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As a phosphorus-containing molecule, nicotinamide adenine dinucleotide is visible by phosphorus magnetic resonance spectroscopy (

Importance of the redox status of nicotinamide adenine dinucleotide (NAD), including its oxidized (NAD

(1)H magnetic resonance spectroscopy (MRS) with the multiple quantum coherence (MQC) technique allows for the detection of lactate, an end product of glycolysis, in the environment of lipids. The method can also be used to detect alanine, a byproduct of glutaminolysis. An issue is that when both lactate and alanine are detected together by the MQC technique, a phase mismatch arises between lactate and alanine signals due to off-resonance rotations and the difference in double quantum coherence frequencies between the two molecules. Such phase mismatch can cause errors in spectral fitting and metabolite quantification. In this study, we designed two pulse sequences that eliminate such phase differences of lactate and alanine while suppressing lipid signals by modifications of the Selective Multiple Quantum Coherence (Sel-MQC) sequence, a well-known MQC technique. Using the product operator formalism and the off-resonance rotation matrices, the phase evolutions of lactate and alanine during the spectrally selective pulses and the free precession times of the sequence at the single quantum, double quantum and zero quantum coherence states of these molecules were calculated. The multiple quantum (MQ) evolution time t(1) that can remove the phase difference of lactate and alanine at the echo was calculated and fine-tuned with experiments. The lactate and alanine signal intensities and the editing efficiencies from the two modified Sel-MQC sequences were theoretically predicted by using the product operator evolutions and compared with the experimental data. The J-coupled lipid signals were successfully suppressed by both sequences. One of the two developed sequences was applied to a human body with a phantom of lactate and alanine, which resulted in successful in-phase editing of lactate and alanine and suppression of the lipid signals from the body. The study sets an important foundation for the noninvasive detection of lactate and alanine from tumors of cancer patients.

Objective. The selective multiple quantum coherence (Sel-MQC) sequence is a magnetic resonance spectroscopy (MRS) technique used to detect lactate and suppress co-resonant lipid signals in vivo. The coherence pathways of J-coupled lipids upon the sequence, however, have not been studied, hindering a logical design of the sequence to fully attenuate lipid signals. The objective of this study is to elucidate the coherence pathways of J-coupled lipids upon the Sel-MQC sequence and find a strategy to effectively suppress lipid signals from these pathways while keeping the lactate signal. Approach. The product operator formalism was used to express the evolutions of the J-coupled spins of lipids and lactate. The transformations of the product operators by the spectrally selective pulses of the sequence were calculated by using the off-resonance rotation matrices. The coherence pathways and the conversion rates of the individual pathways were derived from them. Experiments were performed on phantoms and two human subjects at 3 T. Main results. The coherence pathways contributing to the various lipid resonance signals by the Sel-MQC sequence depending on the gradient ratios and RF pulse lengths were identified. Theoretical calculations of the signals from the determined coherence pathways and signal attenuations by gradients matched the experimental data very well. Lipid signals from fatty tissues of the subjects were successfully suppressed to the noise level by using the gradient ratio −0.8:−1:2 or 1:0.8:2. The new gradient ratios kept the lactate signal the same as with the previously used gradient ratio 0:−1:2. Significance. The study has elucidated the coherence pathways of J-coupled lipids upon the Sel-MQC sequence and demonstrated how lipid signals can be effectively suppressed while keeping lactate signals by using information from the coherence pathway analysis. The findings enable applying the Sel-MQC sequence to lactate detection in an environment of high concentrations of lipids.

Adipose tissue (AT) mass, especially visceral (VAT), is reduced in active acromegaly and rises with treatment. Although the effect of acromegaly and its therapy on marrow AT(MAT) is unknown, data in other populations and in vitro, suggest a reciprocal relationship between GH and marrow adiposity. In other groups, VAT and MAT are associated with reduced bone quality and increased vertebral fracture (VF) risk. Therefore, since acromegaly patients have an increased VF incidence, we examined the relationships of VAT and MAT to bone quality in acromegaly. We studied 65 acromegaly subjects (40 men, 25 women, range 18.7-74 yr.) before (n=20) or before and after (n=45) acromegaly therapy by total body multi-slice MRI(n=159)(measurement of VAT, subcutaneous (SAT) and total (TAT) adipose tissue mass), DXA (BMD (n=120) and body composition (n=145)) and HRpQCT (n=35) (microarchitecture of the tibia and radius). Marrow lipid spectra of the tibial diaphysis were acquired by 1H MRS (PRESS technique)(1.5T MR scanner, Philips) and percentages of bone marrow lipids were quantified (n=53). GH and IGF-1 (n=159) and bone turnover markers (BTM)(n=49) were measured. We examined the relationship between MAT or VAT and GH, IGF-1, age, weight, mass of other MRI measured AT depots, and selected DXA and HRpQCT parameters previously shown to differ in acromegaly compared to healthy subjects and to be associated in other groups with fracture. Data were analyzed by Pearson correlation and the generalized estimating equation (GEE). MAT directly correlated with VAT (r=.249, p=.023) and by HRpQCT (n=13) with bone size (radius: total area (r=.678, p=.01), tibia: total area (r=.535, p=.05)) and trabecular number (r=.543, p=.055). VAT was inversely associated with GH (β= -.017, p

GH and IGF-I have important roles in the maintenance of substrate metabolism and body composition. However, when in excess in acromegaly, the lipolytic and insulin antagonistic effects of GH may alter adipose tissue (AT) deposition.The purpose of this study was to examine the effect of surgery for acromegaly on AT distribution and ectopic lipid deposition in liver and muscle.This was a prospective study before and up to 2 years after pituitary surgery.The setting was an academic pituitary center.Participants were 23 patients with newly diagnosed, untreated acromegaly.We determined visceral (VAT), subcutaneous (SAT), and intermuscular adipose tissue (IMAT), and skeletal muscle compartments by total-body magnetic resonance imaging, intrahepatic and intramyocellular lipid by proton magnetic resonance spectroscopy, and serum endocrine, metabolic, and cardiovascular risk markers.VAT and SAT masses were lower than predicted in active acromegaly, but increased after surgery in male and female subjects along with lowering of GH, IGF-I, and insulin resistance. VAT and SAT increased to a greater extent in men than in women. Skeletal muscle mass decreased in men. IMAT was higher in active acromegaly and decreased in women after surgery. Intrahepatic lipid increased, but intramyocellular lipid did not change after surgery.Acromegaly may present a unique type of lipodystrophy characterized by reduced storage of AT in central depots and a shift of excess lipid to IMAT. After surgery, this pattern partially reverses, but differentially in men and women. These findings have implications for understanding the role of GH in body composition and metabolic risk in acromegaly and other clinical settings of GH use.

Contains fulltext : 51298.pdf (Publisher’s version ) (Closed access) The standardization and reproducibility of techniques required to acquire anatomically localized 31P MR spectra non-invasively while studying tumors in cancer patients in a multi-institutional group at 1.5 T are reported. This initial group of patients was studied from 1995 to 2000 to test the feasibility of acquiring in vivo localized 31P MRS in clinical MR spectrometers. The cancers tested were non-Hodgkin's lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best accrual and spectral quality were achieved with the non-Hodgkin's lymphomas. The initial analysis of the spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates in a homogeneous sample of 32 NHL patients studied by in vivo (31)P MRS showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional NHL data (2.28 +/- 0.64, mean +/- standard error; n = 17, vs 2.08 +/- 0.14, n = 15). The preliminary data reported demonstrate that the institutions involved in this trial are obtaining reproducible 31P MR spectroscopic data non-invasively from human tumors. This is a fundamental prerequisite for the international cooperative group to be able to demonstrate the clinical value of the normalized determination of phosphoethanolamine plus phosphocholine by 31P MRS as predictor for treatment response in cancer patients.

Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) has been utilized to study energy, carbohydrate, and phospholipid metabolism in vitro and in vivo in live tissues non-invasively. Despite its lack of sensitivity, its application has extended to in situ human tissues and organs since proper signal localization was devised. Follow-up of phosphocreatine in neuromuscular diseases and schizophrenia and follow-up of phospholipid-related molecules in tumors are described here to demonstrate the value of31P-MRS as an imaging technique to determine in vivo markers of disease and in the diagnosis, prognosis, and follow-up of human diseases.

Rationale and objectives Phosphoethanolamine and phosphocholine, shown to be elevated in tumors and possibly related to apoptotic signaling, have the potential to be prognostic variables of cancer treatment. Materials and methods The sum of phosphoethanolamine and phosphocholine normalized by nucleotide-triphosphates was determined in tumors of non-Hodgkin’s lymphoma (NHL) patients via in vivo 31 P MR spectroscopy. Results The normalized sum of phosphoethanolamine and phosphocholine showed significant differences in tumors of patients who had a complete response to treatment against those who did not ( t -test: 1.45 ± 0.15, mean ± standard error, n = 10 vs. 2.28 ± 0.15, n = 17, P P P P P Conclusion The normalized sum of phosphoethanolamine and phosphocholine measured before treatment successfully predicts long-term response to treatment and time to treatment failure in non-Hodgkin’s lymphoma, particularly when combined with the IPI.

Levels of phospholipid-related metabolites of chronic lymphocytic leukemia lymphocytes (CLL) and normal human lymphocytes were quantified using phosphorus magnetic resonance spectroscopy. The CLL cells versus normal lymphocytes showed significant increases of phosphoethanolamine(Etn-P) (8.11+/-2.10 mean+/-S.E., micromol/g wet weight, n=12 versus 3.63+/-1.10, n=3, Por=0.002), phosphocholine (2.10+/-0.37, n=12 versus 0.36+/-0.09, n=3, Por=0.01), glycerophosphoethanolamine (0.26+/-0.03, n=10 versus 0.11+/-0.05, n=3, Por=0.004), and glycerophosphocholine (0.33+/-0.03, n=10 versus 0.17+/-0.05, n=3, Por=0.003). Further, the phospholipid precursor ethanolamine (Eth) was studied in blood and was found significantly lowered in CLL patients (4.6+/-1.6 microM, n=25) compared to normal volunteers (7.7+/-2.5, n=12, Por=0.001). Increased intermediates with depletion of precursors suggest the presence of sustained phospholipid metabolism activation in CLL.

Contains fulltext : 142496.pdf (Publisher’s version ) (Closed access) RATIONALE AND OBJECTIVES: Combinations of chemotherapy and fractionated radiation therapy are the currently preferred nonsurgical treatment methods for squamous cell carcinoma of the head and neck, but to the authors' knowledge there is no reliable marker for predicting therapeutic response. Early identification of nonresponders would allow prompt replacement of ineffective, toxic therapy by alternative, potentially more effective procedures. Frequent regional node involvement facilitates surface coil investigation with phosphorus-31 magnetic resonance spectroscopy. MATERIALS AND METHODS: P-31 magnetic resonance spectra were acquired from 12 patients before radiation therapy or chemotherapy. In vivo three-dimensional localized P-31 nuclear magnetic resonance chemical shift imaging was performed with a 1.5-T clinical imager and a dual-tuned H-1/P-31 surface coil. Proton decoupling and nuclear Overhauser enhancement were used to improve sensitivity and resolve overlapping signals in the phosphomonoester region of the spectrum. RESULTS: The average pretreatment ratio of phosphomonoester to beta-nucleoside triphosphate was significantly smaller in complete responders (n = 4) than in incomplete responders (partial responders plus nonresponders, n = 8) (0.0 +/- 0.0 vs 1.22 +/- 0.17 [P = .004]). CONCLUSION: Results of this preliminary study suggest that H-1-decoupled P-31 magnetic resonance spectroscopy may prove to be a useful predictor of therapeutic response in head and neck cancers.

Balanced pools of deoxyribonucleoside triphosphate precursors are required for DNA replication, and alterations of this balance are relevant to human mitochondrial diseases including mitochondrial neurogastrointestinal encephalopathy. In this disease, autosomal recessive TYMP mutations cause severe reductions of thymidine phosphorylase activity; marked elevations of the pyrimidine nucleosides thymidine and deoxyuridine in plasma and tissues, and somatic multiple deletions, depletion and site-specific point mutations of mitochondrial DNA. Thymidine phosphorylase and uridine phosphorylase double knockout mice recapitulated several features of these patients including thymidine phosphorylase activity deficiency, elevated thymidine and deoxyuridine in tissues, mitochondrial DNA depletion, respiratory chain defects and white matter changes. However, in contrast to patients with this disease, mutant mice showed mitochondrial alterations only in the brain. To test the hypothesis that elevated levels of nucleotides cause unbalanced deoxyribonucleoside triphosphate pools and, in turn, pathogenic mitochondrial DNA instability, we have stressed double knockout mice with exogenous thymidine and deoxyuridine, and assessed clinical, neuroradiological, histological, molecular, and biochemical consequences. Mutant mice treated with exogenous thymidine and deoxyuridine showed reduced survival, body weight, and muscle strength, relative to untreated animals. Moreover, in treated mutants, leukoencephalopathy, a hallmark of the disease, was enhanced and the small intestine showed a reduction of smooth muscle cells and increased fibrosis. Levels of mitochondrial DNA were depleted not only in the brain but also in the small intestine, and deoxyribonucleoside triphosphate imbalance was observed in the brain. The relative proportion, rather than the absolute amount of deoxyribonucleoside triphosphate, was critical for mitochondrial DNA maintenance. Thus, our results demonstrate that stress of exogenous pyrimidine nucleosides enhances the mitochondrial phenotype of our knockout mice. Our mouse studies provide insights into the pathogenic role of thymidine and deoxyuridine imbalance in mitochondrial neurogastrointestinal encephalopathy and an excellent model to study new therapeutic approaches. © 2014 The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

We report acquisition of 3D image-guided localized proton spectroscopy (1H-MRS) in the human brain on a standard clinical imager. 3D coverage is achieved with a hybrid of chemical shift imaging (CSI) and transverse Hadamard spectroscopic imaging (HSI). 16 x 16 x 4 arrays of 3.5 and 1 ml voxels were obtained in 27 min. The spatially selective HSI 90 degrees pulses incorporate naturally into a PRESS double spin-echo sequence to subdivide the VOI into four partitions along its short axis. 2D CSI (16 x 16) is performed along the other long axes. Because the hybrid excites the spins in the entire VOI, a square-root-N signal-to-noise-ratio (SNR) gain per given examination time is realized compared with sequentially interleaving N 2D slices. A two-fold gain in sensitivity is demonstrated in the brain for N = 4.

Contains fulltext : 140536.pdf (Publisher’s version ) (Closed access) Based on their association with malignant proliferation, using noninvasive phosphorus MR spectroscopic imaging ((31)P MRSI), we measured the tumor content of the phospholipid-related phosphomonoesters (PME), phosphoethanolamine and phospholcholine, and its correlation with treatment outcome in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) receiving standard first-line chemotherapy.The PME value normalized to nucleoside triphosphates (PME/NTP) was measured using (31)P MRSI in tumor masses of 20 patients with DLBCL before receiving standard first-line chemotherapy. Response at 6 months was complete in 13 patients and partial in seven. Time to treatment failure (TTF) was ≤11 months in eight patients, from 18 to 30 months in three, and ≥60 months in nine.On a t test, the pretreatment tumor PME/NTP mean value (SD, n) of patients with a complete response at 6 months was 1.42 (0.41, 13), which was significantly different from the value of 2.46 (0.40, 7) in patients with partial response (P < .00001). A Fisher test significantly correlated the PME/NTP values with response at 6 months (sensitivity and specificity at 0.85, P < .004) while a Cox proportional hazards regression significantly correlated the PME/NTP values with TTF (hazard ratio = 5.21, P < .02). A Kaplan-Meier test set apart a group entirely composed of patients with TTF ≤ 11 months (hazard ratio = 8.66, P < .00001).The pretreatment tumor PME/NTP values correlated with response to treatment at 6 months and time to treatment failure in newly diagnosed patients with DLBCL treated with first-line chemotherapy, and therefore they could be used to predict treatment outcome in these patients.

Multivoxel, heteronuclear interleaved two-dimensional proton and three-dimensional 1H-decoupled 31P CSI of human brain is demonstrated. This method offers efficient use of limited examination time as patient preparation, coil tuning, shimming and imaging are done only once and the CSI data sets from both nuclei are obtained concurrently. Effective interleaving of 31P and 1H is possible due to the shorter T1s of proton brain metabolites, allowing a 1H acquisition cycle to be inserted into each 31P TR. This way, the entire MRS time is available to both nuclei, increasing their SNR per-unit-time by approximately 12% for 31P and approximately 80% for 1H, compared with sequential detection of equal (45-50 min) length. The spectral resolution and SNR of 31P are further increased through bi-level 1H-decoupling and NOE.

Antenatal surveillance is inefficient for accurately detecting fetal compromise. A noninvasive technique for assessing fetal metabolic status would be useful for clinical management.Fetal magnetic resonance spectroscopy was performed at 20 weeks in a pregnancy complicated by severe intrauterine growth restriction to determine if lactate, a metabolite associated with fetal hypoxia, was present. Two-dimensional, single-slice proton magnetic resonance spectroscopy was carried out at 1.5 T using a volume-selective, double-spin echo technique. Lactate was detected in fetal back muscle. Fetal death occurred the next day.Although this initial report is purely experimental, further development of this technique may prove to be a valuable noninvasive tool in the management of suspected fetal hypoxia.

The importance and the difficulty of achieving good B 0 homogeneity over the volume of interest in in vivo NMR spectroscopy are well known A fast, reliable, versatile, and fully automatic shimming procedure has been developed, using 3D chemical-shift imaging to measure the field distribution using only the water peak in the sample of interest, The procedure minimizes the mean-square error in the field distribution with respect to a constant held where the signal exists (e,g., the head). This produces a set of linear equations that can be solved by standard matrix methods. The procedure has been applied on a commercial imager producing water linewidths from the entire head as low as 8 Hz at 1.5 T. The mean linewidth and standard deviation from 94 head studies were 11.7 ± 1.9 Hz.

Se hace un estudio donde se identifica la necesidad de herramientas virtuales de aprendizaje de bajo coste para la enseñanza en nanotecnología y se propone el diseño de un simulador educativo para un equipo de microscopía electrónica de barrido SEM referencia JEOL NeoScope JCM 5000 para implementarse en el entorno de desarrollo de videojuegos Unity para el fomento del aprendizaje significativo con estudiantes de básica secundaria, tomando como población de estudio los aprendices del programa de la Tecnoacademia nodo Cazuca del Servicio Nacional de Aprendizaje SENA. Se espera lograr identificar la diferencia en la implementación de éstas herramientas en el aprendizaje de técnicas de caracterización y el impacto que pueden generar éstas en el área de influencia.

The authors’ laboratory was the first to demonstrate that 31P NMR spectroscopy was able to detect early metabolic changes in subcutaneous tumors in mice in response to chemotherapy, radiation therapy, and hyperthermia.1 In addition, the authors and others2,3 showed that nuclear magnetic resonance (NMR) detectable changes during untreated growth reflected changes in tumor perfusion, energetics, and pH, which could serve as sensitive predictors of therapeutic response. These seminal observations were subsequently translated into the clinic and led to the initiation of a National Institutes of Health supported multi-institutional program to evaluate the potential utility of 31P magnetic resonance spectroscopy (MRS) for the prediction and early detection of therapeutic response. This program was initially headed by Dr Truman Brown at the Fox Chase Cancer Center and included Memorial Sloan-Kettering, Wayne State University, Duke, University of California in San Francisco (UCSF), Johns Hopkins, and The Royal Marsden and St George’s Hospitals in London. Initially the study included 4 malignancies rgR exhibited approximately a 50:50 response rate—non-Hodgkin lymphoma (NHL), squamous cell carcinoma of the head and neck (HNSCC), soft tissue sarcomas (STS), and locally advanced breast cancer (LABC). Because of limited accrual, HNSCC, STS, and LABC were dropped from the study, and Wayne State, Duke, and UCSF left the study. However, the Radboud University Nijmegen Medical Center in the Netherlands joined the study. The participants call themselves Cooperative Group for NMR Spectroscopy of Cancer. While the participants in this program have continued to work together for over a decade, some have changed institutions. Dr Brown moved from Fox Chase to Columbia Presbyterian Medical Center and more recently to the Medical College of South Carolina, but a new principal investigator (PI), Dr Fernando Arias-Mendoza, has remained at Columbia. The Johns Hopkins Group under Dr Glickson moved to the University of University of Pennsylvania in 1996, and St George’s group under Dr Griffiths recently transferred to Cambridge University in the United Kingdom. Despite changes of institutions among some of the participants, and the use of different commercial imaging systems (General Electric, Siemens, and Philips), a uniform protocol has been developed for acquisition and analysis of MRS data,4 with statistical evaluation being performed at the PI institution (Columbia). Both the Columbia and University of Pennsylvania programs are participating in this report. Until now, all the 31P studies were performed on 1.5 T instruments, although future plans are to continue the studies at 3 T. Because of the limited sensitivity of 31P MRS, studies have been limited to large (≥3 × 3 × 3 cm3) mostly superficial lesions in the axial, inginal, or head and neck lymph nodes. Data were generally analyzed from a single voxel, although data acquisition was performed by 2-dimensional chemical shift imaging followed by voxel shifting to optimally localize the tumor in one voxel (Fig. 1). Visualization of the tumor was achieved by T2-weighted 1H magnetic resonance imaging (MRI). Recently, a number of institutions have initiated 1H MRS (lactate [Lac]) or (total choline [tCho]) and MRI (diffusion-weighted imaging [DWI]), which can accommodate substantially smaller lesions (approximately 1 cm3 for Lac and tCho and smaller for DWI).

Context: GH and IGF-I are nitrogen retaining and anabolic, but the impact of long-term exposure to supraphysiological GH and IGF-I, either from endogenous overproduction in acromegaly or exogenous sources, on skeletal muscle (SM) mass is not clear. Objectives: The objectives of the study were to assess SM mass by whole-body magnetic resonance imaging (MRI) in acromegaly and test the hypothesis that dual-energy x-ray absorptiometry (DXA) lean tissue mass-derived estimates of SM accurately estimate true SM mass. Design, Setting, and Patients: The design was a cross-sectional study in 27 acromegaly patients compared with predicted models developed in 315 nonacromegaly subjects and to matched controls. Outcome Measures: Mass of SM from whole-body MRI and lean tissue from DXA were measured. Results: SM mass did not differ from predicted or control values in active acromegaly: 31.75 ± 8.6 kg (acromegaly) vs. 33.06 ± 8.9 kg (predicted); SM was 95.6 ± 12.8% of predicted (range 66.7–122%) (P = 0.088). Lean tissue mass (DXA) was higher in acromegaly than controls: 65.91 ± 15.2 vs. 58.73 ± 13.5 kg (P < 0.0001). The difference between lean tissue mass (DXA) and SM in acromegaly patients was higher than that in controls (P < 0.0001) consistent with an enlarged non-SM lean compartment in acromegaly. SM mass predicted by DXA correlated highly with SM mass by MRI (r = 0.97, P < 0.0001). SM (MRI) to SM (DXA predicted) ratio was 1.018 (range 0.896–1.159), indicating high agreement of these measures of SM. Conclusions: SM mass in active acromegaly patients did not differ from predicted values. SM mass estimated from DXA agreed highly with SM by MRI, supporting the validity of the DXA model in assessing SM in acromegaly and other disorders of GH/IGF-I secretion.

A multienzymatic method for the measurement of pyruvate, dihydroxyacetone phosphate, oxaloacetate, and acetoacetate is presented. The determination procedure is considered suitable because it is simple, sensitive, and its advantages could be demonstrated by comparison with the original methods.

Contains fulltext : 57307.pdf (Publisher’s version ) (Closed access) A multi-institutional group has been created to demonstrate the utility of in vivo 31P magnetic resonance spectroscopy (31P-MRS) to study human cancers in vivo. This review is concerned with the novel problems concerning quality control in this large multinational trial of 31P MRS. Our results show that the careful and systematic performance of the quality control tests depicted here (standardized dual 1H/31P tuned radiofrequency probe, quality control procedures, routine use of 1H irradiation while acquiring 31P MR signals) has ensured comparable results between the different institutions. In studies made in vitro, the root-mean-square error was 3.6 %, and in muscle of healthy volunteers in vivo the coefficients of variance for the ratios phosphocreatine/nucleotide-triphosphates, phosphocreatine/noise and nucleotide-triphosphate/noise were 12.2, 7.0 and 10.8 %, respectively. The standardization of the acquisition protocol for in vivo-localized 31P MR spectroscopy across the different institutions has resulted in comparable in vivo data, decreasing the possible problems related to a research study carried out under a multi-institutional setting.

Magnetic resonance spectroscopy (MRS) has been utilized to study several metabolic pathways in vivo and in live tissues in vitro non-invasively. Despite its inherited lack of sensitivity, its application has extended all the way to in situ human tissues and organs since proper technical advancements were devised. Examples of its application described here demonstrate the value of in vivo MRS as a technique that determines parameters of mitochondrial dysfunction directly and indirectly which could be of value for the diagnosis, prognosis, and follow-up of mitochondrial disorders.

The contrast of MR images can be made sensitive to the average motion of water molecules (diffusivity) giving rise to diffusion-weighted imaging (DWI). Intensity maps of the apparent diffusion constant (ADC) of water can be generated from the DWI information and average ADC values of anatomical regions can be assessed. Malignant tissues generally exhibit hypercellularity, increased nucleus-to-cytoplasm ratios, and an increased amount of macromolecules resulting in decreased water diffusivity (lower ADC). Additionally, a response-related ADC increase has been demonstrated in malignancies under therapy. We previously reported that the ADC mean value (in 10-3 mm2 s-1 [SD, n]) of masses of refractory lymphoma patients prior to a new treatment was lower than the ADC mean value of lymph nodes of healthy volunteers (0.91 [0.23, 15] vs. 1.13 [0.14, 10], respectively). This difference was significant (p < 0.01) despite of a large dispersion on the ADC data from the patients. Given this dispersion, we wanted to prove if refractory lymphoma patients with lower ADC values responded differently than those with higher ADC values. Experimental Design: Under ethical review board approval, refractory lymphoma patients underwent a pretreatment MR exam. DWI was acquired using echo-planar imaging with fat suppression and b-values of 0 and 1000 s/mm2 and the ADC of water in the tumor obtained. Time to treatment failure (TTF) was defined as the time between the end of one treatment and the start of a new one. Results: ADC and TTF were obtained in 12 refractory lymphoma patients and divided into those with TTF ≤ 75 days and those with TTF > 75 days. The ADC mean value [SD, n] in patients with TTF ≤ 75 days was 0.73 [0.20, 5] while in those with TTF > 75 days was 1.04 [0.20, 7]. These mean values were significantly different (p < 0.02). Furthermore, the comparison of the ADC mean value of lymph nodes of healthy volunteers with the ADC mean value of refractory patients with TTF ≤ 75 days was highly significant (p < 0.0005) while the comparison between healthy volunteers and patients with TTF > 75 days was not. Discussion: Our results demonstrate that refractory lymphoma patients with tumor masses displaying abnormally low ADC values prior to the start of treatment have poorer treatment outcome than those patients with ADC tumor values that are comparable to those in normal lymph nodes. If low ADC is due to increased tumor cellularity in patients with poorer outcome, this could produce reduced drug availability, thus explaining the substandard outcome. Our results demonstrate an important predictive value of the ADC determination by DWI in refractory lymphoma patients. This together with the fact that DWI is a noninvasive technique and its acquisition is fairly quick makes the ADC a parameter that could become critical for the clinical examination of the patient with refractory lymphoma. Citation Format: Fernando Arias-Mendoza, Hamed Mojahed, Ahmed Sawas, Owen A. O'Connor. Correlation of the apparent diffusion coefficient of water assessed by diffusion-weighted imaging with treatment outcome in refractory lymphoma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4296. doi:10.1158/1538-7445.AM2014-4296

A frequent problem in analysis is the need to find two matrices, closely related to the underlying measurement process, which when multiplied together reproduce the matrix of data points. Such problems arise throughout science, for example, in imaging where both the calibration of the sensor and the true scene may be unknown and in localized spectroscopy where multiple components may be present in varying amounts in any spectrum. Since both matrices are unknown, such a decomposition is a bilinear problem. We report here a solution to this problem for the case in which the decomposition results in matrices with elements drawn from positive additive distributions. We demonstrate the power of the methodology on chemical shift images (CSI). The new method, Bayesian spectral decomposition (BSD), reduces the CSI data to a small number of basis spectra together with their localized amplitudes. We apply this new algorithm to a 19 F nonlocalized study of the catabolism of 5-fluorouracil in human liver, 31 P CSI studies of a human head and calf muscle, and simulations which show its strengths and limitations. In all cases, the dataset, viewed as a matrix with rows containing the individual NMR spectra, results from the multiplication of a matrix of generally nonorthogonal basis spectra (the spectral matrix) by a matrix of the amplitudes of each basis spectrum in the the individual voxels (the amplitude matrix). The results show that BSD can simultaneously determine both the basis spectra and their distribution. In principle, BSD should solve this bilinear problem for any dataset which results from multiplication of matrices representing positive additive distributions if the data overdetermine the solutions.

Introduction The contrast of MR images can be made sensitive to the average motion of water molecules (diffusivity) in the various tissue compartments giving rise to diffusion-weighted imaging (DWI). Intensity maps of the apparent diffusion constant (ADC) of water can be generated from the DWI information and average ADC values of anatomical regions of interest can be assessed. Malignant tissues generally exhibit hypercellularity, increased nucleus-to-cytoplasm ratios, and an increased amount of macromolecular proteins, resulting in decreased water diffusivity (i.e., lower ADC). Additionally, a response-related ADC increase has been demonstrated in malignancies under therapy. We previously reported that the ADC mean value (in 10-3 mm2 s-1 [SD, n]) of tumor masses of refractory non-Hodgkin lymphoma (NHL) patients prior to start a new treatment was lower than the ADC mean value of lymph nodes of healthy volunteers (0.91 [0.23, 15] vs. 1.13 [0.14, 10], respectively). This difference was statistically significant (p< 0.01) despite of a large dispersion on the ADC data from the refractory NHL patients. Given this dispersion, we wanted to assess if refractory NHL patients with lower ADC values prior to therapy responded differently than patients with higher ADC values. Experimental Design Under ethical review board approval, refractory NHL patients underwent a pretreatment MR exam using a 1.5T Philips Achieva whole body scanner (Philips Healthcare, Best, The Netherlands), which included clinical MRI and DWI. DWI was acquired using echo-planar imaging with fat suppression and b-values of 0 and 1000 s/mm2 to obtain the ADC of water in the tumor. Treatment outcome was assessed determining the time to treatment failure (TTF) defined as the time between the end of one treatment and the start of a new one. Results DWI and TTF were obtained in 12 NHL patients refractory to previous treatments. Patients were divided into those with TTF ≤ 75 days and those with TTF > 75 days. The ADC mean value [SD, n] in refractory NHL patients with TTF ≤ 75 days was 0.73 [0.20, 5] while in patients with TTF > 75 days was 1.04 [0.20, 7]. When compared, these mean values were significantly different (p< 0.02). Furthermore, the comparison of the ADC mean value of lymph nodes of healthy volunteers with the ADC mean value of refractory NHL patients with TTF ≤ 75 days was highly significant (p< 0.0005) while the comparison of ADC mean values between healthy volunteers and patients with TTF > 75 days was not significantly different. Discussion Our results demonstrate that refractory NHL patients with tumor masses displaying abnormally low ADC values prior to the start of treatment have poorer treatment outcome than those patients with ADC tumor values that are comparable to values in normal lymph nodes. Although the appropriate biophysical interpretation of the ADC value remains controversial, the restricted diffusivity of water indicated by ADC reduction is considered secondary to increased tumor cellularity. The correlation between outcome and tumor cellularity could be possibly explained by reduced drug availability in the tumor when cellularity increases, thus explaining the substandard outcome in patients with lower ADC values. However, even though the correlation between lower ADC and poorer outcome is not yet understood, our results demonstrate an important predictive value of the ADC determination by DWI in refractory patients with NHL. This together with the fact that DWI is a noninvasive technique that requires no administration of contrast medium and its acquisition is fairly short makes the determination of ADC by DWI a technique that could become critical for the clinical examination of the patient with refractory NHL. Disclosures: No relevant conflicts of interest to declare.

Broad resonances that lie underneath the familiar small molecule profile of in vivo 31P NMR spectra can make accurate spectral integration of these mobile phosphates difficult. The two major broad components are the phosphate contained in the hydroxyapatite in cranial bone and the phosphodiester moiety in partially mobile membrane phospholipids. They can be removed with post-acquisition processing but this results in distortion of lineshapes and intensities and interferes with accurate quantitation. We have employed an off-resonance saturation procedure to eliminate the bone resonance and isolate the signal from the membrane phospholipids by subtraction. Selective saturation of the phospholipid resonance increases the clarity of the sharp peaks downfield from the phosphocreatine peak. Selective saturation 3-D chemical shift imaging techniques were used to create a localized phospholipid profile of the entire brain simultaneously. Monitoring localized phospholipid concentration may be important in studying demyelinating diseases.

Abstract 3104 Diffuse large B-cell lymphoma (DLBCL) is the most common sub-type of non-Hodgkin's lymphoma.1 DLBCL is a heterogeneous, clinically aggressive disease, which has recently been sub-categorized based upon gene expression profiling. The prognosis of patients with DLBCL is presently assessed by the International Prognostic Index (IPI), which predicts estimated five-year survival based on clinical criteria.1,2 Over the past decade, a number of reports have established that the intra-tumoral content of the phospholipid-related metabolites phosphoethanolamine and phosphocholine (Etn-P and Cho-P) is increased in clinically aggressive malignant disease, and decreases when the malignancy responds to anticancer treatment. These data suggest that phospholipid metabolism is an intrinsic part of the disease process.3,4 Based on these observations, we hypothesized that intra-tumor levels of Etn-P and Cho-P may be a reliable predictive biomarker for therapeutic outcome in aggressive malignant diseases. To test this hypothesis, we measured noninvasively the tumor content of the sum of Etn-P plus Cho-P normalized by the tumor content of nucleoside triphosphates ([Etn-P+Cho-P]/NTP) in patients with DLBCL prior to initiating therapy. These data show that the pretreatment metabolic ratio (PMR) of [Etn-P+Cho-P]/NTP, is a potentially valuable biomarker of outcome, which identifies a subset of DLBCL patients likely to experience early failure to standard therapy, and for whom alternatives to therapy should be considered. Methods: Under ethical review board approval, 27 previously untreated DLBCL patients prior to receiving standard doxorubicin-based therapy were studied noninvasively using 3D localized, 1H-decoupled, nuclear Overhauser-enhanced phosphorus MR spectroscopy at 1.5 T. Result: As only complete response (CR) is clinically meaningful in achieving durable remissions of DLBCL, we divided these patients by response at six months into CR and all the other responses (not complete response, NCR). In the 17 CR patients, the PMR was significantly lower than in the ten NCR patients (PMR mean ± 95% CI, 1.46 ± 0.21 vs. 2.47 ± 0.24, p < 3 × 10-6). The prediction of response using a Fisher test was significant for the PMR alone (p < 1 × 10-4; sensitivity of 1.00, specificity of 0.70) and improved further when combined with the IPI (p < 2 × 10-6; sensitivity of 1.0, specificity of 0.90). The progression-free survival (PFS) strongly correlated with the PMR alone (p < 4 × 10-8) and with the PMR and IPI as covariates (p < 1 × 10-7) by the Cox regression model. Using the Kaplan-Meier model, the PMR discriminated 64% of patients with PFS below 11 months (p < 1 × 10-7), while as covariate with the IPI it discriminated 82% of these patients (p < 2 × 10-7). Discussion: Our results show that the PMR contains information that predicts outcome to standard therapy in DLBCL patients. This prediction improves when the PMR is combined with the IPI. While the PME alone identifies 64% of those patients who will go on to show an extremely poor response with a progression-free survival below 11 months, the combination of the PME and IPI identify 82% of these patients. In conclusion, we have successfully demonstrated that the PMR can be an important determinant in predicting response to treatment in patients with DLBCL, especially when integrated with the IPI. References: 1) Cancer: principles and practice of oncology. 6th ed. Philadelphia, PA, Lippincott, Williams & Wilkins, 2001; 2) Smith MR, Non-Hodgkin's lymphoma. St. Louis, MO, Mosby, 1966; 3) Arias-Mendoza F, Brown TR, Dis. Markers, 2003;19:49-68; 4)Griffiths JR, et al, Lancet 1983;1:1435-6 Disclosures: No relevant conflicts of interest to declare.

8070 Background: We have previously reported that a lower pretreatment tumor value of the phospholipid-related intermediates phosphoethanolamine plus phosphocholine normalized to nucleoside triphos...

8565 Background: To determine if the intracellular tumor marker of phosphoethanolamine plus phosphocholine normalized by nucleotide triphosphates (PPN) monitored non-invasively by phosphorus MR spectroscopy (31P-MRS) correlate with indicators of treatment response in non-Hodgkin's lymphoma (NHL) subtypes. Methods: The PPN value was obtained in 33 diffuse large B-cell lymphomas (DLBCL), 18 follicular lymphomas (FL) and 16 other types (OT) of NHL using in vivo 3D-localized, 1H-irradiated 31P-MRS prior to standard treatment. Results: The PPN values (mean ± standard error) for complete responses (CR) and not complete responses (NCR) in DLBCL were significantly different (CR: 1.42±0.10, n=19 and NCR: 2.25±0.15, n=14; p No significant financial relationships to disclose.

A simple one-step method to fix and extract ATP from rat liver samples is described. The results show that this method is suitable for fixation and extraction of the hepatic ATP content, whereas its simplicity leads to consider it the procedure of choice.

No reliable method of imaging prostate cancer currently exists. These prostate tissue‐typing studies aim to improve the effectiveness of biopsy guidance and treatment monitoring by developing better imaging methods for identifying cancerous prostate tissue. Success will reduce the false‐negative rate of biopsies and treatment side‐effects. Ultrasonic (US) radio‐frequency (rf) echo‐signal data acquired during biopsy examinations were used to compute spectral parameters. These spectral parameters along with clinical parameters, e.g., PSA, were used to train a neural network classifier using biopsy results as the gold standard. Cancer‐likelihood scores from a look‐up table were used to generate tissue‐type images (TTIs). The ROC‐curve area for US neural‐network‐based classification was 0.844±0.018 vs 0.638±0.031 for B‐mode‐based classification, and the sensitivity of neural‐network based classification was superior to that of B‐mode‐guided biopsies. These classification methods are being extended to include magnetic‐resonance spectral (MRS) techniques that use the choline to citrate ratio‐to‐distinguish cancerous from noncancerous prostate tissue. 3D renderings of prostatectomy histology, US, and MR images show encouraging correlations, and combining MRS parameters with US spectral parameters appears to have potential to further improve prostate‐cancer imaging. [Work supported in part by NIH Grant CA053561.]