBJECTIVE: The objective of this study was to assess suitability of dual-time-point 18F-FDG [(18F)-fluoro-2-deoxyglucose]-PET imaging for differentiating between malignant and benign pulmonary lesions, whose size and maximal standardized uptake values (SUVs) are greater than 10 mm and 2.5, respectively. METHODS: A total of 38 patients, 27 with malignant lesions (n = 30), and 11 with benign lesions (n = 22), were investigated by performing two static acquisitions started at mean times t = 79 and t = 158 min after the tracer injection. A model analysis involving tissue 18F-FDG uptake and release has been developed and applied. RESULTS: Malignant lesions showed a SUV increase between the two acquisitions for 27 of 30 lesions, and a SUV decrease or constancy for the other three. Benign lesions showed a SUV increase in 19 of 22 lesions, and a SUV decrease in three (both increase and decrease were observed for multiple benign lesions in two patients). CONCLUSION: It is recommended that dual-time-point 18F-FDG-PET imaging is not indicated to differentiate between malignant and benign pulmonary lesions, whose size and maximal SUV are greater than 10 mm and 2.5, respectively. Furthermore, a model analysis suggests that the variation in SUV observed between early and delayed scans may be explained by different values of the 18F-FDG release/uptake ratio.

A randomized phase II trial assessing in advanced non-small cell lung cancer patients with stable disease after two courses of cisplatin-gemcitabine an early modification of chemotherapy doublet with paclitaxel-gemcitabine versus continuation of cisplatin-gemcitabine chemotherapy (GFPC 03-01 Study).

BACKGROUND: There is no consensus on the optimal treatment for patients with advanced non-small cell lung cancer and stable disease after cisplatin-based chemotherapy. The objective of the trial was to evaluate a switch to a different dual-agent chemotherapy. METHODS: Patients with stage IV non-small cell lung cancer and stable disease after two cycles of cisplatin (P) and gemcitabine (G) (P day1 (d(1)): 75 mg/m(2), G: 1250 mg/m(2) d(1) and d(8) every 3 weeks) were randomized to receive either two further cycles of PG (arm A) or paclitaxel (100 mg/m(2) d(1), d(8), d(15)) plus gemcitabine (1250 mg/m(2) d(1) and d(8), every 4 weeks) (arm B). RESULTS: Two-hundred-twenty-eight patients were enrolled between October 2003 and August 2006. After two cycles of PG, 98 patients (43%) had stable disease; 87 were randomized: 45 to arm A and 42 to arm B. The objective response rates were 15.6% (6.5-29.4) and 21.4% (10.3-36.8) in arms A and B. Overall survival after randomization was 9.6 months (7.0-13.8) in arm A and 9.3 months (7.4-13.3) in arm B. Adverse events were similar in the two arms for hematological and non hematological toxicities. CONCLUSIONS: Sequential first-line chemotherapy in these patients is feasible with no difference in response rates. These results do not warrant a phase III trial.

Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma.

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by different patterns of airway remodeling, which all include an increased mass of bronchial smooth muscle (BSM). A remaining major question concerns the mechanisms underlying such a remodeling of BSM. Because mitochondria play a major role in both cell proliferation and apoptosis, we hypothesized that mitochondrial activation in BSM could play a role in this remodeling. We describe that both the mitochondrial mass and oxygen consumption were higher in the BSM from asthmatic subjects than in that from both COPD and controls. This feature, which is specific to asthma, was related to an enhanced mitochondrial biogenesis through up-regulation of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, nuclear respiratory factor-1, and mitochondrial transcription factor A. The priming event of such activation was an alteration in BSM calcium homeostasis. BSM cell apoptosis was not different in the three groups of subjects. Asthmatic BSM was, however, characterized by increased cell growth and proliferation. Both characteristics were completely abrogated in mitochondria-deficient asthmatic BSM cells. Conversely, in both COPD and control BSM cells, induction of mitochondrial biogenesis reproduced these characteristics. Thus, BSM in asthmatic patients is characterized by an altered calcium homeostasis that increases mitochondrial biogenesis, which, in turn, enhances cell proliferation, leading to airway remodeling.

Fraktalkine produced by airway smooth muscle cells contributes to mast cell recruitment in asthma.

Human airway smooth muscle cells (HASMC) secrete fractalkine (FKN), a chemokine the concentration of which is increased in asthmatic patients. HASMC also induce mast cell chemotaxis, as a component of asthma inflammation. We therefore evaluated the role of smooth muscle-derived FKN in mast cell migration. We assessed the capacity of recombinant FKN to induce human mast cell chemotaxis. This effect implicates a calcium-independent pathway involving actin reorganization and protein kinase C-delta. We found that HASMC constitutively produce FKN, the synthesis of which is reinforced upon proinflammatory stimulation. Under basal experimental conditions, FKN production by HASMC is not sufficient to induce mast cell chemotaxis. However, pretreatment of mast cells with the neuropeptide vasoactive intestinal peptide (VIP) increases FKN potency to attract mast cells. Since we observed, in asthmatic patients, an increase in both FKN and VIP expression by airway smooth muscle and a positive correlation between VIP staining and mast cell infiltration of the smooth muscle layer, we conclude that HASMC-derived FKN may contribute to mast cell recruitment in asthma.

Primary Lung Small B-Cell Lymphoma versus Lymphoid Hyperplasia: Evaluation of Diagnostic Criteria in 26 Cases.

Primary lung non-Hodgkin's lymphoma is a rare neoplasm mostly represented by low-grade B-cell lymphomas of mucosa-associated lymphoid tissue. Their diagnostic criteria are now well defined on surgical specimens, but pathologists may experience difficulties in distinguishing them on exiguous biopsies from benign lymphoid hyperplasia and other lymphomas. Therefore, we examined a series of 26 lung lymphoid lesions to further define the pathologic features of either lymphoma or lymphoid hyperplasia on small specimens. We observed 16 primary lung non-Hodgkin's lymphomas with a large predominance of low-grade mucosa-associated lymphoid tissue-type lymphomas (87.5%, n = 14). There were no autoimmune disorders, but three patients had a concomitant infectious disease (hepatitis C virus and Helicobacter pylori gastritis). One patient presented with a synchronous pulmonary adenocarcinoma. As well as the classical mucosa-associated lymphoid tissue cellular infiltrate, immunohistochemical characterization of the 14 mucosa-associated lymphoid tissue-type lymphomas revealed the CD20+/CD43+ centrocyte-like cell phenotype in 10 cases (71.5%). Although the lymphoepithelial lesions observed in all lymphomatous cases have been reported in lung lymphoid hyperplasia, the determination of B-cell CD20+/CD43+ phenotype of the intraepithelial lymphocytes highly increased the specificity of lymphoepithelial lesions. A monoclonal immunoglobulin heavy chain gene rearrangement was present in 71.4% of the mucosa-associated lymphoid tissue-type lymphoma specimens. Investigation of H. pylori by polymerase chain reaction detection was negative, even for the two cases associated with H. pylori gastritis.