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Supplementary Figure 4 from Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Supplementary Figure 2 from Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Supplementary Figure Legends from Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2×/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI quantified tumor volumes. Erk1/2, 4E-BP1, and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85%, and 55%, relative to controls, in everolimus, the combination, and sequential groups, respectively (P < 0.01). Survival was longest in the combination group (P < 0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (P < 0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib, and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib. Mol Cancer Ther; 10(6); 1007–17. ©2011 AACR.

Supplementary Figure 3 from Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Supplementary Figure 1 from Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

To evaluate the efficacy of superselective transcatheter arterial embolization (TAE) in the treatment of acute peripancreatic bleeding complications. During a 9-year period, 44 patients with acute bleeding of the peripancreatic arteries underwent TAE in our institution. Thirty-eight patients were treated using microcatheters and 6 patients with a diagnostic catheter. Embolic agents included coils (n = 38), polyvinyl alcohol (PVA) particles (n = 2), isobutyl cyanoacrylate (n = 2), coils plus PVA particles (n = 1), and coils plus isobutyl cyanoacrylate (n = 1). Outcome measures included technical success, clinical success, and the rate of complications. Identified bleeding sources included gastroduodenal artery (n = 14), splenic artery (n = 9), pancreaticoduodenal artery (n = 6), common hepatic artery (n = 5), superior mesenteric artery branches (n = 4), proper hepatic artery (n = 3), and dorsal/transverse pancreatic artery (n = 3). Technical success with effective control of active bleeding was achieved in 41/44 patients (93 %). Clinical success attributed to TAE alone was documented in 40/44 patients (91 %). The rate of major complications was 2 % including death in one patient. Superselective TAE allows effective, minimally invasive control of acute peripancreatic bleeding complications with a low rate of therapeutically relevant complications.

Background and Aim. It is unknown whether sorafenib can be combined with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma. This study assesses the safety and tolerability of a continuous regimen of sorafenib combined with TACE. Methods. This was an open-label phase I study testing a continuous administration of sorafenib (dose escalation from 200 mg twice daily [bid] to 400 mg bid) starting 7 days prior to TACE with doxorubicin (50 mg). Results. Twenty-one patients were screened and 14 received sorafenib combined with TACE. Because there were no dose-limiting toxicities in the first three patients who received sorafenib at a dose of 200 mg bid, subsequent patients received 400 mg bid. Twenty-seven procedures were performed (median, two per patient) and two local therapy–related severe adverse events occurred. The median duration of sorafenib therapy was 246 days (range, 14–547 days). Sorafenib-related adverse events of grade ≥3 were hand–foot skin reaction (n = 3), weight loss (n = 2), diarrhea (n = 1), abdominal pain (n = 1), and thrombocytopenia (n = 3). After treatment with sorafenib and TACE, there was a significant decrease in the concentration of plasma vascular endothelial growth factor (VEGF) from 93 ng/l to 67 ng/l. Conclusions. Continuous administration of sorafenib at a dose of 400 mg bid combined with TACE was tolerable. The adverse event profile of this regimen was comparable with that of sorafenib monotherapy with the exception of thrombocytopenia, which may be more frequent. There were no increases in the circulating VEGF levels after TACE with this combined regimen. (Swiss Association for the Study of the Liver study number 25; ClinicalTrials.gov trial identifier, NCT00478374).

To prospectively compare the diagnostic accuracy of steady-state, high-spatial-resolution magnetic resonance (MR) angiography of the lower leg, performed with a blood pool contrast agent, with selective digital subtraction angiography (DSA) as the reference standard in patients with symptomatic peripheral arterial disease.Local ethics committee approval and written informed consent were obtained. In a nonrandomized trial, selective DSA and MR angiography were performed at 3.0 T with a blood pool contrast agent on 22 calves in 20 patients (mean age, 69.4 years +/- 11.3 [standard deviation]), 16 men (mean age, 67.8 years +/- 12.4) and four women (mean age, 75.6 years +/- 3.6 years), to evaluate 352 arterial segments. DSA and MR angiography were performed within 24 hours of each other and directly compared by three experienced, blinded radiologists by using high-spatial-resolution steady-state MR angiograms. Consensus reading for both DSA and MR angiography served as the reference standard.MR angiography was successful and occurred without serious adverse events in all patients. Seven significantly stenosed and 40 occluded segments were rated equally in both modalities. In three cases, the tibial arteries were shown to be occluded or significantly stenosed at DSA but appeared normal or significantly stenosed at MR angiography. The respective average segment sensitivity, specificity, and accuracy were 98.3% (59 of 60), 98% (113.7 of 116), and 98.1% (172.7 of 176) for DSA and 100% (60 of 60), 100% (116 of 116), and 100% (176 of 176) for MR angiography. Steady-state MR angiography was especially useful for the distal peroneal artery and the proximal anterior tibial artery.MR angiography performed with blood pool agents has an accuracy comparable with that of selective DSA in the lower leg but with less risk involved. Steady-state imaging performed with blood pool agents facilitates evaluation of MR angiography of infrapopliteal arteries.

Objective: Clinical evaluation of computed tomography (CT) fluoroscopy and comparison with conventional CT guidance for monitoring of percutaneous pulmonary biopsy procedures. Methods: Twenty CT-guided pulmonary biopsy procedures were conducted. The interventions have prospectively been performed either with CT fluoroscopy or with conventional CT guidance. About 120 kV and 50 mA with a frame-rate of eight images per second were used for CT fluoroscopy. Number of pleural needle passages, procedure times, radiation doses and histologic results were analyzed separately for both methods. Results: Compared with conventional CT guidance, CT fluoroscopy was associated with less pleural needle passages (1.8±0.6 vs. 1.1±0.3; P =0.003, t -test) and procedure times were shorter than for conventional CT guidance (12.7±2.2 min vs. 26.7±16.4 min; P =0.02). Analysis of estimated patient related radiation exposure and histologic outcome showed no significant difference between conventional and fluoroscopic CT-guided procedures ( P >0.05). Conclusion: CT fluoroscopy facilitates guidance of percutaneous pulmonary biopsy procedures. Compared with conventional CT assistance, procedure times are decreased and less pleural needle passages are required. While patient-related radiation exposure is similar, operator-related radiation exposure remains a disadvantage associated with CT fluoroscopy.

Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2×/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI quantified tumor volumes. Erk1/2, 4E-BP1, and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85%, and 55%, relative to controls, in everolimus, the combination, and sequential groups, respectively (P < 0.01). Survival was longest in the combination group (P < 0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (P < 0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib, and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib. Mol Cancer Ther; 10(6); 1007–17. ©2011 AACR.

To evaluate diffusion-weighted magnetic resonance (MR) imaging of the human placenta in fetuses with and fetuses without intrauterine growth restriction (IUGR) who were suspected of having placental insufficiency.The study was approved by the local ethics committee, and written informed consent was obtained. The authors retrospectively evaluated 1.5-T fetal MR images from 102 singleton pregnancies (mean gestation ± standard deviation, 29 weeks ± 5; range, 21-41 weeks). Morphologic and diffusion-weighted MR imaging were performed. A region of interest analysis of the apparent diffusion coefficient (ADC) of the placenta was independently performed by two observers who were blinded to clinical data and outcome. Placental insufficiency was diagnosed if flattening of the growth curve was detected at obstetric ultrasonography (US), if the birth weight was in the 10th percentile or less, or if fetal weight estimated with US was below the 10th percentile. Abnormal findings at Doppler US of the umbilical artery and histopathologic examination of specimens from the placenta were recorded. The ADCs in fetuses with placental insufficiency were compared with those in fetuses of the same gestational age without placental insufficiency and tested for normal distribution. The t tests and Pearson correlation coefficients were used to compare these results at 5% levels of significance.Thirty-three of the 102 pregnancies were ultimately categorized as having an insufficient placenta. MR imaging depicted morphologic changes (eg, infarction or bleeding) in 27 fetuses. Placental dysfunction was suspected in 33 fetuses at diffusion-weighted imaging (mean ADC, 146.4 sec/mm(2) ± 10.63 for fetuses with placental insufficiency vs 177.1 sec/mm(2) ± 18.90 for fetuses without placental insufficiency; P.01, with one false-positive case). The use of diffusion-weighted imaging in addition to US increased sensitivity for the detection of placental insufficiency from 73% to 100%, increased accuracy from 91% to 99%, and preserved specificity at 99%.Placental dysfunction associated with growth restriction is associated with restricted diffusion and reduced ADC. A decreased ADC used as an early marker of placental damage might be indicative of pregnancy complications such as IUGR.http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10092283/-/DC1.

Objectives:To characterise and quantify short-term changes in local inflammation using magnetic resonance imaging (MRI), and to correlate the findings with clinical disease activity in response to infliximab in patients with spondyloarthritis.Methods:28 consecutive patients with established spondyloarthritis under successful long-term treatment with infliximab underwent MRI immediately before and one week after re-administration of the TNF blocker. C-reactive protein and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were assessed at both time points. The MRI protocol included coronal and sagittal turbo-short T1 inversion recovery (STIR) images as well as contrast-enhanced sagittal T1-weighted, fat-suppressed images. Images were assessed in independent sessions using the ASspiMRI-a score, the signal-difference-to-noise ratios (SDNR) and volumetry to assess oedematous and inflamed tissues.Results:BASDAI values were expectedly low at study entry (3.3, SD 2.3). One week after administration of infliximab, 46% of patients reached a BASDAI 20, 39% a BASDAI 50. Kappa values for qualitative assessments and all measurements were excellent (range between 0.83 and 1.0) The ASspiMRI-a dropped most in the thoracic (3.3 points), less in the lumbar (1.21 points) and least in the cervical spine (0.38 points). The decrease of the ASspiMRI-a, the SDNR and the inflamed volumes in response to infliximab re-treatment was significant (pConclusions:MRI proves to be a valid method to assess and quantify short-term effects of therapy in spondyloarthritis. Comparison between MRI and BASDAI changes show that the BASDAI may underestimate local inflammation. It suggests an explanation for the structural disease progression despite clinical remission.

MR colonography is a powerful noninvasive method to image colorectal masses and inflammatory bowel disease. This article describes current techniques of MR colonography and compares its implementation at 1.5T and 3T.

RATIONALE AND OBJECTIVES. An ex vivo study and a clinical, prospective, patient study were undertaken to evaluate the feasibility of magnetic resonance (MR) colonography with a 1.0-T system. METHODS. An ex vivo colon model was scanned. A cleaned pig colon was prepared with six simulated sessile polyps (diameters of 4–12 mm) and one simulated pedunculated polyp (diameter of 5 mm). Subsequently, five patients (aged 39–81 years; four women, one man) were examined with MR colonography, immediately followed by endoscopic colonoscopy. After preparation for colonoscopy, the colon was filled with a Gd-DTPA/water solution (1:100). A breath-hold 3D gradient-echo sequence was acquired in both the prone and supine positions and after intravenous Gd-DTPA administration. Images were analyzed interactively by using multiplanar projections, maximum-intensity projection, and a virtual endoscopic view. The MR results were compared with the findings of the fiberoptic endoscopy. RESULTS. All seven simulated lesions of the colon model could be detected by MR imaging. In one patient, an advanced colon cancer as well as an additional small polyp was depicted. In the other four patients, single polyps with a diameter of 1 to 2.5 cm and a large adenoma were visualized by MR colonography. Contrast enhancement of the polyps was noted only after subtraction. CONCLUSIONS. The 1.0-T system is feasible for MR colonography. Reduced requirements for hardware could contribute to establish the novel technique as a screening method for colorectal polyps.