The quarterly journal of nuclear medicine : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR)最新文献

Utilization of molecular biology techniques offers attractive options in nuclear medicine for improving cancer imaging and therapy with radiolabeled peptides. Two of these options include utilization of phage-panning to identify novel tumor-specific peptides or single chain antibodies and gene transfer techniques to increase the number of antigen/receptor sites expressed on malignant cells. Our group has focused on the latter approach for improving radiolabeled peptide imaging and therapy. The most widely used gene transfer vectors in clinical gene therapy trials include retrovirus, cationic lipids, and adenovirus. We have utilized adenovirus vectors for gene transfer because of their ability to accomplish efficient in vivo gene transfer. Adenovirus vectors encoding the genes for a variety of antigens/receptors (carcinoembryonic antigen, gastrin-releasing peptide receptor, somatostatin receptor subtype 2 (SSTr2)) have all shown that their expression is increased on cancer cells both in vitro and in vivo following adenovirus infection. Of particular interest has been the adenovirus encoding for SSTr2 (AdCMVSSTr2). Various radioisotopes have been attached to somatostatin analogues for imaging and therapy of SSTr2-positive tumors both clinically and in animal models. The use of these analogues in combination with AdCMVSSTr2 is a promising approach for improving the detection sensitivity and therapeutic efficacy of these radiolabeled peptides against solid tumors. In addition, we have proposed the use of SSTr2 as a marker for imaging the expression of another cancer therapeutic transgene (e.g. cytosine deaminase, thymidine kinase) encoded within the same vector. This would allow for non-invasive monitoring of gene delivery to tumor sites.

Targeting of radiation damage to specific DNA sequences is the essence of antigene radiotherapy. This technique also provides a tool to study molecular mechanisms of DNA repair on a defined, single radiodamaged site. We achieved such sequence-specific radiodamage by combining the highly localized DNA damage produced by the decay of Auger-electron-emitters such as 125I with the sequence-specific action of triplex-forming oligonucleotides (TFO). TFO complementary to polypurine-polypyrimidine regions of human genes were synthesized and labeled with 125I-dCTP by the primer extension method. 125I-TFO were delivered into cells with several delivery systems. In addition, human enzymes capable of supporting DNA single-strand-break repair were isolated and assessed for their role in the repair of this lesion. Also, the mutagenicity and repairability of 125I-TFO-induced double strand breaks (DSB) were assessed by repair of a plasmid possessing a site-specific DSB lesion. Using plasmids containing target polypurine-polypyrimidine tracts, we obtained the fine structure of sequence-specific DNA breaks produced by decay of 125I with single-nucleotide resolution. We showed that the designed 125I-TFO in nanomolar concentrations could bind to and introduce double-strand breaks into the target sequences in situ, i.e., within isolated nuclei and intact digitonin-permeabilized cells. We also showed 125I-TFO-induced DSB to be highly mutagenic lesions resulting in a mutation frequency of nearly 80%, with deletions comprising the majority of mutations. The results obtained demonstrate the ability of 125I-TFO to target specific sequences in their natural environment--within eucaryotic nucleus. Repair of 125I-TFO-induced DNA damage should typically result in mutagenic gene inactivation.

Nuclear imaging techniques such as PET and SPECT imaging are expected to play major roles in evaluating the efficacy of in vivo gene therapy. In particular, the quantification of vector delivery and imaging the efficacy of gene expression are of key interests in testing new treatment paradigms and in designing novel vectors. In this review article we illustrate how nuclear imaging can be used to image novel cell-surface expressed fusion proteins and how this strategy can be used to probe for phenotypic changes in genetically manipulated cells. Since the described approach uses new fusion proteins, typically not present on eukaryotic cells, such "artificial receptors" can be designed to bind radioisotopes currently in clinical use. The described fusion proteins consist of 1) a binding domain such as a peptide based chelator that binds 99mTc oxotechnetate and 2) a membrane anchoring domain. A variety of fusion proteins have been tested so far and the most promising one to date consists of a metallothionein (MT)-derived C-terminal peptide fused to a type II membrane protein markers containing the N-terminal membrane anchoring domain of neutral endopeptidase (PEP). Cell-surface expression of MT in transfected cells has been demonstrated using monoclonal antibodies in vitro. Both in vitro and in vivo transchelation experiments have confirmed expression of 99mTc-binding sites in eukaryotic cells. We expect the described approach to evolve into a useful strategy to "tag" transfected cells with 99mTc and thus assessing efficiency of gene delivery and expression.

This article discusses models of efficacy, design of clinical trials and the role of mathematical modeling in diagnostic technology evaluation and determination of cost-effectiveness. A multi-tiered model of efficacy, which views diagnostic imaging as part of a global process of patient management and outcome, has been described. The first tier involves imaging efficacy, which must be determined by clinical trial. Direct comparison of new and established modalities in a single study population has major advantages over randomized controlled trials, which are extremely costly and time-consuming and are not appropriate for most evaluations of diagnostic modalities. Selection of patients for inclusion in the trial, interpretation and verification of results, and determination of a reference standard are all possible sources of bias, which need to be identified and controlled. Decision analysis modeling can be used to assess diagnostic, therapeutic, patient-outcome and cost efficacy, once imaging efficacy has been evaluated by clinical trial. Decision analysis is easier and less expensive to perform than clinical trials, and results are easily generalizable to other settings. Disadvantages arise from the nondescriptive nature of modeling and lack of transparency, which make it difficult to evaluate the appropriateness of decision tree structures and input data. Modeling is an unavoidable fact of life in technology evaluation, since the resources that would be required for full evaluation of imaging modalities by clinical trial are not available.

Background: Utilities for the health outcomes states (Markov states) of non-small cell lung carcinoma (NSCLC) should be measured to evaluate management options for patients because patients are key participants in the process of care, and their assessment of diagnostic and therapeutic value in the options presented to them ultimately impacts their net health outcomes. This investigation sought to measure utilities for stage-dependent outcomes states of NSCLC.

Methods: Persons (n = 23) with suspected NSCLC based on physical findings and computed tomography completed a short utilities survey. Utility valuations were obtained according to severity of morbidity and varied considerably. Respondents rated these health states according to accuracy measures for 18flurodeoxyglucose (18FDG) positron emission tomography (PET) imaging and medastinoscopy.

Results: The results demonstrate that stage-dependent morbidity is an important consideration for patients with NSCLC and should be included in any decision analysis regarding the evaluation or treatment of NSCLC. Respondents valued the quality of information obtained from non-invasive PET and invasive mediastinoscopy comparably. The utilities obtained from this investigation are useful in clinical decision-making based on Markov processes because they provide an initial estimation of utility assessment for 18FDG-based diagnostic evaluation of lung cancer.

Conclusions: Consequently, these utilities will be useful in future decision analyses that require patient preference in the assignment of the evaluation of decision options (branches).

Background: The growing need for evaluation of the utility of new nuclear medicine technologies has spawned a few economic studies ranging from preliminary indications of cost savings to complete decision analysis models incorporating costs and quality of life. The objective of the current study was to evaluate the methodological quality of economic analyses of nuclear medicine procedures which targeted cost-effectiveness or cost-utility issues published in the medical literature during the years 1985-1999.

Methods: A computerized literature search was used to identify original investigations from the medical literature which included an economic analysis of a nuclear medicine procedure. Each economic analysis article was evaluated by two independent reviewers for adherence to ten accepted methodological criteria.

Results: Of the 29 articles meeting the search criteria, only six (21%) conformed to all ten methodological criteria.

Conclusions: Published economic analyses of nuclear medicine procedures usually do not meet accepted methodological standards and could be significantly improved to achieve overall better quality relative to similar analyses in the literature from other medical fields. Continued improvement in the number and quality of economic studies is critically needed for the future competitiveness of nuclear medicine studies.

This paper provides an overview of the key elements of cost effectiveness analysis (CEA). CEA is a method for evaluating the relative costs and benefits of treatments and procedures. Typically, CEA compares a proposed intervention with (at least) one alternative intervention, yielding an incremental cost effectiveness ratio. This ratio reflects both the longevity and health status of the differing interventions and permits the researcher to more completely compare and evaluate the "payoff" of the interventions. This paper discusses different perspectives CEA studies might adopt, and reviews the major methods for measuring both outcomes and costs.

Background: A review and meta-analysis of the literature on the use of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in the detection of recurrent melanoma was conducted. The goals were to evaluate the quality of data reporting and to determine the overall values for the sensitivity and specificity of whole body FDG PET and management changes.

Methods: Guidelines to evaluate reporting within articles were formulated based on the United States medical payer source criteria for assessing studies reporting information on the utilization of new medical technology. A meta-analysis was conducted using methodology described in the peer reviewed literature.

Results: Our MEDLINE PLUS search resulted in a universe of 89 total articles. Within these 89, 19 were categorized in our targeted content area of which 13 were selected for analysis in our targeted subset, with the remaining 70 covering 24 different related content areas. Five of 13 (38%) articles in the target subset reported data which was adequate for incorporation into modeling objectives based on PET sensitivity and specificity values, with 1 of 13 (8%) in the same target subset reporting data adequate for modeling based on change-in-management data. Through a meta-analysis of the 13 target articles we determined, within a 95% confidence level, an overall sensitivity of 92% (95% confidence level 88.41%-95.82%) and an overall specificity of 90% (95% confidence level 83.26%-96.05%) as calculated by number of lesions, for FDG PET detecting recurrent melanoma throughout the whole body. Furthermore, limited data available for change-in-management suggests an overall FDG PET directed change-in-management value of 22%.

Conclusions: Our review suggests that improvements can be made to more effectively report the results of these FDG PET studies. The overall values determined through the meta-analysis indicate the potential benefits of using FDG PET as a diagnostic/management tool. Furthermore, these values should prove useful to assessing the cost effectiveness of utilizing FDG PET in the management of recurrent melanoma.

Background: In this study, contingent valuation is used to estimate the willingness-to-pay (WTP) for positron emission tomography (PET) imaging by patients with suspected benign or malignant lung disease.

Methods: Patients (n = 87) undergoing thoracic computed tomography were surveyed for their WTP for PET for the evaluation of lung disease in lieu of further testing. Patients were provided background PET information and a two-page self-administered questionnaire. The survey queried basic demographic information, perceived risk of malignancy, and perceived life expectancy given a diagnosis of malignancy.

Results: Patients with increased perception of risk were willing to pay more than those with lower perceived risk. Patients who were self-payers for their health insurance indicated a lower WTP than those who did not pay any out-of-pocket insurance premiums.

Conclusions: Individuals are willing to pay additional out-of-pocket costs for diagnostic imaging to reduce their perception of risk and improve their quality of life.