Characterization of an integrated, endogenous mouse mammary tumor virus-like (MMTV) betaretrovirus genome in a black Syrian hamster (Mesocricetus auratus).

Retroviruses (family Retroviridae) are important agents of humans and animals. This study reports the detection and complete genome characterization of a novel endogenous retrovirus from the black Syrian hamster (Mesocricetus auratus) with a squamous cell skin tumor. The proviral genome, tentatively named black Syrian hamster retrovirus (BSHRV/2013/HUN, MK304634), was 8784 nucleotide in length with typical full-length betaretrovirus genome organization of 5'LTR-gag-pro-pol-env-3'LTR and with a characteristic mouse mammary tumor virus-like (MMTV) betaretrovirus dUTPase domain but without a sag gene. The BSHRV gag (534aa), pro/pol (~1099aa) and env (672aa) proteins had 56%/63%/50% aa identity to the corresponding proteins of MMTV (AF228552). The proviral DNA is detectable in tumor as well as in tumor-free cells by conventional PCR and qPCR but only visible in the tumor cells by in situ hybridization. Low level retroviral RNA expression was found only in the DNase-treated RNA tumor samples using RT/nested PCR. BSHRV/2013/HUN-like betaretrovirus DNA was also identified from a faecal and tissue samples from 1 of the further 3 tested individuals by nested-PCR and qPCR. Further research is needed to investigate the distribution, activity and etiological role of this novel MMTV-like betaretrovirus species in hamster.

Local immune parameters as potential predictive markers in head and neck squamous cell carcinoma patients receiving induction chemotherapy and cetuximab.

BACKGROUND: The aim of this study was to determine whether tumor-associated immune cells may predict response to therapy and disease outcome in head and neck squamous cell carcinoma (HNSCC) patients receiving induction chemotherapy and cetuximab. METHODS: Paraffin-embedded pretreatment biopsy samples from 45 patients with stage III-IV resectable HNSCC were investigated retrospectively by immunohistochemistry for density of different immune cell types based on expression of CD8, FOXP3, CD134, CD137, PD-1, CD20, NKp46, dendritic cell lysosomal-associated membrane protein (DC-LAMP), CD16, CD68, and myeloperoxidase. Results were analyzed for possible correlations with clinicopathologic parameters, response to therapy, and survival. RESULTS: Of the immune cell types studied, we found significant association with response to induction chemotherapy only in the case of DC-LAMP+ mature dendritic cells and PD-1+ lymphocytes; density of DC-LAMP+ cells also correlated with progression-free survival. CONCLUSION: DC-LAMP+ mature dendritic cells and PD-1+ cells may be implicated in response to induction chemotherapy and cetuximab in HNSCC patients.

[Dosimetric evaluation of intracavitary-interstitial image-guided adaptive brachytherapy of cervical cancer and comparison with conventional treatment techniques]. / Méhnyakdaganatok képvezérelt adaptív intersticiális-intrakavitális brahiterápiájának dozimetriai elemzése és a hagyományos kezelési technikákkal való összehasonlítása.

Our aim was the dosimetric evaluation of intracavitary-interstitial high-dose-rate image-guided adaptive cervix brachytherapy, implemented in Hungary. Between 2016 and 2018, 21 patients with cervical cancer were treated with overall 72 fractions. Graphical optimized treatment plans were compared to inverse optimized plans, 3D optimized plans (without needles) and conventional intracavitary 2D plans. Significant difference was found in almost all dose-volume parameters. The most advantageous values came from interstitial plans, inverse optimized plans did not differ dosimetrically from the treatment plans, while intracavitary optimized plans disposed of less appropriate dose-volume parameters, the least of all were intracavitary 2D plans. Needle number showed correlation with conformality, but inverse correlation with Dose Nonuniformity Ratio and D2cm3 of rectum. Volume of High Risk CTV correlated with D2cm3 of bladder, rectum and sigmoid. Although 3D optimization improved the quality of conventional 2D plans, interstitial plans resulted in even more homogeneous dose distribution and significantly lower doses to organs at risks.

[Clinical results of combined intracavitary-interstitial image-guided adaptive brachytherapy in locally advanced cervical cancer]. / Elõrehaladott méhnyakdaganatok képvezérelt adaptív kombinált intrakavitális-intersticiális brahiterápiájának bevezetése Magyarországon.

We present the early clinical results achieved with image-guided adaptive brachytherapy (IGABT) with combined intracavitary-interstitial (IC-IS) technique recently implemented in Hungary in the treatment of locally advanced cervical cancer (LACC). Twenty-one patients were treated with radio-chemotherapy (RCT) followed by combined IC-IS BT. At the end of the RCT we assessed the residual tumour with pelvic MRI. On CT images registered with the applicator in place we contoured the organs at risk and the high-risk clinical target volume, which included the whole cervix and the eventual residual tumour in the parametria. No grade 4 toxicity was noticed. At 11 months follow-up the local control rate was 92.3%, the pelvic control rate 86.5%, the distant metastasis free survival and the disease-free survival were 74%. The combined IC-IS treatment was well tolerated. Our clinical results are similar to those reported in the literature.

[Role of MRI and CT in the evaluation of postirradiation status and complications in head and neck cancer]. / Az MRI és a CT szerepe a sugárterápia utáni státusz értékelésében, szövõdményeinek vizsgálatában, fej-nyaki daganatoknál.

Most head and neck cancer patients are treated with combined modalities such as surgery, radiotherapy (RT), chemotherapy (ChT). Concurrent chemo-radiation has improved treatment outcomes with increased toxic effects. Reactions after RT are divided into early and late changes. Early reactions are seen during the course of therapy or within 3 months; these are reversible in most cases. Late complications are observed 3 months to years after RT and they are generally irreversible. As typical late reaction radiation induced necrosis may occur in soft tissues, cartilage, bones and brain. Tumor recurrence and post-radiation necrosis typically appear at the same time, within 2-3 years after RT; the differentiation may be difficult. Computed tomography (CT) and magnetic resonance imaging (MRI) have become the gold standards not only for staging and assessing tumor response, but also to evaluate posttreatment status, to distinguish residual or recurrent tumor and RT complications. Using baseline CT or MRI between 2-3 months after treatment and performing standard follow-up imaging with strict clinical follow-up are required to establish early salvage treatment.

High-Density Lipoprotein Particles, Cell-Cholesterol Efflux, and Coronary Heart Disease Risk.

Objective- The cell-cholesterol efflux capacity of HDL (high-density lipoprotein) is inversely associated with coronary heart disease risk. ABCA1 (ATP-binding cassette transporter A1) plays a crucial role in cholesterol efflux from macrophages to preß-1-HDL. We tested the hypothesis that coronary heart disease patients have functionally abnormal preß-1-HDL. Approach and Results- HDL cell-cholesterol efflux capacity via the ABCA1 and the SR-BI (scavenger receptor class B type I) pathways, HDL antioxidative capacity, apo (apolipoprotein) A-I-containing HDL particles, and inflammatory- and oxidative-stress markers were measured in a case-control study of 100 coronary heart disease cases and 100 sex-matched controls. There were significant positive correlations between ABCA1-dependent cholesterol efflux and the levels of small lipid-poor preß-1 particles ( R2=0.535) and between SR-BI-dependent cholesterol efflux and the levels of large lipid-rich (α-1+α-2) HDL particles ( R2=0.712). Cases had significantly higher (87%) preß-1 concentrations than controls, but the functionality of their preß-1 particles (preß-1 concentration normalized ABCA1-dependent efflux capacity) was significantly lower (-31%). Cases had significantly lower (-12%) mean concentration of large HDL particles, but the functionality of their particles (α-1+α-2 concentration normalized SR-BI-dependent efflux capacity) was significantly higher (22%) compared with that of controls. HDL antioxidative capacity was significantly lower (-16%) in cases than in controls. There were no significant correlations between either preß-1 functionality or large HDL particle functionality with HDL antioxidative capacity or the concentrations of inflammatory- and oxidative-stress markers. Conclusions- HDL cell-cholesterol efflux capacity is significantly influenced by both the concentration and the functionality of specific HDL particles participating in cell-cholesterol efflux. Coronary heart disease patients have higher than normal preß-1 concentrations with decreased functionality and lower than normal large HDL particle concentrations with enhanced functionality.

EVALUATION OF BONE MINERALIZATION BY COMPUTED TOMOGRAPHY IN WILD AND CAPTIVE EUROPEAN COMMON SPADEFOOTS (PELOBATES FUSCUS), IN RELATION TO EXPOSURE TO ULTRAVIOLET B RADIATION AND DIETARY SUPPLEMENTS.

Captive rearing programs have been initiated to save the European common spadefoot (Pelobates fuscus), a toad species in the family of Pelobatidae, from extinction in The Netherlands. Evaluating whether this species needs ultraviolet B (UVB) radiation and/or dietary supplementation for healthy bone development is crucial for its captive management and related conservation efforts. The bone mineralization in the femurs and the thickest part of the parietal bone of the skulls of European common spadefoots (n = 51) was measured in Hounsfield units (HUs) by computed tomography. One group, containing adults (n = 8) and juveniles (n = 13), was reared at ARTIS Amsterdam Royal Zoo without UVB exposure. During their terrestrial lifetime, these specimens received a vitamin-mineral supplement. Another group, containing adults (n = 8) and juveniles (n = 10), was reared and kept in an outdoor breeding facility in Münster, Germany, with permanent access to natural UVB light, without vitamin-mineral supplementation. The HUs in the ARTIS and Münster specimens were compared with those in wild specimens (n = 12). No significant difference was found between the HUs in the femurs of both ARTIS and Münster adults and wild adults (P = 0.537; P = 0.181). The HUs in the skulls of both captive-adult groups were significantly higher than in the skulls of wild specimens (P = 0.020; P = 0.005). The HUs in the femurs of the adult ARTIS animals were significantly higher than the HUs in the femurs of the adult Münster animals (P = 0.007). The absence of UVB radiation did not seem to have a negative effect on the bone development in the terrestrial stage. This suggests that this nocturnal, subterrestrial amphibian was able to extract sufficient vitamin D3 from its diet and did not rely heavily on photobiosynthesis through UVB exposure.

Influence of HDL particles on cell-cholesterol efflux under various pathological conditions.

It has been reported that low cell-cholesterol efflux capacity (CEC) of HDL is an independent risk factor for CVD. To better understand CEC regulation, we measured ABCA1- and scavenger receptor class B type I (SR-BI)-dependent cell-cholesterol efflux, HDL anti-oxidative capacity, HDL particles, lipids, and inflammatory- and oxidative-stress markers in 122 subjects with elevated plasma levels of triglyceride (TG), serum amyloid A (SAA), fibrinogen, myeloperoxidase (MPO), or ß-sitosterol and in 146 controls. In controls, there were strong positive correlations between ABCA1-dependent cholesterol efflux and small preß-1 concentrations (R2 = 0.317) and SR-BI-dependent cholesterol efflux and large (α-1 + α-2) HDL particle concentrations (R2 = 0.774). In high-TG patients, both the concentration and the functionality (preß-1 concentration-normalized ABCA1 efflux) of preß-1 particles were significantly elevated compared with controls; however, though the concentration of large particles was significantly decreased, their functionality (large HDL concentration-normalized SR-BI efflux) was significantly elevated. High levels of SAA or MPO were not associated with decreased functionality of either the small (preß-1) or the large (α-1 + α-2) HDL particles. HDL anti-oxidative capacity was negatively influenced by high plasma ß-sitosterol levels, but not by the concentrations of HDL particles, TG, SAA, fibrinogen, or MPO. Our data demonstrate that under certain conditions CEC is influenced not only by quantitative (concentration), but also by qualitative (functional) properties of HDL particles.

Epidemiological, Clinicopathological and Virological Features of Merkel Cell Carcinomas in Medical Center of University of Pécs, Hungary (2007-2012).

Merkel cell carcinoma (MCC) is a rare, highly aggressive skin tumour. In 2008, a Merkel cell polyomavirus (MC) was identified in MCCs as a potential etiological factor of MCC. The aims of this retrospective study were to investigate the epidemiological, clinicopathological and virological features of MCCs. Between 2007 and 2012, 11 patients had been diagnosed with MCC by histological methods in University of Pécs, Hungary. In eight MCC cases MC was tested by PCR (in primary skin lesions, lymph nodes/cutan metastases, MCC neighboring carcinomas). Clinicopathological characteristics (age, histological pattern, lymphovascular invasion, co-morbidities) of MC-positive and MC-negative cases were compared. MC was detected in three (37.5%) out of eight patients' primary tumour or metastasis. The average age was 73.8 (64.3 in MC-positive group). Except the youngest, 55 year-old patient (the primary tumour appeared on his leg), all tumours were found at the head and neck region. Immunosuppression (steroid therapy, chronic lymphoid leukaemia, chronic obstructive pulmonary disease) and/or old age were characteristic for all cases. Histological pattern was different in MC-positive and in MC-negative groups: MCCs with MC showed more homogeneous histological pattern, lack of lymphovascular invasion and were associated with better prognosis (mortality rate: 33% versus 80%). MCC associated with oncogenic virus is a newly recognized clinical entity. However, MC could not be detected in all histologically proven MCCs. The well-defined selection of patients/disease groups and better characterization of differences between MC-positive and negative cases is an important step towards the recognition of the etiology and pathogenesis of all MCCs.

[New opportunities, MRI biomarkers in the evaluation of gynaecological cancer]. / Új lehetoségek, MRI-biomarkerek a nogyógyászati daganatok értékelésében.

The determination and classification of gynaecological tumour stage which is based on clinical and pathological examinations became more precise due to the development of imaging techniques. Recently new MRI methods are being introduced which serve functional, tissue-specific, molecular information; beyond the excellent anatomical and contrast resolution with the aid of high resolution morphological measurements as well as quantification can also be performed. Diffusion-weighted MRI (DW-MRI) is based on the mobility of water molecules and provides information about the cell density of a given tissue and the integrity of cell membranes. Quantification can also be performed using an apparent diffusion coefficient (ADC). DW-MRI is a useful tool in determining myometrium invasion in endometrium carcinomas especially if a tumour has the same signal intensity as the makromomyometrium on the T2-weighted images and the use of contrast agents are contraindicated. The extra-uterine tumour invasion, the peritoneal metastatic foci can be determined by DW-MRI as well. Lymph node status is the most important predictive factor regarding survival. Both CT and MRI have low sensitivity (70-80%) in revealing metastatic lymph nodes. DW-MRI is a promising method with a sensitivity of 87% and specificity of 80% in distinguishing benign and malignant lymph nodes. Dynamic contrastenhanced MRI (DCE-MRI), as a marker of angiogenesis, provides information about vascularisation at the tissue level. In endometrial carcinoma with application of T2-weighted sequence together with DCE-MRI in determining the stage MRI has the accuracy about 90%. DCE-MRI has proven to be useful for distinguishing benign from malignant ovarian tumours, for detecting tumour extension; it can help predict peritoneal carcinomatosis. It is proven by high-level evidence that multiparametric MRI (MP-MRI) is the most precise diagnostic tool in determining the status of cervical carcinoma, its accuracy being above 90%. In the case of parametrial tumour invasion the accuracy of the clinical examination is 78%, while that of CT and MRI are 70% and 92%, respectively. DCE-MRI and DWMRI are promising imaging biomarkers in the early assessment of the effectiveness of the therapy and also in detecting residual as well as recurrent tumours.

Pathologic complete remission after preoperative high-dose-rate brachytherapy in patients with operable cervical cancer: preliminary results of a prospective randomized multicenter study.

The role of preoperative intrauterine brachytherapy (BT) in the multidisciplinary treatment of early stage cervical carcinoma (ESCC) is controversial. In 2005, a prospective randomized multicenter study was initiated in Hungary in order to explore the potential advantages of preoperative high-dose-rate (HDR) BT. In this article we evaluate the efficiency of preoperative HDR BT by the rate of pathologic complete remission (pCR) in the first 185 patients enrolled in the study at the National Institute of Oncology and at the Uzsoki Municipal Cancer Center in collaboration with the 1st Department of Gynaecology and Obstetrics of Semmelweis University, Budapest, Hungary. In arm A, patients received 2x8Gy preoperative intracavitary HDR BT, while in arm B no preoperative treatment was given. In both arms patients underwent radical Wertheim (Piver III) hysterectomy. The pCR rate was 25.7% after preoperative HDR BT, while it was only 11.2% with surgery alone (p=0.03), in these cases the tumor was eliminated during the diagnostic excision or conisation. The rate of positive surgical margins was 1.5% after preoperative BT, while it was as high as 11.4% without preoperative RT (p=0.02). There was no significant difference in the local tumor control (LTC), distant metastases free survival (DMFS) and overall survival (OS) between the two arms. According to our preliminary results preoperative intracavitary HDR BT significantly increases the rate of pCR and decreases the rate of positive surgical margins in patients with ESCC. Longer follow-up is required to establish the possible impact of pCR on the ultimate LTC and OS.

Evaluation of the accuracy of preoperative MRI in measuring myometrial infiltration in endometrial carcinoma.

The aim of our study was to evaluate the diagnostic performance of magnetic resonance imaging (MRI) in the pretreatment evaluation of myometrium invasion in endometrial cancer. Our retrospective study concerns 89 patients with endometrial cancer, who had preoperative MR evaluation of myometrium invasion and we compared it with histological results. Considering histological type and grade, we had excluded patients with poor prognosis, and separately evaluated those cases where the depth of myometrium invasion is the main prognostic factor determining the choice treatment. Of the 89 cases MRI had accurately evaluated the depth of myometrial invasion in 75 patients. Based on data from all cases, we found the sensitivity of detection of deep myometrial infiltration by MRI (Sv) 71 %, specificity (Sp) 92 %, accuracy (Acc) 84 %, positive predictive value (PPV) 86 % and negative predictive value (NPV) 83 %. Excluding patients with poor prognosis according to histology and grade, these data were Sv 71 %, Sp 95 %, Acc 87 %, PPV 90 %, NPV 84 %. In conclusion, MRI is an efficient diagnostic tool in assessing myometrial infiltration, which is necessary for proper preoperative staging and therapy planning, including evaluation of the necessity of lymphadenectomy. Certain factors may interfere with evaluation of MRI results, thus hindering the precise determination of the level of myometrial infiltration.

[Endometrial cancer in young patients: report of 17 cases]. / Fiatalkori endometriumcarcinoma. Saját anyagunk 17 esetének ismertetése.

Endometrial cancer of young (less then 40 years old) patients comprises 4-5% of all endometrial cancers in Hungary. The majority of patients did not give birth yet, so fertility sparing is very important. Fertility sparing treatment is possible if the tumor's histology is endometrial type and Grade 1 (well differentiated). The tumor localizes only to the endometrium and there is no myometrium infiltration. The authors present 17 cases of patients treated at the Department of Gynecology of National Institute of Oncology (Budapest, Hungary). In 3 cases conservative therapy (progesterone treatment) was possible, and 14 patients had to undergo surgery, because conservative treatment did fail. Of 17 patients 14 were never pregnant. The average patient's age was 32.35 ± 4.27 years. The mean body weight was 93.13 ± 30.79 kg (from 58 kg up to 147 kg); in 7 cases BMI (body mass index) was more than 30. After surgery histological examination had revealed 2 cases with normal ovaries, 1 case of simple cyst and 1 case of malignant ovarian tumor (serous adenocarcinoma, Grade 2), and 10 cases of polycystic ovaries associated with endometrial cancer. Of 3 cases that had only curettage, the endometrial cancer was Grade 1, and in 1 case radiological imaging showed simplex ovarian cyst. The authors' findings concerning young endometrial cancer patients confirm the results published in the literature. In cases suitable for fertility sparing treatment it is not sufficient to concentrate only on endometrial findings, but is very important to focus on the therapy of cystic ovaries (80% of which is PCO), obesity and diabetes mellitus as well.

[A probable etiological role of Merkel cell polyomavirus in the development of Merkel cell carcinoma]. / Merkel-sejtes polyomavírus mint a Merkel-sejtes carcinoma valószínu kóroka.

Approximately 20% of the tumours in humans are associated with contagious viral agents. Merkel cell carcinoma is a rare and highly aggressive tumour which may originate from the epidermal stratum basale, although the origin is still controversial. This tumour is most commonly found in elderly and immunocompromised patients in sun exposed areas, especially in the head and neck regions. Merkel cell carcinoma often causes a diagnostic challenge with a dramatically increasing incidence. In 2008, a DNA tumour virus, a polyomavirus (Merkel cell polyomavirus) was detected in Merkel cell carcinomas, and this finding helped to understand the etiological background of the disease. The infectious - probably viral - etiology resulted in a paradigm shift in pathogenesis and, hopefully, in therapy as well. This review summarizes the current knowledge related to Merkel cell carcinoma and the first oncogenic human polyomavirus, the Merkel cell polyomavirus, to promote the clinical adaptation of the information.

[Comparison of CT- and MRI-based clinical target volumes for 3-dimensional conformal external-beam radiotherapy of prostate cancer]. / CT és MRI alapján meghatározott céltérfogatok összehasonlítása prosztatarákos betegek 3 dimenziós konformális külso sugárkezelésében.

The aim of the study was to compare clinical target volumes defined by CT and MRI for 3 dimensional conformal external beam radiotherapy of prostate cancer. CT and T2-weighed MRI images with 3 mm slice thickness were acquired for 13 patients with clinically organ-confined prostate cancer. Target volumes were contoured by two clinicians ("AP" and "SZ") experienced in prostate radiotherapy. Two clinical target volumes were defined: prostate (CTVpros) and prostate with a margin including the proximal 1 cm of the seminal vesicles (CTVpvs). Eight clinical target volumes were outlined for all patients: CTVprosAPCT, CTVprosAPMR, CTVpvsAPCT, CTVpvsAPMR, CTVprosSZCT, CTVprosSZMR, CTVpvsSZCT, CTVpvsSZMR. Volumes were measured in cm3. The volumes of different PTVs were compared using the Student's t-test. Mean CTVpros and CTVpvs using CT vs. MRI were 36.9 (range:13.8-121) vs. 32.0 (9.7-120.1) (p=0.0002), and 77.2 (30.5-209.5) vs. 67.6 (29.8-191.1) (p=0.0001), respectively. Mean CTVprosAPCT vs. CTVprosAPMR were 39.2 vs. 32.0 (p<0.00005), respectively. Mean CTVprosSZCT vs. CTVprosSZMR were 34.6 vs. 31.9 (p=0.15). Mean CTVpvsAPCT vs. CTVpvsAPMR were 85.8 vs. 70.9 (p<0.00006). Mean CTVpvsSZCT vs. CTVpvsSZMR were 68.6 vs. 64.4 (p=0.14). Interobserver difference for CTVpros defined by CT images was significant (39.2 vs. 34.6; p=0,0058). However, the difference was not significant using MRI images (32.0 vs. 31.9; p=0.93). Interobserver differences for CTVpvs were significant using either CT (85.8 vs. 68.6; p=0.0001) or MRI (70.9 vs. 64.4; p=0.004). Ratio of mean volumes contoured by the two observers were 1,12 (CT) vs. 1 (MRI) for CTVpros and 1,2 (CT) vs. 1,09 (MRI) for CTVpvs. Clinical target volumes defined for prostate cancer external beam radiotherapy by MRI images are significantly smaller compared to CT image based contouring. The magnitudes of differences are observer dependent. The use of MRI decreases the interobserver difference of mean volumes with 11% and 12% for CTVpvs and CTVpros.

[Complete pathologic remission after preoperative high-dose brachytherapy in patients with operable cervical cancer: preliminary results of a prospective randomized study]. / Patológiai komplett remisszió preoperatív, nagy dózisteljesítményû brachyterápiát követoen operábilis méhnyakdaganatos betegeknél: egy prospektív, randomizált vizsgálat elozetes eredményei.

The purpose of the study was a preliminary evaluation of the efficacy of preoperative intracavitary high-dose-rate brachytherapy (HDR BT) in sterilization of the specimen of operable cervical cancer patients enrolled into a prospective, randomized study. Between 2005 and 2010, 100 operable cervical cancer patients of FIGO stage I/A2 (n=4), I/B1 (n=51), I/B2 (n=19), IIA (n=17), and proximal II/B (n=9) were randomized in two arms: in arm "A" (n=50) allocated treatment was 2x8 Gy preoperative intracavitary HDR BT followed by radical surgery, in arm "B" (n= 50) no preoperative treatment was given before the planned radical Wertheim hysterectomy. The rates of pathologic complete remission (pCR) were compared using the Fisher-exact test. In arm "A" 41 patients (82%), in arm "B" 42 patients (84%) underwent radical hysterectomy. The rate of pCR after preoperative BT was 26.8% (11/41), while in the control group the specimen was free of tumor in 7.1% (3/42; p=0.0204). Preoperative HDR BT for cervical cancer patients significantly increases the rate of pathologically tumor-free specimens. Longer follow-up is needed to evaluate the impact of pCR on local tumor control and survival. Our preliminary results support further enrollment of patients into our randomized clinical trial.

Effects of weight loss, induced by gastric bypass surgery, on HDL remodeling in obese women.

Plasma lipoproteins and glucose homeostasis were evaluated after marked weight loss before and over 12 months following Roux-en-Y gastric-bypass (RYGBP) surgery in 19 morbidly obese women. Standard lipids, remnant-lipoprotein cholesterol (RLP-C); HDL-triglyceride (TG); apolipoproteins (apo) A-I, A-II, E, and A-I-containing HDL subpopulations; lecithin-cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) mass and activity; plasma glucose and insulin levels were measured before and at 1, 3, 6, and 12 months after GBP surgery. Baseline concentrations of TG, RLP-C, glucose, and insulin were significantly higher in obese than in normal-weight, age-matched women, whereas HDL cholesterol (HDL-C), apoA-I, apoA-II, alpha-1 and alpha-2 levels were significantly lower. Over 1 year, significant decreases of body mass index, glucose, insulin, TG, RLP-C, HDL-TG, and prebeta-1 levels were observed with significant increases of HDL-C and alpha-1 levels (all P < 0.05). Changes of fat mass were correlated with those of LDL cholesterol (P = 0.018) and LCAT mass (P = 0.011), but not with CETP mass (P = 0.265). Changes of fasting plasma glucose concentrations were inversely correlated with those of CETP mass (P = 0.005) and alpha-1 level (P = 0.004). Changes of fasting plasma insulin concentrations were positively correlated with those of LCAT mass (P = 0.043) and inversely with changes of alpha-1 (P = 0.03) and alpha-2 (P = 0.05) concentrations. These results demonstrate beneficial changes in HDL remodeling following substantial weight loss induced by RYGBP surgery and that these changes are associated with improvement of glucose homeostasis in these patients.

Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women.

OBJECTIVE: A high degree of inter-individual variability in plasma lipid level response to hormone therapy (HT) has been reported. Variations in the oestrogen receptor alpha gene (ESR1) and in genes involved in lipid metabolism may explain some of the variability in response to HT. Subjects Postmenopausal Caucasian women (n = 208) participating in a placebo-controlled randomized trial of 3.2 years of hormone therapy (HT). METHODS: Plasma triglyceride (TG), remnant lipoprotein cholesterol (RLP-C), and high-density lipoprotein cholesterol (HDL-C) levels and HDL subpopulations were assessed at baseline and at follow up. Single nucleotide polymorphisms (SNPs) in ESR1 and in the ATP binding cassette A1 (ABCA1), cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC), lipoprotein lipase (LPL), and scavenger receptor class B type I (SRB1) genes were assessed for their association with baseline plasma levels and HT-related changes in levels of RLP-C and HDL subpopulations. RESULTS: Carriers of the ESR1 PvuII or IVS1-1505 variants had lower plasma TG concentrations and higher plasma HDL-C and alpha-1 and prealpha-1 HDL particle levels at baseline and showed greater increases in HDL-C, apo A-I and alpha-1 particle levels after HT than wild-type carriers. Carriers of the N291S and D9N variants in the LPL gene had significantly higher remnant lipoproteins and lower alpha-2 HDL particle levels at baseline. The CETP TaqIB SNP was a significant determinant of baseline plasma HDL-C and HDL subpopulation profile. CONCLUSIONS: Single nucleotide polymorphisms in ESR1, CETP and LPL had significant effects on baseline plasma levels of TG-rich and HDL subpopulations. With the exception of ESR1 SNPs, variation in genes involved in lipid metabolism has a very modest effect on lipoprotein response to HT.

Changes in remnant and high-density lipoproteins associated with hormone therapy and progression of coronary artery disease in postmenopausal women.

OBJECTIVE: This study examined the effect of hormone therapy (HT) on the plasma concentration of remnant lipoprotein cholesterol (RLP-C) and high-density lipoprotein (HDL) subpopulations and the contribution of HT-related changes in these lipoproteins to the progression of coronary heart disease (CHD) in postmenopausal women. METHODS: Study participants were 256 women who completed the Estrogen Replacement and Atherosclerosis (ERA) trial, a placebo-controlled, randomized trial that examined the effects of 3.2 years of conjugated equine estrogen (CEE, 0.625 mg/day) or CEE (0.625 mg/day) plus medroxyprogesterone acetate (MPA, 2.5mg/day) on postmenopausal women with established coronary atherosclerosis. Quantitative coronary angiography and plasma RLP-C and HDL subpopulations were assessed at baseline and at follow-up. RESULTS: Relative to placebo, both CEE and CEE+MPA caused a significant reduction in plasma RLP-C concentrations and a significant increase in alpha1 and alpha2 HDL subpopulations. However, in the HT-treated subjects, faster progression of coronary atherosclerosis was observed in women who experienced the greatest reductions in RLP-C and in prebeta1 HDL subpopulations. CONCLUSIONS: Our data suggest that individual variability in RLP-C and HDL subpopulation response to HT is a predictor of CHD progression. Lipoprotein response to HT may be an indirect marker of susceptibility to other harmful effect of HT in postmenopausal women with established CHD or an indication of formation of dysfunctional lipoproteins.