Carolyn Glass

Global Identification of EVI1 Target Genes in Acute Myeloid Leukemia

The ecotropic virus integration site 1 (EVI1) transcription factor is associated with human myeloid malignancy of poor prognosis and is overexpressed in 8–10% of adult AML and strikingly up to 27% of pediatric MLL-rearranged leukemias. For the first time, we report comprehensive genomewide EVI1 binding and whole transcriptome gene deregulation in leukemic cells using a combination of ChIP-Seq and RNA-Seq expression profiling. We found disruption of terminal myeloid differentiation and cell cycle regulation to be prominent in EVI-induced leukemogenesis. Specifically, we identified EVI1 directly binds to and downregulates the master myeloid differentiation gene Cebpe and several of its downstream gene targets critical for terminal myeloid differentiation. We also found EVI1 binds to and downregulates Serpinb2 as well as numerous genes involved in the Jak-Stat signaling pathway. Finally, we identified decreased expression of several ATP-dependent P2X purinoreceptors genes involved in apoptosis mechanisms. These findings provide a foundation for future study of potential therapeutic gene targets for EVI1-induced leukemia.

The role of EVI1 in myeloid malignancies

The EVI1 oncogene at human chr 3q26 is rearranged and/or overexpressed in a subset of acute myeloid leukemias and myelodysplasias. The EVI1 protein is a 135 kDa transcriptional regulator with DNA-binding zinc finger domains. Here we provide a critical review of the current state of research into the molecular mechanisms by which this gene plays a role in myeloid malignancies. The major pertinent cellular effects are blocking myeloid differentiation and preventing cellular apoptosis, and several potential mechanisms for these phenomena have been identified. Evidence supports a role for EVI1 in inducing cellular quiescence, and this may contribute to the resistance to chemotherapy seen in patients with neoplasms that overexpress EVI1. Another isoform, MDS1-EVI1 (or PRDM3), encoded by the same locus as EVI1, harbors an N-terminal histone methyltransferase(HMT) domain; experimental findings indicate that this protein and its HMT activity are critical for the progression of a subset of AMLs, and this provides a potential target for therapeutic intervention.

A Meta-analysis of Preoperative Duplex Ultrasound Vessel Diameters for Successful Radiocephalic Fistula Placement

Background The Kidney Dialysis Outcomes Quality Initiative (K/DOQI) guidelines for vascular access recommend the use of radiocephalic wrist arteriovenous fistulas (RCAVFs) as the initial option for dialysis access. The survival rate of a successfully placed fistula is excellent. However, 10–24% of RCAVFs fail to reach functional status as the result of early thrombosis or maturation failure. Many authors have investigated the utility of preoperative vascular mapping by Duplex ultrasound to predict adequate vessel size for successful fistula placement. This meta-analysis is the first in which preoperative radial arterial (RAD) and cephalic venous diameters (CVD) required for favorable fistula outcomes are reviewed. Methods A literature search was performed by use of the MEDLINE electronic base for “arteriovenous, fistula, ultrasound, and hemodialysis.” The analysis yielded 166 studies, of which 20 studies included preoperative duplex data. Meta-analysis was performed by applying the statistical test of comparing two proportions, assuming equal variances. Results A total of 433 patients were duplexed for preoperative evaluation of the RAD and 386 for CVD. The total number of subjects ranged from 21 to 91, mean age 58.7 years. The subjects were 55.5% male, 39.0% with diabetes mellitus. Meta-analysis yielded 2.0 mm for RAD and 2.0 mm for CVD as designated cutoff vessel diameters. Our study showed the mean fistula success rate was significantly different between RAD >2.0 mm (59%) and RAD >2.0 mm (40%). The mean fistula success rate was also significantly different between CVD > 2.0 mm (71%) and >2.0 mm (29%). Successful fistula placement was defined as a functional fistula at least 4–6 weeks after creation. Conclusion On the basis of our study, the use of Duplex ultrasound is important in determining preoperative vessel diameter size, and subsequent functional success rate of fistula placement.

Costoclavicular Venous Decompression in Patients With Threatened Arteriovenous Hemodialysis Access

BACKGROUND Autologous arteriovenous fistulas are frequently threatened by central venous obstruction. Although this is frequently ascribed to indwelling catheters and neointimal venous remodeling, we believe that extrinsic compression of the subclavian vein as it passes through the costoclavicular junction (CCJ) may play a significant role in a subset of dialysis patients. METHODS We reviewed our experience with CCJ decompression for arteriovenous fistula dysfunction at our institution. Decompression followed principles for venous thoracic outlet syndrome: bony decompression with thorough venolysis, followed by central venography through the fistula and endoluminal treatment, if necessary. Patients underwent transaxillary first rib resection, or claviculectomy in the supine position in cases when reconstruction was anticipated. In all cases, the minimum exposure included 360° mobilization of the subclavian vein with resection of surrounding cicatrix to the jugular/innominate junction. RESULTS A total of 10 patients requiring decompression between November 2008 and February 2010 were included. All had severe arm swelling, four had dialysis dysfunction (postcannulation bleeding or maturation failure), two had severe arm pain, and one had a pseudoaneurysm. All patients had subclavian vein stenosis at the CCJ by venography or intravascular ultrasound. The majority of patients had balloon dilation (mean: 2.3 attempts) without success. Six patients underwent transaxillary first rib resection and four had medial claviculectomy. No patients required surgical venous reconstruction. In all, 80% of fistulas remained functionally patent, and all but one patient (who underwent ligation) had complete relief of upper arm edema. Median hospital length of stay was 2 days and mean follow-up was 7 months (range, 1-13). There was no mortality or significant morbidity. Five patients later required central venoplasty (four subclavian, mean: 1.8 attempts and one innominate) and three had stents placed (two subclavian, one innominate). CONCLUSION A significant number of patients with threatened AV access owing to central venous obstruction have lesions attributable to compression at the CCJ. Surgical decompression by means of first rib or clavicular resection and thorough external venoloysis allowed symptom-free functional salvage in 80% of these patients, all of whom would have lost their access otherwise. Because surgical reconstruction is seldom needed, the transaxillary approach may be preferable to claviculectomy. This lesion should be specifically looked for, and principles of venous thoracic outlet syndrome treatment seem to apply and be effective.

A large-scale study of the upper arm basilic transposition for hemodialysis.

BACKGROUND The incidence of stage 5 chronic kidney disease requiring immediate hemodialysis treatment continues to rise with an increasing number of patients with an unsuitable cephalic vein or failed radio- and brachiocephalic fistulae. In these patients the basilic vein is our next autologous choice. We have previously investigated our preliminary experience and identified common failure modes, and this report describes longer-term outcomes and what we feel are results after the learning curve has been surmounted. METHODS All patients who underwent basilic vein transposition from April 2001 to June 2008 at our institution were retrospectively reviewed. Data collected included demographics, anesthesia type, volume flow at creation, maturation rate, patency rates, post-operative complications, secondary interventions (endovascular and open surgical revision), and overall mortality. RESULTS Two hundred seventeen upper arm basilic vein transposition fistulae were created in 215 patients (53% male). Prior to basilic transposition, patients had a mean of 2.9 previous surgical access attempts. Only 14% of patients had a basilic vein transposition as their initial fistula. Mean flow at time of fistula creation was 347 (range 10-880) mL/minute, with a maturation rate of 87%. The procedural mortality rate was 0.5%. Primary and primary assisted patency rates at 6, 12, and 24 months were 63%, 40%, and 26% and 74%, 56%, and 38%, respectively, while secondary patency rates at 6, 12, and 24 months were 85%, 72%, and 65%, respectively. Fistula thrombosis was the most common complication prior to maturation (16%). Central vein stenosis (22%) was the most frequent cause of fistula failure. CONCLUSION Basilic vein transposition fistulae have excellent initial maturation rates (87%) with reasonably good functional (secondary) patency rates (72% at 1 year). Central venous stenosis is a major postmaturation limiting factor in long-term durability, and revisions are frequent. The optimal order of access in patients without usable cephalic veins remains a difficult challenge, but basilic vein transposition seems to stack up well versus prosthetic grafts in this situation.

Long-term results of endoscopic versus open saphenous vein harvest for lower extremity bypass.

BACKGROUND Endoscopic saphenous vein harvest (EVH) has been shown to lower wound infection rates and cost compared with conventional harvest, although long-term patency data are lacking. A small series of studies has recently suggested that patency is inferior to conventionally harvested vein technique, and we thus sought to explore this question by reviewing our cumulative experience with this technique. METHODS The short- and long-term outcomes of all lower extremity bypasses (LEBPs) using saphenous vein at one institution over a period of 8.5 years were retrospectively reviewed. RESULTS A total of 363 patients averaging 67 ± 24 to 100 years of age had undergone LEBP and had charts available for review. Of these 363 patients, 170 underwent EVH (90% using a noninsufflation technique) and 193 conventional (by means of continuous or skip incisions); 48% of patients reported tissue loss and no differences in indication for surgery were noted between groups. Mean follow-up was 35.1 (range: <1-105) months. Primary patency rates were worse in the EVH group as compared with conventional at six (63.3% ± 4.0% vs. 77.3% ± 3.3%), 12 (50.4% ± 4.2% vs. 73.7% ± 3.6%), and 36 (42.2% ± 4.5% vs. 59.1% ± 4.9%) months (all p < 0.001), although these differences were largely limited to patients with limb-threat and diabetes. However, limb salvage and survival, were identical between groups. Contrary to previous experience, there were no differences in length of stay or wound complication rates. CONCLUSIONS The overall results of this study show an inferior long-term patency rate for endoscopically harvested saphenous vein after LEBP in our series as a whole, and do not confirm the short-term benefit previously shown in a selected cohort. These differences were, however, minimal or absent in patients with claudication or absence of diabetes, and EVH may continue to play a role in these cases.

The perspective of the vascular surgery trainee on new ACGME regulations, fatigue, resident training, and patient safety.

Objective: To assess the opinions of vascular surgery trainees on the new Accreditation Council for Graduate Medical Education (ACGME) guidelines. Methods: A questionnaire was developed and electronically distributed to trainee members of the Society for Vascular Surgery. Results: Of 238 eligible vascular trainees, 38 (16%) participated. Respondents were predominantly 30 to 35 years of age (47%), male (69%), in 2-year fellowship (73%), and at large academic centers (61%). Trainees report occasionally working while fatigued (63%). Fellows were more likely to report for duty while fatigued (P = .012) than integrated vascular residents. Respondents thought further work-hour restrictions would not improve patient care or training (P < .05) and may not lead to more sleep or improved quality of life. Respondents reported that duty hours should vary by specialty (81%) and allow flexibility in the last years of training (P < .05). Conclusions: Vascular surgery trainees are concerned about further duty-hour restrictions on patient care, education, and training and fatigue mitigation has to be balanced against the need to adequately train vascular surgeons.

Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia

A subgroup of leukemogenic mixed-lineage leukemia (MLL) fusion proteins (MFPs) including MLL-AF9 activates the Mecom locus and exhibits extremely poor clinical prognosis. Mecom encodes EVI1 and MDS1-EVI1 (ME) proteins via alternative transcription start sites; these differ by the presence of a PRDI-BF1-RIZ1 (PR) domain with histone methyltransferase activity in the ME isoform. Using an ME-deficient mouse, we show that ME is required for MLL-AF9-induced transformation both in vitro and in vivo. And, although Nup98-HOXA9, MEIS1-HOXA9, and E2A-Hlf could transform ME-deficient cells, both MLL-AF9 and MLL-ENL were ineffective, indicating that the ME requirement is specific to MLL fusion leukemia. Further, we show that the PR domain is essential for MFP-induced transformation. These studies clearly indicate an essential role of PR-domain protein ME in MFP leukemia, suggesting that ME may be a novel target for therapeutic intervention for this group of leukemias.

Importance of Ultrasound Evaluation in the Diagnosis of Venous Insufficiency: Guidelines and Techniques

Recent advances in the treatment of venous insufficiency have led to an increased utilization of venous ultrasonography by practitioners. Knowing the fundamentals of anatomy and physiology are essential to be successful. This article reviews the common uses of ultrasonagraphy for the examination of the lower extremity venous system.

VTOS in the Patient Requiring Chronic Hemodialysis Access

Central venous obstruction (CVO) is the most common cause of failure of Arteriovenous fistulae (AVF) and grafts (AVG) placed for dialysis access. In essentially all reports, including international consensus statements for management of such patients, all CVOs are lumped together, implicitly assuming that all should be treated first with endovascular means. We point out that while stenosis in veins surrounded by soft tissue are appropriate for endoluminal intervention, those that occur at the costoclavicular junction are identical in pathophysiology to and should be treated in a fashion similar to those in patients with “conventional” venous thoracic outlet syndrome. By aggressive use of thoracic outlet decompression in patients with dialysis access dysfunction caused by costoclavicular stenosis we have achieved fistula salvage in approximately two-thirds of patients who would otherwise have required ligation. This lesion should be considered “dialysis-dependent venous TOS” and treated aggressively.