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D A Mankoff

Publications and source records attributed to D A Mankoff.

28 records · Page 2Linked to original sources
PubMed1998

Kinetic analysis of 2-[carbon-11]thymidine PET imaging studies: compartmental model and mathematical analysis.

UNLABELLED: Carbon-11-thymidine is a PET tracer of DNA synthesis and cellular proliferation. Quantitative analysis of [11C]thymidine images is complicated by the presence of significant quantities of labeled metabolites. Estimation of the rate of thymidine incorporation into DNA using [11C]thymidine requires a kinetic model that is capable of describing the behavior of thymidine and labeled metabolites. METHODS: Based on previous studies with labeled thymidine, we constructed a five-compartment model describing the kinetic behavior of 2-[11C]thymidine and its labeled metabolites. In addition, we have performed a series of calculations and simulations to calculate the sensitivity and identifiability of model parameters to estimate the extent to which individual parameters can be estimated; to determine appropriate model constraints necessary for reproducible estimates of the constant describing flux of thymidine from the blood into DNA, i.e., thymidine flux constant; and to determine the potential accuracy of model parameter and thymidine flux constant estimates from PET imaging data. RESULTS: The underlying assumptions in the thymidine compartmental model lead to a description of the thymidine flux constant for DNA incorporation in terms of model parameters. Sensitivity and identifiability analyses suggest that the model parameters pertaining to labeled metabolites will be difficult to estimate independently of the thymidine parameters. Exact evaluation of the kinetic parameters of the labeled metabolites is not the principal goal of this model. Simulations were performed that suggest that it is preferable to tightly constrain these parameters to preset values near the center of their expected ranges. Although it is difficult to estimate individual thymidine model parameters, the flux constant for incorporation into DNA can be accurately estimated (r > 0.9 for estimated versus true simulated flux constant). Flux constant estimates are not affected by modest levels of local degradation of thymidine that may occur in proliferating tissue. CONCLUSION: By using a kinetic model for thymidine and labeled metabolites, it is possible to estimate the flux of thymidine uptake and incorporation into DNA and, thereby, noninvasively estimate regional cellular proliferation using [11C]thymidine and PET.

Carbon Radioisotopes↗
PubMed1998

Carbon-11-thymidine and FDG to measure therapy response.

UNLABELLED: This study was performed to determine if PET imaging with 11C-thymidine could measure tumor response to chemotherapy early after the initiation of treatment. Imaging of deoxyriboneucleic acid biosynthesis, quantitated with 11C-thymidine, was compared with measurements of tumor energetics, obtained by imaging with 18F-fluorodeoxyglucose (FDG). METHODS: We imaged four patients with small cell lung cancer and two with high-grade sarcoma both before and approximately 1 wk after the start of chemotherapy. Thymidine and FDG studies were done on the same day. Tumor uptake was quantified by standardized uptake values (SUVs) for both tracers by the metabolic rate of FDG and thymidine flux constant (K(TdR)) using regions of interest placed on the most active part of the tumor. RESULTS: In the four patients with clinical response to treatment, both thymidine and FDG uptake markedly declined 1 wk after therapy. Thymidine measurements of SUV and K(TdR) declined by 64% +/- 15% and 84% +/- 33%, respectively. FDG SUV and the metabolic rate of FDG declined by 51% +/- 9% and 63% +/- 23%, respectively. In the patient with metastatic small cell lung cancer who had disease progression, the thymidine SUV decreased by only 8% (FDG not done). In a patient with abdominal sarcoma and progressive disease, thymidine SUV was essentially unchanged (declined by 3%), whereas FDG SUV increased by 69%. CONCLUSION: Images show a decline in both cellular energetics and proliferative rate after successful chemotherapy. In the two patients with progressive disease, thymidine uptake was unchanged 1 wk after therapy. In our limited series, K(TdR) measurements showed a complete shutdown in tumor proliferation in patients in whom FDG showed a more limited decrease in glucose metabolism.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Analysis of blood clearance and labeled metabolites for the estrogen receptor tracer [F-18]-16 alpha-fluoroestradiol (FES).

[F-18] 16 alpha-Fluoroestradiol (FES) has been shown to be a tracer of estrogen receptor content in breast tumors; however, quantitative analysis of FES images is complicated by the rapid metabolism of the tracer in vivo. To optimize FES PET imaging studies and to provide an input function for the quantitative analysis of the tracer FES uptake in breast tumors, we studied the clearance and metabolism of FES in 15 breast cancer patients. FES clearance, protein binding, and metabolite production and limited assays to determine the identity of labeled metabolites were performed. These studies show that FES was rapidly cleared from the blood and metabolized; at 20 min only 20% of the circulating radioactivity was unmetabolized FES, and much of this was protein bound. The detectable metabolites in either blood or urine are conjugation products, largely the glucuronide and the sulfate of FES, and these are excreted through the kidneys at a rate comparable to their introduction into the circulation. After 20 min postinjection the blood levels of radioactivity remain fairly constant. Our results, the first report on human metabolites, are in close agreement with previous animal studies of FES metabolism. These studies show that because FES clearance is rapid and metabolite background is nearly constant, imaging starting at 20 to 30 min after injection may provide good visualization of estrogen-containing tissues. Labeled metabolites need to be accounted for in quantifying FES uptake.

Adult↗
PubMed1997

Application of photoshop-based image analysis to quantification of hormone receptor expression in breast cancer.

The benefit of quantifying estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer is well established. However, in routine breast cancer diagnosis, receptor expression is often quantified in arbitrary scores with high inter- and intraobserver variability. In this study we tested the validity of an image analysis system employing inexpensive, commercially available computer software on a personal computer. In a series of 28 invasive ductal breast cancers, immunohistochemical determinations of ER and PR were performed, along with biochemical analyses on fresh tumor homogenates, by the dextran-coated charcoal technique (DCC) and by enzyme immunoassay (EIA). From each immunohistochemical slide, three representative tumor fields (x20 objective) were captured and digitized with a Macintosh personal computer. Using the tools of Photoshop software, optical density plots of tumor cell nuclei were generated and, after background subtraction, were used as an index of immunostaining intensity. This immunostaining index showed a strong semilogarithmic correlation with biochemical receptor assessments of ER (DCC, r = 0.70, p < 0.001; EIA, r = 0.76, p < 0.001) and even better of PR (DCC, r = 0.86; p < 0.01; EIA, r = 0.80, p < 0.001). A strong linear correlation of ER and PR quantification was also seen between DCC and EIA techniques (ER, r = 0.62, p < 0.001; PR, r = 0.92, p < 0.001). This study demonstrates that a simple, inexpensive, commercially available software program can be accurately applied to the quantification of immunohistochemical hormone receptor studies.

Breast Neoplasms↗
PubMed1997

Scintigraphy with indium-111-labeled homologous (donor) platelets in the platelet transfusion refractory bone marrow transplant patient.

Some bone marrow transplant patients who require multiple platelet transfusions as a consequence of post-transplant thrombocytopenia become refractory to these transfusions. As the spleen is the primary site of destruction for senescent and damaged platelets, splenectomy is a potential therapy for persistent thrombocytopenia. Scintigraphy with 111In-labeled platelets has been used to identify increased splenic sequestration and destruction in various platelet disorders, especially idiopathic thrombocytopenic purpura, before consideration of therapeutic splenectomy, but this technique has not been widely described in platelet transfusion refractory bone marrow transplant patients. We report on the results of 111In-labeled platelet scans in two such patients and review the pertinent literature in relation to the possible benefits and limitations of this scanning technique.

Adult↗
PubMed1997

Utility and reproducibility of semiquantitative analysis of sestamibi breast images.

UNLABELLED: Technetium-99m-sestamibi scintimammography has been shown to be a useful diagnostic test in the detection of breast cancer. The purpose of this study was two-fold to: (a) evaluate semiquantitative indices of tracer uptake in lesions and determine if they are helpful in distinguishing benign from malignant breast lesions; and (b) test the reproducibility of these measures of sestamibi uptake in breast images. METHODS: Prone lateral planar imaging was performed on 27 patients after intravenous injection of 20-30 mCi 99mTc-sestamibi. Data were analyzed by creating three regions of interest (ROIs) over designated areas: lesion, normal breast and right chest wall. Lesion-to-normal (L:N) and lesion-to-chest wall (L:CW) ratios were calculated for each patient. Reproducibility was assessed by having two independent observers draw ROIs (interobserver) and one observer draw two independent sets of ROIs (intraobserver). RESULTS: L:N and L:CW ratios were significantly different for malignant versus benign lesions (p < 0.001 for both ratios). Intraobserver and interobserver reproducibility showed good correlation with r = 0.98 (L:CW ratio). CONCLUSION: Semiquantitative analysis of sestamibi breast imaging results in reproducible uptake ratios that may be helpful in objectively interpreting imaging results.

Adult↗
PubMed1996

A graphical analysis method to estimate blood-to-tissue transfer constants for tracers with labeled metabolites.

UNLABELLED: The Patlak graphical analysis technique is a popular tool for estimating blood-to-tissue transfer constants from multiple-time uptake data. Our objective was to extend this technique to tracers with labeled metabolites, the presence of which can cause errors in the standard Patlak analysis. METHODS: Based on previously described formulations, we generalized the graphical technique for use under specific conditions. To test the extended graphical approach, we applied the method to both simulated and patient data using a preliminary compartmental model for the PET tumor proliferation marker, 2-[11C]-thymidine. RESULTS: When given conditions are met, a linear relationship exists between the normalized tissue activity (tissue activity/blood activity) and a new set of graphical analysis basis functions, including a new definition of normalized time, which takes the presence of labeled metabolites into account. Graphical estimations of the tumor thymidine incorporation rate for simulated data were accurate and showed close agreement to the results of detailed compartmental analysis. In patient studies, the graphical and compartmental estimates showed good agreement but a somewhat poorer correlation than in the simulations. CONCLUSION: The extended graphical analysis approach provides an efficient method for estimating blood-tissue transfer constants for tracers with labeled metabolites.

Carbon Radioisotopes↗
PubMed1989

The high count rate performance of a two-dimensionally position-sensitive detector for positron emission tomography.

In positron tomographs using a small number of position-sensitive detectors, each detector must operate at high singles event rates, especially during dynamic studies. To enable the PENN-PET tomography to perform studies involving high data rates, the high count rate behaviour of the position-sensitive scintillation detector used in the tomograph was investigated at singles rates in excess of 2 million counts per second (MCPS). Detector dead-time, minimised through the use of pulse clipping (clipping time, 120 ns), is a maximum of 20% at the highest data rates. At 2 MCPS and 240 ns pulse integration time, the full width at half maximum of the point spread function (PSF) worsens by approximately 20% over its low count rate value of 5.2 mm. Furthermore, at high count rates, pulse pile-up produces long tails in the PSF along the detector's long axis. These tails were reduced or eliminated through the use of a shortened pulse integration time (160 ns instead of 240 ns), an upper level energy discriminator and a local centroid event positioning algorithm. Detector performance was characterised for different combinations of these event processing techniques, and the mechanisms by which pulse pile-up distorts the high count rate PSF were investigated using computer simulations. With the incorporation of the high count rate event processing techniques, the detector's count rate capability enables the PENN-PET tomograph to handle most current imaging protocols.

Scintillation Counting↗
PubMedDate not supplied

Characterizing tumors using metabolic imaging: PET imaging of cellular proliferation and steroid receptors.

Treatment decisions in oncology are increasingly guided by information on the biologic characteristics of tumors. Currently, patient-specific information on tumor biology is obtained from the analysis of biopsy material. Positron emission tomography (PET) provides quantitative estimates of regional biochemistry and receptor status and can overcome the sampling error and difficulty in performing serial studies inherent with biopsy. Imaging using the glucose metabolism tracer, 2 -deoxy-2- fluoro-D-glucose (FDG), has demonstrated PET's ability to guide therapy in clinical oncology. In this review, we highlight PET approaches to imaging two other aspects of tumor biology: cellular proliferation and tumor steroid receptors. We review the biochemical and biologic processes underlying the imaging, positron-emitting radiopharmaceuticals that have been developed, quantitative image-analysis considerations, and clinical studies to date. This provides a basis for evaluating future developments in these promising applications of PET metabolic imaging.

Cell Division↗