Kinetics of Soluble Mesothelin in Patients with Malignant Pleural Mesothelioma during Treatment Bogdan D. Grigoriu1,2*, Bachar Chahine3*, Anil Vachani4, Thomas Gey3, Massimo Conti5, Daniel H. Sterman4, Genevieve Marchandise1, Henri Porte5, Steven M. Albelda4, and Arnaud Scherpereel1,3 1 INSERM Unit 774, Institut Pasteur of Lille, Lille, France; 2Department of Pulmonary Diseases, University of Medicine and Pharmacy, Iasi, Romania; 3 Thoracic Oncology Department, CHRU of Lille, University of Lille II, Lille, France; 4Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania; and 5Department of Thoracic Surgery, CHRU of Lille, University of Lille II, Lille, France Rationale: Previous data suggested that serum levels of soluble mesothelin (SM) are related to tumor size and may have prognostic AT A GLANCE COMMENTARY signiﬁcance in malignant pleural mesothelioma (MPM). Objectives: We tested the hypothesis that this marker could also be Scientiﬁc Knowledge on the Subject useful for monitoring response to treatment. There are no published data (except in some limited Methods: Serial measurements of SM were determined in 40 patients abstracts) on the utility of mesothelin for monitoring diagnosed with MPM and subjected to gene-transfer therapy using response to treatment in malignant pleural mesothelioma. intrapleural infusion of an adenoviral vector expressing human IFN-b or conventional treatment (mainly chemotherapy). Measurements and Main Results: In patients with baseline SM levels What This Study Adds to the Field 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 We show that serum mesothelin measurement could be 6 months. Patients with initial SM below 1 nM/L had a similar but useful in monitoring the evolution of patients with malig- more moderate increase of SM over time. Patients who responded to nant pleural mesothelioma. 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, in- creasing 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 5 0.012). gene therapy, proapoptotic agents (such as inhibitors of histone Conclusions: Increasing serum levels of SM were associated with desacetylases), or antiangiogenic therapies. disease progression and worse outcome, whereas stable or decreas- The evaluation of the response to treatment can be difﬁcult ing values suggested response to treatment. If conﬁrmed in larger for a number of reasons: (1) MPM does not often present as series, SM could be used to monitor patients with malignant pleural a single tumor, but rather as multiple pleural foci that are difﬁcult mesothelioma under treatment. to assess even using the modiﬁed Response Evaluation Criteria in Solid Tumors (RECIST) criteria; (2) the presence of pleural Keywords: pleura; neoplasm; prognosis; marker effusions that are often loculated and chronic can be difﬁcult to differentiate from tumor; (3) the ﬂattened shape (rather than Malignant pleural mesothelioma (MPM) is a severe disease round tumor nodules seen with lung cancer) make the assessment whose incidence is increasing due to previous asbestos expo- of tumor volume by conventional imaging such as CT scan dif- sure. Patient outcome is dismal despite current therapeutic ﬁcult (4); and (4) MPM is often very ﬁbrotic, resulting in small modalities that include surgery, chemotherapy, and irradiation changes in the size of the tumor despite effective tumor cell of the thoracic drainage sites. In early stages, surgery may offer killing. New potential tools may include the use of computerized a chance for a prolonged survival, but patients need to be algorithms for tumor evaluation and [18F]ﬂuorodeoxyglucose- carefully selected; less than 10% of the patients are eligible for positron emission tomography (FDG-PET) scans, which can quan- this therapy (1, 2). In advanced stages, chemotherapy with the tify the amount of metabolically active tissue and may provide new antifolates combined with cisplatin offers a small but information on prognosis and tumor response (5, 6). Data on signiﬁcant survival advantage (3). Other chemotherapeutic these methods are under investigation. Therefore, the availabil- treatment options may include gemcitabine or in the future, ity of a soluble tumor marker which could reﬂect the tumor burden would be of importance in clinical practice. Soluble mesothelin (SM) (also called soluble mesothelin- related peptides) (7–9) and osteopontin (10) have been pro- posed as diagnostic markers in mesothelioma. SM is expressed (Received in original form July 21, 2008; accepted in ﬁnal form February 6, 2009) primarily by the epithelioid subtype of MPM (11), and previous Supported by grants from La Ligue contre le Cancer, comite de l’Aisne (2005), data suggested that serum SM levels increase with tumor growth Pneumologie Developpement (2004) and from RESPIR Association (Lille, 2006) (7) and iare related patient survival (9). Thus, SM may be useful (A.S.) and by a research fellowship from the Societe de Pathologie Thoracique du to monitor the patient response to therapy. Recently, the FDA Nord (B.G.). has approved SM (the MESOMARK enzyme-linked immunoab- * These authors contributed equally to this work. sorbent assay) as a test for monitoring patients treated for Correspondence and requests for reprints should be addressed to Arnaud MPM, but, to our best knowledge, data about the usefulness of Scherpereel, M.D., Ph.D., Pulmonary and Thoracic Oncology Department, Hopi- this test are limited and have been not published. Therefore, we tal Calmette, CHRU of Lille, 59037 Lille cedex, France. E-mail: a-scherpereel@ conducted a multicenter retrospective study of the kinetics of chru-lille.fr SM in MPM patients treated by conventional therapies (i.e., Am J Respir Crit Care Med Vol 179. pp 950–954, 2009 Originally Published in Press as DOI: 10.1164/rccm.200807-1125OC on February 6, 2009 chemotherapy 6 radiotherapy and surgery) or evaluated in Internet address: www.atsjournals.org a clinical trial of gene-transfer therapy using intrapleural Grigoriu, Chahine, Vachani, et al.: Kinetics of Soluble Mesothelin in Mesothelioma 951 infusion of adenoviral vector expressing human interferon-b Evaluation of the tumor volume and of the response to treatment (Ad.huIFN-b). Some of these results have been published in was done using modiﬁed RECIST criteria (14). These criteria use abstract form (12). unidimensional measurement of tumor thickness perpendicular to the chest wall or mediastinum, measured in two sites at three different levels on a CT scan. MATERIAL AND METHODS ELISA Assays Patients The soluble mesothelin was assayed by ELISA using the MESOMARK Patients were recruited in two locations: in the United States (Pulmo- kit (Fujirebio, Malvern, PA or CISbio International, Gif/Yvette, France) nary, Allergy, and Critical Care Division, University of Pennsylvania according to the manufacturers’ instructions. Medical Center, Philadelphia, Pennsylvania) and in France (Thoracic Oncology Department, CHRU of Lille). Statistical Analysis Patients Recruited at the University of Pennsylvania Kaplan-Meier curves and the log-rank test statistic was used to compare Medical Center differences in survival between groups. A two-sided P value of , 0.05 was considered signiﬁcant. Statistical calculations were performed with Sixteen patients were enrolled in one of two Phase 1 immunogene SPSS statistical package (version 12.0F; SPSS, Chicago, IL). transfer trials conducted between August 2003 and June 2007, using The protocol was approved by local ethical committee of both sites. intrapleural infusion of an adenoviral vector expressing human IFN-b Some of these data have been published in abstract form (12). (Ad.huIFN-b). Eighth subjects were enrolled in a single dose trial (reported in Reference 13), whereas eight subjects were enrolled in a two-dose trial, with infusions separated by 2 weeks. Patients were RESULTS eligible if they had a histologically proven diagnosis of malignant The analyzed series include a total of 40 patients (n 5 16 from pleural mesothelioma, were not candidates for resection, had an the United States recruited between August 2003 and June 2007 Eastern Cooperative Oncology Group performance status < 2, and had a residual pleural space. Exclusion criteria included prior surgical and n 5 24 from France recruited between May 2003 and resection, pleurodesis, chemotherapy, or radiotherapy or the presence November 2006). Serum samples were collected before treat- of signiﬁcant cardiac, hepatic, or renal disease. All subjects had serum ment and when possible after 2, 4, and 6 months of treatment. collected at baseline and at 1, 2, 4, and 6 months after infusion. Serum samples were available at two time points in 23 patients, at three time points in nine patients, and at four time points in Patients Recruited in Lille (France) eight patients. The mean age of the patients was 66.1 years (SD Patients were recruited from a series of 167 mesothelioma cases from 10.3 years). There were 11 women and 29 men (Table 1). our prospective regional MPM surveillance program which started in 2003 and involved 20 different pulmonary or thoracic surgery depart- Patients Exhibiting Initial Low Levels of Serum Mesothelin ments from the North and West of France (details in Reference 8). In We separated the patients based on their SM levels at the time 24 cases, we had at least two serum samples and a thoracic CT scan of the ﬁrst determination. Our ﬁrst group included patients with available, enabling us to evaluate tumor evolution and soluble meso- initial SM values lower than 1 nM/L, a level considered as thelin kinetics. Four patients received only supportive therapy due to rapid disease progression and the rest were subjected to chemotherapy normal or ‘‘nondiagnostic’’ for MPM (15, 16). In this group of 15 (mainly pemetrexed with cisplatin, but one received carboplatin with patients (13 with epithelioid mesothelioma, 1 with a sarcomatoid pemetrexed, one was treated by cisplatin and gemcitabine, and a last subtype, and 1 with mixed subtype), the median value of serum one by another regimen). Exclusion criteria were any concomitant SM at the time of diagnosis was 0.58 nM/L (interquartile range infectious disease or patient refusal. Irradiation of chest wall drainage [IQR], 0.33–0.82 nM/L). Eleven patients had progressive disease: points (21 Gy in seven fractions) was done for all patients. The 24 the median SM value of these patients increased progressively recruited patients had similar characteristics as the whole group from 0.58 nM/L (IQR, 0.33–0.82) at diagnosis to 0.73 nM/L (IQR, concerning the age, percentage of epithelioid subtype, or median 0.56–1.5), 1.3 nM/L (IQR, 0.87–1.45), and 3.75 nM/L at 2 months, mesothelin at diagnosis. 4 months, and 6 months after diagnosis, respectively (Figure 1A). Serum samples collected from patients were stored at 2808C until analyzed. Clinical data and outcome of the patients were also collected The median increase of SM after 2, 4, and 6 months of follow-up every 4 weeks. A chest CT scan was performed within 1 week of the were, respectively, 0.15 nm/L (IQR, 0.1120.6), 0.6 nM/L (IQR, serum collection (before delivering the treatment) and afterward every 0.29–0.87), and 3.2 nm/L (two cases only) (Figure 1B). three cycles of chemotherapy. Patients treated with gene therapy had The remaining four patients (all treated by gene therapy) had chest CT evaluations at 2 and 6 months after vector instillation. stable disease on the chest CT scan 2 months after vector TABLE 1. DEMOGRAPHIC DATA OF RECRUITED PATIENTS Treatment Received (Chemotherapy/BSC/ Description n Age (mean 6 SD) M/F (n) Gene Therapy) All patients 40 66.0 6 10.3 29/11 19/5/16 Patients recruited from U.S. 16 68.6 6 11.3 12/4 0/0/16 Europe 24 64.3 6 9.3 17/7 19/5/0 Low initial serum mesothelin level (at diagnosis) 15 70.2 6 7.3 11/4 Progressive disease 11 71.5 6 7.1 8/3 5/2/4 Stable disease 4 66.7 6 1.7 3/1 0/0/4 High initial serum mesothelin level 25 63,5 6 11.1 18/7 Progressive disease 16 65.7 6 11.1 12/4 6/3/7 Stable or response to treatment 9 59.5 6 10.4 6/3 8/0/1 Deﬁnition of abbreviation: BSC 5 best supportive care; F 5 female; M 5 male. 952 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 179 2009 Figure 1. Serum mesothelin ki- netics in patients with low serum mesothelin values at diagnosis and exhibiting progressive disease during follow-up. (A) Individual kinetics. (B) Changes in serum mesothelin level from baseline (time of diagnosis soluble meso- thelin [SM] value). instillation. Their median SM level showed a modest initial SM levels and overall survival. In the subgroup of 17 patients decrease followed by a much more slowly increase: 0.65 nM/L with high initial mesothelin values recruited from France, the (IQR, 0.5–0.75) at diagnosis, 0.4 nM/L (IQR, 0.27–0.5) at change in SM was measured and overall survival was deter- 2 months, 0.7 nM/L (IQR, 0.5–0.8) at 4 months, and 0.85 nM/L mined during long-term follow-up of these patients. An in- (IQR, 0.6–1.02) at 6 months, with a mean change of, respectively, creasing level of SM was deﬁned as an increase of at least 10% 20.25 nM/L (IQR, 20.32 to 0.15), 0.1 nM/L (IQR, 20.05 to in the ﬁrst available serum sample at the end of the treatment 0.15), and 0.25 nM/L (IQR, 0.02–0.4 nM/L) (Figure 2). compared with the pretreatment value. The difference in overall survival between the two groups Patients with Initial Serum Mesothelin Greater than 1 nM/L was signiﬁcant, with a median survival of 27.7 months in the Our second group of patients included those with SM levels group with stable mesothelin values (n 5 7) compared with greater than 1 nM/L. In this group of 25 patients, there were 22 4.4 months in the group (n 5 10) with increasing values (P 5 0.012; epithelioid MPM, one case of mixed MPM and two cases of log-rank test) (Figure 5). MPM classiﬁed as sarcomatoid. Sixteen patients had progres- sive disease despite treatment (gene therapy: n 5 7; chemo- DISCUSSION therapy: n 5 6 and best supportive care: n 5 3). SM values increased by more than 10% of baseline value in 12 patients, The survival of patients with MPM is short, despite efforts to decreased in one (20% decline), and were stable (within 6 10% develop better therapeutic strategies; however, a number of new of baseline value) in three patients. The median increase over therapeutic approaches are being developed and studied (17, 18). baseline (ﬁrst diagnostic time) of SM was 2.1 nM/L at 2 months There are some prognostic factors proposed for MPM in the (IQR, 1.15–4.08), 5.2 nM/L at 4 months (IQR, 0.05–13.9), and literature, such as the histologic subtype, the tumor stage according 1.3 nM/L (IQR, 0.8–1.99) at 3 months. Thus, in this group of to the IMIG staging system, the completeness of resection after patients with progressive disease, the majority demonstrated an surgery, and some basic markers proposed by EORTC/CALGB increase in SM levels, which mirrored the tumor growth seen on and recently updated (e.g., platelet count, hemoglobin, perfor- CT imaging (Figures 3A and 3B). mance status, etc.) (19–22). These parameters are not validated at From the remaining patients (one receiving gene therapy an individual level but rather are used to assess the homogeneity of and eight receiving chemotherapy), three were considered to groups of patients with MPM in a clinical study or trial (18). have an objective response, four had stable disease, and two had Hyaluronic acid level in the pleural ﬂuid may be of interest, but progression at 2 months but stable disease at the 6-month deﬁnitive data are lacking (23). PET scanning is also being evaluation. These nine patients exhibited a clear decrease of SM investigated (5, 24); however, evaluation of patients treated for level, except one patient considered to be stable (Figure 4A). MPM relies mostly on physical examination and CT scan (using The SM decrease was greatest at the 4-month evaluation and modiﬁed RECIST criteria). This is often difﬁcult and suboptimal. after 6 months the serum values tend to return toward the Serum soluble mesothelin measured at the time of diagnosis baseline values (Figure 4B). has been shown to be correlated with tumor volume (7) and survival (9). Until now, these potential biological markers have Relationship of SM Levels and Overall Survival been evaluated as prognostic factors at diagnosis rather than as A second way to evaluate the value of SM levels, independently predictive markers to monitor the response of MPM to treat- of the CT scan data, was to examine the correlation between ment. The goal of this study was to speciﬁcally examine SM Figure 2. Kinetics of serum mesothelin level in patients with initial low values of meso- thelin and exhibiting stable disease during follow-up. (A) Individual patients. (B) Changes in serum mesothelin level compared with baseline (time of diagnosis SM value). Grigoriu, Chahine, Vachani, et al.: Kinetics of Soluble Mesothelin in Mesothelioma 953 Figure 3. Serum mesothelin level in patients exhibiting a progressive disease during follow-up and high initial values of SM. (A) Values for individual patients. (B) Median changes of serum mesothelin from baseline (time of diagnosis SM value). levels in relation to therapeutic response. To study this question of pleural biopsies, they were wrongly classiﬁed as having a non- we used two approaches. The ﬁrst was to compare SM levels epithelioid mesothelioma (25). Later, the tumor growth resulted in with CT and PET scans. Although this is the standard of care, it an increase of the epithelioid component of the MPM with may be inaccurate and thus represent a ‘‘tarnished gold a subsequent elevation of SM level. Thus, serum mesothelin seems standard.’’ Accordingly, in a relatively large and uniform sub- to be an interesting marker for monitoring the response to group (i.e., the French patients undergoing chemotherapy), we treatment in patients with MPM, suggesting that SM blood level applied an independent and more objective standard (survival). could reﬂect the tumor burden. Mesothelin is produced by the For the ﬁrst time, we show here that patients with MPM having tumor itself and expressed at the cell membrane of mesothelial an objective response after chemotherapy exhibited decreasing, tumor cells (26, 27). The mechanism of mesothelin release from the or at least stable, serum SM levels, whereas patients having cell surface into the circulation is unknown, but the available data progressive disease exhibited increasing SM values. We consid- are in favor of a proteolitic cleavage (27–29). Factors modulating ered that a signiﬁcant change in SM level should exceed 10% of this enzymatic pathway may strongly inﬂuence serum mesothelin baseline value because the coefﬁcient of variation of the assay is level and the kinetics of the marker from one patient to another between 4 and 11%, according to the manufacturer-supplied even if both patients would have a similar clinical and radiologic data. We also showed that the survival of patients with de- pattern or the same outcome. Moreover, it is unknown if the creasing/stable values of SM during follow-up is signiﬁcantly therapy may inﬂuence this process of mesothelin release. How- greater than in patients with increasing SM. ever, because there is a strong relationship between the kinetics of Even in the group of patients with ‘‘normal’’ values of SM at serum SM and patient survival, our conclusion that serum meso- the time of diagnosis, we observed an increase of SM exceeding thelin mirrors the tumor evolution under treatment is sustained. 10% over baseline as the result of a progressive disease in Another important ﬁnding was that the relationship between almost all cases. In contrast, patients from this group exhibiting the kinetics of serum SM and the response to treatment held stable disease had a modest absolute initial decrease in serum true no matter which therapy was used (chemotherapy, gene SM levels in three out of four cases. therapy, or multimodal treatment). This conﬁrmed the repro- In patients with SM levels greater than 1 nM/L, progression of ducibility of these ﬁndings and may allow using SM as a pre- the disease was associated with a progressive increase of SM in 12 dictive serum marker in all MPM cases. out of 16 patients (75%), while an increase of less than 10% was One potential pitfall of this marker is that it will likely be encountered in three cases (18.7%). The median increase in serum useful only for epithelioid or mixed-type tumors (which account mesothelin is paradoxically smaller at 6 months than after 4 for the majority of cases). In mixed-type tumors with a low or months of follow-up. We feel this is likely due to the death of the very low epithelioid component, the usefulness of this marker patients, with the most important increases corresponding with the may also be limited, being possibly less sensitive than current most rapid progression of the disease. Conversely, in patients with imaging investigations or clinical examination. an objective response or stable disease, an initial decrease of In conclusion, we demonstrated for the ﬁrst time that SM may serum mesothelin level was observed, followed by a return to near be a useful predictive and prognostic tumor marker in patients baseline values 6 months later, due to disease relapse. with MPM. These results support the use of serum mesothelin in Another interesting ﬁnding of this investigation was the pro- monitoring treated patients with MPM. However, our ﬁndings gressive increase of SM in some patients with nonepithelioid should be interpreted with caution because the number of subtype of MPM and a low SM level at diagnosis. One possible recruited patients was limited, as were the data derived from the explanation could be that these patients had a mixed type MPM survival analysis. Further prospective investigations (from larger with a low epithelial component, and, due to an insufﬁcient number clinical therapeutic trials in MPM, for example) are needed to Figure 4. Kinetics of serum mesothelin level in patients exhibiting a response to treatment or a stable disease during follow-up. (A) Kinetics of individual patients. (B) Median changes in serum mesothelin over baseline. 954 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 179 2009 9. Grigoriu BD, Scherpereel A, Devos P, Chahine B, Letourneux M, Lebailly P, Gregoire M, Porte H, Copin MC, Lassalle P. Utility of osteopontin and serum mesothelin in malignant pleural mesothelioma diagnosis and prognosis assessment. Clin Cancer Res 2007;13:2928–2935. 10. Pass HI, Lott D, Lonardo F, Harbut M, Liu Z, Tang N, Carbone M, Webb C, Wali A. Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. N Engl J Med 2005;353:1564–1573. 11. Ordonez NG. What are the current best immunohistochemical markers for the diagnosis of epithelioid mesothelioma? A review and update. Hum Pathol 2007;38:1–16. 12. Grigoriu B, Chahine B, Conti M, Kedziora L, Gey T, Copin MC, Lassalle P, Marchandise G, Porte H, Scherpereel A. Kinetics of serum soluble mesothelin related peptides and osteopontin in patients with malignant pleural mesothelioma under treatment [abstract]. Am J Respir Crit Care Med 2006;173:A864. 13. Sterman DH, Recio A, Carroll RG, Gillespie CT, Haas A, Vachani A, Kapoor V, Sun J, Hodinka R, Brown JL, et al. A phase I clinical trial of single-dose intrapleural IFN-fbetag gene transfer for malignant Figure 5. Survival of patients with malignant pleural mesothelioma pleural mesothelioma and metastatic pleural effusions: high rate of according to the kinetics of serum mesothelin during follow-up. antitumor immune responses. Clin Cancer Res 2007;13:4456–4466. 14. Byrne M, Nowak A. Modiﬁed RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 2004;15:257–260. establish the use of serum mesothelin levels as a predictive and 15. Creaney J, Christansen H, Lake R, Musk AB, de Klerk N, Robinson prognostic marker in patients with MPM. BW. Soluble mesothelin related protein in mesothelioma. J Thorac Oncol 2006;1:172–174. Conﬂict of Interest Statement: B.D.G. was sponsored by CisBio International to attend the ATS 2006 conference. The total value of the ﬁnal support received was 16. Cristaudo A, Foddis R, Vivaldi A, Guglielmi G, Dipalma N, Filiberti R, about V1,000. B.C. does not have a ﬁnancial relationship with a commercial Neri M, Ceppi M, Paganuzzi M, Ivaldi GP, et al. Clinical signiﬁcance entity that has an interest in the subject of this manuscript. A.V. received $14,300 of serum mesothelin in patients with mesothelioma and lung cancer. in 2006–2008 from Fujirebio Diagnostics as research grants for participating in Clin Cancer Res 2007;13:5076–5081. multicenter clinical trials. T.G. does not have a ﬁnancial relationship with 17. Fennell DA, Gaudino G, O’Byrne KJ, Mutti L, van Meerbeeck J. a commercial entity that has an interest in the subject of this manuscript. M.C. Advances in the systemic therapy of malignant pleural mesothelioma. does not have a ﬁnancial relationship with a commercial entity that has an Nat Clin Pract Oncol 2008;5:136–147. interest in the subject of this manuscript. D.H.S. does not have a ﬁnancial 18. Scherpereel A. Guidelines of the French Speaking Society for Chest relationship with a commercial entity that has an interest in the subject of this manuscript. G.M. does not have a ﬁnancial relationship with a commercial entity Medicine for management of malignant pleural mesothelioma. Respir that has an interest in the subject of this manuscript. H.P. does not have Med 2007;101:1265–1276. a ﬁnancial relationship with a commercial entity that has an interest in the subject 19. Herndon JE II, Green MR, Chahinian AP, Corson JM, Suzuki Y, of this manuscript. S.M.A. served on an advisory board and was a consultant for Vogelzang NJ. Factors predictive of survival among 337 patients with Fujirebio and received $2,000 in 2005. A.S. was reimbursed by Fujirebio for mesothelioma treated between 1984 and 1994 by the Cancer and attending a scientiﬁc meeting (IMIG 2006) and received $600 for speaking at Leukemia Group B. Chest 1998;113:723–731. a conference sponsored by Fujirebio during the same meeting. The A-S 20. Curran D, Sahmoud T, Therasse P, van Meerbeeck J, Postmus PE, institution received research grants from Fujirebio ($30,000) and Cisbio In- Giaccone G. 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