To systematically review the incidence and factors associated with recurrences or new tumors after apparent complete resection of pheochromocytoma or thoraco–abdomino–pelvic paraganglioma.
A systematic review and meta-analysis of published literature was performed.
Pubmed and Embase from 1980 to 2012 were searched for studies published in English on patients with non-metastatic pheochromocytoma or thoraco–abdomino–pelvic paraganglioma, complete tumor resection, postoperative follow-up exceeding 1 month, and recurrence or new tumor documented by pathology, hormonal dosages, or imaging tests. Incidence rates of new events after curative surgery were calculated for each study that had sufficient information and pooled using random-effect meta-analysis.
In total, 38 studies were selected from 3518 references, of which 36 reported retrospective cohorts from the USA, Europe, and Asia. Patient follow-up was neither standardized nor exhaustive in the included studies. A clear description of patient retrieval methods was available for nine studies and the follow-up protocol and patient flow for four studies. Only two studies used multivariable methods to assess potential predictors of postoperative events.
The overall rate of recurrent disease from 34 studies was 0.98 events/100 person-years (95% confidence interval 0.71, 1.25). Syndromic diseases and paragangliomas were consistently associated with a higher risk of a new event in individual studies and in meta-regression analysis.
The risk of recurrent disease after complete resection of pheochromocytoma may be lower than that previously estimated, corresponding to five events for 100 patients followed up for 5 years after complete resection. Risk stratification is required to tailor the follow-up protocol after complete resection of a pheochromocytoma or paraganglioma. Large multicenter studies are needed to this end.
Pheochromocytomas and paragangliomas (PH/PG) are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or sympathetic and parasympathetic paraganglia respectively. Following resection of the primary tumor, most patients are free of tumor with no clinical, biochemical, or imaging evidence of persistent disease. However, tumor-free patients are at a risk of long-term recurrence, defined as the reappearance of disease after complete surgical eradication of the tumor (1). Recurrences may arise at the operated site or may be metastatic, developing in non-chromaffin organs, mainly the lymph nodes, bones, lungs, and liver (2, 3). Patients with inherited tumors may also develop new PH/PGs in the contralateral adrenal gland or in other paraganglia (3, 4). At least 15% of patients undergoing surgery for PH/PG develop new tumors or recurrences, most of which are metastatic (4). Consequently, long-term follow-up is recommended for patients who have undergone surgery for PH/PG (5).
Although there are reports of the prognostic value of various clinical, genetic, and pathological features, there are no robust prognostic indices of recurrence other than the higher probability of new events in patients with inherited tumors and possibly in patients with extra-adrenal or large tumors (4, 5). The total duration of follow-up that is required remains unclear, as new events may occur decades after initial surgery. The optimal combination and sequence of biochemical and imaging tests to detect and monitor recurrences are poorly defined. There have been no comprehensive systematic reviews assessing the incidence of recurrences or new tumors following surgery for PH/PG.
Our primary objective is to systematically review the incidence of local or metastatic recurrences or new tumors in patients who have undergone apparently complete resection of a non-metastatic PH/PG. A secondary objective is to assess the factors associated with recurrences (local or metastatic) or new tumors.
We searched randomized or non-randomized controlled trials, prospective or retrospective cohort studies, and case–control studies published in English in 1980 or later (computed tomography and metanephrine determinations were not universally available before 1980). Studies were eligible if (i) they enrolled at least 20 patients with PH/PG; (ii) patients had reportedly undergone complete tumor resection; (iii) postoperative follow-up exceeded 1month (arbitrarily); and (iv) the number of patients with recurrence or new tumor could be identified.
Information sources and search
We searched Medline and Embase databases from 01/01/1980 to 10/19/2012. We developed a specific search strategy for each database and is presented in
Two physicians, experts in endocrine hypertension (L A and C L), independently made a first selection using the titles, abstracts, and keywords to exclude studies that clearly did not fulfill the inclusion criteria. They independently read the full text of the remaining papers to identify eligible articles. At each stage, disagreements between readers were resolved by discussion or, if necessary, by a third reader (P F P or J L). Journals and authors were not blinded during study selection. In cases of overlapping publications by a given team, only the most comprehensive or most recent was included.
The studies were then further subdivided into two categories: (i) studies on head and neck paraganglioma only and (ii) studies on pheochromocytoma and thoraco–abdomino–pelvic paraganglioma. This review reports only the results of the latter category of studies.
A standardized form was tested on ten articles and two senior experts (P F P and J L) to homogenize further data collection. The form was then used by two abstractors (L A and C L) to extract methodological and clinical data from all included studies. Records were reviewed by a third reader and issues were resolved by discussion. Journals, titles, and authors were not blinded during data abstraction.
The following data were collected from each study: first author and publication year; study design and settings; number of centers, total number and number of operated patients with complete tumor resection; risk of bias; percentage of female patients, mean age, percentage of hypertensive patients, percentage of patients with pheochromocytoma, location of paragangliomas, mean tumor size, percentage of secreting tumors, and percentage of genetic or syndromic diseases; number of patients with follow-up and duration of follow-up; incidence of recurrence, timing of recurrence, and attributable deaths.
No agreed criteria exist for assessing the risk of bias of prognostic studies. We used several resources to compile a list of criteria to assess the risk of bias regarding study participants, prognostic factors, outcome, follow-up, and reporting. Further details are provided in the
Incidence rates of recurrence or new tumor over the entire duration of the follow-up were calculated by dividing the number of events by the number of person-years of follow-up, and then standardized to the number of events/100 person-years. The mean duration of follow-up was multiplied by the number of patients when the number of person-years of follow-up was not reported. When the mean duration of follow-up was not reported, it was approximated by a formula using the median and range when available (6, 7), or by the median in other cases. We assumed the Poisson distribution to estimate 95% confidence intervals for the rate of events presented in forest plots. Meta-analysis was performed on rates and their confidence interval limits. Heterogeneity was assessed using Cochran statistic and the I² inconsistency coefficient. An I² value greater than 50% was considered to be indicative of substantial heterogeneity. Study results were pooled using random-effect meta-analysis. We used Stata SE/MP version 9.2 (StataCorp) for the analyses.
We performed sensitivity analyses based on the availability of the mean duration of follow-up (allowing to compute the exact incidence rate) and by risk of bias. A funnel plot of the event rate according to the number of person-years of follow-up (a substitute for the precision of estimates) was used to assess publication bias.
Meta-regression analysis was used to assess the impact of the following variables on the logarithm of incidence rates: operation year of the first patient, specialty of the author team (surgery vs others), percentage of females, mean age, percentage of familial diseases (genetic or syndromic), percentage of pheochromocytomas, mean size of the tumor, and mean duration of follow-up.
The details of the selection process and reasons for exclusions are depicted in the flow chart (Fig. 1). Bibliographic searches yielded 3518 references, among which 42 on pheochromocytoma and thoraco–abdomino–pelvic paraganglioma were finally selected, reporting 38 different cohorts.
The characteristics of the included studies are reported in Table 1.
Overview of included studies.
|Study||Country||Period||Design||Settings||Number of centers||Total number of patients||Number of curative surgeries|
|Agarwal 2012 (8)||India||1990–2010||Retrospective||Surgery||1||101||100|
|Amar 2005/2006 (9, 10)||France||1975–2006||Retrospective||Medicine||1||261||242|
|Beatty 1996 (11)||Ireland||1970–1991||Retrospective||Mixed||1||41||38|
|Benhammou 2010 (12)||USA||1995–2003||Retrospective||Surgery||1||26||26|
|Brunt 2001/2002 (13, 14)||USA||1993–2000||Retrospective||Surgery||1||35||35|
|Castilho 2009 (15)||Brazil||1995–2006||Retrospective||Surgery||1||24||24|
|Cotesta 2009 (16)||Italy||1992–2008||Retrospective||Medicine||1||91||91|
|de Wailly 2012 (17)||France||1993–2009||Retrospective||Medicine||1||53||48|
|Diner 2005 (18)||USA||1995–2004||Retrospective||Surgery||1||33||33|
|Edström Elder 2003 (19, 20)||Sweden||1976–1999||Retrospective||Mixed||1||85||80|
|Favia 1998 (21)||Italy||1977–1996||Retrospective||Surgery||1||55||50|
|Geoghegan 1998 (22)||UK||1978–1992||Retrospective||Surgery||1||43||42|
|Grozinsky-Glasberg 2010 (23)||Israel||1989–2009||Retrospective||Medicine||2||43||41|
|van der Harst 2002 (24)||The Netherlands||1983–2001||Retrospective||Mixed||1||87||87|
|Hayry 2009 (25)||Finland||1985–2008||Retrospective||Laboratory||1||42||36|
|Iacobone 2011 (26)||Italy||1985–2010||Retrospective||Medicine||1||71||70|
|Jaroszewski 2003 (27)||USA||1992–2001||Retrospective||Surgery||1||47||47|
|Kercher 2002 (28)||USA||1995–2000||Retrospective||Surgery||1||39||39|
|Khorram-Manesh 2005 (29)||Sweden||1950–1997||Retrospective||Medicine||1||121||118|
|Lairmore 1993 (30)||USA||1956–1990||Retrospective||Mixed||3||58||55|
|Zhang 2007/Lang 2008 (31, 32)||China||1998–2005||Retrospective||Surgery||1||103||103|
|Lucon 1997 (33)||Brazil||1974–1994||Retrospective||Mixed||1||50||41|
|Lumachi 1998 (34)||Italy||1977–1996||Retrospective||Surgery||1||55||50|
|Neumann 1999 (35)||Germany||1985–1995||Retrospective||Mixed||1||39||39|
|Noshiro 2000 (36)||Japan||1957–1995||Retrospective||Medicine||1||95||91|
|Obara 1995 (37)||Japan||1981–1994||Retrospective||Surgery||1||87||83|
|Pan 2005 (38)||China||1990–2004||Retrospective||Surgery||1||26||25|
|Park 2011 (39)||Korea||1989–2008||Retrospective||Surgery||1||152||147|
|Pomares 1998 (40)||Spain||1979–1995||Retrospective||Medicine||1||44||43|
|Rodriguez 2008 (41)||Spain||–||Retrospective||Surgery||2||54||54|
|Scholten 2011 (42)||The Netherlands||1959–2010||Retrospective||Surgery||1||61||61|
|Scott 1984 (43)||USA||1950–1983||Retrospective||Surgery||3||69||53|
|Stenström 1988 (44)||Suede||1956–1982||Prospective||Mixed||1||64||64|
|Tiberio 2008 (45)||Italy||2000–2006||RCT||Surgery||1||22||22|
|Timmers 2008 (46)||The Netherlands||1966–2000||Retrospective||Medicine||1||69||64|
|Tormey 2002 (47)||Ireland||1989–2000||Retrospective||Medicine||21||39||32|
|Wilhelm 2006 (48)||USA||1995–2005||Retrospective||Surgery||3||65||64|
|Yip 2004 (49)||USA||1962–2003||Retrospective||Surgery||1||59||58|
All studies were on retrospective cohorts except one on a prospective cohort (44) and one that was a randomized controlled trial (45). Of the 38 studies, 20 were performed in Europe, nine in North America, six in Asia, two in South America, and one in the Middle East. The inception year ranged from 1950 to 2000 (median 1985). Studies involved 1–21 centers; 20 studies were performed by surgical teams, ten by medical teams, seven by both, and one by laboratory physicians.
Risk of bias within studies
Detailed risks of bias of the included studies are reported in the
Patient and disease characteristics
Patient and disease characteristics are reported in Table 2. The percentage of females was reported in 35 studies and was between 36 and 67% (median 54%). The mean or median age was reported in 35 studies and was between 27 and 53 years (median 42 years). The percentage of hypertensive patients was reported in 25 studies and was between 3 and 98% (median 66%). The percentage of syndromic or genetic disease was reported in 32 studies. Of the 32 studies, four involved only patients with a syndromic disease (VHL, NF1, or MEN2). In the remaining 28 studies with phenotypic and/or genetic information, a syndromic or familial disease and/or a mutation in a gene predisposing to PH/PG was between 2 and 97% (median 20%).
Overview of patient and disease characteristics.
|Study||Females (%)||Age (years)||HTN (%)||Pheo (%)||PHPG size (mm)||Secreting tumors (%)||Genetic diseasesa (%)|
|Agarwal 2012 (8)||43||Mean 36 (s.d. 14.6)||81||82||Mean 71 (s.d. 25)||–||–|
|Amar 2005/2006 (9, 10)||52||Mean 42.5 (s.d. 15)||89||87||Mean 54 (s.d. 27)||–||21|
|Beatty 1996 (11)||54||–||90||84||–||–||24|
|Benhammou 2010 (12)||–||Mean 27||–||100||Mean 25||–||100|
|Brunt 2001/2002 (13, 14)||51||Mean 42 (s.d. 17)||54||100||Mean 34 (s.d. 13)||–||57|
|Castilho 2009 (15)||42||Median 46.5 (range 10–75)||83||100||Median 37 (range 5–120)||–||13|
|Cotesta 2009 (16)||52||Mean 48 (range 8–77)||–||92||Mean 43 (range 10–110)||–||23|
|de Wailly 2012 (17)||55||Mean 53 (range 13–88)||–||100||Mean 46 (s.d. 13)||96b||15|
|Diner 2005 (18)||–||Mean 38 (range 10–79)||–||100||Mean 23 (range 8–50)||–||94|
|Edström Elder 2003/2003 (19, 20)||56||Range 14–77||61||82||Range 10–140||–||18|
|Favia 1998 (21)||49||Median 41 (range 10–63)||58||91||Mean 58 (s.d. 30)||–||7|
|Geoghegan 1998 (22)||67||Mean 42 (range 16–73)||56||100||Mean 49 (range 20–130)||–||28|
|Grozinsky-Glasberg 2010 (23)||49||Mean 52.6 (range 16–77)||47||88||Mean 49 (s.d. 20)||–||–|
|van der Harst 2002 (24)||55||Mean 46 (range 9–78)||66||89||Mean 54 (s.d. 31)||–||31|
|Häyry 2009 (25)||–||Mean 46.5||–||95||Mean 47 (s.d. 26)||86c||–|
|Iacobone 2011 (26)||52||Mean 44.8 (range 15–80)||–||93||Mean 54 (s.d. 30)||–||24|
|Jaroszewski 2003 (27)||51||Mean 53.1 (range 16–81)||–||100||Mean 43 (range 10–85)||–||13|
|Kercher 2002 (28)||64||Mean 43 (range 19–59)||95||97||Mean 52 (range 20–121)||95b||10|
|Khorram-Manesh 2005 (29)||56||Mean 47.2 (s.d. 16.8)||84||93||Mean 49 (s.d. 24)||88b||25|
|Lairmore 1993 (30)||57||Mean 32.8 (s.d. 12.2)||57||100||Mean 43 (s.d. 27)||–||100|
|Zhang 2007/Lang 2008 (31, 32)||49||Mean 35.8 (s.d. 13.3)||–||100||Mean 47 (s.d. 23)||–||–|
|Lucon 1997 (33)||56||Median 33 (range 10–64)||86||84||Median 70 (range 30–200)||97b||12|
|Lumachi 1998 (34)||49||Mean 41 (range 10–63)||45||90||–||–||7|
|Neumann 1999 (35)||59||Mean 40 (range 10–76)||–||100||Mean 40 (range 10–90)||–||67|
|Noshiro 2000 (36)||55||Mean 40 (s.d. 14)||88||–||–||–||15|
|Obara 1995 (37)||56||Median 40 (range 11–67)||–||84||Mean 62 (s.d. 26)||92||14|
|Pan 2005 (38)||58||Mean 39.5 (s.d. 8.9)||–||85||Mean 73 (s.d. 35)||0||–|
|Park 2011 (39)||47||Mean 46.5 (range 18–76)||62||90||Mean 67 (s.d. 35)||–||2|
|Pomares 1998 (40)||54||Mean 43 (s.d. 13.7)||37||98||Mean 49 (s.d. 26)||84b||52|
|Rodriguez 2008 (41)||57||Mean 37.4 (range 14–71)||24||100||Mean 45 (range 10–120)||89||100|
|Scholten 2011 (42)||39||Mean 33 (s.d. 12.7)||3||100||–||67||100|
|Scott 1984 (43)||58||Range 9–79||98||77||–||–||12|
|Stenström 1988 (44)||53||Mean 45 (range 15–79)||47||94||–||–||20|
|Tiberio 2008 (45)||36||Mean 51 (range 34–74)||–||100||Mean 40 (range 22–60)||–||–|
|Timmers 2008 (46)||64||Mean 46.1 (s.d. 15.6)||78||88||–||–||20|
|Tormey 2002 (47)||38||Median 36 (range 8–76)||89||87||–||–||59|
|Wilhelm 2006 (48)||62||Mean 48.5 (s.d. 16.1)||68||100||Mean 40 (s.d. 15)||–||14|
|Yip 2004 (49)||58||Median 36||–||95||–||–||97|
The percentage of pheochromocytoma was reported in 37 studies and was between 77 and 100% (median 94%). Of these, 14 studies involved only patients with pheochromocytomas, and the percentage of patients with pheochromocytoma was between 77 and 98% (median 89%) in the 23 remaining studies with information on tumor location. The mean or median tumor size was reported in 28 studies and was between 23 and 73 mm (median 48 mm).
Results of individual studies
Raw results of individual studies are reported in Table 3. The number of patients followed up after complete surgical resection was between 22 and 242 (median 52). The mean or median duration of follow-up was available for 34 studies and was between 14 and 180 months (median 84 months). The percentage of recurrent disease over the entire follow-up was between 1 and 34% (median 6%). Eleven studies (51 events) provided individual data on the time from surgery to recurrent disease, with an overall median time to event of 60 months (range 3–204), and two studies (26 events) provided summary results with median times to event of 17 and 29 months (range 5–195). Two studies (7 events) did not provide any information on the time to the recurrent event.
Overview of treatment and outcomes.
|Study||Cured and followed up||Follow-up duration (months)||Same-site recurrences||Other-site recurrences||Metastases||Attributable death|
|Agarwal 2012 (8)||100||Mean 44 (range 3–160)||0||0||1||0|
|Amar 2005/2006 (9, 10)||242||Mean 102 (range 45.6–158.4)||18||0||18||0|
|Beatty 1996 (11)||38||Mean 84||2||0||4||4|
|Benhammou 2010 (12)||26||Mean 111||3||3||0||0|
|Brunt 2001/2002 (13, 14)||34||Mean 46 (range 2–85)||0||3||0||0|
|Castilho 2009 (15)||24||Mean 74 (range 18–150)||0||0||0||0|
|Cotesta 2009 (16)||43||Range 6–192||2||0||1||2|
|de Wailly 2012 (17)||48||Mean 86||0||1||1||0|
|Diner 2005 (18)||33||Mean 36 (range 3–108)||2||0||0||0|
|Edström Elder 2003 (19, 20)||80||Median 144||2||0||3||2|
|Favia 1998 (21)||50||Mean 88 (range 6–232)||1||1||0||0|
|Geoghegan 1998 (22)||41||Mean 31 (range 9–120)||0||0||0||1|
|Grozinsky-Glasberg 2010 (23)||41||–||0||0||0||0|
|van der Harst 2002 (24)||87||Median 120 (range 3–192)||0||1||14||10|
|Hayry 2009 (25)||36||Mean 103 (range 20–284)||1||0||3||0|
|Iacobone 2011 (26)||70||Median 126 (range 6–300)||2||0||1||–|
|Jaroszewski 2003 (27)||45||Mean 41 (range 10–89)||0||1||0||0|
|Kercher 2002 (28)||39||Mean 14 (range 1–40)||0||0||0||0|
|Khorram-Manesh 2005 (29)||121||Mean 180||2||1||6||4|
|Lairmore 1993 (30)||55||Mean 112.8 (range 8.4–342)||0||12||0||0|
|Zhang 2007/Lang 2008 (31, 32)||103||Range 5–36||0||0||0||0|
|Lucon 1997 (33)||35||Mean 33 (range 0.33–192)||0||0||0||0|
|Lumachi 1998 (34)||50||Mean 88.2 (range 6–232)||1||0||0||0|
|Neumann 1999 (35)||33||Mean 73 (range 16–179)||1||7||0||–|
|Noshiro 2000 (36)||74||Mean 117||1||2||5||4|
|Obara 1995 (37)||83||Median 58 (range 1–164)||0||4||0||1|
|Pan 2005 (38)||25||Median 66 (range 24–132)||0||0||0||0|
|Park 2011 (39)||147||Mean 41.5 (range 0.9–298)||0||0||12||12|
|Pomares 1998 (40)||42||Mean 96 (range 24–216)||0||0||1||0|
|Rodriguez 2008 (41)||54||Mean 92.5 (range 12–178)||0||5||0||0|
|Scholten 2011 (42)||61||Mean 160.8 (range 1.2–501.6)||3||18||0||–|
|Scott 1984 (43)||53||Mean 103 (range 12–348)||0||0||5||4|
|Stenström 1988 (44)||64||Mean 139.2 (range 12–324)||0||2||2||0|
|Tiberio 2008 (45)||22||Mean 35 (range 18–84)||0||0||0||0|
|Timmers 2008 (46)||64||Mean 132 (range 12–456)||2||0||7||7|
|Tormey 2002 (47)||32||–||2||3||0||2|
|Wilhelm 2006 (48)||46||Mean 24 (range 1–84)||1||0||0||0|
|Yip 2004 (49)||58||Median 71||7||3||1||0|
Candidate prognostic markers assessed by one or more individual studies are reported in
Synthesis of results
The new event rate estimates of 34 studies with follow-up duration data showed significant heterogeneity (I² 51%, P<0.001; Fig. 2). Random-effect meta-analysis produced an overall new event rate estimate of 0.95 events/100 person-years (95% confidence interval (CI) 0.68, 1.21). Assuming a steady incidence over time, this converts into a 5-year cumulative incidence of 4.7% (95% CI: 3.4, 6.1; Fig. 2), distributed as follows: new tumors 22%, local recurrences 23%, and metastatic recurrences 55%.
The pooled estimate of event rate was as follows:
0.98 events/100 person-years (95% CI: 0.68, 1.29) across studies allowing the calculation of the exact number of person-years of follow-up;
1.18 events/100 person-years (95% CI: 0.71, 1.66) across studies with the lowest risk of bias (at most five risks regarding participants, outcome, follow-up, or results);
1.11 events/100 person-years (95% CI: 0.56, 1.66) across studies fulfilling both conditions.
Risk of bias across studies
The funnel plot of incidence rate against person-years of follow-up shows that the estimated incidence rate of several studies deviates from the overall estimate (
The percentage of genetic or syndromic disease was associated with the rate of new events (Fig. 3 and
Our review suggests that the risk of recurrent disease following complete resection of a pheochromocytoma or a thoraco–abdomino–pelvic paraganglioma is lower than that previously estimated. However, the risk remains non-negligible, approximately 5% per 5years of follow-up, and late events are possible, up to 15years after surgery in the included studies. Paragangliomas and familial disease are the two main independent risk factors of recurrent disease identified by several studies and by meta-regression analyses across studies. The association between the size of the primary tumor and the risk of recurrence after complete removal was weaker.
Limitations of evidence
The reporting of methodological details and clinical results of the included studies was very heterogeneous. Most studies were retrospective, and patient follow-up was neither standardized nor exhaustive. The time pattern of recurrence risk (early vs late) was not assessed, and data were scarce after the first 10 years of follow-up, precluding any firm conclusion beyond this horizon, although recurrent disease is clearly still possible. Risk factors were not consistently assessed across studies and only a few had available genetic data. It is now estimated that around 40% of all PH/PG arise in patients carrying a germline mutation in one of the 13 susceptibility genes identified so far (50). Individual patient data were not available, and meta-regression analyses were limited by an incomplete description of patients and disease in individual studies.
The overall low frequency of recurrent disease after complete resection of a PH/PG calls into question the need for lifelong follow-up after surgery for all patients. This contradicts the estimates from a previous review of published studies that did not take the varying mean duration of follow-up into account (3). Nonetheless, recurrent disease remains possible even after a long and uneventful follow-up and appears to be more frequent in patients with paragangliomas or familial disease than patients with sporadic pheochromocytoma. The follow-up protocol may need to be tailored according to these and other patient and disease characteristics. In particular, several studies that did not meet our inclusion criteria consistently show that germline mutations, even in apparently sporadic cases, are also associated with more aggressive disease and would benefit from intensive follow-up (5).
The results of this systematic review do not allow any conclusion concerning the necessary length and frequency of follow-up after surgery and further research is warranted. Given the rarity of the disease and the number of candidate risk factors, multicenter studies with consistent documentation of the phenotype and genotype of included patients are needed to overcome the limitations of available evidence and reach the power necessary for multivariate prognostic analyses.
This is linked to the online version of the paper at
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
This research was partly funded by the European Society of Endocrinology.
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