950 by liaoxiuli2


									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
 INSERM Unit 774, Institut Pasteur of Lille, Lille, France; 2Department of Pulmonary Diseases, University of Medicine and Pharmacy, Iasi, Romania;
 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
                                                                                       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.
                                                                                 ELISA Assays
                                                                                 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

                                                                                                                     Treatment Received
                 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-
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

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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. Prognostic factors in patients with pleural mesothelioma:
ternational (V10,000) in 2007 to participate in multicenter studies.
                                                                                              the European Organization for Research and Treatment of Cancer
                                                                                              experience. J Clin Oncol 1998;16:145–152.
                                                                                       21. Bottomley A, Coens C, Efficace F, Gaafar R, Manegold C, Burgers S,
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