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11C-Methionine-PET: a novel and sensitive tool for monitoring of early response to treatment in multiple myeloma.

Lückerath K, Lapa C, Albert C, Herrmann K, Jörg G, Samnick S, Einsele H, Knop S, Buck AK - Oncotarget (2015)

Bottom Line: Treatment reduced both MET and FDG uptake; changes in tracer-retention correlated with a switch from high to low CD138-expression.No significant differences were detected thus early with FDG.Our results suggest that MET is superior to FDG in very early assessment of response to anti-myeloma-therapy.

View Article: PubMed Central - PubMed

Affiliation: University Hospital Wuerzburg, Department of Nuclear Medicine, Wuerzburg, Germany.

ABSTRACT
Multiple myeloma (MM) remains an essentially incurable hematologic malignancy. However, new treatment modalities and novel drugs have been introduced and thus additional tools for therapy monitoring are increasingly needed. Therefore, we evaluated the radiotracers 11C-Methionine (paraprotein-biosynthesis) and 18F-FDG (glucose-utilization) for monitoring response to anti-myeloma-therapy and outcome prediction. Influence of proteasome-inhibition on radiotracer-uptake of different MM cell-lines and patient-derived CD138+ plasma cells was analyzed and related to tumor-biology. Mice xenotransplanted with MM.1S tumors underwent MET- and FDG-μPET. Tumor-to-background ratios before and after 24 h, 8 and 15 days treatment with bortezomib were correlated to survival. Treatment reduced both MET and FDG uptake; changes in tracer-retention correlated with a switch from high to low CD138-expression. In xenotransplanted mice, MET-uptake significantly decreased by 30-79% as early as 24 h after bortezomib injection. No significant differences were detected thus early with FDG. This finding was confirmed in patient-derived MM cells. Importantly, early reduction of MET- but not FDG-uptake correlated with improved survival and reduced tumor burden in mice. Our results suggest that MET is superior to FDG in very early assessment of response to anti-myeloma-therapy. Early changes in MET-uptake have predictive potential regarding response and survival. MET-PET holds promise to individualize therapies in MM in future.

No MeSH data available.


Related in: MedlinePlus

Changes in tracer uptake upon proteasome inhibition are associated with CD138 cell surface levelsFlow cytometric quantification of the percent of CD138+ cells (percent of total; (A)), extent of CD138 expression (geometric mean fluorescent intensity, GeoMean; (B)) and percent CD138high and CD138low MM cells, respectively, (C) is shown as background-corrected means ± standard deviation, related to that of untreated controls (n = 5). Asterisk indicate statistically significant differences (p < 0.02).
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Figure 2: Changes in tracer uptake upon proteasome inhibition are associated with CD138 cell surface levelsFlow cytometric quantification of the percent of CD138+ cells (percent of total; (A)), extent of CD138 expression (geometric mean fluorescent intensity, GeoMean; (B)) and percent CD138high and CD138low MM cells, respectively, (C) is shown as background-corrected means ± standard deviation, related to that of untreated controls (n = 5). Asterisk indicate statistically significant differences (p < 0.02).

Mentions: Analysis of the MM marker and adhesion molecule CD138 at the cell surface demonstrated an almost identical fraction of CD138 expressing cells following incubation with either proteasome inhibitor (Bz, Cz, Iz) when compared to untreated controls (Figure 2A). However, the extent of CD138 expression was significantly reduced (p < 0.02) (Figure 2B); a more detailed evaluation revealed that the ratio of CD138high to CD138low MM cells reversed (Figure 2C). This reversal was positively associated with radiotracer uptake: the larger the reduction in tracer uptake, the less CD138 was present at the cell surface of MM cell lines (Supplementary Figure 1A; see the Supplemental Data Set link at the top of the online article). Results from ELISA-assays suggested that the loss could only in part be explained by enhanced shedding of CD138: while the amount of CD138 in the medium of OPM-2 cells treated with Bz increased 2-fold (compared to untreated cells), it was about the same in MM.1S and half as much in INA-6 (Supplementary Figure 2).


11C-Methionine-PET: a novel and sensitive tool for monitoring of early response to treatment in multiple myeloma.

Lückerath K, Lapa C, Albert C, Herrmann K, Jörg G, Samnick S, Einsele H, Knop S, Buck AK - Oncotarget (2015)

Changes in tracer uptake upon proteasome inhibition are associated with CD138 cell surface levelsFlow cytometric quantification of the percent of CD138+ cells (percent of total; (A)), extent of CD138 expression (geometric mean fluorescent intensity, GeoMean; (B)) and percent CD138high and CD138low MM cells, respectively, (C) is shown as background-corrected means ± standard deviation, related to that of untreated controls (n = 5). Asterisk indicate statistically significant differences (p < 0.02).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480763&req=5

Figure 2: Changes in tracer uptake upon proteasome inhibition are associated with CD138 cell surface levelsFlow cytometric quantification of the percent of CD138+ cells (percent of total; (A)), extent of CD138 expression (geometric mean fluorescent intensity, GeoMean; (B)) and percent CD138high and CD138low MM cells, respectively, (C) is shown as background-corrected means ± standard deviation, related to that of untreated controls (n = 5). Asterisk indicate statistically significant differences (p < 0.02).
Mentions: Analysis of the MM marker and adhesion molecule CD138 at the cell surface demonstrated an almost identical fraction of CD138 expressing cells following incubation with either proteasome inhibitor (Bz, Cz, Iz) when compared to untreated controls (Figure 2A). However, the extent of CD138 expression was significantly reduced (p < 0.02) (Figure 2B); a more detailed evaluation revealed that the ratio of CD138high to CD138low MM cells reversed (Figure 2C). This reversal was positively associated with radiotracer uptake: the larger the reduction in tracer uptake, the less CD138 was present at the cell surface of MM cell lines (Supplementary Figure 1A; see the Supplemental Data Set link at the top of the online article). Results from ELISA-assays suggested that the loss could only in part be explained by enhanced shedding of CD138: while the amount of CD138 in the medium of OPM-2 cells treated with Bz increased 2-fold (compared to untreated cells), it was about the same in MM.1S and half as much in INA-6 (Supplementary Figure 2).

Bottom Line: Treatment reduced both MET and FDG uptake; changes in tracer-retention correlated with a switch from high to low CD138-expression.No significant differences were detected thus early with FDG.Our results suggest that MET is superior to FDG in very early assessment of response to anti-myeloma-therapy.

View Article: PubMed Central - PubMed

Affiliation: University Hospital Wuerzburg, Department of Nuclear Medicine, Wuerzburg, Germany.

ABSTRACT
Multiple myeloma (MM) remains an essentially incurable hematologic malignancy. However, new treatment modalities and novel drugs have been introduced and thus additional tools for therapy monitoring are increasingly needed. Therefore, we evaluated the radiotracers 11C-Methionine (paraprotein-biosynthesis) and 18F-FDG (glucose-utilization) for monitoring response to anti-myeloma-therapy and outcome prediction. Influence of proteasome-inhibition on radiotracer-uptake of different MM cell-lines and patient-derived CD138+ plasma cells was analyzed and related to tumor-biology. Mice xenotransplanted with MM.1S tumors underwent MET- and FDG-μPET. Tumor-to-background ratios before and after 24 h, 8 and 15 days treatment with bortezomib were correlated to survival. Treatment reduced both MET and FDG uptake; changes in tracer-retention correlated with a switch from high to low CD138-expression. In xenotransplanted mice, MET-uptake significantly decreased by 30-79% as early as 24 h after bortezomib injection. No significant differences were detected thus early with FDG. This finding was confirmed in patient-derived MM cells. Importantly, early reduction of MET- but not FDG-uptake correlated with improved survival and reduced tumor burden in mice. Our results suggest that MET is superior to FDG in very early assessment of response to anti-myeloma-therapy. Early changes in MET-uptake have predictive potential regarding response and survival. MET-PET holds promise to individualize therapies in MM in future.

No MeSH data available.


Related in: MedlinePlus