br Table Methodological Quality of the
Table 2. Methodological Quality of the Involved 32 Studies According to the QUADAS Criteria
Quadas criteria No bias Bias Unclear
Was the spectrum of patients representative of the patients who will receive the test in practice? 32 (100)
Is the time period between reference standard and index test short enough to be reasonably sure that the target condition did not change between the two tests? 32 (100)
Did the whole sample or a random selection of the sample, receive verification using a reference standard of diagnosis? 32 (100)
Did patients receive the same reference standard regardless of the index test result? 32 (100)
Was the reference standard independent of the index test (i.e. the index test did not form part of the reference standard)? 32 (100)
Was the execution of the index test described in sufficient detail to permit replication of the test? 32 (100)
Was the execution of the reference standard described in sufficient detail to permit its replication? 32 (100)
Were the index test results interpreted without knowledge of the results of the reference standard? 16 (50.0)
16 (50.0) Were the reference standard results interpreted without knowledge of the results of the index test? 12 (46.15)
20 (30.77) Were the same clinical data available when test results were interpreted as would be available when the test is used in practice? 32 (100)
Figure 2. Forest plots of correlation coefficients between SUVmax derived from 18F-FDG PET and Ki-67 in patients with breast cancer.
Furthermore, we found that SUVmax derived from FLT PET had stronger associations with Ki-67 in BC (0.54). This finding is not unusual. Similar results were reported also for other malignancies. For example, in a meta-analysis investigated relationships between
is phosphorylated by thymidine kinase-1 and is a marker of cells in the S-phase of the Filipin Complex [55,56]. Therefore, the uptake of FLT is linked to cell proliferation rate. Thus, FLT PET is more sensitive than FDG PET to predict proliferation potential.
However, overall, our findings suggest that it is problematically to use SUVmax as predictor of proliferation activity in BC. This finding is difficult to explain. Presumably, glucose metabolism and cell proliferation are not associated directly. Furthermore, Ki-67 is one of numerous proliferation markers. Possibly, glucose metabolism might be stronger associated with other proliferation factors than with Ki-67. In fact, Nishimukai et al. showed that SUVmax correlated stronger with proliferation marker geminin than with Ki-67 . The authors also suggested that geminin is preferable to Ki-67 evaluating the proliferative activity of breast cancer cells .
Figure 3. Forest plots of correlation coefficients between SUVmax derived from 18F-fluorthymidin PET and Ki-67 in patients with breast cancer.
The present analysis identified another interesting aspect. BC represents a heterogenous group of carcinomas with different histopathological features and behavior. Presumably, different subtypes of BC may have also different associations between PET and Ki-67. Further prospective studies are needed to confirm this hypothesis.
Our analysis identified also methodological problems of the previous reports. Half of the acquired studies were of retrospective design. Furthermore, according the QUADAS criteria, 28.12% of the acquired studies had unclear selection criteria. Additionally, 30.77% of the studies may have diagnostic review bias. Clearly, studies with well-defined inclusion and exclusion criteria are needed to investigate associations between PET and Ki-67 in BC.
In conclusion, the present meta-analysis showed that SUVmax correlated moderately with expression of Ki-67 and, therefore, cannot be used as a surrogate marker for tumor proliferation. Further studies are needed to evaluate associations between PET parameters and histopathological findings like hormone receptor status in breast cancer.
Ethics Approval and Consent to Participate
Consent for Publication
Availability of Data and Material
The data that support the findings of this study are available from professor Surov but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of professor Surov.
• AS, HJM, AW made substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data;
• HJM, AW been involved in drafting the manuscript or revising it critically for important intellectual content;
• HJM, AW given final approval of the version to be published. Each author have participated sufficiently in the work to take public responsibility for appropriate portions of the content; and