Beneath the surface of the mud, part II: the dichotomization of continuous biologicvariables by maximizing immunohistochemical method sensitivity.
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Breast Neoplasms↗
Biomedical subjects
Rodney A Schmidt
Publications and source records attributed to Rodney A Schmidt.
Kinetic analysis of 3'-deoxy-3'-fluorothymidine PET studies: validation studies in patients with lung cancer.
UNLABELLED: Assessing cellular proliferation provides a direct method to measure the in vivo growth of cancer. We evaluated the application of a model of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) kinetics described in a companion report to the analysis of FLT PET image data in lung cancer patients. Compartmental model analysis was performed to estimate the overall flux constants (K(FLT)) for FLT phosphorylation in tumor, bone marrow, and muscle. Estimates of flux were compared with an in vitro assay of proliferation (Ki-67) applied to tissue derived from surgical resection. Compartmental modeling results were compared with simple model-independent methods of estimating FLT uptake. METHODS: Seventeen patients with 18 tumor sites underwent up to 2 h of dynamic PET with blood sampling. Metabolite analysis of plasma samples corrected the total blood activity for labeled metabolites and provided the FLT model input function. A 2-compartment, 4-parameter model (4P) was tested and compared with a 2-compartment, 3-parameter (3P) model for estimating K(FLT). RESULTS: Bone marrow, a proliferative normal tissue, had the highest values of K(FLT), whereas muscle, a nonproliferating tissue, showed the lowest values. The K(FLT) for tumors estimated by compartmental analysis had a fair correlation with estimates by modified graphical analysis (r = 0.86) and a poorer correlation with the average standardized uptake value (r = 0.62) in tumor. Estimates of K(FLT) derived from 60 min of dynamic PET data using the 3P model underestimated K(FLT) compared with 90 or 120 min of dynamic data analyzed using the 4P model. Comparison of flux estimates with an independent measure of cellular proliferation showed that K(FLT) was highly correlated with Ki-67 (Spearman rho = 0.92, P < 0.001). Ignoring the metabolites of FLT in blood underestimated K(FLT) by as much as 47%. CONCLUSION: Compartmental analysis of FLT PET image data yielded robust estimates of K(FLT) that correlated with in vitro measures of tumor proliferation. This method can be applied generally to other imaging studies of different cancers after validation of parameter error. Tumor loss of phosphorylated FLT nucleotides (k(4)) is notable and leads to errors when FLT uptake is evaluated using model-independent approaches that ignore k(4), such as graphical analysis or the SUV.
Algorithms↗
Diffuse pulmonary ossification.
Diffuse pulmonary ossification (DPO) is an uncommon condition that is characterized by metaplastic bone formation in the lung parenchyma. It is usually not diagnosed clinically and may be apparent radiographically only when extensive. However, it is occasionally encountered at autopsy or on pathologic evaluation of surgical specimens. This article will review the clinical, histologic, and radiographic manifestations of DPO, focusing primarily on the chest radiograph and CT findings, both of which may be underappreciated, for even experienced radiologists may confuse DPO with other entities such as metastatic calcification as seen in chronic renal failure or chronic granulomatous disease.
Calcinosis↗
In vivo validation of 3'deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) as a proliferation imaging tracer in humans: correlation of [(18)F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors.
PURPOSE: Tumor proliferation has prognostic value in resected early stage non-small cell lung cancer (NSCLC) and can, therefore, predict which NSCLCs are at high risk for recurrence after resection and would benefit from additional therapy. It may also predict which tumor will respond to cell cycle-targeted chemotherapy and help assess the tumor response, besides helping to differentiate benign from malignant lung lesions. We evaluated whether the uptake of the new positron emission tomography (PET) tracer 3'deoxy-3'-[18F]fluorothymidine (FLT) in a series of suspected NSCLCs correlated with tumor proliferation assessed by Ki-67 immunohistochemistry and flow cytometry. EXPERIMENTAL DESIGN: Ten patients with 11 biopsy-proven or clinically suspected NSCLC underwent 2-h dynamic PET imaging after i.v. injection of 0.07 mCi/kg FLT. Tumor FLT uptake was quantitated with the maximum pixel standardized uptake value (maxSUV), the partial volume corrected maxSUV (PV-corr-maxSUV), the average SUV over a small region-of-interest (aveSUV) and with Patlak analysis of FLT flux (aveFLTflux). The lesion diameter from computed tomography was used to correct the maxSUV for PV effects using recovery coefficients determined for the General Electric Advance PET scanner. Two of the 11 lesions were benign inflammatory lesions and 9 were NSCLCs. Immunohistochemistry for Ki-67 (proliferation index marker) was performed on all 11 tissue specimens (10 resections, 1 NSCLC percutaneous biopsy), and the S-phase fraction (SPF) from flow cytometry could be determined for 10. The specimens were reviewed for histology and cellular differentiation (poor, moderate, well). Lesions ranged from 1.6 to 7.7 cm. RESULTS: Excellent correlations were found between SUV measures of FLT uptake and Ki-67 scores [percentage of positive cells; maxSUV versus Ki-67: Rho = 0.78, P = 0.0043 (n = 11); PV-corr-maxSUV versus Ki-67: Rho = 0.83, P = 0.0028 (n = 10); aveSUV versus Ki-67: Rho = 0.84, P = 0.0011 (n = 11)]. Correlation between Ki-67 proliferation scores and Patlak measures of FLT uptake were also strong: aveFLTflux versus Ki-67: Rho = 0.94, P < 0.0001 (n = 11). The correlation between the SPF and all indices of FLT uptake was weaker and reached statistical significance for only two uptake indices [maxSUV versus SPF: Rho = 0.69, P = 0.03 (n = 10); PV-corr-maxSUV versus SPF: Rho = 0.36, P = 0.35 (n = 9); aveSUV versus SPF: Rho = 0.67, P = 0.03 (n = 10); aveFLTflux versus SPF: Rho = 0.46, P = 0.18 (n = 10)]. CONCLUSION: FLT PET may be used to noninvasively assess proliferation rates of lung masses in vivo. Therefore, FLT PET may play a significant role in the evaluation of indeterminate pulmonary lesions, in the prognostic assessment of resectable NSCLC, and possibly in the evaluation of NSCLC response to chemotherapy.
Carcinoma, Non-Small-Cell Lung↗
The Ki-67 index and survival in non-small cell lung cancer: a review and relevance to positron emission tomography.
PURPOSE: We reviewed the current literature to discover the range of studies covering tissue-based and noninvasive methods for determining tumor stage and the prognostic value of staging in non-small cell lung cancer. DESIGN: Despite refinements in staging of non-small cell lung cancer, each stage remains heterogeneous because each stage contains patients who are at higher risk for recurrence than other patients within the same stage. Tissue-based and noninvasive methods have been investigated to complement tumor stage in assessing non-small cell lung cancer prognosis. The prognostic significance of tumor proliferation assessed by Ki-67 protein expression has been demonstrated in non-small cell lung cancer. RESULT: Recent positron emission tomography studies have also shown both prognostic value in non-small cell lung cancer uptake of [F-18] fluorodeoxyglucose (FDG) and correlation between non-small cell lung cancer FDG uptake and tumor proliferation. DISCUSSION: We reviewed the prognostic significance of Ki-67 expression in non-small cell lung cancer and related it to positron emission tomography.
Antigens, Neoplasm↗