In the entanglement of fears, doubts and uncertainties: some reflections on the treatment of pain associated with endometriosis
by Michel Canis and Sun-Wei Guo
Department of obstetric gynecology and reproductive medicine, CHU Clermont Ferrand, Clermont Ferrand, France
Research Institute, Obstetrics and Gynecology Hospital in Shanghai, Fudan University, Shanghai, China
Correspondence addresses:
- Department of obstetric gynecology and reproductive medicine, CHU Clermont Ferrand, Clermont Ferrand, France. E-mail: Mcanis@Chuclermontferrand. FR (MC)
-https://orcid.org/0000-0003-0852-7811; Research Institute, Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China. E-mail: hoxa10@outlook.com (s.-wg) https://orcid.org/0000-0002-8511-7624
Study here : https://pubmed.ncbi.nlm.nih.gov/37023473/
(Translation of the association)
SUMMARY
Pain associated with endometriosis can be treated either by surgery or by hormone therapy. The final decision with regard to the treatment modality to be adopted is based on the possible efficiency and complications of the different treatment methods, the risk of recurrence and the wishes and preferences of the patient. But in the entanglement of fears, doubts and uncertainties, the choice can ultimately be summed up in a compromise between irrational fears and ignorance, on the one hand, and scientific evidence, on the other.
We present the advantages and disadvantages of the two treatment methods and underline the notable drawbacks of hormone therapy, in particular the possible but not quantified risk of long-term hormonal therapy for malignant transformation, perhaps with the exception of combined oral contraceptives. Therefore, when we discuss with patients, we recommend the approach consisting in discussing in detail of the advantages and disadvantages of all therapeutic options, taking into account the advantages and disadvantages known, while perfectly understanding the predictive irrationality of the human being.
For pain associated with endometriosis, surgery is certainly not a failure of medicine, but rather a viable option, especially if we take into account the distrust and dissatisfaction recently expressed by patients with endometriosis towards current hormonal drugs . Above all, it is urgent to fill the lack of knowledge on perioperative interventions intended to reduce the risk of recurrence and to meet the demand for the development of safe and effective non-hormonal therapies.
Keywords: endometriosis, fear, hormonal therapy, malignant transformation, surgery, treatment modality
Surgery or medication?
Today, the methods of treatment of pain associated with endometriosis (EAP) can be roughly grouped into two categories: surgery and medical therapy (Becker et al., 2022).
Thanks to the progress of imaging technology, endometriosis can often be diagnosed without laparoscopy . The current therapeutic arsenal to treat EAP includes non-steroidal anti-inflammatory drugs (NSAIDs) and hormonal drugs such as combined oral contraceptives (COC), progestins, GNRH agonists, aromatase inhibitors and new GNRH antagonists (VannuCcini et al., 2022). All hormonal drugs have in common the cessation of cyclic menstruation, either by removing the ovarian secretion of estrogen, or by inducing a state of pseudo-grossess (Brosens, 1997; Vercellini et al., 2014; Vannuccini et al., 2022).
Surgical treatment aims to alleviate EAP and restore normal anatomy. Unlike medical treatment, surgical treatment can also be considered in case of infertility linked to endometriosis, as surgery improves fertility in women with mild to moderate forms of the disease (Duffy et al., 2014). In addition, surgical removal of endometriosic lesions improves local and systemic inflammation (Monsanto et al., 2016) as well as hypercoagulability and central awareness in patients (He et al., 2010; Wu et al., 2015; Ding et al., 2018), which suggests that the “source” of systemic changes is surgically removed, Systemic improvement follows, probably until new lesions appear and cause symptoms. This is particularly interesting given the growing evidence suggesting that endometriosis is a chronic systemic disease (Taylor et al., 2021). In light of consensus and evidence (Becker et al., 2022; Choi et al., 2023), postoperative hormone therapy reduces the risk of recurrence and is likely to maintain the systemic effect resulting from surgery.
ESHRE guidelines on the management of endometriosis, recently updated, recommend that clinicians adopt a shared decision -making approach and to take into account individual preferences, side effects, individual efficiency, costs and availability when choosing between drugs and EAP surgery, stressing the fact that prospective studies comparing the two approaches are sorely lacking (Becker et al., 2022).
For patients complaining of intense pain, an approach by a multidisciplinary team is often recommended (Allaire et al., 2020; Agarwal et al., 2021), especially when several organs are affected or the case is complex (Becker et al., 2022). The final decision with regard to the treatment modality to be adopted is based on four elements: the possible efficiency and complications of the different treatment methods, the risk of recurrence and the patient's wishes and preferences, if applicable.
While drugs are often the first -line treatment, surgery is particularly indicated if the patient does not respond to hormonal therapy, if she needs histological confirmation of endometriosis or if deep endometriosis leads to dysfunction of pelvic organs and/or a decrease in quality of life (Becker et al., 2022).
But the choice can ultimately be summed up with a compromise between irrational fears and ignorance, on the one hand, and scientific evidence, on the other.
Fear of incision/operation
In reality, the decision concerning the treatment modality to be adopted is motivated, perhaps in large part, by the preference of patients, who may have difficulty understanding and grasping the nuances of the risks and advantages of the different processing methods, and whose perception can also be influenced, even preceded, due to the well-documented information asymmetry, by the point of view of the treating gynecologist surgical skill levels. Consequently, the risk of surgical complications could be exaggerated, as serious complications of intestinal surgery and/or ovarian lesions induced by inadequate surgical procedures have been well described and widely discussed in the literature (Bendifallah et al., 2020). Indeed, most patients with endometriosis do not have an extensive disease or a deep damage to the intestine, as shown in a prospective regional study of 981 patients in whom endometriosis has been newly diagnosed: less than a quarter of patients had a revised stadium IV disease of the American Society for Reproductive Medicine and only 20 % of them had a deep nodule > 2 cm, not always saving the intestine (Tourteur et al., 2019). Most of these patients can therefore be operated on with much lower risks, even when treated for deep lesions that do not avoid the intestine (Vallee et al., 2018).
In addition, ovarian cystectomy is not a simple stripping, as is often described (Reich and McGlynn, 1986); Rather, it must be performed as a meticulous microsurgical dissection (Gordts et al., 1984), longer and technically more demanding than the dissection of other benign ovarian neoplasms. Indeed, the surgeon's experience and skills can have an impact on the quantity of ovarian cortex which is lost during a stripping cytectomy, stressing the fact that inexperienced or less skillful surgeons lose more vital ovarian fabric than skillful surgeons (Muzii et al., 2011). In addition, a greater experience of conservative laparoscopic surgery reduces the risk of recurrence (Carmona et al., 2009).
By accepting these rules, this surgery is not difficult to learn (Canis et al., 2003) and has been widely practiced to preserve the ovary while accepting a possible risk of recurrence rather than a severe ovarian lesion (Give et al., 2010). Ironically, the risk of menopause is reduced in patients who had a recurring endometrioma after surgery, since less ovary damage can cause more ovulatory events and therefore a higher risk of recurrence (Somigliana et al., 2011). Finally, the effectiveness of surgery in pain treatment has been demonstrated in several randomized double -blind clinical trials, which are very difficult to carry out for such indications and are therefore extremely rare in the surgical pain treatment (Sutton et al., 1994; Abbott et al., 2004).
In other words, the risks and benefits of EAP surgical management are well defined and the risk-benefit ratio is acceptable. However, the patient's fear of undergoing a transient colostomy and the fear of the surgeon to be the subject of a trial are probably behind the decision not to operate much more often than it is reasonable to do so.
The drawbacks of hormone therapy
Unlike surgery, specific complications (i.e. side effects) of medical therapy, with the exception perhaps COCs, have not been fully defined when used in the long term (> 1 year) . Although there are long-term security data of COCs and certain progestins (ACOG, 2010; Cibula et al., 2010; Hannaford et al., 2010; Vessey et al., 2010; Iversen et al., 2017), we have very little data to assess the deleterious consequences possible, if there are any, on the lesions themselves. We also do not know what medication or what combination/sequence of drugs should be used optimally and economically for a specific patient, especially when the case is complicated by various comorbidities, symptoms and contraindications. For example, an increased risk of meningiomas has recently been reported after the long -term use of several progestins, cyproterone acetate, nomestrol acetate and chlormadinone acetate (Hage et al., 2022). The risk seems higher when a screening program is organized, with up to 7.1% in patients who have received cyproterone acetate (Samoyeau et al., 2022). The published data seem to confirm the existence of an increased risk of meningioma linked to the use of oral contraceptives (Hage et al., 2022). Consequently, a careful evaluation of long -term and high -dose progestin treatment seems compulsory.
The possibility of malignant transformation of endometriosic lesions is particularly worrying. According to the ASRM practice committee, "endometriosis must be considered a chronic disease that requires a life management plan in order to maximize the use of medical treatment and avoid repeated surgical procedures" (Committee of the American Society for Reproductive, 2014). Since the average age during the first surgical intervention for an ovarian endometrioma is around 36 years (Liu et al., 2008), the duration of medication would be at least 15 years on average. For adolescent patients, the planned duration of medication would be much longer.
Endometriosic lesions have been demonstrated fairly recently shelters mutations associated with cancer (CAM) (Anglesio et al., 2017; Suda et al., 2018; Zou et al., 2018; Praetorius et al., 2022). Although cams can occur in normal tissues and these fabrics with cams are not necessarily clever, malignant transformation can occur and occurs when enough cams with good combinations are accumulated (Guo, 2020). Given the risk, although low, of malignant transformation in endometriosis, in particular in ovarian endometrioma (Guo, 2015), the long -term risk of malignant transformation in the context of hormone therapy has not been evaluated in depth and should deserve special attention. This is particularly worrying when the ovarian endometrioms are diagnosed by imagery without laparoscopy (then removal), because many endometriomal lesions house cam, such as Kras (Kirsten Rat sarcoma virus), Pik3ca (phosphatidylinositol- 4,5-bisphosphate 3-kinase Catalytic Alpha), CTNNB1 (catenin B1), and Arid1a (At-Rich Interaction Domain 1A) (Suda et al, 2018; Praetorius et al., 2022), which are molecular alterations constituting ovary cancer (de Leo et al., 2021).
Although the risk of malignant transformation of ovarian endometrioma is low but clearly present (Pearce et al., 2012; Guo, 2015), and complete surgical removal of lesions considerably reduces the risk (Melin et al., 2013), removal by drug -free drugs of all visible lesions can favor the acquisition and accumulation of CAM with time and therefore increase the risk of Malignity. A prospective study on 485 patients who have suffered the excision of an endometrioma revealed that the four patients who developed ovary cancer had experienced a recurrence before (Haraguchi et al., 2016), which suggests that these patients who have undergone malignant transformation all had apparently active lesions, as all ovarian cancers were developed from The recurrent endometrioma previously operated. Most of the risks associated with very long -term hormone therapy are at best confused and more difficult to grasp by patients and doctors, so that as the ignorance that the absence of taking into account the risk of very late complications can make hormone therapy more acceptable.
A notable exception could be the COCs, which has been shown that their use for more than 10 years was associated with an 80 % reduction in the risk of ovary cancer in women with endometriosis (Modugno et al., 2004). The use of COCs has also been shown to reduce the risk of endometrial cancer (Burchardt et al., 2021). Unfortunately, COCs are contraindicated in patients over 35 who smoke or who have an increased risk of myocardial infarction, stroke or venous thromboembolia (Black et al., 2015). In addition, prolonged use of COCs can lead to slimming of the endometrium which is difficult to rectify by estrogens (Talukdar et al., 2012). There is a significant increased risk of deep endometriosis (ratio of the adjusted dimensions = 16.2; 95 % CI = 7.8-35.3) in women who had taken COCs in the past because of what had been diagnosed as primary dysmenorrhea (Chapron et al., 2011), which suggests that the failure of COCs to contain the pain that may be associated with endometriosis and Content in COCs could lead to lesional progression (Casper, 2017b). Consequently, there seems to be a tendency to use progestin -based drugs only (see, for example, Casper, 2017a, B; Murji et al., 2020; Kim et al., 2022), even for adolescent patients (Ebert et al., 2017).
Bone loss after hormonal therapy is also a problem, especially in young patients using Diénogest (Ebert et al., 2017) and, for adult patients, for a prolonged period. If the annual loss can be minimal, even negligible, the cumulative effect could nevertheless be substantial, especially when the treatment is used throughout life. Similarly, the prolonged use of GNRH agonists and antagonists poses a similar problem, and probably even more serious (Casper, 1991; Mohammed et al., 2018).
In addition, there is also a risk of very late complications, such as brain vascular accidents (Farland et al., 2022), which are probably a consequence of castration and medical treatments, or hypercoagulability in patients with endometriosis (Ding et al., 2018, 2019; Wu et al., 2015). The long -term use of Diénogest also seems to increase the risk, although low, of depression (Moehner et al., 2020). In addition, long -term use of progestins is often associated with significant weight gain, which can also increase this risk (Berlanda et al., 2017). The long -term risk of venous thromboembolia associated with dienogest and GNRH antagonists (with or without extra treatment) must also be carefully evaluated (Dinger et al., 2010).
In addition, there is a tendency to treat all patients with endometriosis as if they came from the same mold, regardless of their age or individuality of their pain, with little, if not at all, of appreciation because there is clearly a variation according to age in the phenotypes of the disease (Ding et al., 2020; Benagiano and Guo, 2022) and that pain is always a very experience Personal, influenced by not only biological, but also psychological and social factors (Vader et al., 2021). For example, NSAIDs were considered one of the first-line drugs to treat EAP (National Institute for Health and Care Excellence Guideline, 2017; Becker et al., 2022), apparently due to the capacity of lesions to produce prostaglandins by induction of cyclo-oxygenase 2. However, emerging data show that if the signaling of the prostaglandine E2 (PGE2) actually plays an inflammatory role in early lesions, it becomes anifibrotic when the progression of lesions progresses, which leads to a reduction in the signaling of PGE2 when the lesions become fibrotics (Huang et al., 2021, 2022). In particular, treatment with PGE2 receptor inhibitors has actually exacerbated endometriosis in mice with induced deep endometriosis (Huang et al., 2021).
Certain hormonal treatments, such as dienogest, tend to cause light to abundant uterine bleeding in patients with adenomyosis (Hirata et al., 2014; Osuga et al., 2017a, B, 2020), which often coexist with endometriosis. This is particularly true for patients with internal adenomyosis (Matsubara et al., 2019), due, ironically, of the antiproliferative and anti-inflammatory capacity of Diénogest (Ruan et al., 2012). Indeed, normal menstrual bleeding requires adequate repair of the endometrium, which requires cell proliferation and controlled inflammation (Critichley et al., 2020; Mao et al., 2022).
Preoperative medical treatment has been shown to cause a higher risk of removal of normal ovarian tissues adjacent to endometriomal lesions during a cytectomy (Matsuzaki et al., 2009), which suggests that treatment can either shrink the lesions, or increase the risk of adhesion as well as fibrosis, thus increasing the risk of lesions ovarian by the removal of normal ovarian tissues. A recent study suggested that progesterone treatment, such as medroxyprogesterone acetate, could facilitate fibrogenesis in endometriosis (Shenoy et al., 2017). In addition, if hormone therapy can contain lesional growth thanks to the cessation of cyclical bleeding (Brosens, 1997) and thus disturb the repeated process of lesion and fabric repair (Retiar) which leads to lesion fibrosis (Guo, 2018), lesions are in all likelihood. They can remain dormant, even atrophic, but can nevertheless progress, although a slower rate, especially when the patient is subject to chronic psychological stress resulting from pain, infertility, abnormal menstrual bleeding or other triggering factors (Long et al., 2016; Guo et al., 2017). The contrast between the rarity of progression in women with asymptomatic rectovaginal endometriosis (Fedele et al., 2004) and the observation of the progression of the disease, measured by the size of the lesions, in women presenting deep endometriosic nodules symptomatic infiltrating rectosigmoid, in particular in cyclic women, is the best illustration al., 2019). This could explain why the amenorrhea induced by the progestins, although effective to attenuate the EAP, can still allow the progression of deep endometriosis (Millochau et al., 2016; Scioscia et al., 2016), the lesions progressing nevertheless, but at a much slower rate. In other words, menstruation is a prerequisite for Retiar, and EAP and stress perpetuate progression (Ding et al., 2020).
Finally, there is a strong underlying current, which has only surfaced recently, of distrust and dissatisfaction with the current hormonal drugs in patients with endometriosis, especially in the youngest, the most educated and the city cars (Burla et al., 2021). Unfortunately, the development of non -hormonal drugs for endometriosis stagnates painfully (Guo and Groothuis, 2018) and the disappointment is palpable (Vercellini et al., 2011).
Generally, the surgery option is discussed when patients have persistent unresolved pain by hormonal therapy. Despite the diversity of hormonal drugs, amenorrhea seems to be a blatant common point among all medicines (Brosens, 1997). However, amenorrhea is often not completely affected by medical treatment, so that cyclical bleeding in lesions lead to a risk of progression of lesions due to Retiar (Guo, 2018; Ding et al., 2020). Patients suffering from deep dyspareunia linked to deep nodules invading the vagina rarely indicate a significant relief of symptoms during medical treatment (Anaf et al., 2002). Pain is exacerbated when pressure is exerted on the vaginal part of the nodule, a phenomenon known as hyperalgesia resulting from a high density of nerve fibers. Thus, the EAP is much less likely to be improved when you induce amenorrhea (Rezende et al., 2022). On the other hand, surgery, in particular ablation, can be more effective in relieving dyspareunia and chronic non -cyclic pelvic pain (Riley et al., 2018). It is conceivable that acyclic EAP is less likely to be improved by amenorrhea induced by drugs.
The reappearance of pain after surgical treatment should not be considered synonymous with recurrence of the disease . Indeed, prospective tests on the effect of EAP surgery have shown that the placebo effect of surgery can persist for 6 months (Sutton et al., 1994; Abbott et al., 2004). Consequently, recurring pain can be considered as proof that surgical treatment was not an effective pain treatment, and that the placebo effect of surgery explains the result observed during the first postoperative months and ultimately suggests that preoperative pain cannot be attributed only to endometriosis, but most likely also to associated causes. This is particularly important for minimal, light or moderate diseases. In other words, in many patients with EAP, the reappearance of pain could be interpreted as the reappearance of the disease, when it probably does not reflect that the end of the placebo effect of surgery. On the other hand, the results at 1 year reported after surgery confirm that pain, and probably the disease, do not always recur (Bourdel et al., 2018; Alborzi et al., 2022). Therefore, we agree that a new surgical intervention is rarely indicated. It should be avoided by adequate surgical management and is rarely, or never, justified by recurring pain.
Very often, the risk of recurrence is used as a major argument against surgery . However, many studies, including very old, have clearly shown that recurring pain is not always associated with recurring disease (Schenken and Malinak, 1978). In addition, even after the treatment of the most serious cases, the risk of recurrence remains low and acceptable (Meuleman et al., 2011). Indeed, surgery does not remove the deep causes of endometriosis, just like medical therapy. It is content to remove existing endometrios lesions when visualized during the operation. However, the resension of lesions, due to incomplete excision, effusion and dissemination, or retrograde menstruation after surgery, can always occur, hence the existence of a risk of recurrence. Unfortunately, so far, we do not know much, or even nothing, on the reasons why endometriosis can persist in some women throughout their lives. Therefore, we don't really know if the disease reappears or under what conditions. The long-term fertility of patients operated on adolescence, close to that of a normal woman, suggests on the contrary that the disease does not recur and does not always worsen (Wilson-Harris et al., 2014; Audebert et al., 2015). In addition, the risk of recurrence is quite low after intestinal surgery (Bendifallah et al., 2020). On the other hand, the persistence of pain is, predictably, very high after the cessation of medical treatment, as evidenced by the persistence of deep lesions or ovarian cysts after treatment with Dienogest, which are likely to cause an EAP (Leonardo-Pinto et al., 2017; Vignali et al., 2020). The persistence of pain a few weeks after stopping hormone therapy is probably induced by the "menstrual reactivation" of persistent lesion (s), the retiar process being relaunched.
Indeed, ultrastructural studies after treatment in Danazol have shown that the gland seemed to be stopped in what seemed to be the proliferative stage (Schweppe et al., 1981). When the amenorrhea is induced by hormonal treatment, we must understand that endometriosic lesions do not disappear simply but are simply contained (in terms of deleted proliferation, attenuated inflammation and reduced production of estrogen), possibly manifesting by atrophy or dormancy. However, there can always be a low-level cellular division and catecholamines resulting from the activation of the hypothalamo-hypophyso-surrenal/sympathetic-adreno-medullary axes due to pain, infertility, to abnormal uterine bleeding or other psychological stresses can still accelerate the progression of lesions via the lesional adrenéceptors, Finally leading to a metaplasia of smooth muscles and therefore to muscle hyperplasia as well as fibrosis (Long et al., 2016; Guo et al., 2017).
Ovarian endometrioms confirmed histologically have not disappeared after 6 months of medical treatment (Schweppe et al., 1981). More recent data on diagnosed cysts as well as ultrasound should be used with caution because many hemorrhagic cysts could be persistent functional cysts rather than real ovarian endometrioms (Martin and Berry, 1990). The fact that after prolonged medical treatment, fibrous healing can prevent the persistent endometrium from starting to have rules at the end of treatment is a possibility that has never been demonstrated. The fact that persistent lesions repel after medical treatment implies that recurrence seems inevitable after hormonal therapy, and therefore the need for prolonged use of drugs. On the other hand, the risk of recurrence after surgery can be reduced if it is facilitated by postoperative amenorrhea, by the prevention of retrograde menstruation on postoperative scars (Schweppe and Ring, 2002), or perhaps by a perioperative intervention (Guo and Martin, 2019).
A sword of damocles against a Russian roulette
Most patients, as well as surgeons, are often afraid of surgery and anesthesia, a moment when we have to entrust our lives to a group of perfect strangers knowing that we will not know what will happen until we wake up . This fear is easily understandable in a world where confidence is often abused and where disinformation and false news are omnipresent. However, for a patient who is preparing to undergo surgery, the operating room is undoubtedly one of the safest places in the world. In the event of a complication, the patient lying on the operating table, unconscious, can count on a full team of anesthesists, surgeons, assistants and nurses immediately available to treat her.
With the advent of mini-invasive surgery, social and professional life of patients can be considerably improved, most of them can resume their normal activities a few days after the operation. As part of medical treatment, the patient is supposed to have a normal life, but many patients feel limited and do not feel quite normal when they use medical treatment. In addition to the financial burden, the side effects, interference with hormonal and menstrual cycles and the change of libido are considered more worrying than the lack of efficiency of the drug T (Burla et al., 2021). Consequently, the long-term impact of hormone therapy on their personal life may not be as good as that of surgery, although there is no direct comparison or cost-benefit analysis .
Finally, it is not always very comfortable for a patient to know herself trapped in her treatment, because the disease is still there and will not fail to reappear with symptoms as soon as she stops taking the pill. The fear of inevitable recurrence of severe pain, such as a sword of damocles, can even discourage them from trying to obtain a spontaneous pregnancy, which is probably possible after the treatment of a minimal, light or limited retroperitoneal disease. Thus, IVF can appear as the only alternative to prevent pain risk. However, IVF is not always an acceptable option for many women and this trend could increase because more and more women are looking for more physiological management of their disease and their infertility problems. Adopting a single approach is not a good management strategy, because it amounts to treating everything like a nail when you only have a hammer.
Conclusions
Human beings are notoriously known for their foreseeable irrationality in situations where information is insufficient or simply missing, especially when they are forced or under pressure. When it comes to the patient's decision to choose the treatment modality to be used, the situation is far from simple, swinging a sword of damocles (the persistence of symptoms when stopping the pill) and a Russian roulette (the risk of postoperative complication).
Therefore, when they discuss with their patients, doctors must detail the advantages and disadvantages of all therapeutic options, taking into account the advantages and disadvantages known, while perfectly understanding the predictive irrationality of human beings: they tend to exaggerate the risk of something that they fear deeply, but to minimize the chances of something that they do not know .
At present, EAP surgery is not a failure of medicine, but rather a viable option. At the same time, there is a significant lack of knowledge with regard to the evaluation of the malignant transformation potential under long -term medical treatment and the feasibility of a perioperative intervention intended to reduce the risk of recurrence.
In addition, endometriosis is increasingly considered as a systemic chronic disease (Taylor et al., 2021), there is an unattended research on a new holistic therapy . In addition, given the need for life care, patients with endometriosis can often seek ways to increase their autonomy and alternative therapies, such as the use of dietetics and cognitive behavioral therapy, which have so far received little attention.
Above all, there is a pressing need to develop safe, efficient and satisfactory non-hormonal therapies.
EAP = pain associated with endometriosis
COC = combined oral contraceptives
Eshre - European Society of Human Reproduction and Embryology
Thanks
We would like to thank Professor Dan Martin for his critical reading of a previous version of this manuscript. We thank the two anonymous assessors for their constructive comments and their suggestions on a previous version of this manuscript.
Role of authors
MC and S.-WG jointly designed the idea and wrote the first project. The two authors participated in the research and revision of the article and approved the final version of the article.
Funding
National Foundation of Natural Sciences of China (82071623 at S.- WG); Shanghai Municipality and Technology Commission (2017zz01016 in S.-WG); Shanghai Shenkang Center for Hospital Development (SHDC2020CR2062B in S.-WG).
Conflict of interest
MC has no conflict of interest to declare. S.-WG provided advice to MSD R&D, Chugai Pharmaceutical Co. and Biohaven Pharmaceuticals and is a member of the Heranova BioSciences Scientific Council, but these activities have not implemented this work. The two authors declare that they have nothing to declare.
