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Michael J Welch

Publications and source records attributed to Michael J Welch.

At least 73 records · Page 4Linked to original sources
PubMed2004

Rapid and reproducible radiosynthesis of [18F] FHBG.

9-(4-[18F] Fluoro-3-hydroxymethylbutyl) guanine ([18F] FHBG), an imaging agent for gene therapy using PET, was prepared in a one-pot, two-step synthesis. Microwave (MW) mediated nucleophilic fluorination of N2, monomethoxytrityl-9-[4-(tosyl)-3-monomethoxytrityl-methylbutyl] guanine using no-carrier-added [18F] fluoride, followed by deprotection with hydrochloric acid and HPLC purification, gave [18F] FHBG. The radiochemical yield (decay corrected) was 12+/-5% (n = 35), the synthesis time was 55-60 min, and the radiochemical purity was >99%. The compound was used for lung imaging and was injected into Sprague-Dawley rats previously infected with the herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene. MicroPET imaging showed accumulation confined to the lungs.

Animals↗
PubMed2004

Comparison of patient preference and ease of teaching inhaler technique for Pulmicort Turbuhaler versus pressurized metered-dose inhalers.

A multicenter, randomized, open-label, crossover study with two 4-week evaluation periods compared patient preference and ease of teaching correct inhaler technique for Pulmicort Turbuhaler versus pressurized metered-dose inhalers (pMDIs). Patients 18 to 65 years of age with stable, mild to moderate asthma, who required or were eligible for inhaled corticosteroid therapy, were randomized to treatment sequences consisting of 4-week evaluation periods with Pulmicort Turbuhaler (budesonide inhalation powder) two puffs (400 microg) bid and one of three inhaled corticosteroids via pMDI: Aerobid-M (flunisolide) four puffs (1 mg) bid, Flovent (fluticasone propionate) two puffs (440 microg) bid, or Vanceril Double Strength (beclomethasone dipropionate) five puffs (420 microg) bid. Patients indicated device preference at study end and completed the Patient Device Experience Assessment (PDEA) questionnaire after each evaluation period. Ease of teaching, time required to master use of the device, percentage of patients demonstrating mastery on the first attempt, and the number of attempts required to demonstrate mastery were assessed. Despite previous use of pMDIs by most patients, Pulmicort Turbuhaler was significantly preferred (p < 0.001) and required significantly less time to master than pMDIs (p < 0.001). Median times to device mastery were 3.67 min for Pulmicort Turbuhaler versus 5.33 min for pMDIs. Patients rated Pulmicort Turbuhaler significantly better than pMDIs on PDEA ease of use (p = 0.0005) and overall satisfaction (p < 0.0001) single-item scales and all four multi-item scales (pharyngeal symptoms, oral sensation, operational use, and inhaler attributes; p < 0.05). Overall, patients preferred Pulmicort Turbuhaler over pMDIs and required less time to be taught how to correctly use Turbuhaler trade mark.

Administration, Inhalation↗
PubMed2004

Monitoring of therapy in androgen-dependent prostate tumor model by measuring tumor proliferation.

UNLABELLED: 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) has been recently described as a radiopharmaceutical for measuring cellular proliferation using PET imaging. Evaluation of tumor proliferative activity by PET using (18)F-FLT could be a procedure to assess the viability of tumor, such as histologic grade, clinical stage, and prognosis as well as the early effects of cancer therapy. This study was undertaken to determine whether (18)F-FLT is useful in the detection of prostate cancer as well as monitoring therapeutic effects in a human tumor model. METHODS: The androgen-dependent human prostate tumor, CWR22, was implanted into athymic mice. This well-established model of prostate cancer was used in all studies. To determine the optimal imaging times for (18)F-FLT, a biodistribution was performed in CWR22 mice. (18)F-FLT (740 kBq [20 micro Ci]) was administered via the tail vein and uptake was determined in selected tissues at 5 min, 20 min, and 1, 2, and 4 h after injection (n = 5, each time point). Androgen ablation studies were conducted in the CWR22 model with either diethylstilbestrol (DES) or surgical castration. Animals received DES every 2 d for 3 wk. The effectiveness of therapy was monitored using (18)F-FLT microPET as baseline, during treatment, and after treatment. Tracer accumulation in the tumor was then analyzed by comparing tumor-to-muscle ratios derived from reconstructed microPET data. RESULTS: At 2 h after injection, the (18)F-FLT uptake in tumor was 0.69 +/- 0.14 percentage injected dose per gram of tissue, showing the highest activity of all organs measured. The microPET study with dynamic imaging showed that (18)F-FLT uptake in blood reached its plateau within 1 min and was rapidly cleared, whereas (18)F-FLT uptake in tumor reached its plateau in 30 min and remained up to 60 min. microPET using (18)F-FLT successfully imaged the implanted CWR22 tumor in the mice at both 1 and 2 h after injection. There was a marked reduction of (18)F-FLT uptake in tumor after castration or DES treatment; however, there were no differences in (18)F-FLT uptake in the tumor in the control group. These changes of (18)F-FLT uptake in tumor parallel the changes of actual tumor measurement. CONCLUSION: These results indicate that (18)F-FLT is a useful tracer for detection of prostate cancer in an animal model. (18)F-FLT has the potential for monitoring the therapeutic effect of androgen ablation therapy in prostate cancer.

Androgens↗
PubMed2003

Filling the AOAC triangle with food-matrix standard reference materials.

Well-characterized reference materials are needed by laboratories in the food testing and nutrition communities to facilitate compliance with nutritional labeling laws, to provide traceability for food exports needed for acceptance in many foreign markets, and to improve the accuracy of nutrition information that is provided to assist consumers in making sound dietary choices. As a result of the enactment of the Nutrition Labeling and Education Act of 1990 and the Infant Formula Act of 1980, the National Institute of Standards and Technology (NIST) has developed a suite of food-matrix Standard Reference Materials (SRMs) characterized for nutrient concentrations. These include SRM 1544 Fatty Acids and Cholesterol in a Frozen Diet Composite, SRM 1546 Meat Homogenate, SRM 1548a Typical Diet, SRM 1566b Oyster Tissue, SRM 1846 Infant Formula, SRM 1946 Lake Superior Fish Tissue, SRM 2383 Baby Food Composite, SRM 2384 Baking Chocolate, SRM 2385 Spinach, and SRM 2387 Peanut Butter. Many of these materials were developed at the request of the food industry to populate a nine-sectored fat-protein-carbohydrate triangle developed by AOAC International. With the completion of SRM 2387, SRMs representing each sector of the triangle are now available. These food-matrix reference materials are intended primarily for validation of analytical methods for the measurement of proximates, fatty acids, vitamins, minerals, and so on in foods of similar composition. They may also be used as "primary control materials" in the value-assignment of in-house, secondary, control materials to confirm accuracy as well as to establish traceability to NIST.

Food Analysis↗
PubMed2003

7alpha- and 17alpha-substituted estrogens containing tridentate tricarbonyl rhenium/technetium complexes: synthesis of estrogen receptor imaging agents and evaluation using microPET with technetium-94m.

To develop technetium and rhenium-labeled imaging agents for estrogen receptor (ER) positive breast tumors, we have prepared tridentate metal tricarbonyl chelates substituted at the 7alpha- and 17alpha-positions of estradiol. Some of the Re(CO)(3) conjugates have high binding for the ER in vitro. The in vivo biodistribution of the highest affinity of these novel metal tricarbonyl conjugates, prepared as the (94m)Tc labeled analogue, was evaluated by tissue dissection and microPET imaging. Although target tissue-selective uptake was not apparent, it is notable that microPET imaging identified the stomach as a major site of activity deposition, a site that might have been missed by standard tissue distribution studies.

Animals↗
PubMed2003

Comparison of isotope dilution mass spectrometry methods for the determination of total homocysteine in plasma and serum.

Two independent methods have been critically evaluated and applied to the measurement of total homocysteine in serum and plasma: solid-phase anion extraction (SPAE) gas chromatography/mass spectrometry (GC/MS) and protein precipitation liquid chromatography/tandem mass spectrometry (LC/MS/MS). In addition, analysis of samples prepared by SPAE was accomplished by liquid chromatography/mass spectrometry (LC/MS) and LC/MS/MS. These methods have been used to determine total homocysteine levels in several existing serum-based Standard Reference Materials (SRMs) from the National Institute of Standards and Technology and in patient plasma samples provided by the Centers for Disease Control and Prevention. The precision of the homocysteine measurements in serum and plasma was critically evaluated, and method comparisons were carried out using Bland-Altman plots and bias analysis. On the basis of the excellent precision and close agreement of the mass spectrometric (MS) methods, the MS-based methods will be used for certification of a serum-based SRM for homocysteine and folates.

Chromatography, Liquid↗
PubMed2003

Enhancing targeted radiotherapy by copper(II)diacetyl- bis(N4-methylthiosemicarbazone) using 2-deoxy-D-glucose.

Most cancer deaths are a consequence of resistance to conventional chemotherapy and radiation therapy. This may be attributable to unique phenotypic characteristics of solid tumors. We have exploited two well-described characteristics of solid tumors commonly associated with treatment failure, high glucose use and hypoxia, to design a unique therapy based on the selective accumulation of two cytotoxic compounds, 2-deoxyglucose (2-DG) and copper(II)diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM). (64)Cu-ATSM localizes to hypoxic regions of tumors and has been used for administering a high local dose of radiation therapy after uptake by cells. 2-DG, a glucose analog, selectively accumulates in cancer cells and interferes with energy metabolism, resulting in cancer cell death. 2-DG has been shown to potentiate the cytotoxic effect of ionizing radiation and certain chemotherapeutic agents. We have tested the effect of 2-DG on tumor response when combined with (64)Cu-ATSM in a mouse breast tumor model using the highly aggressive mouse mammary carcinoma cell line EMT-6. 2-DG administered up to 2 mg/g of body weight daily resulted in no weight loss or systemic symptoms. EMT-6 mammary tumors had similar uptake of [(18)F]fluoro-2-deoxyglucose before and after 2 weeks of 2-DG treatment as determined by microPET imaging, indicating that resistance to 2-DG uptake does not develop. Pretreatment of tumor-bearing mice with 2-DG resulted in increased uptake of (64)Cu-ATSM by tumors compared with nontreated mice. This effect was not observed with the nonhypoxia-specific agent copper(II)pyruvaldehyde-bis(N(4)-methylthiosemicarbazone. When 2-DG was combined with a single dose of (64)Cu-ATSM (2 mCi), tumor growth was inhibited approximately 60% compared with untreated mice, and animals survived approximately 50% longer than untreated mice or animals treated with each agent alone (32 versus 20 days). The maximum effect on tumor growth and survival was observed when 2-DG was administered daily for the lifetime of the mouse. Our results indicate that 2-DG potentiates the effect of (64)Cu-ATSM on tumoricidal activity and animal survival. We hypothesize that 2-DG alters the metabolic state of the cell, leading to increased uptake of (64)Cu-ATSM by the tumor. This would result in a higher local dose of radiotherapy. The continued presence of 2-DG would then prevent the repair of damaged cells, leading to inhibition of tumor growth. Our data indicate that the strategy of combining tumor-specific cytotoxic agents that function by differing mechanisms can result in an effective, selective, tumor-specific cell death with minimal effect on the host.

Animals↗
PubMed2003

Two new standard reference materials for the determination of drugs of abuse in human hair.

Two new standard reference materials (SRM) for drugs of abuse in human hair have been developed. SRM 2379 consists of hair spiked with cocaine, benzoylecgonine, cocaethylene, phencyclidine, amphetamine, and methamphetamine. SRM 2380 consists of hair spiked with codeine, morphine, monoacetylmorphine, and tetrahydrocannabinol (THC). The SRMs were prepared by soaking the hair in a solution of the target analytes in water-dimethylsulfoxide. The concentration of each analyte was determined using two methods, one based upon gas chromatography/mass spectrometry (GC/MS) and one based upon liquid chromatography/mass spectrometry (LC/MS). Both methods used 0.1 M HCl for extraction of all the analytes from the hair, except for THC, which was extracted with 1 M NaOH. For isolation of the analytes from the extracts, the GC/MS-based methods used different clean-up procedures from those used for the LC/MS-based methods. The results from the two methods were in good agreement with mean differences for the analytes ranging from 4% to 16%. These materials will enable laboratories performing analyses of hair for drugs of abuse to test the accuracy of their methods.

Gas Chromatography-Mass Spectrometry↗
PubMed2003

In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM.

Tumor hypoxia is recognized as an important determinant of response to therapy. In this study we investigated the feasibility of clinical imaging with copper-60 diacetyl-bis( N(4)-methylthiosemicarbazone) ((60)Cu-ATSM) in patients with non-small-cell lung cancer (NSCLC) and also assessed whether pretreatment tumor uptake of (60)Cu-ATSM predicts tumor responsiveness to therapy. Nineteen patients with biopsy-proved NSCLC were studied by positron emission tomography (PET) with (60)Cu-ATSM before initiation of therapy. (60)Cu-ATSM uptake was evaluated semiquantitatively by determining the tumor-to-muscle activity ratio (T/M). All patients also underwent PET with fluorine-18 fluorodeoxyglucose (FDG) prior to institution of therapy. The PET results were correlated with follow-up evaluation (2-46 months). It was demonstrated that PET imaging with (60)Cu-ATSM in patients with NCSLC is feasible. The tumor of one patient had no discernible (60)Cu-ATSM uptake, whereas the tumor uptake in the remaining patients was variable, as expected. Response was evaluated in 14 patients; the mean T/M for (60)Cu-ATSM was significantly lower in responders (1.5+/-0.4) than in nonresponders (3.4+/-0.8) (P=0.002). However, the mean SUV for (60)Cu-ATSM was not significantly different in responders (2.8+/-1.1) and nonresponders (3.5+/-1.0) ( P=0.2). An arbitrarily selected T/M threshold of 3.0 discriminated those likely to respond to therapy: all eight responders had a T/M <3.0 and all six nonresponders had a T/M > or =3.0. Tumor SUV for FDG was not significantly different in responders and nonresponders (P=0.7) and did not correlate with (60)Cu-ATSM uptake (r=0.04; P=0.9). (60)Cu-ATSM-PET can be readily performed in patients with NSCLC and the tumor uptake of (60)Cu-ATSM reveals clinically unique information about tumor oxygenation that is predictive of tumor response to therapy.

Aged↗
PubMed2003

Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response-a preliminary report.

PURPOSE: Tumor hypoxia is associated with poor response to therapy. We have investigated whether pretreatment tumor hypoxia assessed by positron emission tomography (PET) with Cu-60 diacetyl-bis(N(4)-methylthiosemicarbazone) ((60)Cu-ATSM) predicts responsiveness to subsequent therapy in cervical cancer. METHODS AND MATERIALS: Fourteen patients with biopsy-proved cervical cancer were studied by PET with (60)Cu-ATSM before initiation of radiotherapy and chemotherapy. (60)Cu-ATSM uptake was evaluated semiquantitatively by determining the tumor-to-muscle activity ratio (T/M) and peak slope index of tumor tracer uptake. All patients also underwent clinical PET with F-18 fluorodeoxyglucose (FDG) before institution of therapy. The PET results were correlated with follow-up evaluation (14-24 months). RESULTS: Tumor uptake of (60)Cu-ATSM was inversely related to progression-free survival and overall survival (log-rank p = 0.0005 and p = 0.015, respectively). An arbitrarily selected T/M threshold of 3.5 discriminated those likely to develop recurrence; 6 of 9 patients with normoxic tumors (T/M < 3.5) are free of disease at last follow-up, whereas all of 5 patients with hypoxic tumors (T/M > 3.5) have already developed recurrence. Similar discrimination was achieved with the peak slope index. The frequency of locoregional nodal metastasis was greater in hypoxic tumors (p = 0.03). Tumor FDG uptake did not correlate with (60)Cu-ATSM uptake (r = 0.04; p = 0.80), and there was no significant difference in tumor FDG uptake between patients with hypoxic tumors and those with normoxic tumors. CONCLUSION: (60)Cu-ATSM-PET in patients with cervical cancer revealed clinically relevant information about tumor oxygenation that was predictive of tumor behavior and response to therapy in this small study.

Adult↗
PubMed2003

Synthesis and biological evaluation of a fluorine-18 labeled estrogen receptor-alpha selective ligand: [18F] propyl pyrazole triol.

The two estrogen receptor subtypes, ERalpha and ERbeta, play important roles in breast cancer. To develop an ERalpha imaging agent, we synthesized fluoropropyl pyrazole triol (FPPT, 2), an analog of our ERalpha-selective ligand PPT. FPPT retains the high ERalpha binding selectivity of its parent PPT. We prepared [(18)F]FPPT ((18)F-2) in high specific activity, but estrogen target tissue uptake in female rats was minimal and was not displaceable by unlabeled estradiol, probably because of the lipophilicity and triphenolic nature of FPPT.

Animals↗
PubMed2003

Production of therapeutic quantities of (64)Cu using a 12 MeV cyclotron.

(64)Cu is a useful radiotracer for positron emission tomography (PET) and a promising radiotherapy agent for the treatment of cancer. Recently, (64)Cu-labeled radiopharmaceuticals were reported to be useful for internal radiation therapy as well as PET monitoring of tumors.(64)Cu was produced at the Fukui Medical University's cyclotron using twelve MeV proton irradiation and the (64)Ni(p,n) (64)Cu nuclear reaction. A (64)Ni target was electroplated on a gold disk at a thickness of 50 to > 100 microm. Electroplating was performed at 2.5 V, at currents between 5-15 mA, and was completed in 12-24 hr. The (64)Ni target was bombarded with a 50 +/- 3 microA proton current. After bombardment, (64)Cu was separated from the (64)Ni target and other contaminants using an anion exchange column. Target (64)Ni was recovered and re-used. The yield of (64)Cu was 0.6 to > 3.0 mCi/microA*h, and averaged 1.983 mCi/microA*h. The radionuclidic purity of (64)Cu was over 99%. In this study, we obtained sufficient qualities and quantities of (64)Cu for therapeutic application and dose monitoring using PET using an ultra-small cyclotron.

Copper Radioisotopes↗
PubMed2003

Intra-tumoral distribution of (64)Cu-ATSM: a comparison study with FDG.

(64)Cu-labeled diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) is a promising agent for internal radiation therapy and imaging of hypoxic tissues. In the present study, the intra-tumoral distribution of (64)Cu-ATSM was investigated by comparing it to that of [(18)F]FDG and histological findings. VX2 tumors were implanted into Japanese white rabbits subcutaneously. (64)Cu-ATSM and [(18)F]FDG were co-injected intravenously and the tumor was dissected and cut into 1 mm thick slices 1 h after the injection. The uptake of (64)Cu-ATSM and [(18)F]FDG was measured using a dual-tracer autoradiographic technique. Histological cell biology was estimated from the optical microscopy of tumor sections. The major accumulation of (64)Cu-ATSM was observed around the outer rim of the tumor masses which consisted mainly of active cells and expected to be hypoxic. [(18)F]FDG was distributed more widely with highest levels in the inner regions where pre-necrotic cells were mainly observed. (64)Cu-ATSM appears to be useful for the detection of hypoxic but active tumor cell regions in vivo.

Animals↗