[Pain reduction by radiosynoviorthesis in rheumatism-induced synovitis of the elbow : Results of a retrospective multicenter data analysis]. / Schmerzreduktion durch Radiosynoviorthese bei rheumatisch bedingter Synovialitis des Ellenbogens : Ergebnisse einer retrospektiven, multizentrischen Datenanalyse.

BACKGROUND: Radiosynoviorthesis (RSO) is a nuclear medical local treatment modality for inflammatory joint diseases. It is indicated in patients with rheumatoid arthritis (RA) in joints with persistent synovitis despite adequate pharmacotherapy. Arthritis of the elbow joint occurs in up to 2/3 of patients with RA. Intra-articular radiotherapy using the beta emitter [186Re] rhenium sulfide leads to sclerosis of the inflamed synovial membrane with subsequent pain alleviation. The clinical efficacy in cubital arthritis, however, has so far only been described in small monocentric studies. OBJECTIVE: The degree of pain alleviation by RSO was analyzed in patients with rheumatoid cubital arthritis, treated in several nuclear medical practices specialized in RSO. MATERIAL AND METHODS: The subjective pain intensity before and after RSO was documented in a total of 107 patients with rheumatic cubital arthritis using a 10-step numeric rating scale (NRS). A difference of ≥ -2 is rated as a significant improvement. Follow-up examinations were done after a mean interval of 14 months after RSO (at least 3 months, maximum 50 months). RESULTS: The mean NRS value was 7.3 ± 2.1 before RSO and 2.8 ± 2.2 after RSO. A significant pain alleviation was seen in 78.5% of all patients treated. The subgroup analysis also showed a significant improvement in the pain symptoms in all groups depending on the time interval between the RSO and the control examination. A significant pain progression was not observed. The degree of pain relief was independent of the time of follow-up. CONCLUSION: Using RSO for local treatment of rheumatoid cubital arthritis leads to a significant and long-lasting pain relief in more than ¾ of the treated patients.

[The Echotherapy as non-invasive treatment option for thyroid diseases]. / Die Echotherapie als nichtinvasives Therapieverfahren von Schilddrüsenveränderungen.

Focused ultrasound is becoming more and more important when it comes to its application in thyroid diseases due to the development of echotherapy. This article provides insights in the application of echotherapy and the treatment process as well as clinical experiences and future perspectives. Studies have already been able to show significant volume reductions and improvement of symptoms after the treatment of benign and symptomatic thyroid nodules. Moreover, a high tolerability and a low profile in risk and side effects has been demonstrated.

PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the "Cancer Integrin" αvß6 with Ga-68-Trivehexin.

PURPOSE: To develop a new probe for the αvß6-integrin and assess its potential for PET imaging of carcinomas. METHODS: Ga-68-Trivehexin was synthesized by trimerization of the optimized αvß6-integrin selective cyclic nonapeptide Tyr2 (sequence: c[YRGDLAYp(NMe)K]) on the TRAP chelator core, followed by automated labeling with Ga-68. The tracer was characterized by ELISA for activities towards integrin subtypes αvß6, αvß8, αvß3, and α5ß1, as well as by cell binding assays on H2009 (αvß6-positive) and MDA-MB-231 (αvß6-negative) cells. SCID-mice bearing subcutaneous xenografts of the same cell lines were used for dynamic (90 min) and static (75 min p.i.) µPET imaging, as well as for biodistribution (90 min p.i.). Structure-activity-relationships were established by comparison with the predecessor compound Ga-68-TRAP(AvB6)3. Ga-68-Trivehexin was tested for in-human PET/CT imaging of HNSCC, parotideal adenocarcinoma, and metastatic PDAC. RESULTS: Ga-68-Trivehexin showed a high αvß6-integrin affinity (IC50 = 0.047 nM), selectivity over other subtypes (IC50-based factors: αvß8, 131; αvß3, 57; α5ß1, 468), blockable uptake in H2009 cells, and negligible uptake in MDA-MB-231 cells. Biodistribution and preclinical PET imaging confirmed a high target-specific uptake in tumor and a low non-specific uptake in other organs and tissues except the excretory organs (kidneys and urinary bladder). Preclinical PET corresponded well to in-human results, showing high and persistent uptake in metastatic PDAC and HNSCC (SUVmax = 10-13) as well as in kidneys/urine. Ga-68-Trivehexin enabled PET/CT imaging of small PDAC metastases and showed high uptake in HNSCC but not in tumor-associated inflammation. CONCLUSIONS: Ga-68-Trivehexin is a valuable probe for imaging of αvß6-integrin expression in human cancers.

In Comparison to PSA, Interim Ga-68-PSMA PET/CT Response Evaluation Based on Modified RECIST 1.1 After 2nd Cycle Is Better Predictor of Overall Survival of Prostate Cancer Patients Treated With 177Lu-PSMA.

BACKGROUND: Prostate-specific membrane antigen (PSMA) targeting radioligands have transformed treatment of prostate cancer. Radioligand therapy (RLT) with 177Lu-PSMA in metastasized castration resistant prostate cancer (mCRPC) achieves objective response and disease stabilization in roughly two third of patients, whereas one third of patients progress. This study was performed to assess the role of interim PSMA PET/CT after the 2nd cycle of RLT for early prediction of overall survival in patients undergoing RLT with 177Lu-PSMA. METHODS: 38 mCRPC patients (68.9 ± 8.1 y) treated with at least two cycles of RLT at 8 week intervals and interim 68Ga-PSMA PET/CT (PET) at 8-10 weeks after the 2nd cycle of RLT were included in this study. Prostate-specific antigen (PSA) response was evaluated according to the Prostate Cancer Working Group 3 criteria. Radiographic response assessment of soft tissue, lymph node, and bone lesions was performed according to RECIST 1.1 including the PET component. Patients' data were collected for follow-up from the local Comprehensive Cancer Center Register. RESULTS: Median follow-up was 19.7 months (4.7-45.3). PSA response after the 2nd therapy cycle showed partial remission (PR) in 23.7%, stable disease (SD) in 50%, and progressive disease (PD) in 26.3% of patients. In comparison, 52.6, 23.7, and 23.7% of patients showed PR, SD, and PD respectively on PET/CT. The strength of agreement between PSA response and PET/CT response criteria was only fair (kappa 0.346). Median overall survival (OS) was 22.5 months (95% CI: 15.8-29.2). Median OS stratified to PSA/PET response was 25.6/25.6 months for PR, 21.7/30.6 months for SD and 19.4/13.1 months for PD (p = 0.496 for PSA and 0.013 for PET/CT response). CONCLUSIONS: Interim PSMA PET/CT based response evaluation at 8-10 weeks after the 2nd cycle of RLT is predictive of overall survival and PD in patients treated with 177Lu-PSMA. On the contrary, PSA appears to have only limited predictive value.

PET/CT in malignant melanoma: a two-tiered healthcare system? Updated healthcare situation regarding initial staging of malignant melanoma with PET/CT.

BACKGROUND: Patients with stage IIC malignant melanoma are recommended to undergo cross-sectional imaging for initial staging. PET/CT is superior to other methods regarding its diagnostic accuracy of the tumor spread in stage III. So far there is no meaningful data on the nationwide availability, usage and cost recovery of this imaging technique. PATIENTS AND METHODS: Questionnaires on the healthcare situation in 2018 were sent to all German dermatology clinics and PET/CT centers in March and April 2019. RESULTS: 61.2 % of the dermatology clinics (71/115) and 48.2 % of the PET/CT centers (77/160) took part in the survey. A total of 22,645 patients with malignant melanoma were seen in these clinics in 2018. 16.8 % of the patients with stage IIC melanoma received a PET/CT for primary staging. The costs of this examination were covered for all statutory and privately insured patients in 40 % and 68 % of dermatology clinics (20/50 and 34/50), respectively. 68.0 % (34/50) of all dermatology clinics reported relevant changes of treatment according to PET/CT findings. Long examination periods by the health insurance companies and the time required to submit the application were the most common reasons for dermatology clinics to reject a request for PET/CT. Relevant incidental findings were reported in 90.2 % (47/51) of all PET/CT centers. CONCLUSIONS: There are clear differences in the nationwide availability and cost coverage of PET/CT in primary staging for stage IIC melanoma. For these reasons, a two-tiered healthcare system may be assumed.

[RSO in clinical practice: Status in Germany 2020]. / RSO im klinischen Alltag: Statuserfassung in Deutschland 2020.

BACKGROUND: Radiosynoviorthesis (RSO) is a local radionuclide therapy of inflammatory joint diseases, successfully performed since several decades mainly as an outpatient-protocol in ambulatory health care centers or nuclear medicine practices. Despite of long-term experience in some centers, only very few valuable or comparable data about the procedure itself and/or the clinical results of this treatment are available. OBJECTIVES: The aim of this online survey is to assess reliable data of the current status in Germany. MATERIALS AND METHODS: A web-based questionnaire was designed to evaluate the status of RSO in Germany including demographic data, training, pretherapeutic diagnostics, clinical procedures, and follow-up. The survey was distributed via the supplier of RSO-nuclides, national nuclear medicine societies, and personal networks. It was available for 28 days and closed on November 30, 2020. RESULTS: A total of 78 specialists in nuclear medicine answered the questionnaire, which corresponds to a response rate of 23 %. Several differences and concordances in pre-therapeutic diagnostics, in the procedure of RSO itself, and follow-up were documented in this survey for the first time. Most important, less than 70 nuclear medicine specialists in Germany perform more than 75 % of all RSO-procedures and most of them are older than 50 years of age. This implies the urgent need of a dedicated advancement of young academics in nuclear medicine and a professional advanced training in RSO to offer this beneficial treatment to future patients. CONCLUSIONS: To achieve these goals, an association of RSO experts would be useful, through which, among other things, an RSO training curriculum is developed and theoretical and practical trainings are organized. Moreover, possible cooperation agreements between ambulant and inpatient institutions would foster the education of young nuclear medicine specialists interested in RSO.

Prostate-Specific Membrane Antigen PET/CT: False-Positive Results due to Sarcoidosis?

We report on a 72-year-old male patient who developed sarcoidosis of the mediastinal lymph nodes, the liver, and the prostate 11 years ago. Seven years later, he underwent transurethral resection of the prostate by laser due to hematuria. Pathology of the resected chips showed a 'granulomatous prostatitis with epitheloid cells'. Malignancy was histologically excluded at that time. Four years later, he was diagnosed with an undifferentiated prostate carcinoma, with a Gleason score of 5 + 4 = 9. After initiation of antihormonal therapy, he underwent radical prostatectomy and pelvic lymphadenectomy, which revealed a pT3b pN1 carcinoma with infiltrated resection margins. Three months later, the prostate-specific antigen level was 1.4 ng/ml, and a local recurrence was suspected by ultrasound; consequently, a 68Ga-prostate-specific membrane antigen (PSMA) PET/CT was performed. This examination seemed to confirm the local recurrence, a right pelvic lymph node metastasis, and a hepatic metastasis. However, ultrasound with contrast medium could not confirm the metastatic spread to the liver. In palliative intention, radiotherapy of the pelvis was done. After 50 Gy, the supposed recurrence had markedly shrunk, and an additional boost dose with 16.2 Gy was applied. Two years later, the patient is still free of disease. Due to this clinical development, we doubt the diagnosis of a fulminant progression of the prostate cancer as suspected by PSMA-PET/CT. Instead, we suspect a recurrence of the previously proven sarcoidosis leading to false-positive results. Our focus in this report is on the interaction between PSMA-PET/CT and sarcoidosis. Another report on a case of sarcoidosis of the spleen seems to confirm this possibility [Kobe et al: Clin Nucl Med 2015;40: 897-898].

Tumor-induced osteomalacia: successful treatment by radio-guided tumor surgery.

Tumor-induced osteomalacia is a rare syndrome characterized by urinary phosphate loss with hypophosphatemic osteomalacia. The proposed pathogenetic mechanism is paraneoplastic secretion of phosphaturic factors (so-called phosphatonins).We describe a 34-year-old male patient who presented with severe pain of the spine and ribs for at least 2 years. Bone scintigraphy using Technetium hydroxymethylene diphosphonate (Tc HDP) showed multiple lesions suggesting metastatic disease. Bone biopsy however revealed osteomalacia. The patient had subnormal plasma phosphate levels (0.42 mmol/L; normal range, 0.87-1.45) and markedly increased phosphate clearance (82.8 mL/min; normal range, 5.4-16.2). The patient was treated with phosphate supplementation (up to 5 g daily) along with calcium (1000 mg daily) and calcitriol (1.5 microg daily). Although this therapy did not correct hypophosphatemia, it resulted in complete relief of pain within several months. (111)In pentetreotide scintigraphy showed a tiny lesion of 1-cm diameter, which could be localized to the left femoral neck in close vicinity to the greater trochanter by MRI and image fusion analysis. This lesion had not been visualized by Tc-99m HDP bone scintigraphy. Intraoperatively, use of a hand-held gamma probe after administration of (111)Indium pentetreotide ((111)In pentetreotide) clearly identified the tumor, which was completely removed and was shown to be a hemangiopericytoma. After removal of the tumor, phosphate metabolism normalized within 1 week without requirement of phosphate supplementation. Hypophosphatemic osteomalacia, although rare, raises an important differential diagnosis. An underlying tumor may be detected only by (111)In pentetreotide scintigraphy. Preoperative labeling with (111)In pentetreotide is a useful tool in detecting these tumors during surgery.This 34 year old man with osteomalacia had a small causative hemangiopericytoma detected in the indium pentetreotide scintography.

Familial influences and obesity-associated metabolic risk factors contribute to the variation in resting energy expenditure: the Kiel Obesity Prevention Study.

BACKGROUND: A low metabolic rate may be inherited and predispose to obesity, whereas a higher metabolic rate in obesity may be acquired by obesity-associated cardiometabolic risk. OBJECTIVE: We aimed to explain the interindividual variation in resting energy expenditure (REE) by assessing 1) the association between REE and body composition, thyroid hormones, and obesity-related cardiometabolic risk factors, and 2) the familial (genetic and environmental) contribution to REE. DESIGN: REE and metabolic risk factors (ie, blood pressure and plasma insulin, glucose, and C-reactive protein concentrations) were assessed in 149 two- or three-generation families, including at least one overweight or obese member. Heritability of REE, respiratory quotient (RQ), thyroid hormones [thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4)], and body composition (fat-free mass and fat mass) were estimated by using variance components-based quantitative genetic models. RESULTS: REE adjusted for body composition, sex, and age (REEadj) significantly correlated with systolic and diastolic blood pressure, plasma insulin and glucose concentrations, and the homeostasis model assessment (HOMA) (r = 0.14-0.31, P < 0.05). Thyroid hormones had a modest influence on REE variance only. Heritability was 0.30 +/- 0.07 for REEadj and 0.29 +/- 0.08 for REE after additional adjustment for thyroid hormones and metabolic risk. Furthermore, heritability was estimated to be 0.22 +/- 0.08 for RQ, 0.37 +/- 0.08 for TSH, 0.68 +/- 0.06 for FT4, and 0.69 +/- 0.05 for FT3 (all significantly larger than zero). CONCLUSIONS: Obesity-related cardiometabolic risk factors contribute to interindividual variation in REE, with hypertension and insulin resistance being associated with a higher REE. REE was moderately heritable, independent of body composition, sex, age, thyroid function, and cardiometabolic risk.

Neuropsychological consequences of endarterectomy and endovascular angioplasty with stent placement for treatment of symptomatic carotid stenosis: a prospective randomised study.

BACKGROUND AND PURPOSE: Previous studies compared carotid endarterectomy (CEA) and carotid artery stent placement (CAS) for treatment of symptomatic carotid artery stenosis. Whereas most previous studies showed both treatment modalities to be associated with a comparable risk of periprocedural cerebrovascular complications, these previous studies have shown significantly more microemboli and significantly more lesions in diffusion-weighted MR imaging after CAS compared to CEA. The clinical relevance of these differences remains unknown. We therefore compared the neuropsychological consequences of CAS and CEA and additionally measured the S100beta protein, a marker of cerebral damage. METHODS: A total of 48 patients with symptomatic carotid artery stenosis greater than 70 % (according to ECST criteria) were enrolled and 45 patients participated in the follow-up. The patients were randomly assigned for CEA (24 patients) or CAS (21 patients). S100beta protein values were evaluated 2 hours before the procedure, as well as one and two hours thereafter. Patients were assessed before treatment, and again 6 and 30 days after treatment using a comprehensive neuropsychological test battery. RESULTS: Patients of the CAS and the CEA groups did not significantly differ in terms of age, gender, education, degree of carotid artery stenosis, cerebrovascular symptoms and vascular risk factors. Following previously used criteria, a cognitive change in patients was assumed to have occurred when there was a decline of more than one standard deviation in two or more tests assessing various cognitive domains. Six days and 30 days after the treatment both groups showed a comparable number of patients with cognitive changes compared to baseline. There were no significant differences in S100beta protein values. CONCLUSION: These results provide some reassurance that CAS is not associated with greater cognitive deterioration than CEA is.

Clinical efficacy of radiation synovectomy in digital joint osteoarthritis.

PURPOSE: Radiation synovectomy was developed for local treatment of rheumatoid arthritis. In this study, the long-term efficacy of radiation synovectomy was retrospectively evaluated in patients with osteoarthritis (activated arthrosis) of the digital joints using an algofunctional score. METHODS: Fifty-three digital joints in 29 patients (mean age 64.8 years) were treated by intra-articular injection of 169Er citrate. All joints were painful despite pharmacotherapy and showed an elevated blood pool pattern in a pretherapeutic three-phase bone scan, indicative for local synovitis. The patients were asked to classify their complaints with respect to different daily manual activities on a ten-step pain scale from 1 (total disability) to 10 (lack of any impairment) prior to and after treatment, with a mean follow-up of 41 months. Local signs of osteoarthritis such as joint swelling or pain were additionally evaluated and were scored from progression of complaints to excellent improvement based on patient self-evaluation. RESULTS: All patients reported a pronounced improvement in their manual activities. The mean total score of 4.73+/-0.58 for all activities prior to treatment increased significantly to 6.79+/-0.47 after radiation synovectomy (p<0.05). The best results were obtained in the thumb base joints, whereas distal interphalangeal joints were frequently resistant to therapy. CONCLUSION: Radiation synovectomy is highly effective in digital joint osteoarthritis with concomitant local synovitis.

CT-guided lymphoscintigraphy in patients with squamous cell carcinoma of the head and neck: a feasibility study.

Accurate knowledge of lymphatic drainage facilitates planning of surgery for patients with squamous cell carcinoma of the head and neck. The aim of this study was to evaluate the feasibility of a new injection technique for lymph node detection in patients with squamous cell carcinoma of the hypopharynx and larynx, in whom simple peritumoural injection is hampered by the tumour localisation. Computed tomography (CT)-guided lymphoscintigraphy was performed in a total of 13 patients with squamous cell carcinoma of the hypopharynx and larynx who could not be injected by simple visual inspection. In a first step, contrast medium-enhanced axial 5-mm-thick CT slices of the neck were obtained. After tumour localisation on these CT images, 1-2 ml contrast medium and, in the event of appropriate distribution, subsequently 50 MBq technetium-99m colloid were injected at one to three peritumoural sites under CT guidance. Peritumoural tracer distribution was controlled by thin-slice CT. Subsequently, planar scintigrams from anterior, right and left lateral views were obtained. In all patients, peritumoural colloid application was feasible, as shown on control CT scans. Post injection, neither severe nor minor complications were noted. The patients complained of only low pain sensations with an average score of 1.8 on a pain scale from 0 to 10. Lymphatic drainage was identified in nine of the 13 patients, with a total of 14 detected lymph nodes. In six patients, ipsilateral sentinel lymph nodes were visualised; bilateral sentinel lymph nodes were identified in one patient and contralateral lymphatic drainage was observed in two patients. CT-guided lymphoscintigraphy is a feasible and minimally invasive diagnostic tool for sentinel lymph node detection in patients with squamous cell carcinoma of the hypopharynx and the larynx. In contrast to endoscopic colloid injection under general anaesthesia, this technique seems to be a well-tolerated method for lymphatic mapping prior to surgical procedures.

Prospective evaluation of factors influencing success rates of sentinel node biopsy in 814 breast cancer patients.

OBJECTIVE: This prospective multicenter study was performed to assess the reliability of sentinel lymph node (SLN) biopsy in breast cancer and to analyze factors potentially influencing success rates. METHODS: In 21 departments, SLN biopsy and consecutive axillary lymph node dissection were performed in 814 breast cancer patients. The 80 surgeons involved were free in the choice of lymphography technique. The detection rate and the sensitivity, as well as the impact of lymphography technique, patient selection, technical procedure and learning curves, were evaluated. RESULTS: The blue dye technique was used in 137 patients, radiocolloid in 169 patients, and combined blue dye/radiocolloid in 508 patients. The identification rate for the sentinel node was 83.9% for the entire group and showed a significant dependence on the lymphography technique (blue dye, 71.6%; radiocolloid, 78.8%; combined blue dye and radiocolloid, 89.6%). The overall sensitivity in detecting lymph node metastases was 91.3%. Immunostaining for cytoceratine revealed micrometastases in 19 (5.1%) of 374 patients in whom H/E staining was negative. The combined subdermal/peritumoral injection of the colloid showed a significantly higher identification rate than subdermal or peritumoral injection alone (96.8%, 84.6%, 78.6%; p < 0.001). There was also a significant higher detection rate in cases of SLN biopsy performed prior to lumpectomy, compared to SLN biopsy following lumpectomy (94.7% versus 82.8%; p < 0.001). Furthermore, there was a close correlation between the number of performed examinations and the detection rate. CONCLUSION: SLN mapping predicts the axillary lymph node status accurately. Learning curves and several technical features influence the detection rate significantly. However, the false negative rate was independent of experience and injection technique.

Radio-tympano-sinu-orthesis with 186Re-colloid: a new treatment modality for chronic otitis media and paranasal mucositis.

UNLABELLED: This preliminary treatment trial was performed to evaluate the safety and clinical efficacy of intracavitary therapy with (186)Re-colloid in patients with recurrent otitis media and paranasal sinusitis, resistant to pharmacotherapy and surgical treatment. METHODS: Thirty-nine applications of 5-35 MBq (186)Re-colloid into the tympanon and the paranasal sinuses were performed in 6 patients. Biodistribution and biokinetics were studied by gamma-camera imaging. Clinical success was documented 6-20 mo after therapy by each patient's self-evaluation and by rhinootologic follow-up, using a 4-step score. RESULTS: No harmful side effects were seen. There was good-to-excellent clinical improvement with a score of +1.44 +/- 0.5 by each patient's self-evaluation and by physicians scoring of +0.81 +/- 0.9 with only negligible extracranial tracer deposition. CONCLUSION: This novel treatment option using intracavitary application of (186)Re-colloid in chronic otitis media and sinusitis is safe and effective. The term "radio-tympano-sinu-orthesis" might be proposed analogously to the well-known radiosynoviorthesis.

Determinants of hyperhomocysteinemia in patients with chronic liver disease and after orthotopic liver transplantation.

BACKGROUND: Homocysteine metabolism may be impaired in chronic liver disease, possibly contributing to fibrogenesis and disease complications. OBJECTIVE: The goal was to investigate the prevalence and determinants of basal and postprandial hyperhomocysteinemia in patients with chronic liver disease and after orthotopic liver transplantation (OLT). DESIGN: This was a cross-sectional study of 323 patients with chronic liver disease (93 with hepatitis, 8 with fatty liver, 168 with cirrhosis, and 54 after OLT) and 25 healthy control subjects. Portohepatovenous gradients of total homocysteine (tHcy) and methionine and postload methionine and tHcy kinetics before and after 10 d of supplementation with folate plus vitamin B-6 were investigated in subgroups. RESULTS: Basal hyperhomocysteinemia was observed in all patient groups (34% of patients with hepatitis, 50% with fatty liver, 54% with cirrhosis, and 52% after OLT). It was more frequently seen in patients with elevated plasma creatinine concentrations and at advanced stages of liver disease. Mean plasma folate was normal in patients with liver disease, but vitamin B-12 was elevated in cirrhosis and vitamin B-6 was low after OLT. There were significant negative associations between tHcy and folic acid or vitamin B-12 concentrations in control subjects and in patients with hepatitis and after OLT. No systematic association between portohepatovenous differences in tHcy and methionine concentrations was found. Cirrhosis was accompanied by impaired methionine clearance. After vitamin supplementation, the area under the tHcy curve improved in cirrhosis at nearly unchanged basal tHcy concentrations. CONCLUSIONS: Basal hyperhomocysteinemia is seen in approximately 50% of patients with cirrhosis and after OLT. Basal tHcy concentrations do not change significantly after supplementation with folate and vitamin B-6, but postprandial Hcy metabolism improves.