[18F]Fluciclatide in the in vivo evaluation of human melanoma and renal tumors expressing αvβ3 and αvβ5 integrins

Purpose

[¹⁸F]Fluciclatide is an integrin-targeted PET radiopharmaceutical. α_vβ₃ and α_vβ₅ are upregulated in tumor angiogenesis as well as on some tumor cell surfaces. Our aim was to use [¹⁸F]fluciclatide (formerly known as [¹⁸F]AH111585) for PET imaging of angiogenesis in melanoma and renal tumors and compare with tumor integrin expression.

Methods

Eighteen evaluable patients with solid tumors ≥2.0 cm underwent [¹⁸F]fluciclatide PET/CT. All patients underwent surgery and tumor tissue samples were obtained. Immunohistochemical (IHC) staining with mouse monoclonal antibodies and diaminobenzidine (DAB) was applied to snap-frozen tumor specimens, and additional IHC was done on formalin-fixed paraffin-embedded samples. DAB optical density (OD) data from digitized whole-tissue sections were compared with PET SUV_{80% max}, and Patlak influx rate constant (K _i) data, tumor by tumor.

Results

Tumors from all 18 patients demonstrated measurable [¹⁸F]fluciclatide uptake. At the final dynamic time-point (55 min after injection), renal malignancies (in 11 patients) demonstrated an average SUV_{80% max} of 6.4?±?2.0 (range 3.8 – 10.0), while the average SUV_{80% max} for metastatic melanoma lesions (in 6 patients) was 3.0?±?2.0 (range 0.7 – 6.5). There was a statistically significant difference in [¹⁸F]fluciclatide uptake between chromophobe and nonchromophobe renal cell carcinoma (RCCs, with SUV_{80% max} of 8.2?±?1.8 and 5.4?±?1.4 (P?=?0.020) and tumor-to-normal kidney (T/N) ratios of 1.5?±?0.4 and 0.9?±?0.2, respectively (P?=?0.029). The highest Pearson's correlation coefficients were obtained when comparing Patlak K _i and α_vβ₅ OD when segregating the patient population between melanoma and RCC (r?=?0.83 for K _i vs. melanoma and r?=?0.91 for K _i vs. RCC). SUV_{80% max} showed a moderate correlation with α_vβ₅ and α_vβ₃ OD.

Conclusion

[¹⁸F]Fluciclatide PET imaging was well tolerated and demonstrated favorable characteristics for imaging α_vβ₃ and α_vβ₅ expression in melanoma and RCC. Higher uptake was observed in chromophobe than in nonchromophobe RCC. [¹⁸F]Fluciclatide may be a useful radiotracer to improve knowledge of integrin expression.     

A comparative study of resource use and costs of renal, liver and heart transplantation

Organ transplantations are among the most expensive surgical treatments performed today, but estimates of the costs of organ transplantations vary widely between settings. The aim of this study is to estimate the costs of renal, liver and heart transplantation in a university hospital, adopting a similar costing methodology for all the three kinds of transplantation. Resource use data were collected from 803 patients transplanted between January 1995 and August 2001. Data about the time physicians and other hospital employees spent per transplantation were based on interviews. All costs from pretransplantation screening up to 3 years post-transplantation were taken into account and divided into costs of patient care and programme-related costs. Mean cost of renal transplantation varied from 70,723 Euros for cadaveric donor transplantations to 76,577 Euros for living donor transplantations. Mean costs of liver transplantation were 141,510 Euros and the mean costs of heart transplantation were 17, 828 Euros. Direct costs of patient care contributed to 79%, 87% and 92% of the costs of renal, liver and heart transplantation respectively. Inpatient hospital days were the largest contributor to the costs of patient care. The mean number of inpatient hospital days from pretransplantation screening to 3 years post-transplantation varied from 46 days for renal transplantation from a living donor to 58 days for renal transplantation from cadaveric donors, 83 days for heart transplantation and 108 days for liver transplantation. In conclusion, costs of liver and heart transplantation were approximately 2.0 and 2.5 times higher than the cost of renal transplantation. Length of inpatient hospital stay for transplantation did not change substantially over time between 1995 and 2001.     

Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment

To assess platelet function profiles in diabetic and nondiabetic patients on aspirin and clopidogrel therapy, two patient populations were included to investigate the 1) acute effects of a 300-mg clopidogrel loading dose (group 1, n = 52) and 2) long-term effects of clopidogrel (group 2, n = 120) on platelet function in diabetic compared with nondiabetic patients already on aspirin treatment. Patients were stratified according to the presence of type 2 diabetes. Platelet aggregation was assessed using light transmittance aggregometry (groups 1 and 2). Platelet activation (P-selectin expression and PAC-1 binding) was determined using whole-blood flow cytometry (group 2). Clopidogrel response was also assessed. In group 1, platelet aggregation was significantly increased in diabetic (n = 16) compared with nondiabetic (n = 36) patients at baseline and up to 24 h following a 300-mg loading dose (P = 0.005). In group 2, platelet aggregation and activation were increased in diabetic (n = 60) compared with nondiabetic (n = 60) subjects (P < 0.05 for all platelet function assays). Diabetic subjects had a higher number of clopidogrel nonresponders (P = 0.04). Diabetic patients have increased platelet reactivity compared with nondiabetic subjects on combined aspirin and clopidogrel treatment. Reduced sensitivity to antiplatelet drugs may contribute to the increased atherothombotic risk in diabetic patients.     

Regulation of Bone Mineral Density in Morbidly Obese Women: A Cross-sectional Study in Two Cohorts Before and After Bypass Surgery

Background  The mechanisms by which increased body weight influence bone mass density (BMD) are still unknown. The aim of our study was to analyze the relationship between anthropometric and body composition variables, insulin growth factor-I (IGF-I), adiponectin and soluble tumor necrosis factor-α receptors (sTNFR) 1 and 2 with BMD in two cohorts of morbid obese patients, before and after bypass surgery. Methods  The first cohort included 25 women aged 48 ± 7.6 years studied before bypass surgery. The second included 41 women aged 46 ± 9.2 years, 12 months after surgery. We studied anthropometric variables obtained from whole body DEXA composition analysis. Serum IGF-I, intact serum parathyroid hormone, 25-hydroxivitamin D₃, plasma adiponectin concentrations, sTNFR1, sTNFR2 concentrations were measured. Results  In the first cohort, the BMI was 44.5 ± 3.6 kg/m², parathyroid hormone, IGF-I, and adiponectin concentrations were lower, and sTNFR1 concentrations were higher than in the second cohort. In the multiple regression analysis, BMD remained significantly associated with body fat percentage (β −0.154, p = 0.01), lean mass (β 0.057, p = 0.016) and phosphate concentration (β 0.225, p = 0.05). In the second cohort, BMI was 31 ± 5.1 kg/m². In the multiple regression analysis, BMD remained significantly associated with lean mass (β 0.006, p = 0.03). Conclusion  The inverse correlation found between body fat and BMD in the first cohort indicates morbid obesity increases the risk of osteoporosis and we found a positive correlation with lean and fat mass before bariatric surgery and with lean mass after bypass surgery.     

Las hepatectomías mayores en pacientes con colangiocarcinoma e ictericia son seguras

Background

Surgical resection is the only possibility of long term survival in patients with Klatskin tumours. However, surgical resection is a challenging problem and hepatic resection is often necessary.

Objective

The aim of our study was to assess the need for biliary drainage, resection rate and outcome of hilar cholangiocarcinoma in a single tertiary referral centre.

Patients and methods

From 2005 to 2008, 26 patients with Klatskin tumours were identified and assessed prospectively with multidetector CT and MR cholangiography in special cases. Seven patients (27%) were deemed to be unresectable in pre-operative staging. A total of 19 surgical procedures were performed, 8 left hepatectomies, 5 right hepatectomies and 6 resections exclusively of the biliary tree.

Results

Resection rate was 73%, transfusion rate 53% and preoperative biliary drainage was performed only in 7 cases (37%). Major complications occurred in 11 (58%), including two post-operative deaths (10%).There were no differences in the epidemiological data, when we separately analysed the outcomes of the 9 patients with bilirubin <15 mg/dL and the 10 patients with bilirubin >15 mg/dL. Biliary drainage was required in 6 (67%) patients in the group with low bilirubin levels vs. 1(10%) in the other group (P=0.02). The mean bilirubin level in the jaundiced group was 22.1±3.9 vs. 4.7±4.3 (P<0.001) in the other group. There were no differences in the postoperative outcome between both groups.

Conclusion

Resection and survival rates have increased recently but still carries the risk of significant morbidity and mortality. Major hepatectomies in selected patients without percutaneous biliary drainage are safe.     

Stage I pure bronchioloalveolar carcinoma: recurrences, survival and comparison with adenocarcinoma of the lung.

OBJECTIVE: Bronchioloalveolar carcinoma (BAC) is considered a subtype of adenocarcinoma of the lung, without pleural, stromal or vascular invasion (World Health Organization (WHO) classification). Previous reports had demonstrated a better prognosis following surgery for patients affected by early stage BAC than those affected by other type of non-small cell lung cancer (NSCLC). We aim to analyse differences between stage I peripheral nodular BAC and stage I peripheral adenocarcinoma of the lung, METHODS: From January 1, 1993 to December 31, 1999, 1158 patients were submitted to surgical resection for NSCLC. Out of them, 28 patients (2.4%) resulted affected by stage I peripheral pure BAC and 80 (6.9%) by stage I peripheral adenocarcinoma. We made a comparison between these two groups. RESULTS: The percentage of females in BAC patients was similar to that registered in adenocarcinoma patients (21.4 vs. 17.5%). No differences were detected between smokers in BAC and adenocarcinoma patients (P=0.331). The upper lobes were the most common sites of the primary tumour in both tumour subtypes (71.4 vs. 67.5%). Relapse of disease was less frequent in BAC than in adenocarcinoma patients (14.2 vs. 33.7%); recurrent disease developed intrathoracic with higher frequency in BAC patients (75 vs. 33.3%). Both 5-year disease-free and long-term survival were significantly higher in patients affected by BAC (81 vs. 51% and 86 vs. 71%, respectively) (P<0.05); when analysis is performed by dividing stage IA from IB tumours, BAC patients resulted to have higher DFS (stage IA, 93 vs. 58% - P=0.044; stage IB, 61 vs. 32.5%) and higher long-term survival (stage IA, 92 vs. 79%; stage IB, 75 vs. 56%). CONCLUSION: Patients with stage I pure BAC have significantly longer disease-free and overall survival than those with similar stage adenocarcinoma. Even if classified as subtype of adenocarcinoma, BAC is characterised by clinical behaviour less aggressive than similar stage adenocarcinoma.     

Superior T-cell suppression by rapamycin and FK506 over rapamycin and cyclosporine A because of abrogated cytotoxic T-lymphocyte induction,impaired memory responses,and persistent apoptosis

Immunosuppressive therapy is best achieved with a combination of agents targeting multiple activation steps of T cells. In transplantation, cyclosporine A (CsA) or tacrolimus (FK506) are successfully combined with rapamycin (Rap). Rap and CsA were first considered for combination therapy because FK506 and Rap target the same intracellular protein and thus may act in an antagonistic way. However, in clinical studies, FK506+Rap proved to be effective. To date, there is no in vitro data supporting these in vivo findings, and it is unclear whether the observed effects are T-cell mediated. In a human polyclonal allogeneic in vitro model, we found that although combined drug treatment markedly reduced expansion of naive T cells, T-cell activation occurred irrespective of the drug combination used. The induction of cytotoxic effector T cells was reduced by CsA+Rap but completely abolished by FK506+Rap. Importantly, combined immunosuppression allowed generation of memory CD4+ and CD8+ T cells and hence did not result in T-cell anergy. However, FK506+Rap treatment resulted in a reduced number of allospecific memory T cells showing a decreased cell-cycle turnover and cytokine producing capacity. In contrast, CsA+Rap treatment led to increased memory T-cell numbers responding with elevated kinetics. The ability of Rap to promote apoptosis, which contributes to T-cell suppression, remained unaffected upon combination with FK506 or CsA. These data support the combined use of FK506+Rap over CsA+Rap for immunosuppressive therapy.     

Comparison of continuous vs. pulsed focused ultrasound in treated muscle tissue as evaluated by magnetic resonance imaging, histological analysis, and microarray analysis

The purpose of this study was to investigate the effect of different application modes of high intensity focused ultrasound (HIFU) to muscle tissue. HIFU was applied to muscle tissue of the flank in C3H/Km mice. Two dose regimes were investigated, a continuous HIFU and a short-pulsed HIFU mode. Three hours after HIFU treatment pre- and post-contrast T1-weighted, T2-weighted images and a diffusion-weighted STEAM sequence were obtained. After MR imaging, the animals were euthenized and the treated, and the non-treated tissue was taken out for histology and functional genomic analysis. T2 images showed increased signal intensity and post-contrast T1 showed a decreased contrast uptake in the central parts throughout the tissue of both HIFU modes. A significantly higher diffusion coefficient was found in the muscle tissue treated with continuous wave focused ultrasound. Gene expression analysis revealed profound changes of 54 genes. For most of the analyzed genes higher expression was found after treatment with the short-pulse mode. The highest up-regulated genes encoded for the MHC class III (FC ≈84), HSP 70 (FC ≈75) and FBJ osteosarcoma related oncogene (FC ≈21). Immunohistology and the immunoblot analysis confirmed the presence of HSP70 protein in both applied HIFU modes. The use of HIFU treatment on muscle tissue results in dramatic changes in gene expression; however, the same genes are up-regulated after the application of continuous or pulsed HIFU, indicating that the tissue reaction is independent of the type of tissue damage. Hundt and Yuh contributed equally to this paper. Supported in part by the Lucas Foundation and the Phil Allen Truse.     

In Vivo Evaluation of a New Embolic Spherical Particle (HepaSphere) in a Kidney Animal Model

HepaSphere is a new spherical embolic material developed in a dry state that absorbs fluids and adapts to the vessel wall, leaving no space between the particle and the arterial wall. The aim of this study was to elucidate the final in vivo size, deformation, final location, and main properties of the particles when reconstituted with two different contrast media (Iodixanol and Ioxaglate) in an animal model. Two sizes of “dry-state” particles (50–100 and 150–200 μm) were reconstituted using both ionic and nonionic contrast media. The mixture was used to partly embolize both kidneys in an animal model (14 pigs). The animals were sacrificed 4 weeks after the procedure and the samples processed. The final size of the particles was 230.2 ± 62.5 μm for the 50- to 100-μm dry-state particles and 314.4 ± 71 μm for the 150- to 200-μm dry-state particles. When the contrast medium (ionic versus nonionic) used for the reconstitution was studied to compare (Student’s t-test) the final size of the particles, no differences were found (p > 0.05). The mean in vivo deformation for HepaSphere was 17.1% ± 12.3%. No differences (p > 0.05) were found in the deformation of the particle regarding the dry-state size or the contrast medium (Mann-Whitney test). We conclude that HepaSphere is stable, occludes perfectly, and morphologically adapts to the vessel lumen of the arteries embolized. There is no recanalization of the arteries 4 weeks after embolization. Its final in vivo size is predictable and the particle has the same properties in terms of size and deformation with the two different contrast media (Iodixanol and Ioxaglate).