The efficacy and safety of closure of brachial access using the AngioSeal closure device: Experience with 161 interventions in diabetic patients with critical limb ischemia

PurposeThis study retrospectively evaluated the efficacy and safety of the 6F Angio-Seal (St. Jude Medical, St. Paul, Minn) as a closure device for transbrachial artery access for endovascular procedures in diabetic patients with critical limb ischemia.MethodsFrom January 2005 and September 2007, 1887 diabetic patients underwent interventional procedures in the lower limbs at a two diabetic foot centers. Patients presented with rest pain (16%), ulcers (80%), or gangrene (4%). Systemic anticoagulation with sodium heparin (70 IU/kg) was obtained for all patients at the beginning of the endovascular treatment. A total of 249 brachial arteries (238 patients) were evaluated for possible Angio-Seal use after endovascular recanalization of the leg. Color Doppler ultrasound imaging of the artery was obtained before revascularization only in patients with previous Angio-Seal placement in the brachial artery. No further imaging studies were done in the remaining brachial arteries where the Angio-Seal was deployed at the operator’s discretion. Impairment or disappearance of the radial pulse or onsets of hand ischemia or hand pain, or impairment of hand function during or at the end of the endovascular revascularization were all regarded as contraindications to Angio-Seal usage. Evidence of a highly calcified plaque of the brachial artery access site at the time of vessel puncture was regarded as an absolute contraindication to the Angio-Seal use. Patients were seen before discharge, at 1, 3, and 8 weeks after the procedure, and at 3-month intervals thereafter. Complications included hemorrhage, pseudoaneurysm, infection, and vessel occlusion.ResultsA total of 1947 Angio-Seal collagen plugs were deployed in 1709 diabetic patients (90.5%). The Angio-Seal was used for brachial artery closure in 159 patients (8.4%) in 161 procedures (159 in the left, 2 in the right brachial artery). In 79 patients (4.2%) in 88 procedures (87 in the left and 1 in the right brachial artery), the device was deemed contraindicated due to small vessel size in 73 patients (92.4%) or presence of calcium at the access site in five patients (6.3%). One patient (1.3%) refused the collagen plug closure after revascularization. The non-Angio-Seal group was evaluated for comparison. The success rate for achieving hemostasis in the Angio-Seal group was 96.9%. Five major complications (3.1%) at 30 days consisted of two puncture site hematomas >4 cm, two brachial artery occlusions, and one brachial artery pseudoaneurysm, with three patients requiring open surgery. Minor complications (7.50%) were three puncture site hematomas < 4 cm, three oozing of blood from the access site, and six patients had mild pain in the cubital fossa. No further complications were recorded in the 14-month follow-up (range 1-25 months) of a total of 140 patients.ConclusionsThis retrospective study shows that the 6F Angio-Seal is a valuable and safe vascular closure device for transbrachial access in diabetic patients undergoing interventional procedures for critical limb ischemia

Role of the Transforming Growth Factor-β in regulating hepatocellular carcinoma oxidative metabolism.

Transforming Growth Factor beta (TGF-β) induces tumor cell migration and invasion. However, its role in inducing metabolic reprogramming is poorly understood. Here we analyzed the metabolic profle of hepatocellular carcinoma (HCC) cells that show diferences in TGF-β expression. Oxygen consumption rate (OCR), extracellular acidifcation rate (ECAR), metabolomics and transcriptomics were performed. Results indicated that the switch from an epithelial to a mesenchymal/migratory phenotype in HCC cells is characterized by reduced mitochondrial respiration, without signifcant diferences in glycolytic activity. Concomitantly, enhanced glutamine anaplerosis and biosynthetic use of TCA metabolites were proved through analysis of metabolite levels, as well as metabolic fuxes from U-13C6-Glucose and U-13C5-Glutamine. This correlated with increase in glutaminase 1 (GLS1) expression, whose inhibition reduced cell migration. Experiments where TGF-β function was activated with extracellular TGF-β1 or inhibited through TGF-β receptor I silencing showed that TGF-β induces a switch from oxidative metabolism, coincident with a decrease in OCR and the upregulation of glutamine transporter Solute Carrier Family 7 Member 5 (SLC7A5) and GLS1. TGF-β also regulated the expression of key genes involved in the fux of glycolytic intermediates and fatty acid metabolism. Together, these results indicate that autocrine activation of the TGF-β pathway regulates oxidative metabolism in HCC cells

miR-125b Acts as a Tumor Suppressor in Breast Tumorigenesis via Its Novel Direct Targets ENPEP, CK2-α, CCNJ, and MEGF9

MicroRNAs (miRNAs) play important roles in diverse biological processes and are emerging as key regulators of tumorigenesis and tumor progression. To explore the dysregulation of miRNAs in breast cancer, a genome-wide expression profiling of 939 miRNAs was performed in 50 breast cancer patients. A total of 35 miRNAs were aberrantly expressed between breast cancer tissue and adjacent normal breast tissue and several novel miRNAs were identified as potential oncogenes or tumor suppressor miRNAs in breast tumorigenesis. miR-125b exhibited the largest decrease in expression. Enforced miR-125b expression in mammary cells decreased cell proliferation by inducing G2/M cell cycle arrest and reduced anchorage-independent cell growth of cells of mammary origin. miR-125b was found to perform its tumor suppressor function via the direct targeting of the 3'-UTRs of ENPEP, CK2-alpha, CCNJ, and MEGF9 mRNAs. Silencing these miR-125b targets mimicked the biological effects of miR-125b overexpression, confirming that they are modulated by miR-125b. Analysis of ENPEP, CK2-alpha, CCNJ, and MEGF9 protein expression in breast cancer patients revealed that they were overexpressed in 56%, 40-56%, 20%, and 32% of the tumors, respectively. The expression of ENPEP and CK2-alpha was inversely correlated with miR-125b expression in breast tumors, indicating the relevance of these potential oncogenic proteins in breast cancer patients. Our results support a prognostic role for CK2-alpha, whose expression may help clinicians predict breast tumor aggressiveness. In particular, our results show that restoration of miR-125b expression or knockdown of ENPEP, CK2-alpha, CCNJ, or MEGF9 may provide novel approaches for the treatment of breast cancer

KCNMA1 Encoded Cardiac BK Channels Afford Protection against Ischemia-Reperfusion Injury

Mitochondrial potassium channels have been implicated in myocardial protection mediated through pre-/postconditioning. Compounds that open the Ca2+-and voltage-activated potassium channel of big-conductance (BK) have a pre-conditioninglike effect on survival of cardiomyocytes after ischemia/reperfusion injury. Recently, mitochondrial BK channels (mitoBKs) in cardiomyocytes were implicated as infarct-limiting factors that derive directly from the KCNMA1 gene encoding for canonical BKs usually present at the plasma membrane of cells. However, some studies challenged these cardio-protective roles of mitoBKs. Herein, we present electrophysiological evidence for paxilline- and NS11021-sensitive BK-mediated currents of 190 pS conductance in mitoplasts from wild-type but not BK-/- cardiomyocytes. Transmission electron microscopy of BK-/- ventricular muscles fibres showed normal ultra-structures and matrix dimension, but oxidative phosphorylation capacities at normoxia and upon re-oxygenation after anoxia were significantly attenuated in BK-/- permeabilized cardiomyocytes. In the absence of BK, post-anoxic reactive oxygen species (ROS) production from cardiomyocyte mitochondria was elevated indicating that mitoBK fine-tune the oxidative state at hypoxia and reoxygenation. Because ROS and the capacity of the myocardium for oxidative metabolism are important determinants of cellular survival, we tested BK-/- hearts for their response in an ex-vivo model of ischemia/reperfusion (I/R) injury. Infarct areas, coronary flow and heart rates were not different between wild-type and BK-/- hearts upon I/R injury in the absence of ischemic pre-conditioning (IP),but differed upon IP. While the area of infarction comprised 28 +/- 3% of the area at risk in wild-type, it was increased to 58 +/- 5% in BK-/- hearts suggesting that BK mediates the beneficial effects of IP. These findings suggest that cardiac BK channels are important for proper oxidative energy supply of cardiomyocytes at normoxia and upon re-oxygenation after prolonged anoxia and that IP might indeed favor survival of the myocardium upon I/R injury in a BK-dependent mode stemming from both mitochondrial post-anoxic ROS modulation and non-mitochondrial localizations

Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients

Low dose rate brachytherapy (LDR-BT) as monotherapy for early stage prostate cancer in Italy: practice and outcome analysis in a series of 2237 patients from 11 institutions

OBJECTIVE: Low-dose-rate brachytherapy (LDR-BT) in localized prostate cancer is available since 15 years in Italy. We realized the first national multicentre and multidisciplinary data collection to evaluate LDR-BT practice, given as monotherapy, and outcome in terms of biochemical failure. METHODS: Between May 1998 and December 2011, 2237 patients with early-stage prostate cancer from 11 Italian community and academic hospitals were treated with iodine-125 ((125)I) or palladium-103 LDR-BT as monotherapy and followed up for at least 2 years. (125)I seeds were implanted in 97.7% of the patients: the mean dose received by 90% of target volume was 145 Gy; the mean target volume receiving 100% of prescribed dose (V100) was 91.1%. Biochemical failure-free survival (BFFS), disease-specific survival (DSS) and overall survival (OS) were estimated using Kaplan-Meier method. Log-rank test and multivariable Cox regression were used to evaluate the relationship of covariates with outcomes. RESULTS: Median follow-up time was 65 months. 5- and 7-year DSS, OS and BFFS were 99 and 98%, 94 and 89%, and 92 and 88%, respectively. At multivariate analysis, the National Comprehensive Cancer Network score (p < 0.0001) and V100 (p = 0.09) were correlated with BFFS, with V100 effect significantly different between patients at low risk and those at intermediate/high risk (p = 0.04). Short follow-up and lack of toxicity data represent the main limitations for a global evaluation of LDR-BT. CONCLUSION: This first multicentre Italian report confirms LDR-BT as an excellent curative modality for low-/intermediate-risk prostate cancer. ADVANCES IN KNOWLEDGE: Multidisciplinary teams may help to select adequately patients to be treated with brachytherapy, with a direct impact on the implant quality and, possibly, on outcome

Corticotroph tumor progression after bilateral adrenalectomy (Nelson’s syndrome):systematic review and expert consensus recommendations

Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing

Multidisciplinary management of acromegaly: A consensus.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence