Biomedical subjects

A F Shields

Publications and source records attributed to A F Shields.

At least 37 records · Page 2Linked to original sources

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

Phase II study of pyrazoloacridine in patients with advanced colorectal carcinoma.

PURPOSE: Pyrazoloacridine (PZA) is an acridine derivative selected for clinical development because of broad preclinical antitumor activity and solid tumor selectivity. Phase I evaluations with PZA have demonstrated predictable toxicity and suggested clinical efficacy. A phase II trial in patients with previously untreated advanced colorectal cancer was conducted. METHODS: PZA was administered at a dose of 750 mg/m2 intravenously over 3 h every 21 days to patients who received a total of 31 courses of PZA. RESULTS: In 15 patients evaluable for response, no responses were observed (0% response rate, 95% confidence interval 0-22%). Toxicity to PZA consisted of myelosuppression and neurotoxicity that was treatment-limiting in several instances. CONCLUSION: PZA at this dose and schedule of administration is inactive in patients with colorectal cancer.

Acridines↗

PubMed1996

Development of labeled thymidine analogs for imaging tumor proliferation.

We have sought nucleoside analogs suitable for labeling with F-18 that could be used to image tumor proliferation with positron emission tomography (PET). The following three thymidine analogs were labeled with tritium and screened for their catabolism and biodistribution in vivo in mice: 5-fluoro-1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl)uracil (FFUdR), 5-fluoro-1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-uracil (FFaraU) and 5-methyl-1-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl)uracil (FTdR). We found that all three compounds were stable to degradation in vivo and when incubated in blood. Of the three analogs tested, only FFUdR showed preferential retention in rapidly proliferating tissues, such as the spleen and implanted tumors, and it attained tissue to blood ratios of 2.1 at 2 h.

Animals↗

PubMed1996

Analysis of 2-carbon-11-thymidine blood metabolites in PET imaging.

UNLABELLED: Carbon-11-thymidine labeled in the ring-2 position was used with PET to image tumor and tissue proliferation. Since thymidine is rapidly degraded in the body, one must consider the generation of metabolites to fully interpret the PET data. METHODS: We have measured the blood time-activity curves of thymidine and its metabolites in arterial blood samples. Blood was processed to obtain three input curves, including the total activity, the activity with CO2 removed and the fraction of CO2-free activity in intact thymidine (% Tdr). RESULTS: We found that CO2 reached a plateau of 65% (+/- 12%) of total blood activity by 11 min after injection. When a 1-min infusion of labeled thymidine is used, the time to 50% degradation to thymine and metabolites other than CO2 (measured in acidified samples by HPLC) was 2.9 +/- 0.6 min. We fit the results of the blood metabolism with a compartmental model. We found that we could accurately determine the % Tdr curve with as few as three measured points with an root mean square (RMS) error of 2% in the integrated curve, compared to the curve using all blood samples (mean of seven samples per patient). The integral of thymidine blood activity serves as the input to thymidine models, so similar errors could be expected in calculations of DNA synthetic rates. We found that the determination of CO2 could be accomplished with as few as five samples, with an RMS error of 4% in plateau %CO2 value. CONCLUSION: While it is essential to take metabolites into account when interpreting results obtained with 11C-thymidine, the reproducibility of these degradation curves may allow the use of a limited number of samples to measure the catabolic products of thymidine. These data from the blood, along with tissue kinetic models, are needed to calculate DNA synthetic rates.

Carbon Dioxide↗

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↗

PubMed1995

Radiosyntheses of labeled beta-pseudothymidine ([C-11]- and [H-3]methyl) and its biodistribution and metabolism in normal and tumored mice.

In order to develop labeled probes for measuring DNA synthetic rates in vivo we investigated [H-3]- and [C-11]methyl labeled beta-pseudothymidine (2a), and report on their radiosyntheses from methyl iodide. We find methylation is rapid and regioselective on N-1 of the acylurea moiety of 2'-deoxy-beta-D-pseudouridine (1a), in the presence of N,N-diisopropylethylamine and N,N-dimethylformamide at 60 degrees C. Although yields are low (11% [C-11]-decay corrected and 4.4% [H-3]), the method is simple and high specific activity tritiated methyl iodide can be used. In contrast to the rapid degradative de-glycosylation of thymidine in blood, beta-pseudothymidine is stable. However, based on biodistribution and metabolite studies, the anticipated uptake of [H-3]methyl-beta-pseudothymidine into mouse DNA of proliferating tissues (e.g. spleen, thymus and duodenum) and implanted tumors was not observed.

Animals↗

PubMed1994

Comparison of initial lymphoma staging using computed tomography (CT) and magnetic resonance (MR) imaging.

While MR is known to be superior to other imaging methods for detecting marrow involvement by lymphoma, MR is also capable of detecting abnormal lymph nodes. Our objective was to determine whether MR employing short TI inversion recovery (STIR) was comparable to CT in the initial staging of 23 patients with Hodgkin's disease (12 patients) and non-Hodgkin's lymphoma (11 patients). MR images of chest, abdomen, pelvis, and femoral marrow were obtained using the STIR and T1-weighted spin-echo (T1-SE) techniques, employing a protocol initially designed for marrow assessment. In all cases, CT-detected adenopathy was also found by MR. Four patients had marrow involvement by MR, undetected by CT. We conclude that MR and CT may be equivalent imaging modalities in the detection of nodal involvement, and that MR has an advantage in its ability to diagnose marrow involvement. Given the high frequency of focal marrow abnormalities detected by MR in patients with Hodgkin's disease and high-grade non-Hodgkin's lymphoma, MR may be the preferred staging modality for these patients.

Adolescent↗

PubMed1993

The effects of pentoxifylline on the generation of human lymphokine-activated killer cell cytotoxicity.

Pentoxifylline (PTX) is a methylated xanthine that has been shown to reduce the toxicity of Interleukin-2 (IL-2) therapy in animal models, possibly by inhibiting secretion of tumor necrosis factor-alpha. However, the use of PTX to reduce IL-2 toxicity in cancer patients would be advantageous only if PTX did not abrogate antitumor effector mechanisms. We therefore tested the effects of PTX on the induction of lymphokine-activated killer (LAK) cell reactivity in human peripheral blood mononuclear cells (PBMCs). LAK precursor and effector activity were defined as lysis of Daudi cells by PBMCs after incubation with IL-2 at 1,000 U/ml (LAKp) or without incubation (LAKe). PBMCs from four healthy subjects were cocultured for 5 days with IL-2 and PTX (0-1.0 mM). LAKp was inhibited in a PTX dose-dependent manner, as the mean % lysis at an E:T ratio of 50:1 was 62, 43, and 8% in the presence of 0, 0.1, and 1.0 mM PTX, respectively. To determine the effect of in vivo PTX on LAKp activity, four healthy subjects were tested after treatment with PTX at 2 g/day for 3 days. LAKp activity was detected in all four and was not inhibited by autologous serum containing PTX and biologically active metabolites. Because lymphocytes "preactivated" by IL-2 in vivo may respond to PTX differently than resting cells, two patients were tested after a 5 day infusion of IL-2 at 6 x 10(6) U/m2/day. PBMCs from both displayed LAKp activity, with far less inhibition by PTX than in resting cells (4, 17, and 37% inhibition at 0.05, 0.1, and 1.0 mM, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1992

Contribution of labeled carbon dioxide to PET imaging of carbon-11-labeled compounds.

11CO2 is one of the major metabolites of many [11C]-labeled radiopharmaceuticals, including glucose, thymidine, acetate, amino acids, and fatty acids. Our data contradict the notion that the contribution of labeled CO2 to PET images can be disregarded because of its rapid elimination through the lungs. We have measured the retention and excretion of 11CO2 in dogs after the intravenous injection of labeled CO2/HCO3-, which had been equilibrated ex vivo with blood. Only 58% of the label was exhaled as CO2 over the first 60 min after injection, with the rest retained in the body. The injection of [11C]thymidine labeled in the ring-2 position or [11C]acetate labeled in the carboxylate position resulted in the production of large amounts of labeled CO2 with the exhalation of about 47% and 23%, respectively, of the injected label over 60 min. At 10 min after injection of either [11C]thymidine and [11C] acetate, approximately 60% to 70% of total blood activity was in labeled CO2 or bicarbonate. On the other hand, the use of [1-11C]glucose only resulted in exhalation of 5% of the injected dose and CO2/HCO3- made up less than 10% of blood activity at 10 min. Our results indicate that retention and distribution of labeled CO2 needs to be considered when interpreting PET data obtained from 11C-labeled compounds.

Acetates↗

PubMed1991

Detection of lymphomatous bone marrow involvement with magnetic resonance imaging.

We reviewed magnetic resonance (MR) staging examinations of 98 patients with malignant lymphoma who failed other therapy and were under evaluation for bone marrow transplantation. MR scan results were compared with blind posterior iliac crest aspirations and biopsies. Images of vertebral, pelvic, and femoral marrow were obtained using a standard T1-weighted, short repetition time (TR), short time to echo (TE) (TR700/TE22), spin-echo (T1-SE) method in 92 patients and short TI inversion recovery (STIR) technique (TR1,500/TE36/TI100) in all. On standard T1-SE sequence, normal marrow is bright due to the predominance of marrow fat, and tumor is dark. With STIR images, water containing tumor has a very high signal intensity in a dark (fat suppressed) background. Thirteen patients had positive MR scans and marrow biopsies, whereas 49 had negative MR scans and biopsies. Of 36 discordant MR/histology results, 10 had positive biopsies and negative MR exams; eight of these had microscopic infiltration (less than or equal to 5%) with tumor. MR detected marrow tumor either in the crests or elsewhere in 25 of 75 (33%) patients with negative study biopsies. We could confirm marrow involvement in 15 of these 25 (60%) by clinical methods. Therefore, up to one third of the patients evaluated with routine biopsies may have occult marrow tumor detectable by MR exam. In patients with negative marrow biopsies, especially those with Hodgkin's disease or intermediate to high-grade non-Hodgkin's lymphomas, MR scans found focal lesions distant from the crests. Biopsy better detected lower grade microscopic involvement. We conclude that optimal marrow staging of lymphoma patients incorporates both biopsy and MR imaging.

Adult↗

PubMed1990

Utilization of labeled thymidine in DNA synthesis: studies for PET.

Carbon-111-thymidine and positron emission tomography (PET) have the potential for noninvasively measuring DNA synthesis in tumors and tissues. In order to validate this potential, one needs to construct accurate biochemical models that reflect the metabolism of thymidine, including its uptake and degradation as well as its incorporation into DNA. Our studies employed thymidine labeled in the methyl position using 11C, 14C, and 3H. Studies with rapidly proliferating tissues of mice demonstrated that most of the activity, 60 min after injection of labeled thymidine, was present in DNA, with smaller amounts found in metabolites. Studies in dogs, however, reveal that more activity was present in metabolites, rather than in the DNA of tumors and spleen tissue. HPLC analysis of canine blood after the injection of thymidine revealed rapid conversion of thymidine to thymine and other metabolites. We have found significant differences in the metabolism of [3H]thymidine versus thymidine labeled with radioactive carbon. These differences, which were not found when comparing 14C and 11C, indicate that [3H]thymidine is not an appropriate standard for comparison with PET studies employing [11C] thymidine. To accurately interpret images of [11C]thymidine as representations of DNA synthesis we are developing kinetic models that take into account the metabolism of thymidine and the contribution of degradation products to the 11C images.

Animals↗

PubMed1989

Bone marrow toxicity of total-body irradiation combined with radiosensitizers.

The effect of the addition of radiosensitizers to low-dose total-body irradiation was studied. SR2508 (1 g/kg) or misonidazole (0.35 g/kg) was given 30 min prior to single-dose total-body irradiation, delivered at 0.1 Gy/min. Six dogs received either SR2508 or misonidazole and 2 Gy irradiation, and 14 dogs served as controls, receiving no drug and either 2 or 3 Gy of total-body irradiation. All dogs had a decline in their white blood cell and platelet counts and were supported with prophylactic antibiotics and platelet transfusions. High plasma levels of both radiosensitizers were achieved. The degree of cytopenia with 2 Gy total-body irradiation when combined with either radiosensitizer was not significantly greater than that seen with 2 Gy alone, and the neutropenia was significantly less than that seen with 3 Gy alone. The only observed toxicity of the drugs was vomiting, which started shortly after the infusion of SR2508 and before the radiation treatment. A single high-dose infusion of a radiosensitizer combined with total-body irradiation appears to cause a mild increase in bone marrow toxicity but is otherwise well tolerated.

Animals↗

PubMed1988

Procainamide-associated pancytopenia.

A 42-year-old male developed thrombocytopenia and anemia along with agranulocytosis during treatment with procainamide. Bone marrow hypoplasia was evident on biopsy, and the patient was without evidence of systemic lupus erythematosis. He had prompt marrow recovery on drug withdrawal. While procainamide-induced agranulocytosis has been reported on a number of occasions, this is only the second case of pancytopenia.

Adult↗

PubMed1988

The use of ranitidine in bone marrow transplantation. A review of 223 cases.

To determine the incidence of ranitidine-induced myelosuppression in the bone marrow transplant setting, we reviewed the records of all patients at our institution (223) who received ranitidine while undergoing bone marrow transplantation. We identified 37 cases in which a myelosuppressive episode was temporally associated with ranitidine use. In-depth analysis of the 37 cases showed 12 in which no alternative cause could be found and in which strong evidence for a ranitidine effect existed. Three of these cases are included herein as case reports. Based on this series, the overall incidence of ranitidine-induced myelosuppression in bone marrow transplant patients was approximately 5% (12/223).

Bone Marrow↗

PubMed1988

Local re-utilization of thymidine in normal mouse tissues as measured with iododeoxyuridine.

Thymidine (TdR) and its analogue, iododeoxyuridine (IdUdr), were used to quantitate nucleoside re-utilisation in vivo. Significantly different results obtained, however, depending upon what form of isotopically labelled iododeoxyuridine is used. No measurable local thymidine re-utilization was found in mouse thymus, spleen or bone marrow when the retention of [3H]IdUdR was compared with [14C]TdR. On the other hand, significant differences were found between the retention of [125I]IdUdR and [3H]IdUdR, which is attributed to de-iodination of iododeoxyuridine. Some thymidine re-utilization was found in duodenum using both [3H]IdUdR and [125I]IdUdR. Information on the in vivo distribution of TdR and the contention that a large degree of TdR re-utilization in the thymus is evidence of extensive cell death must be re-interpreted in the light of these results. In addition, evidence for little or no local re-utilization in some tissues will greatly simplify the use of [11C]TdR as an imaging agent for measuring tissue proliferation in vivo with positron emission tomography (PET).

Animals↗

PubMed1987

Genomic variation of adenovirus type 5 isolates recovered from bone marrow transplant recipients.

We characterized the genomic variation of adenovirus type 5 isolates recovered from bone marrow transplant recipients in Seattle between 1976 and 1982. By restriction endonuclease analysis, we identified three new adenovirus genomic variants, each associated with a single invasive adenovirus infection. In addition, we were able to obtain suggestive evidence for a nosocomial spread of a particular group of isolates within this population. This study demonstrates that the technique of restriction endonuclease analysis is an important epidemiological tool for investigating viral infections.

Adenoviridae Infections↗

PubMed1987

The detection of bone marrow involvement by lymphoma using magnetic resonance imaging.

We used magnetic resonance (MR) to image the bone marrow of 31 patients with lymphoma. Images were obtained of the femoral, pelvic, and vertebral marrow with a 0.15 tesla imaging system using a T1-weighted spin echo sequence (TR600/TE 40). With this pulse sequence, normal marrow produces a high intensity signal that reflects the presence of marrow fat (short T1 relaxation time). We previously reported MR imaging of patients with leukemia in relapse and found a diffusely and symmetrically decreased marrow signal intensity due to the replacement of normal marrow fat by cellular material with a long T1. Unlike leukemia, patients with lymphomatous marrow involvement often had patchy, often discrete, areas of low signal intensity, representing focal marrow infiltration. Five of six patients in this study with lymphoma detected by histologic examination also had marrow lesions seen on MR. An additional four patients had marrow lesions detected by MR that were not detected on initial marrow biopsies; two of these had marrow involvement proven on subsequent biopsies, one had disease isolated to the vertebrae that was never pathologically documented, and one had progression of disease in the marrow documented by MR without biopsy confirmation. These results indicate that marrow involvement with lymphoma can be detected by MR imaging and that MR can complement bone marrow biopsy.

Adult↗

PubMed1987

Cellular sources of thymidine nucleotides: studies for PET.

The relative utilization of endogenously synthesized thymidine nucleotides and exogenously supplied thymidine analog was compared in a number of mammalian cell lines, tissues, and tumors. To measure the relative utilization, cells were incubated in tissue culture media containing the thymidine analog [3H]-5-bromo-2'-deoxyuridine (BUDR). After extraction of the DNA, the degree of substitution of the thymidine by BUDR was determined by density gradient centrifugation. All the cell lines and tissues tested utilized both exogenous BUDR and endogenous thymidine sources to a similar extent. The relative utilization of the exogenous pathway could be manipulated by varying the exogenous concentration of BUDR. Our results demonstrate that one can predict the relative utilization of these two pathways and can calculate the effective specific activity of the intracellular thymidine nucleotide pool. Such information is needed in interpreting 11C-labeled thymidine uptake as measured by positron emission tomography.

Animals↗