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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.

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.