Quantitative coronary arterial stenosis assessment by multidetector CT and invasive coronary angiography for identifying patients with myocardial perfusion abnormalities.

BACKGROUND: Semi-quantitative stenosis assessment by coronary CT angiography only modestly predicts stress-induced myocardial perfusion abnormalities. The performance of quantitative CT angiography (QCTA) for identifying patients with myocardial perfusion defects remains unclear. METHODS: CorE-64 is a multicenter, international study to assess the accuracy of 64-slice QCTA for detecting ≥50% coronary arterial stenoses by quantitative coronary angiography (QCA). Patients referred for cardiac catheterization with suspected or known coronary artery disease were enrolled. Area under the receiver-operating-characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the most severe coronary artery stenosis in a subset of 63 patients assessed by QCTA and QCA for detecting myocardial perfusion abnormalities on exercise or pharmacologic stress SPECT. RESULTS: Diagnostic accuracy of QCTA for identifying patients with myocardial perfusion abnormalities by SPECT revealed an AUC of 0.71, compared to 0.72 by QCA (P = .75). AUC did not improve after excluding studies with fixed myocardial perfusion abnormalities and total coronary arterial occlusions. Optimal stenosis threshold for QCTA was 43% yielding a sensitivity of 0.81 and specificity of 0.50, respectively, compared to 0.75 and 0.69 by QCA at a threshold of 59%. Sensitivity and specificity of QCTA to identify patients with both obstructive lesions and myocardial perfusion defects were 0.94 and 0.77, respectively. CONCLUSIONS: Coronary artery stenosis assessment by QCTA or QCA only modestly predicts the presence and the absence of myocardial perfusion abnormalities by SPECT. Confounding variables affecting the relationship between coronary anatomy and myocardial perfusion likely account for some of the observed discrepancies between coronary angiography and SPECT results.

Characterization of coronary atherosclerosis by dual-source computed tomography and HU-based color mapping: a pilot study.

To assess HU-based color mapping for characterization of coronary plaque, using intravascular ultrasound virtual histology (IVUS-VH) as a standard of reference. Dual-source computed tomography and IVUS-VH were prospectively performed in 13 patients. In five lesions, HU thresholds of the color-coding software were calibrated to IVUS-VH. In a 15-lesion verification cohort, volumes of vessel, lumen and plaque or percentages of lipid, fibrous and calcified components were obtained through use of pre-set HU cut-offs as well as through purely visual adjustment of color maps. Calibrated HU ranges for fatty or fibrous plaque, lumen and calcification were -10-69, 70-158, 159-436 and 437+. Using these cut-offs, HU-based analysis achieved good agreement of plaque volume with IVUS (47.0 vs. 51.0 mm(3)). Visual segmentation led to significant overestimation of atheroma (61.6 vs. 51.0 mm(3); P = 0.04) Correlation coefficients for volumes of vessel, lumen and plaque were 0.92, 0.87 and 0.83 with HU-based analysis or 0.92, 0.85 and 0.71 with visual evaluation. With both methods, correlation of percentage plaque composition was poor or insignificant. HU-based plaque analysis showed good reproducibility with intra-class correlation coefficients being 0.90 for plaque volume and 0.81, 0.94 or 0.98 for percentages of fatty, fibrous or calcified components. With use of optimized HU thresholds, color mapping allows for accurate and reproducible quantification of coronary plaque.

Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor strategy.

Antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial targeting, an absence of drug resistance. To promote tumor regression and to maintain dormancy, antiangiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. As a step toward this goal, we have generated recombinant adeno-associated virus (rAAV) vectors that carry genes coding for angiostatin, endostatin, and an antisense mRNA species against vascular endothelial growth factor (VEGF). These rAAVs efficiently transduced three human tumor cell lines tested. Transduction with an rAAV-encoding antisense VEGF mRNA inhibited the production of endogenous tumor cell VEGF. Conditioned media from cells transduced with this rAAV or with rAAV-expressing endostatin or angiostatin inhibited capillary endothelial cell proliferation in vitro. Antiangiogenic rAAVs may offer a novel gene therapy approach to undermining tumor neovascularization and cancer progression.

Hepatic utilization of exogenous nucleotide precursors for restoration of ATP after cold ischemia in rats.

The study objective was to assess hepatic utilization of exogenous adenosine or adenine to enhance ATP recovery in rat liver after cold ischemia. ATP was measured noninvasively by 31P nuclear magnetic resonance (NMR) in perfused livers before and after 18 h of cold ischemia. The hepatocellular concentration of ATP during the initial postischemic reperfusion without adenosine or adenine coinfusion was 60% of that in fresh liver. The ATP increased significantly (P < 0.001) to 139% and 82% of baseline in postischemic livers coinfused for 90 min with adenosine or adenine (final concentration, 1 mmol/L), respectively. Less than 0.5% of the excess adenosine was catabolized to uric acid. In conclusion, adenosine and, to a lesser extent, adenine are salvaged by liver after extended cold ischemia to enhance ATP restoration. Provision of these ATP precursors, as components of an enteral formulation may facilitate the repletion of liver ATP and foster early resumption of liver function after an ischemic insult.

Liver preservation for transplant. Evaluation of hepatic energy metabolism by 31P NMR.

31P NMR spectroscopy proved to be an excellent, dynamic, nondestructive method for assessing the liver during cold flush and pulsatile perfusion experiments. 31P NMR spectroscopy was used to measure ATP decay, inorganic phosphate appearance, and phosphate chemical shift in the excised mouse livers subjected to cold and warm ischemia. Cold flush followed by cold preservation in saline, Krebs-Henseleit buffer, or Collins' solution showed that Collins' solution resulted in the slowest ATP decay. In temperature-controlled experiments (5 degrees -37 degrees C), ATP decay was much slower with lower temperature. In separate pulsatile perfusion experiments with oxygenated Krebs-Henseleit buffer, hepatic ATP was unchanged for at least 6 hr at 20 degrees C. At 37 degrees C, the NMR spectrum showed changes in the diphosphoesters region, but the ATP remained stable during the 6-hr perfusion. These studies suggest that for long periods of liver preservation, an adequate perfusion method should be developed.

31P nuclear magnetic resonance spectroscopic evaluation of liver preservation solutions.

The individual effects of verapamil and 2 antioxidants on perfused rat liver nucleoside triphosphate (NTP) recovery following cold storage in University of Wisconsin (UW) solution was assessed using 31P nuclear magnetic resonance spectroscopy. The pharmacological agents were added to UW solution and were present only during organ storage. NTP recovery was significantly higher for the 24-hr UW + 40 microM verapamil group as compared with the 24-hr UW group. None of the other pharmacological agents caused a significant increase in NTP recovery. These findings suggest that addition of verapamil to UW organ preservation solution may result in better poststorage liver function.

Hepatic microcirculatory changes after reperfusion in fatty and normal liver transplantation in the rat.

The hepatic microcirculation in fatty and normal liver grafts in ACI rats was investigated using in vivo microscopy. Six groups were studied. They were: normal and fatty control livers (sham operated), 6-hr cold University of Wisconsin solution (UW)-preserved fatty and normal liver grafts (survival conditions, fatty and normal liver grafts), 18-hr cold UW-preserved fatty livers (nonsurvival conditions, fatty liver graft), and 24-hr cold UW-preserved normal livers (nonsurvival conditions, normal liver grafts). Fatty livers in all groups were found to have narrow and irregular sinusoids with blood cell adhesions to endothelial cells. The number of adhesions increased as the preservation time increased. Sinusoidal blood flow area decreased as the preservation time increased and was correlated with survival in both normal and fatty liver grafts. The phagocytic activity of Kupffer cells (corrected for flow) increased as the preservation time increased. The phagocytic Kupffer cell activity of the 18-hr preserved fatty liver group was greater than the activity of any other group. These features may cause liver cell death and contribute to primary graft nonfunction after transplantation of a fatty liver.

In vivo microscopic assessment of hepatic microcirculation during liver allograft rejection in the rat.

The hemodynamic alterations in hepatic microvasculature during acute rejection of rat liver allografts was studied using in vivo fluorescence microscopy. ACI rat livers were transplanted into Lewis (allograft) or ACI (isograft) recipients. Microscopy was performed on days 3 (n = 7) and 6 (n = 7) in allografts, and on day 6 (n = 7) in isografts. Naive ACI livers (n = 7) served as nontransplant controls. Changes in sinusoidal blood perfusion, microvascular structure, and leukocyte-endothelial interactions were observed and quantitated. Six days after transplantation, acinar perfusion was markedly impaired in allografts and was accompanied by a lower percentage of perfused sinusoids (59 +/- 8%, mean +/- SEM, P < 0.01) relative to isografts (89 +/- 3%) and nontransplant controls (100 +/- 0%). The hepatic cord width in allografts was significantly greater than in isografts or in nontransplant controls, indicating swelling of parenchymal and sinusoidal lining cells. Furthermore, the number of leukocytes adhering to the sinusoidal endothelium significantly increased in allografts. Adherence to postsinusoidal venules was more prominent in allograft livers (4025 +/- 1400/mm2 of vascular endothelial surface) compared with that in isografts (574 +/- 77/mm2) and nontransplant controls (185 +/- 28/mm2). These microcirculatory alterations in allografts were significant even on day 3. The results show extensive abnormalities of the microcirculatory hemodynamics in rejecting liver allografts which were associated with increased leukocyte adherence to microvascular endothelium. Our findings may provide strategic information for the prevention and treatment of allograft rejection.

31P NMR assessment of orthotopic rat liver transplant viability. The effect of warm ischemia.

The relationship between NMR visible high energy phosphates and transplant outcome for the case of liver damage by warm ischemia was investigated. In vivo 31P nuclear magnetic resonance (NMR) spectroscopy of rat liver was performed before the induction of warm ischemia in the donor and 20 min after reestablishment of portal blood flow in the recipient. Pretransplant damage was varied by subjecting the livers to 0, 15, 30, or 60 min of warm ischemia prior to harvesting. In the controls (0 min warm ischemia), 4 of 4 rats survived transplantation (one week survival end-point) and the mean NTP recovery was 94 +/- 8%; 3 of 6 rats survived in the 15 min warm ischemia group. Mean NTP recovery was 77 +/- 20% in the 15 min survival subgroup and 32 +/- 20% in the nonsurvival subgroup. Of 6 rats, 1 survived in the 30 min group. NTP recovery was 44% for the 30 min survivor and 37 +/- 5% in the nonsurvival subgroup. Of 4 rats, 1 survived in the 60 min warm ischemia group. NTP recovery was 56% for the 60 min survivor and 28 +/- 7% in the nonsurvival subgroup. Overall, there was a significant difference between the mean NTP recovery of the survival and nonsurvival subgroups (78 +/- 21% versus 31 +/- 18%, P < 0.001). The dividing line between the survival and nonsurvival groups was approximately 50% NTP recovery. Of 9 rats with liver NTP recovery greater than 50%, 8 survived while 10 of 11 rats with less than 50% recovery died. NMR visible NTP recovery 20 min after the reestablishment of portal blood flow was a good indicator of transplant outcome in the case of rat liver damage by warm ischemia.

A rat fatty liver transplant model.

A rat model of fatty liver transplantation has been developed to study primary nonfunction in fatty liver grafts. ACI rats were fed with a diet deficient in choline and methionine for 7, 14, 28, and 42 days. Fat content in the pretransplant livers was examined by gas chromatography and histology. The main constituent of the fatty droplets was determined to be triglyceride. The triglyceride concentration reached a maximum by day 14 and remained constant for an additional 28 days. Histology revealed an absence of necrosis in 14- and 28-day fatty livers but scattered hepatocytic necrosis and inflammation in 42-day fatty livers. After being given cold (UW stored, 4 degrees C) or warm (37 degrees C) ischemia, the fatty liver was orthotopically transplanted into normal ACI rats. The one-week survival of fatty liver grafts after 6, 12, 18, and 24 hr cold preservation was 5/5, 5/6, 3/8, 0/6 for 14-day fatty liver and 5/5, 4/6, 0/8, 0/6 for 42-day fatty livers. The survival of normal liver grafts was 5/5, 6/6, 5/9, 2/8, respectively. Increased survival rate was correlated with the absence of hepatocytic necrosis. The survival after 15 and 30 min warm ischemia prior to transplant was 5/5, 2/6 for normal liver grafts and 4/7, 0/6 for 28-day fatty liver graft, respectively. Fatty livers were less resistant to damage induced by cold or warm ischemia.

Initial experience with SPECT (single-photon computerized tomography) of the brain using N-isopropyl I-123 p-iodoamphetamine: concise communication.

Forty-six patients were studied with N-isopropyl I-123 p-iodoamphetamine (IMP) and the Harvard Scanning Multidetector Brain System. In nine control patients, good differentiation between the gray and white matter of the cerebral cortex and the basal ganglia was evident. Regional uptake was affected by physiologic maneuvers (visual stimulation). In 24 patients studied for stroke, IMP images demonstrated areas that were involved in acute infarction in eight patients whose initial transmission computerized tomography (TCT) was normal; IMP also showed perfusion abnormalities larger than the TCT abnormality in ten patients. Perfusion abnormalities were present in 23/24 of these patients. Seven patients studied with a history of TIA had normal TCT and IMP images. In three patients studied during seizure activity, regions of hyperperfusion corresponded to the EEG seizure focus. Markedly decreased activity was present in three patients with brain tumor and corresponded to the focal abnormality on the TCT study. Our study demonstrates the feasibility of assessing regional brain perfusion using a radiopharmaceutical that is lipid soluble and has a high extraction fraction in the brain, together with single-photon ECT.

Simple liver perfusion model for NMR spectroscopic analysis.

We developed a model to study the perfused mouse liver by nuclear magnetic resonance spectroscopy and to sample perfusate as it exited the liver within a vertical-bore spectrometer. The technique consists of rapidly cannulating the portal vein for perfusate inflow, and then suspending the organ in a bath of perfusate. An outlet at the bottom of the NMR tube provides easy access to concentrated samples of the perfusate exiting the liver. A suction outlet located just above the liver removes excess perfusate from the NMR tube. The perfusing medium is oxygenated Krebs-Henseleit buffer perfused at 8 ml/min. We demonstrated excellent P-31 spectra on the mouse liver. The liver energy charge is maintained as reflected in a constant ATP/Pi. We also showed the effects of ischemia and anoxia upon the liver, and correlated these P-31 spectra with biochemical measurements of liver enzyme release. This model was adapted for use in an Oxford wide-bore (89-mm) 8.4 T magnet with a 2-cm NMR tube to study P-31 spectra, liver enzyme and electrolyte release in ischemic and anoxic livers, but it can be used for spectroscopy of any nuclei in any vertical-bore spectrometer.

Liver adenine nucleotide metabolism during ischemia and reperfusion of mice livers studied by phosphorous-31 nuclear magnetic resonance.

Perfusion experiments were performed at 20 degrees C and 37 degrees C to study liver adenine nucleotide metabolism during ischemia and reperfusion of mouse livers using 31P NMR. Perfusing at 8 mL/min (Krebs-Henseleit buffer), ATP was shown to be stable for 6 hours. There was a progressive decrease in the phosphodiesters (glycerophosphorycholine and glycerophosphorylethanolamine) during the 6-hour period. Liver subjected to cold ischemia at 20 degrees C showed a slow decrease in the beta ATP peak during a 42 +/- 6-minute period with a rise in the inorganic phosphate accompanied by a shift of inorganic phosphate to the high field indicating intracellular acidosis. With reperfusion, the beta ATP returned to previous levels and the inorganic phosphate shifted to its original position. During warm ischemia (37 degrees C) the ATP peak disappeared within 5 +/- 1 minute and only returned to 34% of its original value after 30 minutes of ischemia, indicating damage to a certain percentage of liver cells. When the liver was subjected to multiple short periods of cold ischemia, there was complete recovery of the ATP after six cycles. Reperfusion after each period of cold ischemia resulted in an ATP recovery consistently greater than the initial amount, which gradually decreased to preischemic levels after a short period. This suggests that there is an as yet undelineated mechanism of ATP production during ischemia that attempts to protect the cell against ischemia.

Nuclear magnetic resonance assessment of adenosine triphosphate (ATP) dynamics in ischemic mouse livers perfused with adenine and ribose.

Hepatic energy stores are essential to liver viability. We used a mouse liver perfusion model and MR spectroscopy to study the effect of adding two precursors of ATP (adenine and ribose) on ATP dynamics during ischemia and reperfusion. Using Krebs-Henseleit buffer with or without added adenine and ribose made little difference in the ATP decay rate during ischemia, but the recovery of ATP during reperfusion was more complete when adenine and ribose were added to the buffer. These findings suggest that the addition of the precursors of ATP, adenine and ribose, to perfusate after ischemia can accelerate and enhance ATP recovery.

Hepatic arterial chemoembolization for metastatic neuroendocrine tumors.

BACKGROUND: Patients with neuroendocrine neoplasma, even with metastases to the liver, often have indolent disease and are treated conservatively. However, when debilitating symptoms from hormonal syndromes or mass effect arise, more aggressive treatment may be warranted. METHODS: Thirty-nine chemoembolization procedures were performed in 30 patients with significant symptoms, with carcinoids and islet cell tumors. An emulsification of intraarterial doxorubicin, iodized oil, and water-soluble contrast was followed by embolization with absorbable gelatin powder or pledgets. RESULTS: Twenty-seven patients exhibited subjective improvement in clinical symptoms. Hormonal markers and/or tumor size decreased by at least 50% in 79% of patients. Inclusion of minor responses raises this to 92%. Seven complications were noted, and no procedure-related deaths occurred. Median survival was 24 months after chemoembolization or 53 months after diagnosis. Computed tomographic features of tumor vascularity, distribution of metastatic lesions, and distribution of ethiodized oil were not clearly correlated with outcome. Presence of a nonresected primary tumor had a negative effect on survival. CONCLUSIONS: Compared with previously described treatments for neuroendocrine liver metastases, this technique appears to be more effective and to be associated with less morbidity, and is recommended for patients with significant symptoms who have failed to respond to more conservative therapy and who are not surgical candidates.

Prospective comparison of preoperative imaging and intraoperative ultrasonography in the detection of liver tumors.

A prospective evaluation of the accuracy of preoperative computed tomography (CT), ultrasonography (US), and angiography was performed in 54 patients undergoing resection of hepatic neoplasms. The results were compared with surgical findings and intraoperative ultrasonography (IOUS). A total of 167 lesions was seen by means of IOUS, of which preoperative US enabled detection of 127 (76%). In 48 patients CT allowed detection of 91 of 150 lesions (61%), and in 35 patients angiography showed 56 of 107 lesions (52%). When the detection rate is analyzed according to hepatic segment, the greater overall accuracy of preoperative US may be attributed to a markedly better detection rate in lateral segment of the left lobe of the liver. Lesion size also represented a factor, with preoperative US allowing detection of a greater number of small (less than 2 cm) lesions compared with CT. In patients studied with both CT and US, the combined lesion-detection rate increased to 81% in the right lobe and 76% in the left lobe. Because of this we recommend that preoperative assessment include both CT and US evaluation of the liver. IOUS showed 25% to 35% additional lesions compared with preoperative US and CT. More importantly, 40% of the lesions demonstrated by IOUS were neither visible nor palpable at surgery. We recommend that IOUS be considered in all patients in whom resection of hepatic neoplasm is planned.

Ectopic pelvic spleen.

We are reporting the first, to our knowledge, ectopic pelvic spleen demonstrated preoperatively by means of a liver-spleen scan and a selective splenic arteriogram. Symptoms, consisting of crampy pain in the lower part of the abdomen exacerbated by standing or stooping, were relieved by splenectomy in this 19-year-old woman. Splenopexy, which has been advocated in the past, has no place in the management of this rare and interesting congenital variant. Laxity or failure of development of the phrenicosplenic and gastrosplenic ligaments is thought to account for the splenic descensus.

Multimodality treatment of hepatocellular carcinoma in a hepatobiliary specialty center.

OBJECTIVES: To review the experience of the treatment of hepatocellular carcinoma by a single multimodality team during a 6-year period, including all patients who were referred for possible surgical intervention, to evaluate prognostic factors at presentation, and to determine the results of the different modalities of treatment that were used. DESIGN: Retrospective study of 154 patients who were referred to our Hepatobiliary Surgical Unit with the diagnosis of hepatocellular carcinoma from January 1988 through August 1995. SETTING: Tertiary care center. RESULTS: Methods of treatment included surgical resection (n=49), transplantation (n=22), hepatic artery chemoembolization (n=30), systemic chemotherapy (n=25), and no treatment (n=22). Predictive prognostic factors included coexisting cirrhosis, symptoms at presentation, and abnormal liver function test results. Unfavorable tumor characteristics were size (diameter, >5 cm) and multicentricity. For patients who underwent surgical exploration, advanced staging according to the manual of the American Joint Committee on Cancer, vascular invasion, and a margin of less than 1 cm in the group for patients who underwent resection impacted negatively on the prognosis. The median survival (42.4 months) for the group of patients who underwent resection was significantly higher than that for the groups of patients who did not undergo resection. Chemoembolization was associated with significantly better survival results than was systemic chemotherapy. CONCLUSIONS: Hepatic resection offers the best chance at cure for patients with hepatocellular carcinoma. The high association between hepatocellular carcinoma and cirrhotic liver disease makes surgical resection, even in favorable tumor types, a difficult task based on low hepatic reserve whose tumors are considered unresectable can be considered for chemoembolization. Liver transplantation should be reserved for selected patients with cirrhotic liver disease who have tumors (diameter, <5 cm) in the contest of neoadjuvant protocols.

Congenital renal arteriovenous malformation: angiography in its diagnosis.

Two patients with renal arteriovenous malformations are presented along with the distinct changes shown by urography, arteriography, and pharmacoangiography. The relevant roentgen signs in such patients include multiple small cobblestone-like identations caused by well-formed vascular channels projecting into the collecting structures, no angiographic or urographic evidence of a mass displacing the intrarenal vessels or collecting structures, normal sized arteries and veins leading to and from the malformation, and a decrease in size of the malformation after intra-arterial infusion of epinephrine. These patients may have flank pain or hematuria later in life or may remain asymptomatic. A complete urographic and angiographic examination will help to determine the appropriate therapy. Corrective surgery is usually reserved for symptomatic patients and, when indicated, require only surgical ligation of the vessels feeding and draining the malformation.

Transcatheter embolotherapy for congenital renal arteriovenous malformations. Long-term follow-up.

Transcatheter embolization was performed five times in 3 patients with congenital renal arteriovenous malformations (AVM). The patients were followed for one to seven and a half years. Two patients whose AVM were completely occluded with Gelfoam have been asymptomatic with no evidence of hematuria. A third patient, embolized with Gelfoam and Ivalon without complete occlusion of the AVM, bled ten months after the first procedure, was re-embolized, and later had the AVM removed surgically. Superselective transcatheter embolization should be the initial treatment modality for congenital AVM with the aim to control bleeding and occlude those malformations supplied by the terminal portion of interlobar arteries. Large malformations supplied by multiple feeders may require operative ligation and removal of the AVM when vessels cannot be occluded satisfactorily because of massive shunting.