Epichaperome inhibition targets TP53-mutant AML and AML stem/progenitor cells.

TP 53-mutant acute myeloid leukemia (AML) remains the ultimate therapeutic challenge. Epichaperomes, formed in malignant cells, consist of heat shock protein 90 (HSP90) and associated proteins that support the maturation, activity, and stability of oncogenic kinases and transcription factors including mutant p53. High-throughput drug screening identified HSP90 inhibitors as top hits in isogenic TP53-wild-type (WT) and -mutant AML cells. We detected epichaperomes in AML cells and stem/progenitor cells with TP53 mutations but not in healthy bone marrow (BM) cells. Hence, we investigated the therapeutic potential of specifically targeting epichaperomes with PU-H71 in TP53-mutant AML based on its preferred binding to HSP90 within epichaperomes. PU-H71 effectively suppressed cell intrinsic stress responses and killed AML cells, primarily by inducing apoptosis; targeted TP53-mutant stem/progenitor cells; and prolonged survival of TP53-mutant AML xenograft and patient-derived xenograft models, but it had minimal effects on healthy human BM CD34+ cells or on murine hematopoiesis. PU-H71 decreased MCL-1 and multiple signal proteins, increased proapoptotic Bcl-2-like protein 11 levels, and synergized with BCL-2 inhibitor venetoclax in TP53-mutant AML. Notably, PU-H71 effectively killed TP53-WT and -mutant cells in isogenic TP53-WT/TP53-R248W Molm13 cell mixtures, whereas MDM2 or BCL-2 inhibition only reduced TP53-WT but favored the outgrowth of TP53-mutant cells. Venetoclax enhanced the killing of both TP53-WT and -mutant cells by PU-H71 in a xenograft model. Our data suggest that epichaperome function is essential for TP53-mutant AML growth and survival and that its inhibition targets mutant AML and stem/progenitor cells, enhances venetoclax activity, and prevents the outgrowth of venetoclax-resistant TP53-mutant AML clones. These concepts warrant clinical evaluation.

Early and midterm outcomes after transcatheter embolization of type I endoleaks in 25 patients.

OBJECTIVE: This study reports the technical success and follow-up results of transcatheter embolization of type I endoleak (ELI) in 25 patients after endovascular aortic repair (EVAR). METHODS: Twenty-five patients with ELI (20 men, five women; mean age 80 years; range, 64-96 years) underwent embolization of abdominal ELI (23 proximal, 2 distal endoleaks) after EVAR. All patients were unsuitable for standard endovascular methods for treatment of ELI. The average aneurysm sac size before embolization was 8.2 cm (range, 5.3-12.9 cm). The average time between EVAR and endoleak diagnosis was 685 days (range, 1-4220 days) and from endoleak diagnosis to embolization was 27 days (range, 2-94 days). Onyx (ev3 Endovascular, Inc, Plymouth, Minn) alone or with detachable coils was used for embolization. RESULTS: A total of 27 embolization procedures were performed, with two patients having undergone a repeat procedure. Onyx alone was used in 16 cases and Onyx and coils were used in 11. Immediate technical success with complete isolation of the endoleak on completion angiography was achieved in all procedures. Six procedural complications occurred: three puncture site hematomas and three cases of non-target Onyx embolization. None of the complications had long term sequelae. During the follow-up period (average, 311 days; range, 1-1357 days), seven patients (28%) developed endoleak recurrence, and two underwent a second embolization procedure. Of these, one has had no further endoleak recurrence, but the other developed a recurrent endoleak and died of sac rupture. Two of the other five cases of endoleak recurrence were successfully managed by other procedures, one had a persistent endoleak despite aortic cuff placement, and the other two were deemed unsuitable for further intervention. Three of the four patients with persistent endoleaks died of sac rupture. At the average follow-up time of 311 days, freedom from endoleak recurrence was 80%, and freedom from sac growth was 85%. CONCLUSIONS: Transcatheter embolization of ELI offers a safe, feasible, and sustainable treatment option for patients who are unsuitable for standard methods of ELI treatment. Additional coil embolization before Onyx injection may result in better outcome.

Appearance of the Nellix endovascular aneurysm sealing system on computed tomography: implications for postoperative imaging surveillance.

PURPOSE: To describe the imaging characteristics of the Nellix Endovascular Aneurysm Sealing (EVAS) System on serial computed tomography (CT) surveillance. METHODS: Sixty-eight patients undergoing EVAS were enrolled in a surveillance protocol that included CT scans prior to hospital discharge and at 3, 6, and 9 months postoperatively. Images were analyzed for the presence of gas within the endobag, endoleak, and for maximum radiodensity measured in Hounsfield units (HU) within the uppermost, middle, and lowermost regions of each endobag. RESULTS: Gas was seen within the endobags of all 68 EVAS repairs at the first postoperative CT compared with 2 (5.6%) of 36 undergoing the 3-month scan. The endobags appeared radiodense during initial imaging, and the median (interquartile range) radiodensity of the Nellix polymer decreased from 158.3 HU (149.5; 169.5) at the postoperative CT to 81.0 HU (74.0; 88.0) at 3 months, excluding 3 cases in which contrast pre-fill was utilized. Type I endoleak was seen at the periphery of the aneurysm sac or in the cleft between the endobags, with a substantially different appearance to endoleak after endovascular aneurysm repair. CONCLUSION: The evolution of CT appearances after EVAS was characteristic and predictable. The device endobags were initially radiodense, which may impact the detection of endoleak within 3 months of EVAS. Endoleaks after EVAS were seen in a different anatomical area to endoleaks after conventional stent-graft repair.

Endovascular aneurysm sealing for the treatment of ruptured abdominal aortic aneurysms.

PURPOSE: To assess the feasibility and report preliminary results of ruptured abdominal aortic aneurysm (rAAA) repair with endovascular aneurysm sealing (EVAS), a novel therapeutic alternative whose feasibility has not been established in rAAAs due to the unknown effects of the rupture site on the ability to achieve sealing. CASE REPORT: Between December 2013 and April 2014, 5 patients (median age 71 years, range 57-90; 3 men) with rAAAs were treated with the Nellix EVAS system at a single institution. Median aneurysm diameter was 70 mm (range 67-91). Aneurysm morphology in 4 of the 5 patients was noncompliant with instructions for use (IFU) for both EVAS and standard stent-grafts; the remaining patient was outside the IFU for standard stent-grafts but treated with EVAS under standard IFU for the Nellix system. Median Hardman index was 2 (range 0-3). Two patients died of multiorgan failure after re-laparotomy and intraoperative cardiac arrest, respectively. Among survivors, all devices were patent with no signs of endoleak or failed aneurysm sac sealing at 6 months (median follow-up 9.2 months). CONCLUSION: EVAS for the management of infrarenal rAAAs appears feasible. The use of EVAS in emergency repairs may broaden the selection criteria of the current endovascular strategy to include patients with more complex aneurysm morphology.

Dialysis Access Maintenance: Plain Balloon Angioplasty.

Plain balloon angioplasty remains the first-line treatment for dialysis access stenosis. This chapter reviews the outcomes of plain balloon angioplasty from cohort studies and comparative studies. Angioplasty outcomes are more favourable in arteriovenous fistulae (AVF) compared to arteriovenous grafts (AVG) with primary patency at 6 months ranging from 42-63% compared to 27-61%, respectively, and improved for forearm fistulae compared with upper arm fistulae. Higher pressures are required to treat stenoses in AVFs compared to AVGs. Outcomes are worse in more severe stenoses, increased patient age, previous interventions and fistulae that develop early stenoses. Major complication rates following angioplasty in dialysis access are between 3 and 5%. Repeat treatments and the use of adjuncts such as drug-coated balloons and stents can prolong the patency of dialysis access. Level of Evidence No level of evidence (Review paper).

The Current Use of Drug-Eluting Balloons and Stents in Peripheral Arterial Disease: An Online Survey by the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).

PURPOSE: To assess the current use of drug-eluting devices for peripheral arterial disease (PAD) among interventional radiologists following the controversy caused by the 2018 meta-analysis suggesting an increased mortality risk for paclitaxel-eluting devices. METHODS: An anonymous survey was sent to 7035 CIRSE members via email; only complete responses were included and statistically analysed. RESULTS: Three hundred and seven members (4.4%) completed the survey. Among these, 95.8% indicated that they personally perform peripheral vascular procedures. Thirty-eight percentage of respondents did not see any change of practice since 2018, while 47% reported that the use of drug-eluting devices decreased; for 13%, the use stopped altogether, while it increased in 3% of responses. 45.6% of respondents also felt the impact of the controversy in terms of pricing, availability or directives from hospital administration. A large majority of respondents (83.7%) who perform peripheral vascular procedures consider the use of these devices as safe, 12.9% were undecided and 3.4% did not consider them as safe. Among the respondents who do not perform endovascular procedures, 77% considered these devices as safe and 23% were undecided. CONCLUSION: Although the 2018 meta-analysis had a disruptive impact on the use of drug-eluting devices in PAD, with the increasing body of evidence available, a majority of respondents continue to believe in the safety of these devices for use in femoropopliteal disease.

Clinical experience with a shape memory polymer peripheral vascular embolisation plug: a case series.

BACKGROUND: Shape memory polymers are materials that are manufactured in a certain shape, can be stored in a temporary deformed shape, and then return to - or remember - their original shape upon exposure to external stimuli such as temperature and moisture. This property lends itself to application in endovascular medical devices. Peripheral vasculature embolisation devices incorporating this novel technology have become commercially available and this case series, where the data were collected as part of a post market registry, outlines initial clinical experience with these novel devices. RESULTS: Eight cases are described in this series. The disease state/conditions for which embolisation was indicated were right common iliac artery aneurysms (n = 3), a type II endoleak into the thoracic aorta following thoracic endovascular aneurysm repair (n = 1), a left inferior gluteal artery aneurysm (n = 1), left internal iliac artery aneurysms (n = 2), and a case of splenomegaly, where splenectomy was planned after the embolisation procedure (n = 1). Target arteries were 5-10 mm in diameter. In each case, at least one IMPEDE Embolization Plug (IMP-Device) of an appropriate diameter was used. All procedures were technically successful and target vessel thrombosis was achieved in all cases. Follow-up imaging available during the 45-90-day data collection timeframe showed sustained vessel occlusion. This case series includes examples of situations commonly encountered when embolising the peripheral vasculature, namely, the use of one or multiple devices in a single vessel and in combination with the use of other embolic devices (e.g., microcoils, gelatin sponge, and PVA particles) in the same case. There were no adverse events related to the specific use of the device. CONCLUSIONS: This small series illustrates the safety and efficacy of this novel sponge-based embolic device for the embolisation of small and medium sized arteries and further experience will demonstrate the utility of the shape memory polymer devices.

Secondary Endoleak Management Following TEVAR and EVAR.

Endovascular abdominal and thoracic aortic aneurysm repair and are widely used to treat increasingly complex aneurysms. Secondary endoleaks, defined as those detected more than 30 days after the procedure and after previous negative imaging, remain a challenge for aortic specialists, conferring a need for long-term surveillance and reintervention. Endoleaks are classified on the basis of their anatomic site and aetiology. Type 1 and type 2 endoleaks (EL1 and EL2) are the most common endoleaks necessitating intervention. The management of these requires an understanding of their mechanics, and the risk of sac enlargement and rupture due to increased sac pressure. Endovascular techniques are the main treatment approach to manage secondary endoleaks. However, surgery should be considered where endovascular treatments fail to arrest aneurysm growth. This chapter reviews the aetiology, significance, management strategy and techniques for different endoleak types.

A Review of the Current Status of Percutaneous Endovascular Arteriovenous Fistula Creation for Haemodialysis Access.

Surgical fistulas were first described over 50 years ago and have revolutionized the outlook for millions of dialysis-dependent patients. Despite many developments, results remain sub-optimal with high rates of primary failure and re-intervention to maintain patency. Surgical fistulas are known to fail in part due to intimal hyperplasia leading to stenosis, and vessel manipulation during anastomosis creation can be contributory. New technology is emerging that allows the endovascular creation of fistulas with minimal vessel trauma and the initial results demonstrate encouraging outcomes with high technical success rates, low re-intervention, and failure rates and good usability for hemodialysis. Two such device systems are currently available, and here, we provide an overview of the current global status of endoAVF, patient selection criteria, trial results, technical aspects, re-interventions, and outlook for the future.

Temporary vascular shunts as initial treatment of proximal extremity vascular injuries during combat operations: the new standard of care at Echelon II facilities?

BACKGROUND: Historically, penetrating injuries to the extremities account for up to 75% of wounds sustained during combat and 10% of deaths. Rapid vascular control and perfusion of injured extremities at forward deployed Echelon II surgical facilities is essential to limit loss of life and maximize limb preservation. We review our experience with the management of extremity vascular trauma and report the largest single Echelon II experience to date on temporary vascular shunting (TVS) for proximal extremity vascular injuries. METHODS: Data on combat trauma patients presenting to a US Navy Echelon II forward surgical facility in Iraq were prospectively recorded during a 7-month period. Patients with suspected vascular injuries underwent exploration in the operating room. After vessel control, thrombectomy and instillation of heparinized saline, vascular injuries in the proximal extremity were temporarily shunted in a standardized fashion. Vascular injuries in the distal extremity were routinely ligated. After shunting, patients were transported to an Echelon III facility in the Iraqi Theater and underwent vascular reconstruction. They were followed through transfer to the Continental United States or discharge into the civilian Iraqi medical system. Shunt patency, limb salvage, and survival data were obtained by retrospective review of electronic medical records. RESULTS: Six hundred ten combat trauma patients were treated from August 16, 2006 to February 25, 2007. Thirty-seven patients (6.1%) sustained 73 injuries to major extremity vascular structures. Twenty-three proximal vascular shunts were placed in 16 patients with mean Injury Severity Score of 25 (range, 17-43) and mean mangled extremity severity score (MESS) of 8 (range, 5-10). Twenty-two of 23 shunts (95.6%) were patent upon arrival to the Echelon III facility and underwent successful autologous vein reconstruction. All shunt patients survived their injuries with 100% early limb preservation as followed through their first 30 days of medical care or discharge into the local medical community. CONCLUSIONS: Complex combat injuries to proximal extremity vessels should be routinely shunted at forward-deployed Echelon II facilities as part of the resuscitative, damage control process.

Complications and Reinterventions After Fenestrated and Branched EVAR in Patients with Paravisceral and Thoracoabdominal Aneurysms.

The application of endovascular strategies to treat aneurysms involving the abdominal and thoracoabdominal aorta has evolved significantly since the inception of endovascular aneurysm repair. Advances in endograft technology and operator experience have enabled the management of a wider spectrum of challenging aortic anatomy. Fenestrated endovascular and branched endovascular aneurysm repair represent two technical innovations, which have expanded endovascular treatment options to include patients with paravisceral and thoracoabdominal aortic aneurysms. Although similar in many ways to standard aortic endografts, fenestrated and branched endografts have specific short- and long-term complications due to their unique modular endograft design and their sophisticated deployment mechanisms. This article aims to examine the commonly encountered complications with these devices and the endovascular reintervention strategies.

The Role of Adjustable Scout Lines in Advanced Cervical Spinal Imaging.

STUDY DESIGN/SETTING: Retrospective cohort at a Level 1 trauma center. OBJECTIVE: To compare the anterior-posterior diameter of the cervical central canal using imaging software with both fixed and user-adjustable scout line axial images. SUMMARYOF BACKGROUND DATA: The majority of imaging software programs generate oblique axial images through the lordotic and kyphotic regions of the spine due to a fixed reference line. These oblique axial images are not representative of true canal diameter and often provide inaccurate representation of neural compression. METHODS: Thirty-three consecutive head trauma patients without evidence of pathology in the cervical spine from September 2011 were chosen for the study. The anterior-posterior diameter of the cervical (levels C2-T1) central canal was measured on axial slices using the default non-adjustable ("fixed") reference line on the picture archiving and communication viewer by three observers and then re-measured using an adjustable scout line on the midline sagittal that most bisected the endplates in a parallel fashion. The two measurements from the three independent observers were then compared directly for differences in the AP canal diameter at each level. RESULTS: The average difference between the measurements of the central canal using the fixed scout line versus the adjustable scout line ranged from -1.34±1.59 mm at the C2-C3 level to 1.78±2.32 mm at the C7-T1 level. Standard axial images of the cervical spine underestimated the canal space in the upper cervical spine and overestimated the space in the lower cervical spine. The measurement values using the fixed scout line versus the adjustable scout line did not correlate as indicated by low to moderate Pearson r and ICC values. CONCLUSIONS: There are clear differences between axial slices generated with adjusted and fixed scout lines particularly at disc levels that are not orthogonal to the screen edges.