Population Genetics and Molecular Evolution of DNA Sequences in Transposable Elements. II. Accumulation of Variation and Evolution of a New Subfamily.

In order to understand how DNA sequences of transposable elements (TEs) evolve, extensive simulations were carried out. We first used our previous model, in which the copy number of TEs is mainly controlled by selection against ectopic recombination. It was found that along a simulation run, the shape of phylogeny changes quite much, from monophyletic trees to dimorphic trees with two clusters. Our results demonstrated that the change of the phase is usually slow from a monomorphic phase to a dimorphic phase, accompanied with a growth of an internal branch by accumulation of variation between two types. Then, the phase immediately changes back to a monomorphic phase when one group gets extinct. Under this condition, monomorphic and dimorphic phases arise repeatedly, and it is very difficult to maintain two or more different types of TEs for a long time. Then, how a new subfamily can evolve? To solve this, we developed a new model, in which ectopic recombination is restricted between two types under some condition, for example, accumulation of mutations between them. Under this model, because selection works on the copy number of each types separately, two types can be maintained for a long time. As expected, our simulations demonstrated that a new type arises and persists quite stably, and that it will be recognized as a new subfamily followed by further accumulation of mutations. It is indicated that how ectopic recombination is regulated in a genome is an important factor for the evolution of a new subfamily.

Population genetics and molecular evolution of DNA sequences in transposable elements. I. A simulation framework.

A population genetic simulation framework is developed to understand the behavior and molecular evolution of DNA sequences of transposable elements. Our model incorporates random transposition and excision of transposable element (TE) copies, two modes of selection against TEs, and degeneration of transpositional activity by point mutations. We first investigated the relationships between the behavior of the copy number of TEs and these parameters. Our results show that when selection is weak, the genome can maintain a relatively large number of TEs, but most of them are less active. In contrast, with strong selection, the genome can maintain only a limited number of TEs but the proportion of active copies is large. In such a case, there could be substantial fluctuations of the copy number over generations. We also explored how DNA sequences of TEs evolve through the simulations. In general, active copies form clusters around the original sequence, while less active copies have long branches specific to themselves, exhibiting a star-shaped phylogeny. It is demonstrated that the phylogeny of TE sequences could be informative to understand the dynamics of TE evolution.

A retrospective analysis of 335 Japanese lung cancer patients who responded to initial gefitinib treatment.

BACKGROUND: Gefitinib treatment results in considerably better progression-free survival compared with that of platinum doublets in the first line treatment of nonsmall-cell lung cancer (NSCLC) carrying an activating epidermal growth factor receptor (EGFR) mutation. Some patients who respond to gefitinib have an overall survival (OS) of more than 5 years, whereas other initial responders do less well. Although there has been considerable effort made to elucidate the mechanisms of acquired resistance, there have only been a few studies that addressed the effect of clinical backgrounds and treatment histories on the survival of the patients who had responded to an EGFR-tyrosine kinase inhibitor (TKI). In this study, we especially focused on the clinical benefit of EGFR-TKI administration after progression. PATIENTS AND METHODS: We retrospectively analyzed consecutive patients with advanced NSCLC who were diagnosed before October 2010, treated with gefitinib after July 2002, and responded to it. The primary objective of this study was to evaluate how clinical backgrounds and treatment histories influence survival of the patients who respond to gefitinib. The secondary objectives were to evaluate the safety of long-term gefitinib use and to establish the optimal treatment sequence using a dynamic treatment regimen analysis (DTRA). RESULTS: A total of 335 patients were recruited. Twenty-eight (8.4%) patients survived more than 5 years. Sixty-five and 93 patients received gefitinib as rechallenge and beyond progressive disease (BPD), respectively. A statistically significant difference in OS was observed between the patients who underwent gefitinib rechallenge and those who did not rechallenge (median: 1272 days vs. 774 days; p < 0.001), a result supported by a DTRA. Patients treated with gefitinib BPD also showed a tendency of longer survival. CONCLUSIONS: Gefitinib rechallenge and BPD played a central role in long term survival of the patients who initially responded to gefitinib.

On the estimation of the insertion time of LTR retrotransposable elements.

It has been proposed that the insertion time of a long terminal repeat (LTR) retrotransposon can be estimated by the divergence between the two LTRs at the both ends because their sequences were identical at the insertion event. This method is based on the assumption that the two LTRs accumulate point mutations independently; therefore, the divergence reflects the time since the insertion event. However, if gene conversion occurs between LTRs, the nucleotide divergence will be much smaller than expected with the assumption of the independent accumulation of point mutations. To examine this assumption, we investigated the extent of gene conversion between LTRs by applying a comparative genomic approach to primates (humans and rhesus macaques) and rodents (mice and rats). We found that gene conversion plays a significant role in the molecular evolution of LTRs in primates and rodents, but the extent is quite different. In rodents, most LTRs are subject to extensive gene conversion that reduces the divergence, so that the divergence-based method results in a serious underestimation of the insertion time. In primates, this effect is limited to a small proportion of LTRs. The most likely explanation of the difference involves the minimum length of the interacting sequence (minimal efficient processing segment [MEPS]) for interlocus gene conversion. An empirical estimate of MEPS in human is 300-500 bp, which exceeds the length of most of the analyzed LTRs. In contrast, MEPS for mice should be much smaller. Thus, MEPS can be an important factor to determine the susceptibility of LTRs to gene conversion, although there are many other factors involved. It is concluded that the divergence method to estimate the insertion time should be applied with special caution because at least some LTRs undergo gene conversion.

Disruption of the EGFR E884-R958 ion pair conserved in the human kinome differentially alters signaling and inhibitor sensitivity.

Targeted therapy against epidermal growth factor receptor (EGFR) represents a major therapeutic advance in lung cancer treatment. Somatic mutations of the EGFR gene, most commonly L858R (exon 21) and short in-frame exon 19 deletions, have been found to confer enhanced sensitivity toward the inhibitors gefitinib and erlotinib. We have recently identified an EGFR mutation E884K, in combination with L858R, in a patient with advanced lung cancer who progressed on erlotinib maintenance therapy, and subsequently had leptomeningeal metastases that responded to gefitinib. The somatic E884K substitution appears to be relatively infrequent and resulted in a mutant lysine residue that disrupts an ion pair with residue R958 in the EGFR kinase domain C-lobe, an interaction that is highly conserved within the human kinome as demonstrated by our sequence analysis and structure analysis. Our studies here, using COS-7 transfection model system, show that E884K works in concert with L858R in-cis, in a dominant manner, to change downstream signaling, differentially induce Mitogen-activated protein kinase (extracellular signaling-regulated kinase 1/2) signaling and associated cell proliferation and differentially alter sensitivity of EGFR phosphorylation inhibition by ERBB family inhibitors in an inhibitor-specific manner. Mutations of the conserved ion pair E884-R958 may result in conformational changes that alter kinase substrate recognition. The analogous E1271K-MET mutation conferred differential sensitivity toward preclinical MET inhibitors SU11274 (unchanged) and PHA665752 (more sensitive). Systematic bioinformatics analysis of the mutation catalog in the human kinome revealed the presence of cancer-associated mutations involving the conserved E884 homologous residue, and adjacent residues at the ion pair, in known proto-oncogenes (KIT, RET, MET and FAK) and tumor-suppressor gene (LKB1). Targeted therapy using small-molecule inhibitors should take into account potential cooperative effects of multiple kinase mutations, and their specific effects on downstream signaling and inhibitor sensitivity. Improved efficacy of targeted kinase inhibitors may be achieved by targeting the dominant activating mutations present.

An unusual renal vascular anomaly: common origin of arteries to the lower poles demonstrated by a computed tomography angiography using 16-slice multidetector computed tomography.

Arterial connection between the left and right kidneys is extremely rare. Only eight cases of such anomalous conditions have been reported in the world literature and all were confirmed by invasive angiography or dissection. We report a patient with this vascular anomaly clearly demonstrated by 16-slice multidetector computed tomography.

Fibronectin enhances viability and alters cytoskeletal functions (with effects on the phosphatidylinositol 3-kinase pathway) in small cell lung cancer.

Small cell lung cancer (SCLC) is a rapidly progressive disease with ultimate poor outcome. SCLC has been shown to interact closely with the stromal and extracellular matrix (ECM) components of the diseased host. ECM consists of type I/IV collagen, laminin, vitronectin, and fibronectin (FN) among others. Herein, we investigated the behavior of a SCLC cell line (NCI-H446) on FN-coated surface. Over a course of 72 h, FN (10 micro g/ml) caused both increased survival and proliferation of NCI-H446 cells. Survival under serum-starved conditions increased 1.44-fold and proliferation in the presence of fetal calf serum increased by 1.30-fold. The phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 reduced both survival and proliferation of NCI-H446 cells (0.48- and 0.27-fold, respectively), even on FN-coated surface. We next determined the effects of FN on cytoskeletal function such as cell motility/morphology and adhesion. Over a course of 24 h, FN reduced aggregation of NCI-H446 cells and induced flattened cellular morphology with neurite-like projections after 1 h, however, in the presence of LY294002, the cells rounded up. Adhesion of NCI-H446 cells also increased with FN (4.47-fold) which was abrogated with LY294002 treatment. This correlated with phosphorylation of the cytoskeletal protein p125FAK, on Tyr397, Tyr861 and Ser843 residues with FN. Even in the presence of LY294002, these serine/tyrosine residues were still phosphorylated on FN-coated surface. In contrast, the focal adhesion protein paxillin was not phosphorylated at Tyr31 with FN. In summary, FN stimulation of SCLC cells leads to enhancement of viability and changes in cytoskeletal function that are partially mediated through the PI3-K pathway.

Activated c-Met signals through PI3K with dramatic effects on cytoskeletal functions in small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive illness with early metastases. There are several receptor tyrosine kinases (RTKs) overexpressed in SCLC, including c-Met. c-Met contains an external semaphorin-like domain, a cytoplasmic juxtamembrane domain, tyrosine kinase domain and multiple tyrosines that bind to adapter molecules. We have previously reported that c-Met is abundantly expressed in the NCI-H69 SCLC cell line and now have determined the downstream effects of stimulating c-Met via its ligand hepatocyte growth factor (HGF). Utilizing unique phospho-specific antibodies generated against various tyrosines of c-Met, we show that Y1003 (binding site for c-Cbl and a negative regulatory site), Y1313 (binding site for PI3K), Y1230/Y1234/Y1235 (autophosphorylation site), Y1349 (binding site for Grb2), Y1365 (important in cell morphogenesis) are phosphorylated in response to HGF (40 ng/ml, 7.5 min) in H69 cells. Since multiple biological and biochemical effects are transduced through the PI3K pathway, we determine the role of PI3K in the c-Met/HGF stimulation pathway. We initially determined that by inhibiting PI3K with LY294002 (50 microM over 72 hours), there was at least a 55% decrease in viability of H69 cells. Since H69 SCLC cells form clusters in cell culture, we determined the effects of HGF and LY294002 on cell motility of the clusters by time-lapse video microscopy. In response to HGF, SCLC moved much faster and formed more clusters, and this was inhibited by LY294002. Finally, we determined the downstream signal transduction of HGF stimulation of c-Met with and without inhibition of c-Met (with geldanamycin, an anisamycin antibiotic that inhibits c-Met in SCLC) or PI3K (with LY294002). We show that association of c-Met with PI3K and GAB2 is diminished by inhibiting c-Met. In summary, activation of the c-Met pathway targets the PI3K pathway in SCLC and this may be an important therapeutic target.

Gene therapy utilizing the Cre/loxP system selectively suppresses tumor growth of disseminated carcinoembryonic antigen-producing cancer cells.

Recent clinical trials of cancer gene therapy have shown encouraging results for controlling localized tumors. However, to control metastatic or disseminated tumor cells, further modification of vectors is required to enhance specificity and infectivity against targets. We investigated whether utilization of the Cre recombinase(Cre)/loxP system contributes to enhanced antitumor effects together with minimal adverse reactions in specific gene therapy against disseminated carcinoembryonic antigen (CEA)-producing cancer cells in the peritoneal cavity of mice. CEA-producing cancer would be a good therapeutic target because it is found in lung, stomach and colon sites, which account for most cancers. We constructed a pair of recombinant adenoviral vectors (Ads), one of which expresses the Cre gene under the control of the CEA promoter (Ad.CEA-Cre); the other expresses the herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.lox-TK), or the beta-galactosidase gene (beta-gal) by Cre (Ad.lox-beta-gal). Intraperitoneal coinjection of Ad.CEA-Cre and Ad.lox-beta-gal into mice with peritonitis carcinomatosa by CEA-producing tumor cells showed selective expression of the beta-gal gene in tumor foci. Coinfection of Ad.CEA-Cre and Ad.lox-TK followed by ganciclovir (GCV) administration significantly suppressed the total tumor weight in the peritoneal cavity of the mice to 13% of that of the untreated mice and 22% of that of the mice treated with Ad.CEA-TK/GCV, an Ad that expressed the HSV-TK gene driven by the CEA promoter alone. Moreover, treatment with Ad.CEA-Cre and Ad.lox-TK/GCV completely suppressed tumors in 4 of 10 (40%) mice without significant weight loss, although 2 of 10 mice treated with Ad.CAG-TK/GCV, an adenovirus vector that strongly but nonspecifically expressed the TK gene, died due to severe side effects including diarrhea, weight loss and liver dysfunction. These findings suggest that cell type-specific gene therapy using the Cre/loxP system is effective against disseminated cancer cells without significant side effects.

Clinicopathological study of carcinomas of the lip and the mucosa of the upper and lower lips.

BACKGROUND: Lip carcinomas are rare oral tumors, and there have been few reports of lip carcinoma in Japan. METHODS: Of 914 patients with oral carcinomas treated between January 1980 and December 1998, 12 (1.3%) had lip carcinoma and 5 (0.5%) had lip mucosal carcinoma. We investigated the clinicopathological features of these 17 patients. RESULTS: Of the 12 patients with carcinoma of the lip, 10 had squamous cell carcinomas (9, external lower lip; 1 commissures) and 2 had mucoepidermoid carcinomas (external upper lip). Of the 5 patients with lip mucosal carcinoma, 3 had squamous cell carcinomas (2, mucosa of the lower lip; 1, mucosa of the upper lip), 1 had mucoepidermoid carcinoma (mucosa of the lower lip), and 1 had acinic cell carcinoma (mucosa of the lower lip). Of the 12 patients with lip carcinoma, 9 were classified as stage I, 2 as stage II, and 1 as stage III; all 5 of the patients with lip mucosal carcinoma were stage I. Five patients with lip carcinoma were treated by resection, 5 by a combination of resection and reconstruction, and 2 by radiotherapy alone. All patients with lip mucosal carcinoma were treated by resection. After the initial therapy, 3 patients without neck dissection had regional recurrences and received delayed neck dissection, and 2 died with neck regional recurrence after dissection. The 5-year cumulative survival rates of the patients with lip carcinoma and those with lip mucosal carcinoma were 82.5% and 80.0%, respectively. CONCLUSION: We suggest that early-stage carcinomas of the lip and of the mucosa of the upper and lower lips are frequent, and we found that the outcome of these patients was excellent. However, an aggressive therapeutic approach to the lip carcinoma patient with cervical metastasis appears warranted, in an attempt to improve locoregional control and ultimate survival.

Development status of Terumo implantable left ventricular assist system.

We have been developing an implantable left ventricular assist system (T-ILVAS) featuring a magnetically suspended centrifugal pump (MSCP) since 1995. In vitro and in vivo studies using a prototype MSCP composed of a polycarbonate housing and impeller (196 ml) have demonstrated long-term durability and excellent blood compatibility for up to 864 days, and excellent stability of the magnetic bearing of the MSCP. These preliminary results strongly suggested that the magnetic bearing of the MSCP is reliable and is a most feasible mechanism for a long-term circulatory assist device. We have recently devised a clinical version pump made of titanium (180 ml) with a new position sensor mechanism and a wearable controller with batteries. Cadaver fit study confirmed that the Type IV pump could be implanted in a small patient with a body surface area as small as 1.3. The in vitro performance tests of the Type IV pump demonstrated excellent hydrodynamic performances with an acceptable hemolysis rate. New position sensors for the titanium housing showed more uniform sensor outputs of a magnetic bearing than in the prototype polycarbonate pump. The Type IV pump then was evaluated in vivo in 6 sheep at the Oxford Heart Centre. Four sheep were electively sacrificed at 3 months and were allowed to survive for more than 6 months for long-term evaluation. In this particular series of experiments, no anticoagulant/antiplatelet regimen was utilized except for a bolus dose of heparin during surgery. There was a left ventricular mural thrombi around the inflow cannula in 1 sheep. Otherwise, there was no mechanical failure nor sign of thromboembolism throughout the study.

Serial assessment of left ventricular function during dobutamine stress by means of electrocardiography-gated myocardial SPECT: combination with dual-isotope myocardial perfusion SPECT for detection of ischemic heart disease.

BACKGROUND: Technetium-labeled myocardial perfusion tracers allow simultaneous assessment of myocardial perfusion and left ventricular function by electrocardiography (ECG)-gated myocardial single photon emission computed tomography (SPECT). The purpose of this study was to evaluate left ventricular performance during dobutamine stress by means of ECG-gated myocardial perfusion SPECT with short-time data collection. METHODS AND RESULTS: After administration of Tc-99m sestamibi or tetrofosmin (600-740 MBq), 67 patients with ischemic heart disease, including 35 with prior myocardial infarction, were examined by ECG-gated myocardial perfusion SPECT at rest and during dobutamine stress (at dosages of 4, 8, 12, 16, and 20 microg/kg/min, with increments every 8 minutes). The ECG-gated data collection time was 5 minutes for each dobutamine dosage. After acquisition of gated SPECT data at the highest dose, thallium 201 chloride (111 MBq) was injected, and dual-isotope SPECT was also performed to assess the myocardial ischemia. In 32 patients without prior myocardial infarction, the sensitivity of individual stenosed-vessel detection with dual-isotope perfusion SPECT, with wall motion abnormality obtained from gated SPECT, and with the combined method was 55.9%, 52.9%, and 73.5%, respectively, based on coronary angiography. ECG-gated SPECT during dobutamine infusion revealed regional wall motion abnormalities (worsening or biphasic response) in 19 (57.6%) of 33 infarcted areas with culprit coronary arterial stenosis. The prevalence of reversible perfusion defects on dual-isotope SPECT was higher in segments with wall motion abnormalities than in segments with normal wall motion response (89.5% vs 42.9%, P <.02). CONCLUSIONS: Myocardial perfusion and left ventricular function during dobutamine infusion were analyzed in a single examination by means of the combined method. This procedure has the potential to provide comprehensive information with which to evaluate patients with ischemic heart disease.

Adenovirus-mediated gene therapy specific for small cell lung cancer cells using a Myc-Max binding motif.

Recent clinical trials of gene therapy for patients with thoracic cancers have shown that these treatments were well tolerated with minimal side effects and that we need to further enhance specificity as well as efficiency of gene transfer to target cancer cells. We previously reported that myc-overexpressing SCLC cell lines became selectively sensitive to ganciclovir (GCV) by transducing the herpes simplex virus thymidine kinase (HSV-TK) gene under the control of the Myc-Max response elements (a core nucleotide sequence, CACGTG) and that this construct (MycTK) could be utilized to develop a novel treatment against chemo-radio-resistant SCLC. We report here in vivo antitumor effects and safety of a replication-deficient adenoviral vector containing the Myc-Max binding motif (AdMycTK) on SCLC cells. In vitro infection with AdMycTK selectively rendered myc-overexpressing SCLC cell lines 63- to 307-fold more sensitive to GCV. In vivo injections with AdMycTK followed by GCV administration markedly suppressed the growth of myc-overexpressing tumors established in the subcutis or in the peritoneal cavity of athymic mice. On the other hand, infection with AdMycTK did not significantly affect either in vitro GCV sensitivity of the cells expressing very low levels of the myc genes or the growth of their subcutaneous tumors. Moreover, we observed no apparent side effects of this treatment including body weight loss or biochemical abnormalities in contrast to the treatment with AdCATK that conferred strong but nonspecific expression of the HSV-TK gene. These results suggested that AdMycTK/GCV therapy is effective on SCLC patients whose tumors overexpress myc family oncogenes.

Association of Epstein-Barr virus with tumor cell proliferation: clinical implication in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is characterized by its association with Epstein-Barr virus (EBV) infection. Unlike other upper aerodigestive tract squamous cell carcinomas, clinical and pathologic features are unable to predict outcome in NPC. EBV has been demonstrated to have transforming potential in B-cell systems so that its infection can rapidly and efficiently induce sustained lymphocyte proliferation in vitro. However, the relationship between cell proliferation and EBV infection in NPC has not been previously reported. This study was designed to determine the association of EBV infection and NPC tumor cell proliferation. Cell proliferation index, as measured by two markers, PCNA and Ki-67, were moderately correlated (r=0.534, p=0.033). Quantitative analysis of EBV positivity was highly correlated with both cell proliferation indices (r=0.802, p=0.0039 and r=0.720, p=0.0174 for PCNA and Ki-67, respectively). TNM staging did not demonstrate prognostic significance. NPC patients whose tumors were EBV positive demonstrated increased survival compared with patients whose tumors were EBV negative (p=0.043). These results indicate that EBV infection may regulate cell proliferation in NPC and the presence of EBV can be used as a positive prognostic factor.

Intracranial lipomas: demonstration by computed tomography and magnetic resonance imaging.

We present two cases of a very rare tumor, intracranial lipoma, diagnosed by computed tomography (CT) and magnetic resonance imaging (MRI). In one case, the lipoma was in the superior cerebellar cistern, the other was in the periphery of the corpus callosum. In the case in which MRI was used, identification of the lipoma using a routine MRI examination was difficult. These cases are reported now because the incidental diagnosis of intracranial lipoma is likely to increase due to advanced neuroradiological techniques such as CT and MRI.

Physical model-based indirect measurements of blood pressure and flow using a centrifugal pump.

This article describes a technique offering indirect measurements of pump pressure differential and flow with certain accuracy independent of changes in blood viscosity. This technique is based on noninvasive measurements of the motor current and rotation speed using the physical model equations of the centrifugal pump system. Blood viscosity included in the coefficients of the dynamic equations is first estimated, and then substitution of the estimated viscosity into the steady equations of the model provides pump flow and pressure differential. In vitro tests using a Capiox pump showed a sufficient linear correlation between actual values and their estimates for pressure differential and pump flow. An in vivo test using a 45 kg sheep showed that the proposed algorithm needs robustness for the convergence of estimates of viscosity. An overall evaluation, however, of the developed algorithm/model showed indications of success in terms of efficient computation and modeling.

Terumo implantable left ventricular assist system: results of long-term animal study.

The research group of Terumo Corporation, NTN Corporation, and the Setsunan University have been developing an implantable left ventricular assist system (T-ILVAS) featuring a centrifugal blood pump with a magnetically suspended impeller (MSCP). The present study describes results of chronic animal experiments using the MSCP. The MSCP has been tested ex vivo and in vivo in 6 sheep as a left heart bypass between the left ventricular apex and descending aorta. Ex vivo chronic sheep experiments using Model I demonstrated long-term durability, nonthrombogenicity, low hemolysis (<6 mg/dl), and excellent stability of the magnetic bearing with long-term survival for up to 864 days. Average pump flow rate was 4 L/min at a fixed rotational speed of 2000 rpm. Power spectral analyses of heart rate, aortic pressure, and blood temperature maintained normal 1/f fluctuation during the study. The retrieved pump was completely free from thrombus formation and there was no evidence of infarct in major organs. The implantable Model II was evaluated ex vivo in two sheep and intra-thoracically implanted in a sheep. These experiments were terminated at 70, 79, and 17 days due to blood leakage through the connector system within the housing. No thrombus formation was observed in any of the retrieved pumps. A modified Model II with a new connector system was subsequently intra-thoracically implanted in a sheep. The sheep survived for 482 days without any sign of thromboembolic complication or hemolysis at a fixed rotational speed of 1700 rpm and an average pump flow rate of 5 L/min. There was no intra-device thrombus formation or infarct in major organs. The Model III system, consisting of an implantable controller and a new MSCP with a reduced input power of 13 W, has been developed and implanted in a chronic sheep model. The MSCP was implanted in the left pleural space and the controller in the abdominal wall. The experiment is still in progress for more than 30 days without any significant complication to date. These animal studies strongly suggest the feasibility of the MSCP for use as long-term circulatory assist.

Comparison of Emory and Cedars-Sinai methods for assessment of left ventricular function from gated myocardial perfusion SPECT in patients with a small heart.

To evaluate the effect of left ventricular (LV) size on the calculation of LV function from gated myocardial SPECT with Emory and Cedars-Sinai programs, we performed 99mTc-tetrofosmin gated SPECT on 49 patients with ischemic heart disease. End-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) were semi-automatically calculated by each program. All patients underwent left ventriculography (LVG) within 3 months before and after the SPECT study. We grouped the patients into 22 with a calculated ESV obtained from LVG of over 50 ml (group A) and 27 with an ESV value of 50 ml or below (group B). We then compared the ESV values from gated SPECT with those from LVG in each group. In group A, the ESV from both Emory and Cedars-Sinai programs similarly correlated well with those from LVG (r = 0.92 and r = 0.93, respectively), but in group B, the ESV calculated from the Cedars-Sinai program correlated less with those from LVG (r = 0.53) than those from the Emory program did (r = 0.70). The calculated LV volumes had more errors in the Cedars-Sinai program than in the Emory program, when a patient had a small heart.

Simultaneous assessment of Tc-99m-sestamibi and I-123-BMIPP myocardial distribution in patients with myocardial infarction: evaluation of left ventricular function with ECG-gated myocardial SPECT.

123I-labeled 15-(p-iodophenyl)-3R,S-methyl pentadecanoic acid (BMIPP) is a branched-chain free fatty acid that is used to evaluate various cardiac diseases. The aim of the present study was to investigate the relationship between myocardial perfusion (99mTc-sestamibi) and BMIPP uptake, and to correlate perfusion and metabolic alterations with regional left ventricular dysfunction in patients with myocardial infarction (MI). ECG-gated dual-isotope myocardial SPECT was performed on 130 patients with MI with sestamibi (555 MBq) and BMIPP (148 MBq). The patients were classified into 3 groups according to PTCA therapy and the interval between the onset of infarction and RI injection (OR time). Group A (n = 56) included patients whose OR time was less than one month and who had undergone successful PTCA, Group B (n = 36) had OR times of less than one month and had conservative medical therapy, and Group C (n = 38) had OR times of over one month. The severity scores of the dual-isotope images were calculated from the defect scores in 9 segments. From the ECG-gated SPECT data with sestamibi, the left ventricular ejection fraction (LVEF; %) and regional wall motion were determined automatically using the QGS program LVEF obtained from gated SPECT correlated well with the severity scores for sestamibi and BMIPP (r = -0.68 and -0.76, respectively). The delta severity scores (BMIPP scores - sestamibi scores) of Group A were significantly higher than those of the other two groups (3.6 +/- 3.0 vs. 1.5 +/- 1.7 and 1.0 +/- 1.4, p < 0.001 ). The rate of dysfunctional segments with normal sestamihi distribution was significantly higher in Group A than in Group C (20.7% vs. 6.7%, p < 0.001). ECG-gated dual-isotope SPECT is useful since myocardial perfusion, fatty acid metabolism and left ventricular function can be analyzed during a single examination, so that this procedure has the potential to provide comprehensive information when evaluating patients with ischemic heart disease.