Ignite Creation Date:
2024-05-05 @ 11:53 AM
Last Modification Date:
2024-10-26 @ 9:15 AM
Study NCT ID:
NCT00166855
Status:
UNKNOWN
Last Update Posted:
2005-11-24
First Post:
2005-09-12
Brief Title:
Clinical Implication of Bone Marrow Perfusion Patterns Imaged by Dynamic MRI in Multiple Myeloma
Sponsor:
National Taiwan University Hospital
Organization:
National Taiwan University Hospital
Study Overview
Official Title:
None
Status:
UNKNOWN
Status Verified Date:
2005-05
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background Multiple myeloma MM is a clonal plasma cell neoplasm characterized by proliferation of neoplastic plasma cells in bone marrow BM So far it is an incurable disease and the median survival time of MM patients is only three to four years Till now whether the extent of angiogenesis in BM of MM patients serves as an important and independent prognostic factor is still debated In this study we would like to have the BM perfusion status imaged by dynamic MRI to mimic the macroscopic vascular densities of BM and thereafter the BM perfusion status the clinical outcome of the MM patients and the angiogenesis related biological markers will be correlated
Methods About 35 to 50 MM patients included newly diagnosed patients or the patients who will undertake the special treatment are enrolled in this study The thoraco-lumbar spine is scanned by the MRI and the BM perfusion status is obtained by contrast-enhanced dynamic MRI Meanwhile the patients undertake BM biopsy at one site or two sites and the BM aspirates are also obtained and separated into BM plasma and BM mononuclear cells BMMC by Ficoll-Hypaque centrifugation The angiogenesis related genes expression profiles of the BMMC will be determined by cDNA microarrays and some of them like VEGF bFGF and PDGF will be semiquantified by real-time PCR The levels of related proteins will be determined by ELISA The BM plasma samples are further applied to proteomic analysis to screen the novel molecules with clinical relevance
Prospects BM perfusion patterns imaged by dynamic MRI can predict the clinical outcome of MM and are correlated with the angiogenesis relevant biological markers in BM
Methods About 35 to 50 MM patients included newly diagnosed patients or the patients who will undertake the special treatment are enrolled in this study The thoraco-lumbar spine is scanned by the MRI and the BM perfusion status is obtained by contrast-enhanced dynamic MRI Meanwhile the patients undertake BM biopsy at one site or two sites and the BM aspirates are also obtained and separated into BM plasma and BM mononuclear cells BMMC by Ficoll-Hypaque centrifugation The angiogenesis related genes expression profiles of the BMMC will be determined by cDNA microarrays and some of them like VEGF bFGF and PDGF will be semiquantified by real-time PCR The levels of related proteins will be determined by ELISA The BM plasma samples are further applied to proteomic analysis to screen the novel molecules with clinical relevance
Prospects BM perfusion patterns imaged by dynamic MRI can predict the clinical outcome of MM and are correlated with the angiogenesis relevant biological markers in BM
Detailed Description:
Multiple myeloma MM is a clonal plasma cell neoplasm characterized by proliferation of abnormal plasma cells in bone marrow BM that secrete a monoclonal paraprotein M-protein in serum andor urine and by osteolytic bone destructions So far it is an incurable disease and its pathogenesis is largely unknown The median survival time of MM patients is only three to four years and then the patients will die on either the disease or its complications Barlogie et al 2004
There are several independent prognostic factors for MM like high levels of beta-2 microglobulin hypodiploidy chromosome content deletion of chromosome 13q14 and also the extent of angiogenesis shown by microvascular density MVD in BM Fonseca et al 2004 Kumar et al 2002 Pruneri et al 2002 Sezer et al 2000 It has been suggested that MM progressed from an avascular to a vascular phase active MM accompanied by a significant increase in MVD in BM Rajkumar et al 2002 which is promoted by the angiogenesis related factors like VEGF bFGF and PDGF which were performed like a paracrine or autocrine loops secreted by MM cells per se or the adjacent BM stromal cells Gupta et al 2001 Kumar et al 2003 Ria et al 2003 Vacca et al 2003 It has been reported that higher MVD in BM at the time of initial diagnosis was associated with shorter OS and PFS in patients undergoing autologous transplantation for MM than the patients with lower MVD Kumar et al 2004 Those angiogenesis related factors may provide disease monitoring but also a potent novel therapeutic approach to over come resistance to therapies and thereby improve patient outcome Podar et al 2004 Interestingly the patients with deletion of chromosome 13q14 have higher MVD in BM than the patients without Schreiber 2000 which hinted that the grave prognosis of deletion of chromosome 13q14 might be a result of dysregulation of angiogenesis in BM However on the other hand absence of clinical prognostic value of VEGF and MVD in MM had also been reported by other investigators Ahn et al 2001 Choi et al 2002 In MM whether the MVD in BM and the related biological markers like VEGF bFGF and PDGF can serve as prognostic factors are still debate Rajkumar et al 2001 Vacca et al 2001 There are possible two reasons for the debate the first one is that the distribution of neoplastic foci within the BM of MM are not homogenous therefore the microvascular densities calculated from a single site BM specimen are hard to represent the total angiogenesis within the BM the second one is that the angiogenesis related biological markers such as VEGF bFGF and PDGF in MM are largely studied on the plasmas obtained from peripheral blood rather than BM and this is a critical issue for the cytokines secreted from either MM cells or adjacent stromal cells are mostly paracrines or autocrines and the levels of VEGF bFGF PDGF are higher in BM than in peripheral blood Di Raimondo et al 2000
Reviewing the literature dynamic contrast-enhanced MRI has been used to evaluate the potential of vertebral fractures in MM Scherer et al 2002a 2002b to quantify significant changes of BM microcirculation during conventional treatment Rahmouni et al 1993 or treatment with thalidomide combined with chemotherapy Wasser et al 2004 which may be a novel and non-invasive tool to approach the clinical outcomes of MM patients Moehler et al 2001 In short MR imaging of the spine was performed with a 15-T superconducting system Magnetom Vision Plus Siemens Erlangen Germany A phase-array spine-coil was used and a routine fast spin-echo T1-weighted sequence repletion time msececho time msec 60012 turbo factor of three section thickness 4 mm field of view 28cm was performed in the midsagittal plane and covered the area from T11 through the sacrum A dynamic contrast-enhanced MR study was then performed section thickness 10 mm field of view 28 cm at the midsection of the vertebral body and covered the same area The pulse sequence used was a turbo fast low-grade shot gradient-echo sequence 8540 prepulse inversion time 160 msec flip angle 10 acquisition matrix 72x128 Acquisition time was 089 second with 011-second delay In total 100 dynamic images were obtained within 100 seconds one frame per second in each subject After the initial 100-second scanning the scanning were prolong to 600 seconds with the scan rate 1 frame per 10 seconds 1 seconds scan and 9 seconds delay An injection of 01 mmol per kilogram of body weight gadopentetate dimeglumine Magnevist Schering Berlin Germany was administrated by the power injector through a 21-gauge intravenous catheter that was inserted in the right antecubital vein previously A brief constant injection rate of 20mlsec were used This injection was immediately followed with a 20-ml saline flush at the same injection rate Dynamic imaging started when the injection of the contrast material commenced
Signal intensity values were measured in an operator-defined region of interests ROIs The musculoskeletal radiologist TTFS with 15 years experience places the ROIs were placed with the aid of a cursor and a graphic display device along the border of high-signal-intensity bone marrow on T1 weighted images covered the entire bone marrow of each vertebra One vertebral body was covered by one ROI measurement The ROI was measured separately for each of selected lumbar vertebrae L2 L3 and L4 in each subject The signal intensity values derived from the ROI measured in each vertebral body were then plotted against time to obtain a time-signal intensity curve Fig 1 for each vertebral body The baseline value for signal intensity SIbase on a time- signal intensity curve was defined as the mean signal intensity from the first three images The maximum signal intensity SImax was defined as the maximum value of the first rapidly rising part of the time-signal intensity curve The time to peak contrast enhancement was defined as the time Trise between SIbase and SImax After the peak which usually occurred about 40 seconds after the start of injection the time-signal intensity curve entered an equilibrium phase that lasted about 30 seconds The total 100-second imaging time encompassed both the first rapid rise in the curve and the early equilibrium phase In our study the SIbase and SImax were measured only from the first rapidly rising curve For the semiquantitative analysis the peak enhancement ratio peak was calculated for each ROI as SImax - SIbaseSIbase and average enhancement slope average slope was defined as SImax - SIbase Trise for each ROI The initial slope was measured as the most steep uprising slope from the early rapid-rising part of time intensity curve The mean value was calculated from the parameters of the L3 L3 and L4 vertebrae and represented for each subject In our preliminary study like others Moehler et al 2001 this constructed images performed by dynamic contrast-enhanced MRI which mimic the perfusion status within bone marrow had been correlated with distinct clinical outcomes in our acute myeloid leukemia and MM patients in a preliminary study
Accordingly we would like to have the BM perfusion status imaged by dynamic MRI to mimic the macroscopic vascular densities of BM and thereafter the BM perfusion status the clinical outcome of the MM patients and the angiogenesis related biological markers will be correlated
There are several independent prognostic factors for MM like high levels of beta-2 microglobulin hypodiploidy chromosome content deletion of chromosome 13q14 and also the extent of angiogenesis shown by microvascular density MVD in BM Fonseca et al 2004 Kumar et al 2002 Pruneri et al 2002 Sezer et al 2000 It has been suggested that MM progressed from an avascular to a vascular phase active MM accompanied by a significant increase in MVD in BM Rajkumar et al 2002 which is promoted by the angiogenesis related factors like VEGF bFGF and PDGF which were performed like a paracrine or autocrine loops secreted by MM cells per se or the adjacent BM stromal cells Gupta et al 2001 Kumar et al 2003 Ria et al 2003 Vacca et al 2003 It has been reported that higher MVD in BM at the time of initial diagnosis was associated with shorter OS and PFS in patients undergoing autologous transplantation for MM than the patients with lower MVD Kumar et al 2004 Those angiogenesis related factors may provide disease monitoring but also a potent novel therapeutic approach to over come resistance to therapies and thereby improve patient outcome Podar et al 2004 Interestingly the patients with deletion of chromosome 13q14 have higher MVD in BM than the patients without Schreiber 2000 which hinted that the grave prognosis of deletion of chromosome 13q14 might be a result of dysregulation of angiogenesis in BM However on the other hand absence of clinical prognostic value of VEGF and MVD in MM had also been reported by other investigators Ahn et al 2001 Choi et al 2002 In MM whether the MVD in BM and the related biological markers like VEGF bFGF and PDGF can serve as prognostic factors are still debate Rajkumar et al 2001 Vacca et al 2001 There are possible two reasons for the debate the first one is that the distribution of neoplastic foci within the BM of MM are not homogenous therefore the microvascular densities calculated from a single site BM specimen are hard to represent the total angiogenesis within the BM the second one is that the angiogenesis related biological markers such as VEGF bFGF and PDGF in MM are largely studied on the plasmas obtained from peripheral blood rather than BM and this is a critical issue for the cytokines secreted from either MM cells or adjacent stromal cells are mostly paracrines or autocrines and the levels of VEGF bFGF PDGF are higher in BM than in peripheral blood Di Raimondo et al 2000
Reviewing the literature dynamic contrast-enhanced MRI has been used to evaluate the potential of vertebral fractures in MM Scherer et al 2002a 2002b to quantify significant changes of BM microcirculation during conventional treatment Rahmouni et al 1993 or treatment with thalidomide combined with chemotherapy Wasser et al 2004 which may be a novel and non-invasive tool to approach the clinical outcomes of MM patients Moehler et al 2001 In short MR imaging of the spine was performed with a 15-T superconducting system Magnetom Vision Plus Siemens Erlangen Germany A phase-array spine-coil was used and a routine fast spin-echo T1-weighted sequence repletion time msececho time msec 60012 turbo factor of three section thickness 4 mm field of view 28cm was performed in the midsagittal plane and covered the area from T11 through the sacrum A dynamic contrast-enhanced MR study was then performed section thickness 10 mm field of view 28 cm at the midsection of the vertebral body and covered the same area The pulse sequence used was a turbo fast low-grade shot gradient-echo sequence 8540 prepulse inversion time 160 msec flip angle 10 acquisition matrix 72x128 Acquisition time was 089 second with 011-second delay In total 100 dynamic images were obtained within 100 seconds one frame per second in each subject After the initial 100-second scanning the scanning were prolong to 600 seconds with the scan rate 1 frame per 10 seconds 1 seconds scan and 9 seconds delay An injection of 01 mmol per kilogram of body weight gadopentetate dimeglumine Magnevist Schering Berlin Germany was administrated by the power injector through a 21-gauge intravenous catheter that was inserted in the right antecubital vein previously A brief constant injection rate of 20mlsec were used This injection was immediately followed with a 20-ml saline flush at the same injection rate Dynamic imaging started when the injection of the contrast material commenced
Signal intensity values were measured in an operator-defined region of interests ROIs The musculoskeletal radiologist TTFS with 15 years experience places the ROIs were placed with the aid of a cursor and a graphic display device along the border of high-signal-intensity bone marrow on T1 weighted images covered the entire bone marrow of each vertebra One vertebral body was covered by one ROI measurement The ROI was measured separately for each of selected lumbar vertebrae L2 L3 and L4 in each subject The signal intensity values derived from the ROI measured in each vertebral body were then plotted against time to obtain a time-signal intensity curve Fig 1 for each vertebral body The baseline value for signal intensity SIbase on a time- signal intensity curve was defined as the mean signal intensity from the first three images The maximum signal intensity SImax was defined as the maximum value of the first rapidly rising part of the time-signal intensity curve The time to peak contrast enhancement was defined as the time Trise between SIbase and SImax After the peak which usually occurred about 40 seconds after the start of injection the time-signal intensity curve entered an equilibrium phase that lasted about 30 seconds The total 100-second imaging time encompassed both the first rapid rise in the curve and the early equilibrium phase In our study the SIbase and SImax were measured only from the first rapidly rising curve For the semiquantitative analysis the peak enhancement ratio peak was calculated for each ROI as SImax - SIbaseSIbase and average enhancement slope average slope was defined as SImax - SIbase Trise for each ROI The initial slope was measured as the most steep uprising slope from the early rapid-rising part of time intensity curve The mean value was calculated from the parameters of the L3 L3 and L4 vertebrae and represented for each subject In our preliminary study like others Moehler et al 2001 this constructed images performed by dynamic contrast-enhanced MRI which mimic the perfusion status within bone marrow had been correlated with distinct clinical outcomes in our acute myeloid leukemia and MM patients in a preliminary study
Accordingly we would like to have the BM perfusion status imaged by dynamic MRI to mimic the macroscopic vascular densities of BM and thereafter the BM perfusion status the clinical outcome of the MM patients and the angiogenesis related biological markers will be correlated
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None