Imaging breast cancer using hyperpolarized carbon-13 MRI.

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2-), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2- invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.

Quantifying normal human brain metabolism using hyperpolarized [1-13C]pyruvate and magnetic resonance imaging.

Hyperpolarized 13C Magnetic Resonance Imaging (13C-MRI) provides a highly sensitive tool to probe tissue metabolism in vivo and has recently been translated into clinical studies. We report the cerebral metabolism of intravenously injected hyperpolarized [1-13C]pyruvate in the brain of healthy human volunteers for the first time. Dynamic acquisition of 13C images demonstrated 13C-labeling of both lactate and bicarbonate, catalyzed by cytosolic lactate dehydrogenase and mitochondrial pyruvate dehydrogenase respectively. This demonstrates that both enzymes can be probed in vivo in the presence of an intact blood-brain barrier: the measured apparent exchange rate constant (kPL) for exchange of the hyperpolarized 13C label between [1-13C]pyruvate and the endogenous lactate pool was 0.012 ±â€¯0.006 s-1 and the apparent rate constant (kPB) for the irreversible flux of [1-13C]pyruvate to [13C]bicarbonate was 0.002 ±â€¯0.002 s-1. Imaging also revealed that [1-13C]pyruvate, [1-13C]lactate and [13C]bicarbonate were significantly higher in gray matter compared to white matter. Imaging normal brain metabolism with hyperpolarized [1-13C]pyruvate and subsequent quantification, have important implications for interpreting pathological cerebral metabolism in future studies.

Imaging Glioblastoma Metabolism by Using Hyperpolarized [1-13C]Pyruvate Demonstrates Heterogeneity in Lactate Labeling: A Proof of Principle Study.

Purpose To evaluate glioblastoma (GBM) metabolism by using hyperpolarized carbon 13 (13C) MRI to monitor the exchange of the hyperpolarized 13C label between injected [1-13C]pyruvate and tumor lactate and bicarbonate. Materials and Methods In this prospective study, seven treatment-naive patients (age [mean ± SD], 60 years ± 11; five men) with GBM were imaged at 3 T by using a dual-tuned 13C-hydrogen 1 head coil. Hyperpolarized [1-13C]pyruvate was injected, and signal was acquired by using a dynamic MRI spiral sequence. Metabolism was assessed within the tumor, in the normal-appearing brain parenchyma (NABP), and in healthy volunteers by using paired or unpaired t tests and a Wilcoxon signed rank test. The Spearman ρ correlation coefficient was used to correlate metabolite labeling with lactate dehydrogenase A (LDH-A) expression and some immunohistochemical markers. The Benjamini-Hochberg procedure was used to correct for multiple comparisons. Results The bicarbonate-to-pyruvate (BP) ratio was lower in the tumor than in the contralateral NABP (P < .01). The tumor lactate-to-pyruvate (LP) ratio was not different from that in the NABP (P = .38). The LP and BP ratios in the NABP were higher than those observed previously in healthy volunteers (P < .05). Tumor lactate and bicarbonate signal intensities were strongly correlated with the pyruvate signal intensity (ρ = 0.92, P < .001, and ρ = 0.66, P < .001, respectively), and the LP ratio was weakly correlated with LDH-A expression in biopsy samples (ρ = 0.43, P = .04). Conclusion Hyperpolarized 13C MRI demonstrated variation in lactate labeling in GBM, both within and between tumors. In contrast, bicarbonate labeling was consistently lower in tumors than in the surrounding NABP. Keywords: Hyperpolarized 13C MRI, Glioblastoma, Metabolism, Cancer, MRI, Neuro-oncology Supplemental material is available for this article. Published under a CC BY 4.0 license.

Hyperpolarized 13C MRI of Tumor Metabolism Demonstrates Early Metabolic Response to Neoadjuvant Chemotherapy in Breast Cancer.

Purpose: To compare hyperpolarized carbon 13 (13C) MRI with dynamic contrast material-enhanced (DCE) MRI in the detection of early treatment response in breast cancer. Materials and Methods: In this institutional review board-approved prospective study, a woman with triple-negative breast cancer (age, 49 years) underwent 13C MRI after injection of hyperpolarized [1-carbon 13 {13C}]-pyruvate and DCE MRI at 3 T at baseline and after one cycle of neoadjuvant therapy. The 13C-labeled lactate-to-pyruvate ratio derived from hyperpolarized 13C MRI and the pharmacokinetic parameters transfer constant (K trans) and washout parameter (k ep) derived from DCE MRI were compared before and after treatment. Results: Exchange of the 13C label between injected hyperpolarized [1-13C]-pyruvate and the endogenous lactate pool was observed, catalyzed by the enzyme lactate dehydrogenase. After one cycle of neoadjuvant chemotherapy, a 34% reduction in the 13C-labeled lactate-to-pyruvate ratio resulted in correct identification of the patient as a responder to therapy, which was subsequently confirmed via a complete pathologic response. However, DCE MRI showed an increase in mean K trans (132%) and mean k ep (31%), which could be incorrectly interpreted as a poor response to treatment. Conclusion: Hyperpolarized 13C MRI enabled successful identification of breast cancer response after one cycle of neoadjuvant chemotherapy and may improve response prediction when used in conjunction with multiparametric proton MRI.Published under a CC BY 4.0 license.

Restoration of ovulation after unilateral ovariectomy in a woman with McCune-Albright syndrome: a case report.

INTRODUCTION: McCune-Albright syndrome (MAS) is characterized by peripheral precocious puberty, café-au-lait spots, and polyostotic fibrous dysplasia. This syndrome is due to a post-zygotic mutation of the GNAS1 gene with mosaic distribution and unilateral predominance. Clinical manifestations depend on the tissues carrying the mutation. We describe the ovarian function before and after unilateral ovariectomy in a woman with MAS and bilateral distribution of the GNAS1 gene mutation. CASE REPORT: A 33-year-old patient, previously diagnosed as having MAS, presented irregular menstrual cycles (30-180 days) and monophasic temperature curves. Transvaginal ultrasound and blood tests were repeated at 3-day intervals over 3 months. Findings included a persistent quiescent left ovary, a persistent polycystic right ovary, constantly high estradiol-17beta (E2) levels, and very low FSH and LH levels. She also presented severe persistent pelvic pain. Because of unilateral ovarian activity, a unilateral right ovariectomy was performed as well as biopsy of the remaining left ovary. A GNAS1 gene mutation was identified in both ovaries. A regular monthly menstrual cycle was immediately restored. On day 3 of the menstrual cycle, E2 level was 30 pg/ml, FSH level was 7.5 mIU/ml, and LH level was 6.4 mIU/ml. On day 17, pelvic ultrasound showed one follicle of 25 mm in the left ovary. On day 21, the progesterone level was 13.1 ng/ml. DISCUSSION: This is the first report of ovulation being restored following unilateral ovariectomy in an adult patient suffering from severe MAS with GNAS1 gene mutation identified in both ovaries.

Analytical performance of a new two-step ADVIA Centaur estradiol immunoassay during ovarian stimulation.

Measurement of estradiol is useful in women undergoing ovarian stimulation for in vitro fertilization and embryo transfer (IVF-ET). The analytical performance of a new two-step estradiol assay (ADVIA Centaur) estradiol-6 III from Bayer Diagnostics) was evaluated in 41 sera from 11 women undergoing ovarian stimulation. The results were compared to those obtained with two radioimmunoassays (RIAs; RIA Estradiol Immunotech IM 1663 from Beckmann Coulter and Coat-A-Count Estradiol from Diagnostic Products Corporation) and with one chemiluminescent immunoassay (CLIA; ADVIA Centaur estradiol-6). The ADVIA Centaur) estradiol-6 III assay was the most sensitive assay, with a functional sensitivity of 55 pmol/L. Within- and between-run coefficients of variation calculated for the new ADVIA Centaur assay ranged from 3.3% to 9%, which was better than the precision obtained for the other assays. A dilution test showed serum interferences when estradiol was measured in non-diluted samples. No statistical difference was observed between the estradiol results obtained in diluted sera with the new two-step ADVIA Centaur assay and those measured with the Immunotech RIA and the other CLIA. In conclusion, this new, two-step estradiol assay performed on the ADVIA Centaur system displays suitable sensitivity, precision and intermethod agreement with the Immunotech RIA for the measurement of serum estradiol concentrations in women undergoing ovarian stimulation and IVF-ET. For correct linearity, estradiol measurement should be performed on diluted samples.

Interest of pentoxifylline in ICSI with frozen-thawed testicular spermatozoa from patients with non-obstructive azoospermia.

Selection for intracytoplasmic sperm injection (ICSI) of viable frozen-thawed testicular spermatozoa obtained from patients suffering from non-obstructive azoospermia is very often long, difficult and sometimes impossible. The purpose of this study was to determine if the use of pentoxifylline (PF) could facilitate this selection in stimulating sperm motility. From January 2000 to December 2004, 108 ICSI cycles with non-obstructive azoospermia were performed. From these 108 cycles, in 64 cycles where no motile spermatozoa were observed or when the time search per spermatozoa was above 20 min, 1.5 mmol/l PF was used for 10 min, whereas the 44 other ICSI cycles were performed using spontaneously motile spermatozoa (control group). In all cases, PF either initiated the motility when no motile spermatozoa were observed, or stimulated the motility, reducing dramatically the time search per spermatozoa. The total fertilization rate was 54.2% versus 66.7% in the control group (P < 0.02). Twenty-nine pregnancies out of the 64 PF cycles (45.3% per cycle) occurred, including 20 deliveries of 23 healthy children and eight ongoing pregnancies, whereas 12 pregnancies were obtained in the control group (27.3% per cycle), including nine deliveries of 13 healthy children. In conclusion, in 100% of cycles pentoxifylline allows the selection of viable frozen-thawed testicular spermatozoa with the same outcome after ICSI as that observed with fresh ejaculated spermatozoa.

Contribution of embryo cryopreservation to elective single embryo transfer in IVF-ICSI.

Single embryo transfer is the best way to reduce the risk of multiple pregnancy in IVF-intracytoplasmic sperm injection (ICSI). Between June 2002 and December 2004, all patients (first cycle, female age <38 years) were offered the choice between having one (SET) or two (DET) embryos transferred. Among 493 couples, 428 had at least two good quality embryos, and among them, 32% opted for SET. The SET and DET populations were not comparable (patients in the SET group were younger and had more oocytes retrieved), and therefore a paired, case-control analysis was performed involving 130 SET couples and 130 DET couples, matched according to the female partners' ages and the numbers of embryos available. All of the SET patients, and 82% of the DET group, had at least one embryo cryopreserved, (3.9 versus 2.8 embryos). The option of SET was continued for the frozen-thawed embryo transfers. The pregnancy rate following embryo transfer was significantly lower after SET compared with DET for both fresh (27.6 versus 36.9%; P < 0.05) and frozen-thawed (14.4 versus 23.5%) embryos. However, the cumulative live birth rates following the transfer of fresh and frozen embryos were identical between the two groups (43 versus 45%), with a high prevalence of twins following DET (34 versus 0%).

Nitric oxide donors for patients undergoing IVF. A prospective, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Nitric oxide (NO) is involved in local control of the uterine cycle and in preparation of the uterus for pregnancy. NO donors, acting as vasodilating agents, may therefore have possible therapeutic uses, for example they may be of benefit to patients with a history of implantation failure. In a prospective, comparative, randomized, placebo-controlled study, we assessed the efficacy of nitroglycerin (NTG) administered to 138 IVF patients with a history of implantation failure. METHODS: Controlled ovarian stimulation was performed with long agonist protocol combined with recombinant FSH. Embryos were transferred on day 2 or 3 after oocyte retrieval. Eligible patients were those who had at least two 'good quality' embryos. The NTG patch was administered the day before embryo transfer and continued until either the results of the pregnancy test were known or until menstruation occurred. RESULTS: Ovarian response, implantation rate and pregnancy rate were comparable between both groups. No difference was observed in uterine Doppler findings, particularly the mean pulsatility index. CONCLUSIONS: NTG treatment the day before embryo transfer was no more effective than placebo in improving the implantation or pregnancy rates in a population of IVF patients with a previous history of implantation failures.