Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients.

The integrin alpha v beta3 receptor is upregulated on tumor cells and endothelium and plays important roles in angiogenesis and metastasis. Arg-Gly-Asp (RGD) peptide ligands have high affinity for these integrins and can be radiolabeled for PET imaging of angiogenesis or tumor development. We have assessed the safety, stability, and tumor distribution kinetics of a novel radiolabeled RGD-based integrin peptide-polymer conjugate, 18F-AH111585, and its feasibility to detect tumors in metastatic breast cancer patients using PET. METHODS: The biodistribution of 18F-AH111585 was assessed in 18 tumor lesions from 7 patients with metastatic breast cancer by PET, and the PET data were compared with CT results. The metabolic stability of 18F-AH111585 was assessed by chromatography of plasma samples. Regions of interest (ROIs) defined over tumor and normal tissues of the PET images were used to determine the kinetics of radioligand binding in tissues. RESULTS: The radiopharmaceutical and PET procedures were well tolerated in all patients. All 18 tumors detected by CT were visible on the 18F-AH111585 PET images, either as distinct increases in uptake compared with the surrounding normal tissue or, in the case of liver metastases, as regions of deficit uptake because of the high background activity in normal liver tissue. 18F-AH111585 was either homogeneously distributed in the tumors or appeared within the tumor rim, consistent with the pattern of viable peripheral tumor and central necrosis often seen in association with angiogenesis. Increased uptake compared with background (P = 0.002) was demonstrated in metastases in lung, pleura, bone, lymph node, and primary tumor. CONCLUSION: 18F-AH111585 designed to bind the alpha v beta3 integrin is safe, metabolically stable, and retained in tumor tissues and detects breast cancer lesions by PET in most anatomic sites.     

Histologic dating of bruises in moribund infants and young children

It is generally held that leukocytes are found within bruised subcutaneous tissues within 4–12 h of injury as part of a standard cellular response to trauma. As a corollary, the absence of leukocytes is often cited as evidence of more recent injury. To investigate how long after injury it may be before a leukocyte response occurs selected bruises from three children aged 27, 11, and 3 months, respectively, were examined microscopically. All of the children had sustained lethal head trauma, with survival on life-support equipment for some time in hospital, and with bruises of at least 24-h duration confirmed by medical evaluation (at 30, 44, and 79 h from the time of initial medical evaluation to death). Histologic examination of selected lesions in all three cases revealed extravasation of red blood cells within subcutaneous tissues, but no leukocyte infiltration or other cellular reaction. Other bruises in these children exhibited a standard inflammatory response. This study has shown that selected bruises in three children were present for at least 30 h without a leukocyte infiltrate. Caution should, therefore, be exercised in assigning too rigid a time course to bruising in infants and young children based on a lack of a vital reaction, as the absence of leukocytes within soft tissues of bruised skin in these cases may not necessarily indicate that the injuries are recent. Variability in tissue response may also occur in different bruises in the same individual. Whether severe craniocerebral trauma played a role in delaying the cellular response in these particular injuries is unclear.     

Graft injury in relation to graft size in right lobe live donor liver transplantation: a study of hepatic sinusoidal injury in correlation with portal hemodynamics and intragraft gene expression

OBJECTIVE: To investigate the degree and mechanism of hepatic sinusoidal injury in different graft sizes in right lobe live donor liver transplantation (LDLT). SUMMARY BACKGROUND DATA: Liver grafts from living donors are likely to be small-for-size for adult recipients. Graft injury after reperfusion is common, but the mechanism and degree of injury remain unclear. The hepatic sinusoidal injury in different graft sizes and its relationship with portal hemodynamics and intragraft gene response at the early phase after reperfusion have not been studied in right lobe LDLT. METHODS: From May 2000 to November 2001, 40 adults receiving right lobe LDLT had portal pressure measured continuously before and after reperfusion. Liver biopsies were taken before and after reperfusion for detection of vasoregulatory genes (endothelin-1 and endothelial nitric oxide synthase) and heat shock genes (heat shock protein 70 and heme oxygenase-1), and electron microscope examination. Blood samples from the portal vein and suprahepatic inferior vena cava were taken for the measurement of plasma nitric oxide level. RESULTS: The recipients were grouped according to the ratio of graft weight to estimated standard liver weight: group 1 (n = 10), less than 40%; group 2 (n = 21), 40% to 60%; and group 3 (n = 9), more than 60%. The portal pressures recorded after reperfusion in group 1 were significantly higher within 30 minutes of reperfusion than those in groups 2 and 3. After reperfusion, the intragraft endothelin-1 mRNA level in group 1 increased by 161% of the basal level but decreased by 31.5% and 62% of the basal level in groups 2 and 3, respectively. The intragraft mRNA level of heme oxygenase-1 in groups 1 and 2 decreased by 75.5% and 25.3% of the basal level respectively but increased by 41% of basal level in group 3. The intragraft protein level of heat shock protein 70 decreased by 50 ng/mL after reperfusion in group 1 but increased by 12.4 ng/mL and 0.6 ng/mL in groups 2 and 3, respectively. The portal vein plasma nitric oxide level decreased more significantly after reperfusion in group 1 than in group 2. Electron microscope examination of liver biopsies in group 1 showed tremendous mitochondrial swelling as well as irregular large gaps between the sinusoidal lining cells. There were two hospital deaths in group 1 and none in the other two groups. CONCLUSIONS: Patients implanted with grafts less than 40% of standard liver weight suffered from transient portal hypertension early after reperfusion. The phenomenon was accompanied by intragraft upregulation of endothelin-1 and ultrastructural evidence of sinusoidal damage. The transient portal hypertension after reperfusion, subsequent endothelin-1 overexpression, and plasma nitric oxide level reduction, together with downregulation of heme oxygenase-1 and heat shock protein 70, may account for the small-for-size graft injury.     

Reoperative cryopreserved root and ascending aorta replacement for acute aortic prosthetic valve endocarditis

BACKGROUND: Prosthetic aortic valve endocarditis (PVE) is an important complication of aortic valve replacement (AVR) and is a particularly difficult situation after an operation combining AVR with ascending aortic replacement. METHODS: From 1988 through 2000, 27 patients with aortic valve PVE after previous ascending aortic replacement (aortic root replacement in 13, aortic valve replacement with a supracoronary graft in 14) underwent reoperation for aortic root replacement with a cryopreserved aortic allograft and prolonged intravenous antibiotic therapy. All patients were considered to have active PVE (25 with positive cultures); root abscess formation was present in 89% and aortoventricular discontinuity in 41%. RESULTS: One patient (3.7%) died in-hospital, and permanent pacemakers were required in 10 patients (37%). Mean postoperative follow-up interval was 3.9 +/- 3.0 years, and survival at 1, 2, 5, and 7.5 years was 92%, 88%, 70%, and 56%, respectively. One patient underwent reoperation for recurrent PVE 8 months after operation. CONCLUSIONS: Radical debridement of infected prosthetic material and tissue, and allograft aortic root and ascending aorta replacement, combined with intravenous antibiotic therapy, appears to achieve a low hospital mortality and a high degree of freedom from recurrent infection for patients with PVE after AVR and ascending aortic replacement.     

Peak oxygen intake and cardiac mortality in women referred for cardiac rehabilitation

OBJECTIVES: This study investigated the prognostic importance of measured peak oxygen intake (VO(2peak)) in women with known coronary heart disease referred for outpatient cardiac rehabilitation. BACKGROUND: Exercise capacity is a powerful predictor of prognosis in men with known or suspected coronary disease. Similar findings are described in women, but fewer studies have utilized measured VO(2peak), the most accurate measure of exercise capacity. METHODS: A single-center design took data from 2,380 women, age 59.7 +/- 9.5 years (1,052 myocardial infarctions, 620 coronary bypass procedures, and 708 with proven ischemic heart disease), who underwent cardiorespiratory exercise testing. They were followed for an average of 6.1 +/- 5 years (median 4.5 years, range 0.4 to 25 years) until cardiac and all-cause death. RESULTS: We recorded 95 cardiac deaths and 209 all-cause deaths. Measured VO(2peak) was an independent predictor of risk, values > or =13 ml/kg/min (3.7 multiples of resting metabolic rate) conferring a 50% reduction in cardiac mortality (hazard ratio [HR] 0.5, p = 0.001). Considered as a continuous variable, a 1 ml/kg/min advantage in initial VO(2peak) was associated with a 10% lower cardiac mortality. Adverse predictors were diabetes (HR 2.73, p = 0.0005) and antiarrhythmic therapy (HR 3.93, p = 0.0001). CONCLUSIONS: As in men, measured VO(2peak) is a strong independent predictor of cardiac mortality in women referred for cardiac rehabilitation.     

Localization of denaturation bubbles in random DNA sequences

We study the thermodynamic and dynamic behaviors of twist-induced denaturation bubbles in a long, stretched random sequence of DNA. The small bubbles associated with weak twist are delocalized. Above a threshold torque, the bubbles of several tens of bases or larger become preferentially localized to AT-rich segments. In the localized regime, the bubbles exhibit "aging" and move around subdiffusively with continuously varying dynamic exponents. These properties are derived by using results of large-deviation theory together with scaling arguments and are verified by Monte Carlo simulations.     

Addition of a topoisomerase I inhibitor to trimodality therapy [cis-diamminedichloroplatinum(II)/heat/radiation] in a murine tumor

The cytotoxicity of the topoisomerase I inhibitors, camptothecin and topotecan, toward exponentially growing EMT-6 murine mammary carcinoma cells under various conditions of oxygenation, pH and temperature was assessed. Under normal pH (pH 7.40) conditions both camptothecin and topotecan were more cytotoxic toward normally oxygenated cells. Both agents were more cytotoxic under acidic pH (pH 6.45) and the differential in cytotoxicity due to the cellular oxygenation level disappeared. Neither camptothecin nor topotecan was enhanced in cytotoxicity by hyperthermia (42°C or 43°C, 60 min) during drug exposure. Both camptothecin and topotecan killed increasing numbers of FSaIIC tumor cells with increasing dose of the drugs in vivo in a log/linear manner. Local hyperthermia (43°C, 30 min) increased the tumor cell killing of the drugs but decreased the toxicity of these agents to the bone marrow granulocyte/macrophage-colony-forming units. Topotecan was a more effective modulator of cisplatin than was camptothecin, as determined by FSaIIC tumor cell survival assay and by FSaIIC tumor growth delay. Although both camptothecin and topotecan were effective additions to a treatment regimen including cisplatin and daily fractionated radiation (5×3Gy), neither of these topoisomerase I inhibitors increased the tumor growth delay produced by the trimodality regimen of cisplatin/hyperthermia/radiation.Abbreviations Cisplatin cis-diamminedichloroplatinum(II) - GM-CFU granulocyte-macrophage progenitor colony-forming unit This work was supported by NCI grants RO1-47379 and RO1-50174