Arnaud Scherpereel

Pulmonary Embolism in Patients with Unexplained Exacerbation of Chronic Obstructive Pulmonary Disease: Prevalence and Risk Factors

Context Pulmonary embolism (PE) is common in patients with chronic obstructive pulmonary disease (COPD) exacerbations, and the 2 conditions present similarly. Content For 45 months, every patient presenting with severe COPD exacerbation of unknown cause received an evaluation for PE that included a spiral computed tomography scan and color Doppler ultrasonography of the legs. Twenty-five percent of 197 patients had PE. Malignant disease, history of thromboembolism, and a decrease in Paco 2 level relative to baseline were the only factors associated with PE. Cautions This was a single-center study. Implications We need additional studies to confirm the high prevalence of PE in unexplained severe exacerbations of COPD and to study the value of routine testing for PE in patients with this clinical presentation. The Editors The management of patients with suspected acute pulmonary embolism (PE) has greatly improved in recent years because of clinical assessment of the probability of PE, pretest probability, ultrasonography, ventilationperfusion scanning, and spiral computed tomography angiography (CTA) (1, 2). However, clinical diagnosis of acute PE is difficult in patients with chronic obstructive pulmonary disease (COPD). Pulmonary embolism resembles COPD exacerbation so closely that these 2 entities are often impossible to distinguish clinically (3). The reported incidence of PE in studies done postmortem of patients with COPD ranges from 28% to 51% (4, 5). Pulmonary embolism is known to increase the rate of death from COPD at 1 year (6), but the clinical probability of PE and the value of noninvasive tests to rule out the diagnosis in patients with COPD have not yet been clearly assessed. To date, 2 studies have evaluated PE in patients with this disorder (3, 7). In the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, Lesser and colleagues (3) examined the characteristics of 108 patients with COPD and suspected PE; 21 (19%) received diagnoses of PE by pulmonary angiography. In this population, risk factors, symptoms, and arterial blood gas values were similar in patients with and without PE. The second study (7) showed that the presence of COPD does not affect the diagnostic performance of d-dimer testing, CTA, or pulmonary angiography for PE (7). The true frequency of PE in patients with COPD in whom PE is clinically suspected ranges from 19% to 29% (3, 7-9). Thus, clinical detection of PE in these patients is particularly difficult. In this study, we prospectively evaluated PE in patients with COPD exacerbation of unknown origin and examined factors associated with the presence of PE, including the Geneva score (1). Methods Study Objectives The objectives of our study were to assess the presence of PE in patients with COPD exacerbation of unknown origin and to explore factors associated with the presence of PE, including the Geneva score. Study Group Between April 1999 and December 2002, all consecutive patients with COPD referred to the Lung Department at the 59-bed Lille University Hospital for severe exacerbation of unknown origin were assessed for PE. Chronic obstructive pulmonary disease was diagnosed and its severity was determined according to the criteria of the American Thoracic Society (10). All patients smoked or were former smokers. Patients with asthma were not included in the study. Severe exacerbation was defined as acute deterioration from a stable condition that required hospitalization. The absence of a lower respiratory tract infection (increased sputum volume and/or increased sputum purulence, fever, history of cold, and sore throat); absence of pneumothorax and iatrogenic intervention; presence of parenchymal condensation without fever and chills; or presence of a discrepancy between clinical and radiologic features and hypoxemia severity classified the exacerbation as of unknown origin. Physicians were required to discuss each case of COPD with 1 of the referring physicians. Patients requiring invasive mechanical ventilation were referred to the intensive care unit and were not included in the study. Intervention All patients were examined within 48 hours of admission to the hospital and had spiral CTA of pulmonary circulation and color Doppler and venous lower-limb ultrasonography. These are the first-line diagnostic tests for acute PE at our institution. The decision to perform additional examinations, including d-dimer determination and ventilationperfusion scanning, was left to the discretion of the attending physician. Our local ethics committee approved the study protocol, which did not require informed patient consent. Spiral CTA In 1999, spiral CTA of pulmonary circulation was performed with a Somatom Plus 4A (Siemens Medical Systems, Forchheim, Germany) using a collimation of 3 mm3 mm, a pitch of 2, and a scanning time of 0.75 second per revolution. The results were read during the clinical work-up as previously described (9, 11-13). Because the equipment at our institution was upgraded during this study, spiral CTA of pulmonary circulation between January 2000 and December 2002 was performed with a multislice spiral computed tomography (CT) scanner, using a collimation of 4 mm1 mm, a pitch of 2, and a rotation time of 0.5 second. All patients with negative results on spiral CTA had a 3-month follow-up visit after inclusion in the study to assess critical events that were potentially related to PE. A chest physician reported death, subsequent admission to the hospital, new symptoms, and use of anticoagulant medications. Ultrasonography Venous compression ultrasonography of both legs was done from the common femoral vein and including the calf vein. Lack of compressibility was considered to indicate deep venous thrombosis. Definition Patients were classified as PE positive (positive results on spiral CTA or negative results on spiral CTA and positive results on ultrasonography) or PE negative (negative results on spiral CTA and negative results on ultrasonography or negative results on spiral CTA and no recurrence of PE at follow-up 3 months later). Assessment of the Geneva Score Because the Geneva score (1) was published by the time our study ended in 2001, we evaluated this score a posteriori in our sample before reviewing the data on PE. The probability of PE was expressed as low (a score 4), intermediate (a score of 5 to 8), or high (a score 9) (Table 1) (1). Table 1. The Geneva Score and the Modified Geneva Score Statistical Analysis Statistical analysis was done by using Epi Info software, version 3.3.2 (Centers for Disease Control and Prevention, Atlanta, Georgia), and CIs were calculated with StatExact and Stata, version 7 (Stata Corp., College Station, Texas). We calculated risk ratios and exact CIs for the various risk factors and clinical symptoms and determined P values using the Fisher exact test. A P value less than 0.05 indicated statistical significance. Role of the Funding Source No funding was received for this study. Results Study Group A total of 211 consecutive patients with COPD were referred for severe exacerbation of unknown origin. Fourteen patients were not included in the study because the results of the spiral CTA and ultrasonography were inconclusive (8 patients) or because of iodine intolerance (6 patients). Thus, the study group included 197 patients with COPD and severe exacerbation of unknown origin. There were 165 men and 32 women, and their mean age was 60.5 years (SD, 12.1). A total of 136 patients (69%) were referred from the emergency department, and 61 (31%) were inpatients who developed severe exacerbation while hospitalized. Arterial blood gas values on room air were 61.9 mm Hg (SD, 10.9) for Pao 2 and 42 mm Hg (SD, 9) for Paco 2. The mean number of risk factors for PE per patient was 0.87 (SD, 0.7). In 160 of the 197 study patients, results of a pulmonary function test performed within 3 months of the severe exacerbation were available. The mean FEV1 was 1.56 L (SD, 0.6), 52% (SD, 19%) of the predicted value. The mean FEV1vital capacity ratio was 56.4% (SD, 14.8%). The severity of respiratory disease was assessed according to the criteria of the American Thoracic Society (10): grade I, FEV1 greater than 50% of the predicted value (66 patients [41%]); grade II, FEV1 between 35% and 50% of predicted (67 patients [42%]); and grade III, FEV1 less than 35% of predicted (27 patients [17%]). Forty-nine (25%) patients were receiving long-term oxygen therapy. Pulmonary Embolism All patients had spiral CTA (37 patients had a single-slice CT scan, and 160 had a multislice CT scan), and 180 had venous ultrasonography (Table 2). None of the 197 study patients were thought to have clinical recurrence of PE during the 3 months of follow-up. Forty-three patients had positive results on CT. Twenty-five patients had deep venous thrombosis on ultrasonography; of these patients, 6 had negative results on spiral CTA. Nineteen (44%) of the 43 patients with positive results on spiral CTA also had positive results on ultrasonography. One hundred forty-eight patients did not have PE, on the basis of negative results on CT and ultrasonography and negative findings at 3-month follow-up. Thus, the prevalence of PE in our study group was 49 of 197 patients (25% [95% CI, 19% to 32%]). Table 2. Results of Spiral Computed Tomography Angiography in Patients Initially Referred for Suspected Acute Pulmonary Embolism Clinical Characteristics according to the Presence or Absence of Pulmonary Embolism The 49 patients with COPD who had PE did not differ statistically significantly from the 148 patients with COPD who did not have PE in terms of referral location (data not shown). We performed a bivariate analysis of baseline characteristics (Table 3) and clinical characteristics at admission (Table 4) that were potentially associated with PE. Clinical symptoms, such as change in dyspnea, pleuritic pain, hemoptysis, tachycardia (pulse rate >100 beats/m

Randomized Phase III Trial of Maintenance Bevacizumab With or Without Pemetrexed After First-Line Induction With Bevacizumab, Cisplatin, and Pemetrexed in Advanced Nonsquamous Non–Small-Cell Lung Cancer: AVAPERL (MO22089)

PURPOSE Maintenance therapy is associated with improved survival in patients with non-small-cell lung cancer (NSCLC), but few studies have compared active agents in this setting. AVAPERL evaluated the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment. PATIENTS AND METHODS Patients with advanced nonsquamous NSCLC received first-line bevacizumab 7.5 mg/kg, cisplatin 75 mg/m(2), and pemetrexed 500 mg/m(2) once every 3 weeks for four cycles. Those achieving response or stable disease were randomly assigned at a ratio of 1:1 to maintenance bevacizumab 7.5 mg/kg or bevacizumab 7.5 mg/kg plus pemetrexed 500 mg/m(2) once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) after random assignment. RESULTS In total, 376 patients received induction treatment, 71.9% achieved disease control, and 67.3% were randomly assigned to maintenance therapy, with 125 and 128 receiving single-agent bevacizumab and bevacizumab plus pemetrexed treatment, respectively. At a median follow-up of 8.1 months, PFS from random assignment was significantly improved in the bevacizumab plus pemetrexed arm (median, 3.7 v 7.4 months; hazard ratio, 0.48; 95% CI, 0.35 to 0.66; P < .001) per a stratified model. The PFS benefit extended across age, performance status, smoking history, and induction response (stable disease v partial response) subgroups. Any grade, grade ≥ 3, and serious adverse events occurred more often with bevacizumab plus pemetrexed maintenance. No new safety signals were observed. CONCLUSION In an unselected population of patients with nonsquamous NSCLC who had achieved disease control with platinum-based chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance was associated with a significant PFS benefit compared with bevacizumab alone. The combination was well tolerated.

Utility of osteopontin and serum mesothelin in malignant pleural mesothelioma diagnosis and prognosis assessment.

Purpose: Malignant mesothelioma is a highly aggressive tumor and is often diagnosed too late for a curative treatment. We compared diagnostic and prognostic values of mesothelin and osteopontin in 172 patients suspected of malignant pleural mesothelioma (MPM) and in a control group of 112 asymptomatic asbestos-exposed subjects. Experimental Design: Osteopontin and mesothelin were assayed with commercial ELISA kits in a series of 43 patients with pleural metastases of various carcinomas, 33 patients with benign pleural lesions associated with asbestos exposure, 96 patients with MPMs, and 112 asbestos-exposed healthy subjects. Results were correlated with patients diagnosis and survival. Results: Serum osteopontin level was higher in MPM patients compared with healthy asbestos-exposed subjects and had a good capability to distinguish between these two populations. However, osteopontin was unable to distinguish between MPM and pleural metastatic carcinoma or benign pleural lesions associated with asbestos exposure. Neither plasma nor pleural fluid osteopontin were more powerful in this respect. Serum mesothelin had a good ability for diagnosing MPM but was unable to identify patients with nonepithelioid mesothelioma subtypes. Survival analysis identified tumor histologic subtype along with serum osteopontin and serum mesothelin as independent prognostic factors in mesothelioma patients. Conclusions: Osteopontin has a lower diagnostic accuracy than mesothelin in patients suspected of MPM. Insufficient specificity limits osteopontin utility as diagnostic marker. Both molecules have a potential value as prognostic markers.

Serum Mesothelin for Diagnosing Malignant Pleural Mesothelioma: An Individual Patient Data Meta-Analysis

PURPOSE Mesothelin is currently considered the best available serum biomarker of malignant pleural mesothelioma. To examine the diagnostic accuracy and use of serum mesothelin in early diagnosis, we performed an individual patient data (IPD) meta-analysis. METHODS The literature search identified 16 diagnostic studies of serum mesothelin, measured with the Mesomark enzyme-linked immunosorbent assay. IPD of 4,491 individuals were collected, including several control groups and 1,026 patients with malignant pleural mesothelioma. Mesothelin levels were standardized for between-study differences and age, after which the diagnostic accuracy and the factors affecting it were examined with receiver operating characteristic (ROC) regression analysis. RESULTS At a common diagnostic threshold of 2.00 nmol/L, the sensitivities and specificities of mesothelin in the different studies ranged widely from 19% to 68% and 88% to 100%, respectively. This heterogeneity can be explained by differences in study population, because type of control group, mesothelioma stage, and histologic subtype significantly affected the diagnostic accuracy. The use of mesothelin in early diagnosis was evaluated by differentiating 217 patients with stage I or II epithelioid and biphasic mesothelioma from 1,612 symptomatic or high-risk controls. The resulting area under the ROC curve was 0.77 (95% CI, 0.73 to 0.81). At 95% specificity, mesothelin displayed a sensitivity of 32% (95% CI, 26% to 40%). CONCLUSION In patients suspected of having mesothelioma, a positive blood test for mesothelin at a high-specificity threshold is a strong incentive to urge further diagnostic steps. However, the poor sensitivity of mesothelin clearly limits its added value to early diagnosis and emphasizes the need for further biomarker research.

Endocan Expression and Relationship with Survival in Human Non–Small Cell Lung Cancer

Purpose: We evaluated the expression of endocan, a soluble lung- and kidney-selective endothelial cell-specific dermatan sulfate proteoglycan, in non–small cell lung tumors compared with normal lung and studied the significance of high levels of circulating endocan in patients with non–small cell lung cancer. Material and Methods: Endocan and vascular endothelial growth factor mRNA expression were evaluated by semiquantitative PCR in tumoral and nontumoral lung tissue samples from a first series of 24 patients submitted to curative surgery. Relationships between survival, time to tumor progression, and serum levels of endocan were evaluated in a second series of 30 previously untreated patients addressed for staging. Results: In non–small cell lung cancers, endocan mRNA was overexpressed compared with control lung. Immunohistochemistry shows that endocan was expressed only by tumor endothelium in all cases, especially in the periphery of the tumors, with no differences between adenocarcinoma and squamous cell carcinoma. Endocan and vascular endothelial growth factor mRNA expression was positively correlated in lung tumors. Serum endocan levels, as well as tumor, node, and metastasis status, were correlated with both survival and time to tumor progression. However, endocan serum level was not an independent prognostic factor due to its correlation with the presence of metastasis. Conclusion: Endocan is overexpressed in non–small cell lung tumors compared with healthy lung and probably represents a response of tumoral endothelium to proangiogenic growth factor stimulation. Circulating levels of endocan might reflect tumor angiogenic stimulation and present prognostic significance.

Malignant pleural mesothelioma: The standard of care and challenges for future management

This review addresses the management of MPM. In an introductory section, the etiology, epidemiology, presentation, diagnosis and staging of MPM will be reviewed. The evidence was collected by a systematic analysis of the literature (2000-2009) using the databases Medline (National Library of Medicine, USA), Embase (Elsevier, Netherlands), Cochrane Library (Great Britain), National Guideline Clearinghouse (USA), HTA Database (International Network of Agencies for Health Technology Assessment - INAHTA), NIH database (USA), International Pleural Mesothelioma Program - WHOLIS (WHO Database) with the following keywords and filters: pleura, cancer, mesothelioma, guidelines, treatment, surgery, chemotherapy, radiotherapy, palliation, supportive care, pleurodesis, review.

Valproate–doxorubicin: promising therapy for progressing mesothelioma. A phase II study

No treatment is recommended for patients with malignant mesothelioma (MM) failing after first-line cisplatin-based chemotherapy. In vitro data suggested that valproic acid, a histone deacetylase inhibitor (HDACi), had a proapoptotic effect and synergised with doxorubicin to induce apoptosis in MM cells. Our primary end-point was to determine response rate of combined valproic acid and doxorubicin in patients with unresectable MM failing after platinum-based chemotherapy. Treatment consisted of doxorubicin (60 mg·m-2) plus valproic acid. An interim analysis for response rate was planned after the first 16 registered patients. All the cases were centrally reviewed. From July 2006 to March 2009, 45 eligible patients with pleural MM were registered. The majority of the patients were male (73%), had a performance status (PS) ≥80 (76%) and an epithelioid subtype (80%). There were seven partial responses (response rate 16%; 95% CI 3–25%), all in patients with PS 80–100. The best disease control rate was 36% (95% CI 22–51%). Two toxic deaths were observed (febrile neutropenia and cerebral thrombotic event), both in patients with poor PS (60–70). Valproic acid, an HDACi, plus doxorubicin appeared an effective chemotherapy regimen in good PS (80–100) patients with refractory or recurrent MM, for which no standard therapy was available.

Valproate, in combination with pemetrexed and cisplatin, provides additional efficacy to the treatment of malignant mesothelioma.

Purpose: Present chemotherapeutic regimens are marginally efficient in tumor cells being particularly resistant to radiotherapy and/or chemotherapy. We hypothesized that unresponsiveness of tumors to conventional therapeutic agents might be due to inappropriate gene expression resulting from epigenetic modifications and leading to transcriptional silencing. The goal of this study was to evaluate the anticancer effect of a histone deacetylase inhibitor, valproate, on mesothelioma cells in combination with pemetrexed and cisplatin, the usual first-line regimen of chemotherapy for this tumor. Experimental Design and Results: We show that valproate augments apoptosis induced by pemetrexed and cisplatin in mesothelioma cell lines and in tumor cells from patients biopsies. Onset of apoptosis involves both extrinsic and intrinsic pathways requiring enzymatic activities of caspases 8 and 9, respectively. Valproate but not suberoylanilide hydroxamic acid efficiently stimulates the production of reactive oxygen species. The free radical scavenger N-acetylcysteine inhibits apoptosis, indicating that reactive oxygen species are major mediators of valproate activity. As expected, valproate alone or combined with pemetrexed and cisplatin triggers hyperacetylation of histone H3. Bid protein processing in truncated t-Bid and cytochrome c release from mitochondria are significantly increased in the presence of valproate, providing a mechanistic rationale for improvement of the proapoptotic efficacy of cisplatin and pemetrexed. Finally, valproate when combined with pemetrexed and cisplatin prevents tumor growth in mouse models of epithelioid mesothelioma. Conclusions: These observations support the potential additional efficacy of valproate in combination with pemetrexed and cisplatin for treatment of malignant mesothelioma.

Kinetics of soluble mesothelin in patients with malignant pleural mesothelioma during treatment.

RATIONALE Previous data suggested that serum levels of soluble mesothelin (SM) are related to tumor size and may have prognostic significance in malignant pleural mesothelioma (MPM). OBJECTIVES We tested the hypothesis that this marker could also be useful for monitoring response to treatment. METHODS Serial measurements of SM were determined in 40 patients diagnosed with MPM and subjected to gene-transfer therapy using intrapleural infusion of an adenoviral vector expressing human IFN-beta or conventional treatment (mainly chemotherapy). MEASUREMENTS AND MAIN RESULTS In patients with baseline SM levels greater than 1 nM/L and disease progression after therapy, SM levels increased by 2.1 nM/L at two, 5.2 nM/L at four and 1.3 nM/L at 6 months. Patients with initial SM below 1 nM/L had a similar but more moderate increase of SM over time. Patients who responded to treatment or were considered stable had an initial small decrease of SM followed by a return to baseline values after 6 months of follow-up. In patients with baseline SM levels greater than 1 nM/L, increasing levels were associated with a significantly shorter median survival than in patients with stable or decreasing SM levels (4.4 vs. 27.7 months; P = 0.012). CONCLUSIONS Increasing serum levels of SM were associated with disease progression and worse outcome, whereas stable or decreasing values suggested response to treatment. If confirmed in larger series, SM could be used to monitor patients with malignant pleural mesothelioma under treatment.

Assessment of Non–Small Cell Lung Cancer Perfusion: Pathologic-CT Correlation in 15 Patients

PURPOSE To assess tumor perfusion with multi-detector row computed tomography (CT) in patients with non-small cell lung carcinoma and to correlate CT findings with pathologic results. MATERIALS AND METHODS This study was approved by the local Ethics Committee, and all patients provided written informed consent, which included information on the radiation exposure at the CT examinations. Fifteen consecutive patients (mean age, 60.5 years ± 7.7 [standard deviation]), including 14 men (mean age, 59.9 years ± 7.5) and one woman (age, 70 years) with histologically proved non-small cell lung carcinoma were prospectively enrolled. Overall, pathologic-CT correlations were examined in 31 focal tumoral zones. Comparative analysis was performed by using the χ(2) or the Fisher exact test for categoric data. For numeric data, group comparisons were performed by using the Mann-Whitney test. RESULTS Whole-tumor coverage (mean height, 4.3 cm ± 2.1) was possible in all patients with generation of colored parametric maps of volume transfer constant (K(trans)) and blood volume (BV) by using Patlak analysis. Of the 12 areas that showed high BV, 10 (83%) had a high K(trans); in all 12 cases, the vascular score was high, confirming the presence of numerous tumoral vessels. Nineteen areas showed low BV; when observed concurrently with a high K(trans) (seven of 19), the mean vessel number per area was significantly higher than that seen in areas with low BV and low K(trans) (12 of 19) (P = .038), suggestive of tumoral vessels associated with high interstitial pressure. CONCLUSION Whole-tumor perfusion analysis is technically feasible with 64-detector row CT, with two patterns suggestive of high tumoral vascularity. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100181/-/DC1.