The impact of global budget on the diffusion of innovations: the example of positron emission tomography in Taiwan.

BACKGROUND: The essence of global budget is to set a cap on the total national health insurance expenditure for a year, which is one form of prospective payment systems. It has always been argued that prospective payment, such as global budgeting, will deter the development of high-tech services in the healthcare industry. The objectives of this study are to explore the impact of global budgeting on the diffusion of high tech equipment in terms of utilization by using Positron Emission Tomography (PET) as an example. METHODS: The study population is the hospitals in Taiwan. We tried to compare the diffusion patterns of Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and PET scanners among these hospitals by analyzing the National Health Insurance (NHI) Database from 1997 to 2010. RESULTS: From 2004 to 2010, 79,380 PET scans in total were performed under the NHI scheme. By the year 2010, the annual reimbursed scans have reached 19,700. The volume curve of cumulative PET services resembles an S diffusion curve with the R2 at 0.95. The results indicated the growth of cumulative PET service volume does correspond with the innovation diffusion model. The cumulative utilizations of CT, MRI and PET demonstrate good correlation with no significant difference in their growth rates. CONCLUSIONS: Therefore, we can infer that even though PET was reimbursed after the implementation of global budgeting, its diffusion was not deterred by this cost containment measure when compared with CT and MRI in the same time span after the inauguration of the NHI.

Harnessing Preclinical Molecular Imaging to Inform Advances in Personalized Cancer Medicine.

Comprehensive molecular analysis of individual tumors provides great potential for personalized cancer therapy. However, the presence of a particular genetic alteration is often insufficient to predict therapeutic efficacy. Drugs with distinct mechanisms of action can affect the biology of tumors in specific and unique ways. Therefore, assays that can measure drug-induced perturbations of defined functional tumor properties can be highly complementary to genomic analysis. PET provides the capacity to noninvasively measure the dynamics of various tumor biologic processes in vivo. Here, we review the underlying biochemical and biologic basis for a variety of PET tracers and how they may be used to better optimize cancer therapy.

Small molecule PET-radiopharmaceuticals.

This review describes several aspects required for the development of small molecule PET-tracers. Design and selection criteria are important to consider before starting to develop novel PET-tracers. Principles and latest trends in (11)C and (18)F-radiochemistry are summarized. In addition an update of some new developments in regulatory aspects is supplied.

Positive progress in immunoPET--not just a coincidence.

The identification of tumor tissue biomarkers has led to the production, validation, and Food and Drug Administration-approval of a number of antibody-based targeted therapeutics in the past two decades. As a result of the significant role that these immunotherapeutics play in the management of cancer, and the potential utility of complementary imaging agents, immunoPET imaging has generated considerable interest. This update discusses the important factors to consider when designing a PET (positron emission tomography) imaging agent from the molecular target to the biological targeting molecule and radionuclide combination and also reviews recent preclinical and clinical findings in the immunoPET field. Although there are a variety of radionuclides that are currently utilized in PET studies, this update focuses on four of the positron emitters commonly used in labeling proteins: iodine-124, zirconium-89, copper-64, and fluorine-18. Notable advances in the preclinical setting include the continued development of immunoPET probes to predict the biodistribution of related radioimmunotherapeutics, the success of nontraditional radionuclide and antibody fragment combinations, the broader use of zirconium-89, and the recent emergence of (18)F-labeled diabodies for same-day imaging. Antibody-based PET probes constitute a valuable class of molecular imaging agents, and the progress made preclinically should expedite the transition of these targeted diagnostics to clinical applications.

Noninvasive radiologic imaging of the large intestine: a valuable complement to optical colonoscopy.

PURPOSE OF REVIEW: Radiologic imaging of the large intestine continues to evolve and expand the potential for noninvasive diagnosis. The aim of this review is to provide an update on current and emerging clinical capabilities for a variety of radiologic diagnostic imaging tools for evaluating the colon and rectum. RECENT FINDINGS: The utility of computed tomography for the evaluation of symptomatic inflammatory and neoplastic conditions of the colon is well established, but the clinical role of computed tomography colonography is rapidly evolving. In addition to a number of diagnostic indications, computed tomography colonography is emerging as a potential frontline colorectal screening test for cancer prevention. MRI has become increasingly valuable for rectal cancer staging and inflammatory bowel disease but has yet to gain momentum for polyp evaluation. PET imaging has been primarily utilized for oncologic indications, but also holds considerable potential for inflammatory conditions. Other imaging modalities, such as the barium enema, conventional radiography, and ultrasound, play a much more limited role. SUMMARY: Advances in radiologic imaging of the colorectum will continue to expand the capabilities and clinical indications for noninvasive diagnosis, allowing for a greater emphasis on the complementary roles of tissue sampling and therapy with optical colonoscopy.

Quantitative small animal PET.

Small animal PET is increasingly utilized to assess efficacy of therapeutic interventions; and in parallel, to validate the use of current and novel imaging agents and targets for translation to the clinic. One of the many advantages of PET imaging is that it offers quantifiable measures of the underlying biology. With that in mind, we review kinetic modeling in quantifying small animal PET images. The review provides a primer on PET image quantification followed by a brief discussion on factors that may affect PET image quantification. We will conclude with application of quantitative imaging in metabolic imaging and delve into advanced topics on voxel-by-voxel kinetic modeling.

Cocaine abuse and sensitization of striatal dopamine transmission: a critical review of the preclinical and clinical imaging literature.

Much effort has been devoted in the preclinical addiction literature to understanding the phenomenon of sensitization, an enhanced dopaminergic response in the nucleus accumbens that occurs after repeated exposure to psychostimulant drugs. Although sensitization has been reported in preclinical studies, studies of sensitization in humans measuring behavioral and physiological responses have been mixed and inconclusive. However, imaging studies with positron emission tomography (PET) and single photon emission computed tomography (SPECT) using a stimulant challenge to induce dopamine (DA) release provide a unique opportunity to probe DA transmission in cocaine dependent human subjects. In contrast to the basic science literature that predicted sensitization, three independent cohorts have shown a blunted DA response, or the opposite of sensitization, in human cocaine dependent subjects. This article reviews the methodological differences between the preclinical and clinical PET studies that have investigated DA sensitization in order to address the discrepancy between the human and animal literature.

Newer imaging modalities to assist with target localization in the radiation treatment of prostate cancer and possible lymph node metastases.

Precise localization of prostate cancer and the drainage lymph nodes is mandatory to define an accurate clinical target volume for conformal radiotherapy. Better target definition and delineation on a daily basis is surely important in quality assurance for fractionated radiation therapy. This article reviews the evidence for major emerging techniques that show promise in better identifying the clinical target volume. Partial prostate boost by brachytherapy, intensity-modulated radiation therapy, or protons has become possible not only with standard imaging techniques but also with the availability of metabolic images obtained by magnetic resonance spectroscopy. Even though fluorine-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography has not been found to be useful, novel radiolabeled tracers may eventually prove of value in the diagnosis and treatment planning of prostate cancer. For the metastatic lymph nodes, lymphotropic nanoparticle-enhanced magnetic resonance imaging using ultra-small superparamagnetic iron oxide particles has greater accuracy as compared with conventional techniques and has been instrumental in delineating the lymphatic drainage of the prostate gland. These novel investigational techniques could further help in optimizing conformal radiotherapy for patients with prostate cancer. The concepts of biologic target volume, real target volume, and multidimensional conformal radiotherapy are being explored.

Functional neuroimaging and headache pathophysiology: new findings and new prospects.

In the last ten years pathophysiology of primary headaches has received new insights from neuroimaging studies. Positron emission tomography (PET) showed activation of specific brain structures, brainstem in migraine and hypothalamic grey in trigeminal autonomic cephalalgias. This brain activation suggests it may intervene both in a permissive or triggering manner and as a response to pain driven by the first division of the trigeminal nerve. Voxel-based morphometry has suggested that there is a correlation between the brain area activated specifically in acute cluster headache - the posterior hypothalamic grey matter - and an increase in grey matter in the same region. New insights into mechanisms of head pain have emerged thanks to neuroimaging obtained in experimentally induced headaches, and during peripheral and central neurostimulation.

A review of diagnostic and functional imaging in headache.

The neuroimaging of headache patients has revolutionised our understanding of the pathophysiology of primary headaches and provided unique insights into these syndromes. Modern imaging studies point, together with the clinical picture, towards a central triggering cause. The early functional imaging work using positron emission tomography shed light on the genesis of some syndromes, and has recently been refined, implying that the observed activation in migraine (brainstem) and in several trigeminal-autonomic headaches (hypothalamic grey) is involved in the pain process in either a permissive or triggering manner rather than simply as a response to first-division nociception per se. Using the advanced method of voxel-based morphometry, it has been suggested that there is a correlation between the brain area activated specifically in acute cluster headache--the posterior hypothalamic grey matter--and an increase in grey matter in the same region. No structural changes have been found for migraine and medication overuse headache, whereas patients with chronic tension-type headache demonstrated a significant grey matter decrease in regions known to be involved in pain processing. Modern neuroimaging thus clearly suggests that most primary headache syndromes are predominantly driven from the brain, activating the trigeminovascular reflex and needing therapeutics that act on both sides: centrally and peripherally.

99mTc-Fanolesomab: affinity, pharmacokinetics and preliminary evaluation.

Localization of infection is critical for both diagnosis and treatment. Several radioactive compounds such as (67)Gallium citrate, (111I)ndium and (99m)Technetium-labeled leukocytes, peptides and antibodies have been used to localize sites of bacterial infection and phlegmons when anatomical imaging techniques failed. With labeled leukocytes the major concern besides the cost, was the in vitro procedure requiring more than 2 h and trained personnel to handle blood samples. Such limitations paved the way for the emergence of new agents like human immunoglobulin, interleukin-1, peptides and monoclonal antibodies. Following the intensive study of 10 monoclonal antibodies the anti SSEA-1 antibody specific for CD15 antigen was found to have a high Kd value of 1.6x10(-11) M for human neutrophils. Labeling of anti CD15 antibody (NeutroSpec) with (99m)Tc and its FDA approval was a boon to diagnostic imaging as it promised to eliminate many of the well known drawbacks of the in vitro WBC labeling. This antibody has a large number of antigenic binding sites: 5.1x10(5) per circulating human neutrophil. It has been established that very little CD15 antigen is expressed on the other blood cell lines. Upon intravenous administration to patients there was no adverse reaction except in those with underlying cardiovascular compromise or chronic pulmonary obstructive disease. Another advantage is that, this particular monoclonal antibody has not produced significant human antimouse antibody in research volunteers and patients. Twenty-four hour imaging, SPECT or planar was not required. The following pages describe the various stages of the research activity carried out towards NeutroSpec.

Imaging of infection and inflammation with 99mTc-Fanolesomab.

(99m)Tc-fanolesomab, a murine M class antigranulocyte antibody, is injected directly into patients, avoiding in vitro leukocyte labeling. Normal distribution includes reticuloendothelial system, genitourinary tract, and blood pool. Small bowel activity appears within 4 h, colonic activity by 24 h. Accumulation in infection is via two mechanisms: binding to circulating neutrophils that migrate to the infection and binding to neutrophils and neutrophil debris containing CD-15 receptors already sequestered in the infection. (99m)Tc-fanolesomab is valuable in atypical appendicitis. Its sensitivity, specificity, and accuracy, in 200 patients were 91%, 86%, and 87%, respectively. This agent is comparable to (111)In- labeled leukocytes for diagnosing osteomyelitis in the appendicular skeleton in general and in diabetic patients with pedal ulcers. Preliminary experience suggests (99m)Tc-fanolesomab might replace in vitro labeled leukocytes for other indications as well. Initial clinical investigations found the agent was safe. A transient decrease in circulating leukocytes within 20 min after injection occurred, but with no associated clinical complaints. Recovery averaged about 20 min. One study found no statistically significant HAMA titer elevation and no adverse reactions following injection. In another investigation 5 out of 30 subjects who received two separate antibody injections, exhibited HAMA induction with no serious or severe adverse events. Forty-nine adverse events, including 4 severe ones, were reported among 523 subjects in clinical trials. In 2004, (99m)Tc-falosomab was approved in the United States for use in patients with equivocal presentation of appendicitis. However, following postmarketing reports of serious adverse events, including two fatalities, the agent was withdrawn in late 2005, and its future is uncertain.

[Positron emission tomography (PET) for diagnosis and monitoring of treatment for urological tumors]. / Positronenemissionstomographie (PET) zur Diagnostik und zum Therapiemonitoring bei urologischen Tumoren.

Positron emission tomography (PET) using ((18)F)2-fluoro-D-2-desoxyglucose (FDG) has been shown to be a highly sensitive and specific imaging modality in the diagnosis of primary and recurrent tumors and in the control of therapies in numerous non-urologic cancers. It was the aim of this review to validate the significance of PET as a diagnostic tool in malignant tumors of the urogenital tract. A systematic review of the current literature concerning the role of PET for malignant tumors of the kidney, testicles, prostate, and bladder was carried out. The role of FDG PET for renal cell cancer can be seen in the detection of recurrences after definitive local therapy and metastases. The higher sensitivity of PET in comparison to other therapeutic modalities (CT, ultrasound, MRI) in recurrent and metastatic renal cell cancer suggests a supplemental role of this diagnostic procedure to complement other imaging modalities.The clinical value of PET is established for the identification of vital tumor tissue after chemotherapy of seminomatous germ cell tumors. This diagnostic method has little significance for primary tumor staging and diagnosis of non-seminomatous germ cell tumor because of the high probability of false-negative results in adult teratomas. FDG PET is not sensitive enough in the diagnosis of primary or recurrent tumors in prostate or bladder cancer. Also PET did not prove to be superior to conventional bone scintigram in the detection of mostly osteoblastic metastases in prostate cancer. The recent use of alternative tracers, which are partly not eliminated by urinary secretion (acetate, choline) has increased the sensitivity and specificity of PET also in this tumor entity so that further clinical investigations are needed to validate these technical modifications in their significance for this imaging modality. PET appears to be sufficiently evaluated only for the diagnostic follow-up of patients with seminomatous germ cell tumors after chemotherapy to regard it is the diagnostic tool of first choice. For all other tumors of the urogenital tract this proof is still awaited.