The autoimmune bases of infertility and repeated implantation … YANG.pdf · At the meantime, with...

The autoimmune bases of infertility and repeated

implantation failure after IVF/ICSI-ET

Dongzi Yang, M.D., Ph.D. Professor, Chief Physician

Medical center of Human Reproduction, Dept. Ob/Gyn

Memorial Hospital, Sun Yat-Sen University,

Guangzhou, China

The maternal immune system at the time of implantation is characterized by significant immunological changes which play a critical role in successful implantation.

There is a growing interest in using immune-modulating treatments in women with RIF and RPL to correct potential immune imbalances. However, the nature of immune alterations in RIF and RPL remains ill-defined with limited evidence for suitable immune biomarkers to identify patients that may be suited for such immune-modulating treatment.

At the meantime, with few exceptions such as SLE or APS, the impact of autoimmune diseases on reproductive health variables is largely overlooked in clinical practice and in research. the contribution of autoimmunity to impaired fertility remains controversial..

The autoimmune disorders and infertility and RIF

Howard JA Carp, Carlo Selmi, Yehuda Shoenfeld: J Autoimmunity, 2012, 38:J266-J274 Chelsea Fox, Scott Morin, et al: Fertil Steril, 2016, 105(4):873-884

Xian Chen, Yong Zeng, et al: J Reproductive Immunology 2017, 122:14-20 Syed B Ali, Yogesh Jeelall, Graig E Pennell, et al: Am J Ewprod Immunol, 2017, e12784

The key pathophysiological features of Systemic lupus erythematosus (SLE) are the generation of autoantibodies and the deposition of antibody-

antigen complexes in the basal membranes of the organs where they evoke inflammatory responses and injury.

Anti-phospholipid antibodies (aPL) are the serological markers of the anti-phospholipid syndrome (APS), a systemic autoimmune condition characterized by vascular thrombosis and/or pregnancy morbidity.

SLE/APS has been well realized and there has been the guideline for management of SLE/APS patients during their peri-pregnancy.

SLE and APS

Andreoli L, et al. Ann Rheum Dis 2016;0:1–10.

C.B. Chighizola et al. : Autoimmunity Reviews 15 (2016) 493–500

The autoimmune disorders and ART

ARTs are generally safe for SLE/APS patients if the patient has quiescent disease

In women with APS (primary or SLE-APS), risk factors include high-risk aPL profile (lupus anticoagulant, multiple aPL, moderate to high titre aPL) (1/A), coexisting SLE (2/B), history of vascular/thrombotic APS (2/B) and of previous adverse pregnancy complications (2/B).

Appropriate antithrombotic treatment if aPL positive， some general measures for prophylaxis such as the type(low-dose aspirin (LDA); low molecular weight heparin(LMWH)) and dosage (prophylactic vs full anticoagulant) of antithrombotic treatment in aPL-positive women undergoing ovarian stimulation has been suggested.

Andreoli L, et al. Ann Rheum Dis 2016;0:1–10.

Howard JA Carp, Carlo Selmi, Yehuda Shoenfeld: J Autoimmunity, 2012, 38:J266-J274

Chelsea Fox, Scott Morin, et al: Fertil Steril, 2016, 105(4):873-884

Xian Chen, Yong Zeng, et al: J Reproductive Immunology 2017, 122:14-20

Numerous autoimmune diseases, including but not limited to SLE and APS, may be associated with infertility and pregnancy loss

The process involve microvascular pathology, prethrombotic state, inflammation and immune reaction in endometrium, villus and deciduas.

The normal condition

Positive auto

antibodies

Symptom and sign of connective

tissue disease

Undifferent-iated

connective tissue

disease（UCTD）

Connective tissue

disease （SLE,APS）

The progression of autoimmune diseases

Outline

The role of auto antibody mediated

autoimmune disorders in infertility and RIF.

Immune modulation treatments in ART and RIF

Outline

Immune modulation treatments in RIF

Autoimmune diseases may be associated with infertility and pregnancy loss through different putative mechanisms.

First, serum autoantibodies such as anti-phospholipid(aPL), anti-thyroid, or antinuclear antibodies(ANA) may be directly associated with infertility, regardless of the presence of a clinically overt autoimmune disease.

Second, autoimmunity may affect all stages of fertility, via ovarian failure, testicular failure, implantation failure, and pregnancy loss.

Third, infertility may also be secondary to vasculitis associated

with other conditions such as SLE and diabetes mellitus

The autoimmune disorders and infertility and RIF

Howard J.A. Carp , Carlo Selmi , Yehuda Shoenfeld: Journal of Autoimmunity 38 (2012) J266eJ274

Khaled M. Zohni, Itai GAT, Clifford Librach, Minerva Ginecologica, 2016,Decem. 68(6):653-67

Auto-immune disease is one of the factors of RIF

Evidence-base investigations for patients with RIF

Immunological Screening Proposal

Mekinian A, et al. Am J Reprod Immunol. 2016;76(1):8-28.

There are few studies demonstrating a physiopathological implication of these detectable autoantibodies, but their presence could help the physician to discuss the need for immunomodulatory strategy.

Pregnancy test results

Viable pregnancy

Case control studies on APS and ART outcome

Di Nisio M, et al. Blood. 2011;118(10):2670-2678.

The relationship between ART failure and thrombophilia remains largely inconclusive. But all the studies were with small number of patients.

Live birth

Di Nisio M, et al. Blood. 2011;118(10):2670-2678.

Case control studies on APS and ART outcome

Chighizola CB, et al. Autoimmun Rev. 2016;15(6):493-500.

Meta analysis of APS and ART outcome

Chighizola CB, et al. Autoimmun Rev. 2016;15(6):493-500.

Anti-phospholipid syndrome and ART outcome

Conclusions:

No association between anti-phospholipid antibodies (aPL)

positivity and ART outcome in the majority of studies.

aPL should not be included in the investigation of women

undergoing ART.

Inclusion of healthy controls and spontaneous pregnancy could have led to a biased comparison.

APA positivity can occur as a transient epiphenomenon during ovarian stimulation for ART（false positive）.

The lack of confirmation of persistence of APAs can be regarded a serious limitation of all these studies, leading to overestimation of an effect of APAs on ART outcome.

Possible explanations

Ata B, et al. J Assist Reprod Genet. 2016;33(10):1305-1310.

APA testing should be standardized, with regard to both APAs to be tested and cut-off levels for positivity.

Study populations should be standardized, e.g., women undergoing

ART versus women with recurrent implantation failure. APA positivity should be confirmed on two separate occasions as

suggested in the Sapporo criteria. APA testing should be required 6～12 weeks before ovarian

stimulation.

Future studies

Signs and symptoms suggestive of a rheumatic disorder, but that do not fulfill the established criteria for a rheumatic disease;

The presence of antinuclear antibodies (ANA) at a titer ≥1:80

The definition

● Undifferentiated connective tissue diseases (UCTD) are probably relatively common among women of reproductive age and can be frequently encountered by obstetricians both before and during pregnancy.

Spinillo A, et al. Am J Reprod Immunol. 2017 Dec;78(6).

Undifferentiated connective tissue disease (UCTD)

Biological mechanisms causing poor reproductive outcome in UCTD

the auto-antibodies increase thrombosis of placental vessels, defective placentation, defective trophoblast invasion.

The term defines any condition associated with an increased risk of thrombosis.

Microvascular occlusion at the decidua due to thrombophilia has

been suggested as a potential cause of implantation failure in ART cycles.

The changes in ovarian stimulation for ART increase the risk for

thrombosis and thromboembolism. Damage of decidual or chorionic vessels, or reduction of trophoblast

invasiveness, could prevent embryo implantation.

Thrombophilia

Zohni KM. Minerva Ginecol. 2016;68(6):653-667.

Thrombophilia and RIF

The association between trombophilia and RIF were uncertain

Most were case-control studies.

The overall methodologic quality was poor.

Only a few of the case-control studies used a representative control.

Bates SM. Hematology Am Soc Hematol Educ Program. 2014;2014(1):379-386.

The research of Thrombophilia and RIF

A prospective cohort analysis of the association between Individual and cumulative thrombophilic single nucleotide polymorphisms and IVF outcome .

1717 patients, 4169 embryos, the first fresh cycle of IVF

Patounakis G, et al. J Assist Reprod Genet. 2016;33(1):67-73.

Thrombophilic genotypes and IVF outcome

● Individual and cumulative thrombophilic single nucleotide polymorphisms do not affect IVF outcomes.

The relationship of congenital thrombophilia with ART outcome is dubious.

Testing for and treatment of congenital thrombophilia are not indicated in patients undergoing ART in the absence of a personal or family history of venous thromboembolism.

Current evidence does not support routinely testing or treatment for thrombophilia in the setting of ART nor in couples with implantation failure.

Thrombophilia and ART outcome

A prospective cohort study, first IVF/ICSI treatment

Chen X, et al. J Reprod Immunol. 2017;122:14-20.

A prospective cohort study of auto-antibodies

The presence of aCL-IgG, aCL-IgM and aβ2GPI-IgG might exert a

detrimental effect on IVF/ICSI outcomes.

Chen X, et al. J Reprod Immunol. 2017;122:14-20.

A prospective cohort study of autoantibodies

Percentage of abnormally elevated antiphospholipid antibody serum concentrations including anticardiolipin antibodies (CL,ACA),antiphospatidylethanolamine (PE), antiphosphatidylinositol, antiphosphatidic acid (PA), antiphosphatidylglycerol (PG), antiphopatidylcholine(PC), and antiphosphatidylserine (PS) among groups.

A =IgG, B =IgM, and C =IgA

Sauer. Correspondence. Fertil Steril 2010.

Age (years) 36.46±4.64

BMI (kg/m2) 21.91±2.95

FSH (IU/L) 9.68±5.13

LH (IU/L) 4.68±3.54

AMH (μg/L) 3.02±3.65

Duration of infertility (years) 6.81±3.91

Total cycles 4.61±2.22

Unpublished data from Sun Yat-Sen Memorial Hospital,Sun Yat-Sen University, 2015-2018

Baseline condition of 337 RIF patients in our center

Recurrent implantation failure refers to failure to achieve a clinical pregnancy after transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40 years . C Coughlan， et al: Reproductive BioMedicine Online (2014) 28, 14– 38

74.06%

61.07%

25.86%

25.29%

18.48%

12.43%

11.72%

11.11%

0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% 80.00%

Natural killer cell↑

Platelet aggregation function↑

Anti-thyroglobulin antibody↑

Anti-thyroid peroxidase antibody↑

Antinuclear antibody（+）

Anti-β2-glycoprotein1 antibody（+）

D-Dimer↑

Protein C↓

Antithrombin III activity↓

Protein S↓

Anti-dsDNA antibody（+）

Anti-a-Fodrin A antibody（+）

Anticardiolipin IgG antibody（+）

Anti-C1q antibody (+)

Anti-nucleosome antibody（+）

Abnormity rate

Immunological and coagulation function of 337 patients with RIF from 2015-2018

For those RIF patients with positive auto-antibodies without typical symptoms and signs of autoimmune diseases, the immune modulating treatment remains uncertainty and controversy.

Positive auto

antibodies

tissue disease

Undifferent-iated

connective tissue

disease（UCTD）

Connective tissue

The progression of autoimmune diseases

Outline

Immune modulation treatments in ART and RIF

Antirheumatic drugs

Intravenous immunoglobulin (IVIg)

Corticosteroids

Low dose of Aspirin (LDA)

Low molecular weight heparin(LMWH)

Immune modulation treatments

EULAR (european league against rhumatism) recommendations for SLE/APS

Andreoli L, et al. Ann Rheum Dis. 2017;76(3):476-485.

EULAR recommendations for ART in SLE/APS patients

Pregnancy rate is comparable with that in the general population (up to 30%).

Assisted reproduction techniques are generally safe if the patient

has quiescent disease and is on appropriate antithrombotic treatment if antiphospholipid antibodies positive.

The type (low-dose aspirin (LDA); low molecular weight heparin (LMWH) and dosage (prophylactic vs full anticoagulant) of antithrombotic treatment should be recommended as during pregnancy according to the individual risk profile.

Assisted reproduction techniques

EULAR recommendations for antithrombotic treatment during ART in SLE/APS patients

LDA should be stopped three days before egg retrieval and resumed the following day.

Patients taking LMWH should stop it at least 12 hours prior to the procedure and resume it the very same day as long as there is no bleeding.

Patients with positive antiphospholipid antibodies who are not taking LDA during the ovarian stimulation period should start LDA on the day of the embryo transfer, usually in combination with LMWH (which will be continued during pregnancy).

The antithrombotic treatment

ART outcome in SLE/APS patients

18 cases，8 of them got live birth after ART. One of them tried 4 cycles of IVF-ET . All took antirheumatic drugs, LDA and LMWH during ART.

age obstetrical history

AMH(ng/ml)

Immune antibody

diagnosis COH Protoc

No. egg

No.Availble

embryos

ET pregnancy

outcome

others

30 G0P0 补体C3 1180mg/L 补体C4 165mg/L ESR 50↑mm/h

ANA 1.51 抗dsDNA 0.845

Infertility, SLE, PCOS, MS Long protocol INF

10 7 2 No pregnancy

SLE flair

32 G0P0 2.12 未查及检查报告 Infertility, SLE, EM Long protocol IVF

14 12 2

Live birth single

32 G2A2，自然流产2次

1.52 ANA+阳性斑点型抗dsDNA 弱阳性炎症TNFa 9.44↑

Infertility, SLE, RSA, IR 双侧输卵管炎

OI IVF 4 3 取消鲜胚移植宫腔因素 (内膜薄)

2015-11 NC+FET2个

Live birth twin

33 G0P0 3.82 ANA++阳性斑点型抗dsDNA 弱阳性 ESR 40mm/h炎症

ANA 3.328 ↑ 抗dsDNA 3.159↑

Infertility, SLE Antagonist protocol IVF

12 取消移植宫腔因素 (内膜薄)

2016-3 NC+FET 2个

Clinical pregnancy

Spontaneous

abortion

35 G0P0 1.04 补体C3 669mg/L 补体C4 72↓mg/L

ESR 20mm/h ANA 3.572↑

抗dsDNA 2.007↑

Infertility, SLE 盆腔粘连（松解术后）

双侧输卵管阻塞多发性子宫内膜息肉（电切术

后）不完全子宫中隔（电切术后）

CIN III（锥切术后）

子宫腺肌症

Antagonist protocol IVF

4 取消移植珍贵胚胎 2016-3 促排周期

FET3个

Clinical pregnancy

Spontaneous

abortion

SLE flair

32 G1A1，自然流产1次

0.57 未查及检查报告 Infertility, POI SLE

Mild stimulation IVF+ICSI

5 2 2 Biochemical

pregnancy

37 Infertility, POI SLE

Mild stimulation ICSI

2 2 2 Live birth single

24 G3A1E2，人流1次，异位妊娠2

3.5 补体C3 626↓mg/L 补体C4 57↓mg/L

ESR 15mm/h ANA 4.52↑

抗dsDNA 2.23↑

双侧输卵管缺如（切除术后）宫颈轻度鳞状上皮不典型增生

Long protocol IVF

14 12 2 Live birth single

ART outcome of SLE/APS patients in our clinic

Averag age of 32 year，clinical pregnancy rate 75%， live birth rate 50%，SLE flare in 2 cases during ART

The challenges of the diagnosis and interventions of undifferentiated autoimmune disorders

For those atypical autoimmune disorders with infertility, their diagnosis is still not well defined and the evidence for the management is weak

Positive auto

antibodies

tissue disease

Undifferent-iated

connective tissue

disease（UCTD）

Connective tissue

Khaled M. Zohni, Itai GAT, Clifford Librach, Minerva Ginecologica, 2016,Decem. 68(6):653-67

Identifying the patients for proper interventions

Interventions for RIF and their benefit

Zohni KM. Minerva Ginecol. 2016;68(6):653-667.

Immune modulation treatments

indications

Treatment of UCTD with infertility

All types of studies investigating the effects of IVIG

alone or in conjunction with heparin or aspirin on IVF

or ICSI outcomes were included. The use of IVIG was

in the random effects model in comparison with placebo

or no treatment.

Li J, et al. Am J Reprod Immunol. 2013;70(6):434-447.

IVIg in RIF and ART outcome

Am J Reprod Immunol 2013; 70: 434–447

IVIg in RIF and ART outcome Implantation rate

Live birth rate

Clinical pregnancy rate

Miscarriage rate

IVIG is a useful treatment option for women undergoing repeated IVF failure.

Li J, et al. Am J Reprod Immunol. 2013;70(6):434-447.

The use of IVIG was associated with a significantly higher implantation rate, and the RR was 2.708 (95%CI: 1.302–5.629, I2 = 65.0%) in the random effects model in comparison with placebo or no treatment.

The use of IVIG was associated with a significantly higher pregnancy rate, and the RR was 1.475 (95%CI: 1.191–1.825, I2 = 65.7%) in the random effects model.

The use of IVIG was effective in increasing the rate of live birth compared with placebo or no treatment, and the pooled RR was 1.616 (95%CI: 1.243–2.101, I2 = 58.2%) in the random effects model.

The use of IVIG was effective in decreasing the rate of miscarriage compared with placebo or no treatment

Nardo LG, et al. Hum Fertil (Camb). 2015;18(1):2-15.

Guidance and recommendations

Increased number of peripheral natural killer cells or cytotoxicity Abnormal T helper (Th)1:Th2 ratio Positive anti-thyroid antibody or anti-phospholipid antibody (APL)

test Increased TNF-α level or human leukocyte antigen (HLA) antigens

similarity

Indications for Intravenous immunoglobulin(IVIG)

Elevated NK cells Presence of auto-antibodies including ACA, anti-thyroid, ANA and

anti-ovarian antibodies

There is a lack of robust evidence to support the routine use of corticosteroids empirically as an adjuvant in IVF cycles.

There is limited evidence that corticosteroids may improve pregnancy rates in women undergoing conventional IVF and in the subgroup of women with auto-immunity or unexplained implantation failure.

Corticosteroids

Recommendation

Various studies and seven meta-analyses have provided conflicting evidence.

There is lack of proven efficacy for routine use of aspirin as an adjuvant in IVF cycles.

Aspirin

Recommendation

Three meta-analyses evaluating the efficacy of heparin in women undergoing IVF treatment cycles, albeit having a different objective, gave similar results.

Evidence for the efficacy of LMWH is weak such that its routine use in the wide population of women undergoing IVF treatment is not warranted. However, it should be carefully considered in women with thrombophilia.

Heparin

Recommendation

Sung N, et al. Clin Exp Reprod Med. 2017;44(1):1-7.

Guidelines for IVIG from Korean

Clin Exp Reprod Med 2017;44(1):1-7

Guidelines of IVIG

400 mg/kg per each treatment Every 3 to 4 weeks from the early stage of pregnancy in

women with RPL or from the beginning of the IVF cycle for RIF patients (evidence level C).

● The end-point of IVIG treatment and the need for further laboratory tests can be determined by the clinician’s decision, depending on the patient’s state.

The recommended protocol for IVIG

Prior to IVIG infusion in all patients, the blood level of immunoglobulin A must be determined and renal function tests are required.

Mild side effects: fever, malaise, myalgia, and headache. Severe side effects: myocardial infarction, renal failure,

alopecia, aseptic meningitis, and renal necrosis. With the proper regimen of IVIG in well-selected patients, the

occurrence of side effects is very rare. There is no report of significant side effects in neonates.

The safety of IVIG therapy

Boomsma CM, et al. Cochrane Database Syst Rev. 2012;(6):CD005996.

Cochrane Database of Systematic Reviews Corticosteroids

Cochrane Database of Systematic Reviews 2017, Issue 3. Art. No.: CD004752. DOI: 10.1002/14651858.CD004752.pub2

Kalampokas T, et al. Cochrane Database Syst Rev. 2017;3:CD004752.

There is insufficient evidence to determine the effectiveness of glucocorticoid administration in women undergoing IVF/ICSIcycle.

Corticosteroids

Cochrane Database of Systematic Reviews 2017, Issue 3. Art. No.: CD004752. DOI: 10.1002/14651858.CD004752.pub2

Robertson SA, et al. Hum Reprod. 2016;31(10):2164-2173.

Human Reproduction, Vol.31, No.10 pp. 2164–2173, 2016

Corticosteroids

Population: 2653 women with subfertility Intervention: Low-dose aspirin Comparison: Placebo or no treatment. An identical dose of the intervention was administered in most of the

studies and most reported a similar timing of the initiation of aspirin intake.

The duration of trial varied across the studies, but was sufficient to

provide data on the reported outcomes.

Siristatidis CS, et al. Cochrane Database Syst Rev. 2016;11:CD004832.

Key results: There was no evidence of a difference between

the groups in rates of live birth, clinical pregnancy, ectopic

pregnancy, multiple pregnancy, miscarriage or vaginal bleeding.

Conclusion: There is no evidence to support the use of LDA

treatment in order to improve pregnancy rates for a general

IVF population.

Low Dose Aspirin (LDA)

Cochrane Database of Systematic Reviews 2016, Issue 11. Art.

No.: CD004832.DOI: 10.1002/14651858.CD004832.pub4.

Hviid MM, et al. Fertil Steril. 2017;107(6):1284-1293.

differ significantly in design, participants, intervention, and outcome measures

Overview of RCT’s testing Aspirin intervention

Treatment with low-dose aspirin does not improve pregnancy

outcome in terms of implantation, clinical pregnancy, ongoing

pregnancy, or live-birth rates in an unselected population of

women undergoing IVF or ICSI.

The available studies differ significantly in design, participants,

intervention, and outcome measures, making the conclusions

drawn from these studies hard to interpret.

Low Dose Aspirin (LDA)

Potdar N, et al. Hum Reprod Update. 2013;19(6):674-684.

A significant improvement in the LBR and a reduction in the miscarriage rate in RIF patients with LMWH compared with controls.

Conclusion: In women with ≥3 RIF, the use of adjunct LMWH significantly improves LBR by 79% compared with the control group.

This is to be considered with caution, since the overall number of

participants in the studies was small. Further evidence from adequately powered multi-centered RCTs is

required prior to recommending LMWH for routine clinical use.

Potdar N, et al. Hum Reprod Update. 2013;19(6):674-684.

The evidence supporting the value of heparin as a putative

effective immuno modulating treatment in IVF is weak.

There may be some support for its use in a younger group of

women with three or more failed attempts and at least one

thrombophilia disorder, but further high-quality trials are required

before this can be advocated.

A six-center two-arm retrospective cohort study, but still small sample size.

The addition of LMWH at the day of ET until the β-HCG test

Siristatidis C, et al. Gynecol Endocrinol. 2018 Feb 21:1-5.

Different voice about LMWH

There is no evidence to

support the standard

addition of LMWH in

patients with two or more

unsuccessful IVF/ICSI

cycles.

Siristatidis C, et al. Gynecol Endocrinol. 2018 Feb 21:1-5.

Given the lack of evidence to support improved IVF outcomes,

there is good evidence to recommend against the routine use of low-dose aspirin to improve the outcome of live birth in ART cycles in the general population.(Grade A). There is good evidence to recommend against the routine use of corticosteroids during stimulation to improve the outcome of live birth in ART cycles in the general population.(Grade A). There is good evidence to recommend against the routine use of corticosteroids during the implantation window to improve the outcome of live birth in ART cycles in the general population.(Grade A). There is insufficient evidence to recommend for or against local G-CSF to improve endometrial thickness in women with thin endometrium or clinical pregnancy rates with IVF (Grade C). There is insufficient evidence to recommend for or against G-CSF or GM-CSF administered locally or systemically to improve IVF outcomes. (Grade C). There is insufficient evidence to routinely recommend intravenous fat emulsions for infertile women pursuing IVF. (Grade C). There is insufficient evidence to recommend IVIG administration as part of IVF to improve IVF outcomes. (Grade C).

Practice Committee of the American Society for Reproductive Medicine: Fertil Steril 2018;110:387–400

Agaist the routine use immunotheapy in unselected population

The role of immunotherapy in in vitro fertilization: a guideline of ASRM

Conclusions The role of auto antibody mediated autoimmune diseases in infertility and

RIF remains an area of active investigation. The impact of autoimmune diseases on ART outcome, the testing evaluation, as well as the intervention remains controversial.

In women with autoimmune diseases such as SLE/APS, UCTD, the thrombophilia may be the potential cause of adverse fertility outcome. Antithrombotic treatment is recommeded in those patients undergoing ovarian stimulation. The routine use of immuno-therapy in unselected population has been against .

Evidence for the Immunological Screening in RIF needed further reseach. The study in this field should be standardized in the perspectives of antibody testing,cut-off levels for positivity, study populations .

Well designed large sample RCT is needed for the evidence-base of immunotheapy.

My colleagues and postgraduates Perticularly to：

Professor Dai Lie, Dr. Pan Ping, Dr.Liang Zhu

Thanks

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

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