The impact of visceral adipose tissue on postoperative renal function after radical nephrectomy for renal cell carcinoma.

BACKGROUND: The objective of this study was to evaluate the usefulness of pre-operative visceral (VAT) and subcutaneous adipose tissue (SAT) evaluation in the prediction of acute kidney injury (AKI) and decrease of eGFR at 12 months after radical nephrectomy (RN). METHODS: We relied on 112 patients who underwent RN between January 2010 and March 2017 at a single institution. Images from the pre-operatory CT scan were analyzed and both SAT and VAT assessments were carried out on a cross-sectional plane. eGFR was measured before surgery, at 7 days, and 12 months after surgery. ROC analysis was used to compare the diagnostic value of BMI, VAT ratio, and abdominal circumference in predicting AKI. Logistic regression models were fitted to predict the new onset of AKI, and the progression from chronic kidney disease (CKD) stage 1-3a to CKD stage 3b or from 3b to 4 at 12 months follow-up. Two logistic regression models were also performed to assess the predictors for AKI and CKD stage progression. The predictive accuracy was quantified using the receiver operating characteristic-derived area under the curve. RESULTS: Sixty-six patients (58.9%) had AKI after RN. Thirty-five (31.3%) patients were upgraded to CKD IIIb or from CKD stage IIIb to CKD IV. In the ROC analysis, VAT% performed better than the BMI and abdominal circumference (AUC=0.66 vs. 0.49 and 0.54, respectively). At multivariable analyses, VAT reached an independent predictor status for AKI (OR: 1.03) and for CKD stage at 12-month follow-up (OR: 1.05). Inclusion of VAT% into the multivariable models was associated with the highest accuracy both for AKI (AUC=0.700 vs. 0.570) and CKD stage progression (AUC=0.848 vs. 0.800). CONCLUSIONS: In patients undergoing RN, preoperative visceral adipose tissue ratio significantly predicts AKI incidence and is significantly predictive of 12-month CKD stage worsening.

Characterization of high- and low-risk hepatocellular adenomas by magnetic resonance imaging in an animal model of glycogen storage disease type 1A.

Hepatocellular adenomas (HCAs) are benign tumors, of which the most serious complications are hemorrhage and malignant transformation to hepatocellular carcinoma (HCC). Among the various subtypes of HCA, the ß-catenin-activated subtype (bHCA) is associated with greatest risk of malignant transformation. Magnetic resonance imaging (MRI) is an important tool to differentiate benign and malignant hepatic lesions, and preclinical experimental approaches may help to develop a method to identify MRI features associated with bHCA. HCAs are associated with various pathologies, including glycogen storage disease 1a (GSD1a). Here, we utilized a mouse model for GSD1a that develops HCA and HCC, and analyzed the mice in order to distinguish low-risk from high-risk tumors. Animals were scanned by MRI using a hepato-specific contrast agent. The mice were sacrificed after MRI and their lesions were classified using immunohistochemistry. We observed that 45% of the animals developed focal lesions, and MRI identified four different patterns after contrast administration: isointense, hyperintense and hypointense lesions, and lesions with peripheral contrast enhancement. After contrast administration, only bHCA and HCC were hypointense in T1-weighted imaging and mildly hyperintense in T2-weighted imaging. Thus, high-risk adenomas display MRI features clearly distinguishable from those exhibited by low-risk adenomas, indicating that MRI is a reliable method for early diagnosis and classification of HCA, necessary for correct patient management.

Iodixanol versus iopromide in cancer patients: Evidence from a randomized clinical trial.

To assess the safety profile of iso-osmolar contrast medium (CM) versus low osmolar CM in cancer patients with an estimated glomerular filtration rate (eGFR) >60 ml/min. In this multicenter, blind trial of patients seeking a chest-abdomen-pelvis contrast enhanced computed tomography (CT) with iodated CM, participants were centrally randomized to iodixanol or iopromide. Contrast induced nephropathy (CIN) at 24 and/or 72 hr were our primary outcomes. We further considered irreversible CIN, average eGFR percentage variation (%Δ), and adverse events (AEs). Overall, 607 patients were enrolled. Among them, 497 eligible patients were randomized to iodixanol (N: 247) or iopromide (N: 250). No differences emerged by descriptive characteristics. Seven and 3 CIN at 24 hr (p = 0.34) and 8 and 2 CIN at 72 hr (p = 0.11) occurred in the iopromide and iodixanol group, respectively. Within the subgroup of individual patients who developed CIN (N: 17), the event rate was higher in the iopromide arm (p = 0.045). No cases of permanent CIN or significant differences in terms of AEs or GFR %Δ were observed. Our results suggest a more favorable safety profile of iodixanol versus iopromide. Adequately sized trials with similar design are warranted to confirm our findings and clarify the underlying biological mechanisms.

Predictability, efficacy and safety of radiosensitization of glioblastoma-initiating cells by the ATM inhibitor KU-60019.

We have previously shown that pharmacological inhibition of ataxia telangiectasia mutated (ATM) protein sensitizes glioblastoma-initiating cells (GICs) to ionizing radiation (IR). Herein, we report the experimental conditions to overcome GIC radioresistance in vitro using the specific ATM inhibitor KU-60019, two major determinants of the tumor response to this drug and the absence of toxicity of this treatment in vitro and in vivo. Repeated treatments with KU-60019 followed by IR substantially delayed GIC proliferation in vitro and even eradicated radioresistant cells, whereas GIC treated with vehicle plus radiation recovered early and expanded. The tumor response to the drug occurred under a cutoff level of expression of TP53 and over a cutoff level of expression of phosphatidylinositol 3-kinase (PI3K). No increased clastogenicity or point mutagenicity was induced by KU-60019 plus radiation when compared to vehicle plus radiation. No significant histological changes to the brain or other organs were observed after prolonged infusion into the brain of KU-60019 at millimolar concentrations. Taken together, these findings suggest that GIC-driven tumors with low expression of TP53 and high expression of PI3K might be effectively and safely radiosensitized by KU-60019.

Use of the semiconductor nanotechnologies "quantum dots" for in vivo cancer imaging.

Non-invasive in vivo imaging offers great potential to facilitate translational drug development research at the animal testing phase. The emerging luminescent nanoparticles or quantum dots provide a new type of biological agents that can improve these applications. The advantages of luminescent nanoparticles for biological applications include their high quantum yield, color availability, good photo-stability, large surface-to-volume ratio, surface functionality, and small size. These properties could improve the sensitivity of biological detection and imaging by at least 10- to 100-fold and make them an exceptional tool for live-cell imaging. In this review patents on applications of semiconductor quantum dots for in vivo imaging are discussed.

Enhanced antitumor efficacy of clinical-grade vasculature-targeted liposomal doxorubicin.

PURPOSE: In vivo evaluation of good manufacturing practice-grade targeted liposomal doxorubicin (TVT-DOX), bound to a CD13 isoform expressed on the vasculature of solid tumors, in human tumor xenografts of neuroblastoma, ovarian cancer, and lung cancer. EXPERIMENTAL DESIGN: Mice were implanted with lung, ovarian, or neuroblastoma tumor cells via the pulmonary, peritoneal, or orthotopic (adrenal gland) routes, respectively, and treated, at different days post inoculation, with multiple doses of doxorubicin, administered either free or encapsulated in untargeted liposomes (Caelyx) or in TVT-DOX. The effect of TVT-DOX treatment on tumor cell proliferation, viability, apoptosis, and angiogenesis was studied by immunohistochemical analyses of neoplastic tissues and using the chick embryo chorioallantoic membrane assay. RESULTS: Compared with the three control groups (no doxorubicin, free doxorubicin, or Caelyx), statistically significant improvements in survival was seen in all three animal models following treatment with 5 mg/kg (maximum tolerated dose) of TVT-DOX, with long-term survivors occurring in the neuroblastoma group; increased survival was also seen at a dose of 1.7 mg/kg in mice bearing neuroblastoma or ovarian cancer. Minimal residual disease after surgical removal of neuroblastoma primary mass, and the enhanced response to TVT-DOX, was visualized and quantified by bioluminescence imaging and with magnetic resonance imaging. When treated with TVT-DOX, compared with Caelyx, all three tumor models, as assayed by immunohistochemistry and chorioallantoic membrane, showed statistically significant reductions in cell proliferation, blood vessel density, and microvessel area, showing increased cell apoptosis. CONCLUSION: TVT-DOX should be evaluated as a novel angiostatic strategy for adjuvant therapy of solid tumors.