Immunotherapy and the Interventional Oncologist: Challenges and Opportunities-A Society of Interventional Oncology White Paper.

Interventional oncology is a subspecialty field of interventional radiology that addresses the diagnosis and treatment of cancer and cancer-related problems by using targeted minimally invasive procedures performed with image guidance. Immuno-oncology is an innovative area of cancer research and practice that seeks to help the patient's own immune system fight cancer. Both interventional oncology and immuno-oncology can potentially play a pivotal role in cancer management plans when used alongside medical, surgical, and radiation oncology in the care of cancer patients.

Distribution of reported StarClose SE vascular closure device complications in the manufacturer and user facility device experience database.

PURPOSE: To evaluate the type and frequency of complications associated with the StarClose SE vascular closure device reported to the U.S. Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database for comparison with complications reported in clinical trials. MATERIALS AND METHODS: Complications reported in the MAUDE database related to use of the StarClose SE vascular closure device were reviewed. Keyword searches by device and manufacturer were performed for a 16-month period from July 2009-October 2010. Reports were analyzed according to complication type, frequency, and resolution, if specified. These data were compared with data on StarClose SE device complications, which included three prospective randomized trials and five prospective nonrandomized trials. RESULTS: Keyword searches returned 1,107 total records and 1,118 categorizable StarClose SE device complications from the 16-month MAUDE database-reporting period. Complications in order of frequency (absolute number and relative frequency, respectively) included failure to achieve hemostasis (409, 36.6%), inability to complete the deployment sequence (268, 24.0%), entrapped deployment device (224, 20%), clip not deployed (151,13.5%), late bleeding or oozing from dermatotomy site (25, 2.2%), vessel occlusion (19, 1.7%), retroperitoneal hematoma (12, 1.1%), pseudoaneurysm formation (6, 0.5%) and death (4, 0.4%). The distribution of complications differed appreciably from the combined adverse events compiled from the published trials evaluating the StarClose SE device. There were no records describing inability to remove the deployment device in the published trials, whereas this represented the third most common complication reported to the MAUDE database. Bleeding or oozing from the dermatotomy site, the most frequent relative complication reported in the published literature (53.4%), represented 2.2% of the total complications reported to the MAUDE database. CONCLUSIONS: The type and frequency of complications reported in the MAUDE database on the StarClose SE vascular closure device differ from those published in clinical trials both in relative distribution and in type. Although these differences may reflect in part reporting biases, the distribution of complications reported to the MAUDE database may represent useful information in the use of this device.

Gender Disparity in Inpatient Mortality After Transjugular Intrahepatic Portosystemic Shunt Creation in Patients Admitted With Hepatorenal Syndrome: A Nationwide Study.

PURPOSE: The aim of this study was to evaluate inpatient mortality after transjugular intrahepatic portosystemic shunt (TIPS) creation compared with medical management (MM) in patients with hepatorenal syndrome (HRS). METHODS: Patients with cirrhosis admitted with HRS between 2005 and 2014 were identified using associated International Classification of Diseases, Ninth Revision, codes in the National Inpatient Sample (n = 153,112). Non-TIPS candidates and patients with parenchymal renal disease were excluded (n = 73,454). The remaining admissions were assigned to groups of TIPS (International Classification of Diseases, Ninth Revision, code 39.1; n = 971) or MM (n = 78,687). Inpatient mortality was analyzed by treatment type and patient gender using χ2 tests. Logistic regression was performed to control for baseline differences in patient demographics, comorbid disease, and pretreatment mortality risk. RESULTS: Baseline patient demographics were similar. Patients treated medically had higher baseline disease severity (median mortality risk score, 8.3 with MM versus 6.1 with TIPS; P < .01). Inpatient mortality was strongly modified by patient gender. TIPS creation conferred inpatient mortality benefit in men (28% of the MM group versus 10% of the TIPS group, P < .01) independent of all covariates (odds ratio, 0.4; 95% confidence interval, 0.17-0.78; P < .01). Women treated with TIPS creation experienced no mortality benefit (29% MM versus 32% TIPS; odds ratio, 1.5; 95% confidence interval, 0.75-3.23; P = .23). CONCLUSIONS: TIPS creation is associated with reduced inpatient mortality in men, but not women, admitted with HRS. Drivers of this gender-based disparity are currently unclear and warrant focused investigation.

Heparin-Induced Thrombocytopenia and Thrombosis: Preventing your Thrombolysis Practice from Taking a HITT.

Heparin-induced thrombocytopenia and thrombosis (HITT) is an under-recognized cause of deep venous thrombosis treatment failure and of complications during catheter-directed thrombolysis. After a review of HITT pathophysiology, diagnosis, and management, three different cases are presented in this article. Each case highlights subtleties and challenges of HITT diagnosis and management. An example of a practical approach to the diagnosis of HITT is presented.

The law of unintended consequences: current design challenges in inferior vena cava filters.

INTRODUCTION: Venous thromboembolic disease (VTD) encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) is a commonly encountered condition with potentially fatal sequelae. When unable to be adequately anticoagulated, patients require a mechanical means to prevent PE. This review discusses the history of inferior vena cava interruption and the development of inferior vena cava filters (IVCF). Areas covered: Milestone innovations in the mechanical treatment of VTD, their successes and shortcomings are discussed. The unforeseen complications that have occurred with implantation of IVCF have a profound impact on the present utilization of retrievable filters. Particular attention is dedicated to the evidence for safe and effective use of IVCF and the challenges presented to further improvement of these technologies. Expert commentary: While evidence suggests that IVCF are effective in preventing PE, the recent 'de-volution' from permanent to retrievable design has unleashed an epidemic device-related complications. Retrievable filter design is reliant on a 'Goldilocks' premise: make the device stable (so it doesn't migrate), but not too stable (so you can still retrieve it). Efforts must be aimed at optimizing utilization using decision support tools, meticulous follow up after deployment, and conversion from retrievable to permanent devices if the patient requires lifelong mechanical prophylaxis.

Proteomic changes associated with diabetes in the BB-DP rat.

These studies were structured with the aim of utilizing emerging technologies in two-dimensional (2D) gel electrophoresis and mass spectrometry to evaluate protein expression changes associated with type 1 diabetes. We reasoned that a broad examination of diabetic tissues at the protein level might open up novel avenues of investigation of the metabolic and signaling pathways that are adversely affected in type 1 diabetes. This study compared the protein expression of the liver, heart, and skeletal muscle of diabetes-prone rats and matched control rats by semiquantitative liquid chromatography-mass spectrometry and differential in-gel 2D gel electrophoresis. Differential expression of 341 proteins in liver, 43 in heart, and 9 (2D gel only) in skeletal muscle was detected. These data were assembled into the relevant metabolic pathways affected primarily in liver. Multiple covalent modifications were also apparent in 2D gel analysis. Several new hypotheses were generated by these data, including mechanisms of net cytosolic protein oxidation, formaldehyde generation by the methionine cycle, and inhibition of carbon substrate oxidation via reduction in citrate synthase and short-chain acyl-CoA dehydrogenase.

32P labeling of protein phosphorylation and metabolite association in the mitochondria matrix.

Protein phosphorylations, as well as phosphate metabolite binding, are well characterized post-translational mechanisms that regulate enzyme activity in the cytosol, but remain poorly defined in mitochondria. Recently extensive matrix protein phosphorylation sites have been discovered but their functional significance is unclear. Herein we describe methods of using (32)P labeling of intact mitochondria to determine the dynamic pools of protein phosphorylation as well as phosphate metabolite association. This screening approach may be useful in not only characterizing the dynamics of these pools, but also provide insight into which phosphorylation sites have a functional significance. Using the mitochondrial ATP synthetic capacity under appropriate conditions, inorganic (32)P was added to energized mitochondria to generate high specific activity gamma-P(32)-ATP in the matrix. In general, SDS denaturing and gel electrophoresis was used to primarily follow protein phosphorylation, whereas native gel techniques were used to observe weaker metabolite associations since the structure of mitochondrial complexes was minimally affected. The protein phosphorylation and metabolite association within the matrix was found to be extensive using these approaches. (32)P labeling in 2D gels was detected in over 40 proteins, including most of the complexes of the cytochrome chain and proteins associated with intermediary metabolism, biosynthetic pathways, membrane transport, and reactive oxygen species metabolism. (32)P pulse-chase experiments further revealed the overall dynamics of these processes that included phosphorylation site turnover as well as phosphate-protein pool size alterations. The high sensitivity of (32)P resulted in many proteins being intensely labeled, but not identified due to the sensitivity limitations of mass spectrometry. These low concentration proteins may represent signaling proteins within the matrix. These results demonstrate that the mitochondrial matrix phosphoproteome is both extensive and dynamic. The use of this, in situ, labeling approach is extremely valuable in confirming protein phosphorylation sites as well as examining the dynamics of these processes under near physiological conditions.

Use of (32)P to study dynamics of the mitochondrial phosphoproteome.

Protein phosphorylation is a well-characterized regulatory mechanism in the cytosol, but remains poorly defined in the mitochondrion. In this study, we characterized the use of (32)P-labeling to monitor the turnover of protein phosphorylation in the heart and liver mitochondria matrix. The (32)P labeling technique was compared and contrasted to Phos-tag protein phosphorylation fluorescent stain and 2D isoelectric focusing. Of the 64 proteins identified by MS spectroscopy in the Phos-Tag gels, over 20 proteins were correlated with (32)P labeling. The high sensitivity of (32)P incorporation detected proteins well below the mass spectrometry and even 2D gel protein detection limits. Phosphate-chase experiments revealed both turnover and phosphate associated protein pool size alterations dependent on initial incubation conditions. Extensive weak phosphate/phosphate metabolite interactions were observed using nondisruptive native gels, providing a novel approach to screen for potential allosteric interactions of phosphate metabolites with matrix proteins. We confirmed the phosphate associations in Complexes V and I due to their critical role in oxidative phosphorylation and to validate the 2D methods. These complexes were isolated by immunocapture, after (32)P labeling in the intact mitochondria, and revealed (32)P-incorporation for the alpha, beta, gamma, OSCP, and d subunits in Complex V and the 75, 51, 42, 23, and 13a kDa subunits in Complex I. These results demonstrate that a dynamic and extensive mitochondrial matrix phosphoproteome exists in heart and liver.

Functional consequences of mitochondrial proteome heterogeneity.

Potential functional consequences of the differences in protein distribution between the mitochondria of the rat liver, heart, brain, and kidney, as determined in the companion paper in this issue (Johnson DT, French S, Blair PV, You JS, Bemis KG, Wang M, Harris RA, and Balaban RS. The tissue heterogeneity of the mammalian mitochondrial proteome. Am J Physiol Cell Physiol292: C689-C697, 2006), were analyzed using a canonical metabolic pathway approach as well as a functional domain homology analysis. These data were inserted into the Kyoto Encyclopedia of Genes and Genomes pathway framework to give global and metabolic pathway-specific information on the impact of the differential protein distribution on mitochondrial function. Custom pathway analysis was also performed using pathways limited to the mitochondrion. With the use of this approach, several well-known functional differences between these mitochondrial populations were confirmed. These included GABA metabolism in the brain, urea synthesis in the liver, and the domination of oxidative phosphorylation in the heart. By comparing relative protein amounts of mitochondria across tissues, a greater understanding of functional emphasis is possible as well as the nuclear "programming" required to enhance a given function within the mitochondria. For proteins determined to be mitochondrial and lacking a defined role functional domain BLAST analyses were performed. Several proteins associated with DNA structural modification and a novel CoA transferase were identified. A protein was also identified capable of catalyzing the first three steps of de novo pyrimidine synthesis. This analysis demonstrates that the distribution of nuclear encoded proteins significantly modifies the overall functional emphasis of the mitochondria to meet tissue-specific needs. These studies demonstrate the existence of mitochondrial biochemical functions that at present are poorly defined.

Tissue heterogeneity of the mammalian mitochondrial proteome.

The functionality of the mitochondrion is primarily determined by nuclear encoded proteins. The mitochondrial functional requirements of different tissues vary from a significant biosynthetic role (liver) to a primarily energy metabolism-oriented organelle (heart). The purpose of this study was to compare the mitochondrial proteome from four different tissues of the rat, brain, liver, heart, and kidney, to provide insight into the extent of mitochondrial heterogeneity and to further characterize the overall mitochondrial proteome. Mitochondria were isolated, solubilized, digested, and subjected to quantitative liquid chromatography-mass spectroscopy. Of the 16,950 distinct peptides detected, 8,045 proteins were identified. High-confidence identification threshold was reached by 1,162 peptides, which were further analyzed. Of these 1,162 proteins, 1,149 were significantly different in content (P and q values < 0.05) between at least 2 tissues, whereas 13 were not significantly different between any tissues. Confirmation of the mitochondrial origin of proteins was determined from the literature or via NH(2)-terminal mitochondrial localization signals. With these criteria, 382 proteins in the significantly different groups were confirmed to be mitochondrial, and 493 could not be confirmed to be mitochondrial but were not definitively localized elsewhere in the cell. A total of 145 proteins were assigned to the rat mitochondrial proteome for the first time via their NH(2)-terminal mitochondrial localization signals. Among the proteins that were not significantly different between tissues, three were confirmed to be mitochondrial. Most notable of the significantly different proteins were histone family proteins and several structural proteins, including tubulin and intermediate filaments. The mitochondrial proteome from each tissue had very specific characteristics indicative of different functional emphasis. These data confirm the notion that mitochondria are tuned by the nucleus for specific functions in different tissues.

A discordance in rosiglitazone mediated insulin sensitization and skeletal muscle mitochondrial content/activity in Type 2 diabetes mellitus.

Skeletal muscle mitochondrial dysfunction is hypothesized to contribute to the pathophysiology of insulin resistance and Type 2 diabetes. Whether thiazolidinedione therapy enhances skeletal muscle mitochondrial function as a component of its insulin-sensitizing effect is unknown. To test this, we evaluated skeletal muscle mitochondria and exercise capacity in Type 2 diabetic subjects with otherwise normal cardiopulmonary function in response to rosiglitazone therapy. Twenty-three subjects were treated for 12 wk and underwent pre- and posttherapy metabolic stress testing and skeletal muscle biopsies. Rosiglitazone significantly ameliorated fasting glucose, insulin, and free fatty acid levels but did not augment the subjects' maximal oxygen consumption (Vo(2max)) or their skeletal muscle mitochondrial copy number. The baseline Vo(2max) correlated strongly with muscle mitochondrial copy number (r = 0.56, P = 0.018, n = 17) and inversely with the duration of diabetes (r = -0.67, P = 0.004, n = 23). Despite the global lack of effect of rosiglitazone-mediated insulin sensitization on skeletal muscle mitochondria, subjects with the most preserved functional capacity demonstrated some plasticity in their mitochondria biology as evidenced by an upregulation of electron transfer chain proteins and in citrate synthase activity. This study demonstrates that the augmentation of skeletal muscle mitochondrial electron transfer chain content and/or bioenergetics is not a prerequisite for rosiglitazone-mediated improved insulin sensitivity. Moreover, in diabetic subjects, Vo(2max) reflects the duration of diabetes and skeletal muscle mitochondrial content. It remains to be determined whether longer-term insulin sensitization therapy with rosiglitazone will augment skeletal muscle mitochondrial bioenergetics in those diabetic subjects with relatively preserved basal aerobic capacity.

Mitochondrial matrix phosphoproteome: effect of extra mitochondrial calcium.

Post-translational modification of mitochondrial proteins by phosphorylation or dephosphorylation plays an essential role in numerous cell signaling pathways involved in regulating energy metabolism and in mitochondrion-induced apoptosis. Here we present a phosphoproteomic screen of the mitochondrial matrix proteins and begin to establish the protein phosphorylations acutely associated with calcium ions (Ca(2+)) signaling in porcine heart mitochondria. Forty-five phosphorylated proteins were detected by gel electrophoresis-mass spectrometry of Pro-Q Diamond staining, while many more Pro-Q Diamond-stained proteins evaded mass spectrometry detection. Time-dependent (32)P incorporation in intact mitochondria confirmed the extensive matrix protein phosphoryation and revealed the dynamic nature of this process. Classes of proteins that were detected included all of the mitochondrial respiratory chain complexes, as well as enzymes involved in intermediary metabolism, such as pyruvate dehydrogenase (PDH), citrate synthase, and acyl-CoA dehydrogenases. These data demonstrate that the phosphoproteome of the mitochondrial matrix is extensive and dynamic. Ca(2+) has previously been shown to activate various dehydrogenases, promote the generation of reactive oxygen species (ROS), and initiate apoptosis via cytochrome c release. To evaluate the Ca(2+) signaling network, the effects of a Ca(2+) challenge sufficient to release cytochrome c were evaluated on the mitochondrial phosphoproteome. Novel Ca(2+)-induced dephosphorylation was observed in manganese superoxide dismutase (MnSOD) as well as the previously characterized PDH. A Ca(2+) dose-dependent dephosphorylation of MnSOD was associated with an approximately 2-fold maximum increase in activity; neither the dephosphorylation nor activity changes were induced by ROS production in the absence of Ca(2+). These data demonstrate the use of a phosphoproteome screen in determining mitochondrial signaling pathways and reveal new pathways for Ca(2+) modification of mitochondrial function at the level of MnSOD.