Physician-Modified Endografts for Repair of Complex Abdominal Aortic Aneurysms: Clinical Perspectives and Medico-Legal Profiles.

Standard endovascular aortic repair (EVAR) has become the standard of care for treating infrarenal abdominal aortic aneurysms (AAAs) in patients with favorable anatomies, while patients with challenging AAA anatomies, and those with suprarenal or thoraco-abdominal aneurysms, still need alternative, more complex, solutions, including custom-made branched or fenestrated grafts, which are constrained by production delay and costs. To address urgent needs and complex cases, physicians have proposed modifying standard endografts by manually creating graft fenestrations. This allows for effective aneurysm exclusion and satisfactory patency of visceral vessels. Although physician-modified grafts (PMEGs) have demonstrated high technical success, standardized creation processes and long-term safety data are still lacking, necessitating further study to validate their clinical and legal standing. The aim of this article is to illustrate the state of the art with regard to this surgical technique, summarizing its origin, evolution, and the main clinical evidence supporting its effectiveness. The paper also aims to discuss the main medico-legal issues related to the use of PMEGs, with particular reference to the issue of safety related to the standardization of the surgical technique, medical liability profiles, and informed consent.

Multicenter Study on Physician-Modified Endografts for Thoracoabdominal and Complex Abdominal Aortic Aneurysm Repair.

BACKGROUND: Physician modified endografts (PMEGs) have been widely used in the treatment of complex abdominal aortic aneurysm and thoracoabdominal aortic aneurysm, however, previous data are limited to small single center studies and robust data on safety and effectiveness of PMEGs are lacking. We aimed to perform an international multicenter study analyzing the outcomes of PMEGs in complex abdominal aortic aneurysms and thoracoabdominal aortic aneurysms. METHODS: An international multicenter single-arm cohort study was performed analyzing the outcomes of PMEGs in the treatment of elective, symptomatic, and ruptured complex abdominal aortic aneurysms and thoracoabdominal aortic aneurysms. Variables and outcomes were defined according to the Society for Vascular Surgery reporting standards. Device modification and procedure details were collected and analyzed. Efficacy outcomes included technical success and safety outcomes included major adverse events and 30-day mortality. Follow-up outcomes included reinterventions, endoleaks, target vessel patency rates and overall and aortic-related mortality. Multivariable analysis was performed aiming at identifying predictors of technical success, 30-day mortality, and major adverse events. RESULTS: Overall, 1274 patients were included in the study from 19 centers. Median age was 74 (IQR, 68-79), and 75.7% were men; 45.7% were complex abdominal aortic aneurysms, and 54.3% were thoracoabdominal aortic aneurysms; 65.5% patients presented electively, 24.6% were symptomatic, and 9.9% were ruptured. Most patients (83.1%) were submitted to a fenestrated repair, 3.6% to branched repair, and 13.4% to a combined fenestrated and branched repair. Most patients (85.8%) had ≥3 target vessels included. The overall technical success was 94% (94% in elective, 93.4% in symptomatic, and 95.1% in ruptured cases). Thirty-day mortality was 5.8% (4.1% in elective, 7.6% in symptomatic, and 12.7% in ruptured aneurysms). Major adverse events occurred in 25.2% of cases (23.1% in elective, 27.8% in symptomatic, and 30.3% in ruptured aneurysms). Median follow-up was 21 months (5.6-50.6). Freedom from reintervention was 73.8%, 61.8%, and 51.4% at 1, 3, and 5 years; primary target vessel patency was 96.9%, 93.6%, and 90.3%. Overall survival and freedom from aortic-related mortality was 82.4%/92.9%, 69.9%/91.6%, and 55.0%/89.1% at 1, 3, and 5 years. CONCLUSIONS: PMEGs were a safe and effective treatment option for elective, symptomatic, and ruptured complex aortic aneurysms. Long-term data and future prospective studies are needed for more robust and detailed analysis.

Use of a novel device for intraoperative wire management during fenestrated endovascular type 4 thoracoabdominal aortic aneurysm repair.

Endovascular procedures are minimally invasive approaches to treat conditions affecting blood vessels without the need for large incisions. The benefits are less blood loss and faster recovery. One condition commonly treated endovascularly is aortic aneurysmal disease often secondary to atherosclerosis or chronic hypertension. As endovascular aneurysm repair becomes increasingly complex and sophisticated, the intraoperative organization and management of wires from multiple access sites becomes paramount. Often, the physician selects visceral or great vessels for delivery of stent grafts to maintain vessel patency. Loss of wire in critical target vessels and wire contamination pose significant patient risks. WireWatch (BioTex Inc. Houston, Texas, USA) is a novel device designed for intraoperative wire management to improve surgical field organization, provide wire stabilization, and prevent dropped wires. This case describes its use in a 73-year-old female undergoing a fenestrated endovascular aneurysm repair of 5.6 cm types IV thoracoabdominal aortic aneurysm.

Reinterventions and sac dynamics after fenestrated endovascular aortic repair with physician-modified endografts for index aneurysm repair and following proximal failure of prior endovascular aortic repair.

OBJECTIVE: The high frequency of reinterventions after fenestrated endovascular aortic repair (FEVAR) with physician-modified endografts (PMEGs) has been well-studied. However, the impact of prior EVAR on reinterventions and sac behavior following these procedures remains unknown. We analyzed 3-year rates of reinterventions and sac dynamics following PMEG for index aneurysm repair compared with PMEG for prior EVAR with loss of proximal seal. METHODS: We performed a retrospective analysis of 122 consecutive FEVARs with PMEGs at a tertiary care center submitted to the United States Food and Drug Administration in support of an investigational device exemption trial. We excluded patients with aortic dissection (n = 5), type I to III thoracoabdominal aneurysms (n = 13), non-elective procedures (n = 4), and prior aortic surgery other than EVAR (n = 8), for a final cohort of 92 patients. Patients were divided into those who underwent PMEG for index aneurysm repair (primary FEVAR) and those who underwent PMEG for rescue of prior EVAR with loss of proximal seal (secondary FEVAR). The primary outcomes were freedom from reintervention and sac dynamics (regression as ≥5 mm decrease, expansion as ≥5 mm increase, and stability as <5 mm increase or decrease) at 3 years. Secondary outcomes were perioperative mortality and 3-year survival. RESULTS: Of the 92 patients included, 56 (61%) underwent primary FEVAR and 36 (39%) underwent secondary FEVAR. Secondary FEVAR patients were older (78 years [interquartile range (IQR), 74.5-83.5 years] vs 73 years [IQR, 69-78.5 years]; P < .001), more frequently male (86% vs 68%; P = .048), and had larger aneurysms (72.5 mm [IQR, 65.5-81 mm] vs 59 mm [IQR, 55-65 mm]; P < .001). Perioperative mortality was 1.8% for primary FEVAR and 2.7% for secondary FEVAR (P = .75). At 3 years, overall survival was 84% for primary FEVAR and 71% for secondary FEVAR (P = .086). Freedom-from reintervention was significantly higher for primary FEVAR than secondary FEVAR, specifically 82% vs 38% at 3 years (P < .001). Primary FEVAR also had more desirable sac dynamics relative to secondary FEVAR at 3 years (primary: 54% stable, 46% regressed, 0% expanded vs secondary: 33% stable, 28% regressed, and 39% expanded; P = .038). CONCLUSIONS: FEVAR for primary aortic repair and FEVAR for rescue of prior EVAR with loss of proximal seal are two distinct entities. Following primary FEVAR, less than a quarter of patients have undergone reintervention at 3 years, and sac expansion was not seen in our cohort. Comparatively, 3 years after secondary FEVAR, over one-half of patients have undergone reintervention and over one-third have had ongoing sac expansion. Vigilant surveillance and a low threshold for further interventions are crucial following secondary FEVAR.

The effect of Fiber Optic RealShape technology on the reduction of radiation during complex endovascular surgery.

OBJECTIVE: Despite the advantages that fenestrated endovascular aortic repair has over open repair, it is accompanied by the consequence of radiation exposure, which can result in long-term complications for both the patient and surgical staff. Fiber Optic RealShape (FORS) technology is a novel advancement that uses emitted light from a fiber optic wire and enables the surgeon to cannulate vessels in real time without live fluoroscopy. This technology has been implemented at select centers to study its effectiveness for cannulation of target vessels and its impact on procedural radiation. METHODS: We collected prospective data on physician-modified endograft (PMEG) cases before and after the introduction of FORS technology. FORS PMEGs were matched with up to three conventional fluoroscopy cases by number of target vessels, inclusion of a bifurcated device below, aneurysm extent, and patient body mass index. The procedural radiation parameters were compared between these cohorts. Within the FORS cohort, we analyzed the rate of successful target vessel cannulation for all cases done with this technology (including cases other than PMEGs), and we compared the radiation between the cannulations using only FORS with those that abandoned FORS for conventional fluoroscopy. RESULTS: Nineteen FORS PMEGs were able to be matched to 45 conventional fluoroscopy cases. Procedures that used FORS technology had significantly reduced total air kerma (527 mGy vs 964 mGy), dose area product (121 Gy∗cm2 vs 186 Gy∗cm2), fluoroscopy dose (72.1 Gy∗cm2 vs 132.5 Gy∗cm2), and fluoroscopy time (45 minutes vs 72 minutes). There was no difference in procedure length, total contrast, or digital subtraction angiography. Within FORS cases, 66% of cannulations were completed using only FORS. Cannulations using only FORS had significant reduction of navigation air kerma (5.0 mGy vs 26.5 mGy), dose area product (1.2 Gy∗cm2 vs 5.1 Gy∗cm2), and fluoroscopy time (0.6 minutes vs 2.3 minutes) compared with cannulations abandoning FORS for conventional fluoroscopy. CONCLUSIONS: This study demonstrates the advantages of FORS for total procedural radiation as well as during individual cannulation tasks. The implementation of FORS for target vessel catheterization has the potential to decrease the total degree of radiation exposure for the patient and surgical staff during complex endovascular aortic surgeries.

Transvenous Access for Emergent Thoracic and Thoracoabdominal Aortic Aneurysm Repair in Patients Without Femoral Access.

PURPOSE: To describe the technique of transvenous access for emergent endovascular repair of thoracic and thoracoabdominal aneurysms exemplified with 2 cases. TECHNIQUE: Transvenous access to the aorta is described as an alternative access method to deliver aortic endografts in emergency situations. A 68-year-old female patient with severely compromised iliac and subclavian artery access was treated for a ruptured extent V thoraco-abdominal aortic aneurysm with a t-Branch (Cook Medical, Bjaeverskov, Denmark) delivered through a transcaval access. To avoid severe aortocaval shunting a balloon-expandable covered stent was deployed through a carotid access due to severe bilateral subclavian ostial stenosis. A 71-year-old man with an acute type B aortic dissection and bilateral narrow long-segment stenting of the iliac arteries was treated with a physician-modified thoracic endovascular aortic repair using an arteriovenous fenestration created at the level of the common iliac artery. We describe the access creation by fenestration using a transseptal needle. CONCLUSION: Transvenous access for thoracic and thoraco-abdominal aortic aneurysm repair is safe and feasible in selected emergent cases. CLINICAL IMPACT: A transvenous approach may be helpful in selected patients when an endovascular repair needs to be performed but no arterial femoral access is available. This approach proved to be feasible even with large-bore introducer sheaths, taking its place in the armamentarium of the vascular surgeon for emergent complex endovascular aortic repairs.

A hemodynamic analysis of fenestrated physician-modified endograft repair for complicated aortic dissections involving the visceral arteries.

OBJECTIVE: The aim of this study is to perform patient-specific hemodynamic simulations of the patients with complicated aortic dissection underwent Physician-modified endograft (PMEG) and evaluate the treatment outcome. METHOD: 12 patient-specific models were reconstructed from computed tomography angiography (CTA) data of 6 patients with complicated aortic dissection before and after the PMEG. Hemodynamic simulations were conducted with the same time-varying volumetric flow rate extracted from the literature and 3-element Windkessel model (3 EWM) boundary conditions were applied at the aortic outlet. Hemodynamic indicators such as time-averaged wall shear stress (TAWSS), relative residence time (RRT) and endothelial cell activation potential (ECAP) were obtained to evaluate the postoperative effect of PMEG. RESULTS: Comparing with the preoperative models, the flow rates of most visceral arteries were increased in the postoperative models (PSMA = 0.012, PRRA = 0.013, and PLRA = 0.005). Pressure and TAWSS in visceral regions were significantly reduced (PP = 0.003 and PTAWSS = 0.017). With the false lumens (FL) covered by the stent grafts, the average TAWSS level increased in the regions of postoperative abdominal aorta (P = 0.002), and the average RRT and ECAP values decreased significantly (PRRT = 0.02 and PECAP = 0.003). CONCLUSION: This study shows that PMEG, as a new technique for the treatment of complicated aortic dissection involving the distal tears in the visceral region, can effectively restore the abnormal blood supply of the visceral arteries, reduce the risk of aortic rupture, the formation of aortic dissection aneurysm (ADA), and thrombosis. This corresponds well with clinical retrospective studies and 1-year follow-up outcomes. The findings of this study are of great significance for the development of PMEG.

Comparative outcomes of physician-modified fenestrated/branched endovascular aortic aneurysm repair in the setting of prior failed endovascular aneurysm repair.

OBJECTIVE: Endovascular treatment of aortic aneurysms involving renal-mesenteric arteries, especially in the setting of prior failed endovascular aneurysm repair (EVAR) typically requires fenestrated/branched endovascular aneurysm repair (F/BEVAR) with a custom-made device (CMD). CMDs are limited to select centers, and physician-modified endografts are an alternative treatment platform. Currently, there is no data on the outcomes of physician-modified F/BEVAR (PM-F/BEVAR) in the setting of failed prior EVAR. The purpose of this study was to evaluate the use of PM-F/BEVAR in patients with prior failed EVAR. METHODS: A prospective database of consecutive patients treated at a single center with PM-F/BEVAR between March 2021 and November 2022 was retrospectively reviewed. The cohort was stratified by presence of a failed EVAR (type Ia endoleak or aneurysm development proximal to a prior EVAR) prior to PM-F/BEVAR. Demographics, operative details, and postoperative complications were compared between the groups using univariate analysis. One-year survival and freedom from reintervention were compared using the Kaplan-Meier method. RESULTS: A total of 103 patients underwent PM-F/BEVAR during the study period; 27 (26%) were in the setting of prior EVAR. Patients with prior failed EVAR had similar age (75.2 ± 7.7 vs 71.5 ± 8.8 years; P = .058), male gender (n = 24 ; 89% vs n = 57 ; 75%; P = .130), and comorbid conditions except higher incidence of moderate-to-severe chronic obstructive pulmonary disease (n = 7 ; 26% vs n = 7 ; 9%; P = .047). Overall, aneurysm diameter was 65.5 ± 13.9 mm with aneurysms categorized as juxta-/pararenal in 43% and thoracoabdominal in 57%, with no differences between the groups. Twelve patients (14%) presented with symptomatic/ruptured aneurysms. The average number of target arteries incorporated per patient was 3.8. Four different aortic devices were modified with a greater proportion of Terumo TREO devices used in the failed EVAR group (P = .03). There was no difference in procedure time, radiation dose, or iodinated contrast use between groups. Overall technical success was 99%. Rates of 30-day mortality (n = 0 ; 0% vs n = 3 ; 4%; P = .565) and major adverse events (n = 6 ; 22% vs n = 16 ; 21%; P = 1.0) were similar between groups. For the overall cohort, rates of type 1 or 3 endoleak, branch vessel stenosis/occlusion, and reintervention were 2%, 1%, and 8%, respectively, with no difference between groups. One-year survival (failed EVAR 94% vs no EVAR 82%; P = .756) was similar between groups. CONCLUSIONS: PM-F/BEVAR is a safe and effective treatment for patients with aneurysms involving the renal-mesenteric arteries in the setting of prior failed EVAR where additional technical challenges may be present. Additional follow-up is warranted to demonstrate long-term efficacy, but early results are encouraging and similar to those using CMDs.

The financial burden associated with endovascular repair of thoracoabdominal and pararenal aortic aneurysms using physician-modified fenestrated-branched endografts.

OBJECTIVE/BACKGROUND: Endovascular thoracoabdominal and pararenal aortic aneurysm repair is more complex and requires more devices than infrarenal aneurysm repair. It is unclear if current reimbursement covers the cost of delivering this more advanced form of vascular care. The objective of this study was to evaluate the economics of fenestrated-branched (FB-EVAR) physician-modified endograft (PMEG) repairs. METHODS: We obtained technical and professional cost and revenue data for four consecutive fiscal years (July 1, 2017, to June 30, 2021) at our quaternary referral institution. Inclusion criteria were patients who underwent PMEG FB-EVAR in a uniform fashion by a single surgeon for thoracoabdominal/pararenal aortic aneurysms. Patients in industry-sponsored clinical trials or receiving Cook Zenith Fenestrated grafts were excluded. Financial data were analyzed for the index operation. Technical costs were divided into direct costs that included devices and billable supplies and indirect costs including overhead. RESULTS: 62 patients (79% male, mean age: 74 years, 66% thoracoabdominal aneurysms) met inclusion criteria. The mean aneurysm size was 6.0 cm, the mean total operating time was 219 minutes, and the median hospital length of stay was 2 days. PMEGs were created with a mean number of 3.7 fenestrations, using a mean of 8.6 implantable devices per case. The average technical cost per case was $71,198, and the average technical reimbursement was $57,642, providing a net negative technical margin of $13,556 per case. Of this cohort, 31 patients (50%) were insured by Medicare remunerated under diagnosis-related group code 268/269. Their respective average technical reimbursement was $41,293, with a mean negative margin of $22,989 per case, with similar findings for professional costs. The primary driver of technical cost was implantable devices, accounting for 77% of total technical cost per case over the study period. The total operating margin, including technical and professional cost and revenue, for the cohort during the study period was negative $1,560,422. CONCLUSIONS: PMEG FB-EVAR for pararenal/thoracoabdominal aortic aneurysms produces a substantially negative operating margin for the index operation driven largely by device costs. Device cost alone already exceeds total technical revenue and presents an opportunity for cost reduction. In addition, increased reimbursement for FB-EVAR, especially among Medicare beneficiaries, will be important to facilitate patient access to such innovative technology.

BCG Aortitis, a Rare Complication of BCG Therapy.

Introduction: Intravesical Bacillus Calmette-Guerin (BCG) is an effective treatment for in situ bladder carcinomas; however, extravesical BCG infection may occur in remote organs in patients with underlying primary immunodeficiency and is a potentially serious complication in 3-5% of cases. It includes granulomatous pneumonia, hepatitis as well as specific dermatological, ophthalmic, and haematopoietic manifestations. Diagnosis is difficult and often based on high clinical suspicion as in many cases Mycobacterium bovis is not isolated. This report presents a rare case of BCGaortitis treated in a tertiary care centre. Report: A 74 year old man, with a history of bladder cancer treated with BCG therapy over a year ago, presented with malaise, abdominal pain, anorexia, and significant weight loss for several months associated with acute on chronic renal failure and a tender aneurysm. He was diagnosed with hepatic BCGitis and pararenal BCGaortitis. He was considered too high risk for open surgery after a multidisciplinary team meeting and was treated with a four vessel physician modified endograft (PMEG) and antituberculous therapy. At seven month follow up, he was clinically well and control computed tomography showed a patent endograft with complete exclusion of the aortic aneurysm. Discussion: Infectious BCG complications after intravesical BCG administration for in situ bladder carcinomas can lead to severe early and late complications. In the present case, the patient presented with both liver and aortic BCG infection. The lack of positive microbiological data should not discourage clinicians from considering BCG infection even if several months have passed since the last BCG instillation.

Physician-Modified Endografts Versus Chimney/Snorkel for Ruptured and Symptomatic Juxtarenal and Paravisceral Aneurysms in the Vascular Quality Initiative.

OBJECTIVES: Ruptured and symptomatic juxtarenal and paravisceral aneurysms present technical challenges during endovascular repair. We sought to compare physician modification and fenestrated (PMEG) versus chimney/periscope/snorkel (CHIMPS) repair techniques for the treatment of ruptured and symptomatic paravisceral and juxtarenal aortic aneurysms (r/sPJAA). METHODS: Patients in the thoracic and complex endovascular aneurysm module of the Vascular Quality Initiative (VQI) national registry undergoing CHIMPS and PMEG for r/sPJAA were included. Patients who underwent thoracic aneurysm repair with only celiac intervention or who had coverage or occlusion only of one renal or visceral branch vessel were excluded. One-year mortality was the primary outcome. Secondary outcomes included peri- and postoperative endoleak, hospital and ICU length of stay, reintervention, and other local and systemic complications. RESULTS: A total of 81 CHIMPS and 47 PMEG patients were identified. Patients undergoing PMEG were more frequently symptomatic, had a history of CHF and were taking aspirin, statin and P2Y12 antiplatelet medications. Patients undergoing CHIMPS presented more frequently with rupture. There was no significant survival advantage for CHIMPS over PMEG patients (P = 0.5). There were no apparent long-term differences in the numbers of endoleaks or in the rates of subsequent reinterventions between the two groups. CONCLUSIONS: It does not appear that the procedure type (CHIMPS versus PMEG) is associated with postoperative survival in patients with r/sPJAA. Not surprisingly, survival is associated with postoperative complications, particularly myocardial infarction and intestinal ischemia. Further research should evaluate reasons for failure to rescue from and the impact of postoperative complications on the postoperative survival after endovascular repair of r/sPJAA.

Tightrope Technique for facilitating complex endovascular aortic repair in patients with severely angulated neck.

An 84-year-old presented with a large, symptomatic juxtarenal abdominal aortic aneurysm. Owing to severe angulation of the infrarenal neck, advancement of the distal bifurcated component caused dramatic lateral movement of the proximal physician-modified endovascular graft (PMEG) fenestrated device. This procedure risked aneurysm sac perforation and possible PMEG device displacement. To avoid this complication, the distal aspect of the PMEG device was tethered in place using endoscopic forceps to provide countertraction, similar to pulling a tightrope. This technique allowed for the uneventful placement of the distal bifurcated component without complication. This technique can overcome device placement challenges within an angulated aorta caused by large aneurysms.

Superior mesenteric artery outcomes after large fenestration strut relocation with the Zenith Fenestrated endoprosthesis.

BACKGROUND: The Zenith® Fenestrated (ZFen) stent-graft is frequently configured with a strut-spanning large fenestration for superior mesenteric artery (SMA) incorporation. This has led some to relocate struts to create a strut-free fenestration and place a bridging stent. The aim of this study was to compare SMA outcomes with and without large fenestration strut relocation. METHODS: We performed a retrospective review of a prospective database of patients undergoing fenestrated endovascular repair with ZFen between 2013 and 2019. Those with SMA incorporation using large fenestrations were included and separated into strut relocation (SR) and no relocation (NR) groups. Endpoints included procedural metrics, technical success, major adverse events, and target-vessel instability. RESULTS: A total of 121 patients (77% male; mean age 76.1 ± 7.1 years) met inclusion criteria, including 94 with SR (78%) and 27 with NR (22%). A total of 369 target-vessels were incorporated, with a mean of 3.0 ± 0.2 per patient, and no differences between groups. Mean operative time, contrast volume, estimated blood loss, fluoroscopy time and radiation dose were lower (p < 0.001) with SR, attributed to increased experience with time. Overall technical success (SR: 100%, NR: 96%, p = 0.22) was 99%. At a mean follow-up of 32 months, there were two endovascular interventions for mesenteric ischemia. One resulted in SMA dissection requiring bypass in the NR group, the other was successful ballooning of the bridging stent with symptom resolution in the SR group. CONCLUSIONS: Relocating the spanning struts does not negatively impact procedural metrics or midterm outcomes. It may facilitate future endovascular interventions.

The state of complex endovascular abdominal aortic aneurysm repairs in the Vascular Quality Initiative.

BACKGROUND: Endovascular repair of complex abdominal aortic aneurysms has become increasingly common, but reports have mostly been limited to single centers and single devices. METHODS: We studied all endovascular repairs of complex abdominal aortic aneurysms (zone 6 or caudal) from 2014 to 2018 in the Vascular Quality Initiative. This included all commercially available fenestrated endovascular aneurysm repair (FEVAR), chimney/snorkel repairs, and physician-modified endografts (PMEGs), exclusive of investigational device exemptions and clinical trial devices. We used inverse probability-weighted multilevel logistic regression to compare rates of perioperative outcomes including death, acute kidney injury (AKI), and major adverse cardiac events (MACEs; the composite of death/stroke/myocardial infarction) and Cox regression for long-term mortality. RESULTS: During the study period, surgeons performed 1396 complex endovascular repairs: 1308 (94%) elective, 63 (4.5%) for symptomatic aneurysms, and 25 (1.8%) for rupture. The number of centers performing complex endovascular repairs expanded steadily from 39 in 2014 to 81 in 2017. There were 880 FEVAR (63%), 256 PMEG (18%), and 260 chimney/snorkel repairs (19%). In elective cases, 3214 visceral vessels were incorporated and revascularized; 120 repairs (9%) involved one vessel, 481 (38%) repairs involved two vessels, 560 (44%) involved three vessels, and 113 (9%) involved four vessels. The mean number of arteries incorporated was 2.5 ± 0.8, with PMEGs involving the most arteries (3.3 ± 0.8 for PMEG vs 2.5 ± 0.6 for FEVAR and 1.9 ± 0.9 for chimney/snorkel; P < .001). PMEGs were used to treat more extensive aneurysms, and more incorporated the celiac and superior mesenteric arteries. There was no change in aneurysm extent, but the length of proximal seal extended over time. Chimney/snorkel cases employed more arm or neck access, had longer procedure times, and used more contrast material. Rates of perioperative death (3.4% for FEVAR vs 2.7% for PMEG vs 6.1% for chimney/snorkel; P = .13) and AKI (17% vs 18% vs 19%; P = .42) were similar, but chimney/snorkel was associated with higher rates of stroke (0.8% vs 0.9% vs 3.3%; P = .03) and MACEs (6.1% vs 5.4% vs 11.7%; P = .02). After adjustment, rates of perioperative death, AKI, and overall complications remained similar, but chimney/snorkel was associated with significantly higher odds of stroke (odds ratio [OR], 7.3 [1.5-36.4]; P = .015), myocardial infarction (OR, 18.7 [2.6-136.8]; P = .004), and MACEs (OR, 11.1 [2.1-58.9]; P = .005). Overall survival after elective repair was 91% at 1 year and 88% at 3 years, with no difference between repair types in crude or adjusted analysis. CONCLUSIONS: The Vascular Quality Initiative provides a unique opportunity to study the real-world application and outcomes of complex endovascular aneurysm repair. Perioperative morbidity appears to be higher after chimney/snorkel repair, but further study is needed to confirm these findings and to establish the durability of these novel technologies.

Utilization of 1,3-Dioxolanes in the Synthesis of α-branched Alkyl and Aryl 9-[2-(Phosphonomethoxy)Ethyl]Purines and Study of the Influence of α-branched Substitution for Potential Biological Activity.

Syntheses of α-branched alkyl and aryl substituted 9-[2-(phosphonomethoxy)ethyl]purines from substituted 1,3-dioxolanes have been developed. Key synthetic precursors, α-substituted dialkyl [(2-hydroxyethoxy)methyl]phosphonates were prepared via Lewis acid mediated cleavage of 1,3-dioxolanes followed by reaction with dialkyl or trialkyl phosphites. The best preparative yields were achieved under conditions utilizing tin tetrachloride as Lewis acid and triisopropyl phosphite. Attachment of purine bases to dialkyl [(2-hydroxyethoxy)methyl]phosphonates was performed by Mitsunobu reaction. Final α-branched 9-[2-(phosphonomethoxy)ethyl]purines were tested for antiviral, cytostatic and antiparasitic activity, the latter one determined as inhibitory activity towards Plasmodium falciparum enzyme hypoxanthine-guanine-xanthine phosphoribosyltransfesase. In most cases biological activity was only marginal.

Aortic neck dilation is not associated with adverse outcomes after fenestrated endovascular aneurysm repair.

OBJECTIVE: Long-term outcomes after endovascular aneurysm repair (EVAR) are threatened by aortic neck dilation (AND), graft migration, and subsequent endoleak development. The aim of this study was to determine the rate of AND and the occurrence of endoleaks after fenestrated EVAR of juxtarenal aneurysms with physician-modified endovascular grafts (PMEGs). METHODS: The study included 77 patients presenting with asymptomatic and ruptured juxtarenal abdominal aortic aneurysms treated with PMEGs who received radiologic follow-up. Analysis of computed tomography images took place on a three-dimensional workstation (TeraRecon, San Mateo, Calif). Aortic neck diameter was measured before and after EVAR at the lowest patent renal artery outer wall to outer wall. Significant AND was defined as >3-mm increase between baseline and follow-up, and sac regression >5 mm was considered significant. The patient's 1-month initial postoperative computed tomography measurement was considered baseline. The rate of AND was measured by comparing the baseline measurement with measurements at 6 months, 12 months, and annually thereafter up to 4 years. RESULTS: In this cohort of patients, 75% were men with a mean age of 74 ± 7.9 years. Median preoperative aneurysm size was 62 (57-73) mm, and median follow-up was 12 (3.5-30) months. Mean endograft oversizing was 17% ± 12.5%, and mean seal zone length was 41 ± 11 mm. At 1-year follow-up, the median aortic neck increase was 1.7 (0-3) mm. Maximum aneurysm size decreased dramatically during the first postoperative year, with significant sac regression in 65% of the patients. Aortic neck diameter at 1 year did correlate positively with the percentage of device oversizing. No other correlations were found. During the 4-year follow-up, there were no cases of type IA endoleaks. CONCLUSIONS: AND does not influence outcome after endovascular repair of juxtarenal aneurysms using PMEGs. These midterm results support the applicability of PMEGs in juxtarenal aneurysm repair.

Tanovea® for the treatment of lymphoma in dogs.

Tanovea® (first named GS-9219, then VDC-1101, generic name: rabacfosadine) is a pro-prodrug or "double" prodrug of PMEG [9-(2-phosphonylmethoxyethyl)guanine], which has been conditionally approved by the US FDA (Food and Drug Administration) for the treatment of lymphoma in dogs. Tanovea has been demonstrated to be effective against non-Hodgkin's lymphoma (NHL) in dogs, as well as canine cutaneous T-cell lymphoma, spontaneous canine multiple myeloma, naïve canine multicentric lymphoma and relapsed canine B-cell lymphoma. As a double prodrug of PMEG, GS-9219 is first converted intracellularly by hydrolysis to cPr-PMEDAP, then deaminated to PMEG, which is then phosphorylated twice to its active metabolite PMEGpp, acting at the level of the cellular DNA polymerases.

A novel lipid prodrug strategy for sustained delivery of hexadecyloxypropyl 9-[2-(phosphonomethoxy)ethyl]guanine (HDP-PMEG) on unwanted ocular proliferation.

Proliferative vitreoretinopathy (PVR) is a blinding eye disease and there is no effective pharmacological measure to prevent PVR development. The difficulty comes from lack of potent antiproliferative agent and lack of sustained delivery to cover high-risk time window for PVR to develop. Lipid prodrug of PMEG, hexadecyloxypropyl 9-[(2-phosphonomethoxy)ethyl]guanine (HDP-PMEG), was prepared and was evaluated as a pharmacological adjuvant to surgical management of PVR. A dose-escalation study determined that the highest nontoxic dose for intravitreal use in pigmented rabbits was 3 µg per eye. The genotoxicity of HDP-PMEG was harnessed as a perioperative preventative measure against PVR in a rabbit eye model while the sustained intravitreal pharmacological effect was evaluated on a laser-induced fibrovascular model in rat eye. After intravitreal 3 µg, HDP-PMEG particles in the rabbit vitreous was visible for at least 6 weeks. A single 50-min intravitreal infusion of HDP-PMEG demonstrated significant inhibition of PVR formation when compared with the eyes infused with only BSS (BSS vs. HDP-PMEG: estimate = 1.14, OR = 3.1, p = .027). A single intravitreal 104 ng (equivalent to 3 µg for rabbit eye) of HDP-PMEG significantly inhibit laser-induced fibrovascular proliferation in rat eye by 55% (least square mean pixel, BSS = 4763569.5 vs. HDP-PMEG = 2148129.7, p < .0001, generalized estimating equation [GEE]). Retinal fluorescein angiography showed the odds for BSS intervened eyes to have higher-rated FA leaking grades were 38.5 times compared with HDP-PMEG treated eyes (p < .0001, GEE). Our study results indicate that single intravitreal HDP-PMEG may be a promising ocular drug delivery as a perioperative intervention to prevent PVR reoccurrence following primary surgical management.

Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia.

Acyclic nucleoside phosphonates (ANPs) are well-known for their antiviral properties, three of them being approved for the treatment of human immunodeficiency virus infection (tenofovir), chronic hepatitis B (tenofovir and adefovir) or human cytomegalovirus retinitis (cidofovir). In addition, cidofovir is mostly used off-label for the treatment of infections caused by several DNA viruses other than cytomegalovirus, including papilloma- and polyomaviruses, which do not encode their own DNA polymerases. There is considerable interest in understanding why cidofovir is effective against these small DNA tumor viruses. Considering that papilloma- and polyomaviruses cause diseases associated either with productive infection (characterized by high production of infectious virus) or transformation (where only a limited number of viral proteins are expressed without synthesis of viral particles), it can be envisaged that cidofovir may act as antiviral and/or antiproliferative agent. The aim of this review is to discuss the advances in recent years in understanding the mode of action of ANPs as antiproliferative agents, given the fact that current data suggest that their use can be extended to the treatment of non-viral related malignancies.

Dancing with chemical formulae of antivirals: a personal account.

A chemical structure is a joy forever, and this is how I perceived the chemical structures of a number of antiviral compounds with which I have been personally acquainted over the past 3 decades: (1) amino acid esters of acyclovir (i.e. valaciclovir); (2) 5-substituted 2'-deoxyuridines (i.e. brivudin); (3) 2',3'-dideoxynucleoside analogues (i.e. stavudine); (4) acyclic nucleoside phosphonates (ANPs) (i.e. cidofovir, adefovir); (5) tenofovir disoproxil fumarate (TDF) and drug combinations therewith; (6) tenofovir alafenamide (TAF, GS-7340), a new phosphonoamidate prodrug of tenofovir; (7) pro-prodrugs of PMEG (i.e. GS-9191 and GS-9219); (8) new ANPs: O-DAPy and 5-aza-C phosphonates; (9) non-nucleoside reverse transcriptase inhibitors (NNRTIs): HEPT and TIBO derivatives; and (10) bicyclam derivatives (i.e. AMD3100).