ACR Appropriateness Criteria® Central Venous Access Device and Site Selection.

The use of central venous access devices is ubiquitous in both inpatient and outpatient settings, whether for critical care, oncology, hemodialysis, parenteral nutrition, or diagnostic purposes. Radiology has a well-established role in the placement of these devices due to demonstrated benefits of radiologic placement in multiple clinical settings. A wide variety of devices are available for central venous access and optimal device selection is a common clinical challenge. Central venous access devices may be nontunneled, tunneled, or implantable. They may be centrally or peripherally inserted by way of veins in the neck, extremities, or elsewhere. Each device and access site presents specific risks that should be considered in each clinical scenario to minimize the risk of harm. The risk of infection and mechanical injury should be minimized in all patients. In hemodialysis patients, preservation of future access is an additional important consideration. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

A Pilot Study of Hepatic Irradiation with Yttrium-90 Microspheres Followed by Immunotherapy with Ipilimumab and Nivolumab for Metastatic Uveal Melanoma.

Background: Liver metastases from uveal melanoma carry a very poor prognosis. Hepatic artery infusions with Yttrium-90 (90Y) resin microspheres have some activity in this disease, and radiation and immunotherapy may be synergistic. The primary objective of this study was to determine the safety and tolerability of sequential 90Y resin microspheres and immunotherapy with ipilimumab and nivolumab in metastatic uveal melanoma. Materials and Methods: Twenty-six patients with uveal melanoma with hepatic metastases were entered into a pilot study. Treatment consisted of two infusions of 90Y resin microspheres, one to each lobe of the liver, followed in 2-4 weeks by immunotherapy with ipilimumab and nivolumab every 3 weeks for four doses, then maintenance immunotherapy with nivolumab alone. Results: Initial dosing of both 90Y and immunotherapy resulted in excessive toxicity. With decreasing the dosage of 90Y to limit the normal liver dose to 35Gy and lowering the ipilimumab dose to 1 mg/kg, the toxicity was tolerable, with no apparent change in efficacy. There was one complete and four confirmed partial responses, for an objective response rate of 20% and a disease control rate of 68%. The median progression-free survival was 5.5 months (95% confidence interval [CI]: 1.3-9.7 months), with a median overall survival of 15 months (95% CI: 9.7-20.1 months). Conclusions: With dose reductions, sequential therapy with 90Y and immunotherapy with ipilimumab and nivolumab is safe and tolerable, and has activity in metastatic uveal melanoma. These results justify a controlled trial to demonstrate whether 90Y resin microspheres add to the utility of combination immunotherapy in this disease. Clinical Trial Registration number: NCT02913417.

Imaging Predictors of Elevated Lung Shunt Fraction in Patients Being Considered for Yttrium-90 Radioembolization.

PURPOSE: To identify imaging findings associated with elevated lung shunt fraction (LSF) in patients being considered for yttrium-90 ((90)Y) radioembolization. MATERIALS AND METHODS: During the period 2009-2014, 152 consecutive patients underwent planning hepatic arteriography with technetium-99m ((99m)Tc) macroaggregated albumin (MAA) injection. Computed tomography (CT) or magnetic resonance imaging performed before the procedure for each patient was assessed for hepatic vein (HV) tumor thrombus or occlusion from external compression by tumor. When imaging was a multiphase CT scan (117 patients), the arterial phase was evaluated for evidence of early HV opacification (relative to unaffected HVs), indicating hepatic venous shunting. These factors were correlated with LSF determined by (99m)Tc-MAA imaging. RESULTS: Median LSF was 6.7% (range, < 0.1%-71%), significantly higher for HCC (8.0% vs 6.3% for other tumors, P = .048). Larger tumor size was associated with higher LSF in univariate analysis (P = .001). There was high interobserver agreement for determining hepatic venous shunting (97%, κ = 0.847), which was associated with higher LSF (P < .001; 78% sensitivity, 93% specificity). Of 5 cases of HV tumor thrombus, all had high (> 20%) LSF (P < .001). HV occlusion was also associated with higher LSF (P = .039). Multivariate analysis confirmed that early HV opacification and either HV tumor thrombus or occlusion were associated with higher LSF. CONCLUSIONS: Early HV opacification and HV tumor thrombus or occlusion on cross-sectional imaging performed before radioembolization are associated with elevated LSF, which may contraindicate or limit the dose delivered in (90)Y radioembolization. This information could be helpful during patient counseling for anticipating the most appropriate mode of liver-directed therapy.

Clinical outcomes of percutaneous drainage of breast fluid collections after mastectomy with expander-based breast reconstruction.

PURPOSE: To determine clinical outcomes of patients who underwent imaging-guided percutaneous drainage of breast fluid collections after mastectomy and breast reconstruction. MATERIALS AND METHODS: A retrospective review was performed including all consecutive patients who underwent percutaneous drainage of fluid collections after mastectomy with tissue expander-based reconstruction between January 2007 and September 2012. During this period, 879 mastectomies (563 patients) with expander-based breast reconstruction were performed. Fluid collections developed in 28 patients (5%), which led to 30 imaging-guided percutaneous drainage procedures. The median follow-up time was 533 days. Patient characteristics, surgical technique, microbiology analysis, and clinical outcomes were reviewed. RESULTS: The mean age of patients was 51.5 years (range, 30.9-69.4 y), and the median time between breast reconstruction and drainage was 35 days (range, 4-235 d). Erythema and swelling were the most common presenting symptoms. The median volume of fluid evacuated at the time of drain placement was 70 mL. Drains were left in place for a median 14 days (range, 6-34 d). Microorganisms were detected in the fluid in 12 of 30 drainage procedures, with Staphylococcus aureus being the most common microorganism. No further intervention was needed in 21 of 30 drainage procedures (70%). However, surgical intervention (removal of expanders) was needed after 6 (20%) drainage procedures, and additional percutaneous drainage procedures were performed after 3 (10%) drainage procedures. CONCLUSIONS: Percutaneous drainage is an effective means of treating postoperative fluid collections after expander-based breast reconstruction and can obviate the need for repeat surgery in most cases.

Efficacy of TACE in TIPS patients: comparison of treatment response to chemoembolization for hepatocellular carcinoma in patients with and without a transjugular intrahepatic portosystemic shunt.

PURPOSE: To compare treatment response after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) in patients with and without a transjugular intrahepatic portosystemic shunt (TIPS). MATERIALS AND METHODS: A retrospective review of patients who underwent conventional TACE for HCC between January 2005 and December 2009 identified 10 patients with patent TIPS. From the same time period, 23 patients without TIPS were selected to control for comparable Model for End-Stage Liver Disease and Child-Pugh-Turcotte scores. The two groups showed similar distribution of Barcelona Clinic Liver Cancer and United Network of Organ Sharing stages. Target HCC lesions were evaluated according to the modified response evaluation criteria in solid tumors (mRECIST) guidelines. Transplantation rate, time to tumor progression, and overall survival (OS) were documented. RESULTS: After TACE, the rate of complete response was significantly greater in non-TIPS patients compared with TIPS patients (74 vs. 30 %, p = 0.03). Objective response rate (complete and partial response) trended greater in the non-TIPS group (83 vs. 50 %, p = 0.09). The liver transplantation rate was 80 and 74 % in the TIPS and non-TIPS groups, respectively (p = 1.0). Time to tumor progression was similar (p = 0.47) between the two groups. OS favored the non-TIPS group (p = 0.01) when censored for liver transplantation. CONCLUSION: TACE is less effective in achieving complete or partial response using mRECIST criteria in TIPS patients compared with those without a TIPS. Nevertheless, similar clinical outcomes may be achieved, particularly in TIPS patients who are liver-transplantation candidates.

High-risk retrieval of adherent and chronically implanted IVC filters: techniques for removal and management of thrombotic complications.

PURPOSE: To evaluate the safety and efficacy of aggressive techniques for retrieving adherent and chronically implanted inferior vena cava (IVC) filters. MATERIALS AND METHODS: A single-center retrospective review was performed on all patients who underwent attempted filter retrieval from October 2007 through October 2008. Patients were included in the study if they had an adherent filter, refractory to standard retrieval techniques, and underwent high-risk retrieval after procedural risks were deemed lower than risks of long-term filter implantation. RESULTS: Fourteen patients were diagnosed with an adherent filter, 13 (93%) of whom were candidates for high-risk retrieval. These patients included seven men and six women (mean age, 40 years; age range, 18-71 years). Nine of the 13 patients (69%) were referred from an outside hospital. Filter retrieval was performed for the following indications: to avoid the risk of long-term thrombotic complications in a young patient (n= 6), to treat symptomatic filter-related IVC stenosis (n= 5), to treat symptomatic filter penetration (n= 1), and to avoid the need for lifelong anticoagulation (n= 1). There were eight Günther-Tulip filters (mean dwell time, 356 days; range 53-1,181 days), two Optease filters (mean dwell time, 62 days; range, 52-72 days), one G2 filter (dwell time, 420 days), and two Recovery filters (mean dwell time, 1,630 days; range, 1,429-1,830 days). Three IVC occlusions necessitated recanalization to facilitate retrieval. High-risk retrieval with use of various techniques with aggressive force was successful in all 13 patients (100%). Partial caval thrombosis occurred in the first four patients (31%) but did not occur after procedural modifications were implemented. There were no complications at clinical follow-up (mean, 221 days; range, 84-452 days). CONCLUSIONS: Alternative techniques can be used to retrieve adherent IVC filters implanted for up to 3-5 years. Although caval thrombosis was an observed complication, protocol modifications appeared to reduce this risk.

Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation.

Previous studies have suggested that the HIF transcription factors can both activate and inhibit gene expression. Here we show that HIF1 regulates the expression of mir-210 in a variety of tumor types through a hypoxia-responsive element. Expression analysis in primary head and neck tumor samples indicates that mir-210 may serve as an in vivo marker for tumor hypoxia. By Argonaute protein immunoprecipitation, we identified 50 potential mir-210 targets and validated randomly selected ones. The majority of these 50 genes are not classical hypoxia-inducible genes, suggesting mir-210 represses genes expressed under normoxia that are no longer necessary to adapt and survive in a hypoxic environment. When human head and neck or pancreatic tumor cells ectopically expressing mir-210 were implanted into immunodeficient mice, mir-210 repressed initiation of tumor growth. Taken together, these data implicate an important role for mir-210 in regulating the hypoxic response of tumor cells and tumor growth.

Decreased aortic growth and middle aortic syndrome in patients with neuroblastoma after radiation therapy.

BACKGROUND: Long-term CT follow-up studies are required in pediatric patients who have received intraoperative radiation therapy (IORT) and external beam radiation therapy (EBRT) to assess vascular toxicities and to determine the exact complication rate. OBJECTIVE: To analyze with CT the effects of radiation therapy (RT) on the growth of the aorta in neuroblastoma patients. MATERIALS AND METHODS: Abdominal CT scans of 31 patients with intraabdominal neuroblastoma (stage II-IV), treated with RT (20 IORT+/-EBRT, 11 EBRT alone), were analyzed retrospectively. The diameter of the abdominal aorta was measured before and after RT. These data were compared to normal and predicted normal aortic diameters of children, according to the model of Fitzgerald, Donaldson and Poznanski (aortic diameter in centimeters = 0.844 + 0.0599 x age in years), and to the diameters of a control group of children who had not undergone RT. Statistical analyses for the primary aims were performed using the chi-squared test, t-test, Mann-Whitney test, nonparametric Wilcoxon matched-pairs test and analysis of variance for repeated measures. Clinical files and imaging studies were evaluated for signs of late vascular complications of neuroblastoma patients who had received RT. RESULTS: The mean diameter before and after RT and the growth of the aorta were significantly lower than expected in patients with neuroblastoma (P<0.05 for each) and when compared to the growth in a control group with normal and nonirradiated aortas. Among the patients who had received RT, there was no difference due to the type of RT. Seven patients from the IORT+/-EBRT group developed vascular complications, which included hypertension (five), middle aortic syndrome (two), death due to mesenteric ischemia (one) and critical aortic stenosis, which required aortic bypass surgery (two). CONCLUSION: Patients with neuroblastoma who had received RT showed impaired growth of the abdominal aorta. Significant long-term vascular complications occurred in seven patients who received IORT+/-EBRT. Thus, CT evaluation of patients with neuroblastoma who receive RT should include not only reports of changes in tumor extension, but also documentation of perfusion, and the size and growth of the aorta and its branches over time.

Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model.

Preclinical and clinical evidence shows that antiangiogenic agents can decrease tumor vessel permeability and interstitial fluid pressure (IFP) in a process of vessel "normalization." The resulting normalized vasculature has more efficient perfusion, but little is known about how tumor IFP and interstitial fluid velocity (IFV) are affected by changes in transport properties of the vessels and interstitium that are associated with antiangiogenic therapy. By using a mathematical model to simulate IFP and IFV profiles in tumors, we show here that antiangiogenic therapy can decrease IFP by decreasing the tumor size, vascular hydraulic permeability, and/or the surface area per unit tissue volume of tumor vessels. Within a certain window of antiangiogenic effects, interstitial convection within the tumor can increase dramatically, whereas fluid convection out of the tumor margin decreases. This would result in increased drug convection within the tumor and decreased convection of drugs, growth factors, or metastatic cancer cells from the tumor margin into the peritumor fluid or tissue. Decreased convection of growth factors, such as vascular endothelial growth factor-C (VEGF-C), would limit peritumor hyperplasia, and decreased VEGF-A would limit angiogenesis in sentinel lymph nodes. Both of these effects would reduce the probability of lymphatic metastasis. Finally, decreased fluid convection into the peritumor tissue would decrease peritumor edema associated with brain tumors and ascites accumulation in the peritoneal or pleural cavity, a major complication with a number of malignancies.

Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models.

The role of placenta growth factor (PlGF) in pathologic angiogenesis is controversial. The effects of PlGF on growth, angiogenesis, and metastasis from orthotopic tumors are not known. To this end, we stably transfected three human cancer cell lines (A549 lung, HCT116 colon, and U87-MG glioblastoma) with human plgf-2 full-length cDNA. Overexpression of PlGF did not affect tumor cell proliferation or migration in vitro. The growth of PlGF-overexpressing tumors grown orthotopically or ectopically was impaired in all three tumor models. This decrease in tumor growth correlated with a decrease in tumor angiogenesis. The PlGF-overexpressing tumors had decreased vessel density and increased vessel diameter, but vessel permeability was not different from the parental tumors. Tumors overexpressing PlGF exhibited higher levels of PlGF homodimers and PlGF/vascular endothelial growth factor (VEGF) heterodimers but decreased levels of VEGF homodimers. Our study shows that PlGF overexpression decreases VEGF homodimer formation and inhibits tumor progression.

A 2-D/3-D model-based method to quantify the complexity of microvasculature imaged by in vivo multiphoton microscopy.

This paper presents model-based information-theoretic methods to quantify the complexity of tumor microvasculature, taking into account shape, textural, and structural irregularities. The proposed techniques are completely automated, and are applicable to optical slices (3-D) or projection images (2-D). Improvements upon the prior literature include: (i) measuring local (vessel segment) as well as global (entire image) vascular complexity without requiring explicit segmentation or tracing; (ii) focusing on the vessel boundaries in the complexity estimate; and (iii) added robustness to image artifacts common to tumor microvasculature images. Vessels are modeled using a family of super-Gaussian functions that are based on the superquadric modeling primitive common in computer vision. The superquadric generalizes a simple ellipsoid by including shape parameters that allow it to approximate a cylinder with elliptical cross-sections (generalized cylinder). The super-Gaussian is obtained by composing a superquadric with an exponential function giving a form that is similar to a standard Gaussian function but with the ability to produce level sets that approximate generalized cylinders. Importantly, the super-Gaussian is continuous and differentiable so it can be fit to image data using robust non-linear regression. This fitting enables quantification of the intrinsic complexity of vessel data vis-a-vis the super-Gaussian model within a minimum message length (MML) framework. The resulting measures are expressed in units of information (bits). Synthetic and real-data examples are provided to illustrate the proposed measures.

A genetic Xenopus laevis tadpole model to study lymphangiogenesis.

Lymph vessels control fluid homeostasis, immunity and metastasis. Unraveling the molecular basis of lymphangiogenesis has been hampered by the lack of a small animal model that can be genetically manipulated. Here, we show that Xenopus tadpoles develop lymph vessels from lymphangioblasts or, through transdifferentiation, from venous endothelial cells. Lymphangiography showed that these lymph vessels drain lymph, through the lymph heart, to the venous circulation. Morpholino-mediated knockdown of the lymphangiogenic factor Prox1 caused lymph vessel defects and lymphedema by impairing lymphatic commitment. Knockdown of vascular endothelial growth factor C (VEGF-C) also induced lymph vessel defects and lymphedema, but primarily by affecting migration of lymphatic endothelial cells. Knockdown of VEGF-C also resulted in aberrant blood vessel formation in tadpoles. This tadpole model offers opportunities for the discovery of new regulators of lymphangiogenesis.

Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases.

The recent landmark Phase III clinical trial with a VEGF-specific antibody suggests that antiangiogenic therapy must be combined with cytotoxic therapy for the treatment of solid tumors. However, there are no guidelines for optimal scheduling of these therapies. Here we show that VEGFR2 blockade creates a "normalization window"--a period during which combined radiation therapy gives the best outcome. This window is characterized by an increase in tumor oxygenation, which is known to enhance radiation response. During the normalization window, but not before or after it, VEGFR2 blockade increases pericyte coverage of brain tumor vessels via upregulation of Ang1 and degrades their pathologically thick basement membrane via MMP activation.

Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors.

Elevated interstitial fluid pressure, a hallmark of solid tumors, can compromise the delivery of therapeutics to tumors. Here we show that blocking vascular endothelial growth factor (VEGF) signaling by DC101 (a VEGF-receptor-2 antibody) decreases interstitial fluid pressure, not by restoring lymphatic function, but by producing a morphologically and functionally "normalized" vascular network. We demonstrate that the normalization process prunes immature vessels and improves the integrity and function of the remaining vasculature by enhancing the perivascular cell and basement membrane coverage. We also show that DC101 induces a hydrostatic pressure gradient across the vascular wall, which leads to a deeper penetration of molecules into tumors. Thus, vascular normalization may contribute to the improved survival rates in tumor-bearing animals and in colorectal carcinoma patients treated with an anti-VEGF antibody in combination with cytotoxic therapies.

Two-photon fluorescence correlation microscopy reveals the two-phase nature of transport in tumors.

Transport parameters determine the access of drugs to tumors. However, technical difficulties preclude the measurement of these parameters deep inside living tissues. To this end, we adapted and further optimized two-photon fluorescence correlation microscopy (TPFCM) for in vivo measurement of transport parameters in tumors. TPFCM extends the detectable range of diffusion coefficients in tumors by one order of magnitude, and reveals both a fast and a slow component of diffusion. The ratio of these two components depends on molecular size and can be altered in vivo with hyaluronidase and collagenase. These studies indicate that TPFCM is a promising tool to dissect the barriers to drug delivery in tumors.

Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer.

The effects of vascular endothelial growth factor (VEGF) blockade on the vascular biology of human tumors are not known. Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure and the number of viable, circulating endothelial and progenitor cells, and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients. These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors.