Monitoring response to chemotherapy of non-Hodgkin's lymphoma xenografts by T(2)-weighted and diffusion-weighted MRI.

An effective method for in vivo detection of early therapeutic response of patients with non-Hodgkin's lymphoma would enable personalized clinical management of cancer therapy and facilitate the design of optimal treatment regimens. This study evaluates the feasibility of T(2)-weighted MRI (T2WI) and diffusion-weighted MRI (DWI) for in vivo detection of response of human diffuse large B-cell lymphoma xenografts in severe combined immunodeficient mice to chemotherapy. Each cycle of combination chemotherapy with cyclophosphamide, hydroxydoxorubicin, Oncovin, prednisone, and bryostatin 1 (CHOPB) was administered to tumor-carrying mice weekly for up to four cycles. T2WI and DWI were performed before the initiation of CHOPB and after each cycle of CHOPB. In order to corroborate the MRI results, histological analyses were carried out on control tumors and treated tumors after completion of all MRI studies. DWI revealed a significant (P < 0.03) increase in the mean apparent diffusion coefficient in CHOPB-treated tumors as early as 1 week after initiation of CHOPB. However, a significant (P < 0.03) decrease in mean T(2) was observed only after two cycles of CHOPB. Both MRI methods produced high-resolution (0.1 x 0.1 x 1.0 mm(3)) maps of regional therapeutic response in the treated tumors based on local apparent diffusion coefficient and T(2). Only a specific region of the tumors (in 3 of the 5 tumors) corresponding to about one third of the tumor volume exhibited a response-associate increase in ADC and decrease in T(2). An adjacent region exhibited an increase in T(2) and no change in ADC. The rest of the tumor was indistinguishable from sham-treated controls by MRI criteria. The therapeutic response of the treated tumors detected by MRI was accompanied by changes in tumor cell density, proliferation and apoptosis revealed by histological studies performed upon completion of the longitudinal study. The mechanism producing the regional response of the tumor remains to be elucidated.

In vivo MRS markers of response to CHOP chemotherapy in the WSU-DLCL2 human diffuse large B-cell lymphoma xenograft.

To identify 1H-MRS molecular biomarkers of early clinical therapeutic response in non-Hodgkin's lymphoma, an in vivo longitudinal study was performed on human non-Hodgkin's diffuse large B-cell lymphoma xenografts (WSU-DLCL2) grown in the flanks of female SCID mice. 31P-MRS measurements, which have been demonstrated to be prognostic clinical indices of response (Arias-Mendoza et al. Acad. Radiol. 2004; 11: 368-376) but which provide lower spatial resolution, were included for comparison. The animals received CHOP (cyclophosphamide, hydroxydoxorubicin, oncovin and prednisone) chemotherapy for three 1-week cycles, resulting in stable disease based on tumor volume. Localization of total choline and phosphorus metabolites in vivo was achieved with stimulated echo acquisition mode and image selected in vivo spectroscopy sequences, respectively. Significant decreases in lactate were detected by the selective multiple quantum coherence spectral editing technique after the first cycle of CHOP, whereas total choline and the phosphomonoester/nucleoside triphosphate ratio did not change until the third cycle. Ex vivo extract MRS of tumors corroborated the in vivo results. Histological staining with antibodies to Ki67 revealed a decrease in proliferation rate in CHOP-treated tumors that coincided with the decrease in lactate. This study demonstrates the utility of lactate as an early proliferation-sensitive indicator of therapeutic response in a mouse model of non-Hodgkin's lymphoma and serves as a basis for future clinical implementation of these methods.

In vivo monitoring response to chemotherapy of human diffuse large B-cell lymphoma xenografts in SCID mice by 1H and 31P MRS.

RATIONALE AND OBJECTIVES: A reliable noninvasive method for in vivo detection of early therapeutic response of non-Hodgkin's lymphoma (NHL) patients would be of great clinical value. This study evaluates the feasibility of (1)H and (31)P magnetic resonance spectroscopy (MRS) for in vivo detection of response to combination chemotherapy of human diffuse large B-cell lymphoma (DLCL2) xenografts in severe combined immunodeficient (SCID) mice. MATERIALS AND METHODS: Combination chemotherapy with cyclophosphamide, hydroxy doxorubicin, Oncovin, prednisone, and bryostatin 1 (CHOPB) was administered to tumor-bearing SCID mice weekly for up to four cycles. Spectroscopic studies were performed before the initiation of treatment and after each cycle of the CHOPB. Proton MRS for detection of lactate and total choline was performed using a selective multiple-quantum-coherence-transfer (Sel-MQC) and a spin-echo-enhanced Sel-MQC (SEE-Sel-MQC) pulse sequence, respectively. Phosphorus-31 MRS using a nonlocalized, single-pulse sequence without proton decoupling was also performed on these animals. RESULTS: Significant decreases in lactate and total choline were detected in the DLCL2 tumors after one cycle of CHOPB chemotherapy. The ratio of phosphomonoesters to beta-nucleoside triphosphate (PME/betaNTP, measured by (31)P MRS) significantly decreased in the CHOPB-treated tumors after two cycles of CHOPB. The control tumors did not exhibit any significant changes in either of these metabolites. CONCLUSIONS: This study demonstrates that (1)H and (31)P MRS can detect in vivo therapeutic response of NHL tumors and that lactate and choline offer a number of advantages over PMEs as markers of early therapeutic response.