Long-term follow-up after lymphodepleting autologous haematopoietic cell transplantation for treatment-resistant systemic lupus erythematosus.

OBJECTIVE: Autologous haematopoietic cell transplantation (AHSCT) improves immunologic dysfunction in patients with SLE. However, the curative potential of this therapy remains uncertain. This study reports outcomes in SLE patients receiving a lymphodepleting, reduced intensity regimen for AHSCT in SLE. METHODS: Eight patients with SLE refractory to treatment, including i.v. cyclophosphamide (CYC), were enrolled. Five had LN and three CNS involvement as primary indications for transplant. Haematopoietic cell mobilization with CYC, G-CSF and rituximab was followed by collection of CD34+ positively selected cells. The conditioning regimen consisted of concurrent administration of CYC, fludarabine and rituximab. All immunosuppressive medications were discontinued at the start of mobilization and CS were rapidly tapered after the transplant. RESULTS: Five of eight patients achieved a complete response, including a decline in the SLEDAI to zero, which was sustained in four patients for a median of 165 months (range 138-191). One patient achieved a partial response, which was followed by relapse at month 18. Two patients with nephritis and underlying comorbidities in most organs had early deaths from infection and multiorgan failure. AHSCT resulted in profound lymphodepletion, followed by expansion of Treg cells and repopulation of naive T and B cells. Patients with a complete response showed a sustained suppression of the SLE-associated IFN-induced gene signature, marked depletion of memory and plasmablast B cells and resultant sustained elimination of anti-dsDNA antibody. CONCLUSION: Durable clinical and serologic remissions with suppression in the IFN gene signature can be achieved in refractory SLE following lymphodepleting AHSCT. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00076752.

Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL.

PURPOSE: CD19 chimeric antigen receptor (CD19-CAR) T cells induce high response rates in children and young adults (CAYAs) with B-cell acute lymphoblastic leukemia (B-ALL), but relapse rates are high. The role for allogeneic hematopoietic stem-cell transplant (alloHSCT) following CD19-CAR T-cell therapy to improve long-term outcomes in CAYAs has not been examined. METHODS: We conducted a phase I trial of autologous CD19.28ζ-CAR T cells in CAYAs with relapsed or refractory B-ALL. Response and long-term clinical outcomes were assessed in relation to disease and treatment variables. RESULTS: Fifty CAYAs with B-ALL were treated (median age, 13.5 years; range, 4.3-30.4). Thirty-one (62.0%) patients achieved a complete remission (CR), 28 (90.3%) of whom were minimal residual disease-negative by flow cytometry. Utilization of fludarabine/cyclophosphamide-based lymphodepletion was associated with improved CR rates (29/42, 69%) compared with non-fludarabine/cyclophosphamide-based lymphodepletion (2/8, 25%; P = .041). With median follow-up of 4.8 years, median overall survival was 10.5 months (95% CI, 6.3 to 29.2 months). Twenty-one of 28 (75.0%) patients achieving a minimal residual disease-negative CR proceeded to alloHSCT. For those proceeding to alloHSCT, median overall survival was 70.2 months (95% CI, 10.4 months to not estimable). The cumulative incidence of relapse after alloHSCT was 9.5% (95% CI, 1.5 to 26.8) at 24 months; 5-year EFS following alloHSCT was 61.9% (95% CI, 38.1 to 78.8). CONCLUSION: We provide the longest follow-up in CAYAs with B-ALL after CD19-CAR T-cell therapy reported to date and demonstrate that sequential therapy with CD19.28ζ-CAR T cells followed by alloHSCT can mediate durable disease control in a sizable fraction of CAYAs with relapsed or refractory B-ALL (ClinicalTrials.gov identifier: NCT01593696).

The MEK inhibitor selumetinib reduces spinal neurofibroma burden in patients with NF1 and plexiform neurofibromas.

BACKGROUND: Spinal neurofibromas (SNFs) in neurofibromatosis type 1 (NF1) can cause progressive spinal cord compression and neurological dysfunction. The MEK inhibitor selumetinib shrinks the majority of plexiform neurofibromas (PNs) in patients with NF1. We assessed the effect of selumetinib on SNF. METHODS: Pediatric and adult patients with NF1 and inoperable PN participating in phase 2 studies of selumetinib for PN were included in this analysis if they had SNF and serial spine magnetic resonance imaging (MRI). Selumetinib was administered orally at the recommended dose of 25 mg/m2/dose twice daily (max 50 mg b.i.d.; 1 cycle = 28 days). We qualitatively assessed the effect of selumetinib on SNF-related spinal canal distortion, cerebrospinal fluid distribution, and spinal cord deformity on MRI. RESULTS: Twenty-four patients (18 male), median age 16.9 years (range, 6.2-60.3), had SNF, 22 of which were associated with the same nerves as the target PN assessed on the clinical trial. Twenty patients had spinal cord deformity. Twenty-three patients completed at least 12 treatment cycles to date. Eighteen patients showed subtle to a marked improvement in SNF burden, 5 remained stable, and no worsening was observed during treatment. CONCLUSIONS: This is the first study describing the effect of selumetinib on SNF. Of 24 patients, 18 exhibited some improvement of SNF burden on imaging. These findings suggest that selumetinib may prevent the worsening of cord compression, potentially reducing the need for surgical interventions in select patients or benefitting patients who do not have a surgical option. Prospective evaluation of the clinical benefit of selumetinib for SNF is warranted.

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

PURPOSE: To characterize the molecular genetics of autosomal recessive Noonan syndrome. METHODS: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction. RESULTS: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings. CONCLUSION: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.

Spontaneously regressing brain lesions in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a metabolic disorder caused by an inborn error of cholesterol synthesis that affects the development of many organ systems. Malformations in the central nervous system typically involve midline structures and reflect abnormal growth and differentiation of neurons and supporting cells. Despite these defects in central nervous system development, brain tumor formation has only rarely been reported in association with SLOS. We present three individuals with SLOS and lesions in the basal ganglia or brainstem detected by MRI that were concerning for tumor formation. However, the individuals' clinical and neurological course remained stable, and the lesions regressed after several years. These lesions have similarities to spongiotic changes observed in individuals with neurofibromatosis type 1 (NF1). Notably, impaired activity of small GTPases is present in both SLOS and NF1, perhaps giving mechanistic insight into the formation of these lesions.

Somatic AKT1 mutations cause meningiomas colocalizing with a characteristic pattern of cranial hyperostosis.

Somatic genetic mutations in meningiomas are associated with histologic subtypes, anatomical location, and grade. Concomitant hyperostosis occurs with some meningiomas and the pathogenesis is not well understood. Cranial hyperostosis and meningiomas are common in patients with Proteus syndrome, which is caused by a somatic activating mutation in AKT1 c.49G>A. This same mutation has also been found in 6-9% of sporadic non-syndromic meningiomas. Sixty-one patients with Proteus syndrome meeting clinical diagnostic criteria were evaluated at the NIH from 1997 to 2014. Of these 61, 52 had a somatic activating mutation (c.49G>A, p.Glu17Lys) in AKT1 confirmed from affected tissue samples. Photographs, physical examination and/or autopsy, X-rays, CT, and/or MRI scan of the head were reviewed in 29/52 patients. Of the 29 patients, the most common intracranial tumor was meningioma, all co-localizing with cranial hyperostosis, and diagnosed at younger ages than typical for isolated, non-syndromic meningiomas. These patients had progressive cranial overgrowth that consisted primarily of diploic space expansion, and was characterized by unilateral, parasagittal, and frontal bone involvement. We hypothesize that sporadic meningothelial and transitional subtype meningiomas are a forme fruste or microform of Proteus syndrome, and activation of the AKT/PI3K pathway drives hyperostosis in both non-syndromic, and Proteus-related meningiomas. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

Evaluation of disease progression in INCL by MR spectroscopy.

OBJECTIVE: Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury. As part of a pilot study to evaluate treatment benefits of cysteamine bitartrate and N-acetylcysteine, we quantitatively measured brain metabolite levels using magnetic resonance spectroscopy (MRS). METHODS: A subset of two patients from a larger treatment and follow-up study underwent serial quantitative single-voxel MRS examinations of five anatomical sites. Three echo times were acquired in order to estimate metabolite T2. Measured metabolite levels included correction for partial volume of cerebrospinal fluid. Comparison of INCL patients was made to a reference group composed of asymptomatic and minimally symptomatic Niemann-Pick disease type C patients. RESULTS: In INCL patients, N-acetylaspartate (NAA) was abnormally low at all locations upon initial measurement, and further declined throughout the follow-up period. In the cerebrum (affected early in the disease course), choline and myo-inositol were initially elevated and fell during the follow-up period, whereas in the cerebellum and brainstem (affected later), choline and myo-inositol were initially normal and rose subsequently. INTERPRETATION: Choline and myo-inositol levels in our patients are consistent with patterns of neuroinflammation observed in two INCL mouse models. Low, persistently declining NAA was expected based on the progressive, irreversible nature of the disease. Progression of metabolite levels in INCL has not been previously quantified; therefore the results of this study serve as a reference for quantitative evaluation of future therapeutic interventions.

Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study.

BACKGROUND: Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative lysosomal storage disease caused by mutations in the gene (CLN1 or PPT1) encoding palmitoyl-protein thioesterase-1 (PPT1). We have previously reported that phosphocysteamine and N-acetylcysteine mediate ceroid depletion in cultured cells from patients with this disease. We aimed to assess whether combination of oral cysteamine bitartrate and N-acetylcysteine is beneficial for patients with neuronal ceroid lipofuscinosis. METHODS: Children between 6 months and 3 years of age with infantile neuronal ceroid lipofuscinosis with any two of the seven most lethal PPT1 mutations were eligible for inclusion in this pilot study. All patients were recruited from physician referrals. Patients received oral cysteamine bitartrate (60 mg/kg per day) and N-acetylcysteine (60 mg/kg per day) and were assessed every 6-12 months until they had an isoelectric electroencephalogram (EEG, attesting to a vegetative state) or were too ill to travel. Patients were also assessed by electroretinography, brain MRI and magnetic resonance spectroscopy (MRS), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Children also underwent physical and neurodevelopmental assessments on the Denver scale. Outcomes were compared with the reported natural history of infantile neuronal ceroid lipofuscinosis and that of affected older siblings. This trial is registered with ClinicalTrials.gov, number NCT00028262. FINDINGS: Between March 14, 2001, and June 30, 2012, we recruited ten children with infantile neuronal ceroid lipofuscinosis; one child was lost to follow-up after the first visit and nine patients (five girls and four boys) were followed up for 8 to 75 months. MRI showed abnormalities similar to those in previous reports; brain volume and N-acetyl aspartic acid (NAA) decreased steadily, but no published quantitative MRI or MRS studies were available for comparison. None of the children acquired new developmental skills, and their retinal function decreased progressively. Average time to isoelectric EEG (52 months, SD 13) was longer than reported previously (36 months). At the first follow-up visit, peripheral leukocytes in all nine patients showed virtually complete depletion of GRODs. Parents and physicians reported less irritability, improved alertness, or both in seven patients. No treatment-related adverse events occurred apart from mild gastrointestinal discomfort in two patients, which disappeared when liquid cysteamine bitartrate was replaced with capsules. INTERPRETATION: Our findings suggest that combination therapy with cysteamine bitartrate and N-acetylcysteine is associated with delay of isoelectric EEG, depletion of GRODs, and subjective benefits as reported by parents and physicians. Our systematic and quantitative report of the natural history of patients with infantile neuronal ceroid lipofuscinosis provides a guide for future assessment of experimental therapies. FUNDING: National Institutes of Health.

Measurements of the pons as a biomarker of progression for pediatric DIPG.

Treatment of pediatric diffuse intrinsic pontine glioma (DIPG) remains challenging, and reliable biomarkers of response are lacking. Radiographic response is a primary endpoint in many investigational studies of brain tumors, but there is no standard method of tumor measurement for DIPG, significant inter-observer variability exists given the invasive nature of these tumors, and tumor measurements are not predictive of outcome. Because DIPGs involve a significant portion of the pons, we evaluated the reliability and prognostic value of one-dimensional (1D) and two-dimensional (2D) pons measurements using anatomical landmarks rather than tumor boundaries. Patients with DIPG (n = 75) were evaluated longitudinally at our institution using MRI. Four readers independently performed 1D and 2D measurements of the pons using FLAIR images. Agreement and inter-reader variability were evaluated using differences among the six reader pairs and the coefficient of variation (CV). Prognostic value of pons measurements was calculated using Cox proportional hazards models, where relative hazard (RH) represents risk of death. Readers evaluated 384 exams. Agreement of readers' 1D and 2D measurements was strong (median difference between reader pairs 3.1 and 5.4%, respectively), with low inter-reader variability (median CV = 3.1% and median CV = 4.8%, respectively). Increases in 1D and 2D pons measurements over time indicated poorer prognosis (RH = 2.29, p = 0.0025 and RH = 1.13, p = 0.0016, respectively), with shorter overall survival. Pons measurements had low inter-reader variability compared to previously reported tumor measurement techniques and correlated with outcome in children with DIPG. Measurements of the pons (as opposed to direct measurements of tumor) are a viable in vivo biomarker for DIPG.

Brain magnetic resonance imaging findings in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a neurodevelopmental disorder caused by inborn errors of cholesterol metabolism resulting from mutations in 7-dehydrocholesterol reductase (DHCR7). There are only a few studies describing the brain imaging findings in SLOS. This study examines the prevalence of magnetic resonance imaging (MRI) abnormalities in the largest cohort of patients with SLOS to date. Fifty-five individuals with SLOS (27 M, 28 F) between age 0.17 years and 25.4 years (mean = 6.2, SD = 5.8) received a total of 173 brain MRI scans (mean = 3.1 per subject) on a 1.5T GE scanner between September 1998 and December 2003, or on a 3T Philips scanner between October 2010 and September 2012; all exams were performed at the Clinical Center of the National Institutes of Health. We performed a retrospective review of these imaging studies for both major and minor brain anomalies. Aberrant MRI findings were observed in 53 of 55 (96%) SLOS patients, with abnormalities of the septum pellucidum the most frequent (42/55, 76%) finding. Abnormalities of the corpus callosum were found in 38 of 55 (69%) patients. Other findings included cerebral atrophy, cerebellar atrophy, colpocephaly, white matter lesions, arachnoid cysts, Dandy-Walker variant, and type I Chiari malformation. Significant correlations were observed when comparing MRI findings with sterol levels and somatic malformations. Individuals with SLOS commonly have anomalies involving the midline and para-midline structures of the brain. Further studies are required to examine the relationship between structural brain abnormalities and neurodevelopmental disability in SLOS.

Brain morphological abnormalities in 49,XXXXY syndrome: A pediatric magnetic resonance imaging study.

As a group, people with the sex chromosome aneuploidy 49,XXXXY have characteristic physical and cognitive/behavioral tendencies, although there is high individual variation. In this study we use magnetic resonance imaging (MRI) to examine brain morphometry in 14 youth with 49,XXXXY compared to 42 age-matched healthy controls. Total brain size was significantly smaller (t=9.0, p<.001), and rates of brain abnormalities such as colpocephaly, plagiocephaly, periventricular cysts, and minor craniofacial abnormalities were significantly increased. White matter lesions were identified in 50% of subjects, supporting the inclusion of 49,XXXXY in the differential diagnosis of small multifocal white matter lesions. Further evidence of abnormal development of white matter was provided by the smaller cross sectional area of the corpus callosum. These results suggest that increased dosage of genes on the X chromosome has adverse effects on white matter development.

Measurement of glutathione in normal volunteers and stroke patients at 3T using J-difference spectroscopy with minimized subtraction errors.

PURPOSE: To develop and optimize a (1)H magnetic resonance spectroscopy (MRS) method for measuring brain glutathione (GSH) levels. MATERIALS AND METHODS: Phantom experiments and density operator simulations were performed to determine the optimal TE for measuring GSH at 3T using J-difference spectral editing. In vivo data collected from 11 normal volunteers (43 measurements) and five stroke patients (10 measurements) were processed using a new spectral alignment method (adaptive spectral registration). RESULTS: In phantom experiments and density operator simulations where relaxation effects were ignored, close to maximum GSH signal (2.95 ppm) was obtained at TE approximately 131 msec with minimum N-acetyl-aspartate (NAA) signal interference. Using adaptive spectral registration, GSH levels in healthy volunteers were found to be 1.20 +/- 0.14 mM (mean +/- standard deviation [SD]). GSH levels in stroke patients were found to be 1.19 +/- 0.24 mM in lesion and 1.25 +/- 0.19 mM in contralateral normal tissue. In comparison, the SDs were significantly larger when only the NAA singlet (2.01 ppm) was used as a navigator for spectral alignment. CONCLUSION: Spectral editing using J-differences is a reliable method for measuring GSH levels in volunteers and stroke patients.

Inter-observer variability in the measurement of diffuse intrinsic pontine gliomas.

Diffuse intrinsic pontine glioma (DIPG) is an invasive pediatric brainstem tumor with a poor prognosis. Patients commonly enter investigational trials, many of which use radiographic response as an endpoint for assessing drug efficacy. However, DIPGs are difficult to measure on magnetic resonance imaging (MRI). In this study, we characterized the reproducibility of these commonly performed measurements. Each of four readers measured 50 MRI scans from DIPG patients and inter-observer variability was estimated with descriptive statistics. Results confirmed that there is wide variability in DIPG tumor measurements between readers for all image types. Measurements on FLAIR imaging were most consistent. For patients on clinical trials, measurement of DIPG should be performed by a single reader while comparing prior images side-by-side. Endpoints for clinical trials determining efficacy in this population should also include more objective measures, such as survival, and additional endpoints need to be investigated.

Detection and characterization of neurotoxicity in cancer patients using proton MR spectroscopy.

OBJECTIVE: The study objective was to detect abnormalities and identify relationships between brain metabolic ratios determined by proton magnetic resonance spectroscopic imaging ((1)H-MRSI) and neuropsychological (NP) function in cancer patients at risk for neurotoxicity. METHODS: Thirty-two patients received (1)H-MRSI using a multi-slice, multi-voxel technique on a 1.5T magnet. Cho/NAA, NAA/Cr, and Cho/Cr ratios were identified in seven pre-determined sites without tumor involvement. A battery of age-appropriate NP tests was administered within 7 days of imaging. Relationships were examined between test scores and metabolite ratios. CONCLUSIONS: This study identifies relationships between brain metabolite ratios and cognitive functioning in cancer patients. (1)H-MRSI may be useful in early detection of neurotoxic effects, but prospective longitudinal studies in a homogeneous population are recommended to determine the prognostic value.

Adding in vivo quantitative 1H MR spectroscopy to improve diagnostic accuracy of breast MR imaging: preliminary results of observer performance study at 4.0 T.

PURPOSE: To determine whether the addition of in vivo quantitative hydrogen 1 (1H) magnetic resonance (MR) spectroscopy can improve the radiologist's diagnostic accuracy in interpreting breast MR images to distinguish benign from malignant lesions. MATERIALS AND METHODS: The study was approved by the institutional review board and, where appropriate, was compliant with the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Fifty-five breast MR imaging cases-one lesion each in 55 patients aged 24-66 years with biopsy-confirmed findings-were retrospectively evaluated by four radiologists. Patients were examined with contrast material-enhanced fat-suppressed T1-weighted 4.0-T MR imaging. The concentration of total choline-containing compounds (tCho) was quantified by using single-voxel 1H MR spectroscopy. For each case, the radiologists were asked to give the percentage probability of malignancy, the Breast Imaging and Reporting Data System category, and a recommendation for patient treatment. Two interpretations were performed for each case: The initial interpretation was based on the lesion's morphologic features and time-signal intensity curve, and the second interpretation was based on the lesion's morphologic features, time-signal intensity curve, and tCho concentration. Receiver operating characteristic (ROC), Wilcoxon signed rank, kappa statistic, and accuracy (based on the area under the ROC curve) analyses were performed. RESULTS: Of the 55 lesions evaluated, 35 were invasive carcinomas and 20 were benign. The addition of 1H MR spectroscopy resulted in higher sensitivity, specificity, accuracy, and interobserver agreement for all four radiologists. More specifically, two of the four radiologists achieved a significant improvement in sensitivity (P=.03, P=.03), and all four radiologists achieved a significant improvement in accuracy (P = .01, P = .05, P = .009, P < .001). CONCLUSION: Current study results suggest that the addition of quantitative 1H MR spectroscopy to the breast MR imaging examination may help to improve the radiologist's ability to distinguish benign from malignant breast lesions.

Neoadjuvant chemotherapy of locally advanced breast cancer: predicting response with in vivo (1)H MR spectroscopy--a pilot study at 4 T.

PURPOSE: To determine if changes in the concentration of choline-containing compounds (tCho) from before primary systemic therapy (PST) to within 24 hours after the first treatment enable prediction of clinical response in patients with locally advanced breast cancer. MATERIALS AND METHODS: Sixteen women with biopsy-confirmed locally advanced breast cancer scheduled to undergo doxorubicin-based PST were recruited. Magnetic resonance (MR) imaging and spectroscopy were performed at 4 T prior to treatment, within 24 hours after the first dose, and after the fourth dose. Lesion size was assessed by using gadolinium-enhanced MR imaging. Lesion tCho concentration was quantified by using single-voxel hydrogen 1 MR spectroscopy. Statistical analysis was performed by using the Pearson correlation coefficient and the Wilcoxon rank sum test. RESULTS: Fourteen of 16 patients completed the protocol. In one patient, the level of tCho was not measurable because of unfavorable lesion morphology for MR spectroscopy voxel placement. Of the remaining 13 patients, four had inflammatory breast cancer, six had invasive ductal carcinoma, two had invasive lobular carcinoma, and one had mixed invasive ductal and lobular carcinoma. On the basis of the Response Evaluation Criteria in Solid Tumors, eight of 13 patients had an objective response and five had no response. The change in concentration of tCho from baseline to within 24 hours after the first dose of PST showed significant positive correlation with the change in lesion size (R = 0.79, P = .001). Change in tCho concentration within 24 hours after first dose was significantly different between patients with objective response and those with no response (P = .007). CONCLUSION: These results suggest that the change in tCho concentration between baseline and 24 hours after the first dose of PST can serve as an indicator for predicting clinical response to doxorubicin-based chemotherapy in locally advanced breast cancer.

In vivo quantification of choline compounds in the breast with 1H MR spectroscopy.

This work describes a methodology for quantifying levels of total choline-containing compounds (tCho) in the breast using in vivo (1)H MR spectroscopy (MRS) at high field (4 Tesla). Water is used as an internal reference compound to account for the partial volume of adipose tissue. Peak amplitudes are estimated by fitting one peak at a time over a narrow frequency band to allow measurement of small metabolite resonances in spectra with large lipid peaks. This quantitative method significantly improves previously reported analysis methods by accounting for the variable sensitivity of breast (1)H MRS measurements. Using this technique, we detected and quantified a tCho peak in 214 of 500 in vivo spectra. tCho levels were found to be significantly higher in malignancies than in benign abnormalities and normal breast tissues, which suggests that this technique could be used to diagnose suspicious lesions and monitor response to cancer treatments.

Eliminating spurious lipid sidebands in 1H MRS of breast lesions.

Detecting metabolites in breast lesions by in vivo (1)H MR spectroscopy can be difficult due to the abundance of mobile lipids in the breast which can produce spurious sidebands that interfere with the metabolite signals. Two-dimensional J-resolved spectroscopy has been demonstrated in the brain as a means to eliminate these artifacts from a large water signal; coherent sidebands are resolved at their natural frequencies, leaving the noncoupled metabolite resonances in the zero-frequency trace of the 2D spectrum. This work demonstrates that using the zero-frequency trace-or equivalently the average of spectra acquired with different echo times-can be used to separate noncoupled metabolite signals from the lipid-induced sidebands. This technique is demonstrated with simulations, phantom studies, and in several breast lesions. Compared to the conventional approach using a single echo time, echo time averaging provides increased sensitivity for the study of small and irregularly shaped lesions.