Validation and Application for the Berlin Grading System of Moyamoya Disease in Adult Patients.

BACKGROUND: Traditional moyamoya disease (MMD) classification relies on morphological digital subtraction angiography (DSA) assessment, which do not reflect hemodynamic status, clinical symptoms, or surgical treatment outcome. OBJECTIVE: To (1) validate the new Berlin MMD preoperative symptomatology grading system and (2) determine the clinical application of the grading system in predicting radiological and clinical outcomes after surgical revascularization. METHODS: Ninety-six MMD patients (192 hemispheres) with all 3 investigations (DSA, magnetic resonance imaging [MRI], Xenon-CT) performed preoperatively at our institution (2007-2013) were included. Two clinicians independently graded the imaging findings according to the proposed criteria. Patients' modified Rankin Score (mRS) scores (preoperative, postoperative, last follow-up), postoperative infarct (radiological, clinical) were collected and statistical correlations performed. RESULTS: One hundred fifty-seven direct superficial temporal artery-middle cerebral artery bypasses were performed on 96 patients (66 female, mean age 41 yr, mean follow-up 4.3 yr). DSA, MRI, and cerebrovascular reserve capacity were independent factors associated hemispheric symptomatology (when analyzed individually or in the combined grading system). Mild (grade I), moderate (grade II), severe (grade III) were graded in 45, 71, and 76 hemispheres respectively; of which, clinical symptoms were found in 33% of grade I, 92% of grade II, 100% of grade III hemispheres (P < .0001). Two percent of grade I, 11% of grade II, 20% of grade III hemispheres showed postoperative radiological diffusion weighted image-positive ischemic changes or hemorrhage on MRI (P = .018). Clinical postoperative stroke was observed in 1.4% of grade II, 6.6% of grade III hemispheres (P = .077). The grading system also correlated well to dichotomized mRS postoperative outcome. CONCLUSION: The Berlin MMD grading system is able to stratify preoperative hemispheric symptomatology. Furthermore, it correlated with postoperative new ischemic changes on MRI, and showed a strong trend in predicting clinical postoperative stroke.

Three-dimensional ultrasound molecular imaging of angiogenesis in colon cancer using a clinical matrix array ultrasound transducer.

OBJECTIVES: We sought to assess the feasibility and reproducibility of 3-dimensional ultrasound molecular imaging (USMI) of vascular endothelial growth factor receptor 2 (VEGFR2) expression in tumor angiogenesis using a clinical matrix array transducer and a clinical grade VEGFR2-targeted contrast agent in a murine model of human colon cancer. MATERIALS AND METHODS: Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice with human colon cancer xenografts (n = 33) were imaged with a clinical ultrasound system and transducer (Philips iU22; X6-1) after intravenous injection of either clinical grade VEGFR2-targeted microbubbles or nontargeted control microbubbles. Nineteen mice were scanned twice to assess imaging reproducibility. Fourteen mice were scanned both before and 24 hours after treatment with either bevacizumab (n = 7) or saline only (n = 7). Three-dimensional USMI data sets were retrospectively reconstructed into multiple consecutive 1-mm-thick USMI data sets to simulate 2-dimensional imaging. Vascular VEGFR2 expression was assessed ex vivo using immunofluorescence. RESULTS: Three-dimensional USMI was highly reproducible using both VEGFR2-targeted microbubbles and nontargeted control microbubbles (intraclass correlation coefficient, 0.83). The VEGFR2-targeted USMI signal significantly (P = 0.02) decreased by 57% after antiangiogenic treatment compared with the control group, which correlated well with ex vivo VEGFR2 expression on immunofluorescence (ρ = 0.93, P = 0.003). If only central 1-mm tumor planes were analyzed to assess antiangiogenic treatment response, the USMI signal change was significantly (P = 0.006) overestimated by an average of 27% (range, 2%-73%) compared with 3-dimensional USMI. CONCLUSIONS: Three-dimensional USMI is feasible and highly reproducible and allows accurate assessment and monitoring of VEGFR2 expression in tumor angiogenesis in a murine model of human colon cancer.

Ultrasound for molecular imaging and therapy in cancer.

Over the past decade, molecularly-targeted contrast enhanced ultrasound (ultrasound molecular imaging) has attracted significant attention in preclinical research of cancer diagnostic and therapy. Potential applications for ultrasound molecular imaging run the gamut from early detection and characterization of malignancies to monitoring treatment responses and guiding therapies. There may also be a role for ultrasound contrast agents for improved delivery of chemotherapeutic drugs and gene therapies across biological barriers. Currently, a first Phase 0 clinical trial in patients with prostate cancer assesses toxicity and feasibility of ultrasound molecular imaging using contrast agents targeted at the angiogenic marker vascular endothelial growth factor receptor type 2 (VEGFR2). This mini-review highlights recent advances and potential applications of ultrasound molecular imaging and ultrasound-guided therapy in cancer.

Performance of multidetector computed tomographic angiography in determining surgical resectability of pancreatic head adenocarcinoma.

OBJECTIVE: To evaluate the performance of multidetector computed tomographic angiography (MDCTA) in assessing the surgical resectability of pancreatic head adenocarcinoma. METHODS: With institutional review board approval, radiographic, surgical, and pathological records of 203 consecutive patients with adenocarcinoma of the pancreatic head were analyzed retrospectively. Patients were imaged with MDCT scanners using our institution's CTA pancreatic protocol. Images were compared with surgical outcomes to determine the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MDCTA in determining resectability. RESULTS: Data were analyzed twice, once with equivocal findings on MDCTA assumed as resectable and again with equivocal cases assumed as unresectable. All equivocal cases were ultimately unresectable; when this was assumed, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were determined to be 100%, 71%, 85%,100% and 89%. Twelve patients deemed resectable by preoperative MDCTA were found to be unresectable on surgical exploration owing to vascular involvement (n = 4), liver metastases (n = 4), and peritoneal involvement (n = 4). CONCLUSIONS: Multidetector CT angiography offers accurate and valuable preoperative assessment of surgical resectability of pancreatic ductal adenocarcinoma. Liver and peritoneal metastases and vascular invasion still remain important pitfalls in preoperative evaluation.

Genetic targeting of the endoderm with claudin-6CreER.

A full description of the ontogeny of the beta cell would guide efforts to generate beta cells from embryonic stem cells (ESCs). The first step requires an understanding of definitive endoderm: the genes and signals responsible for its specification, proliferation, and patterning. This report describes a global marker of definitive endoderm, Claudin-6 (Cldn6). We report its expression in early development with particular attention to definitive endoderm derivatives. To create a genetic system to drive gene expression throughout the definitive endoderm with both spatial and temporal control, we target the endogenous locus with an inducible Cre recombinase (Cre-ER(T2)) cassette. Cldn6 null mice are viable and fertile with no obvious phenotypic abnormalities. We also report a lineage analysis of the fate of Cldn6-expressing embryonic cells, which is relevant to the development of the pancreas, lung, and liver.