A European survey on treatment of hydrosalpinges in infertile women on behalf of the European Society for Gynaecological Endoscopy (ESGE) Special Interest Group (SIG) on Reproductive Surgery.

A questionnaire-based survey was conducted among members of the European Society for Gynaecological Endoscopy (ESGE), with the aim of increasing awareness of the diagnosis and surgical treatment of tubal disease as an alternative to in-vitro fertiliszation (IVF). Seventeen participants (34%) occasionally used a test for prediction of the ovarian reserve before surgery, and the most commonly used test was anti-mullerian hormone assay (39/50; (80%). Laparoscopy was the preferred method for staging tubal disease (43/50; 86%).Thirty-seven (76%) participants always performed salpingectomy or tubal occlusion before the first IVF attempt. Thirty (60%) of the gynaecological surgeons considered the outcome with tubal surgery and IVF to be similar in mild tubal disease, whereas for severe disease, 31/50 (62%) felt that surgery had worse outcome. Among other factors to be considered in choosing a strategy for treating infertility, 20/50 (40%) of respondents listed the stage of disease. The findings of this survey suggest that first-line treatment for women younger than 35 years old with minor tubal pathology, is tubal surgery. IVF appears to be offered if there are other infertility factors, if the patient is >38 years old and if moderate to severe tubal disease is present.

A European survey on the conservative surgical management of endometriotic cysts on behalf of the European Society for Gynaecological Endoscopy (ESGE) Special Interest Group (SIG) on Endometriosis.

The mainstay of endometrioma management, when treatment is required, is surgical. Although laparoscopy is considered to be the gold standard for endometriosis surgery, there is no clarity on the preferred laparoscopic technique, which may depend on whether the primary goalis treatment of infertility or pelvic pain, prevention of recurrence or preservation of ovarian reserve. The aim of this survey to assess the surgical practice of the members of the European Society for Gynaecological Endoscopy (ESGE) on the conservative management of endometiotic cysts in women of reproductive age. The current survey showed that practice for the conservative management of endometriotic cysts was that laparoscopy accounted for 84.9% of the cases, expectant management for 12.1%, and laparotomy for 3%. The preferred surgical approach was cystectomy in 69% of the cases, while the parameters that determined the preferred surgical method were the diameter of the cyst (62%) and the bilaterality or non-location (53%). The type of energy used was in most cases bipolar (83%), 71.4% of surgeons did not reconstitute the ovary and 41% of responses included the administration of adhesion barrier agents. The primary surgical end-point was ovarian reserve (50%), which was tested preoperatively in 51.8%, mainly with an anti-mullerian hormone. In case of an incidentally deep-infiltrating endometriosis, 55.4% of the responses included concomitant treatment thereof, while 71% of the participants considered that a "pelvic surgeon", who could more effectively treat co- existing pelvic and intestinal disease, should be the ideal one to effectively manage endometriosis. The majority of participants (74%) in this survey consider that there is insufficient scientific evidence regarding the conservative management of endometriotic cysts. The treatment of ovarian endometrioma should be individualised, taking into consideration not only the relief of symptoms, pregnancy rates or recurrence rates, but also ovarian function and reserve after surgery.

Incidence of unexpected uterine malignancies after electromechanical power morcellation: a retrospective multicenter analysis in Germany.

PURPOSE: During the last decade, electromechanical power morcellation (EMM) was more frequently used but it may be associated with the dissemination of occult malignancies. The aim of the present study was to determine the frequency of unexpected uterine malignancies after EMM. METHODS: This retrospective study consisted of patients who were treated at three departments of Gynecology in Germany from 2008 to 2017. We identified women who underwent an operation with the use of EMM. Clinical records, risk factors, and the outcomes of the patients were reviewed. RESULTS: We performed an analysis of 1683 patients who had undergone laparoscopic supracervical hysterectomy (LASH), total hysterectomy, or myomectomy (LM) (48.6%, 8.4%, and 43.0%, respectively). Unexpected malignancies were detected in 4 of 1683 patients (0.24%). In all cases, the malignancy proved to be a sarcoma and was detected after LASH. All patients with occult sarcomas were older than 45 years and the most common (75%) risk factor was the appearance of a solitary tumor. The patients underwent secondary laparotomy for complete oncological staging, and no histological dissemination of the sarcoma was registered. Two patients had a recurrence. At the final follow-up investigation all four patients were in good general health. CONCLUSION: Occult malignancies are liable to spread after EMM, although the overall risk of being diagnosed with an occult malignancy and the risk of dissemination appear to be low. Once the preoperative diagnostic investigation has yielded no suspicious findings, laparoscopic morcellation may be considered a safe method, especially LM in patients of reproductive age.

Prevalence of occult leiomyosarcomas and atypical leiomyomas after laparoscopic morcellation of leiomyomas in reproductive-age women.

STUDY QUESTION: What is the prevalence of leiomyosarcomas and atypical leiomyomas after laparoscopic morcellation of fibroids in reproductive age women? SUMMARY ANSWER: No case of leiomyosarcomas but seven atypical leiomyomas were found in 1216 subjects. WHAT IS KNOWN ALREADY: Although uterine sarcoma is a rare entity affecting usually older peri- or post-menopausal women, the Food and Drug Administration discourages use of laparoscopic power morcellation of uterine fibroids. STUDY DESIGN, SIZE, DURATION: Retrospective review of data extracted from a single center database of 1216 consecutive women who underwent laparoscopic morcellation of 2582 unsuspicious leiomyomas between June 2003 and December 2015 and were followed-up until December 2016. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: A total of 1216 women, aged 18-45 years, underwent laparoscopic morcellation of 2582 apparently benign leiomyomas by the same surgeon and all specimen slides were examined by the same experienced pathologist. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of leiomyosarcomas and atypical leiomyomas was 0% (95% CI: 0-0.3%) and 0.6% (95% CI: 0.23-1.18%) (six atypical-bizarre and one mitotically active leiomyoma) respectively. In addition, there were identified 34 cases of adenomyomas, 45 leiomyomas with infarcts, 81 cellular leiomyomas and 133 degenerated leiomyomas. No morcellator-associated complication was recorded and none of the patients included in this study required conversion to laparotomy. LIMITATIONS, REASONS FOR CAUTION: Retrospective and single referral center study design. WIDER IMPLICATIONS OF THE FINDINGS: Laparoscopic morcellation of unsuspicious leiomyomas after careful preoperative work up seems to be safe in women of reproductive age. STUDY FUNDING/COMPETING INTEREST(S): None.

Novasure impedance control system versus microwave endometrial ablation for the treatment of dysfunctional uterine bleeding: a double-blind, randomized controlled trial.

PURPOSE OF INVESTIGATION: To compare the efficacy and safety of two different second-generation ablation devices, Novasure impedance control system and microwave endometrial ablation (MEA), in cases of abnormal uterine bleeding (AUB). MATERIALS AND METHODS: This is a randomized controlled trial that took place in a single Gynecological Department of a University Hospital. Sixty-six women with dysfunctional uterine bleeding (DUB), unresponsive to medical treatment, were included in the trial. The ratio of women allocated to bipolar radio-frequency ablation or MEA was 1:1. Follow-up assessments were carried out at three and 12 months post-ablation. The present main outcome measure was amenorrhea rates 12-months post-treatment. RESULTS: The rate of amenorrhea at 12-months post-ablation was significantly higher in women treated by Novasure (25/33; 75.8%) as compared to those treated by MEA (8/33; 24.2%) (rate difference: +51.5%, 95% CI: +27.8 to +67.7). CONCLUSION: In women with DUB, endometrial ablation with Novasure bipolar radiofrequency impedance-controlled system is associated with increased rates of amenorrhea at 12-months post-treatment as compared to the MEA method.

Immune system function, stress, exercise and nutrition profile can affect pregnancy outcome: Lessons from a Mediterranean cohort.

Pregnancy is associated with major physiological and future psychosocial changes, and maternal adaptation to these changes is crucial for normal foetal development. Psychological stress in pregnancy predicts an earlier birth and lower birth weight. Pregnancy-specific stress contributes directly to preterm delivery. The importance of nutrition and exercise during pregnancy with regard to pregnancy outcome has long been acknowledged. This importance has only been further emphasized by the recent changes in food quality and availability, lifestyle changes and a new understanding of foetal programming's effects on adult outcomes. We hypothesised that for a successful pregnancy certain events at a nutritional, immune, psycho-emotional and genetic level should be tightly linked. Therefore, in this study we followed an 'integrative' approach to investigate how maternal stress, nutrition, pregnancy planning and exercise influence pregnancy outcome. A key finding of our study is that there was a significant reduction in the intake of alcohol, caffeine-containing and sugary drinks during pregnancy. However, passive smoking in the household remained unchanged. In terms of immune profile, a significant inverse correlation was noted between difficulty to 'fight' an infection and number of colds (r=-0.289, P=0.003) as well as the number of infections (r=-0.446, P<0.0001) during pregnancy. The vast majority of the pregnant women acquired a more sedentary lifestyle in the third trimester. In planned, but not in unplanned, pregnancies stress predicted infant weight, independent of age and body mass index (BMI). Notably, in mothers with negative attitudes towards the pregnancy, those with an unplanned pregnancy gave birth to infants with significantly higher weights than those with planned pregnancies. Collectively these data suggest that there is a higher order of complexity, possibly involving gene-environment interactions that work together to ensure a positive outcome for the mother as well as the foetus.

Laparoscopic management of unexpected borderline ovarian tumors in women of reproductive age.

PURPOSE OF INVESTIGATION: The aim of this study was to review the clinical features of women with unexpected borderline ovarian tumours. METHODS: Between October 1992 and December 2010, 1332 out of 4016 laparoscopies were performed for adnexal masses in women of reproductive age and 1838 cysts were removed. When ultrasonographic findings did not meet the criteria for low risk malignancy, tumour markers, colour Doppler and MRI/CT were applied. At laparoscopy any solid component or papilla was sent for rapid frozen section. RESULTS: Borderline ovarian tumours were found in eight (0.6%) out of 1332 patients, two of which were bilateral. The mean age was 28.75 +/- 9.27 years and the mean diameter of the cysts was 5.1 +/- 1.7 cm. In two cases unexpected malignancy was discovered during the diagnostic and in six cases during the operative phase of the intervention. CONCLUSION(S): Risk of failure to diagnose cancer could be minimised with careful patient selection preoperatively. Adequate training on laparoscopic oncology is the necessary prerequisite for a safe laparoscopic approach.

GnRH-agonist versus GnRH-antagonist IVF cycles: is the reproductive outcome affected by the incidence of progesterone elevation on the day of HCG triggering? A randomized prospective study.

BACKGROUND: In view of the current debate concerning possible differences in efficacy between the two GnRH analogues used in IVF stimulated cycles, the current study aimed to explore whether progesterone control in the late follicular phase differs when GnRH antagonist is used as compared with GnRH agonist, and if so, to what extent the progesterone rise affects the probability of pregnancy. METHODS: Overall 190 patients were randomized: 94 in the GnRH-agonist group and 96 in the GnRH-antagonist group. The GnRH-agonist long protocol started on Day 21 of the preceding cycle with intranasal buserelin (600 mg per day). The GnRH-antagonist protocol started on Day 6 of the stimulation with ganirelix or cetrorelix (each 0.25 mg). All blood samples were analysed with the Elecsys analyzer. An intention-to-treat analysis was applied. RESULTS: A progesterone rise >1.5 ng/ml was noticed in 23.0% of the antagonist group, comparable with 24.1% incidence within the agonist group. Per patient randomized, delivery rates were also comparable: 28.1% in the antagonist group and 24.5% in the agonist group (odds ratio = 1.21, 95% confidence interval: 0.63-2.31, P= 0.56). However, there was a reduction in delivery rates when progesterone exceeded the threshold of 1.5 ng/ml, both in the agonist group (9.5 versus 31.8%, P= 0.03) and in the antagonist group (14.3 versus 34.3%, P= 0.07). CONCLUSIONS: Although the incidence of a progesterone rise was similar between the two analogues, our findings reconfirm previous observations that insufficient progesterone control (>1.5 ng/ml) on the day of ovulation triggering is related to poor delivery rates in both protocols. The current study has shown that the reproductive outcomes with the two GnRH analogues are comparable. Possible modes of action to circumvent late follicular progesterone rise should be explored. TRIAL REGISTRATION NUMBER: NCT01191710.

Obstetric and neonatal outcome after assisted fertilization and spontaneous conception: a comparative study.

PURPOSE: The widespread use of assisted reproduction technology (ART) is accompanied by concerns for potential adverse outcomes. The aim of the present study was to evaluate the impact of ART in obstetric and neonatal outcome. METHODS: Data from labor ward records from 913 consecutive births were analyzed retrospectively, and the obstetric and neonatal outcomes of pregnancies after ART were compared with those after natural conception. RESULTS: No major complications were noted after ART. A higher probability of cesarean section, lower gestational age at birth, lower birth weight and hospitalization in the Neontal Intensive Care Unit (NICU) was noted after ART, as compared with spontaneous conception. However, after exclusion of multifetal pregnancies, there was no significant difference in outcomes, except for cesarean section rates. CONCLUSIONS: The higher proportion of multiple pregnancies after ART is associated with lower gestational age at birth, lower birth weights and higher NICU hospitalization rates.

Gynaecological endoscopic evaluation of 4% icodextrin solution: a European, multicentre, double-blind, randomized study of the efficacy and safety in the reduction of de novo adhesions after laparoscopic gynaecological surgery.

BACKGROUND: Gynaecological laparoscopic surgery outcomes can be compromised by the formation of de novo adhesions. This randomized, double-blind study was designed to assess the efficacy and safety of 4% icodextrin solution (Adept(®)) in the reduction of de novo adhesion incidence compared to lactated Ringer's solution (LRS). METHODS: Patients undergoing laparoscopic surgery for removal of myomas or endometriotic cysts were treated with randomized solution as an intra-operative irrigant and 1l post-operative instillate. De novo adhesion incidence (number of sites with adhesions), severity and extent were independently scored at a second-look procedure and the efficacy of the two solutions compared. The effect of surgical covariates on adhesion formation was also investigated. Initial exploratory analysis of individual anatomical sites of clinical importance was progressed. RESULTS Of 498 patients randomized, 330 were evaluable (160 LRS--75% myomectomy/25% endometriotic cysts; 170 Adept--79% myomectomy/21% endometriotic cysts). At study completion, 76.2% LRS and 77.6% Adept had ≥ 1 de novo adhesion. The mean (SD) number of de novo adhesions was 2.58 (2.11) for Adept and 2.58 (2.38) for LRS. The treatment effect difference was not significant (P = 0.909). Assessment of surgical covariates identified significant influences on the mean number of de novo adhesions regardless of treatment, including surgery duration (P = 0.048), blood loss in myomectomy patients (P = 0.019), length of uterine incision in myomectomy patients (P < 0.001) and number of suture knots (P < 0.001). There were 15 adverse events considered treatment-related in the LRS patients (7.2%) and 18 in the Adept group (8.3%). Of 17 reported serious adverse events (9 LRS; 8 Adept) none were considered treatment-related. CONCLUSIONS: The study confirmed the safety of Adept in laparoscopic surgery. The proportion of patients with de novo adhesion formation was considerably higher than previous literature suggested. Overall there was no evidence of a clinical effect but various surgical covariates including surgery duration, blood loss, number and size of incisions, suturing and number of knots were found to influence de novo adhesion formation. The study provides direction for future research into adhesion reduction strategies in site specific surgery.

Prevention of intra-peritoneal adhesions in gynaecological surgery: theory and evidence.

Post-operative adhesions are a significant complication of all abdominal surgical procedures. The major strategies for adhesion prevention in gynaecological surgery are focused on the optimization of surgical technique and use of anti-adhesive agents, which fall into two main categories: pharmacological agents and barriers. Surgical technique that minimizes peritoneal trauma can reduce, but cannot prevent post-operative adhesion formation. Various local and systemic drugs that can alter the local inflammatory response, inhibit the coagulation cascade and promote fibrinolysis have been evaluated. Limited data support the administration of post-operative corticosteroids in addition to systemic intra-operative corticosteroids for the prevention of adhesions after gynaecological surgery. None of the remaining pharmacological agents have been found effective for the reduction of post-operative adhesions. Barriers are currently considered the most useful adjuncts, which may reduce adhesion formation. They act by separating the traumatized peritoneal surfaces during the healing period. The separation can be achieved by solid barriers or fluids. There is limited evidence from randomized clinical trials that support the beneficial effect of most of these barrier agents in the prevention of intra-peritoneal adhesions after gynaecological surgery. However, the evidence is not adequate for definite conclusions to be drawn and further research in this field is warranted.

Prenatal management and postnatal separation of omphalopagus and craniopagus conjoined twins.

Two cases of prenatally diagnosed conjoined twins are presented: a set of omphalopagus twins sharing a common liver, and a set of craniopagus with involvement limited to the skull. In both cases, prenatal diagnosis allowed accurate planning of pre- and postnatal management. Prenatal management involved serial imaging and counseling with participation of different specialists according to imaging findings. In the rare case of conjoined twins, an interdisciplinary approach is required, with feto-maternal specialists playing a pivotal role in co-ordinating teamwork and planning successive stages of management.

[Changes in lipid profile and paraoxonase activity in obese patients as a result of orlistat treatment]. / Obes betegek lipidprofiljának és paraoxonáz aktivitásának változása orlistat kezelést követóen.

257 patients from 33 centres were involved in a six-month study, the aim of which was to assess the effect of orlistat together with a diet. The authors examined how the treatment effected the anthropometrical and lipid parameters, extending the study to the aspect of paraoxonase activity in case of 25 patients. 44 patients dropped out during the study period due to the lack of sufficient diet compliance, whereas 3 patients had to stop the therapy because of the adverse event of flatus with discharge. On the average, the body mass of the patients decreased from 100.8 +/- 18.9 to 91.3 +/- 18.6 kg, i.e. by 9.5 kgs, while their BMI was reduced from 36.1 +/- 5.6 to 32.5 +/- 5.2 kg/m2 and the circumference of the waist changing from 119.1 +/- 20 to 108.3 +/- 15.1 cm, i.e. by 10.8 cms. The blood sugar level significantly decreased from 5.7 to 5.4, while the cholesterol concentration significantly dropped from 5.9 to 5.5, the triglyceride level being reduced from 2.4 to 2.1 mmol/l and blood pressure falling significantly from 136.6/86.9 to 129.9/81.6. All the above changes showed a significant decrease. However, the HDL-cholesterol level did not change. The serum paraoxonase activity significantly increased (143 +/- 49 vs 166 +/- 43 UL) along with the standardised values for HDL (PON/HDL), even compared to the control diet group. From the above results it may be concluded that orlistat tends to have an antioxidant effect.

Oocyte donation: clinical and practical aspects.

Oocyte donation is an effective treatment modality for women lacking functioning ovaries, but also for women in whom repetitive in-vitro fertilization (IVF) cycles did not result in the development of adequate number of oocytes as well as for those at risk of transmitting genetic diseases. In women with ovarian failure, artificial menstrual cycles are required in order to produce endometrial growth and differentiation similar to that in women with normal ovarian function. Synchronization of donor's and recipient's cycles is mandatory, since the window of implantation is rather limited. The excellent results of oocyte donation treatment confirm that this assisted reproduction technique can provide a novel approach for the treatment of infertility in these groups of patients. Nevertheless, pregnancies in women of advanced reproductive age are associated with significantly more obstetrical complications and higher perinatal morbidity and mortality rates. Furthermore, aging parents have considerably higher chances to develop serious or life-threatening diseases. Thus, careful medical screening and extensive counselling is mandatory, taking into account the psychosocial ramifications of the procedure and, especially, the best interest of the child-to-be.

[Major nutrition-related risk factors of ischemic heart disease: dyslipoproteinemia, obesity, hypertension, glucose intolerance]. / Az ischaemiás szívbetegség táplálkozással összefüggö fö rizikófaktorai: dyslipoproteinaemia, elhízás, hypertonia, glükóz-intolerancia.

Of the major risk factors of coronary heart disease dyslipoproteinemia, obesity, hypertension, and diabetes are nutrition related and can be considered of metabolic origin. Dyslipoproteinemia affects 2/3 of the adult population. The risk of coronary heart disease can be decreased 2-5 fold by lowering hypercholesterinemia; atherosclerosis in the coronaries may regress and total mortality may decrease. Atherogenic dyslipidemia (i.e. hypertriglyceridaemia, low HDL cholesterol levels, elevated concentrations of small dense LDL) increases the risk as part of the metabolic syndrome. Obesity is already highly prevalent, and it is affecting ever growing proportions of the adult population. Abdominal obesity furthermore predisposes patients to complications. No effective therapy is available for obesity. 3/4 of hypertensive patients are obese and more than half of them have insulin resistance. By decreasing blood pressure, the risk of stroke decreases by about 40%, that of coronary heart disease by 14-30%. Slimming cures are the most important non-pharmacological way of treating hypertension. 5% of the population has diabetes mellitus, and a further 5% has impaired glucose tolerance. Type 2 diabetes predisposes patients to macrovascular complications. The risk of coronary heart disease can be decreased by controlling diabetes by e.g. metformin.

[Incidence of familial defective apolipoprotein B-100 in cases of patients diagnosed with familial hypercholesterolemia]. / A familiáris defektív apolipoprotein B-100 elöfordulási gyakorisága klinikailag familiáris hypercholesterinaemiásnak tartott betegek között.

Familial Hypercholesterolemia (FH) and Familial Defective Apolipoprotein B-100 (FDB) are monogenic, autosome, dominantly inherited diseases appearing as type II/a primary hypercholesterolemia. The frequency of the heterozygositic forms is 1:700-1:500 in European population. Both forms of hypercholesterolemia causes early onset coronary heart diseases (CHD). According to the recommendations of the international MED-PED program (Make Early Diagnoses--Prevent Early Death), we found 73 FH cases and their 377 first relatives (parents, siblings, children) were also assessed. 156 patients were diagnosed clinically FH (131 alive and 25 deceased), and 31.8% of the males and 32.4% of females suffered from early onset CHD. One family with FH consists of 5.46 members on the average and there are 2.39 FH patients in one family. In our FH cohort four patients with FDB (R3500Q mutation) were diagnosed with allelspecific PCR, and the mutation was detectable also in 9 cases out of 11 living family members. The plasma total cholesterol level of the FDB patients--especially at younger age--was very close to the normal values, which is in contrast to the findings in FH patients. Nevertheless, FDB can be one of the independent causes of the early onset CHD. Therefore, in families with high frequency of cardiovascular diseases the R3500Q mutation has to be considered.

Preparation of endometrium for egg donation.

Nowadays oocyte donation is a well established method of assisted reproduction and offers the unique opportunity to treat patients with various clinical indications, with or without ovarian function, in a novel way. In women with ovarian failure, artificial menstrual cycles are required before proceeding to oocyte donation. Oestrogen may be delivered in the form of oral tablets, transdermal patches in order to bypass the gastrointestinal tract thus avoiding first pass metabolism and by vaginal application. Our regimen is oestradiol valerate given in various concentrations, in order to mimic the regular cyclic fluctuations throughout the cycle. Progesterone may be administered in the form of oral tablets, intravaginal suppositories or rings and i.m. injections. Our results, as of most other groups, strongly support the vaginal route of progesterone administration. In women with retained ovarian function, synchronization of donor-recipient cycle presents a special problem, as there is strong evidence that a temporal window of maximal endometrial receptivity exists. Cryopreservation of donated embryos may be used to overcome the problem, but this approach has the important drawback of embryonic loss occurring after freezing and thawing. The method of choice is the administration of gonadotrophin-releasing hormone agonists (GnRHa) to render the patients functionally agonadal in order to circumvent cycle asynchrony between the donor and recipient.

Pituitary-testicular axis in men with beta-thalassaemia major.

Delayed puberty and hypogonadism are frequently observed in patients with homozygous beta-thalassaemia. We evaluated the pituitary-testicular axis in 30 thalassaemic men, aged from 17 to 35 years who were regularly transfused and underwent chelation therapy, while emphasis was given to pituitary reserves of gonadotrophins and the correlation of hormones with serum ferritin (SF). The investigation included endocrinological examination, evaluation of serum basal levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), free testosterone and gonadotrophin-releasing hormone (GnRH) test and also spermiograms. According to the results, patients were divided into three groups: group A, which included 18 eugonadal patients with moderately elevated SF, group B which included six patients who had hypogonadotrophic hypogonadism and excessive elevation of SF, and group C, which included six patients characterized as intermediate, with regard to sexual maturation and SF levels. In conclusion, beta-thalassaemia major leads to variable pituitary iron overload and thus hypophyseal damage. This endocrine disturbance is becoming less frequent nowadays with early and intensive chelation therapy.