Abstract
Objective. To analyze the characteristics of anti-RNA polymerase III antibodies (anti-RNAP3)− positive patients with systemic sclerosis (SSc) in the European League Against Rheumatism Scleroderma Trials and Research group (EUSTAR) registry with a focus on the risk of cancer and the characteristics of malignancies, and the aim to provide guidelines about potential cancer screening in these patients.
Methods. (1) Analysis of the EUSTAR database: 4986 patients with information on their anti-RNAP3 status were included. (2) Case-control study: additional retrospective data, including malignancy history, were queried in 13 participating EUSTAR centers; 158 anti-RNAP3+ cases were compared with 199 local anti-RNAP3− controls, matched for sex, cutaneous subset, disease duration, and age at SSc onset. (3) A Delphi exercise was performed by 82 experts to reach consensus for cancer screening in anti-RNAP3+ patients.
Results. In the EUSTAR registry, anti-RNAP3 were associated in multivariable analysis with renal crisis and diffuse cutaneous involvement. In the case-control study, anti-RNAP3 were associated with gastric antral vascular ectasia, rapid progression of skin involvement, and malignancies concomitant to SSc onset (OR 7.38, 95% CI 1.61–33.8). When compared with other anti-RNAP3+ patients, those with concomitant malignancies had older age (p < 0.001) and more frequent diffuse cutaneous involvement (p = 0.008). The Delphi exercise highlighted the need for malignancy screening at the time of diagnosis for anti-RNAP3+ patients and tight followup in the following years.
Conclusion. Anti-RNAP3+ patients with SSc have a high risk of concomitant malignancy. These results have implications for clinical practice and suggest regular screening for cancer in anti-RNAP3+ patients.
Systemic sclerosis (SSc) is characterized by considerable heterogeneity of clinical manifestations in affected individuals1,2,3. Autoantibodies are seen in almost all patients and might have a pathogenic role4. They are currently considered the best available markers to stratify patient’s heterogeneity: different autoantibodies are associated with clinically and genetically distinct disease subsets2,4, identifying patients at highest risk of particular clinical manifestations and providing longterm prognostic information5.
In particular, anti-RNA polymerase III antibodies (anti-RNAP3) have specificity for SSc and association with diffuse cutaneous involvement and renal crisis6,7. The development of ELISA, more suited to routine use8, allowed the identification of novel clinical correlates of anti-RNAP3, such as gastric antral vascular ectasia (GAVE)9,10, and increased risk of malignancy diagnosis11,12,13,14,15,16.
However, the prevalence of anti-RNAP3 in SSc is very heterogeneous among studies, probably because of geographic/ethnic factors17. Their prognostic value still needs to be better focused and the previous studies, mostly based on monocentric series and/or with low to moderate sample size, precluded firm conclusions. This is even more important because of data showing a link between RNAP3 gene mutations, the emergence of tumor cells, and immune response leading to anti-RNAP3 production18.
We took advantage of the worldwide registry of the European League Against Rheumatism (EULAR) Scleroderma Trials and Research group (EUSTAR). We first queried the EUSTAR database, and then asked centers to participate in a retrospective case-control study, providing additional data not included in the database. In particular, we sought data on the history of malignancies, with the aim of defining the time relationship and the characteristics of anti-RNAP3+ SSc and malignancies. Finally, a Delphi exercise was performed to obtain expert-based conclusions for clinical practice.
MATERIALS AND METHODS
Analysis of the EUSTAR database
This database records the minimal essential dataset (MEDS) of a longitudinally followed cohort of patients with SSc2,3. Data were extracted from the registry in March 31, 2014, when 11,399 patients from 118 centers fulfilling either the 1980 American College of Rheumatology (ACR) or the 2013 ACR/EULAR classification criteria for SSc centers were recorded19,20. Data on malignancy were not recorded in the EUSTAR database at that time. Data on anti-RNAP3 were recorded since December 2008. MEDS variables were defined as previously reported2,3.
Patients were included in our study when anti-RNAP3 status was available in at least 1 visit, whereas patients with no information or unknown status in the registry were excluded. Patients were considered positive for anti-RNAP3 when the test was positive in at least 1 determination at the baseline or during the followup. Patients positive both for anti-RNAP3 and for other SSc-specific antibodies [anticentromere antibodies (ACA) or antitopoisomerase I (anti-topo I)] were excluded from comparisons between anti-RNAP3+ and anti-RNAP3− patients. To evaluate the association between anti-RNAP3 and other demographic, clinical, and laboratory variables, the MEDS data from the last available visit were used. The method of anti-RNAP3 detection was at the discretion of the participating center according to local practice and was not recorded in the database.
Ethics approval was obtained from each site [Brescia, Spedali Civili di Brescia, n.1072; Zurich, Ethic committee Canton of Zurich, number PB_2016-01515; Lund, Regionala Etikprövningsnämnden, Lund (regional ethics board) n.590/2008; Pecs, Hungarian National Ethics Committee, n.430/PI/20I2, 426/2013; Gent, Universitair Ziekenhuis Gent, n.385/2008; Verona, Azienda Ospedaliera e Istituti Ospitalieri Verona progetto n.1570, n.24934; Roma, Azienda Policlinico Umberto I, n.1469; Lille, Ethical Committee Ile de France III n.2561; Haifa, Rambam Helsinki committee, n.2440; Strasbourg, Ethical Committee Ile de France III n.2561; Lisboa, Centro Hospitalar de Lisboa Central, n.160/2014; Paris, Ethical Committee Ile de France III n.2561].
Case-control study
EUSTAR centers were invited to participate in a specifically designed case-control study. Retrospective data for all the anti-RNAP3+ patient of the participating centers (cases) were collected through a dedicated form. Anti-RNAP3+ patients also positive for other SSc-specific antibodies were excluded. Centers were asked to provide 1 or, if possible, 2 local controls (anti-RNAP3−) for each case, matched for sex, disease duration, cutaneous subset as defined by Leroy, et al21, and age at disease onset (by 5-yrs class of age). All patients included in our analysis were tested for anti-RNAP3. Data on anti-RNA polymerase I were not collected. The method of anti-RNAP3 detection, as well as the panel of SSc-specific autoantibody tests, was at the discretion of the participating center and was recorded in a dedicated form, also collecting the time of SSc onset (defined as the onset of the first non-Raynaud symptom; T0), progression of skin involvement evaluated by the modified Rodnan Skin Score (mRSS) at T0 and at 6, 12, and 24 months after T0, peak of mRSS and its time interval from T0, renal crisis, gastrointestinal involvement, malignancies and their histologic type, and date of diagnosis. Malignancies were classified as “synchronous” with SSc when the diagnosis was made between 6 months before and 12 months after SSc onset12,15, or in separate analyses in a larger interval including 2 years before and after SSc onset16.
Delphi exercise on possible screening for malignancies in anti-RNAP+ patients with SSc
A Web-based approach was used to address the questions concerning possible screening for malignancies in anti-RNAP3+ patients with SSc. First, the results of the EUSTAR cohort analysis were presented to all EUSTAR centers. Centers were then asked to participate in a Delphi exercise, voting on the opportunity of screening for malignancies in anti-RNAP3+ patients and its modality. In the second stage of this exercise, questions that remained unsolved at the first step and new suggestions from experts were re-proposed. Finally, possible recommendations were drafted and participants were asked to vote on them in stage 3 of the Delphi exercise. The level of agreement for each statement was voted using a 10-point visual analog scale (10 = fully agree).
Statistical analysis
Frequencies and percentages of categorical variables were compared using the chi-square test with Pearson correction or Fisher’s exact test, and continuous variables using the Student t test, Mann-Whitney U test, or ANOVA, as appropriate.
A multivariate logistic regression analysis (adjusted for sex, age, and disease duration) was performed with calculation of OR estimates and 95% CI. Besides a priori potential confounders, variables associated with p < 0.05 in univariable analysis were considered. Bonferroni correction for multiple comparison was applied.
The Kaplan-Meier method and the log-rank test were applied to analyze the progression of mRSS and survival.
RESULTS
Clinical associations of anti-RNAP3 based on the analysis of the EUSTAR database
Data on anti-RNAP3 were available in 4986 patients with SSc recorded in the EUSTAR database (Figure 1). No difference was observed between them and those for whom information on anti-RNAP3 status was not available.
Patient selection process for inclusion in the study. EUSTAR: European League Against Rheumatism Scleroderma Trials and Research group; anti-topo I: antitopoisomerase I; anti-RNAP3: anti-RNA polymerase III antibodies; ACA: anticentromere antibodies.
Among evaluable patients, 223 (4.5%) were reported as anti-RNAP3+ in at least 1 visit, while 4763 were always reported as anti-RNAP3−. Among anti-RNAP3+ patients, 47 were also positive for other SSc-specific antibodies in at least 1 visit (15 for ACA, 30 for anti-topo I, and 2 for both) and were excluded from further analysis, which finally compared 176 anti-RNAP3+ and 4763 anti-RNAP3− patients with SSc.
In univariable analysis (Table 1), positivity for anti-RNAP3 was associated with male sex (p < 0.0001), arterial hypertension (p = 0.03), diffuse cutaneous involvement (p < 0.0001), renal crisis (p < 0.0001), and joint contractures (p < 0.0001).
Results of the univariable and multivariable analysis (adjusted on sex, age at disease onset, and disease duration) comparing anti-RNAP3− and anti-RNAP3+ patients at the last visit (n = 4939). Values are no./no. available data (%) unless otherwise specified.
In the multivariable model (adjusted for sex, age at disease onset, and disease duration; Table 1), anti-RNAP3 positivity was independently associated with renal crisis (p < 0.0001) and diffuse cutaneous involvement (p < 0.0001).
Association of anti-RNAP3 with cancer based on the case-control study
Thirteen EUSTAR centers participated in the case-control study, collecting retrospective data from 158 anti-RNAP3+ SSc cases (95.9% of which were included in the EUSTAR database) and 199 anti-RNAP3− local SSc controls, matched for sex, disease duration, cutaneous subset, and age at disease onset. Among controls, 48% were anti-topo I+ and 22% ACA+. The interval between diagnosis and the last visit available was shorter in anti-RNAP3+ cases than in controls [median (interquartile range; IQR) 77 (38–132) mos vs 100 (52–155), p = 0.008]. There was no difference in the number of deaths and their causes between cases (n = 25: 13 due to SSc, 10 to cancer, 2 to other reasons) and controls (n = 31: 15 due to SSc, 6 to cancer, 8 to other reasons, and 2 unknown). Cumulative survival was not different between the 2 groups [at 5 yrs after SSc diagnosis, anti-RNAP3+ 91.6% (SE 2.3) vs anti-RNAP3− 94.4% (SE 1.7); at 10 years, anti-RNAP3+ 87.0% (SE 3.2) vs anti-RNAP3− 84.0% (SE 3.2), log-rank test p = 0.72].
In multivariable analyses, anti-RNAP3 positivity was negatively associated with gastroesophageal reflux disease (p = 0.003), but was positively associated with renal crisis (p = 0.0005) and GAVE (p = 0.0009; Table 2). No difference was observed between the 2 groups for peak of mRSS. However, Kaplan-Meier analysis showed that the time to reach the peak of mRSS was shorter in anti-RNAP3+ patients than in matched controls (p = 0.013). In particular, the peak of mRSS was reached within 1 or 2 years in 71% and 87% of anti-RNAP3+ patients, respectively, as compared with 62% and 74% of controls.
Results of the univariable analysis comparing anti-RNAP3+ patients with SSc (cases) and anti-RNAP3− SSc controls, matched for sex, disease duration, cutaneous subset, and age at disease onset. Anti-RNAP3 positivity was identified by ELISA in 91 patients, by line immunoassay in 38, and by immunoprecipitation in 29. Anti-RNAP3− patients were evaluated by ELISA, line immunoassay, and immunoprecipitation in 132, 30, and 37 cases, respectively. Values are no./no. available data (%) unless otherwise specified.
The overall rate of malignancies was higher in anti-RNAP3+ patients than in controls (17.7% vs 9.0%, p = 0.015; Table 2). In particular, cancers synchronous with SSc were more frequent, considering those diagnosed either between 6 months before and 12 months after SSc onset (7.0% vs 1.0%, p = 0.004), or within a larger time interval extended to 2 years before and after SSc onset (9.0% vs 2.5%, p = 0.007). In particular, cancer was diagnosed after the SSc diagnosis within the first 2 years in 9 patients (with a median delay of 4 mos).
On the other hand, the risk of cancer was not increased beyond 2 years since SSc diagnosis (Table 2).
Looking at the malignancy type, the frequency of solid tumors in anti-RNAP3+ patients was higher than in controls (p = 0.012), particularly for breast cancers (p = 0.03). Notably, the diagnosis of breast cancer was synchronous (± 2 yrs) to the onset of SSc in 7 out of 155 evaluable anti-RNAP3+ patients and in none of 199 anti-RNAP3− matched SSc controls (p = 0.003). The percentage of women with breast cancer diagnosis synchronous to the onset of SSc was 6.0% (95% CI 3.0–12.0).
When the 14 anti-RNAP3+ patients with malignancies synchronous to SSc onset were compared with the other 144 anti-RNAP3+ patients (Table 3), they had an older mean age at SSc onset (p < 0.001) and an increased proportion of diffuse cutaneous involvement (p = 0.008). In fact, in patients with diffuse cutaneous involvement, the prevalence of synchronous malignancies was higher among anti-RNAP3+ than anti-RNAP3− patients (p = 0.001), but no differences were observed comparing anti-RNAP3+ and anti-RNAP3− patients with limited cutaneous SSc. Conversely, among anti-RNAP3+ patients, the prevalence of synchronous malignancies was higher in those with diffuse than with limited cutaneous involvement (p = 0.009). A trend for increased proportion of men was also observed comparing patients with malignancies synchronous to SSc onset with other anti-RNAP+ patients (p = 0.058; Table 3). In particular, the risk of non-breast cancer synchronous with SSc was much higher in male than in female patients (43% vs 0.8%, p < 0.001, OR 95.2, 95% CI 10.2–890).
Results of the univariable analysis comparing anti-RNAP3+ patients with or without synchronous cancer. Values are no./available data no. (%) unless otherwise specified.
Based on our results, the number of anti-RNAP3+ patients needed to screen to find 1 synchronous malignancy was 17.
Delphi exercise on possible screening for malignancies in anti-RNAP3+ patients with SSc
To derive a possible list of recommendations guiding clinicians in everyday practice to screen anti-RNAP3+ patients with SSc for cancer, a Web-based Delphi approach was used. Eighty-two experts from EUSTAR centers participated in the third stage of the Delphi exercise by voting on possible recommendations. The results are shown in Table 4.
Results of the Delphi exercise. Degree of agreement with the proposed recommendations about screening for synchronous cancer in anti-RNAP3+ patients with SSc among 82 EUSTAR experts (1–10, with 10 = fully agree).
A high level of agreement was achieved on the indication to screen for malignancies at the time of diagnosis in these patients.
Possible recommendations included:
screening for breast cancer in women;
screening for other malignancies, guided by clinical suspicion and patient age and sex, at least with noninvasive tests (e.g., fecal occult blood, gynecological evaluation, prostatic-specific antigen, ultrasound studies);
tight surveillance in the first years after SSc diagnosis. The length of this period of tight control was one of the most-discussed points, even if we and others14 did not demonstrate an increased risk of cancer diagnosis beyond 2 or 3 years after SSc diagnosis.
Experts recommended prospective studies to clarify some still debated issues such as the use of positron emission tomography (PET)/computed tomography (CT) and longterm followup.
DISCUSSION
In our study, we analyzed the clinical associations of anti-RNAP3 in SSc, taking advantage of the EUSTAR collaborative group, focusing particularly on the association with malignancies.
Previous reports described a more severe cutaneous involvement in anti-RNAP3+ than in anti-topo I+ patients6,7,22,23 and a shorter interval between the appearance of Raynaud phenomenon and the first non-Raynaud SSc symptom24. Our study confirms that skin thickening progression is particularly rapid in anti-RNAP3+ patients11. Because organ complications, such as renal crisis or GAVE, usually develop early during the disease course9,10,25, these features indicate that anti-RNAP3 identify a SSc subset characterized by particularly rapid onset and progression. This scenario might be in accordance with the hypothesis of a disease induced by some trigger, which in some cases might be identified in a concomitant malignancy.
The identification of anti-RNAP3 as a marker of a disease subset with concomitant onset of cancer and SSc was first made by a single-center American study in which anti-RNAP3 were evaluated both by immunoprecipitation and ELISA11. This was subsequently confirmed by several reports, whatever the geographic origin of the patients, despite some differences in research design12,13,14,15,16. The OR for diagnosis of cancer in anti-RNAP3+, as compared with other patients with SSc, was calculated at 5.08 (95% CI 1.60–16.1)16 and 5.83 (95% CI 3.1–10.9)14, in an interval of 2 or 3 years around the onset of SSc, respectively. We herein extend these findings using our large cohort, showing an OR of 7.38 (95% CI 1.61–33.8) within an interval between 6 months before and 12 months after SSc onset.
We also observed an increased overall prevalence of cancer in anti-RNAP3+ patients, with a low OR, similar to what is found in a previous study14, but not in others including smaller numbers of cancer cases13,15,16. In years distant from the onset of SSc, we like others14 did not observe any increased frequency of cancer in anti-RNAP3+ patients. Therefore, no available data thus far suggest that the risk of cancer is extended beyond an interval of a few years around SSc onset.
The large majority of malignancies associated with the onset of anti-RNAP3+ SSc were solid cancers; in particular, anti-RNAP3+ patients were more likely to develop breast cancer within 2 years as compared with matched SSc controls with an OR of 20.2. Although the CI were wide, it is noteworthy that a similar OR of 19.0 as compared with ACA+ patients within a 3-year interval was previously reported14.
Many previously published case series described a higher incidence of breast cancer in patients with SSc compared with the general population, and close temporal relationship with SSc onset was frequently reported26,27,28. A metaanalysis demonstrated the association of SSc with lung and hematological malignancies, but did not confirm the association with breast cancer29. However, the analysis excluded breast cancer cases diagnosed before SSc, which are fairly common in the years close to SSc onset in anti-RNAP3+ patients16. Taken together, these data suggest that the mechanisms underlying the association of SSc with lung and hematological neoplasms, in which DNA oxidative damage and the use of alkylating agents may be relevant29, are different from those explaining the association with breast cancer.
Indeed, genetic alterations in the POLR3A gene, encoding for RNAP3 polypeptide A, and humoral and cell-mediated immune response against this mutated antigen were demonstrated in anti-RNAP3+ patients, but not in patients with other SSc-specific antibodies and cancer30. These data suggest that an autoimmune response initiated by mutation in the autoantigen in the cancer cells may explain the onset of SSc as a paraneoplastic disease in these patients18. These genetic alterations were found not only in cases of breast cancer30, and therefore this putative mechanism of cancer-induced autoimmune response as a trigger of SSc may be not limited to this type of malignancy.
From a practical point of view, in our series, the crude frequency of having a diagnosis of cancer within 2 years before or after SSc onset in anti-RNAP3+ patients was 11%. In our experience, as in other series13,14,15,16, around half of these malignancies were breast cancers.
These results suggest the possible need of a cancer screening program for anti-RNAP3+ patients, similar to what is generally applied in dermatomyositis18, considering that the number of patients needed to screen to find 1 synchronous malignancy would be relatively low.
We also herein defined clinical and demographic features characteristic of anti-RNAP3+ patients with SSc who have simultaneous malignancy. Patients with older age or diffuse cutaneous involvement were particularly at risk, and malignancies other than breast cancers were much more frequent in men. These risk factors may help in clinical practice to institute appropriate cancer screening at SSc diagnosis in these individuals.
EUSTAR experts agreed to recommend such screening in these patients. Minimal tests to be performed at diagnosis should include screening for breast cancer in women and noninvasive tests guided by clinical suspicion and patient age for other malignancies. Although most experts agreed on the proposed statements, some degree of discordance was found on the use of PET/CT and the program of longterm followup. In particular, lower agreement was found for the duration of tight surveillance and which examinations would be most indicated to be repeated, even if a first determination is negative. The experts strongly agreed that prospective studies are needed to clarify these issues.
Besides the association of anti-RNAP3 with malignancy, our analysis of the large EUSTAR registry confirmed the associations with renal crisis and diffuse cutaneous involvement4,6,7,13,31. The associations with arterial hypertension and joint contractures, already reported13, were not confirmed by multivariable analysis, suggesting that they may be indirectly explained by covariates. The higher frequency of men among anti-RNAP3+ patients was probably due to the high prevalence of women among ACA+ patients13,22,23,32, whereas we, like others, did not observe differences in the sex distribution between anti-RNAP3+ and anti-topo I+ patients4,6,7,13,22,23. We also confirmed the association of anti-RNAP3 with GAVE9,10, a complication associated with renal crisis, hypertension, reduced DLCO/alveolar volume, and telangiectasia9,33,34,35, thus reinforcing the characterization of anti-RNAP3 as markers of an SSc subset particularly prone to microangiopathic complications.
Accordingly, anti-RNAP3 were associated with increased risk of pulmonary hypertension (PH)36. This could not be confirmed, but the phenotyping of PH in the EUSTAR cohort (initially based on echocardiographic data) was only recently improved, and thus our analysis could not yet include enough patients with proven diagnosis of PH. Further studies are therefore needed to clarify this important issue.
Limitations are inherent in the design of a large, international, and multicenter study based, as far as the association between SSc and cancer, on retrospective data. However, because the awareness of increased risk of malignancy in anti-RNAP3+ patients has arisen among clinicians only recently, it is unlikely that the results of our retrospective analysis (which enrolled all historic patients among participating centers) were biased by more rigorous cancer screening in anti-RNAP3+ than in other patients with SSc. Although methods of anti-RNAP3 evaluation were at the discretion of the participating center, ELISA and line immunoassay tests for anti-RNAP3 have good sensitivity and a specificity higher than 90% when compared with the gold standard of the immunoprecipitation method37,38,39,40. Moreover, the association with malignancies was recognized by previous studies irrespective of the method of antibody detection11,12,13,14,15,16. Intrapatient variability in anti-RNAP3 levels was observed in longitudinal studies41, and it is possible that positivity for anti-RNAP3 disappears during the course of the disease. Because the diffusion of anti-RNAP3 tests is relatively recent, we cannot exclude that an initial anti-RNAP3 positivity was not recognized. This might lead to a false-negative classification of patients. However, if false-negative data were included in our analysis, the clinical associations of anti-RNAP3 observed here would be weakened.
In fact, it is noteworthy that, when available in the literature, data derived from single-center observational studies on the relative risk of cancer simultaneous to the onset of SSc14,16 were very similar to the results of our study, even for specific tumors such as breast cancers14.
Anti-RNAP3 antibodies are associated with poor prognostic manifestations of SSc, including increased risk of malignancy diagnosis (in particular of breast cancer) close to the SSc onset. Despite the clear potential benefit of anti-RNAP3 evaluations, they are still not always routinely evaluated. Although anti-RNAP3 and other SSc-specific autoantibodies are in most cases mutually exclusive11,37, a reasonable strategy might be to evaluate anti-RNAP3 not only in all patients with SSc negative for anti–topo I and ACA, but also in all patients with diffuse cutaneous involvement, particularly in older patients and in men, and in all conditions with discrepancies between antibodies status and clinical course. When anti-RNAP3+ SSc is diagnosed, the association with synchronous cancer requires careful screening and followup for malignancies.
Acknowledgment
We thank Dr. Katarzyna Romanowska-Próchnicka (Department of Pathophysiology, Medical University of Warsaw and Department of Connective Tissue Diseases, Institute of Rheumatology, Warsaw, Poland) for providing patient data. Participants to the Delphi exercise are acknowledged: Sabine Adler (Switzerland), Nihal Ahmed Fathi (Egypt), Juan José Alegre Sancho (Spain), Martin Aringer (Germany), Marko Barešić (Croatia), Mike Becker (Germany), Radim Bečvář (Czech Republic), Laura Belloli (Italy), Emma Beltran-Catalan (Spain), Francesco Boin (USA), Yolanda Braun-Moscovici (Israel), Daniel Brito De Araujo (Brasil) Cosimo Bruni (Italy), Patricia Carreira (Spain), Carlo Chizzolini (Switzerland), Lorinda Chung (USA), Veronica Codullo (Italy), Franco Cozzi (Italy), Melanie-Ivana Čulo (Croatia), Maurizio Cutolo (Italy), Laszlo Czirjak (Hungary), José A.P. Da Silva (Portugal), Thomas Daikeler (Switzerland), Nemanja Damjanov (Serbia), Ellen De Langhe (Belgium), Christopher Denton (UK), Marcella Di Gangi (Italy), Jörg Distler (Germany), Jo Dockerty (New Zealand), Merete Engelhart (Denmark), Julia Fantana (Germany), Paloma Garcia De La Peña Lefebvre (Spain), Brigitte Granel (France), Claudia Günther (Germany), Paul Hasler (Switzerland), Ariane Herrick (UK), Nicolas Hunzelmann (Germany), Florenzo Iannone (Italy), Bernard Imbert (France), Francesca Ingegnoli (Italy), Ruxandra Ionescu (Romania), Henes Joerg (Germany), Dinesh Khanna (USA), David Launay (France), Nicolai Leuchten (Germany), Francisco Javier Lopez Longo (Spain), Dusanka Martinovic Kaliterna (Croatia), Marco Matucci-Cerinic (Italy), Britta Maurer (Switzerland), Øyvind Midtvedt (Norway), Marcin Milchert (Poland), Jadranka Morović-Vergles (Croatia), Ulf Müller-Ladner (Germany), Pavel Novikov (Russia), Marzena Olesinska (Poland), Voon Ong (UK), Predrag Ostojic (Serbia), Serghei Popa (Moldova), Mislav Radic (Croatia), Gabriela Riemekasten (Germany), Edoardo Rosato (Italy), Lidia Rudnicka (Poland), Maria João Salvador (Portugal), Lelita Santos (Portugal), Elena Schiopu (USA), Tim Schmeiser (Germany), Alenka Šipek (Slovenia), Simon Stebbings (New Zeland), Alberto Sulli (Italy), Gabriella Szucs (Hungary), Carmen Tineo (Dominican Republic), Michal Tomcik (Czech Republic), Alessandra Vacca (Italy), Antonia Valenzuela (USA), Frank Van Den Hoogen (Netherlands), Carlos Alberto Von Muhlen (Brasil), Ulrich Walker (Switzerland), Dong Xu (China), Sule Yavuz (Turkey), and Thierry Zenone (France).
- Accepted for publication November 16, 2016.
