Paul Germonpre

Role of tachykinins in asthma.

The sensory neuropeptides substance P (SP) and neurokinin A (NKA) are localized to sensory airway nerves, from which they can be released by a variety of stimuli, including allergen, ozone, or inflammatory mediators. Sensory nerves containing these peptides are relatively scarce in human airways, but it is becoming increasingly evident that inflammatory cells such as eosinophils, macrophages, lymphocytes, and dendritic cells can produce the tachykinins SP and NKA. Moreover, immune stimuli can boost the production and secretion of SP and NKA. SP and NKA have potent effects on bronchomotor tone, airway secretions, and bronchial circulation (vasodilation and microvascular leakage) and on inflammatory and immune cells. Following their release, tachykinins are degraded by neutral endopeptidase (NEP) and angiotensin‐converting enzyme. The airway effects of the tachykinins are largely mediated by tachykinin NK1 and NK2 receptors. Tachykinins contract smooth muscle mainly by interaction with NK2 receptors, while the vascular and proinflammatory effects are mediated by the NK1 receptor. In view of their potent effects on the airways, tachykinins have been put forward as possible mediators of asthma, and tachykinin receptor antagonists are a potential new class of antiasthmatic medication.

Remediastinoscopy after neoadjuvant therapy for non-small cell lung cancer

Despite technical difficulties due to mediastinal fibrosis, remediastinoscopy can be a valuable tool in the restaging of non-small cell lung cancer after neoadjuvant therapy. The aim of our study was to evaluate the feasibility, sensitivity and accuracy of remediastinoscopy. From November 1994 to July 2001 we performed a remediastinoscopy in 27 patients after neoadjuvant therapy. Their age ranged from 35 to 80 years (mean 61.9+/-11.9). In all 27 patients it was possible to perform a remediastinoscopy without major technical difficulties and take biopsies of the lymph nodes that were initially invaded by tumour. Remediastinoscopy was positive in 11 patients (40.7%) and negative in 16 (59.3%). In the 11 patients with a positive remediastinoscopy a complete resection was not judged possible and therefore, an unnecessary thoracotomy was avoided. In four patients, remediastinoscopy turned out to be false negative. So, in our series, sensitivity was 73%, specificity 100% and accuracy 85%. The positive and negative predictive values were 100 and 75%, respectively. Previous mediastinoscopy is no contra-indication for a repeat one after neoadjuvant therapy. Although sensitivity and accuracy are lower than that of a first mediastinoscopy, remediastinoscopy is useful to select patients for surgical resection after induction therapy.

Validation of Computational Fluid Dynamics in CT-based Airway Models with SPECT/CT

PURPOSE To compare the results obtained by using numerical flow simulations with the results of combined single photon emission computed tomography (SPECT) and computed tomography (CT) and to demonstrate the importance of correct boundary conditions for the numerical methods to account for the large amount of interpatient variability in airway geometry. MATERIALS AND METHODS This study was approved by all relevant institutional review boards. All patients gave their signed informed consent. In this study, six patients with mild asthma (three men; three women; overall mean age, 46 years ± 17 [standard deviation]) underwent CT at functional residual capacity and total lung capacity, as well as SPECT/CT. CT data were used for segmentation and computational fluid dynamics (CFD) simulations. A comparison was made between airflow distribution, as derived with (a) SPECT/CT through tracer concentration analysis, (b) CT through lobar expansion measurement, and (c) CFD through flow computer simulation. Also, the heterogeneity of the ventilation was examined. RESULTS Good agreement was found between SPECT/CT, CT, and CFD in terms of airflow distribution and hot spot detection. The average difference for the internal airflow distribution was less than 3% for CFD and CT versus SPECT/CT. Heterogeneity in ventilation patterns could be detected with SPECT/CT and CFD. CONCLUSION This results of this study show that patient-specific computer simulations with appropriate boundary conditions yield information that is similar to that obtained with functional imaging tools, such as SPECT/CT. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100322/-/DC1.

Diagnostic Performance of Soluble Mesothelin and Megakaryocyte Potentiating Factor in Mesothelioma

RATIONALE Soluble mesothelin (SM) is currently the reference serum biomarker of malignant pleural mesothelioma (MPM). Megakaryocyte potentiating factor (MPF), which originates from the same precursor protein, is potentially more sensitive, yet lacks validation. OBJECTIVES To analyze the diagnostic performance of MPF as an MPM biomarker and compare this performance with SM. METHODS A total of 507 participants were enrolled in six cohorts: healthy control subjects (n = 101), healthy asbestos-exposed individuals (n = 89), and patients with benign asbestos-related disease (n = 123), benign respiratory disease (n = 46), lung cancer (n = 63), and MPM (n = 85). Sera were analyzed for SM and MPF levels using the Mesomark and Human MPF ELISA kit, respectively. MEASUREMENTS AND MAIN RESULTS SM and MPF levels differed significantly between patients with MPM and participants from each other cohort (P < 0.001). Receiver operating characteristics curve analysis did not reveal a significant difference between both markers in area under curve (AUC) for distinguishing MPM from all cohorts jointly (SM = 0.871, MPF = 0.849; P = 0.28). At 95% specificity, SM and MPF had a sensitivity of 64% (cutoff = 2.00 nmol/L) and 68% (cutoff = 12.38 ng/ml), respectively. Combining both markers did not improve the diagnostic performance. CONCLUSIONS In this prospective multicenter study, MPF is validated as a highly performant MPM biomarker. The similar AUC values of SM and MPF, together with the limited difference in sensitivity, show that both serum biomarkers have an equivalent diagnostic performance.

A randomized phase II study of bortezomib and pemetrexed, in combination or alone, in patients with previously treated advanced non-small-cell lung cancer

BACKGROUND This is a phase II randomized study to evaluate the efficacy and safety of bortezomib and pemetrexed alone or in combination, in patients with previously treated advanced non-small-cell lung cancer (NSCLC). The primary end point was assessment of response rate. METHODS A total of 155 patients were randomized (1:1:1) to pemetrexed (500mg/m(2)) on day 1 plus bortezomib (1.6mg/m(2)) on days 1 and 8 (Arm A) or pemetrexed (500mg/m(2)) on day 1 (Arm B) or bortezomib (1.6mg/m(2)) on days 1 and 8 (Arm C) of a 21 day cycle. Response rate was assessed by investigators using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and toxicity assessed by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading system. RESULTS Response rate was 7% in Arm A, 4% in Arm B, and 0% in Arm C; disease control rates were 73%, 62%, and 43%, respectively. Median overall survival was 8.6 months in Arm A, 12.7 months in Arm B, and 7.8 months in Arm C; time to progression was 4.0 months, 2.9 months, and 1.4 months, respectively. Most common reported adverse events >/=grade 3 were neutropenia (19%), thrombocytopenia (15%), and dyspnea (13%) in Arm A, neutropenia (10%) in Arm B, and dyspnea (13%) and fatigue (10%) in Arm C. CONCLUSION In previously treated NSCLC the addition of bortezomib to pemetrexed was well tolerated but offered no statistically significant response or survival advantage versus pemetrexed alone, while bortezomib alone showed no clinically significant activity.

Soluble mesothelin, megakaryocyte potentiating factor, and osteopontin as markers of patient response and outcome in mesothelioma

Introduction: Soluble mesothelin (SM), megakaryocyte potentiating factor (MPF), and osteopontin (OPN) are blood biomarkers of mesothelioma. This study evaluates their use as markers of response to therapy and outcome. Methods: Sixty-two patients with malignant pleural mesothelioma were included in an observational multicenter study. Blood samples and matched computed tomography scans were collected at diagnosis and, when possible, during and after therapy. For each patient, the best overall radiological response was compared with the changes in serum SM, MPF, and plasma OPN levels across corresponding time points. Results: In five patients, blood sampling was done shortly before and after extrapleural pneumonectomy. SM and MPF levels markedly decreased after surgery, whereas OPN levels showed a median increase. Fifty-seven patients were surveilled during (and after) chemotherapy, of whom 27 (47%) had stable disease, 14 (25%) partial response, and 16 (28%) progressive disease. In patients with stable disease, SM and MPF levels did not change significantly across the corresponding time points, whereas OPN levels significantly decreased. In those with partial response, SM and MPF levels significantly decreased, whereas OPN levels showed no significant change. In patients with progressive disease, all three biomarker levels significantly increased. Patient responses correlated with a 15% change in all three biomarkers, although SM and MPF appeared more accurate than OPN. Low baseline OPN levels were independently associated with favorable progression-free survival and overall survival. Neither SM nor MPF showed prognostic value. Conclusions: SM and MPF levels were more closely associated with disease course than OPN and might prove useful in monitoring patient response in mesothelioma. Baseline OPN levels were an independent negative predictor of survival. These promising results require further validation.

Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors

INTRODUCTION Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs. AREAS COVERED This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal-epithelial transition factor (MET) amplification, epithelial-mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or poly (ADP-ribose) polymerase in addition to mammalian target of rapamycin (mTOR), monoclonal antibodies against the insulin-like growth factor-1 receptor, and fulvestrant-mediated oestrogen receptor regulation. CONCLUSION Improved understanding of mechanisms underlying resistance to EGFR TKIs emphasises the importance of a genotype-guided approach to therapy. Elucidation of resistance mechanisms is indeed crucial to target innovative therapeutic approaches and to improve the efficacy of anticancer regimes in NSCLC.

Are patients' preferences for information and participation in medical decision-making being met? Interview study with lung cancer patients

We examined the degree to which newly diagnosed patients with advanced lung cancer wanted to be informed and involved in medical decision-making, and whether the patients felt their preferences were met. Patients from 13 hospitals in Flanders were interviewed with a standard questionnaire. A total of 128 patients (68%) participated. Of the patients who wanted to be informed about life expectancy, half (53%) reported they were informed, and of those who wanted to be informed about palliative care and end-of-life decisions, 25% and 31% said they were informed, respectively. With regard to participation in medical decision-making (in general, about treatment, transfer or end-of-life), patients who preferred the doctor to make decisions or those who preferred to make the decision themselves often achieved this (in their perception), while patients who wanted an in-between position with some involvement, often did not. To conclude, preferences of patients with lung cancer for information concerning delicate topics and for shared decision-making with the physician were not well met.

The effect of clinical covariates on the diagnostic and prognostic value of soluble mesothelin and megakaryocyte potentiating factor

BACKGROUND Soluble mesothelin (SM) and megakaryocyte potentiating factor (MPF) are serum biomarkers of mesothelioma. This study examined the effect of clinical covariates on biomarkers levels and their diagnostic and prognostic value. METHODS Five hundred ninety-four participants were enrolled in a multicenter study, including 106 patients with mesothelioma and 488 control subjects. Multiple linear regression analyses were used to identify which covariates were independently associated with SM and MPF levels. The effect of these covariates on the diagnostic accuracy was evaluated with receiver operating characteristics curve analysis. In patients with mesothelioma, survival analysis was performed with Cox regression. RESULTS SM and MPF levels were independently associated with age, glomerular filtration rate (GFR), and BMI in control subjects and with GFR and tumor stage in patients with mesothelioma. The diagnostic accuracy of SM and MPF was significantly affected by the distribution of these covariates in the study population. The patients with mesothelioma were best discriminated from the control subjects with either the youngest age, the highest GFR, or the largest BMI. Furthermore, the control subjects were significantly better differentiated from stage II to IV than from stage I mesothelioma. MPF, not SM, was an independent negative prognostic factor, but only if adjusted for the biomarker-associated covariates. CONCLUSIONS SM and MPF levels were affected by the same clinical covariates, which also had a significant impact on their diagnostic and prognostic value. To improve the interpretation of biomarker results, age, GFR, and BMI should be routinely recorded. Approaches to account for these covariates require further validation, as does the prognostic value of SM and MPF.

Preferred and Actual Involvement of Advanced Lung Cancer Patients and Their Families in End-of-Life Decision Making: A Multicenter Study in 13 Hospitals in Flanders, Belgium

CONTEXT Death is often preceded by medical decisions that potentially shorten life (end-of-life decisions [ELDs]), for example, the decision to withhold or withdraw treatment. Respect for patient autonomy requires physicians to involve their patients in this decision making. OBJECTIVES The objective of this study was to examine the involvement of advanced lung cancer patients and their families in ELD making and compare their actual involvement with their previously stated preferences for involvement. METHODS Patients with Stage IIIb/IV non-small cell lung cancer were recruited by physicians in 13 hospitals and regularly interviewed between diagnosis and death. When the patient died, the specialist and general practitioner were asked to fill in a questionnaire. RESULTS Eighty-five patients who died within 18 months of diagnosis were studied. An ELD was made in 52 cases (61%). According to the treating physician, half of the competent patients were not involved in the ELD making, one-quarter shared the decision with the physician, and one-quarter made the decision themselves. In the incompetent patients, family was involved in half of cases. Half of the competent patients were involved less than they had previously preferred, and 7% were more involved. Almost all of the incompetent patients had previously stated that they wanted their family involved in case of incompetence, but half did not achieve this. CONCLUSION In half of the cases, advanced lung cancer patients-or their families in cases of incompetence-were not involved in ELD making, despite the wishes of most of them. Physicians should openly discuss ELDs and involvement preferences with their advanced lung cancer patients.