Abstract

BackgroundThis study aimed to explore how clinical and radiological profiles of patients undergoing carotid endarterectomy (CEA) have changed over the past 40 years.

MethodsWe included our three Japanese case series of CEA in the late 1980s (n = 73), the 2000s (n = 142), and the 2010s (n = 108). We precisely compared the patients’ demographics, clinical features, radiological findings, and short- and long-term outcomes among the three cohorts. CEA was performed with general anesthesia, routine use of an internal shunt tube, intraoperative monitoring using somatosensory evoked potential or near-infrared spectroscopy, precise and bloodless manipulation using an operating microscope, and primary closure.

ResultsThe mean age of patients significantly increased from 55 years to 73.6 years during these 40 years (P P P P P

ConclusionThis study demonstrates significant differences in the demographics, radiological findings, and clinical results among patients undergoing CEA over 40 years, probably because of the patient’s lifestyle, advances in imaging techniques, understanding of the pathophysiology, advances in medical therapy, selection criteria of candidates for CEA, and treatment guidelines.

Keywords: Carotid artery stenosis, Carotid endarterectomy, Change, Long-term study, Profile

INTRODUCTION

Carotid plaque occurs from the intima of the carotid arteries and is composed of cholesterol, fatty deposits, and other substances. Carotid plaque can narrow the lumen of carotid arteries, restricting blood flow to the brain. In addition, carotid plaque can be the source of emboli in the retina and brain. Both mechanisms increase the risk of amaurosis fugax, retinal ischemia, transient ischemic attack (TIA), and ischemic stroke.[ 27 , 35 , 38 , 39 , 42 ] Carotid endarterectomy (CEA) has a history of over 70 years, starting in the 1950s with Dr. DeBakey’s pioneering work.[ 9 ] Since then, the procedure has undergone continuous refinement and has been supported by numerous landmark studies, including the North American Symptomatic CEA Trial (NASCET) and European Carotid Surgery Trial, which solidified its role in preventing strokes in patients with symptomatic carotid stenosis.[ 36 , 37 ] The main goal of CEA is to prevent subsequent cerebrovascular events such as TIA and ischemic stroke by removing the carotid plaque. Based on the results of randomized clinical trials, the procedure is typically recommended for patients who have significant stenosis of the carotid arteries, especially if they have experienced symptoms such as TIAs or minor strokes or if the degree of stenosis is severe (70% or more) in asymptomatic patients.[ 36 , 37 ] Therefore, CEA is an important surgical intervention to treat carotid artery stenosis, and it can help prevent life-threatening complications like stroke in high-risk patients.[ 2 , 14 , 40 , 41 ]

On the other hand, carotid artery stenting (CAS) is a minimally invasive alternative to CEA for treating carotid artery stenosis, particularly in high-risk patients. The number of CAS procedures performed worldwide has fluctuated in recent years due to evolving clinical guidelines, advancements in technology, and differing healthcare practices among various countries, with an increasing trend due to aging demographics and the development of a robust healthcare infrastructure.[ 4 , 32 ]

Historically, the degree of stenosis was considered the gold standard for determining treatment eligibility in patients with carotid artery stenosis. Specifically, a stenosis of 70% or greater was typically used as the threshold for recommending CEA or CAS.[ 36 , 37 ] In recent years, however, the approach to deciding treatment has evolved to consider not only the degree of stenosis but also the composition and vulnerability of the plaque.[ 5 , 25 ] Advances in plaque imaging technologies have allowed us to more detailed assessments of plaque characteristics, and these are increasingly being used to guide treatment decisions. New imaging techniques such as ultrasound and magnetic resonance imaging (MRI) now enable the assessment of plaque composition and can identify the factors, including the presence of vulnerable or unstable plaques that are prone to rupture or embolization and the amount of lipid-rich necrotic core in the plaque.[ 7 , 21 , 44 ] This concept is supported by a recent prospective multicenter cohort study (Plaque At RISK; PARISK). This study included 239 patients with cerebral or monocular TIA or minor stroke due to mild-to-moderate (<70%) carotid stenosis and evaluated the incidence of ipsilateral cerebral or monocular ischemic stroke or TIA for 5 years. Interestingly, intraplaque hemorrhage (IPH) presence and total plaque volume were significantly associated with recurrent ipsilateral ischemic stroke or TIA (hazard ratio: 2.12 and 1.07, respectively).[ 34 , 47 ] Therefore, it is now recognized that the composition of the plaque is a critical factor, and a nonocclusive but unstable or highly inflamed plaque may pose a greater risk of stroke than a stable plaque, even if the degree of stenosis is lower.[ 5 , 22 ] This has led to a paradigm shift in clinical decision-making, where patients with high-risk plaque features may be considered for intervention even if their stenosis is not so severe.[ 5 ]

Based on these observations, we aimed to explore how clinical and radiological profiles of patients who underwent CEA and the use of imaging in CEA have evolved over the past 40 years because these data were previously limited.

MATERIALS AND METHODS

Patients

In this study, patients were recruited from three case series we have previously reported on clinical results of CEA. The first is a paper written by the first author and published in 1994, which is a case series of 73 sides of 63 patients who underwent CEA, mainly in the late 1980s (1985–1991).[ 31 ] Moreover, the second is a paper published in 2011 by the first author as the corresponding author, which is a case series of 142 sides of 135 cases of CEA performed mainly in the 2000s (1998–2007).[ 19 ] The third paper was published in 2016 by the first author as the corresponding author. This paper included cases in which CEA was performed from 2012 to 2015,[ 1 ] but for the present study, the cases for which CEA was performed up to 2019 were also added to create a case series of 100 cases with 108 sides. Thus, the three case series addressed in this study are primarily cohorts from the late 1980s (n = 73), 2000s (n = 142), and 2010s (n = 108).

Candidates for CEA

In the late 1980s, CEA was performed in symptomatic cases with ≥75% carotid stenosis and in asymptomatic cases with ≥80% carotid stenosis; in the 2000s, CEA was performed in symptomatic and asymptomatic cases with ≥70% carotid stenosis; in the 2010s, CEA was performed in symptomatic cases with ≥70% carotid stenosis. In addition, CEA was performed in all symptomatic cases with “unstable” plaque on MRI. In this era, we recommended CAS for asymptomatic patients with ≥70% carotid stenosis, but CEA was indicated in asymptomatic patients with >70% carotid stenosis in whom CAS was considered unsafe or difficult to perform because of patients’ anatomical and general conditions.

Imaging

The diagnosis of cerebral infarction was mainly made by computed tomography (CT) in the late 1980s, but since the 2000s, MRI, especially diffusion-weighted images, has been employed in all cases. In the late 1980s, cerebral angiography was used in all cases, but in the 2000s, cerebral angiography was used in the first half of the decade, and three-dimensional CT angiography was used in the second half.

Since the late 2000s, plaque component was routinely evaluated using a 1.5-T MRI scanner. To characterize the plaque component, the long-axis and axial images of the carotid artery were obtained from the 3D gradient-echo sequence by targeting the area with the highest degree of stenosis. Representative sequence for spin echo T1-weighted images included a field of view, 200 mm/100%; repetition time, 500 msec; echo time, 11 msec; and slice thickness, 4 mm. The signal intensity ratio (SIR) was calculated as the ratio of the signal intensity of carotid plaque to that of the adjacent sternocleidomastoid muscle on T1-weighted images. According to the previous report, when the SIR value was less than 1.2 (iso-intensity), the plaque was considered fibrous; when the SIR value was between 1.2 and 1.5 (relatively high intensity), the plaque was considered lipid-rich or necrotic core (LR/NC). If the SIR value was greater than 1.5 (high intensity), the plaque was considered to be mainly composed of IPH.[ 33 ]

Cerebral hemodynamics were examined in all cohorts using single-photon emission computed tomography (SPECT) to measure resting cerebral blood flow and cerebral vasoreactivity (CVR) to acetazolamide.[ 29 , 30 , 48 , 49 ]

Surgical procedure and perioperative management

In the late 1980s, antiplatelet agents were stopped before surgery, but thereafter, they were not stopped before surgery. Surgical procedures were almost identical through the late 1980s and 2010s. Briefly, CEA was performed under general anesthesia using a T-shaped silicone shunt system (Intermedical Co., Nagoya, Japan).[ 18 ] During surgery, somatosensory evoked potential (SEP) was used to monitor neurophysiological function in the late 1980s. Subsequently, cerebral oxygenation status was monitored continuously by near-infrared spectroscopy (NIRS) through the frontal scalp in the 2000s and 2010s. The dissection of the carotid artery was performed under surgical microscopy. When dissecting the internal carotid artery (ICA), the utmost care was taken to avoid embolic fragmentation from the plaque. It is quite important to keep the operative field dry and blood-free during surgery to shorten the operating time and prevent postoperative wound hematoma. Atheromatous plaque removal was also performed under surgical microscopy. The border between the atheromatous plaque and the media was carefully identified at the highest magnification to enable complete plaque removal. Following the removal of plaque, the carotid arteries were primarily closed with a 6-0 monofilament thread. Immediately after surgery, SPECT was performed to identify postoperative cerebral ischemia or hyperperfusion.[ 19 ]

Statistical analysis

In this study, a detailed comparison of age, gender, history, comorbidity, carotid artery stenosis, cerebral hemodynamics, perioperative complications, and recurrent cerebrovascular events in the three cohorts was performed. The numerical data were expressed as a mean ± standard deviation. Statistical analysis was performed using a one-factor analysis of variance or Chi-square test as appropriate, with P < 0.05 set as a significant difference.

RESULTS

Figure 1 shows the distribution of patients’ age in the three cohorts. The mean age was 55.0 ±7.3 years, 69.5 ± 7.5 years, and 73.6 ± 6.5 years in the late 1980s, the 2000s, and the 2010s, respectively. The age significantly increased over 40 years (P < 0.01). The difference in mean age between the late 1980s and the 2010s was 23.6 years. As shown in Figure 2 , the prevalence of male patients gradually increased from 89% to 93% to 96% over 40 years, but there was no significant difference among the three cohorts (P = 0.283).

Figure 1:

Age distribution of three cohorts undergoing carotid endarterectomy over 40 years. Note a significant increase in age over time.

Figure 2:

Sex difference of three cohorts undergoing carotid endarterectomy over 40 years.

Clinical diagnoses in the late 1980s included TIA (33%), reversible ischemic neurological deficit (10%), ischemic stroke (48%), and asymptomatic (10%). In the 1990s, however, the patients were diagnosed with TIA (23%), ischemic stroke (67%), and asymptomatic (10%). In the 2010s, the prevalence of TIA further decreased to 10%, while the prevalence of ischemic stroke increased up to 80% (P < 0.01), [ Figure 3 ].

Figure 3:

The prevalence of clinical diagnosis, including transient ischemic attack (TIA), reversible ischemic neurological deficit, ischemic stroke, and asymptomatic in three cohorts undergoing carotid endarterectomy over 40 years. Note a significant increase in the prevalence of TIA but a significant decrease in that of ischemic stroke.

The incidence of comorbidity was compared among the three cohorts. Hypertension and hyperlipidemia significantly increased over 40 years in patients who underwent CEA (P < 0.01 and P < 0.05, respectively). The incidence of coronary artery disease also significantly increased over 40 years (P < 0.01); [ Table 1 ].

Table 1:

The incidence of comorbidity and history of vascular disorders.

The stenosis degree of the carotid artery was compared among the three cohorts [ Figure 4 ]. Among patients who underwent CEA, the incidence of patients with more than 90% carotid stenosis significantly decreased from 54.9% to 24.5% over 40 years (P < 0.01). On the other hand, the incidence of patients with less than 50% carotid stenosis significantly increased from 4.2% to 29.4% between the 2000s and 2010s (P < 0.01). In addition, the percentage of patients with reduced CVR on SPECT decreased significantly from 41% in the late 1980s to 30% in the 2000s and to 21% in the 2010s (P < 0.01); [ Figure 5 ].

Figure 4:

The incidence of stenosis degree of three cohorts undergoing carotid endarterectomy over 40 years. Note a significant decrease in patients with 90% or more stenosis and a significant increase in those with <50% stenosis.

Figure 5:

The incidence of patients with reduced cerebrovascular reactivity (CVR) to acetazolamide in three cohorts undergoing carotid endarterectomy over 40 years. Note a significant decrease in patients with reduced CVR.

In the late 1980s, perioperative complications occurred in 7/73 (9.6%; 95% confidential interval [CI], 6.2–13.0%). There were four cases of ipsilateral ischemic stroke, one case of transient hypoglossal nerve palsy, one case of fulminant hepatitis, and one case of pneumonia. In the 2000s, however, it occurred in 4/142 (3.1%; 95% CI, 1.6-4.5%), including two cases of ipsilateral ischemic stroke and two cases of hoarseness. In addition, another case died of multiorgan failure (mortality rate = 1/142; 0.7%). In the 2010s, it occurred in 8/108 (7.4%; 95% CI, 4.9–9.8%), including ipsilateral ischemic stroke (n = 2), contralateral ischemic stroke (n = 1), hoarseness (n = 1), transient hypoglossal nerve palsy (n = 2), and pneumonia (n = 2). In addition, two cases developed severe post-CEA hyperperfusion and required sedative agents and intratracheal intubation for several days. As a result, the 30-day morbidity and mortality rate was 4/73 (5.5%; 95% CI, 2.8–8.2%), 3/142 (2.1%; 95% CI, 0.9–3.3%), and 3/108 (2.8%; 95% CI, 1.4–4.6%) in the late 1980s, the 2000s, and the 2010s, respectively.

We compared the events that occurred during follow-up periods in each cohort: in the late 1980s cohort, ischemic stroke occurred in 4/73 (5.5%) during an average period of 24.5 months. There were three cases of ipsilateral ischemic stroke and one case of ischemic stroke in the vertebrobasilar artery system. Thus, the risk of recurrent ipsilateral ischemic stroke was 2.0%/year (95% CI, 0.4–3.6%); one patient died of myocardial infarction. The death rate was 0.8%/year (95% CI, −0.2–1.8%). On the other hand, in the 2000s cohort, cerebrovascular events occurred in 12/142 (8.5%) over an average of 38.7 months. Two patients had an ipsilateral ischemic stroke, 5 had a contralateral ischemic stroke, and 4 had an ischemic stroke in the vertebrobasilar artery system; one patient developed intracerebral hemorrhage. Thus, the risk of recurrent ipsilateral stroke was 0.4%/year (95% CI, −0.1–0.9%). In addition, newly identified cardiovascular diseases during the follow-up period included coronary artery disease (n = 6), abdominal aortic aneurysm (n = 2), and induction of hemodialysis due to chronic renal failure (n = 3). Nine patients died during this period, and the causes of death included malignancy (n = 6), stroke (n = 1), and pneumonia (n = 2). The death rate was 2.1%/year (95% CI, 0.9–3.3%). In the 2010s cohort, cerebrovascular events occurred in 5/108 (4.6%) over an average of 60.1 months. One patient had an ipsilateral ischemic stroke, and 4 had contralateral ischemic stroke. Thus, the risk of recurrent ipsilateral stroke was 0.2%/year (95% CI, −0.2–0.6%). In addition, there were newly identified cardiovascular diseases, including coronary artery disease (n = 8), atherosclerosis obliterans (n = 2), and induction of hemodialysis due to chronic renal failure (n = 2). Totally 15 patients died during this period, and the causes of death included malignancy (n = 4), myocardial infarction (n = 4), chronic renal failure (n = 1), pneumonia (n = 2), old age (n = 2), and unknown cause (n = 2). The death rate was 2.2%/year (95% CI, 0.8–3.6%).

DISCUSSION

In this study, three cohorts of patients who underwent CEA from the first author’s experience over 40 years as a resident or surgeon were examined in detail with regard to their clinical and imaging presentations. The results revealed that many changes have occurred over the past 40 years that may not have been noticed in daily practice [ Figure 6 ].

Figure 6:

Summary diagram of this study demonstrates the 40-year changes in clinical and radiological features of patients undergoing carotid endarterectomy.

Demographic data

There are very few studies that denoted how the profile of patients eligible for CEA and the use of imaging have evolved over the past 30–40 years. However, over the last several decades, the profile of patients undergoing CEA may have shifted due to improvements in cardiovascular disease management, changes in demographics, selection criteria of candidates for CEA, and clinical guidelines. In this study, therefore, we aimed to highlight the important changes in patient demographics, risk factors, and the use of advanced imaging techniques. First, the patient’s age markedly increased from 55.0 ± 7.3 years to 73.6 ± 6.5 years over the 40 years in this study. In fact, the mean age of 328 symptomatic patients who underwent CEA for severe carotid stenosis in NASCET between 1988 and 1991 was 65 years.[ 36 ] On the other hand, the mean age of 857 symptomatic patients who underwent CEA in the International Carotid Stenting Study (ICSS) between 2001 and 2008 was 70 years.[ 3 ] Over only about 20 years, the age of patients eligible for CEA increased by 5 years. The fact may reflect the recent increase in life expectancy because of the development of medical care and improved environmental factors.[ 8 , 15 , 20 ] There was no significant difference in the incidence of male sex between the two trials, NASCET and ICSS (68% vs. 71%).[ 3 , 36 ] On the other hand, the incidence of male sex is 90% or more in this study, being higher than in the Western cohorts. Furthermore, the incidence of male patients gradually increased from 89% to 93% to 96% over 40 years, although there was no significant change. Racial differences between Asian and Western populations may have a significant impact on the sex difference in the occurrence of atherosclerosis in the carotid arteries.[ 43 ]

This study also shows that the patients undergoing CEA now often present with more comorbid conditions such as hypertension and hyperlipidemia. Especially the prevalence of hypertension increased from 71% to 94% over 40 years. The incidence of patients with coronary artery diseases also increased from 16% to 32% over 40 years. As described above, one reason may be the aging of the patients undergoing CEA in recent years. This shift may increase the complexity of surgical procedures and perioperative management for patients undergoing CEA, and thus, we should more carefully select surgical candidates for CEA than before for safe surgery.[ 46 ]

Radiological findings

In this study, the frequency of patients with more than 90% stenosis among those who underwent CEA has decreased over time, while the frequency of patients requiring CEA, even with less than 50% stenosis, has increased. This finding is consistent with the fact that the frequency of patients with reduced CVR has also decreased over time. At the same time, clinical diagnoses have also shown a rapid decrease in the frequency of TIA patients and a rapid increase in the frequency of patients with ischemic stroke over time. As aforementioned, the last few decades have seen significant advances in imaging techniques used to assess the composition of carotid plaque. Nowadays, we can highly predict the vulnerable plaque, including LR/NC and IPH, before surgery. According to recent knowledge, these vulnerable plaques are histologically rich in activated macrophages and fragile, abnormal vessels. Such vessels can easily rupture regardless of the stenosis degree and induce the distal embolism in the retinal and/or intracranial arteries. Therefore, vulnerable plaques are more likely to develop mild to severe ischemic stroke due to the migration of emboli into the retinal and/or intracranial arteries at a less advanced stage of stenosis. Stable plaques, however, consist of fibrous components and rarely rupture. As a result, stable plaques do not develop vascular events until the stenosis becomes severe enough to deteriorate cerebral hemodynamics, which more frequently leads to amaurosis fugax and TIA. These advancements in our knowledge may influence our decision-making process when deciding the candidates for CEA, particularly with respect to identifying vulnerable plaques and assessing stroke risk.[ 5 , 22 , 23 , 26 ]

Taken together, we speculate as follows: in the past, many Japanese patients had fibrous plaques and often developed transient vascular events only when the degree of stenosis was advanced. Over time, however, the frequency of patients with ischemic stroke has increased due to the vulnerable plaques with a high degree of inflammation, and the target population for CEA has shifted to patients with less severe stenosis than before, and finally, the number of patients with normal cerebral hemodynamics has increased. This phenomenon may be related to dietary changes not only in Japan but also in other countries and regions.[ 6 , 10 , 17 ] Of course, the results of this study may also be influenced by the fact that we have changed our treatment strategy for CEA after we recognized that patients with fragile plaques, even with mild stenosis, often require CEA to prevent recurrent cerebrovascular events.[ 22 ]

Clinical diagnosis

Clinical diagnosis in patients undergoing CEA has also changed dramatically over the past 40 years. The incidence of TIA decreased while that of ischemic stroke increased. This major change most probably reflects the widespread use of diffusion-weighted images around 2000, which made it easier to detect minute fresh cerebral infarcts that CT/MR could not detect before that time[ 1 , 18 , 22 ] and as well as the fact that TIA has shifted from time-based definition to tissue-based definition in the 2000s.[ 11 ] Another major factor may be the increase in the number of patients who develop ischemic stroke due to artery-to-artery embolism from mild to moderate stenosis with vulnerable plaques rather than TIA due to impaired cerebral hemodynamics caused by severe stenosis, as described above.

Surgical results and outcome

We have been performing CEA for 40 years using a largely consistent technique for generations, including general anesthesia, routine use of an internal shunt tube, intraoperative monitoring using SEP or NIRS, precise and bloodless manipulation using an operating microscope, and primary closure.[ 19 , 28 ] As the results, 30-day morbidity was 5.5%, 2.1%, and 2.8% in the late 1980s, the 2000s, and the 2010s, respectively. Likewise, the mortality rate was 0%, 0.7%, and 0%, respectively. The results strongly suggest that our long-standing surgical techniques may be one of the best choices.

The annual risk of ipsilateral stroke during follow-up periods has also decreased from 2.1% to 0.4% to 0.2% over time. We speculate that recent advancements in medical care may play an important role in decreasing the incidence of subsequent ischemic events. However, vascular events outside the realm of CEA, such as ischemic events in the contralateral carotid and vertebrobasilar artery territories, myocardial infarction, angina pectoris, aortic aneurysm, and chronic renal failure have not been uncommon throughout any era. Therefore, we should more carefully follow up with the patients for a long time after CEA.[ 19 , 28 ]

In this study, the plaque composition was not evaluated in all three cohorts because we started to evaluate it with MRI in the late 2000s. Therefore, it is unclear how plaque vulnerability was involved in the occurrence of perioperative morbidity/mortality and cerebrovascular events during follow-up periods over 40 years. However, there is increasing evidence that plaque vulnerability plays a major role in the development of perioperative complications and vascular events after CEA.[ 12 , 13 , 24 , 45 ] Especially coronary artery diseases and chronic renal failure are closely associated with vulnerable carotid plaque.[ 13 , 24 ] These facts may be quite natural in view of the fact that vulnerable carotid plaques are not a localized disease specific to the carotid artery but the tip of an iceberg of chronic inflammation that is persistent throughout the entire body.[ 26 ]

In interpreting the present results, several cautions need to be considered. First, the three cohorts used in the present study are only data from a single institution to which the authors belonged. Second, it should be noted that, unlike drug therapy, it is difficult to standardize the technique and skill level of the surgical team at all institutions, so the results of the present study may not be applicable to every institution. Third, all three cohorts in this study consisted of Japanese patients, and we should be careful when we apply the present results to all racial groups because there are large racial differences in atherosclerotic diseases. Thus, White and Native American populations exhibit higher rates of carotid stenosis than Hispanics, Blacks, and Asians. Of these, Asians demonstrated the lowest prevalence of carotid stenosis among these races. On the other hand, the Caucasian population tended to have more extracranial carotid plaques with vulnerable characteristics than the Chinese.[ 16 ] Therefore, the trends observed in this study may be more notable in the western countries. Similar studies in each race are warranted to overcome this limitation of this study.

Although we have performed CEA over the generations using almost the same techniques as a single-family team, perioperative management has been refined little by little, which may have affected the incidence of perioperative complications. In addition, medical therapies such as antiplatelets, antihypertensive agents, and statins have drastically changed over the past 40 years, which may also have a significant impact on the long-term outcome after CEA. However, these changes are gradual, and it is difficult to clearly delineate and analyze these clinical factors in each of the three cohorts used in this study. Finally, when interpreting these results, we should consider the changes in many factors over about 40 years. These factors include many social and medical factors, including the healthcare systems, the health status of the Japanese population, surgical procedures, perioperative management, and medical treatments. In fact, the mean life expectancy of Japanese males has increased significantly from 75.9 years in 1990 to 81.4 years in 2019. On the other hand, the Japanese medical insurance system has not changed significantly during this period. Therefore, it can be assumed that there was no obvious change in access to health care during this period.

CONCLUSION

This study clearly demonstrated significant differences in the demographics, radiological findings, and clinical results among patients undergoing CEA over 40 years. These observed changes over time may result from multiple factors, including the patients’ lifestyle, advances in imaging techniques, understanding of the pathophysiology, advances in medical therapy, decision-making of candidates for CEA, and treatment guidelines. To validate the present results, we should address the changes in patient background, imaging, and outcomes of CEA over a 30–40-year period in other geographic and racial regions, such as Western countries. In addition, a prospective multicenter study of CEA based on detailed plaque imaging analysis should be conducted.

Ethical approval

The research/study was approved by the Institutional Review Board at Toyama University Hospital, number R2019057, dated August 30, 2019.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

Acknowledgment

The authors express a special thanks to Prof. Hiroyasu Kamiyama, a Visiting Professor University of Toyama, Toyama, Japan, for his long-standing and continuous, passionate mentorship.

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