It'S Not A Mystery, It'S In The History: Multidisciplinary Management Of Multiple Endocrine Neoplasia Type 1

The patient (ML) was followed at the Mayo Clinic in Rochester, Minnesota, from 2009 to 2012, at The University of Texas MD Anderson Cancer Center from 2013 to 2016, and at Intermountain Healthcare of Utah from 2017 onward. ML is a 41 year old male who, in August 2009 at the age of 30 years, presented to his internist with abdominal pain and hypercalcemia of 10.8 mg/dL (normal range, 8.9-10.1 mg/dL). He had facial angiofibromas and lipomas. Laboratory testing revealed an inappropriately normal intact parathyroid hormone (iPTH) level of 44 pg/mL (normal range, 15-65 pg/mL), a normal 25-hydroxy vitamin D3 level of 33 ng/mL (normal range, 25-80 ng/mL), and high-normal 24-hour urinary calcium of level 237 mg (normal range, 25-300 mg), which was concerning for primary hyperparathyroidism (PHPT). He reported a family history of nephrolithiasis, constipation, and metastatic thymic neuroendocrine tumor (NET) in his father and pituitary macroadenoma in his paternal uncle. He underwent germline genetic testing that found a heterozygous, pathogenic variant in the MEN1 gene, confirming a diagnosis of MEN1. In addition to PHPT, his fasting laboratory tests showed an elevated pancreatic polypeptide (PP) level of 1600 pg/mL (normal, ≤ 249 pg/mL) with normal gastrin, insulin, C-peptide, chromogranin A (CgA), prolactin, and insulin-like growth factor 1 (IGF-1) levels. Endoscopic ultrasound (EUS) in October 2009 identified 1.0 cm and 1.2 cm solid lesions in the head and tail of the pancreas, respectively, and multiple 2 mm to 3 mm hyperechoic lesions. Fine-needle aspiration (FNA) of the head of pancreas lesion was consistent with a well differentiated grade 1 (Ki-67 2%) pancreatic NET (pNET). In 2011, dual energy x-ray absorptiometry (DXA) demonstrated decreased bone mineral density for age at the lumbar spine (T-score, −2.9; Z-score, −2.7) and otherwise normal BMD. He underwent a subtotal parathyroidectomy and bilateral cervical thymectomy in November 2011. Subsequent serum calcium and iPTH levels have remained within normal limits. The patient's initial chest computed tomography (CT) in 2009 and subsequent images were without evidence of a thoracic NET. Pituitary magnetic resonance imaging (MRI) in 2009 was normal, but repeat MRI in 2012 identified a possible 2.3 mm pituitary microadenoma (Fig. 1) that has remained stable. Pituitary hormone levels have always been normal. The multifocal pNETs were followed with alternating EUS and abdominal MRI. By 2016, the pancreatic head NET had grown in size to 1.9 cm and, by July 2017, the same lesion had grown further to 3.0 cm (Fig. 2). He underwent a pylorus-preserving pancreaticoduodenectomy in August 2017. Pathology documented a 2.1 cm well differentiated grade 2 (Ki-67 4.7%) NET and innumerable microadenomas (pT2N0M0). His postoperative course was complicated by delayed gastric emptying. He is followed by yearly abdominal MRI, which shows stable lesions in the pancreatic remnant. The patient has 2 healthy children, both of whom underwent predictive genetic testing. His daughter was negative for the familial MEN1 variant, whereas predictive testing in his son at age 2 years was positive. His son undergoes annual clinical and laboratory assessment and is without MEN1 manifestations. At presentation, the patient was a young man diagnosed with PHPT, facial angiofibromas, and lipomas. Up to 15% of PHPT cases are caused by an underlying inherited predisposition (e.g., MEN1, MEN2, hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia).1 This is important to recognize because hereditary disease influences prognosis, surgical strategy, and the risk of other syndromic manifestations and has important implications for family members.2 The characteristics of this patient should prompt an evaluation for genetic causes of PHPT because the factors associated with hereditary PHPT are young age at diagnosis (<40 years), the presence of syndromic features/tumors, contributory family history, and multigland disease.1-5 Male sex is also a factor to consider because there is a female predominance in sporadic PHPT.3 We support consideration of genetic testing for any patient with PHPT presenting at a young age (with the cutoff varying from <30 to 45 years or from <40 to 45 years with multigland disease), harboring syndromic features, or having a positive family history of PHPT and/or other syndromic tumors. Regarding age of diagnosis as the sole indicator for genetic testing, data are more limited on the yield of genetic testing in this population,4, 6-9 but several professional societies, including the American Association of Endocrine Surgeons and the European Society of Endocrine Surgeons, support genetic testing in any patient who is diagnosed with PHPT diagnosed at age <40 years.1, 10 Individuals with MEN1 are likely to develop multiple types of benign skin lesions, including facial angiofibromas, lipomas, and collagenomas. The combination of PHPT, angiofibromas, and lipomas in this young man should prompt an MEN1-focused family history, which, in this case, revealed a paternal family history of other MEN1-associated neoplasms (thymic NET and pituitary macroadenoma) and nephrolithiasis. At this point, a referral is recommended to genetic counseling for further risk assessment and definitive genetic testing. There are 3 ways by which a diagnosis of MEN1 is made—clinical, familial, or genetic, as outlined in Table 1.11 In the current case, before genetic testing, no diagnostic criteria for MEN1 are met because neither the patient nor any family member individually meet clinical diagnostic criteria. However, having 2 closely related family members with MEN1-associated tumors is enough information to counsel the patient on a presumptive diagnosis of MEN1. A consultation with a certified genetic counselor before formal genetic testing gives the patient the opportunity to discuss the unique medical, psychosocial, and familial aspects of hereditary disease. In addition, they are expertly trained to counsel the patient and family regarding all possible results, including positive, negative, and uncertain or inconclusive genomic findings. In the current case, genetic testing may include only the MEN1 gene or a panel of genes associated with hereditary PHPT. Genetic testing was diagnostic in this case, documenting the presence of a pathogenic variant in the MEN1 gene. Based on history, this variant was almost certainly paternally inherited. Site-specific testing is recommended for all first-degree and other potentially affected or at-risk family members. Any family member who tests positive for this variant, regardless of personal history, would have a diagnosis of MEN1 and needs to initiate age-appropriate screening. In most cases, at-risk children undergo genetic testing around the age of 5 years because this has been the youngest age of clinically apparent MEN1 disease. Furthermore, we would counsel the patient on options regarding reproductive risk and family planning, including the option of preimplantation genetic testing, if desired, to reduce the chances of passing MEN1 to future biological children. After a diagnosis of MEN1, the patient should be advised to undergo screening for additional clinical manifestations and remain under lifelong surveillance in a center with specific MEN1 expertise. Given the current lack of prophylactic treatment, the goal of screening and surveillance is the early detection of MEN1-related tumors to mitigate hormonal hypersecretion and the risk of metastatic NET through timely intervention. There are no known genotype-phenotype correlations in MEN1.11, 12 Therefore, the specific MEN1 germline variant cannot be used to individualize screening. As the clinical course of MEN1 is heterogeneous and the penetrance of manifestations differs even within families, the family history should not be used solely to determine the surveillance strategy. Even if asymptomatic, the patient with MEN1 should undergo comprehensive screening for tumors that are part of the MEN1 spectrum: duodenopancreatic NETs (dpNETs), pituitary adenomas (PAs), thoracic NETs (bronchopulmonary and thymic), adrenal tumors, and gastric NETs. Women with MEN1 may be at increased risk for breast cancer, but this has not been reported in men.13, 14 Attention should also be paid to skin lesions and lipomas (Fig. 3). Recommendations for screening and surveillance in MEN1 can be found in several guidelines, the most relevant being the 2012 MEN1 guidelines11 and the National Comprehensive Cancer Network guidelines.15 These recommendations are mostly based on retrospective studies and expert opinion. Because of the long latency period for disease manifestations and the indolent natural course of many small NETs, clinical judgment should be considered when prospectively monitoring a patient with MEN1. Annual clinical and biochemical screening is recommended for all patients. The 2012 MEN1 guidelines suggest measuring fasting levels of serum calcium, iPTH, prolactin, IGF-1, fasting gastrin, insulin and glucose, glucagon, PP, vasoactive intestinal peptide, and CgA.11 Although the positive predictive value is approximately 70%, CgA, PP, and glucagon have low accuracy for the diagnosis of dpNET, and consideration can be given to more limited biochemical screening in asymptomatic patients.16, 17 Regular abdominal, thoracic, and pituitary imaging is also an important component of screening. After completing initial screening, the patient was diagnosed with PHPT. There was no evidence of renal dysfunction, urolithiasis, or loss of bone mass (DXA should be performed at the initial diagnosis of PHPT). Therefore, given the mild hypercalcemia (<1 mg/dL above the upper limit) and mild subjective symptoms, options are to proceed with surgery directly or to initially observe. The timing of surgical intervention for MEN1-associated PHPT is not straightforward. The lifetime risks of significantly low or declining bone mass and renal function should be considered because these processes may start early, even in asymptomatic patients.18 In addition, many patients with PHPT who are considered asymptomatic may manifest neurocognitive symptoms, with improvement in quality of life after parathyroidectomy.19 Although the timing of surgery must be individualized, taking into account other clinical manifestations and patient preference, we recommend earlier parathyroidectomy to prevent or reduce these effects.18, 20, 21 We favor intervention when there is documented bone loss, urolithiasis, declining renal function, longstanding hypercalcemia or rising serum calcium levels, and/or symptoms clearly attributable to hypercalcemia. However, initial observation after multidisciplinary discussion may be considered in patients who have a recent diagnosis of MEN1 or mild hypercalcemia, especially in pediatric patients and young adults. Furthermore, it is imperative to balance the need for surgical intervention with the psychosocial well-being of the patient who must cope with multiple endocrine neoplasias. Although not applicable in this case, it is also important to consider that, in patients with hypergastrinemia, correction of hypercalcemia has resulted in regression of gastrinomas.22, 23 In this case, observation was chosen initially, and the patient should be educated about the signs and symptoms of PHPT and the importance of maintaining adequate hydration. Serum calcium, iPTH, 25-hydroxy vitamin D3, and renal function should be monitored yearly, and a DXA, including the distal forearm, should be assessed every 2 years. In 2011, the low bone mass for age prompted the decision for surgery. In MEN1, the initial surgical intervention of choice is subtotal parathyroidectomy.24 Total parathyroidectomy with autotransplantation of parathyroid tissue to the forearm as an initial operation risks the devastating sequelae of hypoparathyroidism.25 Concomitant transcervical thymectomy is suggested at the initial operation to decrease the rate of recurrence, as supernumerary glands in the thymus can occur, and theoretically lessen the risk of thymic NET development.25 This was also the operation that was performed in our patient. The goal of the operation is to achieve eucalcemia for as long a time as possible. Nearly one-half of patients recur by 15 years,11, 26, 27 thus leaving a large clip next to the remnant parathyroid should be considered to facilitate future debulking surgery. After parathyroidectomy, annual monitoring should continue because PHPT can recur secondary to hyperplasia of the remnant parathyroid or the presence of supernumerary/ectopic glands. Our patient has had durable normocalcemia until the present day, 9 years after his initial operation. For initial screening to detect dpNETs, our patient underwent EUS screening at another institution to allow the simultaneous detection and biopsy of suspected dpNETs. For initial evaluation, we likely would have recommended abdominal/pancreatic MRI instead. Although the 2012 MEN1 guidelines recommend either CT, MRI, or EUS, practice patterns have led to a preference to recommend abdominal/pancreatic MRI, preferring MRI over CT to limit radiation exposure and for better diagnostic sensitivity.28 Although EUS has the highest sensitivity for detection of dpNETs, it is also invasive, operator-dependent, does not provide complete abdominal imaging, and may detect lesions with limited clinical relevance. EUS-FNA allows for dpNET tissue confirmation and grading (using Ki-67 staining), which may have prognostic implications. However, cytopathologic assessment of the Ki-67 index and grading has been shown to correlate to the histologic specimen with only 70% to 80% accuracy and cannot be used alone to guide management.29, 30 In addition, the prognostic role of EUS-FNA based Ki-67 staining in MEN1 has not been evaluated. Furthermore, EUS-FNA is associated with a low rate of postprocedure pancreatitis, which may complicate future imaging surveillance.31 As such, consensus guidelines do not recommend routine EUS-FNA for the diagnosis of dpNET but, rather, a combination of MRI and EUS that is compatible with the psychosocial well-being of the patient.32 We favor referral for EUS and FNA after the identification of an equivocal pancreatic lesion on MRI for confirmation of equivocal findings, if there is clinical suspicion of a dpNET but conventional imaging is negative, if there is rapid growth of a dpNET, or as necessary to guide surgical management. After his initial evaluation, the patient was found to have multifocal pNETs (grade 1; largest, 1.2 cm) associated with an asymptomatic, elevated PP level. Several criteria are used to guide the surgical management of dpNETs: tumor size, growth rate, grade, and hormone secretion. The North American Neuroendocrine Tumor Society (NANETS) guidelines suggest that nonfunctioning (NF)-dpNETs <1 cm can be safely observed, whereas tumors >2 cm should be resected to prevent metastases and increase survival.33-35 However, the decision to resect or observe tumors <2 cm must be individualized, with relatively rapid growth over 6 to 12 months or histologic grade 2 or more favoring resection.15, 32 This patient has a clinically nonfunctioning tumor, but nongastrinoma functional dpNETs causing clinical symptoms should be resected because of the hormone production, regardless of size. For pharmacologically controlled gastrinomas in the setting of MEN1, there is controversy about the indication and timing of surgical intervention. Some groups advocate intervention for poorly controlled symptoms, pancreatic-dominant disease, and tumors >2 cm. Others have shown that resection of duodenal gastrinomas, regardless of symptoms, prolongs survival.36, 37 In our patient, given the pNET size and absence of a clinical syndrome, we decided to proceed with active surveillance. Surveillance of prevalent dpNETs should be individualized based on size, tumor grade (if available), and growth over time, in addition to available resources and patient preference. There is currently no consensus on the optimal imaging modality and interval for follow-up.32 After diagnosis, repeat imaging at 6-month to 12-month intervals is generally recommended and, if small dpNETs remain stable, this can possibly be lengthened to every 1 or 2 years.11, 28, 32 MRI is preferred over CT, and consideration can be given to follow-up with alternating EUS and MRI.28, 32 The role of somatostatin receptor (SSTR) imaging in screening and surveillance of nonmetastatic MEN1-related dpNETs is still in evolution. A recent systematic review on the diagnosis of NF-dpNETs in MEN1 concluded that the sensitivity of SSTR-positron emission tomography (PET) was demonstrated to be size-dependent (best in tumors >10 mm), and the major advantage was the detection of metastases, which could change patient management.28 Therefore, considering the costs and radiation exposure, SSTR-PET is not a preferred primary screening/surveillance modality. A recent consensus statement recommends SSTR-PET when dpNETs are >10 mm or growing.32 Although not applicable in this case, patients suspected of gastrinoma/fasting hypergastrinemia should have regular upper endoscopy (with or without EUS) to monitor for duodenal and gastric NETs and complications of hypergastrinemia. In our patient, surveillance EUS after 6 months was stable, and the patient was followed with yearly imaging. Given the demonstrated growth over time (progression from 1.2 cm to 1.9 cm over 7 years), lengthening the imaging to every 2 years would not have been recommended. If initial screening had been negative, we would have suggested follow-up MRI in 3 years or earlier, as symptoms or laboratory results indicate. From 2016 to 2017, the size and rapid growth of the dominant lesion (from 1.9 to 3.0 cm) prompted the decision to proceed to surgery. Given the rapid growth, we likely would have recommended SSTR-PET to comprehensively stage the disease before surgery. Regarding the extent of surgery, decision making must balance the multifocality of disease while preserving pancreatic function. In both functional NETs and NF-dpNETs, multifocality usually dictates more extended resections, but enucleation may be considered with a single dominant tumor and a favorable location.32, 38 Major pancreatic resections have been associated with higher cure rates and improved overall survival compared with enucleation, yet they also have higher rates of postoperative complications and long-term morbidity.39-41 Minimally invasive distal pancreatectomy has become a widely accepted surgical intervention, and large retrospective analyses have demonstrated less blood loss and shorter hospital stays with comparable morbidity and oncologic outcome.42, 43 Techniques are continually evolving,44, 45 most significantly with the emergence of the robotic surgery platform.46 In case of suspected gastrinomas, surgical intervention requires a thorough exploration of the duodenum through duodenotomy with systematic peripancreatic lymphadenectomy in the event pancreaticoduodenectomy is not performed. Because of the location and size of the dominant tumor, our patient underwent an open pylorus-preserving pancreaticoduodenectomy. Recent advances in interventional gastroenterology have allowed for novel nonoperative adjuncts such as EUS-guided radiofrequency ablation and endoscopic ethanol ablation. EUS-guided radiofrequency ablation used in 4 patients with insulinoma resulted in complete clinical resolution of symptoms in all patients within 10 to 12 months, although follow-up data are limited.47, 48 In 2015, Park et al. published results from a series of 11 patients with 14 lesions (3 of which were functional) who underwent endoscopic ethanol ablation with complete resolution seen in > 60% of lesions and symptomatic resolution in the functional lesions.49 These emerging interventions for the management of dpNET show promise but require further investigation. Although these interventions were not considered in our patient due to the nonfunctionality of his tumor, they remain a strong consideration in patients who may not be appropriate surgical candidates but would benefit from tumor ablation. After duodenopancreatic surgery, ongoing surveillance is important to detect local or distant recurrence, follow remaining tumors in the remnant pancreas, and detect new primaries. The timing of postsurgical surveillance is similar to imaging intervals before surgery. For follow-up after resection of sporadic dpNETs >2 cm, NANETS guidelines recommend using CT.36 However, in MEN1, the younger age of the patients, the need for lifelong imaging, and the risks of repeated radiation exposure must be considered, which is why MRI is usually preferred. Initial screening was negative for a pituitary adenoma in our patient. Therefore, repeat imaging of the sella is recommend after 3 years or earlier in the setting of laboratory abnormalities or symptoms.11 In this patient, repeat imaging showed a possible microadenoma, which remained stable on subsequent surveillance imaging and was not associated with hormonal hypersecretion. Because nonfunctional microadenomas in MEN1 detected during screening rarely show progression,50, 51 follow-up in this case should only involve periodic MRI and screening for pituitary hormone function. Currently, there is no reason for pituitary intervention in this patient. Urgent and emergent indications for pituitary surgery in MEN1 are pituitary apoplexy (hemorrhage into an adenoma causing loss of vision and/or hormonal collapse) or a presentation with significant chiasmal compression and risk of blindness. Other indications are no different from those for nonsyndromic tumors and include all functioning adenomas except those that produce prolactin, fail medical therapy, and pose a significant risk of optic nerve impingement or hypopituitarism from gland distortion. Prolactinomas account for 40% to 60% of MEN1-associated PAs and are usually treated with oral dopamine agonists. Although PAs in patients with MEN1 have been previously reported to be more invasive or aggressive than in those without MEN1,52-54 a recent surgical series demonstrated that 82% of the tumors were confined to the sella (Knosp grades 0, 1, and 2) and that rates of remission of hypersecretion and tumor growth matched those in patients without MEN1.55 The recent Mayo Clinic series showed that only 10% of patients with asymptomatic nonfunctional pituitary adenomas progressed to surgery, with a median time between diagnosis and surgery of 99 months.50 Adrenal lesions are surveyed in conjunction with dpNET screening, and many are nonfunctioning with an indolent natural history.11, 56 However, a large published cohort reported that 15% of adrenal lesions were functional, and 13% were adrenocortical carcinoma.56 The adrenocortical carcinomas also occurred after several years of follow-up of small adrenal tumors in a subset of patients.56 Therefore, in patients with MEN1 who have adrenal tumors, hormonal testing and yearly imaging are generally recommended, which may be individualized based on the size and growth rates as well as the planned dpNET surveillance.11 Intrathoracic NETs are the rarest of MEN1 manifestations. Thymic NETs occur more frequently in males and are often aggressive (as evidenced by the disease course of the patient's father), thus contributing to MEN1-related mortality.57 There have been reports of familial clustering.58, 59 Most bronchopulmonary NETs in MEN1 are indolent, with a doubling time of 4 to 12 years.60, 61 However, metastases and death can occur, the risk of which may be related to tumor size and growth. In patients with MEN1, suspicious pulmonary lesions should not automatically be treated as dpNET metastases. Current guidelines suggest screening thoracic imaging (CT or MRI) every 1 or 2 years.11 At a group level, expanding this interval is likely safe with regard to bronchopulmonary NETs, but individual cases of aggressive bronchopulmonary or thymic NET may be missed. As such, we are less likely to expand this interval in men and those with a positive family history. In shared decision making, this patient opted for thoracic CT every 5 years. Another important question is the surveillance of the patient's son. Penetrance of MEN1 manifestations in childhood is significant, although estimates vary from 12% to 73%.62-64 Current guidelines suggest starting prospective clinical and biochemical screening at the age of 5 years. In asymptomatic children, pituitary imaging is suggested from age 5 years onward (every 3 years), with abdominal imaging starting at age 10 years (every 1-3 years) and thoracic imaging starting at age 15 years (every 1-2 years).11 These suggestions are mainly based on expert opinion in combination with the earliest documented age of each manifestation.11 Some groups suggest postponing routine screening of asymptomatic patients until ages 15 or 16 years while counseling parents about typical clinical signs of MEN1 manifestations and contacting providers if they occur.64 We generally recommend annual clinic visits, including biochemical screening and auxological assessment, with a pediatric endocrinologist specialized in MEN1 starting between ages 5 and 10 years. In asymptomatic patients, we generally commence routine radiological screening around age 15 years. The self-diagnosis of MEN1 was a seminal event in my personal and professional development. On a familial level, it allowed me to see a pattern connecting what had previously been deemed an unrelated series of unfortunate events. The deaths of my father, paternal uncle, and grandfather were immediately recontextualized in the setting of a hereditary tumor syndrome, much as a stargazer might suddenly glimpse a constellation in the night sky. And, for the next generation, the 50/50 risk of autosomal dominant transmission bore itself out in my 2 children, a wild-type daughter and a mutant son. In theory, my wife and I could have used preimplantation genetic diagnosis to ensure that our boy did not inherit MEN1 from me but, for a host of reasons, we opted not to; on a near-existential level, I could not stand to apply a technology to his conception that would have erased my own! Also, he is now undergoing longitudinal monitoring with a foresight not afforded to any of his predecessors. As an incipient oncologist, the timing of my discovery could hardly have been better, in the sense that my entire training in cancer medicine took place in the bicameral mindset of the patient-physician. Early in our careers, we are propelled from passive to active learning and tacitly recognize the value of receiving, applying, and then imparting wisdom. In critically appraising evidence, however, we are quick to discount the individual anecdote, because an n of one lacks the power we need to gird our decision making with statistical rigor. However, our patients' understanding of illness is different than ours through the inimitable tutelage of inhabiting a body for years. The physician can only observe the disease course without totally sharing in the experience. This sense of always being a perpetual outsider looking in has particularly irked me as a medical oncologist. In truth, most cancer doctors know not quite what we say when we talk about chemotherapy. As I navigate the MEN1 diagnosis, I now look at adverse events, defined as side effects, complications, toxicity, and/or morbidity of a tested regimen, quite differently. It is my pet peeve when adverse events are addressed too fleetingly. We must reject the sophistry of manageable toxicity and think carefully about the iatrogenic burdens we place on patients, especially those for whom we have the privilege to offer longitudinal care in the setting of germline tumor syndromes like MEN1. MEN1 is a rare, autosomal dominantly inherited syndrome characterized by complex multiglandular disease processes, most commonly affecting the parathyroids, duodenum/pancreas, and pituitary glands. Understanding the natural course of the disease with asynchronous development of multifocal endocrine and nonendocrine tumors, recognizing the frequent indolent course of small NF-NETs, and realizing the malignant potential of MEN1-associated tumors are paramount in managing affected patients and their families. Patients with MEN1 strongly benefit from care at centers that specialize in MEN1. These patients require extensive education regarding disease manifestations and the role of active surveillance throughout their lives. As awareness of MEN1 in the medical community grows, we expect an increased recognition of the disease and improved education of patients and their health care providers. Nevertheless, we must always consider the impact of our longitudinal care on the medical, financial, and psychosocial well-being of our patients as they navigate this challenging disease throughout their lifetimes. As investigations progress in the use of targeted tumor ablation, NET chemoprevention, and MEN1-directed gene therapy, our hope and goal is to improve prediction, prevent tumor development, and pause progression of MEN1-associated malignancies. Arvind Dasari reports research funding from Hutchison MediPharma and Eisai and consulting fees from Xencor, Advanced Accelerator Applications, Lexicon and Ipsen. Nirav Thosani reports consulting fees from Boston Scientific Corp and honoraria from Taewoong Medical. The remaining authors had no disclosures.