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Adrenalectomy for non-neuroblastic pathology in children
Michael D. Traynor Jr.1 . Alaa Sada1 . Geoffrey B. Thompson1 . Christopher R. Moir2 . Irina Bancos3 . David R. Farley1 . Benzon M. Dy1 . Melanie L. Lyden1 . Elizabeth B. Habermann4,5 . Travis J. Mckenzie1
Accepted: 13 October 2019 @ Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract
Background Adrenalectomy for non-neuroblastic pathologies in children is rare with limited data on outcomes. We reviewed our experience of adrenalectomy in this unique population.
Methods Retrospective study of children (age ≤18) who underwent adrenalectomy with non-neuroblastic pathology from 1988 to 2018. Clinical and operative details of patients were abstracted. Outcomes included length of stay and 30-day post- operative morbidity.
Results Forty children underwent 50 adrenalectomies (12 right-sided, 18 left-sided, 10 bilateral). Six patients (15%) pre- sented with an incidental adrenal mass while 4 (10%) had masses found on screening for genetic mutations or prior malig- nancy. The remaining 30 (75%) presented with symptoms of hormonal excess. Nineteen patients (48%) underwent genetic evaluation and 15 (38%) had genetic predispositions. Diagnoses included 9 patients (23%) with pheochromocytoma, 8 (20%) with adrenocortical adenoma, 8 (20%) with adrenocortical carcinoma, 7 (18%) with adrenal hyperplasia, 2 (5%) with metas- tasis, and 6 (14%) with additional benign pathologies. Of 50 adrenalectomies, twenty-five (50%) were laparoscopic. Median hospital length of stay was 3 days (range 0-11). Post-operative morbidity rate was 17% with the most severe complication being Clavien-Dindo grade II.
Conclusion Adrenalectomy for non-neuroblastic pathology can be done with low morbidity. Its frequent association with genetic mutations and syndromes requires surgeons to have knowledge of appropriate pre-operative testing and post-operative surveillance.
Keywords Pediatric adrenalectomy · Laparoscopic adrenalectomy · Adrenocortical carcinoma · Pheochromocytoma . Endocrine · Primary pigmented nodular adrenocortical disease (PPNAD)
Poster Presentation at the American Association of Endocrine Surgeons (AAES) Annual Meeting in Los Angeles, California on April 7, 2019.
☒ Travis J. Mckenzie mckenzie.travis@mayo.edu
1 Department of Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
2 Division of Pediatric Surgery, Mayo Clinic, Rochester, MN, USA
3 Division of Endocrinology, Mayo Clinic, Rochester, MN, USA
4 Division of Health Care Policy and Research, Mayo Clinic, Rochester, MN, USA
5 Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
Introduction
Adrenalectomy for non-neuroblastic pathologies in the pedi- atric population is exceedingly rare, with an incidence of approximately 25 cases of adrenocortical neoplasms and 35 cases of pheochromocytoma in the United States each year [1, 2]. In adults, adrenal lesions are often discovered inci- dentally due to the increased use of advanced imaging tech- niques. Healthy children rarely undergo imaging that might identify incidental adrenal masses; therefore, patients will often present with symptoms of cortical hormone excess, mass effects or, in the case of pheochromocytomas, cat- echolamine excess [3, 4]. There are a number of genetic syndromes that necessitate adrenalectomy; and in these indi- viduals, screening can reveal underlying adrenal pathology at earlier stages, but there is a paucity of data on these rare indications for adrenalectomy to help guide surgeons [4, 5].
Patients referred with non-neuroblastic disease usually undergo considerable workup. Chief concerns for operative planning are whether the lesion has been properly character- ized via imaging and laboratory testing, need for preoperative alpha and beta blockage in pheochromoctyoma, and whether to approach the lesion laparoscopically or open. In studies of adrenocortical lesions and pheochromocytoma among chil- dren, the imaging and pharmacologic blockade have been previously described [4, 6]. The use of laparoscopy in this population is less clear, as the largest series of laparoscopic adrenalectomy are predominately patients with neuroblastic pathology [7-10]. In this unique population, we sought to (1) describe the presentations, imaging, and underlying genetic predispositions of children undergoing adrenalectomy for non- neuroblastic pathologies, (2) review operative approaches, and (3) determine outcomes and complication rates.
Methods
Approval was obtained from the Mayo Clinic Institutional Review Board. We queried a prospectively maintained data- base of adrenalectomies to identify children (age ≤18 years) who underwent adrenalectomy from January 1, 1988 to August 31, 2018. Follow-up was determined by most recent clinic visit or correspondence; data were collected until a patient died or contact was lost. Demographic data, clini- cal presentations, operative details, and pathology results were abstracted. The primary outcome of this study was maximum 30-day post-operative Clavien-Dindo scores as a surrogate for morbidity. Secondary outcomes included operative duration, emergency room visits within 30 days of operation, readmission within 30 days of operation, need for long-term hormone replacement, and recurrence.
Continuous variables with normal distribution were summarized with mean and standard deviation, while non- parametric continuous variables were summarized with medians and ranges. Categorical variables were summarized with frequency counts and percentages. Operative details and outcomes were compared using Chi-square and Fisher’s exact tests for categorical variables and Wilcoxon rank sum for continuous non-parametric variables. Recurrence-free survival curves were constructed using the Kaplan-Meier method. Statistical significance was set at p <0.05. All data analyses were performed using STATA 15.1 (College Sta- tion, TX, USA).
Results
Fifty adrenalectomies were performed in 40 patients [median age 14 years, range (6-18 months), female (n=25, 62%)] for non-neuroblastic pathologies. Six (15%) patients had adrenal masses found incidentally, while 4
(10%) were found while screening individuals with genetic mutations (n=3) or prior malignancy (n=1). The remain- ing 30 patients (75%) had symptoms of hormonal excess. Of 40 patients, 8 (20%) had adrenocortical disease due to adenoma, 8 (20%) had adrenocortical carcinoma (ACC), 7 (18%) had adrenal hyperplasia, 9 (23%) had pheochro- mocytoma, 3 (8%) did not have diagnostic abnormality, 2 (5%) had metastatic disease from a known primary, 1 (2%) had an EBV-associated smooth muscle tumor, 1 (2%) had cytomegaly, and 1 (2%) had a cyst. Nearly half (19, 48%) of children who underwent adrenalectomy had pre- operative or post-operative genetic evaluation. Genetic mutations or syndromes were found in 15 (38%) patients, and these patients had younger median age at adrenalec- tomy compared to patients without genetic syndromes [7 (1 month-18 years) vs 16 (5 months-18 years), p=0.01). Demographic characteristics, clinical presentations, genet- ics, and operative approach for patients with a final diag- nosis of adrenal adenoma, ACC, adrenal hyperplasia, or pheochromocytoma are found in Table 1.
Adrenalectomy for adrenocortical disease secondary to adenoma
Half (n=4, 50%) of patients had functioning adenomas, including two patients with Cushing syndrome and two patients with aldosteronomas. Two patients with familial adenomatous polyposis (FAP) had adrenal masses con- cerning for malignancy discovered on abdominal ultra- sound performed for hepatoblastoma screening. One patient had abdominal ultrasound performed in the set- ting of isolated hemihypertrophy, discovering an adrenal mass. MRI and ultrasound were used to characterize and follow the lesion, and the mass was removed after interval growth. Ultrasound to examine the genitourinary system in a female patient with Turner Syndrome discovered the final incidentaloma.
Adrenalectomy for adrenocortical disease secondary to ACC
All ACCs were functional tumors, and none were discov- ered incidentally. CT scan was utilized in all but one patient (88%) to characterize the lesion. MRI of the abdomen was performed during workup for Cushing syndrome in the remaining patient. One patient (13%) had genetic evalua- tion confirming Beckwidth-Wiedemann Syndrome (BWS). Tumors were ESNAT/AJCC stage I in 1 (12%), stage II in 3 (38%), stage III in 3 (38%), and stage IV in 1 (12%). His- tology was low-grade in 3 (38%), intermediate-grade in 3 (38%), and high-grade in 2 (24%).
| Adrenal adenoma | Adrenal cortical carcinoma | Adrenal hyperplasia | Pheochromocytoma | |
|---|---|---|---|---|
| Factor | ||||
| Level | ||||
| N | 8 | 8 | 7 | 9 |
| Age at adrenalectomy, median (range) | 9 (7 months-18 years) | 8 (6 months-18 years) | 14 (8-18 years) | 15 (4-18 years) |
| Sex, n (%) | ||||
| Male | 2 (25%) | 1 (13%) | 2 (29%) | 6 (67%) |
| Female | 6 (75%) | 7 (88%) | 5 (71%) | 3 (33%) |
| Race, n (%) | ||||
| White | 6 (75%) | 5 (63%) | 6 (86%) | 8 (89%) |
| Black or African American | 0 (0%) | 0 (0%) | 1 (14%) | 0 (0%) |
| Hispanic or Latin American | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Other | 1 (13%) | 1 (12%) | 0 (0%) | 0 (0%) |
| Unknown | 1 (12%) | 2 (25%) | 0 (0%) | 1 (11%) |
| Incidental finding, n (%) | 4 (50%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Found on screening, n (%) | 0 (0%) | 0 (0%) | 0 (0%) | 3 (33%) |
| Pre-operative imaging, n (%)a | ||||
| CT | 7 (88%) | 7 (88%) | 5 (71%) | 7 (78%) |
| Ultrasound | 5 (63%) | 1 (13%) | 1 (14%) | 3 (33%) |
| MRI | 3 (38%) | 1 (13%) | 0 (0%) | 3 (33%) |
| MIBG scintigraphy | 0 (0%) | 0 (0%) | 0 (0%) | 2 (22%) |
| FDG-PET | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Gallium-68 dotatate scan | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Underwent genetic evaluation, n (%) | 4 (50%) | 1 (13%) | 4 (57%) | 9 (100%) |
| Syndrome or confirmed mutation, n (%) | ||||
| None | 4 (50%) | 7 (87%) | 4 (57%) | 3 (33%) |
| Familial adenomatous polyposis | 2 (25%) | 0 (0%) | ||
| Isolated Hemihypertrophy Syndrome | 1 (13%) | 0 (0%) | ||
| Turner Syndrome | 1 (13%) | 0 (0%) | ||
| Beckwith-Wiedemann Syndrome | 0 (0%) | 1 (13%) | ||
| Carney complex | 2 (29%) | |||
| Congential adrenal hyperplasia | 1 (14%) | |||
| MEN 2A | 1 (11%) | |||
| MEN 2B | 1 (11%) | |||
| VHL | 3 (33%) | |||
| SDH mutation | 1 (11%) | |||
| Laterality | ||||
| Left | 4 (50%) | 4 (50%) | 0 (0%) | 3 (33%) |
| Right | 4 (50%) | 4 (50%) | 0 (0%) | 3 (33%) |
| Bilateral | 0 (0%) | 0 (0%) | 7 (100%) | 3 (33%) |
| Open or laparoscopic | ||||
| Open | 1 (13%) | 8 (100%) | 2 (29%) | 4 (44%) |
| Laparoscopic | 7 (88%) | 0 (0%) | 5 (71%) | 5 (56%) |
aPatients may have had more than one imaging study performed
Adrenalectomy for adrenal hyperplasia
All patients with adrenal hyperplasia underwent bilateral adrenalectomy. Three (43%) patients had primary pigmented
adrenocortical nodular hyperplasia (PPAND), and two of these patients had a diagnosis of Carney Complex. Two (29%) patients had Cushing disease without remission after transphenoidal pituitary resections, and decisions were
made to proceed with bilateral adrenalectomies. One (14%) patient had Cushing syndrome secondary to ectopic ACTH secretion from metastatic small bowel carcinoid, requiring bilateral adrenal resection for remission of Cushings. The final patient (14%) had CAH with salt-wasting 21-alpha hydroxlase deficiency and poor hormonal control. CT scan in 5 patients (71%) revealed normal adrenal glands in 4 and bilateral nodular adrenal hyperplasia in 1. Ultrasound was performed in a 14-year-old female with Congenital Adrenal Hyperplasia (CAH) for an unrelated reason that demon- strated normal adrenal glands.
Adrenalectomy for pheochromocytoma
One third (n =3) of patients presented with pheochromo- cytomas noted on surveillance screening conducted due to known mutations for multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B (MEN 2B), and von-Hippel-Lindau disease (VHL). The imaging modality of choice was computed tomography (n=7, 78%), but MRI was utilized as the primary imaging technique in 2 (22%) patients. MRI was performed as a secondary study in 1 patient (11%) where it was used to rule out synchronous disease in the contralateral adrenal gland in a patient with MEN 2B. Two patients (22%) underwent iodine-123 meta- iodobenzylguanidine (MIBG) scan, in search of synchronous
paragangliomas in 1 and to assess for malignant spread in the other. All patients with pheochromocytoma underwent genetic evaluation. Six (66%) patients had underlying ger- mline mutations, including MEN2A (age 15), MEN2B (age 16), VHL (ages 4, 7, 14), and succinate dehydrogenase com- plex (SDH) (age 12).
Bilateral resections were required in 3 (33%). Two patients with VHL had bilateral disease found upon workup for hypertension and spells. The final patient had MEN2B and multiple pheochromocytomas found in the contralateral adrenal gland 33 months after first adrenalectomy.
Surgery
Adrenalectomies were left-sided in 18 (45%), right-sided in 12 (30%), and bilateral in 10 (25%) children. Endocrine surgeons performed the majority (n=32, 64%) of resections followed by pediatric (n= 15, 30%) and general or urologic (n=3, 6%) surgeons. Table 2 demonstrates operative details and pathologic diagnoses for the cases. Median size of 32 adrenal masses on final pathology was 4.4 cm (1.2-15).
Of 50 adrenalectomies, half (n =25, 50%) were per- formed laparoscopically. The youngest patient undergo- ing laparoscopy was 7 months of age while the youngest patient undergoing open adrenalectomy was 1 month old. Among patients less than 5 years of age, there were 13
| Factor | Level | |
|---|---|---|
| N | 50 | |
| Surgical approach | Transperitoneal | 47 (94%) |
| Retroperitoneal | 2 (4%) | |
| Thoracoabdominal | 1 (2%) | |
| Operative time (min), median (range) | 119.5 (30-484) | |
| Estimated blood loss (mL), median (range)ª | 20 (5-4500) | |
| Greatest dimension on final pathology (cm), median (range)b | 4.4 (1.2-15) | |
| Malignant, n (%) | 10 (20%) | |
| Pathologic diagnosis, n (%) | Pheochromocytoma | 12 (24%) |
| Cortical adenoma | 8 (16%) | |
| Hyperplasia | 8 (16%) | |
| Adrenocortical carcinoma | 7 (14%) | |
| PPAND | 6 (12%) | |
| Without diagnostic abnormality | 3 (6%) | |
| Metastasis | 2 (4%) | |
| Adrenocortical neoplasm of unclear malignant potential | 1 (2%) | |
| EBV-associated smooth muscle tumor | 1 (2%) | |
| Cytomegaly | 1 (2%) | |
| Cyst | 1 (2%) | |
aFive patients with missing data for EBL
bOnly 32 of 50 adrenalectomies had a lesion to measure
adrenalectomies performed, 3 (23%) laparoscopic and 10 (77%) open. Lesion selected for laparoscopic approach had smaller median size compared to lesions approached via open adrenalectomy (2.65 cm versus 6.25 cm, p=0.023). All malignant lesions (20%) underwent an open resection, including 7 adrenocortical carcinomas, 1 adrenocortical car- cinoma of unclear malignant potential, 1 metastatic papillary renal cell carcinoma, and 1 metastatic extrarenal rhabdoid tumor. There were no conversions from laparoscopic to open approach. Comparison of operative details between open and laparoscopic adrenalectomy demonstrated that laparoscopic cases had shorter median operative durations (102 min versus 175 min, p<0.001), and lower median blood loss (10 mL versus 100 mL, p=0.002).
Overall morbidity was low in the study population and there were no peri-operative deaths. Hospitalization and complication data are described in Table 3. Intraoperative morbidity occurred in three patients who had open surgery, while no patients with laparoscopic surgery experienced intraoperative complications. Two patients had unexpected intraoperative hemorrhage, and one experienced an inad- vertent diaphragm injury that was recognized intraop- eratively and repaired primarily. Bilateral adrenalectomy had longer median operative times compared to unilateral (134 min vs 91 min, p<0.04), but no difference was seen in in hospital length of stay, transfusion, emergency depart- ment (ED) visits, readmission, or maximum Clavien-Dindo scores (all p>0.05). Excluding patients with malignancy, laparoscopic approach showed less median blood loss (10 vs 100 mL, p=0.01) and shorter intensive care unit (2 vs 3 days, p=0.03) and hospital (2 vs 4, p<0.01) stays, but no difference in operative times, transfusion, emergency depart- ment (ED) visits, readmission, or maximum Clavien-Dindo scores (all p>0.05).
Follow-up
Follow-up time was between 1 month and 22 years with a median of 3 years. All bilateral adrenalectomies required long-term steroid replacement. Overall recurrence of non- neuroblastic adrenal disease occurred in 4 patients (10%), Fig. 1. Three patients with ACC had distant metastatic disease. One patient with MEN2B developed multiple pheochromocytomas in the contralateral adrenal gland, requiring a second operation. There were three recorded deaths: two in patients with metastatic ACC, each two years following open adrenalectomy, and one patient who died 7 years following bilateral adrenalectomy for ectopic ACTH disease secondary to metastatic small bowel carcinoid.
1.00
Kaplan-Meier estimates for recurrence-free survival
0.75
0.50
0.25
0.00
0
24
48
72
96
120
144
168
192
Months
Adrenocortical carcinoma
Pheochromocytoma
| Factor | Level | |
|---|---|---|
| N | 40 | |
| Overall length of stay (days), median (range) | 3 (0-11) | |
| ICU stay, n (%) | 18 (45%) | |
| ICU length of stay (days), median (range) | 2 (1-4) | |
| Blood transfusion, n (%) | 4 (10%) | |
| Readmission within 30 days of operation, n (%) | 2 (5%) | |
| Number of ED visits within 30 days of operation, n (%) | None 33 (85%) | |
| 1 5 (13%) | ||
| 2 | 1 (3%) | |
| Maximum 30-day Clavien-Dindo score, n (%) | No complications 33 (82%) | |
| I 5 (12%) | ||
| II 2 (5%) | ||
Discussion
In this study we demonstrate that symptoms of hormo- nal excess and genetic disease are critical to the diagnosis among children who undergo adrenalectomy for non-neu- roblastic disease. Patients with genetic mutations or syn- dromes had adrenalectomy performed at younger ages, and screening helped identify malignant and potentially malig- nant lesions. These findings underscore that multidisci- plinary involvement is important for young patients with non-neuroblastic pathologies due to the varied pathology, genetics, and potential for malignancy. The results support the use of laparoscopic adrenalectomy in instances where malignancy is unlikely and find that adrenalectomy can be performed in children with low morbidity.
Underlying genetics played an important role in the diagnosis and management of potentially malignant adrenal pathologies in our study. Genetic evaluation and subsequent screening facilitate early diagnosis of lesions with malignant potential and have been associated with improved clinical outcomes [4]. None of our patients had malignant pheochromocytomas, and the knowledge of underlying genetics allowed for early detection and appropriate resection at ages as young as age 4. Thus, our work supports the work of others who have recommended that all children with pheochromocytomas (and paragan- gliomas) undergo genetic testing and imaging to rule out synchronous and detect metachronous disease in follow-up [11, 12]. In our study, the lesions with malignant potential were mainly pheochromocytomas, but adrenal masses also occurred in children with FAP and Beckwith-Wiedemann Syndrome. These lesions were found incidentally due to surveillance for hepatoblastoma, and early diagnosis of ACC has been associated with improved outcome [1, 13]. While the malignant potential of these lesions was not entirely clear on final pathology, there have been reports of ACC associated with both familial cancer syndromes [14]. In BWS, FAP, and Li-Fraumeni Syndrome patients pre- senting with adrenal masses, ACC should be considered, and these patients benefit from a multidisciplinary team to include endocrinology and medical genetics [1, 15].
CT scan was the most frequent imaging modality used to identify and/or further characterize the adrenal patholo- gies in this series. In adults, CT scan is the imaging modal- ity of choice to evaluate adrenal-based lesions [16]. Due to the long-term risks of ionizing radiation in children, ultrasound is the preferred modality to workup abdominal masses found on examination or fetal ultrasound, but a minority of patients in our study underwent ultrasound imaging. Non-neuroblastic adrenal pathologies often pre- sent with hormonal excess, making ultrasound unneces- sary if further advanced imaging techniques such as CT
scan are necessary for diagnosis and management [17, 18]. In a study of 125 children presenting with Cushing syn- drome, CT scan identified 72% of adrenal lesions among 25 patients with a final diagnosis adrenocortical neoplasm [19]. MRI has increasing applications for the diagnosis of adrenal lesions in children [20]. Indeed, our analysis showed that 1 in every 5 patients had MRI imaging of their adrenal lesion. Of note, when suspicion of either an adrenal cortical neoplasm or pheochromocytoma is high and CT does not identify a lesion, MRI can aid in the diag- nosis of these lesions. We also find that it can help detect synchronous disease in the contralateral adrenal gland in patients with genetic reasons for pheochromocytoma. For pheochromocytoma, MIBG scan is an important tool as it can identify lesions that may not be visible on ultrasound or multiple sites of disease in patients with bilateral dis- ease or synchronous paraganglioma [17].
This study confirmed the findings of other series of lapa- roscopic adrenalectomies in pediatric patients, with a similar range of age, pathologies, and rate of complications. The largest multicenter series of laparoscopic adrenalectomy in children demonstrate that young age or low weight do not preclude laparoscopic approaches [9, 10]. Despite excluding neuroblastic disease, we found that laparoscopic adrenalec- tomy could be performed in patients less than 5 years old. In our study, the lesions approached laparoscopically were smaller in size; this decision, however, was also influenced by pathology. Current consensus is that suspected or con- firmed ACC should be approached via open techniques, and size appears to correlate with malignancy in adrenocortical tumors [1]. Furthermore, surgeons can expect difficulty with the extent of resection that ACC may require, since stage 3 ACC will often require extensive retroperitoneal lymph node dissection [18]. With careful patient selection, laparo- scopic surgery can occur in the setting of malignancy. Some authors have argued that anatomical characteristics, such as evidence of invasion of surrounding structures on imag- ing, should guide the selection of children for laparoscopic resection [9, 10]. Using such an approach, Fascetti-Leon et al. found that laparoscopic approaches were suitable for neuroblastoma and even a single case of ACC [10]. We find that all non-neuroblastic lesions in children should be considered for a minimally invasive approach, as it seems to result in less blood loss and shorter hospital stays. The decision regarding which approach to utilize should ulti- mately depend on surgeon experience and suspicion of ACC or other locally-invasive malignancies, as both open and laparoscopic techniques had similar morbidity in our study.
This analysis has several limitations worth mention- ing. First, this study was a retrospective review spanning 30 years. A number of changes in the diagnostic and thera- peutic approaches to non-neuroblastic pathologies have occurred during the study period. These changes may have
introduced bias regarding the results. Second, the recur- rence-free survival curve for pheochromocytoma patients fails to account for metachronous paragangliomas seen in MEN2B, SDH mutations, and VHL. Finally, the small sam- ple size and heterogeneity of pathology in this study intro- duces the possibility of both confounding and type II error. Readers should interpret the results comparing laparoscopic and open approaches with caution. Additionally, the small sample size precluded our ability to make meaningful sub- group analysis for recurrence-free survival. This limitation, however, is shared by all series of laparoscopic adrenalec- tomies that include both neuroblastic and non-neuroblastic lesions.
Conclusion
Adrenalectomy for non-neuroblastic pathology among the pediatric population can be performed with low morbidity. The diversity of pathology and frequent association with a variety of genetic mutations and syndromes requires sur- geons to have knowledge of appropriate pre-operative test- ing, post-operative surveillance, and multidisciplinary team involvement.
Funding No funding was necessary for conduct of this study.
Compliance with ethical standards
Conflict of interest All authors declare no conflicts of interest.
Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the insti- tutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Mayo Clinic IRB.
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